title: The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study. A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, non-psychotic major depression. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in major depressive disorder: a placebo-controlled, randomized study. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants. Components of variance and intraclass correlations for the design of community-based surveys and intervention studies: data from the Health Survey for England 1994. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. A randomized, double-blind, and placebo-controlled trial of quetiapine augmentation of fluoxetine in major depressive disorder The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder: A Second Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Efficacy and tolerability of extended release quetiapine fumarate monotherapy as maintenance treatment of major depressive disorder: a randomized, placebo-controlled trial. Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. Amisulpride versus imipramine and placebo in dysthymia and major depression. Amisulpride Study Group. A novel augmentation strategy for treating resistant major depression. Amisulpride in medium-term treatment of dysthymia: a six-month, double-blind safety study versus amitriptyline Risperidone for Treatment-Refractory Major Depressive Disorder A comparison of paroxetine and amisulpride in the treatment of dysthymic disorder. Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study. Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome. Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind, randomized, placebo-controlled study. Faster response on amisulpride 50 mg versus sertraline 50-100 mg in patients with dysthymia or double depression: a randomized, double-blind, parallel group study A double-blind, randomised, controlled clinical trial of acetyl-l-carnitine vs. amisulpride in the treatment of dysthymia A Double-Blind, Randomized Study of Olanzapine and Olanzapine/Fluoxetine Combination for Major Depression With Psychotic Features Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. Amisulpride versus fluoxetine in patients with dysthymia or major depression in partial remission: a double-blind, comparative study. Efficacy and safety of amisulpride 50 mg versus paroxetine 20 mg in major depression: a randomized, double-blind, parallel group study Amisulpride versus Amineptine and Placebo for the Treatment of Dysthymia Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study. Efficacy of risperidone augmentation to antidepressants in the management of suicidality in major depressive disorder: a randomized, double-blind, placebo-controlled pilot study. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials 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).
abstract: OBJECTIVE To assess the efficacy and safety of aripiprazole versus placebo as adjunctive treatment to st and ard antidepressant therapy ( ADT ) in patients with major depressive disorder ( MDD ) who showed an incomplete response to 1 prospect i ve and 1 to 3 historical courses of ADT within the current episode . METHOD The study comprised a 7- to 28-day screening phase , an 8-week prospect i ve treatment phase , and a 6-week double-blind treatment phase . Patients with DSM-IV-TR-defined MDD were enrolled between June 16 , 2004 , and April 27 , 2006 . During prospect i ve treatment , patients received ADT : escitalopram , fluoxetine , paroxetine controlled-release , sertraline , or venlafaxine extended-release , each with single-blind , adjunctive placebo . Incomplete responders continued ADT and were r and omly assigned to double-blind , adjunctive placebo or adjunctive aripiprazole ( 2 - 15 mg/day with fluoxetine or paroxetine ; 2 - 20 mg/day with all others ) . The primary efficacy endpoint was the mean change from end of prospect i ve treatment to end of double-blind treatment ( week 14 , last observation carried forward ) in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score ( analysis of covariance ) . RESULTS A total of 178 patients were r and omly assigned to adjunctive placebo and 184 to adjunctive aripiprazole . Baseline demographics were similar between groups ( mean MADRS total score of 26.0 ) . Mean change in MADRS total score was significantly greater with adjunctive aripiprazole ( -8.8 ) than adjunctive placebo ( -5.8 ; p < .001 ) . Adverse events ( AEs ) that occurred in > or = 10 % of patients with adjunctive placebo or adjunctive aripiprazole were akathisia ( 4.5 % vs. 23.1 % ) , headache ( 10.8 % vs. 6.0 % ) , and restlessness ( 3.4 % vs. 14.3 % ) . Discontinuations due to AEs were low with adjunctive placebo ( 1.7 % ) and adjunctive aripiprazole ( 2.2 % ) ; only 1 adjunctive aripiprazole-treated patient discontinued due to akathisia . CONCLUSIONS In patients with MDD who showed an incomplete response to ADT , adjunctive aripiprazole was efficacious and well tolerated . CLINICAL TRIALS REGISTRATION Clinical Trials.gov identifier NCT00095823 OBJECTIVE To evaluate the efficacy and tolerability of once-daily extended release quetiapine fumarate ( quetiapine XR ) as monotherapy treatment for major depressive disorder ( MDD ) . METHOD This 8-week ( 6-week active-treatment , r and omized phase ; 2-week posttreatment drug-discontinuation/tapering phase ) , multicenter , double-blind , r and omized , parallel-group , placebo- and active-controlled , phase 3 study was conducted between April 2006 and May 2007 . In total , 612 patients with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition (DSM-IV)-defined MDD were r and omly assigned to quetiapine XR 150 mg/day or 300 mg/day , duloxetine 60 mg/day ( active control ) , or placebo . The primary endpoint was the change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score . RESULTS At week 6 , both doses of quetiapine XR ( p < .001 ) and duloxetine ( p < .01 ) significantly reduced mean MADRS total score versus placebo . A significant reduction was seen at week 1 with quetiapine XR 150 mg/day and 300 mg/day versus placebo ( p < .01 ) , but not with duloxetine . Response rates ( > or= 50 % reduction in MADRS total score ) at week 6 were significantly higher for both doses of quetiapine XR ( p < .01 ) and duloxetine ( p < .05 ) versus placebo . Remission rates ( MADRS score < or= 8) were significantly higher for quetiapine XR 300 mg/day and duloxetine versus placebo ( p < .05 ) , but not for quetiapine XR 150 mg/day . Hamilton Rating Scale for Depression , Hamilton Rating Scale for Anxiety , and Clinical Global Impressions-Severity of Illness total scores and the proportion of patients with Clinical Global Impressions-Improvement scores of 1 or 2 ( " much/very much improved " ) were significantly improved with both doses of quetiapine XR and duloxetine versus placebo . The most common adverse events reported were dry mouth , sedation , and somnolence for quetiapine XR and nausea , headache , dizziness , and dry mouth for duloxetine . CONCLUSION Quetiapine XR monotherapy ( 150 mg/day and 300 mg/day ) is effective , with safety and tolerability consistent with the known profile of quetiapine XR , in the treatment of patients with MDD , with onset of symptom improvement demonstrated at week 1 . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00321490 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 Based on preliminary evidence of its usefulness in treatment-resistant depression ( TRD ) , an olanzapine/fluoxetine combination ( OFC ) was examined in comparison with olanzapine , fluoxetine , and venlafaxine in a TRD population . In this 12-week double-blind study , 483 subjects with unipolar , nonpsychotic TRD , with historic failure on a selective serotonin reuptake inhibitor ( SSRI ) and prospect i ve failure on open-label venlafaxine , were r and omized to an OFC or to an olanzapine , fluoxetine , or venlafaxine monotherapy group . Venlafaxine was continued r and omly in the double-blind acute phase to explore the benefits of continuation versus switching therapy . The Montgomery-Asberg Depression Rating Scale ( MADRS ) total change score at end point was the primary outcome measure . The OFC group had significantly greater improvement in depressive symptoms by week 1 of treatment ( MADRS mean change = -7.2 , baseline = 29.6 ) , in comparison to olanzapine ( -4.8 , P=.03 ) , fluoxetine ( -4.7 , P=.03 ) , or venlafaxine ( -3.7 , P=.002 ) groups and maintained its statistical separation from all three monotherapy groups through week 6 . At end point , the OFC group was significantly different only from the olanzapine group ( -14.1 vs. -7.7 , P<.001 ) . Analysis of a subgroup of subjects who had an SSRI failure in their current depressive episode ( n=334 ) revealed statistical separation from both olanzapine and fluoxetine ( but not venlafaxine ) at end point : OFC ( -14.6 ) versus olanzapine ( -9.4 , P<.001 ) versus fluoxetine ( -10.7 , P=.006 ) versus venlafaxine ( -14.7 , P=.98 ) . The OFC had a safety profile comparable to its component monotherapies ( i.e. , olanzapine and fluoxetine ) , showed a rapid onset of antidepressant effect , and was effective in this TRD sample . At the study end point , OFC , fluoxetine , venlafaxine , and low-dose OFC all appeared to be similarly effective BACKGROUND Evaluate the efficacy and tolerability of extended release quetiapine fumarate ( quetiapine XR ) once-daily monotherapy for patients with major depressive disorder ( MDD ) . METHODS In this 10-week , ( 8-week active treatment phase and 2-week drug-discontinuation/tapering phase ) , multicenter , parallel-group , placebo-controlled , double-blind , r and omized , Phase III study ( D1448C00003 : Opal ) , patients initially received quetiapine XR 150 mg/day or placebo . At Week 2 , inadequate responders ( < 20 % reduction in MADRS total score ) were up-titrated to 300 mg/day quetiapine XR or matching placebo for the final 6 weeks . Primary endpoint : change from r and omization to Week 8 in MADRS total score . Secondary endpoints included : MADRS response ( ≥50 % reduction in total score from r and omization ) and changes from r and omization to Week 8 in HAM-D and CGI-S. RESULTS 310 patients were r and omized . At Week 8 , quetiapine XR significantly reduced mean MADRS total score versus placebo ( -16.49 vs -13.10 , respectively ; p<0.01 ) . Mean MADRS score was significantly reduced by quetiapine XR versus placebo at Week 1 ( p<0.05 ) . MADRS response rates were significantly greater at Week 8 for quetiapine XR versus placebo ( 61.9 % vs 48.0 % , respectively ; p<0.05 ) . Significant changes in HAM-D total score and CGI-S were seen at Week 8 for quetiapine XR versus placebo . Withdrawal rates due to AEs were 9.9 % and 2.6 % for quetiapine XR and placebo , respectively . Common AEs ( > 10 % any group during the r and omized phase ) for quetiapine XR and placebo , respectively were dry mouth ( 32.9 % and 6.5 % ) , sedation ( 21.7 % and 1.9 % ) , somnolence ( 20.4 % and 5.2 % ) , and headache ( 10.5 % and 10.3 % ) . LIMITATIONS The study was not design ed to compare quetiapine XR 150 mg/day and 300 mg/day ; it was intended to reflect dose titration that might occur in clinical practice . CONCLUSIONS Quetiapine XR monotherapy is effective in patients with MDD , with symptom improvement seen as early as Week 1 , and tolerability results consistent with the known profile of quetiapine BACKGROUND Due to their favorable side-effect profile , atypical antipsychotic agents offer important therapeutic advantages in mood disorders .  Ziprasidone , an atypical antipsychotic agent with strong 5-HT(1A ) agonist activity , may be particularly useful when used in conjunction with st and ard antidepressants in treatment-resistant depression . The purpose of this study is to test this hypothesis in depressed out patients who have not experienced significant clinical improvement following an adequate trial of a selective serotonin reuptake inhibitor ( SSRI ) . METHOD Twenty patients with major depressive disorder ( MDD ) who had failed to experience a clinical response to an adequate trial of an SSRI were treated with open-label ziprasidone in addition to their SSRI for 6 weeks between February 2002 and December 2002 . MDD was diagnosed with the Structured Clinical Interview for DSM-IV Axis I disorders . Clinical response was defined as a 50 % or greater decrease in depressive symptoms during the course of the trial ( baseline to endpoint ) , as measured by the HAM-D-17 total score . RESULTS Thirteen of 20 patients ( 65.0 % ) completed the trial . Using a completer analysis , 8 patients ( 61.5 % ) were classified as responders . An intent-to-treat ( ITT ) analysis result ed in 10 responders ( 50.0 % ) . The overall proportion of remitters was 5 of 13 ( 38.5 % ) using a completer analysis and 5 of 20 ( 25.0 % ) using the ITT analysis . Ziprasidone administration appeared to be safe , with no clinical ly significant QTc prolongation or severe adverse events observed in any of the study participants . CONCLUSION These results suggest a possible augmentation role for ziprasidone when used in conjunction with SSRIs in SSRI-resistant MDD 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 ) The authors estimated components of variance and intraclass correlation coefficients ( ICCs ) to aid in the design of complex surveys and community intervention studies by analyzing data from the Health Survey for Engl and 1994 . This cross-sectional survey of English adults included data on a range of lifestyle risk factors and health outcomes . For the survey , households were sample d in 720 postal code sectors nested within 177 district health authorities and 14 regional health authorities . Study subjects were adults aged 16 years or more .  ICCs and components of variance were estimated from a nested r and om-effects analysis of variance . Results are presented at the district health authority , postal code sector , and household levels . Between-cluster variation was evident at each level of clustering . In these data , ICCs were inversely related to cluster size , but design effects could be substantial when the cluster size was large . Most ICCs were below 0.01 at the district health authority level , and they were mostly below 0.05 at the postal code sector level . At the household level , many ICCs were in the range of 0.0 - 0.3 . These data may provide useful information for the design of epidemiologic studies in which the units sample d or allocated range in size from households to large administrative areas OBJECTIVE Two parallel , 8-week double-blind studies compared olanzapine/fluoxetine combination , olanzapine , and fluoxetine in out patients with treatment-resistant depression ( TRD ) . METHOD Treatment-resistant depression was defined as a documented history of current-episode antidepressant failure plus a prospect i ve failure on fluoxetine .  Following an 8-week fluoxetine lead-in , 605 nonresponders with DSM-IV major depressive disorder were r and omly assigned to olanzapine/fluoxetine combination , olanzapine , or fluoxetine . The primary outcome measure was baseline-to-endpoint mean change on the Montgomery-Asberg Depression Rating Scale ( MADRS ) . The study was conducted from April 2002 to May 2005 . RESULTS After 8 weeks of double-blind treatment , Study 1 revealed no statistically significant therapy differences in MADRS mean change  ( olanzapine/fluoxetine combination : -11.0 , fluoxetine : -9.4 , olanzapine : -10.5 ) . In Study 2 , olanzapine/fluoxetine combination demonstrated significantly greater MADRS improvement ( -14.5 ) than fluoxetine ( -8.6 , p < .001 ) and olanzapine ( -7.0 , p < .001 ) . Pooled study results revealed significant differences for olanzapine/ fluoxetine combination ( -12.7 ) versus fluoxetine ( -9.0 , p < .001 ) and olanzapine ( -8.8 , p < .001 ) . Pooled remission rates were 27 % for olanzapine/ fluoxetine combination , 17 % for fluoxetine , and 15 % for olanzapine .  Adverse events were consistent with previous studies . Cholesterol mean change ( mg/dL ) was + 15.1 for olanzapine/ fluoxetine combination , + 0.8 for fluoxetine , and + 2.7 for olanzapine .  Mean weight change ( kg ) was + 4.9 for olanzapine/fluoxetine combination , + 0.4 for fluoxetine , and + 5.5 for olanzapine .  Nonfasting glucose mean change ( mg/dL ) was + 11.4 for olanzapine/fluoxetine combination , + 4.9 for fluoxetine , and + 9.9 for olanzapine . CONCLUSION Patients with TRD ( defined as treatment failure on 2 antidepressants ) taking olanzapine/fluoxetine combination demonstrated significantly greater improvement in depressive symptoms than patients taking olanzapine or fluoxetine in 1 of 2 studies and in the pooled analysis . When considered within the context of all available evidence , olanzapine/fluoxetine combination is an efficacious therapy for patients with TRD . CLINICAL TRIALS REGISTRATION Clinical Trials.gov identifier : NCT00035321 The objective of this study was to investigate whether quetiapine , when compared with placebo , can speed the onset of action and improve the quality of response to fluoxetine treatment in patients suffering from major depressive disorder . A total of 114 patients with major depressive disorder were enrolled in an 8-week treatment study . Patients were initiated on a course of fluoxetine treatment and r and omized to quetiapine or placebo . Quetiapine was flexibly dosed starting at 25 mg to a maximum of 100 mg daily . Mixed-effects regression showed that quetiapine plus fluoxetine did not achieve 50 % reduction in the Montgomery – Åsberg Depression Rating Scale score or improvement in Hamilton Anxiety Scale , Clinical Global Improvement (CGI)-Severity , and CGI-Improvement scores sooner than the fluoxetine plus placebo group ; however both groups improved in all scores over time . Mixed-effects linear regression of insomnia scores showed that the quetiapine plus fluoxetine group improved significantly more rapidly compared with the fluoxetine plus placebo group . The study indicates that quetiapine plus fluoxetine did not achieve a reduction in the Montgomery – Åsberg Depression Rating Scale score or improvement in Hamilton Anxiety Scale or CGI scores from baseline sooner than the fluoxetine plus placebo group . The combination of quetiapine and fluoxetine , however , improved sleep over fluoxetine alone over the first few weeks of treatment Nonresponse to one or more antidepressants is common and an important public health problem . This study evaluated the efficacy and safety of adjunctive aripiprazole or placebo to st and ard antidepressant therapy ( ADT ) in patients with major depressive disorder who showed an inadequate response to at least 1 and up to 3 historical and 1 additional prospect i ve ADT . The study comprised a 7 - 28-day screening , an 8-week prospect i ve treatment , and a 6-week r and omization phase . During prospect i ve treatment , patients experiencing a major depressive episode ( 17-item Hamilton Rating Scale for Depression total score ≥18 ) received single-blind adjunctive placebo plus clinicians ' choice of ADT ( escitalopram , fluoxetine , paroxetine controlled-release , sertraline , or venlafaxine extended-release ) . Subjects with inadequate response were r and omized to adjunctive placebo ( n = 190 ) or adjunctive aripiprazole ( n = 191 ) ( starting dose 5 mg/d , dose adjustments 2 - 20 mg/d , mean end-point dose of 11.0 mg/d ) . The primary efficacy endpoint was the mean change in Montgomery-Åsberg Depression Rating Scale total score from end of prospect i ve treatment phase to end of r and omized treatment phase ( last observation carried forward ) . Mean change in Montgomery-Åsberg Depression Rating Scale total score was significantly greater with adjunctive aripiprazole than placebo ( −8.5 vs −5.7 ; P = 0.001 ) . Remission rates were significantly greater with adjunctive aripiprazole than placebo ( 25.4 % vs 15.2 % ; P = 0.016 ) as were response rates ( 32.4 % vs 17.4 % ; P < 0.001 ) . Adverse events occurring in 10 % of patients or more with adjunctive placebo or aripiprazole were akathisia ( 4.2 % vs 25.9 % ) , headache ( 10.5 % vs 9.0 % ) , and fatigue ( 3.7 % vs 10.1 % ) . Incidence of adverse events leading to discontinuation was low ( adjunctive placebo [ 1.1 % ] vs adjunctive aripiprazole [ 3.7 % ] ) . Aripiprazole is an effective and safe adjunctive therapy as demonstrated in this short-term study for patients who are nonresponsive to st and ard ADT BACKGROUND PRIMARY OBJECTIVE evaluate the efficacy ( time to recurrence of depressive symptoms ) of once daily extended release quetiapine fumarate ( quetiapine XR ) as maintenance monotherapy treatment to prevent relapse for major depressive disorder ( MDD ) . METHODS Time-to-event ( maximum 52 weeks ) , double-blind , multicenter , r and omized withdrawal , placebo-controlled study of quetiapine XR ( 50 - 300 mg/day ) comprising four treatment phases : enrollment ( up to 28 days ) , open-label run-in ( 4 - 8 weeks ) , open-label stabilization ( 12 - 18 weeks ) , and r and omization ( up to 52 weeks ) . Seven hundred and seventy-six patients stabilized on quetiapine XR were eligible for r and omization ( Montgomery-Åsberg Depression Rating Scale [ MADRS ] score ≤12 and Clinical Global Impression-Severity of Illness [ CGI-S ] score ≤3 ) ; 391 received quetiapine XR and 385 received placebo ( same dose as last open-label visit ) . Primary endpoint : time to recurrence of depressive event from r and omization . Secondary outcomes included changes from r and omization in MADRS total , CGI-S , Pittsburgh Sleep Quality Index ( PSQI ) global , and Hamilton Anxiety Rating Scale ( HAM-A ) total scores . Adverse events were recorded throughout . RESULTS Risk of recurrence of depressive event was significantly ( P<.001 ) reduced by 66 % ( HR=.34 ; 95 % CI : .25 , .46 ) in patients r and omized to continue with quetiapine XR versus patients r and omized to switch to placebo . During the r and omized phase , quetiapine XR maintained improvements in secondary outcomes ( P<.001 for all ) : MADRS ( 0.15 versus 2.03 ) , CGI-S ( -0.03 versus 0.23 ) ; PSQI global ( 0.06 versus 1.35 ) , and HAM-A total score ( 0.20 versus 1.58 ) , respectively . The most common AEs ( > 10 % any group ) during the r and omized period were headache and insomnia . CONCLUSIONS Quetiapine XR maintenance therapy significantly reduced the risk of a depressive event in patients with MDD stabilized on quetiapine XR , with a safety and tolerability profile consistent with the known profile of quetiapine OBJECTIVE To determine the efficacy and tolerability of aripiprazole , a dopamine D2 and 5-HT1A receptor partial agonist , as augmentation of antidepressant treatment of partially responding and nonresponding patients with major depressive disorder . METHOD Fifteen patients with major depressive disorder ( diagnosed with a site-generated form described in the text ) and an incomplete response or no response to > or = 8 weeks of antidepressant ( selective serotonin reuptake inhibitor , venlafaxine , or bupropion ) monotherapy  were treated with aripiprazole augmentation in an 8-week , open-label study . Data were gathered from July 2003 to March 2004 . RESULTS The mean duration of antidepressant monotherapy at baseline was 43.1 weeks . At baseline , mean Clinical Global Impressions-Severity of Illness scale and Hamilton Rating Scale for Depression ( HAM-D ) scores were 4.3 and 18.9 , respectively . After initiation of aripiprazole augmentation , 6 of 15 patients achieved remission ( HAM-D score < or = 7 ) at week 1 , and 9 of 15 patients remitted by week 2 . All 8 completers achieved remission by study endpoint . Akathisia in 2 patients who withdrew prematurely prompted a reduction in the starting dose of aripiprazole from 10 mg/day to 2.5 mg/day , result ing in a 50 % reduction in attrition due to akathisia ( 2/7 withdrew due to akathisia with the 10-mg starting dose , 1/8 withdrew due to akathisia with the 2.5-mg starting dose ) . Discontinuation rates after 4 weeks of treatment were lower for the 2.5-mg starting dose ( 1/8 patients ) than for the 10-mg starting dose ( 3/7 patients ) . Overall discontinuation rates at endpoint were lower for the 2.5-mg dose ( 3/8 patients ) than the 10-mg dose ( 4/7 patients ) . Response to aripiprazole augmentation did not appear to be related to the antidepressant used at study initiation . CONCLUSION Aripiprazole is an effective augmentation strategy for improving therapeutic response in patients with treatment-resistant major depressive disorder when administered in combination with st and ard antidepressant therapy . Based on this clinical signal , a double-blind , placebo-controlled trial is warranted Amisulpride , a selective antagonist of D2 and D3 dopamine receptors , acts preferentially on presynaptic receptors increasing dopaminergic transmission at low doses . In a multicentre , 6 months , placebo-controlled trial , amisulpride ( 50 mg/daily ) was compared to imipramine ( 100 mg/daily ) in the treatment of patients with DSM-III-R criteria for primary dysthymia , dysthymia with major depression or major depression in partial remission . A total of 219 patients were included . Both analyses ( intention-to-treat and " per protocol ' analysis ) detected significant differences between groups ( active treatment vs. placebo ) on all main rating scales ( CGI , MADRS , ERD , and SANS ) . The number of patients reporting at least one adverse event was higher in the imipramine group than in the two other , mainly due to anticholinergic effects . Endocrine symptoms were more frequent in female patients treated with amisulpride . These results confirm the interest of a drug acting on dopaminergic transmission such as amisulpride in the treatment of depressed patients OBJECTIVE Treatment-resistant depression is a significant public health concern ; drug switching or augmentation often produce limited results . The authors hypothesized that fluoxetine could be augmented with olanzapine to successfully treat resistant depression . METHOD An 8-week double-blind study was conducted with 28 patients who were diagnosed with recurrent , nonbipolar , treatment-resistant depression without psychotic features . Subjects were r and omly assigned to one of three groups : olanzapine plus placebo , fluoxetine plus placebo , or olanzapine plus fluoxetine . RESULTS Fluoxetine monotherapy produced minimal improvement on various scales that rate severity of depression . The benefits of olanzapine monotherapy were modest . Olanzapine plus fluoxetine produced significantly greater improvement than either monotherapy on one measure and significantly greater improvement than olanzapine monotherapy on the other measures after 1 week . There were no significant differences between treatment groups on extrapyramidal measures nor significant adverse drug interactions . CONCLUSIONS Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone Two hundred and fifty patients participated in a 6-month , double-blind study to evaluate safety and e¤cacy of a medium-term treatment with amisulpride 50 mg/day versus amitriptyline 2575 mg/day in dysthymia . Patients in treatment groups ( 165 amisulpride ; 85 amitriptyline ) were well balanced for demographic and baseline characteristics . A total of 139 patients ( 93 amisulpride , 46 amitriptyline ) completed the study with no statistically signifcant di¡erences in reasons for premature termination between the two groups . A tendency towards a higher incidence of treatment-emergent adverse events with amitriptyline was observed ( 73 % versus 64 % amisulpride ) . In the amitriptyline group , a statistically signifcantly higher incidence of central nervous system ( 41 % versus 24 % , p=0.004 ) and autonomic nervous system disorders ( 45 % versus 16 % , p50.0001 ) was reported . Conversely , endocrine disorders were more frequent with amisulpride ( 18 % versus 7 % , p=0.023 ) . E¤cacy was a secondary end-point . Results of the symptom rating scales indicate that both drugs were equally e¡ective : 60 % and 62 % of patients under amisulpride and amitriptyline , respectively , achieved a reduction 550 % of the Montgomery and Asberg Rating Scale total score at end-point . On the item ` global improvement ' of the Clinical Global Impression , 67 % of amisulpride and 68 % of amitriptyline patients were rated as ` very much ' or ` much ' improved . Results of the present study in a large patient population further confrm the safe use of amisulpride in dysthymia and support its administration upon a medium-term treatment period 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 ) . BACKGROUND The purpose of this study was to provide preliminary data on the effects of paroxetine and amisulpride on depressive dimensions , analyzed by factor analysis , in dysthymic patients . METHODS One hundred and eighteen patients with DSM IV criteria for DD without concurrent major depression were enrolled in this 8-week , open study , and 100 completed it . Symptom dimensions were identified by principal components analysis with the SAS Factor procedure . RESULTS Results of the symptom rating scales indicated that both drugs were equally effective . Response rate was 65 % both in the paroxetine and the amisulpride group and the proportions of patients achieving a final HRSD score < or = 7 were 46.7 and 55 % , respectively . MADRS factor analysis identified two factors at baseline : the first corresponding to the global severity of depression and the second to somatic symptoms . After 8 weeks of treatment only one factor could be substantiated . At week 4 both paroxetine and amisulpride produced significant improvements on factor 1 while at week 8 mean changes of factor 1 were greater in the amisulpride-treated patients . LIMITATIONS The main limitation was the open-label design . CONCLUSIONS Both paroxetine and amisulpride appear to be effective in the short-term management of DD , improving its most characteristic symptoms OBJECTIVE This 6-week , r and omized , double-blind study evaluated efficacy and safety of adjunctive extended-release ( XR ) quetiapine in patients with major depressive disorder ( MDD ) and an inadequate response to > or= 1 antidepressant . METHOD Male or female patients aged 18 to 65 years with DSM-IV-TR MDD were r and omly assigned to receive quetiapine XR ( 150 or 300 mg/day ) or placebo adjunctive to continuing antidepressant . Primary endpoint was change from r and omization to week 6 in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score . Secondary variables included MADRS response ( > or= 50 % reduction in score from r and omization ) at weeks 1 and 6 , MADRS remission ( < or= 8 total score ) at week 6 , and week 6 change in Hamilton Rating Scale for Depression and Hamilton Rating Scale for Anxiety total scores . Safety was assessed throughout the study . The study was conducted between May 8 , 2006 , and April 7 , 2007 . RESULTS Four hundred ninety-three patients were r and omly assigned . Mean change from r and omization to week 6 in MADRS score was -15.26 and -14.94 for quetiapine XR 150 mg/day and 300 mg/day , respectively ( both p < .01 vs. placebo [ -12.21 ] ) . Quetiapine XR showed separation from placebo in MADRS score from week 1 ( p < .001 ) onward . The MADRS response rates were 55.4 % , 57.8 % , and 46.3 % for quetiapine XR 150 mg/day ( p = .107 vs. placebo ) , 300 mg/day ( p < .05 ) , and placebo , respectively ; MADRS remission rates were 36.1 % ( p < .05 vs. placebo ) , 31.1 % ( p = .126 ) , and 23.8 % for quetiapine XR 150 mg/day , 300 mg/day , and placebo , respectively . Withdrawal rates due to adverse events were 6.6 % , 11.7 % , and 3.7 % with quetiapine XR 150 mg/day , 300 mg/day , and placebo , respectively . The most common adverse events were dry mouth ( 20.4 % , 35.6 % , and 6.8 % ) and somnolence ( 16.8 % , 23.3 % , and 3.1 % ) . CONCLUSIONS Adjunctive quetiapine XR ( 150 mg/day and 300 mg/day ) was effective  in patients with MDD who had shown an inadequate response to antidepressant treatment . Significant reduction of depressive symptoms occurred as early as week 1 . Findings were consistent with the known safety and tolerability profile of quetiapine . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00351910 In a multicenter , double-blind , parallel group trial , the efficacy of risperidone ( RIS ) was compared with a combination of haloperidol and amitriptyline ( HAL/AMI ) over 6 weeks in patients with coexisting psychotic and depressive symptoms with either a schizoaffective disorder , depressive type , a major depression with psychotic features , or a nonresidual schizophrenia with major depressive symptoms according to DSM-III-R criteria . A total of 123 patients ( 62 RIS ; 61 HAL/AMI ) were included ; the mean daily dosage at endpoint was 6.9 mg RIS versus 9 mg HAL combined with 180 mg AMI .  Efficacy results for those 98 patients ( 47 RIS ; 51 HAL/AMI ) who completed at least 3 weeks of double-blind treatment revealed in both treatment groups large reductions in the Positive and Negative Syndrome Scale-derived Brief Psychiatric Rating Scale ( RIS 37 % ; HAL/AMI 51 % ) and the Bech-Rafaelsen Melancholia Scale total scores ( RIS 51 % ; HAL/AMI 70 % ) . The reductions in the Brief Psychiatric Rating Scale and the Bech-Rafaelsen Melancholia Scale scores in the total group were significantly larger in the HAL/AMI group than in the RIS group ( p < 0.01 ) , mostly because of significant differences in the subgroup of patients suffering from depression with psychotic features , whereas treatment differences in the other diagnostic subgroups were not significant . The incidence of extrapyramidal side effects as assessed by the Extrapyramidal Symptom Rating Scale was slightly higher under RIS ( 37 % ) than under HAL/AMI ( 31 % ) . Adverse events were reported by 66 % of RIS and 75 % of HAL/AMI patients . The results of this trial suggest that the therapeutic effect of HAL/AMI is superior to RIS in the total group of patients with combined psychotic and depressive symptoms . However , subgroup differences have to be considered INTRODUCTION Once-daily extended release quetiapine fumarate ( quetiapine XR ) monotherapy was evaluated in major depressive disorder ( MDD ) . METHOD This was an 8-week ( 6-week r and omized-phase ; 2-week drug-discontinuation/tapering phase ) , double-blind , parallel-group , placebo-controlled study . The primary outcome measure was Montgomery-Asberg Depression Rating Scale ( MADRS ) total score r and omization-to-Week 6 change . Other assessment s included the Hamilton Rating Scale for Depression , the Hamilton Rating Scale for Anxiety , and adverse events ( AEs ) . RESULTS 723 patients were r and omized : 182 , 178 , 179 , and 184 to quetiapine XR 50 , 150 , 300 mg/day , and placebo , respectively . At Week 6 , significant reductions occurred in MADRS score with quetiapine XR 50 mg/day ( -13.56 ; P<.05 ) , 150 mg/day ( -14.50 ; P<.01 ) and 300 mg/day ( -14.18 ; P<.01 ) versus placebo ( -11.07 ) ; at Day 4 , reductions for quetiapine XR ( titrated to 50 or 150 mg/day according to dose group ) versus placebo ( -2.9 ) were : -4.7 ( P<.01 ) , -5.2 ( P<.001 ) , and -5.1 ( P<.001 ) , respectively . At endpoint , MADRS response ( > or=50 % reduction in score ) was 42.7 % ( P<.01 ) , 51.2 % ( P<.001 ) , and 44.9 % ( P < or= .001 ) for quetiapine XR 50 , 150 , and 300 mg/day , respectively ; 30.3 % for placebo . Overall , quetiapine XR 150 mg/day provided consistently more positive secondary efficacy results than 50 mg/day and 300 mg/day versus placebo . The most common AEs in quetiapine XR-treated patients were dry mouth , sedation , somnolence , headache , and dizziness . CONCLUSION In patients with MDD , quetiapine XR monotherapy ( 50/150/300 mg/day ) is effective in reducing depressive symptoms , with improvement from Day 4 onwards . Safety and tolerability were consistent with the known profile of quetiapine Amisulpride ( 50 mg o.d . ) was compared with sertraline ( 50 - 100 mg o.d . ) for 12 weeks in a double-blind , parallel-group study in 313 out patients with dysthymia ( DSM-IV ± episode of major depression ) . Full response rate [ ≥ 50 % decrease in Hamilton Depression Rating Scale ( HAMD ) total score ] was higher with amisulpride after 4 weeks ( 63 % versus 50 % , P < 0.02 ) and 8 weeks ( 82 % versus 69 % , P < 0.009 ) . Time to initial improvement ( ≥ 25 % decrease in HAMD total score ) and to ≥ 50 % HAMD decrease were significantly shorter with amisulpride ( P < 0.0033 and P < 0.0080 , respectively ) . A faster response was also present in the subgroup of patients with pure dysthymia . The improvement in HAMD , Montgomery and Asberg Depression Rating Scale and Social and Occupational Assessment Scale total scores , as well as Clinical Global Impression improvement , was significantly greater with amisulpride after 4 weeks . Both drugs were equally effective at week 12 . The tolerability of both drugs was satisfactory . Amisulpride is significantly more effective than sertraline during the first weeks of treatment in dysthymia AIM Evaluation of the effect of acetyl-L-carnitine ( ALCAR ) vs. amisulpride measured by total Hamilton Depression Rating Scale score ( HAM-D(21 ) ) in patients with pure dysthymia ( DSM IV ) . Two hundred and four patients were r and omised and treated with ALCAR 500 mg b.i.d . or amisulpride 50 mg u.i.d . in a double-blind study , for 12 weeks . RESULTS A solid improvement of HAM-D(21 ) was observed in both treatment groups throughout the study . The results did not disclose statistically significant differences between treatments , although the confidence interval for the non-inferiority of the primary end-point exceeded the pre-established limit of 2 by 0.46 points . According to a non-inferiority margin of 3 ( considered acceptable by recent published data ) the primary end-point could have been fully satisfied . CDRS , MADRS and CGI , employed to further measure the clinical outcome , reported similar results in both treatment groups . The greater tolerability of ALCAR is of clinical relevance considering the chronicity of  dysthymia  , which often requires prolonged treatment Abstract : The purpose of this study was to compare the efficacy and safety of olanzapine ( OLZ ) monotherapy and an olanzapine/fluoxetine combination ( OFC ) with placebo ( PLA ) for unipolar major depression with psychotic features . Under a single protocol , two 8-week , double-blind trials were conducted at 27 sites . Patients ( n = 124 trial 1 , n = 125 trial 2 ) were r and omized to 1 of 3 treatment groups : OLZ ( 5 to 20 mg/d ) , PLA , or OFC ( olanzapine 5 to 20 mg/d + fluoxetine 20 to 80 mg/d ) . The primary outcome measure was the 24-item Hamilton Depression Rating Scale total score . For trial 1 , endpoint improvement for the OLZ group ( −14.9 ) was not significantly different from the PLA or OFC groups . The OFC group had significantly greater endpoint improvement ( −20.9 ) than the PLA group ( −10.4 , P = 0.001 ) ; this significant difference was present within 7 days of therapy and maintained at every subsequent visit . The OFC group also had significantly higher response rate ( 63.6 % ) than the PLA ( 28.0 % , P = 0.004 ) or OLZ ( 34.9 % , P = 0.027 ) groups . For trial 2 , there were no significant differences among treatment groups on the 24-item Hamilton Depression Rating Scale total scores or response rates . The combination exhibited a comparable safety profile with OLZ monotherapy and no significant increases in extrapyramidal symptoms compared with placebo . Patients with major depression with psychotic features treated with OLZ monotherapy did not demonstrate significant depressive symptom improvement compared with placebo in either trial ; however , an olanzapine/fluoxetine combination was associated with significant improvement compared with placebo in one trial and was well tolerated BACKGROUND This 8-week , double-blind , multicenter study was undertaken to replicate , in a larger sample of patients with treatment-resistant major depressive disorder ( MDD ; DSM-IV criteria ) , the results of a pilot study of the olanzapine/fluoxetine combination . METHOD The study was begun in August 1999 . The primary entry criterion was a history of failure to respond to a selective serotonin reuptake inhibitor ( SSRI ) . Patients ( N = 500 ) who subsequently failed to respond to nortriptyline during an open-label lead-in phase were r and omly assigned to 1 of 4 treatment groups : olanzapine ( 6 - 12 mg/day ) plus fluoxetine ( 25 - 50 mg/day ) combination , olanzapine ( 6 - 12 mg/day ) , fluoxetine ( 25 - 50 mg/day ) , or nortriptyline ( 25 - 175 mg/day ) . The primary outcome measure was baseline-to-endpoint mean change in score on the Montgomery-Asberg Depression Rating Scale ( MADRS ) . RESULTS At the 8-week study endpoint , MADRS total scores decreased by a mean 8.7 points from baseline ( 28.5 ) with the olanzapine/fluoxetine combination , 7.0 points from baseline ( 28.4 ) with olanzapine ( p = .08 ) , 8.5 points from baseline ( 28.4 ) with fluoxetine ( p = .84 ) , and 7.5 points from baseline ( 28.8 ) with nortriptyline ( p = .30 ) , with no significant differences among the therapies . The olanzapine/fluoxetine combination was associated with significantly ( p < or = .05 ) greater improvement ( decrease ) in MADRS scores than olanzapine at weeks 2 , 4 , 6 , and 7 ; than fluoxetine at weeks 2 through 5 ; and than nortriptyline at weeks 1 through 4 . A post hoc analysis of a subgroup of patients who had an SSRI treatment failure during their current MDD episode ( N = 314 ) revealed that the olanzapine/fluoxetine combination group had a significantly ( p = .005 ) greater decrease in MADRS scores than the olanzapine group at endpoint . Safety data for the olanzapine/fluoxetine combination were similar to those for its component monotherapies . CONCLUSIONS The olanzapine/fluoxetine combination did not differ significantly from the other therapies at endpoint , although it demonstrated a more rapid response that was sustained until the end of treatment . The results raised several method ological questions , and recommendations are made regarding the criteria for study entry and r and omization BACKGROUND Many questions remain regarding the use of atypical neuroleptics as antidepressant augmentation agents . To date , there have been no reports in the literature regarding the effectiveness of these drugs when trials of one or more of them have failed previously as antidepressant augmentation . METHOD This retrospective chart review was conducted to determine the effectiveness of olanzapine , risperidone , quetiapine , and ziprasidone when given in a fee-for-service setting as anti-depressant augmentation agents to patients with treatment-resistant , nonpsychotic major depressive disorder ( DSM-IV ) . Prospect i ve ( Global Assessment of Functioning [ GAF ] ) along with retrospective ( Clinical Global Impressions-Improvement [ CGI-I ] and -Severity of Illness scales ) ratings were completed for each patient . Analyses were conducted in an attempt to identify factors that appeared to correlate with response , including order of administration and Thase-Rush staging of treatment resistance . RESULTS In this study of 76 medication trials in 49 patients , the overall response rate based on the CGI-I ratings was 65 % ( 32/49 ) . Individual rates of response were 57 % ( 21/37 ) for olanzapine , 50 % ( 7/14 ) for risperidone , 33 % ( 6/18 ) for quetiapine , and 10 % ( 1/10 ) for ziprasidone . None of the differences between neuroleptics in rates of response were significant . The difference between baseline and final GAF scores was statistically significant only in the olanzapine ( p < .001 ) and risperidone ( p = .047 ) groups . Rates of discontinuation did not vary significantly between agents , though trends were present . Crossover trials from one atypical neuroleptic to another in the event of nonresponse appeared to be effective . CONCLUSIONS Although limited by its design , this study suggests atypical neuroleptic augmentation of antidepressants may be a viable option in treatment-resistant major depressive disorder In a multicentre , double blind , parallel group study 281 patients with DSM III-R diagnosis of dysthymia or a single episode of major depression in partial remission were r and omised to 3 months of treatment with amisulpride  50 mg/day or fluoxetine  20 mg/day . The baseline Montgomery and Asberg Depression Rating Scale ( MADRS ) total score was reduced by at least 50 % in 74.1 % of patients ( 103/139 ) with amisulpride and 67.4 % ( 87/129 ) with fluoxetine ( P = 0.230 ) . No significant differences between treatment groups were found in the reductions in mean total score with the MADRS , Widlöcher psychomotor retardation scale , Sheehan disability scale , and CGI . Anxiety measured by HAM-A total mean score decreased significantly more with amisulpride ( 63 % ) than with fluoxetine ( 54 % ; P = 0.021 ) . There were 13 dropouts due to adverse events with amisulpride and ten with fluoxetine . The number of patients reporting at least one adverse event was similar in the two groups ( amisulpride 47.5 % ; fluoxetine 40.9 % ) . As expected , in the amisulpride group endocrine-like adverse events in female patients were the most common , while nausea , dyspepsia , anorexia and insomnia occurred more frequently with fluoxetine The efficacy of amisulpride in depressive disorders has been demonstrated in dysthymia and in double depression . Limited data are available in major depression . A r and omized , double-blind , parallel group , multicentre study was set up to compare the efficacy and tolerability of amisulpride ( 50 mg o.d . ) and paroxetine ( 20 mg o.d . ) for 8 weeks in 272 patients with major depression ( DSM-IV and baseline Hamilton Depression Rating Scale ( HAMD ) score ≥18 ) . The study was design ed as a non-inferiority trial based on the proportion of responders ( ≥50 % decrease in HAMD total score ) at end-point , with a maximal allowable difference of 15 % ; secondary end-points included HAMD total and cluster scores , Montgomery and Asberg Depression Rating Scale score and responders rates and Clinical Global Impression improvement . The tolerability evaluation was based on incidence of adverse events and routine laboratory tests . The results did not disclose statistically significant differences between treatments , although the hypothesis of an efficacy difference between the two treatments within the set limit at day 56 could not be accepted . The issue of non-inferiority trials is discussed Amisulpride , a selective antagonist for D2 and D3 dopamine receptors , acts preferentially on presynaptic receptors increasing dopaminergic transmission at low doses . In a multicentre , 3-month , placebo-controlled study , amisulpride ( 50 mg/day ) was compared to amineptine ( 200 mg/day ) in the treatment of primary dysthymia . A total of 323 patients were enrolled .  Amisulpride and amineptine were found to be statistically superior to placebo ( p < 0.0001 ) on the Clinical Global Impression ( item 2 ) : 63 , 64 and 33 % responders , respectively ; improvement of Montgomery-Asberg Depression Rating Scale and Scale for the Assessment of Negative Symptoms scores following amisulpride or amineptine treatment was twice as high as with placebo ( p < 0.0001 ) . The adverse event profile of amisulpride was similar to that of placebo except for endocrine symptoms in female patients ; amineptine showed mainly events linked to psychic activation ( insomnia , nervousness ) . Results show that amisulpride can improve symptoms of chronic depression in dysthymia This study evaluated once-daily extended-release quetiapine fumarate ( quetiapine XR ) as adjunctive therapy in patients with major depressive disorder ( MDD ) with inadequate response to ongoing antidepressant treatment . In this 8-wk ( 6-wk active treatment/2-wk post-treatment drug-discontinuation/follow-up ) , multicentre , double-blind , placebo-controlled , Phase III study , 446 patients were r and omized to quetiapine XR 150 mg/d , 300 mg/d , or placebo adjunct to ongoing antidepressant treatment . The primary endpoint was the change from r and omization to week 6 in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score . At week 6 , MADRS total scores significantly improved with quetiapine XR 300 mg/d vs. placebo ( -14.7 vs. -11.7 , p<0.01 ) . Quetiapine XR 300 mg/d showed significant improvements vs. placebo for : MADRS total score from week 1 onwards ; MADRS response [ ( > or = 50 % total score reduction ) 58.9 % vs. 46.2 % , p<0.05 ] and remission [ ( total score < or = 8) 42.5 % vs. 24.5 % , p<0.01 ] rates ; Hamilton Depression Rating Scale ( HAMD ) ( -13.53 vs. -10.80 , p<0.01 ) and Clinical Global Impression-Severity of illness ( CGI-S ) change ( -1.52 vs. -1.23 , p<0.05 ) at week 6 . For quetiapine XR 150 mg/d , improvements were not significantly different vs. placebo , except for MADRS ( weeks 1 and 2 ) and HAMD ( week 6 ) total scores . Withdrawal rates due to adverse events ( AEs ) were : quetiapine XR 150 mg/d 11.5 % , 300 mg/d 19.5 % , and placebo 0.7 % . The most common AEs ( > 10 % ) with quetiapine XR were dry mouth , somnolence , sedation , dizziness , constipation , nausea , insomnia , headache , and fatigue . In this study , quetiapine XR 300 mg/d as adjunctive therapy in patients with MDD with an inadequate response to ongoing antidepressant treatment was effective at week 6 . However , the difference from placebo for quetiapine XR 150 mg/d at week 6 was not statistically significant . Both doses studied ( 150 and 300 mg/d ) were effective at week 1 and generally well tolerated OBJECTIVE Major depressive disorder ( MDD ) is a severe mental illness with high risk of suicidality . Antidepressant treatment alone is not sufficient for the acute management of risk-taking symptoms of depression . This pilot study was design ed to investigate the efficacy of risperidone augmentation to antidepressants in the acute management of suicidality and other core symptoms in MDD with suicidality . METHOD Twenty-four adult men and women diagnosed with MDD ( DSM-IV ) , having a depressive episode with suicidality despite taking an antidepressant , were enrolled in an 8-week double-blind , placebo-controlled study . Subjects were r and omly assigned to receive risperidone ( 0.25 - 2 mg/day ) or placebo while continuing on their antidepressant therapy .  Clinical efficacy in suicidality , depressive symptoms , and impulsivity were assessed after treatment with study drugs for 4 days , weekly for 4 weeks , then every other week for 4 weeks . Adverse events were also recorded at each visit . The study was conducted from June 2004 to April 2007 . RESULTS Risperidone significantly reduced suicidal ideations in MDD patients , and the overall effect of risperidone appeared to be superior to placebo . The effect of risperidone was rapid , with onset at 2 weeks ' treatment , and was sustained along the course of 8 weeks ' treatment . Furthermore , risperidone demonstrated superiority to placebo in improving other symptoms related to suicidality and having better trial completion rate , and the low dose risperidone was well tolerated by subjects in this study . CONCLUSION Data from this pilot study suggest that risperidone is beneficial as an augmenting treatment in MDD patients who have developed high-risk suicidal ideation during a depressive episode . The antisuicidality effect of risperidone is especially valuable in the acute management of severe depressive symptoms . Although the pilot study is limited by small sample size , the promising results warrant further larger scale investigation in the efficacy of atypical antipsychotics in the treatment of severe depression with suicidality . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00167154 The CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials . Kenneth Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating experience . To encourage dissemination of the CONSORT 2010 Statement , this article is freely accessible on bmj.com and will also be published in the Lancet , Obstetrics and Gynecology , PLoS Medicine , Annals of Internal Medicine , Open Medicine , Journal of Clinical Epidemiology , BMC Medicine , and Trials To comprehend the results of a r and omised controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through total transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by use of a checklist and flow diagram . The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect , or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of a trial ( enrollment , intervention allocation , follow- up , and analysis ) . The diagram explicitly shows the number of participants , for each intervention group , included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results 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
target: There were some beneficial effects compared to placebo or antidepressants but tolerability was worse .
  Quetiapine was more effective than placebo treatment .
  Aripiprazole and quetiapine and partly also olanzapine and risperidone augmentation showed beneficial effects compared to placebo .
  Some evidence indicated beneficial effects of low-dose amisulpride for dysthymic people .
  Most SGAs showed worse tolerability
background: BACKGROUND Major depressive disorder ( MDD ) is a common condition with a lifetime prevalence of 15 % to 18 % , which leads to considerable suffering and disability .
  Some antipsychotics have been reported to induce remission in major depression , when added to an antidepressant .
  OBJECTIVES To evaluate the effects of second-generation antipsychotic ( SGA ) drugs ( alone or augmentation ) compared with placebo or antidepressants for people with MDD or dysthymia .