Persisting low use of antipsychotics in the treatment of major depressive disorder with psychotic features. Response of psychotic depression subtypes to pharmacotherapy. Impact of prior pharmacotherapy on remission of psychotic depression in a randomized controlled trial. Patterns of pharmacological maintenance treatment in a community mental health services bipolar disorder cohort study (SIN-DEPRES). Comparing augmentation with non-antidepressants over sticking to antidepressants after treatment failure in depression: a naturalistic study. The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. Psychotic vs. nonpsychotic depression: comparison of treatment response. Risperidone for Treatment-Refractory Major Depressive Disorder
OBJECTIVE Practice guidelines recommend the use of a combination of an antidepressant and an antipsychotic for the pharmacologic treatment of major depressive disorder with psychotic features ( MD-Psy ) . We assessed the extent to which the  pharmacotherapy  received by patients with MD-Psy under usual care conforms to these recommendations . METHOD We assessed the  pharmacotherapy  received under usual care conditions by 100 patients with MD-Psy prior to enrollment in STOP-PD ( Study of the Pharmacotherapy of Psychotic Depression ) , a 12-week r and omized , controlled trial comparing olanzapine plus sertraline to olanzapine plus placebo . Our assessment took place from January 2003 to May 2004 . The strength of antidepressant trials was rated using the Antidepressant Treatment History Form ( ATHF ) . The strength of antipsychotic trials or combinations of antidepressants and antipsychotics was rated using a modified version of the ATHF . We also determined whether the strength of antipsychotic or combination trials was associated with age , the duration of the current depressive episode , medical burden , cognitive status , or the severity of depressive or psychotic symptoms . RESULTS Most patients with MD-Psy were treated with antidepressants ( N = 82 , 82 % ) or antipsychotics ( N = 65 , 65 % ) . About half of the patients ( N = 48 , 48 % ) received therapeutic doses of an antidepressant ; 10 % ( N = 10 ) received an intermediate dose of an antipsychotic , and 6 % ( N = 6 ) received a high dose . Overall , only 5 % ( N = 5 ) received a combination of an adequate dose of an antidepressant and a high dose of an  antipsychotic .  The strength of both antipsychotic trials ( p = .021 ) and combination trials ( p = .039 ) was significantly associated only with a longer duration of the current depressive episode . CONCLUSIONS These findings show a persisting low use of  antipsychotics  in the treatment of MD-Psy . Given the high morbidity rates associated with MD-Psy , it is important to continue to educate clinicians regarding its identification and treatment . CLINICAL TRIALS REGISTRATION Clinical Trials.gov identifier NCT00056472 Patients with psychotic depression respond well when treated with a combination of an antidepressant and antipsychotic medication . We previously reported that they will respond in a similar fashion when treated with amoxapine monotherapy . There are few prospect i ve studies on the pharmacologic treatment response of psychotic depression subtypes . We treated 37 in patients , 21 with mood congruent ( MC ) psychotic depression and 16 with mood incongruent ( MI ) psychotic depression , in a r and omized double-blind fashion with either the combination of amitriptyline and perphenazine or with amoxapine for 4 weeks . Depression and psychosis ratings improved in a similar manner in both the MC or MI patients irrespective of medication treatment group . Global response rates were similar in the MI patients and MC patients . The data suggest that classifying psychotic depression into MC versus MI subtypes may have limited acute prognostic value in pharmacotherapy response rates Having failed to respond to an adequate antidepressant treatment course predicts poorer treatment outcomes in patients with major depression . However , little is known about the impact of prior treatment on the outcome of  major depression with psychotic features ( MDpsy ) . We examined the effect of prior treatment history on the outcome of pharmacotherapy  of MDpsy in patients who participated in the STOPD-PD study , a r and omized , double-blind , clinical trial comparing a combination of olanzapine plus sertraline vs. olanzapine plus placebo . The strength of treatment courses received prior to r and omization was classified using a vali date d method . A hierarchy of outcomes was hypothesized based on treatments received prior to r and omization and r and omized treatment . A high remission rate was observed in subjects with a history of no prior treatment or inadequate treatment who were treated with a combination of olanzapine and sertraline .  A low remission rate was observed in subjects who had previously failed to respond to an antidepressant alone and who were treated with olanzapine monotherapy . A low remission rate was also observed in subjects who had previously failed to respond to a combination of an antipsychotic and an antidepressant . Similar to patients with major depression , these results emphasize the impact of prior pharmacotherapy on treatment outcomes in patients with MDpsy Maintenance therapy in bipolar disorder ( BD ) is usually required to prevent relapses and improve residual symptoms . Therefore , in this study , we describe patterns of pharmacological maintenance treatment and identify associated clinical features . This prospect i ve multicentre epidemiological study recruited a cohort of 739 consecutive out- patients with clinical ly stable BD . Clinical stability was assessed at baseline with the Clinical Global Impression scale for BD and depressive symptoms with the Hamilton Depression Rating Scale .  Psychotropic medications were classified and analysed according to their mechanism as well as use . Logistic regression models were used to examine the associations between pharmacological strategies and clinical features . Longer time since last episode [ odds ratio ( OR ) 1.002 , p < 0.0001 ] and family history of psychiatric disorders ( OR 1.911 , p = 0.028 ) were associated with lithium in monotherapy ;  manic polarity of the most recent episode ( OR 3.300 , p = 0.006 ) and longer duration of clinical stability ( OR 1.009 , p = 0.034 ) with antipsychotic in monotherapy ;  depressive polarity of the most recent episode ( OR 2.567 , p = 0.003 ) and bipolar II disorder diagnosis ( OR 2.278 , p = 0.008 ) with antidepressant combination ;  no ongoing psychiatric co-morbidity ( OR 0.230 , p = 0.004 ) with lithium and anticonvulsant ;  manic polarity of the most recent episode ( OR 3.774 , p < 0.0001 ) with lithium and antipsychotic ;  manic polarity of the most recent episode ( OR 2.907 , p = 0.028 ) with lithium , anticonvulsant and antipsychotic . The pharmacological patterns followed published recommendations , except for the excessive use of antidepressants . This study reveals clinical factors closely related to prescription patterns INTRODUCTION Non-response to an antidepressant monotherapy in unipolar depression is quite common . Therefore strategies for subsequent treatment steps are necessary . However , there is a lack of direct comparisons of these different strategies . In this naturalistic study we compared the outcome to different strategies after failure of the primary antidepressant treatment . METHODS Failure of primary antidepressant monotherapy occurred in 135 patients . 98 of these patients have been administered 4 treatment strategies of the physicians ' choice : lithium augmentation ( Li-Augm ) , switching to another antidepressant ( AD-Switch ) , combination of 2 antidepressants ( AD-Comb ) or augmentation with second generation antipsychotic ( SGA-Augm ) . Primary outcome measure was the 17-item Hamilton rating scale for depression ( HRSD ) . RESULTS Patients who received Li-Augm or augmentation with SGAs showed significantly greater improvement in HRSD and BDI compared to patients with antidepressant switch or antidepressant combination . Remission rates for Li-Augm and SGA-Augm were 89.3 % and 86.2 % compared to 40.7 % for AD-Switch and 42.9 % for AD-Comb . DISCUSSION Changing to another pharmacological class ( Li-Augm or augmentation with SGAs ) showed better treatment results than sticking to the class of antidepressants ( AD-Switch and AD-Comb ) after primary failure in response to antidepressant monotherapy in unipolar depression . The lack of r and omization and absence of a non-response definition are design flaws . Controlled studies are required to confirm the findings of this trial OBJECTIVES A growing number of atypical antipsychotics are available for clinicians to choose from in the treatment of psychotic disorders . However , a number of important questions concerning medication selection , dosing and dose equivalence , and the management of inadequate response , compliance problems , and relapse have not been adequately addressed by clinical trials . To aid clinical decision-making , a consensus survey of expert opinion on the pharmacologic treatment of psychotic disorders was undertaken to address questions not definitively answered in the research literature . METHOD Based on a literature review , a written survey was developed with 60 questions and 994 options . Approximately half of the options were scored using a modified version of the R AND 9-point scale for rating the appropriateness of medical decisions . For the other options , the experts were asked to write in answers ( e.g. , average doses ) or check a box to indicate their preferred answer . The survey was sent to 50 national experts on the pharmacologic treatment of psychotic disorders , 47 ( 94 % ) of whom completed it . In analyzing the responses to items rated on the 9-point scale , consensus on each option was defined as a non r and om distribution of scores by chi-square " goodness-of-fit"test . We assigned a categorical rank ( first line/preferred choice , second line/alternate choice , third line/usually inappropriate ) to each option based on the 95 % confidence interval around the mean rating . Guideline tables indicating preferred treatment strategies were then developed for key clinical situations . RESULTS The expert panel reached consensus on 88 % of the options rated on the 9-point scale . The experts overwhelmingly endorsed the atypical antipsychotics for the treatment of psychotic disorders . Risperidone was the top choice for first-episode and multi-episode patients , with the other newer atypicals rated first line or high second line depending on the clinical situation . Clozapine and a long-acting injectable atypical ( when available)were other high second line options for multi-episode patients . The expert 's dosing recommendations agreed closely with the package inserts for the drugs , and their estimates of dose equivalence among the antipsychotics followed a linear pattern . The experts considered 3 - 6 weeks an adequate antipsychotic trial , but would wait a little longer ( 4 - 10 weeks ) before making a major change in treatment regimen if there is a partial response . The experts recommended trying to improve response by increasing the dose of atypical and depot antipsychotics before switching to a different agent ; there was less agreement about increasing the dose of conventional antipsychotics before switching , probably because of concern about side effects at higher doses . If it is decided to switch because of inadequate response , risperidone was the expert 's first choice to switch to , no matter what drug was initially tried . Although there was some disparity in the expert 's recommendations concerning how many agents to try before switching to clozapine , the expert 's responses suggest that switching to clozapine should be Clozapine was also the antipsychotic of choice for patients with suicidal behavior . When switching oral antipsychotics , the experts considered cross-titration the preferred strategy . When switching to an injectable antipsychotic , the experts stressed the importance of continuing the oral antipsychotic until therapeutic levels of the injectable agent are achieved . The experts considered psychosocial interventions the first choice strategy for partially compliant patients , with pharmacologic interventions the first choice for patients with clear evidence of noncompliance . However , because it can be difficult to distinguish partially compliant from noncompliant patients , the editors recommended combining psychosocial and pharmacologic interventions to improve compliance whenever possible . When patients relapse because of compliance problems or if there is any doubt about compliance , the experts recommended the use of a long-acting injectable antipsychotic and would select an injectable atypical when this option becomes available . The experts would also consider using an injectable atypical antipsychotic ( when available ) in many clinical situations that do not involve compliance problems . The experts stressed the importance of monitoring for health problems-especially obesity , diabetes , cardiovascular problems , HIV risk behaviors , medical complications of substance abuse , heavy smoking and its effects , hypertension , and amenorrhea-in patients being treated with antipsychotics . Although many patients are prescribed adjunctive treatments , multiple antipsychotics , and combinations of different classes of drugs ( e.g. , antipsychotics plus mood stabilizers or antidepressants ) in an effort to enhance response , the experts gave little support to any of these strategies , with the exception of antidepressants for patients with  dysphoria/depression  , antidepressants or ECT for patients with suicidal behavior , and mood stabilizers for patients with aggression/violence . When asked about indicators of remission and recovery , the experts considered acute improvement in psychotic symptoms the most important indicator of remission , whereas they considered more sustained improvement in multiple outcome domains ( e.g. , occupational/educational functioning , peer relationships , independent living ) important in assessing recovery . CONCLUSIONS The experts reached a high level of consensus on many of the key treatment questions in the survey . Within the limits of expert opinion and with the expectation that future research data will take precedence , these guidelines provide direction for addressing common clinical dilemmas that arise in the pharmacologic treatment of psychotic disorders . They can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions . Clinicians should keep in mind that no guidelines can address the complexities involved in the care of each individual patient and that sound clinical judgment based on clinical experience should be used in applying these recommendations This retrospective study compared the treatment responses of 34 primary , unipolar depressives without psychotic features and 30 with psychotic features . Patients were diagnosed by Research Diagnostic Criteria and received trials of tricyclic antidepressants , antipsychotics , the combination of the two , electroconvulsive therapy , or placebo and psychotherapy . Only three of 18 psychotic patients vs. 17 of 23 nonpsychotic patients responded to antidepressants alone . Electroconvulsive therapy and the combination of antipsychotic and antidepressant medication gave better responses . These data suggest that major depressive disorder with psychotic features is best considered as a distinct subtype rather than a severe variant of major depression Context Does augmentation with an atypical antipsychotic improve symptoms in patients with major depression that is suboptimally responsive to antidepressant monotherapy ? Contribution This double-blind r and omized trial found that 6 weeks of treatment with risperidone improved symptoms more than placebo in 274 adults with major depression that was suboptimally responsive to antidepressant monotherapy . Risperidone , compared with placebo , result ed in more remissions ( 25 % vs. 11 % ) , as well as more cases of somnolence ( 5 % vs. 2 % ) and dry mouth ( 5 % vs. 1 % ) . Caution The trial duration was short , and 19 % of risperidone recipients did not complete treatment . Implication Risperidone augmentation may improve symptoms in some patients with suboptimal response to antidepressant monotherapy . The Editors Major depressive disorder is the leading cause of disability worldwide ( 1 ) , affecting nearly 121 million people . It is associated with increased overall mortality ( 2 , 3 ) ; premature cardiovascular-related death ( 4 , 5 ) ; and morbidity , including disability , lost productivity , and decreased wages , compared with individuals without depression ( 6 ) . Selective serotonin reuptake inhibitors ( SSRIs ) and serotoninnorepinephrine reuptake inhibitors are generally considered first-line treatments for depression . Despite a sufficient dose and duration of antidepressant treatment , symptoms do not resolve in 30 % to 40 % of patients with major depressive disorder ( 710 ) . Remission , defined as the virtual absence of depressive symptoms , is important because it is associated with improved patient prognosis and functioning relative to response ( generally defined as 50 % reduction in symptoms ) ( 11 , 12 ) . In an effort to improve the therapeutic efficacy of antidepressant monotherapy , several pharmacologic strategies to modulate different or additional neurotransmitters ( 1315 ) are commonly used , despite a paucity of evidence from r and omized clinical trials . These strategies include switching monotherapy within ( 10 , 1618 ) or between antidepressant classes ( 10 , 1921 ) , combination regimens consisting of 2 antidepressants ( 2226 ) , and augmentation of antidepressants with nonst and ard treatmentsfor example , thyroid hormone ( 27 ) ; S-adenosyl-l-methionine ( 28 ) ; lithium ( 29 ) ; cyclooxygenase-2 inhibitors ( 30 ) ; or an atypical antipsychotic ( 3133 ) , such as risperidone . Findings of several open-label studies ( 3135 ) suggest that atypical antipsychotic augmentation provides benefit in major depressive disorder that is suboptimally responsive to antidepressant monotherapy . Risperidone , whose activity includes blockade of certain serotonin and dopamine receptors , is considered an atypical antipsychotic . It is approved in the United States for treatment of bipolar mania and schizophrenia and in other countries for additional uses . The efficacy of risperidone has also been studied for various psychoses and behavioral disorders , including treatment-resistant depression and anxiety spectrum disorders ( 34 , 3639 ) . We hypothesized that low-dose risperidone augmentation would reduce symptoms of major depressive disorder , enhance clinical response and remission rates , and reduce disability and improve quality of life compared with continued antidepressant monotherapy . Preliminary data suggest that persons with a confirmed suboptimal response to previous treatment may respond to risperidone augmentation within 4 to 6 weeks ( 38 ) . We therefore conducted a large , multicenter , double-blind , placebo-controlled trial to assess the clinical efficacy of risperidone augmentation from the clinician and patient perspectives and to evaluate tolerability in patients with major depressive disorder who continue to experience symptoms despite an adequate trial of st and ard antidepressants . Methods Design Consenting persons entered a 4-week prospect i ve open-label run-in period during which they received their current antidepressant monotherapy at the dosages recommended in product labeling , so that we could confirm an insufficient response to st and ard monotherapy . The run-in period was followed by a 6-week double-blind treatment phase ; during this phase , patients who continued to experience depressive symptoms , defined as a Clinical Global ImpressionSeverity of illness ( CGI-S ) score of 4 or greater and a Carroll Depression Scale ( 40 ) score of 20 or greater , were r and omly assigned to receive risperidone augmentation therapy or placebo . A 4-week follow-up phase of open-label risperidone augmentation therapy was available to participants who completed at least 4 weeks of double-blind treatment ( results not shown ) . Setting and Participants Out patients 18 to 65 years of age who had received antidepressant monotherapy for at least 4 weeks and met the Diagnostic and Statistical Manual of Mental Disorders , fourth edition ( 41 ) , criteria for unremitting major depressive disorder ( single or recurrent episodes ) and a CGI-S score of 4 or more ( 42 ) at the start of both the open-label and double-blind phases were eligible . The CGI-S is scored on a scale of increasing intensity from 1 to 7 , with 4 representing moderate illness . We recruited participants by using various methods , including media advertisements , and enrolled persons from 75 public and private primary care ( n= 41 ) and psychiatric ( n= 34 ) centers in the United States between 19 October 2004 and 17 November 2005 . Ethical approval was obtained from the institutional review board of each site , and written informed consent was obtained from all patients . Exclusion criteria were pregnancy ; serious suicidal risk or serious medical or neurologic illness ; active substance or alcohol use disorders ; or current treatment with a tricyclic antidepressant , monoamine oxidase inhibitor , mood stabilizer , antiepileptic , or a central ly acting agent for attention deficit disorder/attention deficit hyperactivity disorder or narcolepsy . R and omization and Interventions Patients who were eligible for r and omization continued their st and ard antidepressant regimen and dosage and were assigned to receive risperidone or placebo . Tablets were identical in appearance . The investigators , study staff , and patients were blinded to the treatment assignment . The r and omization code was central ly generated and administered by a telephone interactive voice response system , was stratified by antidepressant class ( SSRI or non-SSRI ) and center , and occurred in r and om permuted blocks . An independent statistician provided the r and omization codes . The dosing schedule was 0.25 mg for the first 3 days , 0.5 mg on days 4 to 15 , and 1.0 mg on days 16 to 28 . On day 29 , patients with insufficient treatment response in the opinion of the investigator could continue augmentation at the current dosage , have the dosage increased to 2 mg/d , or discontinue double-blind treatment . Concomitant medications were allowed as necessary for medical conditions . Sedative agents ( zolpidem , 2.5 to 10 mg/d , or zaleplon , 5 to 20 mg/d , as needed ) were allowed for insomnia . During double-blind treatment , benztropine mesylate was permitted as needed for potential treatment-emergent motor effects . Measurements and Outcomes At each visit ( end of the open-label phase and weeks 1 , 2 , 4 , and 6 ) , trained personnel administered the grid version of the 17-item Hamilton Rating Scale for Depression ( HRSD-17 ) ( 43 , 44 ) and the CGI-S ( 42 ) , both clinician-rated instruments . Scores on the HRSD-17 range from 0 to 52 ; higher scores indicate more severe depression . Patients also independently rated their response by using the telephone interactive voice response system at baseline and weekly thereafter . Other patient-reported outcomes were scores on 3 vali date d instruments : the Quality of Life Enjoyment and Satisfaction Question naire ( Q-LES-Q ) ( 45 ) , the Patient Global Improvement Scale ( 7-point rating from 1 [ very much improved ] to 7 [ very much worse ] ) , and the Sheehan Disability Scale ( SDS ) . Change in HRSD-17 total score from baseline to study end was the a priori primary efficacy measure . Response ( 50 % reduction in HRSD-17 total score from baseline ) and remission ( HRSD-17 total score 7 ) were assessed at each time point . Secondary measures were changes in the CGI-S , Q-LES-Q , SDS , and Patient Global Improvement Scale scores . Follow-up Patients underwent physical examination , including assessment of vital signs , at regular intervals . Research staff maintained records of trial medication and assessed treatment compliance by matching doses taken with the number of treatment days . To assess adverse effects , patients were interviewed at each study visit with open-ended questions about potential adverse events ; spontaneous reports were also taken into account . All adverse events were recorded , and the investigator assessed each event for severity and relationship to the study drug ( probable , possible , not related ) . Statistical Analysis A sample of 116 patients per group was anticipated to have 90 % power to detect an arbitrary difference in change in mean HRSD-17 total score of 3.0 units , assuming a common SD of 7.0 using a 2-group t test and a 2-sided significance level of 0.05 . We also assumed that approximately 30 % of the participants would not complete double-blind treatment and planned for 332 persons to undergo r and omization . We further assumed that during the open-label run-in phase , 30 % of participants would discontinue the study and 20 % would respond to st and ard antidepressant treatment and therefore be ineligible for r and omization ; thus , we sought 592 persons for the open-label run-in phase . All analyses were performed by using SAS , version 8.2 ( SAS Institute , Cary , North Carolina ) , and statistical analysis personnel were blinded to patient group assignment . Baseline patient characteristics were summarized by using descriptive statistics . Efficacy and safety analyses were based on the intention-to-treat population ( that is , all persons who underwent r and omization and received at least 1 dose of medication in the double-blind phase ) .
Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo .
Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone
BACKGROUND Evidence is limited regarding the most effective pharmacological treatment for psychotic depression :  combination of an antidepressant plus an antipsychotic , monotherapy with an antidepressant or monotherapy with an antipsychotic .
This is an up date of a review first published in 2005 and last up date d in 2009 .
OBJECTIVES 1 .
To compare the clinical efficacy of pharmacological treatments for patients with an acute psychotic depression :  antidepressant monotherapy , antipsychotic monotherapy and the combination of an antidepressant plus an antipsychotic , compared with each other and /or with placebo.2 .
To assess whether differences in response to treatment in the current episode are related to non-response to prior treatment .