title: Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Subverting randomization in controlled trials. Size is everything – large amounts of information are needed to overcome random effects in estimating direction and magnitude of treatment effects Quetiapine Versus Placebo in Combination With Lithium or Divalproex for the Treatment of Bipolar Mania Effectiveness of aripiprazole v. haloperidol in acute bipolar mania: double-blind, randomised, comparative 12-week trial. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. The importance of quality of primary studies in producing unbiased systematic reviews. Variation in the placebo effect in randomised controlled trials of analgesics: all is as blind as it seems A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group. Mood stabilisers plus risperidone or placebo in the treatment of acute mania. International, double-blind, randomised controlled trial. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Recovery and functional outcomes following olanzapine treatment for bipolar I mania. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: A 47-week study Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Risperidone and paroxetine given singly and in combination for bipolar depression. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. Olanzapine compared to lithium in mania: a double-blind randomized controlled trial. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol Efficacy of Quetiapine Monotherapy in Bipolar I and II Depression: A Double-blind, Placebo-controlled Study (The BOLDER II Study) Quetiapine or haloperidol as monotherapy for bipolar mania—a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial Ziprasidone in Acute Bipolar Mania: A 21-Day Randomized, Double-Blind, Placebo-Controlled Replication Trial A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Olanzapine versus placebo in the treatment of acute mania Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Olanzapine versus divalproex in the treatment of acute mania. Risperidone Compared with Both Lithium and Haloperidol in Mania: A Double‐Blind Randomized Controlled Trial Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression.
abstract: OBJECTIVE This study evaluated the efficacy and safety of risperidone monotherapy in the treatment of acute bipolar mania . METHOD Patients with DSM-IV bipolar I disorder experiencing an acute manic episode ( baseline Young Mania Rating Scale score > /== " BORDER="0">20 ) were r and omly assigned to 3 weeks of treatment with risperidone ( flexible dose : 1 - 6 mg/day ) or placebo . The primary efficacy measure was the mean baseline-to-endpoint change in total score on the Young Mania Rating Scale . Secondary efficacy measures included the Clinical Global Impression ( CGI ) severity rating and scores on the Montgomery-Asberg Depression Rating Scale , Positive and Negative Syndrome Scale , and Global Assessment Scale ( GAS ) . Safety assessment s consisted of monitoring adverse events , vital signs , electrocardiogram and laboratory results , and scores on the Extrapyramidal Symptom Rating Scale . RESULTS Subjects ( N=259 ) received treatment with either risperidone ( N=134 ) or placebo ( N=125 ) . The mean modal dose of risperidone was 4.1 mg/day . Improvement in mean Young Mania Rating Scale total score ( adjusted for covariates ) was significantly greater in the risperidone than in the placebo group at endpoint ( mean change=-10.6 [ SD=9.5 ] versus -4.8 [ SD=9.5 ] , respectively ) , with significant between-group differences seen as early as 3 days after start of treatment ( change with risperidone : mean=-6.8 [ SD=5.8 ] ; change with placebo : mean=-4.0 [ SD=5.8 ] ) and continuing throughout all time points . Improvements in CGI severity ratings and scores on the Montgomery-Asberg Depression Rating Scale , Positive and Negative Syndrome Scale , and GAS were also significantly greater among patients receiving risperidone than those given placebo . The most common adverse event reported among risperidone patients was somnolence . While Extrapyramidal Symptom Rating Scale scores were significantly greater in patients receiving risperidone , mean total and subscale scores were low . CONCLUSIONS Risperidone monotherapy was significantly more efficacious than placebo in the treatment of acute mania and demonstrated a rapid onset of action . Risperidone was well tolerated by patients in this study Recent empirical evidence supports the importance of adequate r and omization in controlled trials . Trials with inadequate allocation concealment have been associated with larger treatment effects compared with trials in which authors reported adequate allocation concealment . While that provides empirical evidence of bias being interjected into trials , trial investigators rarely document the sensitive details of subverting the intended purpose of r and omization . This article relates anonymous accounts run the gamut from simple to intricate operations , from transillumination of envelopes to search ing for code in the office files of the principal investigator . They indicate that deciphering is something more frequent than a rate occurrence . These accounts prompt some method ological recommendations to help prevent deciphering . R and omized controlled trials appear to annoy human nature -- if properly conducted , indeed they should Abstract  Variability  in patients ' response to interventions in pain and other clinical setting s is large . Many explanations such as trial methods , environment or culture have been proposed , but this paper sets out to show that the main cause of the variability may be r and om chance , and that if trials are small their estimate of magnitude of effect may be incorrect , simply because of the r and om play of chance . This is highly relevant to the questions of ‘ How large do trials have to be for statistical accuracy ? ’ and ‘ How large do trials have to be for their results to be clinical ly valid ? ’ The true underlying control event rate ( CER ) and experimental event rate ( EER ) were determined from single‐dose acute pain analgesic trials in over 5000 patients . Trial group size required to obtain statistically significant and clinical ly relevant ( 0.95 probability of number‐needed‐to‐treat within ±0.5 of its true value ) results were computed using these values . Ten thous and trials using these CER and EER values were simulated using varying group sizes to investigate the variation due to r and om chance alone . Most common analgesics have EERs in the range 0.4–0.6 and CER of about 0.19 . With such efficacy , to have a 90 % chance of obtaining a statistically significant result in the correct direction requires group sizes in the range 30–60 . For clinical relevance nearly 500 patients are required in each group . Only with an extremely effective drug ( EER>0.8 ) will we be reasonably sure of obtaining a clinical ly relevant NNT with commonly used group sizes of around 40 patients per treatment arm . The simulated trials showed substantial variation in CER and EER , with the probability of obtaining the correct values improving as group size increased . We contend that much of the variability in control and experimental event rates is due to r and om chance alone . Single small trials are unlikely to be correct . If we want to be sure of getting correct ( clinical ly relevant ) results in clinical trials we must study more patients . Credible estimates of clinical efficacy are only likely to come from large trials or from pooling multiple trials of conventional ( small ) size Abstract : Quetiapine ( QTP ) combined with lithium ( Li ) or divalproex ( DVP ) for the treatment of mania was evaluated in 2 double-blind , placebo-controlled studies . Patients were r and omized to 3 or 6 weeks of treatment with QTP plus Li/DVP or placebo ( PBO ) plus Li/DVP . Quetiapine was dosed up to 800 mg/d ; Li was dosed to achieve serum concentrations of 0.7 - 1.0 mEq/L and DVP to 50 - 100 μg/mL. A total of 402 patients were r and omized : 197 to QTP + Li/DVP and 205 to PBO + Li/DVP . The mean quetiapine dose in responders was 492 ( ±204 ) mg/d . Improvement in the Young Mania Rating Scale ( YMRS ) at day 21 in the QTP + Li/DVP group ( −15.29 ) was statistically superior to the PBO + Li/DVP group ( −12.19 ) ( P < 0.05 ) . A statistically significant difference in favor of quetiapine was observed within the first week ( P < 0.05 ) . Significantly more QTP + Li/DVP patients achieved a response ( ≥50 % decrease in the YMRS ) at day 21 ( QTP + Li/DVP , 55.7 % ; PBO + Li/DVP , 41.6%;P < 0.01 ) . Improvements in Clinical Global Impression-Bipolar Severity of Illness scores by day 21 were also significantly greater in QTP + Li/DVP-treated patients ( −1.59 ) versus PBO + Li/DVP ( −1.19 ) ( P < 0.01 ) . Common adverse events ( ≥5 % and twice that in the PBO + Li/DVP group ) in the QTP + Li/DVP group were somnolence , dry mouth , and asthenia . Quetiapine combined with Li/DVP was not associated with extrapyramidal symptoms ( including akathisia ) or emergent depression . More QTP + Li/DVP-treated patients completed the trial , and there was no difference in discontinuation rates due to adverse events between the two groups . Quetiapine , in combination with lithium or divalproex , is well tolerated and has superior efficacy to lithium or divalproex alone in the treatment of bipolar mania BACKGROUND Despite several treatmentoptions , adherenceto therapy is poor in patients with bipolar disorder . AIMS A double-blind , controlled comparison of aripiprazole and haloperidol in patients with bipolar I disorder experiencing acute manic or mixed episodes . METHOD Patients ( n=347 ) were r and omised to receive aripiprazole or haloperidol  in this 12-week , multicentre study . The primary outcome measure was the number of patients in response ( greater , similar 50 % improvement from baseline in Young Mania Rating Scale score ) and receiving therapy at week 12 . RESULTS At week 12 , significantly more patients taking aripiprazole ( 49.7 % ) were in response and receiving therapy compared with those taking haloperidol ( 28.4 % ; P < 0.001 ) . Continuation rates differed markedly between treatments ( week 12 : aripiprazole , 50.9 % ; haloperidol , 29.1 % ) . Extrapyramidal adverse events were more frequent with haloperidol than aripiprazole ( 62.7 % v. 24.0 % ) . CONCLUSIONS Aripiprazole showed superior levels of response and tolerability to haloperidol in the treatment of an acute manic episode for up to 12 weeks OBJECTIVE Evaluate the efficacy and tolerability of quetiapine ( QTP ) combined with lithium ( Li ) or divalproex ( DVP ) in the treatment of acute mania . METHODS Patients were r and omized to 21 days of double-blind treatment with QTP plus Li/DVP , or placebo ( PBO ) plus Li/DVP . QTP was rapidly dosed up to a maximum of 800 mg/day ; Li was dosed to 0.7 - 1.0 mEq/L ; or DVP to 50 - 100 microg/mL. RESULTS Fifty-six of 91 ( 61.5 % ) individuals in the  QTP + Li/DVP group compared with 49 of 100 ( 49 % ) taking PBO + Li/DVP  completed the study . A significantly greater mean reduction in total Young Mania Rating Scale ( YMRS ) score was observed at end-point in patients receiving QTP + Li/DVP compared with those in the PBO + Li/DVP group ( -13.76 versus -9.93 ; p = 0.021 ) . The response rate ( > or = 50 % YMRS improvement ) was significantly higher in the QTP + Li/DVP group than in PBO + Li/DVP-treated patients ( 54.3 % versus 32.6 % ; p = 0.005 ) , as was the proportion of patients achieving clinical remission ( YMRS < 12 ) ( 45.7 % versus 25.8 % ; p = 0.007 ) . Patients receiving QTP + Li/DVP also had a significantly greater improvement in Clinical Global Impressions-Bipolar ( CGI-BP ) Severity of Illness scores ( -1.38 versus -0.78 ; p = 0.001 ) . The mean last-week dose of QTP was 584 mg/day in patients meeting response criteria . Common adverse events ( at least 10 % and twice the rate of Li/DVP ) in the QTP + Li/DVP group included somnolence , dry mouth , asthenia , and postural hypotension . CONCLUSIONS Quetiapine combined with either Li or DVP has superior efficacy compared with Li or DVP monotherapy for treating patients with bipolar mania . Combination therapy was well-tolerated and most adverse events were mild , withdrawal because of adverse events being only 5 % compared with 6 % on Li or DVP monotherapy BACKGROUND Traditional and largely qualitative review s of evidence are now giving way to much more structured systematic overviews that use a quantitative method to calculate the overall effect of treatment . The latter approach is dependent on the quality of primary studies , which may introduce bias if they are of poor method ologic quality . OBJECTIVE To test the hypothesis that the inclusion of poor- quality trials in meta-analyses would bias the conclusions and produce incorrect estimates of treatment effect . METHODS An overview of r and omized trials of antiestrogen therapy in subfertile men with oligospermia was performed to test the hypothesis . Data sources included online search ing of MEDLINE and Science Citation Index data bases between 1966 and 1994 , scanning the bibliography of known primary studies and review articles , and contacting experts in the field . After independent , blind assessment , nine of 149 originally identified studies met the inclusion criteria and were selected . We assessed study quality independently . Outcome data from each study were pooled and statistically summarized . RESULTS There was a marginal improvement in pregnancy rate with antiestrogen treatment ( odds ratio , 1.6 ; 95 % confidence interval , 0.9 to 2.6 ) . Sensitivity analyses on the basis of method ologic quality demonstrated that poor- quality studies produced a positive effect with treatment , whereas no benefit was observed with high- quality studies . CONCLUSION The results of a meta- analysis are influenced by the quality of the primary studies included . Method ologically , poor studies tend to exaggerate the overall estimate of treatment effect and may lead to incorrect inferences & NA ; The objective was to investigate the relationship between pain relief scores produced by placebo and by active interventions in r and omised controlled trials ( RCTs ) . Individual patient categorical pain relief scores from 5 placebo‐controlled single‐dose parallel‐group RCTs in acute postoperative pain were used to calculate the percentage of the maximum possible pain relief score ( % maxTOTPAR ) for the different treatments . One hundred and thirty of the 525 patients in the 5 trials had a placebo .  Individual patients ' scores with placebo varied from 0 to 100 % of the maximum possible pain relief . The proportion who obtained more than 50 % of the maximum possible pain relief with placebo varied from 7 % to 37 % across the trials ; with the active drugs the variation was from 5 to 63 % . Mean placebo scores were related to the mean score for the active treatments in each study ; the higher the mean active score , the higher the mean placebo score . This relationship disappeared when median values were used . Medical folklore has it that the amount of relief obtained with placebo is one‐third of the maximum possible ( and does not vary ) , and that one‐third of patients respond to placebo . The results show that the amount of relief obtained with placebo varies considerably between patients , that 38 % of patients obtained more than 10 % of the maximum possible relief , and 16 % obtained greater than 50 % . In double‐blind , r and omised parallel‐group studies of high quality placebo scores should not vary . Despite these conditions being met the placebo scores did vary . The previous explanation , of a relationship between the mean placebo scores and the mean scores for the active treatments was not supported OBJECTIVE Determine the efficacy and tolerability of olanzapine/fluoxetine combination ( OFC ) for treatment of acute bipolar I depression compared with lamotrigine . METHOD The 7-week , acute phase of a r and omized , double-blind study compared OFC ( 6/25 , 6/50 , 12/25 , or 12/50 mg/day ; N = 205 ) with lamotrigine ( [ LMG ] titrated to 200 mg/day ; N = 205 ) in patients with DSM-IV-diagnosed bipolar I disorder , depressed . The study was conducted from November 2003 to August 2004 . RESULTS Completion rates were similar between treatments ( OFC , 66.8 % vs. LMG , 65.4 % ; p = .835 ) . OFC-treated patients had significantly greater improvement than lamotrigine-treated patients in change from baseline across the 7-week treatment period on the Clinical Global Impressions-Severity of Illness scale ( primary outcome ) ( p = .002 , effect size = 0.26 ) , Montgomery-Asberg Depression Rating Scale ( MADRS ) ( p = .002 , effect size = 0.24 ) , and Young Mania Rating Scale total scores ( p = .001 , effect size = 0.24 ) . Response rates did not significantly differ between groups when defined as > or = 50 % reduction in MADRS score ( OFC , 68.8 % vs. LMG , 59.7 % ; p = .073 ) . Time to response was significantly shorter for OFC-treated patients ( median days [ 95 % CI ] = OFC , 17 [ 14 to 22 ] vs. LMG , 23 [ 21 to 34 ] ; p = .010 ) . There was a significant difference in incidence of " suicidal and self-injurious behavior " adverse events ( OFC , 0.5 % vs. LMG , 3.4 % ; p = .037 ) . Somnolence , increased appetite , dry mouth , sedation , weight gain , and tremor occurred more frequently ( p < .05 ) in OFC-treated patients than lamotrigine-treated patients . Weight , total cholesterol , and triglyceride levels were significantly elevated in OFC-treated patients compared with lamotrigine-treated patients ( all p < or = .001 ) . CONCLUSIONS Patients with acute bipolar I depression had statistically significantly greater improvement in depressive and manic symptoms , more treatment-emergent adverse events , greater weight gain , and some elevated metabolic factors with OFC than lamotrigine . Treatment differences were of modest size BACKGROUND Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder . Aims To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse , compared with lithium or valproate alone . METHOD Patients achieving syndromic remission after 6 weeks'treatment with olanzapine plus either lithium ( 0.6 - 1.2 mmol/l ) or valproate ( 50 - 125 microg/ml )  received lithium or valproate plus either olanzapine 5 - 20 mg/day ( combination therapy ) or placebo ( monotherapy ) , and were followed in a double-masked trial for 18 months . RESULTS The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse ( median time to relapse : combination therapy 94 days , monotherapy 40.5 days ; P=0.742 ) , but was significant for symptomatic relapse ( combination therapy 163 days , monotherapy 42 days ; P=0.023 ) . CONCLUSIONS Patients taking olanzapine  added to lithium or valproate experienced sustained symptomatic remission , but not syndromic remission , for longer than those receiving lithium or valproate monotherapy BACKGROUND This r and omized controlled trial compares the efficacy and safety of olanzapine vs haloperidol , as well as the quality of life of patients taking these drugs , in patients with bipolar mania . METHODS The design consisted of 2 successive , 6-week , double-blind periods and compared flexible dosing of olanzapine ( 5 - 20 mg/d , n = 234 ) with haloperidol ( 3 - 15 mg/d , n = 219 ) . RESULTS Rates of remission ( Young-Mania Rating Scale score of < or = 12 and 21-item Hamilton Rating Scale for Depression score of < or = 8 at week 6 ) were similar for  olanzapine- and haloperidol-treated patients ( 52.1 % vs 46.1 % , respectively ; P = .15 ) . For the subgroup of patients whose index episode did not include psychotic features , rates of remission were significantly greater for the olanzapine group compared with the haloperidol group ( 56.7 % vs 41.6 % , P = .04 ) . Relapse into an affective episode ( mania and /or depression ) occurred in 13.1 % and 14.8 % of olanzapine- and haloperidol-treated patients , respectively ( P = .56 ) . Switch to depression occurred significantly more rapidly with haloperidol than with olanzapine when using survival analysis techniques ( P = .04 ) , and significantly more haloperidol-treated patients experienced worsening of extrapyramidal symptoms , as indicated by several measures . Weight gain was significantly greater in the olanzapine group compared with the haloperidol group ( 2.82 vs 0.02 kg , P<.001 ) . The olanzapine group had significant improvement in quality of life on several dimensions compared with the haloperidol group . CONCLUSIONS These data suggest that olanzapine does not differ from haloperidol in achieving overall remission of bipolar mania . However , haloperidol carries a higher rate of extrapyramidal symptoms , whereas olanzapine is associated with weight gain OBJECTIVE The authors compared the efficacy and safety of aripiprazole , a novel antipsychotic , to placebo for treatment of patients in an acute manic or mixed episode of bipolar disorder . METHOD This 3-week , multicenter , double-blind study r and omly assigned 262 bipolar disorder patients in an acute manic or mixed episode to  aripiprazole , 30 mg/day ( reduced to 15 mg/day if needed for tolerability ) , or placebo .  Patients remained hospitalized for at least 2 of the weeks . The primary efficacy measure was mean change from baseline in total score on the Young Mania Rating Scale ; response was defined as a decrease in score of > or = 50 % . RESULTS Aripiprazole produced statistically significant mean improvements in total score on the Young Mania Rating Scale compared with placebo ( -8.2 versus -3.4 , respectively ) and produced a significantly higher response rate ( 40 % versus 19 % ) . For key efficacy variables ( response per Young Mania Rating Scale ; Clinical Global Impression-Bipolar Version scores for severity of illness [ mania ] and change from preceding phase [ mania ] ) , aripiprazole separated from placebo by day 4 . The completion rate was significantly higher with aripiprazole than with placebo ( 42 % versus 21 % ) . Discontinuations due to adverse events did not differ significantly between the aripiprazole and placebo groups . There were no significant changes in body weight versus placebo , and aripiprazole was not associated with elevated serum prolactin or QTc prolongation . CONCLUSIONS Aripiprazole had significantly greater efficacy than placebo for the treatment of bipolar disorder patients in acute manic or mixed episodes and was safe and well tolerated in this r and omized controlled trial BACKGROUND We compared the efficacy and safety of olanzapine vs placebo for the treatment of acute bipolar mania . METHODS Four-week , r and omized , double-blind , parallel study . A total of 115 patients with a DSM-IV diagnosis of bipolar disorder , manic or mixed , were r and omized to  olanzapine , 5 to 20 mg/d ( n = 55 ) , or placebo ( n = 60 ) . The primary efficacy measure was the Young-Mania Rating Scale ( Y-MRS ) total score . Response and euthymia were defined , a priori , as at least a 50 % improvement from baseline to end point and as a score of no less than 12 at end point in the Y-MRS total score , respectively . Safety was assessed using adverse events , Extrapyramidal Symptom ( EPS ) rating scales , laboratory values , electrocardiograms , vital signs , and weight change . RESULTS Olanzapine-treated patients demonstrated a statistically significant greater mean ( + /- SD ) improvement in Y-MRS total score than placebo-treated patients ( -14.8 + /- 12.5 and -8.1 + /- 12.7 , respectively ; P<.001 ) , which was evident at the first postbaseline observation 1 week after r and omization and was maintained throughout the study ( last observation carried forward ) . Olanzapine-treated patients demonstrated a higher rate of response ( 65 % vs 43 % , respectively ; P = .02 ) and euthymia ( 61 % vs 36 % , respectively ; P = . 01 ) than placebo-treated patients . There were no statistically significant differences in EPSs between groups . However , olanzapine-treated patients had a statistically significant greater mean ( + /- SD ) weight gain than placebo-treated patients ( 2.1 + /- 2.8 vs 0.45 + /- 2.3 kg , respectively ) and also experienced more treatment-emergent somnolence ( 21 patients [ 38.2 % ] vs 5 [ 8.3 % ] , respectively ) . CONCLUSION Olanzapine demonstrated greater efficacy than placebo in the treatment of acute bipolar mania and was generally well tolerated BACKGROUND Few double-blind trials have examined the efficacy of a combination of a mood stabiliser and an atypical antipsychotic  in acute mania . AIMS To determine the efficacy of risperidone in combination with a mood stabiliser in acute mania . METHOD Patients taking a mood stabiliser were r and omised to 3 weeks ' treatment with risperidone ( n=75 ) or placebo ( n=76 ) . RESULTS Young Mania Rating Scale ( YMRS ) scores improved rapidly with significantly greater reductions at week 1 in the risperidone group compared with the placebo group . At end-point YMRS scores decreased by 14.5 and 10.3 points in the risperidone and placebo groups , respectively . Significant improvements v. placebo ( P<0.05 ) were noted in the risperidone group on several other clinical ly meaningful measures . Additionally , a post hoc analysis excluding carbamazepine-treated patients ( plasma concentrations of risperidone active moiety were 40 % lower in this group ) revealed significantly greater reductions ( P=0.047 ) in YMRS scores in the risperidone group than in the placebo group . Incidence of adverse events was similar in both groups . CONCLUSIONS Risperidone is superior to placebo when used in combination with lithium or divalproex in acute mania BACKGROUND A 6-week double-blind , r and omized , placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes . METHODS The primary objective was to evaluate the efficacy of olanzapine ( 5 - 20 mg/d ) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale ( YMRS ) scores . Patients with bipolar disorder ( n = 344 ) , manic or mixed episode , who were inadequately responsive to more than 2 weeks of lithium or valproate therapy , were r and omized to receive cotherapy  ( olanzapine + mood-stabilizer ) or monotherapy ( placebo + mood-stabilizer ) . RESULTS Olanzapine cotherapy improved patients ' YMRS total scores significantly more than monotherapy ( -13.11 vs -9.10 ; P = .003 ) . Clinical response rates ( > or = 50 % improvement on YMRS ) were significantly higher with cotherapy ( 67.7 % vs 44.7 % ; P < .001 ) . Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale ( HAMD-21 ) total scores significantly more than monotherapy ( 4.98 vs 0.89 points ; P < .001 ) . In patients with mixed-episodes with moderate to severe depressive symptoms ( DSM-IV mixed episode ; HAMD-21 score of > or = 20 at baseline ) , olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy ( P < .001 ) . Extrapyramidal symptoms ( Simpson-Angus Scale , Barnes Akathisia Scale , Abnormal Involuntary Movement Scale ) were not significantly changed from baseline to end point in either treatment group . Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence , dry mouth , weight gain , increased appetite , tremor , and slurred speech . CONCLUSION Compared with the use of valproate or lithium alone , the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes BACKGROUND Typical experimental categorizations of treatment responses in bipolar disorder ( BPD ) patients may have limited relationship to clinical recovery or functional status , and there is inadequate research on such clinical ly important outcomes . METHODS We analyzed data from a study of open continuation of olanzapine treatment following a 3-week placebo-controlled trial involving initially hospitalized adult subjects with DSM-IV BP-I mania to estimate rates and times to symptomatic remission ( low scores on st and ardized symptomatic assessment s ) and clinical recovery ( remission sustained > or=8 weeks ) , associated clinical factors , and functional outcomes . RESULTS During treatment with olanzapine for 27.9+/-20.1 weeks , symptomatic remission was attained by 70 % of subjects , half by 8 weeks ( 95 % CI 6 - 10 ) weeks , and later lost by 82 % of remitted subjects ; remitted ( versus non-remitted ) subjects had slightly lower baseline clinical global impression scores and greater trial-completion . Sustained clinical recovery was attained by only 40 of 113 ( 35 % ) of subjects , half by 36 ( 95 % CI 20 - 40 ) weeks , and later lost by 45 % . Subjects with above-median ( > 12 ) initial  Hamilton-Depression rating scale depression scores were half as likely to recover ( p=0.016 ) and did so much later ( 36 versus 12 weeks ) than those with lower scores . At final assessment , self-rated well being ( SF-36 psychosocial functioning scores ) improved substantially more among recovered versus non-recovered subjects ( mean changes : 87 % versus 23 % ) , and two-thirds of recovered subjects remained unemployed-for-pay while half received disability-compensation . CONCLUSIONS Clinical ly meaningful symptomatic remission and recovery in relatively severely ill adult bipolar I manic patients were achieved slowly and sustained by only some patients within an average of 7 months of continuous treatment . These clinical ly relevant outcomes were worse with relatively high initial dysphoria ratings . Well-being was rated higher by recovered subjects , but their ability to work and live independently were markedly impaired . These findings underscore the emerging view that BPD can often be severe , slow to remit , and disabling , particularly in association with prominent depression-dysphoria symptoms . Improved treatments for BPD are needed , guided by longitudinal assessment s of clinical ly meaningful measures of symptomatic recovery and functional outcome OBJECTIVE Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder . The authors report a 47-week comparison of olanzapine and divalproex . METHOD This 47-week , r and omized , double-blind study compared flexibly dosed olanzapine ( 5 - 20 mg/day ) to divalproex ( 500 - 2500 mg/day ) for manic or mixed episodes of bipolar disorder ( N=251 ) . The only other psychoactive medication allowed was lorazepam for agitation . The primary efficacy instrument was the Young Mania Rating Scale ; a priori protocol -defined threshold scores were > or = 20 for inclusion , < or = 12 for remission , and > or = 15 for relapse . Analytical techniques included mixed model repeated- measures analysis of variance for change from baseline , Fisher 's exact test ( two-tailed ) for categorical comparisons , and Kaplan-Meier estimates of time to events of interest . RESULTS Over 47 weeks , mean improvement in Young Mania Rating Scale score was significantly greater for the  olanzapine group .  Median time to symptomatic mania remission was significantly shorter for olanzapine , 14 days , than for divalproex , 62 days . There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks ( 56.8 % and 45.5 % , respectively ) and subsequent relapse into mania or depression ( 42.3 % and 56.5 % ) . Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence , dry mouth , increased appetite , weight gain , akathisia , and high alanine aminotransferase levels ; those for divalproex were nausea and nervousness . CONCLUSIONS In this 47-week study of acute bipolar mania , symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex , but rates of bipolar relapse did not differ OBJECTIVE The authors compared the efficacy of olanzapine and lithium in the prevention of  mood episode relapse/recurrence . METHOD Patients with a diagnosis of bipolar disorder ( manic/mixed ) , a history of two or more manic or mixed episodes within 6 years , and a Young Mania Rating Scale total score > or = 20 entered the study and received open-label co-treatment with olanzapine and lithium for 6 - 12 weeks . Those meeting symptomatic remission criteria ( Young Mania Rating Scale score < or = 12 ; 21-item Hamilton depression scale score < or = 8) were r and omly assigned to 52 weeks of double-blind monotherapy with olanzapine , 5 - 20 mg/day ( N=217 ) , or lithium ( target blood level : 0.6 - 1.2 meq/liter ) ( N=214 ) . RESULTS Symptomatic relapse/recurrence ( score > or = 15 on either the Young Mania Rating Scale or Hamilton depression scale ) occurred in 30.0 % of olanzapine-treated and 38.8 % of lithium-treated patients . The noninferiority of olanzapine relative to lithium ( primary objective ) in preventing relapse/recurrence was met , since the lower limit of the 95 % confidence interval on the 8.8 % risk difference ( -0.1 % to 17.8 % ) exceeded the predefined noninferiority margin ( -7.3 % ) . Secondary results showed that compared with lithium , olanzapine had significantly lower risks of manic episode and mixed episode relapse/recurrence . Depression relapse/recurrence occurred in 15.7 % of olanzapine-treated and 10.7 % of lithium-treated patients . Mean weight gain during open-label co-treatment was 2.7 kg ; during double-blind monotherapy , weight gain was significantly greater with olanzapine ( 1.8 kg ) than with lithium ( -1.4 kg ) . CONCLUSIONS These results suggest that olanzapine was significantly more effective than lithium in preventing manic and mixed episode relapse/recurrence in patients acutely stabilized with olanzapine and lithium co-treatment . Both agents were comparable in preventing depression relapse/recurrence BACKGROUND Bipolar depression is a major clinical problem that remains under- research ed . The current study was intended to evaluate the effects of the novel antipsychotic risperidone , the selective serotonin reup-take inhibitor ( SSRI ) paroxetine , and the combination in patients with bipolar disorder . METHOD Thirty patients with DSM-IV bipolar ( I or II ) disorder , depressed phase , who were receiving a stable dose of a mood stabilizer were r and omly assigned to 12 weeks of double-blind treatment with risperidone ( plus placebo ) , paroxetine ( plus placebo ) , or the combination of risperidone and paroxetine . Data were gathered from August 1999 to September 2001 . RESULTS All 3 groups experienced significant reductions in depression ratings from baseline to endpoint ; there were no significant differences in outcome between groups . There were statistically significant differences in paroxetine dose contrasting paroxetine plus placebo against the combined condition . The switch rate into mania or hypomania was very low , with only 1 patient in the paroxetine plus placebo condition experiencing mild hypomania . CONCLUSION These results suggest that risperidone , paroxetine , and the combination of risperidone and paroxetine are equally but modestly effective when added to a mood stabilizer in bipolar depression . The paroxetine dose differed between groups , possibly because of drug-drug interactions . Using another SSRI in the combined condition could have produced a more robust effect and should be tested BACKGROUND This study compared the efficacy , safety , and tolerability of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder . METHOD This r and omized , 12-week , double-blind , parallel-group , multicenter study included DSM-IV-defined bipolar disorder type I patients hospitalized for acute mania and r and omly assigned to treatment with divalproex or olanzapine .  After an inpatient period of up to 21 days , subjects were followed as out patients . Dose adjustment was permitted during the inpatient period . Efficacy was assessed using change from baseline in Mania Rating Scale ( MRS ) score to day 21 ; other efficacy measures included the Brief Psychiatric Rating Scale , the Hamilton Rating Scale for Depression , and the Clinical Global Impressions-Part I , Severity of Illness scale . The primary safety endpoint was change from baseline in weight . Other safety and tolerability endpoints included spontaneous adverse event reporting and changes from baseline in laboratory measures and vital signs . RESULTS 120 subjects ( N = 63 divalproex , N = 57 olanzapine ) were r and omly assigned to treatment . No significant differences between groups were found for any efficacy variable for change from baseline to day 21 . Mean MRS score changes from baseline to day 21 were -14.8 for divalproex and -17.2 for olanzapine ( p = .210 ) . A significantly ( p < .05 ) greater proportion of olanzapine-treated subjects experienced somnolence , weight gain , edema , rhinitis , and speech disorder ( slurred speech ) ; no adverse events were significantly greater in the divalproex group . A number of laboratory measures also demonstrated significant treatment differences , but the clinical significance of many of these is uncertain . Mean body weight changes were significantly greater in the olanzapine group ( + 8.8 lb [ + 4.0 kg ] ) than the divalproex group ( + 5.5 lb [ + 2.5 kg ] , p < .050 ) . One death occurred during the study ( olanzapine group , diabetic ketoacidosis ) . CONCLUSION No significant difference in efficacy was found between treatment groups . Divalproex was associated with a more favorable adverse event profile and significantly less weight gain than olanzapine Neuroleptics are of established efficacy in mania . Controlled data on the use of olanzapine in mania is however , absent . In this study , 30 patients meeting DSM-IV criteria for mania were r and omly allocated to receive either olanzapine or lithium in a 4 week double-blind r and omized controlled design . There were no significant outcome differences between the two groups on any of the primary outcome measures , the Brief Psychiatric Rating Scale  ( lithium 28.2 ; olanzapine 28.0 ; P = 0.44 ) ; Clinical Global Impression ( CGI ) improvement scale  ( lithium 2.75 , olanzapine 2.36 ; P = 0.163 ) or the Mania Scale  ( lithium 13.2 , olanzapine 10.2 ; P = 0.315 ) . Olanzapine was however , significantly superior to lithium on the CGI-severity scale at week 4 ( lithium 2.83 , olanzapine 2.29 ; P = 0.025 ) . Olanzapine did not differ from lithium in terms of treatment emergent extrapyramidal side-effects as measured by the Simpson-Angus Scale .  Olanzapine appears to be at least as effective as lithium in the treatment of mania OBJECTIVE Little is known about clinical features associated with the risk of recurrence in patients with bipolar disorder receiving treatment according to contemporary practice guidelines . The authors looked for the features associated with risk of recurrence . METHOD The authors examined prospect i ve data from a cohort of patients with bipolar disorder participating in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder ( STEP-BD ) study for up to 24 months . For those who were symptomatic at study entry but subsequently achieved recovery , time to recurrence of mania , hypomania , mixed state , or a depressive episode was examined with Cox regression . RESULTS Of 1,469 participants symptomatic at study entry , 858 ( 58.4 % ) subsequently achieved recovery . During up to 2 years of follow-up , 416 ( 48.5 % ) of these individuals experienced recurrences , with more than twice as many developing depressive episodes ( 298 , 34.7 % ) as those who developed manic , hypomanic , or mixed episodes ( 118 , 13.8 % ) . The time until 25 % of the individuals experienced a depressive episode was 21.4 weeks and until 25 % experienced a manic/hypomanic/mixed episode was 85.0 weeks . Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence . Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic , hypomanic , or mixed episode recurrence . CONCLUSIONS Recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery . Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce risk of recurrence OBJECTIVE The study evaluated the efficacy and tolerability of ziprasidone , compared with placebo , in the treatment of adult patients with acute bipolar mania . METHOD Patients with a primary DSM-IV diagnosis of bipolar I disorder and a current manic or mixed episode ( confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders , Patient Edition ) ( N=210 ) were r and omly assigned in a 2:1 ratio to 3 weeks of double-blind treatment with ziprasidone ( 40 - 80 mg twice daily ) or placebo . Efficacy was assessed with the Schedule for Affective Disorders and Schizophrenia , Change Version ( which contains the Mania Rating Scale ) , Positive and Negative Syndrome Scale , Clinical Global Impression ( CGI ) severity scale , CGI improvement scale , and Global Assessment of Functioning Scale . Primary efficacy variables were differences from baseline to endpoint ( last observation carried forward ) in mean Mania Rating Scale and CGI severity scale scores between the ziprasidone and placebo groups . Safety evaluations included monitoring of adverse events , vital signs , electrocardiogram results , and clinical laboratory values and assessment of movement disorders and akathisia . RESULTS Ziprasidone produced rapid , sustained improvements relative to baseline and placebo on all primary and most secondary efficacy measures at endpoint . Significant improvements were typically observed within 2 days after treatment commenced and were maintained throughout the 3 weeks . Ziprasidone was well tolerated and associated with a low rate of extrapyramidal symptoms ; neither weight gain nor clinical ly significant changes in vital signs or other safety parameters were observed with ziprasidone . CONCLUSIONS Ziprasidone monotherapy was significantly superior to placebo in reducing symptoms of acute mania in patients with bipolar I disorder . Onset of action was rapid , and tolerability of ziprasidone was generally comparable to that of placebo BACKGROUND Severe mania is life-threatening , carries an increased risk of suicide and has a serious impact on patients and their families . Efficient and rapid control of episodes of acute mania is needed . AIMS To evaluate the safety and efficacy of risperidone monotherapy for acute mania . METHOD In a 3-week , r and omised , double-blind trial , 290 in- patients with bipolar I disorder with current manic or mixed episode and a baseline Young Mania Rating Scale ( YMRS ) score of 20 or more received flexible doses of risperidone ( 1 - 6 mg per day ) or placebo . RESULTS Risperidone was received by 146 patients and placebo by144 . Their mean baseline YMRS score was 37.2 ( s.e.=0.5 ) . Significantly greater improvements were observed with risperidone than with placebo at weeks 1 and 2 and at end-point ( total YMRS : P < 0.01 ) . Extrapyramidal symptoms were the most frequently reported adverse events in the risperidone group . CONCLUSIONS In patients with severe manic symptoms , risperidone produced significant improvements in YMRS scores as early as week 1 and substantial changes at end-point . Treatment was well tolerated This study compares the efficacy , safety , and tolerability of a partial dopamine agonist , aripiprazole , with placebo in the treatment of patients with bipolar I disorder experiencing an acute manic or mixed episode . In total , 272 hospitalized patients were r and omized to aripiprazole 30mg/day or placebo in this 3-week , double-blind , placebo-controlled trial . Dosing could be reduced to 15mg/day for tolerability and , subsequently , increased to 30mg/day based on clinical response . Primary efficacy measure was mean change from baseline to endpoint in Young Mania Rating Scale ( YMRS ) total score ; response was defined as 50 % decrease from baseline YMRS score . Aripiprazole-treated patients demonstrated significantly greater improvement from baseline to endpoint in mean YMRS total scores compared with placebo-treated patients as early as Day 4 and sustained through Week 3 . A significantly higher response rate was observed in aripiprazole-treated patients ( 53 % vs. 32 % at endpoint ) . Aripiprazole produced significantly greater improvements from baseline on other efficacy assessment s compared with placebo , including Clinical Global Impression – Bipolar Version Severity and Improvement scores . The 30mg/day dose was maintained by 85 % of aripiprazole-treated patients . Incidence of discontinuations due to adverse events was similar for aripiprazole ( 8.8 % ) and placebo ( 7.5 % ) . Aripiprazole treatment result ed in no significant difference from placebo in change in mean body weight and was not associated with elevated serum prolactin or QTc prolongation . In conclusion , aripiprazole demonstrated superior efficacy to placebo in the treatment of patients with bipolar I disorder presenting with acute manic or mixed episodes , and exhibited a favourable safety and tolerability profile In a r and omized , double-blind trial , patients with acute bipolar mania received 1 - 6 mg/day of risperidone , 2 - 12 mg/day of haloperidol , or placebo for 3 weeks , followed by double-blind risperidone or haloperidol for 9 weeks . Of 438 patients , 154 were r and omized to risperidone , 144 to haloperidol , and 140 to placebo .  The mean+/-S.D. modal doses were 4.2+/-1.7 mg/day of risperidone and 8.0+/-3.6 mg/day of haloperidol during the initial 3-week phase and 4.1+/-1.8 and 7.4+/-3.7 mg/day during the 12-week period . At week 3 , mean Young Mania Rating Scale ( YMRS ) score reductions from baseline were significantly greater in patients receiving risperidone than placebo ( p<0.001 ) . Differences between risperidone and haloperidol on this efficacy measure were not significant . Further reductions in YMRS scores were seen in patients receiving risperidone or haloperidol during the subsequent 9 weeks . No unexpected adverse events were reported . Extrapyramidal disorder and hyperkinesias , the most commonly reported adverse events with antipsychotic use , occurred less frequently with risperidone than haloperidol . We conclude that risperidone monotherapy was an effective and well-tolerated treatment for bipolar mania and that efficacy was maintained over the long term This study evaluated the efficacy and tolerability of quetiapine monotherapy for depressive episodes in patients with bipolar I or II disorder ( Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition ) who were r and omized to 8 weeks of double-blind treatment with quetiapine ( 300 or 600 mg/d ; once daily , evening dosing ) or placebo .  Patients were assessed weekly using the Montgomery-Åsberg Depression Rating Scale ( MADRS ) and Hamilton Depression Rating Scale ( HAM-D ) . The primary end point was change in MADRS total score from baseline to Week 8 ( analysis of covariance/last-observation-carried-forward analysis ) . Of 509 patients r and omized , 59 % completed the study . Improvements from baseline in mean MADRS total scores were significantly greater with quetiapine 300 and 600 mg/d than with placebo from first evaluation ( Week 1 ) through Week 8 ( both P ≤ 0.001 vs. placebo ) . Therapeutic effect sizes at Week 8 were 0.61 and 0.54 for quetiapine 300 and 600 mg/d , respectively . Improvements in mean HAM-D scores were also significantly greater with both quetiapine doses than with placebo ( P < 0.001 ) as early as Week 1 and throughout the study . The MADRS response and remission rates were also significantly greater in both quetiapine dose groups compared with placebo . Improvements in primary and secondary outcomes were observed with both 300 and 600 mg/d quetiapine without major differences between the doses . Common adverse events included dry mouth , sedation , somnolence , dizziness , and constipation . The incidence of treatment-emergent mania or hypomania was lower with quetiapine treatment than placebo . This study demonstrates that quetiapine monotherapy is an effective and well-tolerated treatment for depressive episodes in bipolar disorder , confirming the results observed from a previous study ( BipOLar DEpRession [ BOLDER ] I ) METHODS Patients ( n=302 ) with bipolar I disorder ( manic episode ) were r and omised to 12 weeks ' double-blind treatment with quetiapine ( flexibly dosed up to 800 mg/day ) , placebo , or haloperidol ( up to 8 mg/day ) . The primary efficacy outcome variable was change from baseline to Day 21 in Young Mania Rating Scale ( YMRS ) score . RESULTS YMRS score improved with quetiapine at Day 21 ( -12.29 versus -8.32 for placebo ; P<0.01 ) . The difference in favor of quetiapine increased by Day 84 ( -17.52 versus -9.48 ; P<0.001 ) . Haloperidol also showed an advantage over placebo at Days 21 and 84 ( P<0.001 ) . There was no significant difference in efficacy measures between quetiapine and haloperidol groups at any assessment except Day 21 . The only common adverse event with quetiapine was somnolence ( 12.7 % ) . Extrapyramidal symptoms ( EPS ) , including akathisia , occurred at 59.6 % with haloperidol , 12.7 % with quetiapine , 15.8 % with placebo . Most quetiapine responders ( 84 % ) received a dose of 400 - 800 mg/day . CONCLUSIONS Quetiapine was effective and well tolerated . The efficacy and tolerability profile of haloperidol ( including its propensity for EPS ) supported study validity Background : In an earlier 21-day , placebo-controlled trial , ziprasidone was efficacious in improving symptoms of mania and was well tolerated . To confirm these results , a similarly design ed 21-day trial was conducted . Methods : In patients with bipolar I disorder , manic or mixed , were r and omized to ziprasidone ( 40 to 80 mg BID ) or placebo . Efficacy rating scales were derived from the Schedule for Affective Disorders and Schizophrenia-Change Bipolar Scale ( SADS-CB ) . SADS-CB-derived Mania Rating Scale ( MRS ) total score was the primary efficacy parameter . Secondary SADS-CB-derived efficacy parameters included Manic Syndrome and Behavior and Ideation Subscales , Hamilton Depression Rating Scale ( HAM-D ) , and the Montgomery Asberg Depression Rating Scale ( MADRS ) . The Clinical Global Impression-Severity Scale ( CGI-S ) , the Global Assessment of Functioning ( GAF ) , and the Positive and Negative Syndrome Scale ( PANSS ) were also assessed . Results : Sixty-five placebo and 137 ziprasidone patients were evaluable for efficacy . Baseline-to-endpoint mean changes in MRS scores were −11.1 for ziprasidone and −5.6 for placebo ( all patients , last observation carried forward [ LOCF ] ; P < 0.01 ) . Ziprasidone produced significantly greater improvements in Manic Syndrome ( P ≤ 0.01 ) and Behavior and Ideation Subscales ( P ≤ 0.001 ) , CGI-S score , ( P ≤ 0.001 ) , PANSS Total ( P ≤ 0.01 ) and Positive Subscale ( P ≤ 0.001 ) scores , and GAF ( P ≤ 0.001 ) . With ziprasidone , significant improvements were observed from Day 2 onward for MRS and CGI-S at all time points except Day 4 for MRS . Treatment-related discontinuations due to adverse events were 5.8 % for ziprasidone and 1.5 % for placebo ( P = 0.20 ) . Conclusions : Ziprasidone was well tolerated , rapidly efficacious , and superior to placebo in improving symptoms and global illness severity in these in patients with acute bipolar mania , both manic and mixed episodes OBJECTIVE There is a major unmet need for effective options in the treatment of bipolar depression . METHOD Five hundred forty-two out patients with bipolar I ( N=360 ) or II ( N=182 ) disorder experiencing a major depressive episode ( DSM-IV ) were r and omly assigned to 8 weeks of quetiapine ( 600 or 300 mg/day ) or placebo . The primary efficacy measure was mean change from baseline to week 8 in the Montgomery-Asberg Depression Rating Scale total score . Additional efficacy assessment s included the Hamilton Depression Rating Scale , Clinical Global Impression of severity and improvement , Hamilton Anxiety Rating Scale , Pittsburgh Sleep Quality Index , and Quality of Life Enjoyment and Satisfaction Question naire . RESULTS Quetiapine at either dose demonstrated statistically significant improvement in Montgomery-Asberg Depression Rating Scale total scores compared with placebo from week 1 onward . The proportions of patients meeting response criteria ( > or = 50 % Montgomery-Asberg Depression Rating Scale score improvement ) at the final assessment in the groups taking 600 and 300 mg/day of quetiapine were 58.2 % and 57.6 % , respectively , versus 36.1 % for placebo . The proportions of patients meeting remission criteria ( Montgomery-Asberg Depression Rating Scale < or = 12 ) were 52.9 % in the groups taking 600 and 300 mg/day of quetiapine versus 28.4 % for placebo . Quetiapine at 600 and 300 mg/day significantly improved 9 of 10 and 8 of 10 Montgomery-Asberg Depression Rating Scale items , respectively , compared to placebo , including the core symptoms of depression . Treatment-emergent mania rates were low and similar for the quetiapine and placebo groups ( 3.2 % and 3.9 % , respectively ) . CONCLUSIONS Quetiapine monotherapy is efficacious and well tolerated for the treatment of bipolar depression OBJECTIVE The primary intent of this study was to compare the efficacy and safety of olanzapine and placebo in the treatment of acute mania . METHOD The design involved a r and om-assignment , double-blind , placebo-controlled parallel group study of 3 weeks ' duration . After a 2- to 4-day screening period , qualified patients were assigned to either olanzapine ( N = 70 ) or placebo ( N = 69 ) . Patients began double-blind therapy with either olanzapine , 10 mg , or placebo given once per day . After the first day of treatment , the daily dose could be adjusted upward or downward , as clinical ly indicated , by one capsule ( olanzapine , 5 mg/day ) within the allowed range of one to four capsules . The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale . Clinical response was defined a priori as a decrease of 50 % or more from baseline in Young Mania Rating Scale total score . RESULTS The olanzapine group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the placebo group . On the basis of the clinical response criteria , significantly more olanzapine-treated patients ( 48.6 % ) responded than those assigned to placebo ( 24.2 % ) . Somnolence , dizziness , dry mouth , and weight gain occurred significantly more often with olanzapine . There were no statistically significant differences between the olanzapine-treated and placebo-treated patients with respect to measures of parkinsonism , akathisia , and dyskinesias . No discontinuations of treatment due to adverse events occurred in the olanzapine treatment group . CONCLUSIONS The results from this study suggest that compared with placebo , olanzapine has superior efficacy for the symptoms of acute mania OBJECTIVE In a placebo-controlled , double-blind study , the authors investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolar I disorder . METHOD Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder ( Young Mania Rating Scale [ YMRS ] total score < or = 12 and 21-item Hamilton Depression Rating Scale [ HAM-D ] score < or = 8) at two consecutive weekly visits following 6 - 12 weeks of open-label acute treatment with 5 - 20 mg/day of olanzapine were r and omly assigned to double-blind maintenance treatment with olanzapine ( N=225 ) or placebo ( N=136 ) for up to 48 weeks . The primary measure of efficacy was time to symptomatic relapse into any mood episode ( YMRS score > or = 15 , HAM-D score > or = 15 , or hospitalization ) . RESULTS Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine ( a median of 174 days , compared with a median of 22 days in patients receiving placebo ) . Times to symptomatic relapse into manic , depressive , and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo . The relapse rate was significantly lower in the olanzapine group ( 46.7 % ) than in the placebo group ( 80.1 % ) . During olanzapine treatment , the most common emergent event was weight gain ; during the open-label phase , patients who received olanzapine gained a mean of 3.1 kg ( SD=3.4 ) . In double-blind treatment , placebo patients lost a mean of 2.0 kg ( SD=4.4 ) and patients who continued to take olanzapine gained an additional 1.0 kg ( SD=5.2 ) . CONCLUSIONS Compared to placebo , olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode OBJECTIVE The effects of olanzapine and divalproex for the treatment of mania were compared in a large r and omized clinical trial . METHOD A 3-week , r and omized , double-blind trial compared flexibly dosed olanzapine ( 5 - 20 mg/day ) to divalproex ( 500 - 2500 mg/day in divided doses ) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes . The Young Mania Rating Scale and the Hamilton Depression Rating Scale were used to quantify manic and depressive symptoms , respectively . Safety was assessed with several measures . RESULTS The protocol defined baseline-to-endpoint improvement in the mean total score on the Young Mania Rating Scale as the primary outcome variable . The mean Young Mania Rating Scale score decreased by 13.4 for patients treated with olanzapine ( N=125 ) and 10.4 for those treated with divalproex ( N=123 ) . A priori categorizations defined response and remission rates : 54.4 % of olanzapine-treated patients responded ( > or = 50 % reduction in Young Mania Rating Scale score ) , compared to 42.3 % of divalproex-treated patients ; 47.2 % of olanzapine-treated patients had remission of mania symptoms ( endpoint Young Mania Rating Scale < or = 12 ) , compared to 34.1 % of divalproex-treated patients . The decrease in Hamilton depression scale score was similar in the two treatment groups . Completion rates for the 3-week study were similar in both groups . The most common treatment-emergent adverse events ( incidence > 10 % ) occurring more frequently during treatment with olanzapine were dry mouth , increased appetite , and somnolence . For divalproex , nausea was more frequently observed . The average weight gain with olanzapine treatment was 2.5 kg , compared to 0.9 kg with divalproex treatment . CONCLUSIONS The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol -defined remission , compared with the divalproex treatment group . Significantly more weight gain and cases of dry mouth , increased appetite , and somnolence were reported with olanzapine , while more cases of nausea were reported with divalproex Case reports and studies of other neuroleptics suggest the efficacy of risperidone in the treatment of mania . Forty-five in patients with DSM-IV mania were studied in a 28-day r and omized , controlled , double-blind trial of either 6 mg daily of risperidone , 10 mg daily of haloperidol , or 800 to 1200 mg daily of lithium . The patients in all three groups showed a similar improvement on the total score for all rating scales at day 28 ( Brief Psychiatric rating scale :  lithium 9.1 , haloperidol 4.9 , risperidone 6.5 , F = 1.01 , df = 2 , p = 0.37 ; Mania rating scale :  lithium 15.7 , haloperidol 10.2 , risperidone 12.4 , F = 1.07 , df = 2 , p = = 0.35 [ analysis of variance ] ) . The Global Assessment of Functioning and Clinical Global Impression data showed a similar pattern of improvement . This study suggests that risperidone is of equivalent efficacy to lithium and haloperidol in the management of acute mania . The extrapyramidal side effects of risperidone and haloperidol were not significantly different OBJECTIVE The study assessed the efficacy and safety of risperidone as an adjunctive agent to mood stabilizers in the treatment of acute mania .  METHOD This 3-week r and omized , double-blind , placebo-controlled study included 156 bipolar disorder patients with a current manic or mixed episode who received a mood stabilizer ( lithium or divalproex ) and placebo , risperidone , or haloperidol .  The primary efficacy measure was the Young Mania Rating Scale . Other assessment s used the Brief Psychiatric Rating Scale , the Clinical Global Impression scale , and safety measures . RESULTS The trial was discontinued by 25 ( 49 % ) of the 51 placebo group patients , 18 ( 35 % ) of the 52 risperidone group patients , and 28 ( 53 % ) of the 53 haloperidol group patients . Mean modal doses were 3.8 mg/day ( SD=1.8 ) of risperidone and 6.2 mg/day ( SD=2.9 ) of haloperidol . Significantly greater reductions in Young Mania Rating Scale scores at endpoint and over time were seen in the risperidone group and in the haloperidol group , compared with the placebo group . Young Mania Rating Scale total scores improved with risperidone and with haloperidol both in patients with psychotic features and in those without psychotic features at baseline . Extrapyramidal Symptom Rating Scale total scores at endpoint were significantly higher in the haloperidol patients than in the placebo patients . Antiparkinsonian medications were received by 8 % , 17 % , and 38 % of patients in the placebo , risperidone , and haloperidol groups , respectively . CONCLUSIONS Risperidone plus a mood stabilizer was more efficacious than a mood stabilizer alone , and as efficacious as haloperidol plus a mood stabilizer , for the rapid control of manic symptoms and was well tolerated BACKGROUND Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers , relatively few controlled studies have examined treatment strategies for bipolar depression . OBJECTIVE To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression . DESIGN Double-blind , 8-week , r and omized controlled trial . SETTING Eighty-four sites ( inpatient and outpatient ) in 13 countries . Patients A total of 833 r and omized adults with bipolar I depression with a Montgomery-Asberg Depression Rating Scale ( MADRS ) score of at least 20 . Intervention Patients were r and omly assigned to receive placebo ( n = 377 ) ; olanzapine , 5 to 20 mg/d ( n = 370 ) ; or olanzapine-fluoxetine combination , 6 and 25 , 6 and 50 , or 12 and 50 mg/d ( n = 86 ) . MAIN OUTCOME MEASURE Changes in MADRS total scores using mixed-effects model repeated- measures analyses . RESULTS During all 8 study weeks , the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group ( P<.001 for all ) . The olanzapine-fluoxetine group also showed statistically greater improvement than the olanzapine group at weeks 4 through 8 . At week 8 , MADRS total scores were lower than at baseline by 11.9 , 15.0 , and 18.5 points in the placebo , olanzapine , and olanzapine-fluoxetine groups , respectively . Remission criteria were met by 24.5 % ( 87/355 ) of the placebo group , 32.8 % ( 115/351 ) of the olanzapine group , and 48.8 % ( 40/82 ) of the olanzapine-fluoxetine group . Treatment-emergent mania ( Young Mania Rating Scale score < 15 at baseline and > or = 15 subsequently ) did not differ among groups ( placebo , 6.7 % [ 23/345 ] ; olanzapine , 5.7 % [ 19/335 ] ; and olanzapine-fluoxetine , 6.4 % [ 5/78 ] ) . Adverse events for olanzapine-fluoxetine therapy were similar to those for olanzapine therapy but also included higher rates of nausea and diarrhea . CONCLUSIONS Olanzapine is more effective than placebo , and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of  bipolar I depression without increased risk of developing manic symptoms
target: In maintenance trials atypical antipsychotics had significantly fewer relapses to depression or mania than placebo or active comparator .
  Conclusion Atypical antipsychotics are effective in treating both phases of bipolar disorder compared with placebo , and as effective as established drug therapies .
  Atypical antipsychotics produce fewer extrapyramidal symptoms , but weight gain is more common ( with olanzapine ) .
  There is insufficient data confidently to distinguish between different atypical antipsychotics
background: Background Atypical antipsychotics are increasingly used for treatment of mental illnesses like schizophrenia and bipolar disorder , and considered to have fewer extrapyramidal effects than older antipsychotics .