title: Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. Longitudinal course of bipolar I disorder: duration of mood episodes. Combination tricyclic antidepressant and lithium maintenance medication in unipolar and bipolar depressed patients. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Olanzapine/fluoxetine combination vs. lamotrigine in the 6-month treatment of bipolar I depression. Fluoxetine monotherapy of bipolar type II and bipolar NOS major depression: a double-blind, placebo-substitution, continuation study Effectiveness of adjunctive antidepressant treatment for bipolar depression. The Bipolar Interactive Psychoeducation (BIPED) study: trial design and protocol Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Antidepressants in Type II Versus Type I Bipolar Depression: A Randomized Discontinuation Trial Impact of antidepressant continuation after acute positive or partial treatment response for bipolar depression: a blinded, randomized study. Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up. Efficacy and mood conversion rate during long-term fluoxetine v. lithium monotherapy in rapid- and non-rapid-cycling bipolar II disorder. Lithium carbonate and imipramine in prevention of affective episodes. A comparison in recurrent affective illness. Patterns of pharmacological maintenance treatment in a community mental health services bipolar disorder cohort study (SIN-DEPRES). Antidepressants in bipolar depression: The clinical debate 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. Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison. Effectiveness and Safety of the Combination of Fluoxetine and Olanzapine in Outpatients With Bipolar Depression: An Open-Label, Randomized, Flexible-Dose Study in Puerto Rico Efficacy and safety of long-term fluoxetine versus lithium monotherapy of bipolar II disorder: a randomized, double-blind, placebo-substitution study.
abstract: As many as 45 % of patients with major depressive episode also meet DSM-IV criteria for bipolar II ( BP II ) disorder . Although some clinicians advocate using a mood stabilizer in treating BP II depression , antidepressant monotherapy has been less well studied in this disorder . As part of a prospect i ve , placebo-controlled , relapse-prevention study in 839 patients , the efficacy and safety of short- and long-term fluoxetine treatment in patients with BP II major depression compared with patients with unipolar ( UP ) major depression was retrospectively examined . Eighty-nine BP II patients ( mean age , 41+/-11 years ) were compared with 89 age- and gender-matched UP patients and with 661 unmatched UP patients ( mean age , 39+/-11 years ) . All received short-term fluoxetine therapy at 20 mg daily for up to 12 weeks . Complete remission was defined as a final Hamilton Rating Scale for Depression score < or = 7 by week 9 that was then maintained for 3 additional weeks . Remitted patients were then r and omly assigned to receive double-blind treatment with one of the following : ( 1 ) fluoxetine 20 mg daily for 52 weeks ; ( 2 ) fluoxetine for 38 weeks , then placebo for 14 weeks ; ( 3 ) fluoxetine for 14 weeks , then placebo for 38 weeks ; or ( 4 ) placebo for 52 weeks . Antidepressant efficacy was similar in BP and UP patients during short-term therapy . Discontinuation for lack of efficacy was lower in BP II ( 5 % ) than in UP ( 12 % ) patients ( p = not significant [ NS ] ) , whereas dropouts for adverse events were similar in BP II ( 11 % ) and UP ( 9 % ) patients . During long-term relapse-prevention therapy , relapse rates were similar in BP II and UP patients ( p = NS ) . During short-term fluoxetine therapy , three BP II ( 3.8 % ) versus no matched UP ( p = NS ) and 0.3 % unmatched UP ( p = 0.01 ) patients had a " manic switch . " During long-term fluoxetine therapy , one ( 2 % ) BP II and three ( 1 % ) unmatched UP patients ( one taking placebo ) had a manic switch ( p = NS ) . In conclusion , fluoxetine may be a safe and effective antidepressant monotherapy for the short-term treatment of BP II depression with a relatively low manic switch rate . Fluoxetine may also be effective in relapse-prevention therapy in patients with BP II disorder CONTEXT The phenomenology of bipolar I disorder affects treatment and prognosis . OBJECTIVE To describe the duration of bipolar I mood episodes and factors associated with recovery from these episodes . DESIGN Subjects with Research Diagnostic Criteria bipolar I disorder were prospect ively followed up for as long as 25 years . The probability of recovery over time from multiple successive mood episodes was examined with survival analytic techniques , including a mixed-effects grouped-time survival model . SETTING Five US academic medical centers . PARTICIPANTS Two hundred nineteen subjects with bipolar I disorder . MAIN OUTCOME MEASURES Level of psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation every 6 months for the first 5 years of follow-up and annually thereafter . RESULTS The median duration of bipolar I mood episodes was 13 weeks . More than 75 % of the subjects recovered from their mood episodes within 1 year of onset . The probability of recovery was significantly less for an episode with severe onset ( psychosis or severe psychosocial impairment in week 1 of the episode ) ( hazard ratio [ HR ] = 0.746 ; 95 % confidence interval [ CI ] , 0.578 - 0.963 ; P = .02 ) and for subjects with greater cumulative morbidity ( total number of years spent ill with any mood episode ) ( HR = 0.917 ; 95 % CI , 0.886 - 0.948 ; P < .001 ) . Compared with the probability of recovery from a major depressive episode , there was a significantly greater probability of recovery from an episode of mania ( HR = 1.713 ; 95 % CI , 1.373 - 2.137 ; P < .001 ) , hypomania ( HR = 4.502 ; 95 % CI , 3.466 - 5.849 ; P < .001 ) , or minor depression ( HR = 2.027 ; 95 % CI , 1.622 - 2.534 ; P < .001 ) and , conversely , a significantly reduced probability of recovery from a cycling episode ( switching from one pole to the other without an intervening period of recovery ) ( HR = 0.438 ; 95 % CI , 0.351 - 0.548 ; P < .001 ) . CONCLUSIONS The median duration of bipolar I mood episodes was 13 weeks , and the probability of recovery was significantly decreased for cycling episodes , mood episodes with severe onset , and subjects with greater cumulative morbidity In a small study of up to 3 years ' duration comparison of the value of amitriptyline alone versus amitriptyline + lithium in unipolar cases ( 27 patients ) and of that of lithium alone versus amitriptyline + lithium in bipolar cases ( 13 patients ) showed no advantage for the combination treatments in terms of efficacy in reducing depressive relapses . There was no effect of treatment , developing depression or developing hypothyroidism upon the psychological tests which were conducted during this prolonged study . Observer and self ratings detected an increase in depression before relapse was clearly present , but of the various psychological assessment s conducted only arousal showed changes in association with developing and definite relapse . The prescription of lithium but not amitriptyline + lithium or amitriptyline alone was associated with significant increases in blood pressure BACKGROUND To our knowledge , this is the first prospect i ve natural history study of weekly symptomatic status of patients with bipolar I disorder ( BP-I ) during long-term follow-up . METHODS Analyses are based on ongoing prospect i ve follow-up of 146 patients with Research Diagnostic Criteria BP-I , who entered the National Institute of Mental Health ( Bethesda , Md ) Collaborative Depression Study from 1978 through 1981 .  Weekly affective symptom status ratings were analyzed by polarity and severity , ranging from asymptomatic , to subthreshold levels , to full-blown major depression and mania . Percentages of follow-up weeks at each level as well as number of shifts in symptom status and polarity during the entire follow-up period were examined . Finally , 2 new measures of chronicity were evaluated in relation to previously identified predictors of chronicity for BP-I. RESULTS Patients with BP-I were symptomatically ill 47.3 % of weeks throughout a mean of 12.8 years of follow-up . Depressive symptoms ( 31.9 % of total follow-up weeks ) predominated over manic/hypomanic symptoms ( 8.9 % of weeks ) or cycling/mixed symptoms ( 5.9 % of weeks ) . Subsyndromal , minor depressive , and hypomanic symptoms combined were nearly 3 times more frequent than syndromal-level major depressive and manic symptoms ( 29.9 % vs 11.2 % of weeks , respectively ) . Patients with BP-I changed symptom status an average of 6 times per year and polarity more than 3 times per year . Longer intake episodes and those with depression-only or cycling polarity predicted greater chronicity during long-term follow-up , as did comorbid drug-use disorder . CONCLUSIONS The longitudinal weekly symptomatic course of BP-I is chronic . Overall , the symptomatic structure is primarily depressive rather than manic , and subsyndromal and minor affective symptoms predominate . Symptom severity levels fluctuate , often within the same patient over time . Bipolar I disorder is expressed as a dimensional illness featuring the full range ( spectrum ) of affective symptom severity and polarity To determine the efficacy and tolerability of olanzapine/fluoxetine combination ( OFC ) compared with lamotrigine ( Lam ) for long-term treatment of bipolar I depression , this 25-wk , r and omized , double-blind study compared OFC ( 6/25 , 6/50 , 12/25 , or 12/50 mg/d , n=205 ) with Lam titrated to 200 mg/d ( n=205 ) in patients with bipolar I disorder , depressed . A protocol -specified analysis of 7-wk outcomes was previously reported . Outcome measures included Clinical Global Impressions-Severity of Illness ( CGI-S ) ( primary ) , Montgomery-Asberg Depression Rating Scale ( MADRS ) , and Young Mania Rating Scale ( YMRS ) scores .  OFC-treated patients had significantly greater improvement than Lam-treated patients over 25 wk on CGI-S ( p=0.008 ) , MADRS ( p=0.005 ) , and YMRS ( p<0.001 ) scores , and from baseline across visits from week 5 ( titration complete ) to the end of the study on CGI-S ( p=0.043 ) , MADRS ( p=0.017 ) , and YMRS ( p=0.001 ) scores . Of patients in remission after the 7-wk acute phase , there was no significant difference between treatment groups in the incidence of relapse ( MADRS > 15 , p=0.528 ) . Rate of treatment-emergent mania was not significantly different by treatment ( p=0.401 ) . OFC-treated patients had more frequent ( p<0.05 ) somnolence , increased appetite , dry mouth , sedation , weight gain , and tremor ;  Lam-treated patients had more frequent insomnia . There was a significant difference in incidence of treatment-emergent cholesterol > or = 240 ( p<0.001 ) and in weight gain of > or = 7 % ( p<0.001 ) in favour of the Lam group . Patients with bipolar I depression had significantly greater symptom improvement over 25 wk on OFC compared with Lam . There was no treatment difference in incidence of relapse .  OFC-treated patients had more treatment-emergent adverse events and greater incidence of weight gain and hypercholesterolaemia Current guidelines for the treatment of bipolar type II ( BP II ) major depressive episode ( MDE ) recommend using either mood stabilizer monotherapy or the combination of a mood stabilizer with a selective serotonin reuptake inhibitor ( SSRI ) . These guidelines are the result of concern over SSRI-induced manic switch episodes . We previously showed that fluoxetine monotherapy may be effective as an initial treatment for BP II and BP NOS MDE with a low manic switch rate . We now present the results of a double-blind , placebo-substitution continuation study of fluoxetine monotherapy in BP II and BP NOS patients who have recovered from their MDE . This was a two-phase study . In study phase I , patients received open-label fluoxetine monotherapy 20 mg daily for up to 8 weeks . Responders with a final 17-item Hamilton Rating Scale for Depression ( HAM-D ) score≤9 were enrolled into study phase II which consisted of double-blind , placebo-substitution continuation therapy with fluoxetine 20 mg daily for up to 6 months . Outcome measures included the 17-item HAM-D and Young Mania Rating ( YMR ) scales . Changes in YMR scores were assessed using generalized estimating equation analysis . Relapse was assessed using Kaplan – Meier survival analysis and Fisher 's exact test . In study phase II , 43 % of fluoxetine-treated patients and 100 % of placebo-treated patients relapsed during continuation therapy ( P=0.08 ) . The mean increase in YMR score in study phase II was slightly higher in the fluoxetine-treated patients ( 3.0±1.8 ) versus placebo-treated patients ( 0.2±0.4 ) ( P=0.01 ) . However , this difference was not clinical ly meaningful . No hypomanic switch episodes were observed during study phase II . Despite the limited sample size result ing in insufficient power to detect statistical significance in relapse rates or change in YMR scores between treatment conditions , these preliminary data appear to support previous observations demonstrating that initial and continuation fluoxetine monotherapy may be safe and effective for some patients with BP II or BP NOS MDE with a low manic switch rate . Larger-scale studies are needed to confirm these findings BACKGROUND Episodes of depression are the most frequent cause of disability among patients with bipolar disorder . The effectiveness and safety of st and ard antidepressant agents for depressive episodes associated with bipolar disorder ( bipolar depression ) have not been well studied . Our study was design ed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania . METHODS In this double-blind , placebo-controlled study , we r and omly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo , under conditions generalizable to routine clinical care . A st and ardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders , fourth edition , was used at all follow-up visits . The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery ( 8 consecutive weeks of euthymia ) . Secondary effectiveness outcomes and rates of treatment-emergent affective switch ( a switch to mania or hypomania early in the course of treatment ) were also examined . RESULTS Forty-two of the 179 subjects ( 23.5 % ) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery , as did 51 of the 187 subjects ( 27.3 % ) receiving a mood stabilizer plus a matching placebo ( P=0.40 ) . Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes . Rates of treatment-emergent affective switch were similar in the two groups . CONCLUSIONS The use of adjunctive , st and ard antidepressant medication , as compared with the use of mood stabilizers , was not associated with increased efficacy or with increased risk of treatment-emergent affective switch . Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder . ( Clinical Trials.gov number , NCT00012558 [ Clinical Trials.gov ] . ) Background Bipolar disorders affect between 3–5 % of the population and are associated with considerable lifelong impairment . Since much of the morbidity associated with bipolar disorder is caused by recurrent depressive symptoms , which are often only poorly responsive to antidepressants , there is a need to develop alternative , non-pharmacological interventions . Psychoeducational interventions have emerged as promising long-term therapeutic options for bipolar disorder . Methods / design The study is an exploratory , individually r and omised controlled trial . The intervention known as ' Beating Bipolar ' is a psychoeducational programme which is delivered via a novel web-based system . We will recruit 100 patients with a diagnosis of DSM-IV bipolar disorder ( including type I and type II ) currently in clinical remission . The primary outcome is quality of life . This will be compared for those patients who have participated in the psychoeducational programme with those who received treatment as usual . Quality of life will be assessed immediately following the intervention as well as 10 months after r and omisation . Secondary outcomes include current depressive and manic symptoms , number of episodes of depression and mania/hypomania experienced during the follow-up period , global functioning , functional impairment and insight . An assessment of costs and a process evaluation will also be conducted which will explore the feasibility and acceptability of the intervention as well as potential barriers to effectiveness . Discussion Bipolar disorder is common , under-recognised and often poorly managed . It is a chronic , life-long , relapsing condition which has an enormous impact on the individual and the economy . This trial will be the first to explore the effectiveness of a novel web-based psychoeducational intervention for patients with bipolar disorder which has potential to be easily rolled out to patients .Trial registration Current Controlled Trials IS RCT In a double-blind , long-term follow-up study , 117 bipolar patients received lithium carbonate , imipramine hydrochloride , or both and 150 unipolar patients received lithium carbonate , imipramine , both lithium carbonate and imipramine , or placebo . With bipolar patients , lithium carbonate and the combination treatment were superior to imipramine in preventing manic recurrences and were as effective as imipramine in preventing manic recurrences and were as effective as imipramine in preventing depressive episodes . The combination treatment provided no advantage over lithium carbonate alone . With unipolar patients , imipramine and the combination treatment were more effective than lithium carbonate and placebo in preventing depressive recurrences . The combination treatment provided no advantage over imipramine alone . The lithium carbonate-treated group had fewer manic episodes than the other groups . Treatment outcome , which was evaluated primarily in terms of the occurrence of major depression or manic episodes , was significantly related to characteristics of the index episode , ie , the episode that brought the patient into the study 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 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 OBJECTIVE While guidelines for treating patients with bipolar depression recommend discontinuing antidepressants within 6 months after remission , few studies have assessed the implication s of this strategy on the risk for depressive relapse . This study examined the effect of antidepressant discontinuation or continuation on depressive relapse risk among bipolar subjects successfully treated for an acute depressive episode . METHOD Eighty-four subjects with bipolar disorder who achieved remission from a depressive episode with the addition of an antidepressant to an ongoing mood stabilizer regimen were followed prospect ively for 1 year . The risk of depressive relapse among 43 subjects who stopped antidepressant treatment within 6 months after remission ( " discontinuation group " ) was compared with the risk among 41 subjects who continued taking antidepressants beyond 6 months  ( " continuation group " ) . RESULTS A Cox proportional hazards regression analysis indicated that shorter antidepressant exposure time following successful treatment was associated with a significantly shorter time to depressive relapse . Furthermore , patients who discontinued antidepressant treatment within the first 6 months after remission experienced a significantly shorter period of euthymia before depressive relapse over the length of 1-year follow-up . One year after successful antidepressant response , 70 % of the antidepressant discontinuation group experienced a depressive relapse compared with 36 % of the continuation group . By the 1-year follow-up evaluation , 15 ( 18 % ) of the 84 subjects had experienced a manic relapse ; only six of these subjects were taking an antidepressant at the time of manic relapse . CONCLUSIONS The risk of depressive relapse in patients with bipolar illness was significantly associated with discontinuing antidepressants soon after remission . The risk of manic relapse was not significantly associated with continuing use of antidepressant medication and , overall , was substantially less than the risk of depressive relapse . Maintenance of antidepressant treatment in combination with a mood stabilizer may be warranted in some patients with bipolar disorder BACKGROUND Controversy exists over antidepressant use in rapid-cycling bipolar disorder . AIMS Exploratory analysis of safety and efficacy of fluoxetine v. lithium monotherapy in individuals with rapid- v. non-rapid-cycling bipolar II disorder . METHOD R and omised , double-blind , placebo-controlled comparison of fluoxetine v. lithium monotherapy in patients initially stabilised on fluoxetine monotherapy ( trial registration NCT00044616 ) . RESULTS The proportion of participants with depressive relapse was similar between the rapid- and non-rapid-cycling groups ( P = 0.20 ) . The odds of relapse were similar between groups ( P = 0.36 ) . The hazard of relapse was similar between groups ( hazard ratio 0.87 , 95 % CI 0.40 - 1.91 ) . Change in mania rating scores was similar between groups ( P = 0.86 ) . There was no difference between groups in the rate of syndromal ( P = 0.27 ) or subsyndromal ( P = 0.82 ) hypomania . CONCLUSIONS Depressive relapse and treatment-emergent mood conversion episode rates were similar for lithium and fluoxetine monotherapy and placebo during long-term , relapse-prevention therapy of rapid- and non-rapid-cycling bipolar II disorder Patients with recurrent affective illness ( N-122 ) were r and omly assigned to lithium carbonate , imipramine , or placebo therapy for two years following discharge from hospitalization for acute depression . Patients were classified as bipolar or unipolar based on the presence or absence of a history of mania . With bipolar patients lithium carbonate was significantly more effective than imipramine or placebo in preventing affective episodes ( ie , manic or depressive attacks severe enough to require hospitalization or use of non study drugs ) . There was a relatively high incidence of manic episodes on imipramine . Unipolar patients responded equally well to lithium carbonate or imipramine . Both treatments were significantly more effective than placebo . The difference between treatments was due primarily to depressive episodes ; manic episodes occurred infrequently and were evenly distributed across treatment groups . There was no significant difference between  lithium carbonate and imipramine  among unipolar patients 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 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 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 Twenty-seven patients with recurrent unipolar depression and 22 with bipolar II illness in remission for at least six months were r and omly assigned on a double-blind basis to treatment regimens using lithium carbonate , imipramine hydrochloride , lithium carbonate plus imipramine , or placebo . Lithium carbonate was found to help prevent depressive relapse among patients with unipolar disease , and relapse of any type among those with bipolar II disease . No effect or interaction of imipramine  was found in either group . These results add to a growing body of data that suggest the usefulness of lithium carbonate in the prophylaxis of unipolar depressive illness . The relative usefulness of lithium carbonate and imipramine requires further study We studied the effectiveness of olanzapine/fluoxetine combination ( OFC ) treatment of  bipolar depressive episode ( 7 weeks , study period 1 [ SP1 ] ) . Study period 1 responders ( mean modal daily OFC dosage , 10.8/27.8 mg ) were r and omized to OFC continuation treatment or olanzapine ( OLZ ) monotherapy starting at 10 mg ( 12 weeks , SP2 ) . Seventy-three percent of the 114 patients who entered into SP2 completed the trial .  The Montgomery-Åsberg Depression Rating Scale total score changes from baseline in SP1 ( primary outcome ) were significant ( −20 ± 10 , P < 0.001 ) and , during SP2 , worsened for patients in the OLZ group ( OFC vs OLZ , −0.4 ± 7.55 vs + 8.2 ± 14.1 , respectively ; P < 0.001 ) . During SP1 , 69 % responded and 59 % remitted . During SP2 , significantly more patients in the OFC group maintained response ( 31.3 % vs 12.5 % ) and remission ( 71.4 % vs 39.6 % ) than patients in the OLZ group . Treatment-emergent adverse events with OFC ( SP1 and SP2 ) included increased appetite , increased weight , somnolence , anxiety , insomnia , and depressed mood . Since visit 1 , the mean weight increases ( in pounds ) were 4.8 ± 6.8 for SP1 ( P < 0.001 ) and 6.3 ± 10.3 ( OFC ) or 10.7 ± 11.3 ( OLZ ) for SP2 ; 50 % ( OLZ ) and 33 % ( OFC ) of the patients had a 7 % or higher weight increase . For cholesterol , triglycerides , and low-density lipoprotein levels and some hepatic enzymes , there were statistically and clinical ly significant changes in both study periods but no differences between the SP2 groups . Study limitations included the open-label design and exclusion of the SP1 nonresponders from SP2 . These study results suggest that improvements result ing from 7 weeks of acute OFC treatment of a bipolar depressive episode are maintained in responders for an additional 12 weeks with OFC , but switching to OLZ alone may result in symptom worsening 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
target: 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 .
background: 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 .