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 Continuation treatment of delusional depression in older adults. A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: the study of pharmacotherapy of psychotic depression (STOP-PD). Combination antidepressant therapy for major depressive disorder: speed and probability of remission. Adjunctive divalproex and hostility among patients with schizophrenia receiving olanzapine or risperidone. Olanzapine in the treatment of depression with psychotic features: A prospective open-label study Antipsychotic combination using low-dose antipsychotics is as efficacious and safe as, but cheaper, than optimal-dose monotherapy in the treatment of schizophrenia: a randomized, double-blind study Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A Clinical Practice Guideline From the American College of Physicians Effect of Divalproex Combined with Olanzapine or Risperidone in Patients with an Acute Exacerbation of Schizophrenia Antipsychotic efficacy of the antidepressant trimipramine: a randomized, double-blind comparison with the phenothiazine perazine. Efficacy of adjunctive aripiprazole in patients with major depressive disorder whose symptoms worsened with antidepressant monotherapy Risk factors for antidepressant-related switch to mania. ITI-007 for the Treatment of Schizophrenia: A 4-Week Randomized, Double-Blind, Controlled Trial Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants. Treatment of mood-congruent psychotic depression with imipramine. Assessing the adequacy of past antidepressant trials: a clinician's guide to the antidepressant treatment response questionnaire. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial. The impact of chronic depression on acute and long-term outcomes in a randomized trial comparing selective serotonin reuptake inhibitor monotherapy versus each of 2 different antidepressant medication combinations. Three-Year long-term outcome of 458 naturalistically treated inpatients with major depressive episode: severe relapse rates and risk factors Adherence to Antidepressant Combinations and Monotherapy for Major Depressive Disorder: A CO-MED Report of Measurement-Based Care A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, non-psychotic major depression. Aripiprazole augmentation in treatment-resistant bipolar depression: Early response and development of akathisia A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life. Is the Comparison between Exercise and Pharmacologic Treatment of Depression in the Clinical Practice Guideline of the American College of Physicians Evidence-Based?
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 ) . Delusional depression responds poorly to acute antidepressant monotherapy but appears to respond to intensive combination pharmacotherapy , however with poor short-term outcomes after initial improvement , particularly in later life . The authors compared the efficacy and safety of continuation combination therapy to monotherapy among older patients after remission from a delusional depression . Twenty-nine older adults with SCID-diagnosed major depression with delusions received continuation treatment with nortriptyline-plus-perphenazine or nortriptyline-plus-placebo under r and omized double-blind conditions after achieving remission after ECT . Of the 28 subjects included in efficacy analyses , 25 % suffered relapses . The relapse frequency was nonsignificantly greater in combination therapy than in monotherapy subjects . However , combination subjects had significantly more extrapyramidal symptoms , an increased incidence of tardive dyskinesia , and a greater number of falls . Continuation treatment with a conventional antipsychotic does not decrease relapse rates but is associated with significant untoward adverse events in older persons after recovery from a delusional depression CONTEXT Evidence for the efficacy of combination pharmacotherapy has been limited and without positive trials in geriatric patients with major depression ( MD ) with psychotic features . OBJECTIVES To compare remission rates of MD with psychotic features in those treated with a combination of atypical antipsychotic medication plus a serotonin reuptake inhibitor with those treated with antipsychotic monotherapy ; and to compare response by age . DESIGN Twelve-week , double-blind , r and omized , controlled trial . SETTING Clinical services of 4 academic sites . Patients Two hundred fifty-nine subjects with MD with psychotic features r and omized by age ( < 60 or > or = 60 years ) ( mean [ st and ard deviation ( SD ) ] , 41.3 [ 10.8 ] years in 117 younger adults vs 71.7 [ 7.8 ] years in 142 geriatric participants ) . Intervention Target doses of 15 to 20 mg of olanzapine per day plus masked sertraline or placebo at 150 to 200 mg per day . Main Outcome Measure Remission rates of MD with psychotic features . RESULTS Treatment with olanzapine/sertraline was associated with higher remission rates during the trial than olanzapine/placebo ( odds ratio [ OR ] , 1.28 ; 95 % confidence interval [ CI ] , 1.12 - 1.47 ; P < .001 ) ; 41.9 % of subjects who underwent combination therapy were in remission at their last assessment compared with 23.9 % of subjects treated with monotherapy ( chi(2)(1 ) = 9.53 , P = .002 ) . Combination therapy was comparably superior in both younger ( OR , 1.25 ; 95 % CI , 1.05 - 1.50 ; P = .02 ) and older ( OR , 1.34 ; 95 % CI , 1.09 - 1.66 ; P = .01 ) adults . Overall , tolerability was comparable across age groups . Both age groups had significant increases in cholesterol and triglyceride concentrations , but statistically significant increases in glucose occurred only in younger adults . Younger adults gained significantly more weight than older subjects ( mean [ SD ] , 6.5 [ 6.6 ] kg vs 3.3 [ 4.9 ] kg , P = .001 ) . CONCLUSIONS Combination pharmacotherapy is efficacious for the treatment of MD with psychotic features . Future research must determine the benefits vs risks of continuing atypical antipsychotic medications beyond 12 weeks . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00056472 INTRODUCTION Only about a third of patients with an episode of major depressive disorder remit with a given treatment and few remissions occur within the first weeks of treatment . This study tested whether combining escitalopram and bupropion as initial treatment would result in quicker remission and a higher remission rate than monotherapy with either drug . METHOD Two hundred forty-five out patients aged 18 - 65 having non-psychotic , non-bipolar major depression were r and omly assigned to double-blind treatment with bupropion or escitalopram or the combination dosed to a maximum of bupropion 450 mg/d and /or escitalopram 40 mg/d for 12 weeks . A Montgomery-Asberg Depression Rating Scale score of 22 was required for r and omization , while a Hamilton Rating Scale for Depression score ≤ 7 defined remission . We hypothesized that bupropion plus escitalopram would outperform both monotherapies in both earlier onset of remission and higher rate of remission . RESULTS Primary analyses did not demonstrate that dual therapy outperformed both monotherapies in either timing of remission or remission rate . All three treatments were well tolerated . DISCUSSION These results do not support initial use of bupropion plus escitalopram to speed or enhance antidepressant response . CLINICAL TRIALS REGISTRATION NCT00519428 OBJECTIVE This study compared the specific antihostility effects of atypical antipsychotic monotherapy ( olanzapine or risperidone ) with that of combination treatment with divalproex sodium among patients with schizophrenia experiencing an acute psychotic episode . METHODS A total of 249 in patients with schizophrenia were r and omly assigned to receive olanzapine plus placebo , olanzapine plus divalproex , risperidone plus placebo , or risperidone plus divalproex in a double-blind , 28-day multicenter trial . The target daily dose was 15 milligrams for olanzapine , 6 milligrams for risperidone , and up to 30 milligrams per kilogram ( minimum , 15 milligrams per kilogram ) for divalproex . The hostility item of the Positive and Negative Syndrome Scale ( PANSS ) was the principal outcome measure . Covariates included the PANSS items reflecting positive symptoms of schizophrenia ( delusions , suspiciousness/persecution , gr and iosity , unusual thought content , conceptual disorganization , and hallucinatory behavior ) . RESULTS Combination treatment with risperidone or olanzapine plus divalproex was associated with different scores on the hostility item of the PANSS compared with antipsychotic monotherapy . Combination therapy had a significantly greater antihostility effect at days 3 and 7 than monotherapy . This result was not seen beyond the first week of treatment , but there was a trend toward a difference in effect for the entire treatment period . The effect on hostility appears to be statistically independent of antipsychotic effect on other PANSS items reflecting delusional thinking , a formal thought disorder , or hallucinations . CONCLUSIONS Divalproex sodium may be useful as an adjunctive agent in specifically reducing hostility in the first week of treatment with risperidone or olanzapine among patients with schizophrenia experiencing an acute psychotic episode Objective . Depression with psychotic features is a severe subtype of major depression associated with the presence of delusions , hallucinations and specific neurobiological features . Despite clinical consensus and guideline recommendations , data comparing the efficacy of combining antipsychotics with antidepressants compared to antidepressants alone remain inconclusive . The aim of the study was to investigate effectiveness and tolerability of the atypical antipsychotic olanzapine in acute depression with psychotic features . Methods . Seventeen in patients with major depressive disorder with psychosis ( MDDp ) were treated with a combination of an antidepressant and olanzapine for 6 weeks in a prospect i ve open-label study . Depressive and psychotic symptoms , extrapyramidal and general side effects were assessed every 2 weeks . Sixteen patients were eligible for final analysis . Results . The Brief Psychiatric Rating Scale ( BPRS ) showed a 30 % symptom reduction after week 2 , a 45 % symptom reduction after week 4 and no considerable improvement thereafter . Depressive symptoms ( Bech – Rafaelsen Melancholia Scale , BRMS ) receded by 37 % after week 2 and 50 % after week 4 . No extrapyramidal side effects occurred . Conclusion . Olanzapine is effective and tolerable in combination with an antidepressant in an MDDp inpatient sample . The results concur with data supporting good efficacy in negative and depressive symptoms of patients with schizophrenic and schizoaffective diseases The use of antipsychotic combination has been increasing during the last decade . This study aim ed to compare the efficacy and safety of low-dose amisulpride plus low-dose sulpiride with full-dose amisulpride in the treatment of acute schizophrenia . In this 6-week , double-blind , fixed-dose study , patients were r and omized to antipsychotic combination ( 400 mg/day amisulpride plus 800 mg/day sulpiride , N=46 ) or monotherapy ( 800 mg/day amisulpride , N=46 ) groups . Efficacy measurements included the Positive and Negative Syndrome Scale ( PANSS ) and subscales , and other scales . Safety and quality of life were also assessed . Response was defined as a 30 % reduction in the PANSS total score . Both groups were similar in terms of the following : ( a ) clinical characteristics at baseline , ( b ) response rates , and ( c ) score changes in all psychopathology measures , quality of life , and all side-effect scales after 6 weeks of treatment . There were also no significant between-group differences in changes in other safety measurement . However , the combination strategy did reduce treatment costs . The current study suggests that an antipsychotic combination of low-dose antipsychotics is as efficacious and safe as , but cheaper than , optimal-dose monotherapy in the treatment of schizophrenia Depressive disorders are a major health care issue and one of the foremost causes of disability in adults around the world , result ing in significant costs to society and health care systems ( 1 ) . The estimated economic burden associated with depression was $ 83.1 billion in 2000 and is probably higher today ( 2 ) . Depressive disorders include major depressive disorder ( MDD ) ; dysthymia ; and subsyndromal depression , including minor depression . Major depressive disorder is the most prevalent depressive disorder , with an estimated lifetime prevalence of 16 % in the United States ( 3 ) . An average of 8 million ambulatory care visits per year result in a primary diagnosis of MDD ( 4 ) . The American Psychiatric Association ( 5 ) defines MDD as depressed mood or loss of pleasure or interest along with other symptoms , including significant change in weight or appetite , insomnia or hypersomnia , psychomotor agitation or retardation nearly every day , fatigue or loss of energy , feelings of worthlessness or excessive or inappropriate guilt , indecisiveness or decreased ability to concentrate , and recurrent thoughts of death or suicide , that last for at least 2 weeks and affect normal functioning . Dysthymia is less severe , but symptoms last for 2 or more years . In contrast , subsyndromal depression is associated with less severe symptoms of depression that do not qualify for MDD or dysthymia diagnoses . The treatment of depression can be characterized by 3 phases ( Figure 1 ) : acute ( 6 to 12 weeks ) , continuation ( 4 to 9 months ) , and maintenance ( 1 year ) ( 7 ) . Relapse is defined as the return of depressive symptoms during the acute or continuation phases and is therefore considered part of the same depressive episode , whereas recurrence is defined as the return of depressive symptoms during the maintenance phase and is considered a new , distinct episode . Response to treatment ( typically defined as 50 % reduction in measured severity ) can be quantified using various tools , such as the Patient Health Question naire-9 ( PHQ-9 ) ( 7 ) or the Hamilton Depression Rating Scale ( HAM-D ) ( 8) . Figure 1 . Phases of treatment of major depression . Adapted from reference 6 . TX = treatment . Various treatment approaches can be used to manage MDD , such as psychotherapy , complementary and alternative medicine ( CAM ) , exercise , and pharmacotherapy . The psychological interventions used to treat depression include acceptance and commitment therapy , cognitive therapy , cognitive behavioral therapy ( CBT ) , interpersonal therapy , and psychodynamic therapies ( Table 1 ) . The CAM treatments include acupuncture , meditation , -3 fatty acids , S-adenosyl-l-methionine ( SAMe ) , St. John 's wort , and yoga . Exercise includes a broad range of activities that can be done for varying duration s , in classes , individually , or in informal groups . For pharmacologic therapy , the scope of this guideline is limited to second-generation antidepressants ( SGAs ) ( selective serotonin reuptake inhibitors , serotonin norepinephrine reuptake inhibitors , and selective serotonin norepinephrine reuptake inhibitors ) . First-generation antidepressants ( tricyclic antidepressants and monoamine oxidase inhibitors ) are very rarely used because SGAs have lower toxicity in overdose than first-generation antidepressants and similar efficacy . Table 1 . Common Psychological Interventions to Treat Depression Guideline Focus and Target Population The purpose of this guideline from the American College of Physicians ( ACP ) is to summarize and grade the evidence on the comparative effectiveness and safety of nonpharmacologic treatments and SGAs ( including serotonin reuptake inhibitors , serotonin norepinephrine reuptake inhibitors , bupropion , mirtazapine , nefazodone , and trazodone ) , alone or in combination , for MDD . The target audience for this guideline includes all clinicians , and the target patient population includes all adults with MDD . These recommendations are based on a background evidence article ( 9 ) and a systematic evidence review sponsored by the Agency for Healthcare Research and Quality ( AHRQ ) ( 6 ) . Methods Systematic Review of the Evidence The systematic evidence review was conducted by the AHRQ 's RTI InternationalUniversity of North Carolina at Chapel Hill Evidence -based Practice Center ( 6 ) . Additional method ological details can be found in the Appendix ) , accompanying background evidence article ( 9 ) , and full report ( 6 ) . Review ers search ed several data bases for studies published in English , German , or Italian from 1 January 1990 through September 2015 . Studies on efficacy were limited to r and omized , controlled trials and systematic review s and meta-analyses , although evidence on harms included observational studies . Review ers combined data when possible using meta- analysis and assessed the risk of bias and quality of studies according to established methods . The study population included adult out patients ( aged 18 years ) with MDD during either an initial or a second treatment attempt who did not remit after an initial adequate trial with an SGA . The review evaluated the following classes of interventions : depression-focused psychotherapy , CAM , exercise , and SGAs . Outcomes assessed included benefits in response ( often defined as 50 % improvement in HAM-D scores ) , remission ( often defined as a HAM-D score 7 ) , speed of response , speed of remission , relapse , quality of life , functional capacity ( as assessed by various scales ) , reduction of suicidality , or reduction of hospitalization . Harms assessed included overall adverse events , withdrawals because of adverse events , serious adverse events , and specific adverse events . Quality of life , functional status , suicidality , and hospitalizations were rarely reported . Grading the Evidence and Developing Recommendations This guideline was developed by the ACP Clinical Guidelines Committee according to the ACP guideline development process , which has been described ( 10 ) . The Clinical Guidelines Committee used the evidence tables in the accompanying systematic review and full report ( 9 ) when reporting the evidence and grade d the recommendations using ACP 's guideline grading system ( Table 2 ) . Table 2 . The American College of Physicians ' Guideline Grading System * Peer Review The AHRQ evidence review was sent to invited peer review ers and posted on the AHRQ Web site for public comments . The guideline was peer- review ed through the journal and was posted online for comments from ACP Governors and Regents . Comparative Benefits of Pharmacologic Versus Nonpharmacologic Treatment Options for Initial Management Refer to Appendix Table 1 and the accompanying systematic review ( 9 ) for additional details of the evidence . Appendix Table 1 . First-Line Treatment for MDD : SGAs Versus Nonpharmacologic Therapies * SGA Versus Psychological Interventions SGA Versus CBT Monotherapy . Moderate- quality evidence from 5 trials ( 1115 ) showed no difference in response when comparing SGAs ( fluoxetine , fluvoxamine , paroxetine , or sertraline ) with CBT in patients with MDD after 8 to 52 weeks of treatment . Low- quality evidence from 3 trials ( 11 , 14 , 15 ) showed no difference between remission rates ( fluoxetine , fluvoxamine , and paroxetine ) and functional capacity ( 14 ) ( fluvoxamine and paroxetine ) for SGAs compared with CBT . Combination Therapy . Low- quality evidence from 2 trials ( 14 , 16 ) showed no difference in response or remission when comparing monotherapy using SGAs ( escitalopram , fluvoxamine , or paroxetine ) with combination therapy using SGAs plus CBT ( problem-solving therapy or telephone-based CBT ) in patients with MDD after 12 to 52 weeks of treatment . Low- quality evidence from 2 trials ( 14 , 16 ) assessed function , and 1 trial showed that patients who received the combination therapy reported more improvement on 3 of 5 work-functioning measures than those who received SGA monotherapy , although clinical ly important differences on these measures are uncertain . SGA Versus Interpersonal Therapy Monotherapy . Low- quality evidence showed no difference in response ( 1 trial ; escitalopram ) ( 17 ) or remission ( 2 trials ; citalopram , escitalopram , or sertraline ) ( 17 , 18 ) for SGAs compared with interpersonal therapy for patients with MDD after 12 weeks of treatment . Combination Therapy . Low- quality evidence from 1 trial ( 19 ) showed increased remission for SGA monotherapy compared with SGA combined with interpersonal therapy ( with nefazodone ) in patients with MDD after 12 weeks of treatment . SGA Versus Psychodynamic Therapies Monotherapy . Low- quality evidence from 1 trial ( 20 ) showed no difference in remission for fluoxetine compared with psychodynamic monotherapy in patients with MDD after 16 weeks of treatment . Low- quality evidence from 2 trials ( 20 , 21 ) showed few differences in functional capacity between the treatments . Combination Therapy . Low- quality evidence from 1 trial ( 21 ) showed no difference in functional capacity for SGA monotherapy compared with SGA plus psychodynamic combination therapy . SGA Versus CAM Interventions SGA Versus Acupuncture Monotherapy . Low- quality evidence from 2 trials ( 22 , 23 ) showed no difference in treatment response when comparing fluoxetine with acupuncture monotherapy for patients with MDD after 6 weeks of treatment . Combination Therapy . Low- quality evidence from 2 trials ( 24 , 25 ) showed that combination therapy of SGAs with acupuncture improved treatment response compared with monotherapy with SGAs ( fluoxetine or paroxetine ) in patients with MDD after 6 weeks of treatment . However , low- quality evidence from 1 trial ( 24 ) showed no difference in remission when comparing paroxetine monotherapy with paroxetine plus acupuncture combination therapy . SGA Versus -3 Fatty Acids Monotherapy . Low- quality evidence from network meta- analysis showed that SGAs ( fluoxetine ) were associated with a greater response than -3 fatty acids in patients with MDD .  SGA Versus SAMe Monotherapy . Low- quality evidence from network meta- analysis showed no difference in response between treatment with escitalopram This double-blind , r and omized , multicenter study investigated the use of divalproex with an antipsychotic agent in patients hospitalized for acute exacerbation of schizophrenia . Patients ( n=249 ) who met DSM-IV criteria for schizophrenia were r and omly assigned to receive olanzapine monotherapy , risperidone monotherapy , divalproex plus olanzapine , or divalproex plus risperidone for 28 days . Divalproex was initiated at 15 mg/kg/day and titrated over 12 days to a maximum dosage of 30 mg/kg/day . Olanzapine and risperidone , were , respectively , initiated at 5 and 2 mg/day and were titrated over the first 6 days to respective target fixed daily dosages of 15 and 6 mg/day . Improvements from baseline were observed at all evaluation points throughout the 28-day treatment period in the two combination therapy and the two antipsychotic monotherapy groups , with statistically significant treatment differences favoring combination therapy as soon as day 3 for Positive and Negative Syndrome Scale ( PANSS ) total score , derived Brief Psychiatric Rating Scale ( BPRSd ) total score , as well as PANSS and BPRSd subscales . These findings were confirmed in post hoc repeated- measures analyses of variance in which treatment differences favoring combination therapy were observed for PANSS total ( p=0.020 ) and PANSS positive scale scores ( p=0.002 ) . Both combination therapy and antipsychotic monotherapy were well tolerated . Treatment with divalproex in combination with an atypical antipsychotic agent result ed in earlier improvements in a range of psychotic symptoms among acutely hospitalized patients with schizophrenia . Further evaluation is warranted to confirm these findings BACKGROUND The tricyclic antidepressant trimipramine exhibits several features ( e. g. , dopaminergic effect , molecular structure similar to a neuroleptic , receptor-binding profile similar to clozapine ) that suggest its potential as an antipsychotic medication . The aim of the study was to investigate the antipsychotic potential of trimipramine in a controlled clinical trial comparing its antipsychotic efficacy with that of a neuroleptic . METHOD In a German multi-center , r and omized , double-blind trial , the antipsychotic efficacy of trimipramine was compared with that of the phenothiazine neuroleptic perazine , using the Brief Psychiatric Rating Scale ( BPRS ) , the Positive and Negative Syndrome Scale ( PANSS ) , and Clinical Global Impressions ( CGI ) . Antidepressant efficacy of both agents was measured by use of the Bech-Rafaelsen Melancholia Scale ( BRMES ) .  Ninety-five patients with acute schizophrenia ( DSM-III-R ) and a BPRS total score > 40 at baseline were treated with either 300 - 400 mg trimipramine or 450 - 600 mg perazine for 5 weeks . RESULTS Therapeutic equivalence of both treatments ( in the dosages used ) could not be demonstrated ( change in BPRS total score , per- protocol [ PP ] analysis , one-sided equivalence testing ) . However , intention-to-treat ( ITT ) as well as PP analysis showed a statistically significant decrease in the BPRS total scores in both treatment groups ( PP : trimipramine , 56.5 + /- 9.8 to 44.1 + /- 17.9 ; perazine , 56.4 + /- 10.8 to 37.9 + /- 12.9 ) . Significant decreases in all BPRS and PANSS subscores as well as CGI results and response rate support the antipsychotic efficacy of trimipramine . The BRMES total scores significantly decreased in both treatment groups without showing a significant difference between the two agents . Trimipramine was better tolerated than perazine and did not elicit extrapyramidal symptoms . CONCLUSION Trimipramine failed to exhibit therapeutic equivalence to perazine in the dosages used . However , there was evidence of a substantial antipsychotic effect of trimipramine . It may be a useful medication if depressive symptoms in psychotic patients require antidepressant treatment or if other antipsychotics can not be administered Introduction Efficacy of depression treatments , including adjunctive antipsychotic treatment , has not been explored for patients with worsening symptoms after antidepressant therapy ( ADT ) . Methods This post-hoc analysis utilized pooled data from 3 similarly design ed , r and omized , double-blind , placebo-controlled trials that assessed the efficacy , safety , and tolerability of adjunctive aripiprazole in patients with major depressive disorder with inadequate response to ADT . The studies had 2 phases : an 8-week prospect i ve ADT phase and 6-week adjunctive ( aripiprazole or placebo ) treatment phase . This analysis focused on patients whose symptoms worsened during the prospect i ve 8-week ADT phase ( worsening defined as > 0 % increase in Montgomery – Åsberg Depressive Rating Scale [ MADRS ] Total score ) . During the 6-week , double-blind , adjunctive phase , response was defined as ≥50 % reduction in MADRS Total score and remission as ≥50 % reduction in MADRS Total score and MADRS score ≤10 . Results Of 1065 patients who failed to achieve a response during the prospect i ve phase , 160 exhibited worsening of symptoms ( ADT-Worseners ) , and 905 exhibited no change/reduction in MADRS scores ( ADT-Non-worseners ) . Response rates for ADT-Worseners at endpoint were 36.6 % ( adjunctive aripiprazole ) and 22.5 % ( placebo ) . Similarly , response rates at endpoint for ADT-Non-worseners were 37.5 % ( adjunctive aripiprazole ) and 22.5 % ( placebo ) . Remission rates at endpoint for ADT-Worseners were 25.4 % ( adjunctive aripiprazole ) and 12.4 % ( placebo ) . For ADT-Non-worseners , remission rates were 29.9 % ( adjunctive aripiprazole ) and 17.4 % ( placebo ) . Conclusion These results suggest that adjunctive aripiprazole is an effective intervention for patients whose symptoms worsen during antidepressant monotherapy . The results challenge the view that benefits of adjunctive therapy with aripiprazole are limited to partial responders to ADT OBJECTIVE Treatment of bipolar depression with antidepressants is strongly debated on the basis of the method ologically poor and insufficient data supporting their use and the widely held belief that antidepressants can induce new episodes of abnormal mood elevation or accelerate the rate of cycling . The present study aim ed at identifying clinical risk factors for switch into hypomania , mania , or mixed states , within 8 weeks after introduction of an antidepressant or after increasing its dosage , in a prospect i ve , longitudinal design . METHOD 221 consecutive DSM-IV-TR depressed bipolar I and II disorder patients were treated with antidepressants , which were added to previously prescribed mood stabilizers and /or atypical antipsychotics . No patient was on antidepressant monotherapy .  The patients were enrolled from October 2005 through January 2010 . The primary outcome was the assessment of switch to mania or hypomania within 8 weeks after the introduction or dose increase of an antidepressant  . Both groups were compared with analysis of variance and χ² procedures . RESULTS Treatment-emergent affective switch was detected in 54 patients ( 24.4 % ) ( switch group ) while 167 patients ( 75.6 % ) ( nonswitch group ) did not experience a treatment-related switch . The main clinical differences significantly associated with the occurrence of an antidepressant-related switch , after performing logistic regression analysis , were higher rate of previous switches ( P < .001 ) in the switch versus the nonswitch group , lower rate of responses to antidepressants ( P < .001 ) in the switch versus the nonswitch group , and earlier age at onset ( P = .026 ) in the switch versus the nonswitch group . DISCUSSION Bipolar patients with an earlier age at onset and an illness course characterized by lower rate of response to antidepressants and higher rate of switches into mania or hypomania were found to be the ones with higher switch risk . Nevertheless , a greater number of previous antidepressant exposures was not associated with the occurrence of an antidepressant-associated switch . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01503489 BACKGROUND An urgent need exists for new treatments of schizophrenia that are effective against a broad range of symptoms and free of limiting safety issues . ITI-007 is a new molecular entity with a pharmacologic profile that combines dose-related monoamine modulation with phosphorylation of intracellular signaling proteins . METHODS A phase II r and omized , double-blind , placebo-controlled , and active-controlled trial was conducted at eight sites in the United States with r and omization of 335 acutely psychotic adults with schizophrenia .  ITI-007 ( 60 mg and 120 mg ) , placebo , and risperidone , included for assay sensitivity , were evaluated as monotherapy for 4 weeks . The primary outcome measure was the Positive and Negative Syndrome Scale total score , with secondary analyses conducted on symptom subscales . RESULTS ITI-007 60 mg ( p = .017 , effect size = .4 ) and risperidone ( p = .013 , effect size = .4 ) demonstrated antipsychotic efficacy superiority over placebo on the primary end point . The results of secondary analyses reflected improvements in negative and depressive symptoms by ITI-007 60 mg . ITI-007 120 mg did not separate from placebo . However , both doses of ITI-007 were well tolerated in this patient population , as evidence d by low discontinuation and adverse event rates , and were associated with a benign metabolic profile as evidence d by significantly lower levels of prolactin , fasting glucose , total cholesterol , and triglycerides than risperidone . CONCLUSIONS The mechanistically novel investigational drug ITI-007 was effective for the treatment of schizophrenia and comparable with placebo on safety measures in this trial . Secondary analyses indicated that ITI-007 improved negative and depression symptoms and might have exp and ed therapeutic efficacy in comparison with current antipsychotic drugs INTRODUCTION Effective management of  major depressive disorder ( MDD ) continues to be a challenging task for psychiatrists and primary care physicians . This trial evaluated the efficacy and safety of adjunctive aripiprazole versus antidepressant monotherapy in patients with MDD and independently replicated the positive findings of two similar trials . METHODS Patients ( N=1,147 ) with MDD experiencing a major depressive episode and a history of inadequate response to antidepressant monotherapy were enrolled ( week 0 ) ; 827 received single-blind adjunctive placebo plus open-label antidepressant ( escitalopram , fluoxetine , paroxetine controlled release , sertraline , or venlafaxine extended release ) for 8 weeks to confirm inadequate response to antidepressants ; 349 patients with inadequate response were r and omized ( 1:1 ) to double-blind , adjunctive placebo ( n=172 ) or adjunctive aripiprazole ( n=177 ; 2 - 20 mg/day ) . Primary outcome was the mean change in Montgomery-Asberg Depression Rating Scale ( MADRS ) Total score from baseline ( week 8) to endpoint ( week 14 ) . RESULTS Clinical ly significant improvements in depressive symptoms as assessed by decreases in the MADRS Total score were greater with adjunctive aripiprazole ( -10.1 ) than placebo ( -6.4 ; P<.001 ) . Remission rates were greater for adjunctive aripiprazole than for adjunctive placebo ( week 14 , 36.8 % vs 18.9 % ; P<.001 ) . Completion rates with adjunctive aripiprazole and placebo were high ( 83 % vs. 87 % ) and discontinuations due to adverse events were low ( 6.2 % vs 1.7 % ) . CONCLUSION For some patients with MDD who do not obtain adequate symptom relief with antidepressant monotherapy , adjunctive therapies can significantly improve depressive symptoms . As reported , adjunctive aripiprazole was associated with a two-fold higher remission rate than adjunctive placebo . This , and previous studies , have shown that discontinuations due to adverse events were low and completion rates were high , and has indicated that both antidepressant and aripiprazole in combination were relatively well-tolerated and safe . This is the third consecutive clinical trial , in the absence of a failed trial , to demonstrate that aripiprazole augmentation to antidepressants is an efficacious and well-tolerated treatment for patients with MDD who do not respond adequately to st and ard antidepressant monotherapy ( Clinical Trials.gov study NCT00105196 ) BACKGROUND Most studies report a poor response of psychotic depressed patients to treatment with a tricyclic antidepressant alone compared to combined treatment with an antipsychotic preparation and compared to non-psychotic depressed patients . However , the issue of optimal treatment of psychotic depressed patients has not been resolved as yet . Previously , we reported a significant difference in response to mirtazapine compared to imipramine in a r and omised , double-blind , fixed-blood-level study with in- patients with major depression . In the current study we focus on the treatment response to imipramine in a group of patients with psychotic depression and compare this to patients who manifest no psychotic features . Our aim in presenting these findings was to contribute to the discussion on the optimal treatment of psychotic depressed patients . METHODS Fifty-two patients with a unipolar major depression ( DSM-IIIR ) , comprising 15 patients with mood-congruent psychotic features and 37 patients with no psychotic features , were commenced on treatment with imipramine after a drug-free and placebo-washout period of 7 days . The dose of imipramine was adjusted for all patients to a predetermined blood level . The Hamilton ( HRSD ) and Montgomery-Asberg ( MADRS ) Depression Rating Scales were used to evaluate treatment response . RESULTS Of the 45 patients who completed the study , nine of the 13 psychotic patients ( 69.2 % ) and 14 of the 32 non-psychotic patients ( 43.8 % ) responded to treatment . The patients with psychotic features demonstrated a lower mean final HRSD score , together with a greater fall in MADRS score over time , compared to the non-psychotic group . Both these findings remained statistically significant after controlling for a number of possible confounding factors . CONCLUSIONS These results demonstrate that , in this group of patients with mood-congruent psychotic depression , imipramine used on its own together with strict control of serum drug levels produced a high treatment response rate of 70 % . CLINICAL IMPLICATION S If replicated , these findings suggest that imipramine with control of blood levels of medication may be a useful first-line treatment for depressed patients with mood-congruent psychotic features . LIMITATIONS Our sample size was modest . This fact may caution against generalisation of the results Many depressed patients do not remit on antidepressant medication despite an adequate dosage and a sufficient duration of treatment.1 This has spawned endeavors to define treatment-resistant depression as a depressive episode that has shown insufficient response to 1 or more adequate trials of an antidepressant.1 What constitutes insufficient , inadequate , or partial response is still a matter of debate . Recently , an operational classification of degree of treatment resistance was proposed,2 with categorical distinctions defined by the percent symptom reduction from baseline as follows : nonresponse , < 25 % reduction ; partial response , 25%–49 % reduction ; and response without remission , ≥ 50 % reduction but without achievement of remission.1 To determine the adequacy and outcome of treatment in a way that can be communicated among clinicians and research ers , it is crucial to employ a reliable and valid instrument . While historical rating of treatment is not as accurate as a prospect i ve trial , there are many instances in which a decision is needed before the next trial is carried out . Several tools have been proposed , such as the  Antidepressant Treatment History Form (ATHF),3 the  Harvard Antidepressant Treatment History (HATH),4 and the Massachusetts General Hospital Antidepressant Treatment Response Question naire (ATRQ).1,5 The ATHF and HATH have the advantage of integrating clinical judgment in the assessment of treatment resistance , but these question naires are quite burdensome.5 The ATRQ ( Appendix 1 ) and accompanying questions are meant to provide clinicians with a user-friendly tool for assessment of prior treatment . It is often the case that a patient remembers whether a past treatment was somewhat helpful , although it is frequently difficult for him or her to remember exactly which antidepressant was taken , how long it was taken , and at what dose . However , it is important that the clinician explore past trials thoroughly using a systematic approach in order to characterize the adequacy of the trial and the degree of improvement . The clinician version of the ATRQ1,5 examines the adequacy of duration and dose of prior and current antidepressant treatments  in a step-by-step procedure . It can not be emphasized enough that , when assessing the duration and dose of clinical trials of antidepressants , clinicians must always inquire about adherence to each treatment trial . In addition , the ATRQ assesses the degree of improvement ( in the most efficacious trial or in all trials during the current episode , depending on the version of the instrument ) on a scale from 0 % ( not improved at all ) to 100 % ( completely improved ) ( Table 1 ) . The previous treatment may have been monotherapy , an augmentation trial , a trial of 2 antidepressants ( combination therapy ) , or a switch to another antidepressant . Our group has adopted conventions to define resistance to each of these approaches . At the outset it is noted that the doses and duration s required for adequate treatment are based on expert consensus1 rather than systematic research . We define an adequate monotherapy trial as a trial lasting at least 6 weeks at a minimum effective dose . In the context of this initial trial , the adequate duration for augmentation or combination treatment is at least 3 weeks . However , a combination trial from the onset ( ie , starting with 2 drugs together ) must be 6 weeks . Six weeks is also required for a switch to a different antidepressant . Each of these trials is considered a new trial . An increase in dose for at least 4 weeks represents optimization and is not considered a new or separate trial . However , if remission is later followed by relapse , a dose increase represents a new trial for the new episode . We recognize that the conventions used to define adequate dose and duration are not established and that other conventions , for example , a duration of 12 weeks , might be preferred . The ATRQ can be adapted to accommo date various definitions of dose and duration . Likewise , the threshold of resistance in terms of percent response may vary , depending on the questions being asked within a given clinical trial OBJECTIVE Various classes of antidepressant medications generally induce remission of major depressive disorder  in only about one-third of patients . In a previous study using mirtazapine or paroxetine alone or in combination from treatment initiation , the rate of patients who remitted within a 6-week period was twice that of patients using either drug alone . In this double-blind study , the authors sought to produce evidence for the superiority of different combinations of antidepressant drugs from treatment initiation . METHOD Patients ( N=105 ) meeting DSM-IV criteria for major depressive disorder were r and omly assigned to receive , from treatment initiation , either fluoxetine monotherapy ( 20 mg/day ) or mirtazapine ( 30 mg/day ) in combination with fluoxetine ( 20 mg/day ) , venlafaxine ( 225 mg/day titrated in 14 days ) , or bupropion ( 150 mg/day ) for 6 weeks . The primary outcome measure was the Hamilton Depression Rating Scale ( HAM-D ) score . RESULTS The overall dropout rate was 15 % , without notable differences among the four groups . Compared with fluoxetine monotherapy , all three combination groups had significantly greater improvements on the HAM-D. Remission rates ( defined as a HAM-D score of 7 or less ) were 25 % for fluoxetine , 52 % for mirtazapine plus fluoxetine , 58 % for mirtazapine plus venlafaxine , and 46 % for mirtazapine plus bupropion . Among patients who had a marked response , double-blind discontinuation of one agent produced a relapse in about 40 % of cases . CONCLUSIONS The combination treatments were as well tolerated as fluoxetine monotherapy and more clinical ly effective . The study results , which add to a growing body of evidence , suggest that use of antidepressant combinations from treatment initiation may double the likelihood of remission compared with use of a single medication IMPORTANCE Bright light therapy is an evidence -based treatment for seasonal depression  , but there is limited evidence for its efficacy in nonseasonal major depressive disorder ( MDD ) . OBJECTIVE To determine the efficacy of light treatment , in monotherapy and in combination with fluoxetine hydrochloride , compared with a sham-placebo condition in adults with nonseasonal MDD . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo- and sham-controlled , 8-week trial in adults ( aged 19 - 60 years ) with MDD of at least moderate severity in outpatient psychiatry clinics in academic medical centers . Data were collected from October 7 , 2009 , to March 11 , 2014 . Analysis was based on modified intent to treat ( r and omized patients with ≥1 follow-up rating ) . INTERVENTIONS Patients were r and omly assigned to ( 1 ) light monotherapy ( active 10,000-lux fluorescent white light box for 30 min/d in the early morning plus placebo pill ) ; ( 2 ) antidepressant monotherapy ( inactive negative ion generator for 30 min/d plus fluoxetine hydrochloride , 20 mg/d ) ; ( 3 ) combination light and antidepressant ; or ( 4 ) placebo ( inactive negative ion generator plus placebo pill ) . MAIN OUTCOMES AND MEASURES Change score on the Montgomery-Åsberg Depression Rating Scale ( MADRS ) from baseline to the 8-week end point . Secondary outcomes included response ( ≥50 % reduction in MADRS score ) and remission ( MADRS score ≤10 at end point ) . RESULTS A total of 122 patients were r and omized ( light  monotherapy , 32 ;  fluoxetine monotherapy , 31 ; combination therapy , 29 ; placebo , 30 ) . The mean ( SD ) changes in MADRS score for the light , fluoxetine , combination , and placebo groups were 13.4 ( 7.5 ) , 8.8 ( 9.9 ) , 16.9 ( 9.2 ) , and 6.5 ( 9.6 ) , respectively . The combination ( effect size [ d ] = 1.11 ; 95 % CI , 0.54 to 1.64 ) and light monotherapy ( d = 0.80 ; 95 % CI , 0.28 to 1.31 ) were significantly superior to  placebo in the MADRS change score , but fluoxetine monotherapy ( d = 0.24 ; 95 % CI , -0.27 to 0.74 ) was not superior to placebo . For the respective placebo , fluoxetine , light , and combination groups at the end point , response was achieved by 10 ( 33.3 % ) , 9 ( 29.0 % ) , 16 ( 50.0 % ) , and 22 ( 75.9 % ) and remission was achieved by 9 ( 30.0 % ) , 6 ( 19.4 % ) , 14 ( 43.8 % ) , and 17 ( 58.6 % ) . Combination therapy was superior to placebo in MADRS response ( β = 1.70 ; df = 1 ; P = .005 ) and remission ( β = 1.33 ; df = 1 ; P = .02 ) , with numbers needed to treat of 2.4 ( 95 % CI , 1.6 to 5.8 ) and 3.5 ( 95 % CI , 2.0 to 29.9 ) , respectively . All treatments were generally well tolerated , with few significant differences in treatment-emergent adverse events . CONCLUSIONS AND RELEVANCE Bright light treatment , both as monotherapy and in combination with fluoxetine , was efficacious and well tolerated in the treatment of adults with nonseasonal MDD .  The combination treatment had the most consistent effects . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00958204 OBJECTIVE To compare sociodemographic and clinical features , acute and continuation treatment outcomes , and adverse events/side effect burden between out patients with chronic ( current episode > 2 years ) versus nonchronic major depressive disorder ( MDD ) who were treated with combination antidepressant therapy or selective serotonin reuptake inhibitor ( SSRI ) monotherapy . METHOD 663 out patients with chronic ( n = 368 ) or nonchronic ( n = 295 ) moderate to severe DSM-IV-TR MDD ( 17-item Hamilton Depression Rating Scale score ≥ 16 ) were enrolled from March 2008 through September 2009 in a single-blind 7-month prospect i ve r and omized trial conducted at 6 primary and 9 psychiatric care sites across the United States . Participants were treated with escitalopram monotherapy plus placebo or 1 of 2 combination treatments ( bupropion sustained-release [ SR ] + escitalopram or venlafaxine extended-release [ XR ] + mirtazapine ) . Analyses compared baseline sociodemographic and clinical characteristics , rates of remission ( at least 1 of the last 2 consecutive scores on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report [ QIDS-SR16 ] < 6 , with the other < 8) , and adverse events/side effect burden ( Frequency , Intensity , and Burden of Side Effects Ratings ) obtained at 12 and 28 weeks . RESULTS Participants with chronic MDD were at greater socioeconomic disadvantage and had greater medical and psychiatric disease burden  . The chronic and nonchronic groups did not differ in rates of remission at 12 weeks ( 35.9 % vs 42.0 % , respectively ; odds ratio [ OR ] = 0.778 , P = .1500 ; adjusted OR [ AOR ] = 0.956 , P = .8130 ) or at 28 weeks ( 41.0 % vs 49.8 % , respectively ; OR = 0.706 , P = .0416 ; AOR = 0.837 , P = .3448 ) . Participants with chronic MDD had higher final QIDS-SR(16 ) scores and smaller overall percent changes in QIDS-SR(16 ) from baseline to exit , but these differences did not remain after adjusting for covariates . There were no significant differences in adverse events or side effect burden . No significant interactions were found between chronicity and type of treatment at 12 or 28 weeks . CONCLUSION Chronicity of illness does not appear to differentially impact acute or longer-term outcomes with SSRI monotherapy or combination antidepressant medication treatment in patients with moderate to severe nonpsychotic MDD . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00590863 In r and omized controlled trials , maintenance treatment for relapse prevention has been proven to be efficacious in patients responding in acute treatment , its efficacy in long-term outcome in “ real-world patients ” has yet to be proven . Three-year long-term data from a large naturalistic multisite follow-up were presented . Severe relapse was defined as suicide , severe suicide attempt , or rehospitalization . Next to relapse rates , possible risk factors including antidepressant medication were identified using univariate generalized log-rank tests and multivariate Cox proportional hazards model for time to severe relapse . Overall data of 458 patients were available for analysis . Of all patients , 155 ( 33.6 % ) experienced at least one severe relapse during the 3-year follow-up . The following variables were associated with a shorter time to a severe relapse in univariate and multivariate analyses : multiple hospitalizations , presence of avoidant personality disorder , continuing antipsychotic medication  , and no further antidepressant treatment . In comparison with other studies , the observed rate of severe relapse during 3-year period is rather low . This is one of the first reports demonstrating a beneficial effect of long-term antidepressant medication on severe relapse rates in naturalistic patients . Concomitant antipsychotic medication may be a proxy marker for treatment resistant and psychotic depression Background . Non-adherence to antidepressant treatment is not routinely measured in practical clinical trials . It has not been related to outcomes in a large sample of adults with chronic and /or recurrent major depressive disorder ( MDD ) or any sample treated with antidepressant combinations . Methods . Adult out patients with chronic and /or recurrent MDD were r and omized to 12 weeks of treatment with bupropion-SR plus escitalopram , venlafaxine – XR plus mirtazapine , or escitalopram plus placebo . We compared non-adherence ( the frequency with which daily medications were not taken ) and specifically the frequency of temporarily stopping and /or skipping medication , or reducing or increasing the dose across treatments in 567 participants using a self-report question naire collected at each visit . We tested the association between non-adherence , and both treatment type and outcomes . Results . A non-adherence rate under 10 % was reported by 77.9 % , 70.9 % , and 71.6 % of participants during weeks 1–4 , 5–12 , and 1–12 , respectively . Antidepressant combinations were associated with a higher non-adherence rate than monotherapy during weeks 1–4 and 1–12 . During weeks 1–4 , 24.1 % stopped/skipped doses and 6.1 % reduced the dose . During weeks 5–12 , 34.7 % stopped/skipped doses and 9.4 % reduced the dose . Across 12 weeks , 43.2 % stopped/skipped doses , and 12.9 % reduced the dose . Stopping/skipping doses during all time frames and dose decreases during weeks 1–12 occurred most frequently with combination treatments . Non-adherence was unrelated to symptom remission , response , or symptom change . Conclusions . With closely monitored treatment , non-adherence is low and unrelated to depressive symptom outcome . Nonadherence is highest with antidepressant combinations . Specific non-adherent events are most often sporadic . ( Journal of Psychiatric Practice 2014;20:118–132 OBJECTIVE Patients ( 30 - 50 % ) with non-psychotic major depression will not respond despite an adequate trial of antidepressant medication . This study evaluated risperidone as an augmenting agent for patients who failed or only partially responded to an adequate trial of an antidepressant medication . METHOD Ninety-seven patients with unipolar non-psychotic major depression who were not responsive to antidepressant monotherapy were r and omized to risperidone ( 0.5 - 3mg/day ) or placebo augmentation in a four-week , double-blind , placebo controlled treatment trial . The primary outcome measure was remission defined by a score of < or = 10 on the Montgomery-Asberg Depression Rating Scale ( MADRS ) . Secondary outcomes measures were the Hamilton Rating Scale for Depression , the Clinician Global Impression of Severity scale and the overall satisfaction item of the Quality of Life and Enjoyment Question naire . RESULTS Subjects in both treatment groups improved significantly over time . The odds of remitting were significantly better for patients in the risperidone vs. placebo arm ( OR=3.33 , p=.011 ) . At the end of 4 weeks of treatment 52 % of the risperidone augmentation group remitted ( MADRS < or = 10 ) compared to 24 % of the placebo augmentation group ( CMH(1)=6.48 , p=.011 ) , but the two groups were converging . Patients in the risperidone group also reported significantly more improvement in quality -of-life than patients in the placebo group . There were no between-group differences in the number of adverse events reported , however , weight gain was significantly higher in the group receiving risperidone . CONCLUSION Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality -of-life There is growing evidence that atypical antipsychotics may be effective in the treatment of acute bipolar depression . Results from r and omized , placebo-controlled trials support the use of quetiapine monotherapy and a combination of olanzapine-fluoxetine in the depressed phase of bipolar disorder , while only limited data exists regarding the use of aripiprazole in this population . To assess the potential effectiveness of aripiprazole in treating acute bipolar depression , a chart review was conducted on 12 patients with treatment-resistant bipolar disorder ( I , II , and not otherwise specified [ NOS ] ) who received aripiprazole augmentation for the relief of an acute major depressive episode . After 8 weeks of treatment , 4 of 12 ( 33 % ) patients demonstrated a response , defined as a 50 % reduction in the Montgomery-Asberg Depression Rating Scale ( MADRS ) score . In addition , 5 of 12 ( 42 % ) patients newly developed akathisia . This report , though limited by its small sample size and naturalistic design , suggests that the usefulness of aripiprazole in the treatment of bipolar depression may be limited by akathisia OBJECTIVE To conduct the first r and omized study comparing the efficacy of an antidepressant alone versus an antidepressant plus a neuroleptic in the treatment of late-life psychotic depression . METHOD The efficacy of nortriptyline plus placebo versus nortriptyline plus perphenazine was compared in 36 patients aged 50 years or older presenting with a major depressive episode with psychotic features ( DSM-III-R criteria ) . Patients were started openly on nortriptyline treatment titrated to therapeutic levels . They were then r and omly assigned under double-blind conditions to addition of perphenazine or placebo . Outcomes were compared in the 2 treatment groups using measures including the Hamilton Rating Scale for Depression ( HAM-D ) and the Brief Psychiatric Rating Scale ( BPRS ) ; side effects were assessed with the Geriatric Movement Disorder Assessment . RESULTS Both treatments were well tolerated . Of the 36 r and omly assigned patients , 2 ( 1 in each group ) dropped out due to treatment-related adverse effects . Four additional patients dropped out for administrative reasons . Thirty patients received nortriptyline for at least 4 weeks combined with either perphenazine ( N = 14 ) or placebo ( N = 16 ) for at least 2 weeks ( median = 9 weeks ) . There was no significant difference between the completers in the 2 treatment groups when comparing their scores on the HAM-D , the BPRS , its psychoticism subscale , or any side effects measure . Rates of response ( defined as resolution of both depression and psychosis ) did not differ significantly in the 2 groups ( nortriptyline-plus-perphenazine group , 50 % vs. nortriptyline-plus-placebo group , 44 % ) . CONCLUSION When treating older patients with psychotic depression , the addition of a moderate dose of a traditional neuroleptic to a tricyclic antidepressant was well tolerated but did not improve efficacy . This finding supports existing data suggesting that the pathophysiology ( and thus the required treatment ) of psychotic depression may be different early and late in life Major depression disorder is most commonly treated with antidepressants . However , due to their side effects clinicians seek non-pharmacologic options , and one of these is exercise . The literature on the benefits of exercise for depression is extensive . Nevertheless , two recent review s focusing on antidepressants vs. other therapies as a basis for clinical practice guidelines recommended mainly antidepressants , excluding exercise as a viable choice for treatment of depression . The aim of this perspective is to analyze the literature exploring the reasons for this discrepancy . Two categories of publications were examined : r and omized controlled trials ( RCTs ) and meta-analyses or systematic review s. Based on this re assessment , RCTs comparing exercise to antidepressants reported that exercise and antidepressants were equally effective . RCTs comparing exercise combined with antidepressants to antidepressants only reported a significant improvement in depression following exercise as an adjunctive treatment . Almost all the review s examining exercise vs. other treatments of depression , including antidepressants , support the use of exercise in the treatment of depression , at least as an adjunctive therapy . The two review s examining pharmacologic vs. non-pharmacologic therapies as a basis for clinical practice guidelines examined limited evidence on exercise vs. antidepressants . In addition , it is possible that academics and health care practitioners are skeptical of viewing exercise as medicine . Maybe , there is a reluctance to accept that changes in lifestyle as opposed to pharmacological treatment can alter biological mechanisms . Longitudinal studies are needed for assessing the effectiveness of exercise in real clinical setting s , as well as studies exploring dose-response relationship between exercise and depression
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 .