Antidepressants in Type II Versus Type I Bipolar Depression: A Randomized Discontinuation Trial Antidepressants in bipolar depression: The clinical debate Number needed to treat analyses of drugs used for maintenance treatment of bipolar disorder Patterns of pharmacological maintenance treatment in a community mental health services bipolar disorder cohort study (SIN-DEPRES). Antidepressant-associated switches from depression to mania in severe bipolar disorder. Group cognitive behavior therapy for bipolar disorder can improve the quality of life An online randomised controlled trial to assess the feasibility, acceptability and potential effectiveness of 'Living with Bipolar': a web-based self-management intervention for bipolar disorder: trial design and protocol. Improving study design for antidepressant effectiveness assessment. Differential outcome of bipolar patients receiving antidepressant monotherapy versus combination with an antimanic drug. A Consecutive Series of Treated Affected Offspring of Parents with Bipolar Disorder: Is Response Associated with the Clinical Profile? Who will benefit from antidepressants in the acute treatment of bipolar depression? A reanalysis of the STEP-BD study by Sachs et al. 2007, using Q-learning Adjunctive psychosocial intervention following Hospital discharge for Patients with bipolar disorder and comorbid substance use: A pilot randomized controlled trial Safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for relapse-prevention of bipolar II depression: A randomized, double-blind, parallel-group, prospective study. Pilot study of a culturally adapted psychoeducation (CaPE) intervention for bipolar disorder in Pakistan Efficacy and safety of long-term fluoxetine versus lithium monotherapy of bipolar II disorder: a randomized, double-blind, placebo-substitution study. Impact of antidepressant continuation after acute positive or partial treatment response for bipolar depression: a blinded, randomized study. Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials?
Background We sought to test the hypothesis that antidepressants ( ADs ) may show preferential efficacy and safety among patients with type II bipolar disorder ( BD , BD-II ) more than patients with type I BD ( BD-I ) . Methods Patients with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , BD-I ( n = 21 ) and BD-II ( n = 49 ) in acute major depressive episodes were treated with ADs plus mood stabilizers to euthymia sustained for 2 months and then r and omized openly to continue or discontinue ADs for up to 3 years . Outcomes were episode recurrences and changes in st and ardized symptom ratings . Results In follow-up averaging 1.64 years , both subgroups showed improvement in depressive episode frequency with AD continuation , but contrary to the hypothesis , more improvement was seen in BD-I than in BD-II ( for type II , mean [ st and ard deviation ] decrease in depressive episodes per year , 0.21 [ 0.26 ] ; for type I , mean ( SD ) decrease , 0.35 [ 0.15 ] ) . Subjects with BD-II who continued on ADs had slightly more depressive , but fewer manic/hypomanic , episodes than subjects with BD-I. No notable differences were seen in either group in time to a recurrence of mood episodes or total time-in-remission . Conclusions The findings do not confirm the hypothesis that long-term AD treatment in patients with BP-II has better outcomes than in patients with BD-I , except somewhat lower risk of manic/hypomanic episodes There are scientific , clinical and cultural aspects to the debate about antidepressants in bipolar depression . In prior communications I ’ve focused on scientific aspects . Over time , as I realized how the scientific evidence seemed unconvincing , I concluded that clinical and cultural aspects were important . Here , besides briefly recapitulating the scientific evidence , I will also comment on clinical and cultural factors . To begin with some rules of clinical research worth making explicit : r and omized data are more valid than observational data , because factors that influence the results besides what we are study ing ( confounding factors ) are only removed by r and omization . Sample size is less relevant ; a large observational study does not contradict a smaller r and omized study . Let ’s keep in mind this basic fact of science ( one can call it evidence -based medicine , EBM , if one wants ) . Given that background , risks and benefits of antidepressants need to be assessed in four categories : acute efficacy , maintenance efficacy , acute manic switch and long-term mood destabilization . These different groupings often overlap and are mixed , leading to confusion Rationale Due to the episodic and chronic nature of bipolar disorder ( BD ) , maintenance therapy represents a critical part of treatment ; however , there is a paucity of studies comparing effectiveness of available long-term treatments . Objective The aim of this study is to determine and compare the efficacy of pharmacological treatments for maintenance treatment of BD by means of the number needed to treat ( NNT ) . Methods The efficacy of drugs used for maintenance treatment of BD , as emerging from the results of r and omized controlled trials , was assessed using the size effect measure of NNT . PubMed search es were conducted on English- language articles published until May 2010 using the search terms “ bipolar disorder , ” “ mania , ” “ mixed episode , ” or “ bipolar depression , ” cross-referenced with trial characteristic search phrases and generic names of medications . The search was supplemented by manually review ing reference lists from identified publications . Results In 15 studies , aripiprazole , olanzapine , quetiapine , risperidone long-acting injection , lithium , lamotrigine , and divalproex proved effectiveness in terms of NNTs ( ≥10 % advantage over placebo ) for prevention of relapse into any mood episode . Quetiapine , lithium , risperidone long-acting injection , aripiprazole , and olanzapine are effective in manic recurrence prevention .  Lamotrigine , quetiapine , and lithium present significant NNTs for prevention of depressive relapses . Conclusions All of the pharmacological agents assessed were effective in the prevention of any kind of mood episode ; however , different efficacy profiles were found for prevention of manic and /or depressive relapses . The comparison of NNT values of the available agents may represent a useful tool in clinical setting s , in order to facilitate implementation of long-term pharmacological interventions in patients with BD 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 OBJECTIVES To determine whether switching from depression to mania is part of the natural history of bipolar illness or results from antidepressant ( AD ) treatment by examining bipolar patients with psychosis early in their illness course . METHODS A multi-facility cohort of 123 first-admission in patients , aged 15 - 60 years , with DSM-IV bipolar disorder ( BD ) with psychotic features , was followed for four years , and 76 individuals experienced at least one episode of depression .  Frequency of and risk factors for switches from depression to mania , time to switch , and duration of the subsequent manic episode were examined in relation to AD use ( with anti-manic and /or antipsychotic medications ) . RESULTS The 76 respondents experienced 113 depressive episodes . Those prescribed ADs had more depressive episodes and spent more time depressed than non-users . A total of 23 depressive episodes in 17 respondents ended in a manic/hypomanic/mixed episode ( 20 % ) . The time to switch and duration of the subsequent manic episode were not significantly different for the seven respondents and nine episodes involving AD treatment versus the 10 respondents and 14 episodes without ADs . None of the risk factors ( age of onset < or=18 years , childhood psychopathology , depressive first episode , substance abuse at index admission , bipolar family history , type of AD used ) was associated with switching . CONCLUSIONS In this sample with severe BD , switching from depression to mania was not associated with AD treatment . Respondents who experienced switching appeared to have a more relentless form of BD . In only a few did ADs appear to be responsible for the switch Bipolar disorder ( BD ) can have an impact on psychosocial functioning and quality of life ( QoL ) . Several studies have shown that structured psychotherapy in conjunction with pharmacotherapy may modify the course of some disorders ; however , few studies have investigated the results of group cognitive behavior therapy ( G-CBT ) for BD . Our objective was to evaluate the effectiveness of 14 sessions of G-CBT for BD patients , comparing this intervention plus pharmacotherapy to treatment as usual ( TAU ; only pharmacotherapy ) .  Forty-one patients with BD I and II participated in this study and were r and omly allocated to each group ( G-CBT : N = 27 ; TAU : N = 14 ) . Thirty-seven participants completed the treatment ( women : N = 66.67 % ; mean age = 41.5 years ) .  QoL and mood symptoms were assessed in all participants . Scores changed significantly by the end of treatment in favor of the G-CBT group . The G-CBT group presented significantly better QoL in seven of the eight sub-items assessed with the Medical Outcomes Survey SF-36 scale . At the end of treatment , the G-CBT group exhibited lower scores for mania ( not statistically significant ) and depression ( statistically significant ) as well as a reduction in the frequency and duration of mood episodes ( P < 0.01 ) . The group variable was significant for the reduction of depression scores over time . This clinical change may explain the improvement in six of the eight subscales of QoL ( P < 0.05 ) . The G-CBT group showed better QoL in absolute values in all aspects and significant improvements in nearly all subscales . These results were not observed in the TAU control group BACKGROUND Bipolar Disorder ( BD ) is a common and severe form of mental illness . Pharmacotherapy is the main treatment offered , but has limited effectiveness , and there is increasing evidence that people with BD respond well to psychological interventions . Inequalities in access to face-to-face psychological interventions mean many people seek support outside of routine health services . AIM To assess a recovery informed web-based self-management intervention for BD to increase access to psychological support . METHOD A small online r and omised controlled trial ( RCT ) will evaluate the feasibility , acceptability and potential effectiveness of the intervention compared to treatment as usual ( TAU ) .  Feasibility and acceptability will be assessed by recruitment , adherence and dropout rates , website usage statistics , user satisfaction scales and a series of qualitative interviews . Effectiveness will be assessed on a range of outcome measures including quality of life , mood symptoms , coping , recovery , and illness beliefs . ANALYSIS Rates of adherence and dropout will be analysed using logistic regression models with health , socioeconomic and treatment factors as explanatory variables . Changes in quality of life mean scores , contrasting between arms , will be assessed using r and om effects models . An exploratory analysis will be performed on the secondary outcomes . Thematic analysis ( Braun & Clarke , 2006 ) will be used to analyse the qualitative interviews . DISCUSSION The benefits , challenges and method ological challenges of developing a web-based intervention and conducting an RCT online are discussed . CONCLUSION The results of this trial will inform a definitive trial ; and the implementation phase will aim to assess the potential for use within the NHS Antidepressants effectiveness in major depressive disorder ( MDD ) is still question ed because the extrapolation of r and omized controlled trial ( RCT ) results to " real life " setting s is problematic . The application of the RCT paradigm in a disorder of this type , where global care plays a central role , raises questions regarding the internal and external validity of this type of study . Outcome measurement , attrition rates , the ability of the double-blind design to control for expectations , placebo response , the representativeness of trial participants and publication bias are major method ological pitfalls . This review discusses these issues . It is illustrated using original data and proposes some alternatives for assessing antidepressant effectiveness via different approaches . Some are easy to implement , such as ecological measures , qualitative approaches , improvement of analytical strategy and improvement of blinding procedures . Some are sophisticated , involving temporary deception to deal with the confounding effect of expectations , and they raise ethical issues . Others resort to external validity , this being the case in observational studies . But all are necessary to explore antidepressant effectiveness INTRODUCTION Despite antidepressants are widely used in treating bipolar depression , there is much debate about their utility and their potential dangers , involving mood switches and suicidality . Our hypothesis was that the pattern of initial antidepressant prescription , i.e. , alone ( AM ) or in combination with stabilizers ( AC ) might impact the long-term outcome of patients with bipolar disorder ( BP ) . We aim ed to test this hypothesis and to identify outcome measures that could be predicted by initial AM or AC treatment in patients with BP . METHODS We included 95 patients with DSM-IV BP from a pool of 138 patients following a BP program .  Patients were rated for initial AM vs. AC treatment when they were first seen in primary care and subdivided into two groups accordingly . Differences in their clinical course were sought investigating course both retrospectively and prospect ively ( mean follow-up 10 years ) . Primary outcome measures comprised suicidality and switch rate . RESULTS There were significantly more patients who switched in the AM group than in the AC group . The number of suicide attempts was higher in the AM group . Significance was retained after performing logistic regression . LIMITATIONS Sample size was small and severe BP patients might be overrepresented in this sample . DISCUSSION Initial AM treatment of patients subsequently diagnosed as BP may entrain a course characterized by higher proneness to switch and suicidal behaviour . Accurate initial diagnosis of bipolar depression should prompt combined treatment with antimanic drugs Objective : In adults with established bipolar disorder ( BD ) , differential response to  mood stabilizers  has been associated with the clinical profile . Long-term treatment studies of youth with BD are lacking . This paper provides longitudinal observations of response to  mood stabilizers  early in the course of illness in youth with BD . Method : We report on 15 research patients who , as adolescents , met DSM-IV lifetime criteria for a bipolar spectrum disorder and required long-term treatment . These youths derived from families with one parent having BD whose course and long-term treatment response were determined in accordance with research criteria . The patients were offered lithium , and if they failed to respond or refused it , they were treated with either an anticonvulsant or an atypical antipsychotic . Using a vali date d scale , an independent rater retrospectively blindly scored the response to long-term treatment . Results : Those patients who stabilized on  lithium  derived from lithium-responsive families , whereas those who stabilized on an  antipsychotic  derived from lithium-nonresponsive families . The clinical course in the youths stabilized by lithium differed from that in the youths stabilized by an atypical antipsychotic . Conclusions : Our findings suggest that the clinical profile may help in selecting effective stabilizing treatment and that a proportion of youth can be stabilized on monotherapy . This is a small case series with nonr and om treatment assignment , and the findings should be considered tentative Background There is substantial uncertainty regarding the efficacy of antidepressants in the treatment of bipolar disorders . Methods Traditional r and omized controlled trials and statistical methods are not design ed to discover if , when , and to whom an intervention should be applied ; thus , other method ological approaches are needed that allow for the practice of personalized , evidence -based medicine with patients with bipolar depression . Results Dynamic treatment regimes operationalize clinical decision-making as a sequence of decision rules , one per stage of clinical intervention , that map patient information to a recommended treatment . Using data from the acute depression r and omized care ( RAD ) pathway of the Systematic Treatment Enhancement Program for Bipolar Disorder ( STEP-BD ) study , we estimate an optimal dynamic treatment regime  via Q-learning . Conclusions The estimated optimal treatment regime presents some evidence that patients in the RAD pathway of STEP-BD who experienced a (hypo)manic episode before the depressive episode may do better to forgo adding an antidepressant to a m and atory mood stabilizer Bipolar disorder and substance use disorders are highly debilitating conditions , and especially when co-occurring , are associated with a variety of negative outcomes . Surprisingly , there is a relative lack of research on feasible and effective psychosocial treatments for individuals with comorbid bipolar and substance use disorder ( BD-SUD ) , and a dearth of literature examining interventions design ed specifically to improve outcomes such as symptoms , functioning , and treatment engagement/adherence following psychiatric hospitalization in this population . In the current paper , we report results of a pilot r and omized controlled trial ( n=30 ) , comparing the recently developed Integrated Treatment Adherence Program , which includes individual and telephone sessions provided to patients and their significant others , versus Enhanced Assessment and Monitoring for those with BD-SUD . Participants who received the Integrated Treatment Adherence Program demonstrated significantly faster and greater improvements in depression , mania , functioning , and values-consistent living than participants r and omized to Enhanced Assessment and Monitoring , and there was a trend for increased treatment adherence over time . Results are discussed in light of existing literature and study limitations , and suggestions for future research are proposed OBJECTIVE Compare the safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for preventing  depressive relapse in bipolar II disorder . METHODS Subjects ≥18 years old with bipolar II depression ( n=129 ) were r and omized to double-blind venlafaxine or lithium monotherapy for 12 weeks . Responders with a ≥50 % reduction in depression score were continued for an additional 6 months of relapse-prevention monotherapy . Primary outcome was depressive relapse during continuation monotherapy . Secondary outcomes included sustained response rate from initiation of treatment to study end-point , relapse hazard , time to relapse , change in mania ratings , and frequency of treatment-emergent sub-syndromal hypomania and /or depressive episodes . RESULTS Venlafaxine produced greater sustained response rate  versus lithium ( p<0.0001 ) ; however , there was no difference in relapse rate  for venlafaxine ( 7.5 % ) versus lithium ( 26.7 % ) ( p=0.079 ) ; relapse hazard ( p=0.073 ) , or time to relapse ( p=0.090 ) between treatment conditions during continuation monotherapy . There were no group differences in mania rating scores over time and no difference in frequency or duration of syndromal or sub-syndromal hypomanic episodes . There were more sub-syndromal depressive episodes  during lithium monotherapy ( p=0.03 ) . LIMITATIONS Sample size was limited by the lower sustained response rate  for lithium versus venlafaxine ; study was not specifically powered to detect differences in treatment-emergent hypomanic or depressive episodes between groups . CONCLUSION Results suggest that continuation venlafaxine monotherapy may provide similar prophylactic effectiveness relative to lithium , with no difference in treatment-emergent hypomanic episodes and without the need for frequent serum lithium level and metabolic monitoring . Larger , prospect i ve trials are needed to confirm these observations Abstract Background Despite the use of maintenance medication , recurrence rates in bipolar affective disorder ( BPAD ) are high . To date , there are no clinical trials that have investigated the use of psychological interventions in bipolar disorder in Pakistan . Aim The purpose of the study was to assess the feasibility and acceptability of a culturally adapted bipolar psychoeducation programme ( CaPE ) in Pakistan . Methods Thirty-four euthymic bipolar I and II out patients were r and omized to either 12 weekly sessions of individual psychoeducation plus Treatment As Usual ( Intervention ) or Treatment As Usual ( TAU ) ( Control ) . Outcomes were assessed using the Young Mania Rating Scale ( YMRS ) , Beck Depression Inventory ( BDI ) , EuroQoL ( EQ-5D ) , Bipolar Knowledge and Attitudes and Question naire ( BKAQ ) , and a self-reported measure of medication adherence ( Morisky Medication Adherence Scale-4 items , MMAS-4 ) . Effect sizes were derived from baseline adjusted st and ardized regression coefficients . Results Retention in the study was good , 80 % of patients in the TAU follow-up assessment and 100 % of patients in the CaPE group attended all 12 sessions . Patient satisfaction was higher in the CaPE group relative to control ( ES = 1.41 ) . Further , there were large effect sizes shown for CaPE versus TAU  for medication adherence ( MMAS-4 : ES = 0.81 ) , knowledge and attitudes towards bipolar ( BKAQ : ES = 0.68 ) , mania ( YMRS : ES = 1.18 ) , depression ( BDI : ES = 1.17 ) and quality of life measures ( EQ-5D : ES ⇒ 0.88 ) . Conclusions Culturally adapted psychoeducation intervention is acceptable and feasible , and can be effective in improving mood symptoms and knowledge and attitudes to BPAD when compared with TAU . Larger scale studies are needed to confirm our findings . Trial registration . Clinical trials.gov identifier OBJECTIVE The authors examined the safety and efficacy of long-term fluoxetine monotherapy , lithium monotherapy , and placebo therapy in preventing relapse and recurrence of bipolar type II major depressive episode . The authors hypothesized that fluoxetine monotherapy would be superior to lithium monotherapy with a similar hypomanic mood conversion rate . METHOD Patients at least 18 years old who recovered from their major depressive episode during initial open-label fluoxetine monotherapy were r and omly assigned to receive 50 weeks of double-blind monotherapy with fluoxetine at 10 - 40 mg/day , lithium at 300 - 1200 mg/day , or placebo . The primary outcome measure was time to relapse or recurrence . Secondary outcome measures included the proportion of patients remaining well and the frequency of hypomanic symptoms . RESULTS There were no significant differences in clinical or demographic characteristics among the fluoxetine ( N=28 ) , lithium ( N=26 ) , and placebo ( N=27 ) groups . The mean time to relapse was 249.9 days for the fluoxetine group , 156.4 days for the lithium group , and 186.9 days for the placebo group . The hazard of relapse was significantly lower with fluoxetine compared with lithium , and the estimated hazard of relapse with lithium was 2.5 times greater than with fluoxetine . There were no statistically significant or clinical ly meaningful differences in hypomanic symptoms among treatment groups over time . One patient taking fluoxetine and one patient taking placebo discontinued treatment because of hypomania . CONCLUSIONS These findings suggest that long-term fluoxetine monotherapy may provide superior relapse-prevention benefit relative to lithium monotherapy after recovery from bipolar II major depressive episode without an increase in hypomanic mood conversion episodes OBJECTIVE To assess long-term outcome in bipolar disorder , subjects were prospect ively followed after receiving acute treatment for bipolar depression . METHOD Eighty-three out patients with DSM-IV bipolar depression who were enrolled between March 1996 and November 2002 and were treated in a 10-week acute double-blind antidepressant treatment trial agreed to participate in a 1-year double-blind continuation of their medication . In the acute antidepressant treatment trial , subjects were treated with a mood stabilizer plus 1 of 3 r and omly assigned antidepressants .  Sixty-one subjects had attained an acute positive antidepressant response ( 50 % improvement on the Inventory for Depressive Symptomatology [ IDS ] or 2-point improvement on the Clinical Global Impression for Bipolar Disorder [ CGI-BP ] ) and 22 subjects achieved only acute partial improvement at the end of the 10-week acute trial . In the blinded continuation phase immediately following the acute trial , subjects continued on the same medications and were rated monthly for up to 1 year using the IDS , CGI-BP , and the Young Mania Rating scale . RESULTS At study endpoint , 42 ( 69 % ) of the 61 acute positive responders maintained positive response and 32 ( 53 % ) achieved remission . Compared to the acute positive responders , 6 ( 27 % ) of the 22 acute partial responders had achieved positive treatment response at study endpoint ( p < .001 ) . Eight acute positive responders ( 13 % ) and 5 acute partial responders ( 22 % ) developed mania . CONCLUSION Patients who achieve a positive acute antidepressant response to 10 weeks of antidepressant treatment adjunctive to a mood stabilizer will probably maintain response with the same continued treatment . Patients who achieve only a partial acute antidepressant response are less likely to further improve when the same treatment is sustained . The switch rate into mania for patients being treated with an antidepressant adjunctive to a mood stabilizer is not higher than the reported rate for patients on mood stabilizer monotherapy Antidepressants , in particular newer agents , are among the most widely prescribed medications worldwide with annual sales of billions of dollars . The introduction of these agents in the market has passed through seemingly strict regulatory control . Over a thous and r and omized trials have been conducted with antidepressants . Statistically significant benefits have been repeatedly demonstrated and the medical literature is flooded with several hundreds of " positive " trials ( both pre-approval and post-approval ) . However , two recent meta-analyses question this picture . The first meta- analysis used data that were su bmi tted to FDA for the approval of 12 antidepressant drugs .  While only half of these trials had formally significant effectiveness , published reports almost ubiquitously cl aim ed significant results . " Negative " trials were either left unpublished or were distorted to present " positive " results . The average benefit of these drugs based on the FDA data was of small magnitude , while the published literature suggested larger benefits . A second meta- analysis using also FDA -su bmi tted data examined the relationship between treatment effect and baseline severity of depression . Drug-placebo differences increased with increasing baseline severity and the difference became large enough to be clinical ly important only in the very small minority of patient population s with severe major depression . In severe major depression , antidepressants did not become more effective , simply placebo lost effectiveness . These data suggest that antidepressants may be less effective than their wide marketing suggests . Short-term benefits are small and long-term balance of benefits and harms is understudied . I discuss how the use of many small r and omized trials with clinical ly non-relevant outcomes , improper interpretation of statistical significance , manipulated study design , biased selection of study population s , short follow-up , and selective and distorted reporting of results has built and nourished a seemingly evidence -based myth on antidepressant effectiveness and how higher evidence st and ards , with very large long-term trials and careful prospect i ve meta-analyses of individual-level data may reach closer to the truth and clinical ly useful evidence
Antidepressants were superior to placebo in reducing new depressive episodes in bipolar disorders without increasing risk of new manic/hypomanic episodes either used as monotherapy or in combination with MS .
Subgroup analyses revealed that greater benefit and lower risk may be achieved in BD II than in BD I. However , compared with MS monotherapy , AD monotherapy significantly increased the risk of affective switch with no improvement in prophylaxis of new depressive episodes .
CONCLUSIONS Reduced new depressive episodes may be achieved by long-term AD treatment with no significantly increased risk of new manic/hypomanic episodes in BD , particularly in BD II .
The elevated risk of affective switch  of AD monotherapy compared with MS monotherapy may be contributed to the protective effect of MS in diminishing manic/hypomanic episodes .
OBJECTIVE Efficacy and safety of long-term use of antidepressants ( AD ) in bipolar disorder ( BD ) patients remains highly controversial .
Here we performed a meta- analysis of r and omized controlled trials ( RCTs ) exploring the efficacy and safety of long-term AD use in BD patients .