Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study. The nature of placebo response in clinical studies of major depressive disorder. Pretreatment neurophysiological and clinical characteristics of placebo responders in treatment trials for major depression Placebo response and antidepressant response. Worsening of depressive symptoms prior to randomization in clinical trials: a possible screen for placebo responders? A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. The use of lithium in affective disorders. 3. A double-blind study of prophylaxis in bipolar illness. A sham-controlled randomized trial of adjunctive light therapy for non-seasonal depression. Topiramate as an adjuvant treatment for obsessive compulsive symptoms in patients with bipolar disorder: a randomized double blind placebo controlled clinical trial. Factors contributing to the increasing placebo response in antidepressant trials. Exploratory analyses of efficacy data from major depressive disorder trials submitted to the US Food and Drug Administration in support of new drug applications. Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international, double-blind, randomised, placebo-controlled studies A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Adjunctive topiramate therapy in patients receiving a mood stabilizer for bipolar I disorder: a randomized, placebo-controlled trial. Methodologic issues in maintenance therapy clinical trials. A double-blind, randomized, placebo-controlled 4-week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania. Assuring that double-blind is blind.
Maintenance studies in bipolar disorder have received increased attention in recent years . The interest is driven by apparent contradictions between results of early placebo-controlled trials of lithium and recent open studies , as well as interest in a new group of drugs with mood-stabilizing properties . The multiple outcome indices that require attention in prophylactic bipolar disorder studies add a dimension not present in acute studies of bipolar disorder . We present the methodology of a recently completed r and omized , double-blind , placebo-controlled , parallel-group comparison of divalproex and lithium . We examine the consequences of salient design features , along with their implication s for future studies . A fundamental conclusion is that such maintenance studies should be design ed and executed to emphasize enrollment of patients with relatively active , severe forms of the illness . This goal is not achieved simply , as inherent features of long-term , placebo-controlled studies drive recruitment and enrollment in the direction of patients with milder forms of bipolar disorder . Attention to the frequency of both manic and depressive episodes and the severity of an index manic episode may aid in the selection of patients most suitable for studies design ed to achieve adequate statistical power OBJECTIVE To review factors influencing placebo response and clinical trial outcome in depression , and suggest ways to optimize trial success in mood disorders . DATA SOURCES PubMed search es were conducted by cross-referencing the terms depression , depressive with placebo , clinical trial , and clinical trials for studies published in English between 1970 and September 2013 . STUDY SELECTION Relevant abstract s were identified in PubMed , including clinical trials , quantitative studies , and qualitative research . We obtained and review ed relevant articles and utilized their information to synthesize the present review . DATA EXTRACTION Included articles were grouped in the following areas of relevance : ( 1 ) biological validity of illness , ( 2 ) baseline severity of illness , ( 3 ) chronicity of the index episode of depression , ( 4 ) age of participants , ( 5 ) medical and psychiatric comorbidity , ( 6 ) probability of receiving placebo , ( 7 ) use of prospect i ve treatment phases ( lead-in ) ( 8) dosing schedule , ( 9 ) trial duration , ( 10 ) frequency of follow-up assessment s , and ( 11 ) study outcome measure . RESULTS Several key elements emerge as critical to the ultimate success of a clinical trial , including the probability of receiving placebo , study duration , dosing schedule , visit frequency , the use of blinded lead-in phases , the use of central ized raters , illness severity and duration , and comorbid anxiety . CONCLUSIONS Our increasing underst and ing of the placebo response in clinical trials of major depressive disorder lends to a , gradually , more predictable phenomenon and , hopefully , to one that becomes lesser in magnitude and variability . Several elements have emerged that seem to play a critical role in trial success , gradually reshaping the design of clinical , translational , as well as mechanistic studies in depression Rationale High placebo response rates are a confound in treatment trials for major depressive disorder ( MDD ) . A method for prospect i ve identification of placebo responders could enhance the efficiency of clinical trials . Objective The objective was to identify the neurophysiological , symptomatic , and cognitive characteristics of subjects who were likely to respond to placebo in clinical trials for MDD . Methods Fifty-one subjects with MDD were treated in clinical trials with either fluoxetine ( n=24 ) or venlafaxine ( n=27 ) versus placebo . All subjects underwent pretreatment assessment with  quantitative electroencephalographic  ( QEEG ) power and cordance , as well as symptom ratings and  neuropsychological testing . After a 1-week single-blind placebo lead-in , subjects were r and omized to double-blind placebo controlled treatment with a medication or placebo . At the end of 8 weeks , the blind was broken and treatment response assessed . Response was defined by a final Hamilton Depression Rating Scale score of ≤10 . Results Of the medication-treated and placebo-treated subjects , 52 % ( 13/25 ) and 38 % ( 10/26 ) responded . Placebo responders had lower pretreatment fronto central cordance in the theta frequency b and than all other subjects ( P<0.006 ) and medication responders in particular ( P<0.004 ) . Placebo responders also had faster cognitive processing time , as assessed by neuropsychological testing , and lower reporting of late insomnia ( P<0.03 ) . Exploratory examination of a multiple variable model for predicting placebo response was conducted using logistic regression , in which these three pretreatment measures accurately identified 97.6 % of eventual placebo responders . Conclusions These findings suggest that combined clinical , neurophysiological , and cognitive assessment s of prospect i ve subjects for clinical trials may be useful for identifying MDD subjects who are likely to show robust response  to  placebo . Prospect i ve validation of these results in a larger , independent sample of subjects is necessary to establish the reliability and usefulness of this method for prospect i ve identification of placebo responders OBJECTIVE Much of the response to an antidepressant is the result of placebo response . The placebo response embedded in drug response confounds studies seeking to identify brain mechanisms essential for pharmacologic response . Exclusion of patients who fail to meet entry criteria at the end of a placebo lead-in phase has been inadequate to reduce the effect of placebo during pharmacologic trials . This study focused on the placebo lead-in phase and examines whether change in severity of depression during placebo lead-in predicts change in depressive symptoms during antidepressant treatment . METHOD The subjects were patients aged 60 - 85 years with nonpsychotic unipolar major depression not attributed to dementing disorders , medical illnesses , or drugs causing depression and had a 24-item Hamilton Depression Rating Scale score of 18 or greater . After a two-week placebo lead-in , subjects with Hamilton Depression Rating Scale score of 18 or greater received 10 mg escitalopram for 12 weeks . RESULTS Worsening or limited change in depression during placebo treatment predicted improvement in depressive symptoms during escitalopram treatment . Limited change in anxiety , melancholia , helplessness , and paranoia during placebo treatment were the strongest predictors of improvement in depression while on escitalopram . CONCLUSIONS These findings , if replicated , may be used to characterize depressed older patients likely to respond to the pharmacologic action of antidepressants rather than the placebo response embedded in drug trials and thus improve the methodology of biomarker studies of antidepressant response . On a clinical level , depressed older patients who improve during a prolonged evaluation may be c and i date s for nonpharmacologic treatments because their drug response may be limited A common practice in depression trials is to exclude patients whose depressive symptoms improve between Screen and Baseline evaluations under the assumption that they are more likely to respond to placebo . The present study investigated this contention by examining the relationship between pre-r and omization changes in Hamilton depression rating scale ( HAMD ) scores to post-r and omization placebo response and drug-placebo separation . Four r and omized , double-blind , placebo-controlled trials ( active medication = fluoxetine or paroxetine ) were conducted in out patients with Major Depressive Disorder using a novel design in which a depressive severity inclusion criterion ( HAMD > /= 22 ) was utilized only at Screen . Patients with no change or minimal ( 1 point ) improvement on the HAMD  between Screen and Baseline had the lowest placebo response and the best drug-placebo separation . Patients with pre-r and  omization improvement of 2 points or greater had moderately higher placebo response and poorer drug-placebo separation . Patients who worsened between Screen and Baseline showed the highest placebo response and the poorest drug-placebo separation . There were no obvious differences in demographic variables between the groups which could account for the findings . In our original analyses 3/4 studies failed to show significant drug-placebo separation . When only patients with no change or pre-r and  omization improvement  of 1 point were used in the analyses , 3/4 studies showed significant drug-placebo separation while the other study approached significance , p < 0.07 . These results suggest that pre-r and omization changes in HAMD scores may predict post-r and omization placebo response and drug-placebo separation . Further , pre-r and omization increases in HAMD scores ( i.e. , worsening ) may be the best predictor of heightened placebo responding and poor drug placebo separation BACKGROUND Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials . This double-blind , placebo-controlled study was conducted to assess the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder . METHODS After an 8- to 16-week open-label phase during which treatment with lamotrigine was initiated and other psychotropic drug regimens were discontinued , patients were r and omized to lamotrigine ( 100 - 400 mg daily ) , lithium ( 0.8 - 1.1 mEq/L ) , or placebo as double-blind maintenance treatment for as long as 18 months . RESULTS Of 349 patients who met screening criteria and entered the open-label phase , 175 met stabilization criteria and were r and omized to double-blind maintenance treatment  ( lamotrigine , 59 patients ; lithium , 46 patients ; and placebo , 70 patients ) . Both lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode  ( lamotrigine vs placebo , P = .02 ; lithium vs placebo , P = .006 ) . Lamotrigine was superior to placebo at prolonging the time to a depressive episode ( P = .02 ) . Lithium was superior to placebo at prolonging the time to a manic , hypomanic , or mixed episode ( P = .006 ) . The most common adverse event reported for lamotrigine was headache . CONCLUSIONS Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode . The results indicate that lamotrigine is an effective , well-tolerated maintenance treatment for bipolar disorder , particularly for prophylaxis of depression The authors studied 52 manic-depressive patients who were assigned to either lithium or placebo during their normal interval phases for periods up to 28 months . Patients receiving lithium had fewer manic and depressive episodes per patient-year than placebo patients . However , this difference may have been due to a sample bias produced by a large dropout rate among patients who had manic episodes . The findings also suggest a relationship between response to lithium and family history of bipolar illness BACKGROUND The aim of the study was to examine the efficacy and safety of morning bright light therapy ( BLT ) in the treatment of patients with a current major depressive episode ( MDE ) in bipolar and unipolar disorder without a seasonal pattern . It was a r and omized , sham-controlled trial . METHODS Adults , ages 18 - 70 years were r and omized to treatment either with BLT or a sham negative ion generator ( as a placebo control ) . The subjects were required to be on a stable and therapeutic dose of psychotropic medication for at least 4 weeks prior to enrollment and their treatment had to be insufficiently effective . Their clinical state was monitored at the baseline and at the end of treatment . The Hamilton Depression Rating Scale-21 items ( HDRS-21 ) , Montgomery-Asberg Depression Rating Scale ( MADRS ) , Beck Depression Inventory ( BDI-II ) , Clinical Global Impression-Severity ( CGI-S ) and Patient Global Impression ( PGI ) were used . The results were analyzed with an intention-to-treat ( ITT ) analysis . RESULTS Ninety-five patients were enrolled ( 50 diagnosed with bipolar disorder and 45 with unipolar depression ) . Fifty-two patients were r and omized to treatment with BLT and forty-three were in the placebo group ( ITT population ) . Eighty-three subjects completed the study . There were 12 dropouts ( 5 in the light group and 7 in the placebo group ) . After 14 days of treatment , a significant improvement was found in all groups ( p<0.001 ) . The subjects treated with BLT did not significantly differ in terms of improvement in HDRS-21 scores at the endpoint when compared to patients treated with placebo ( p=0.2 ) . However , further analysis demonstrated significantly higher response ( 50 % v. 27.9 % , p=0.02 ) and remission rates ( 28.8 % v. 11.6 % , p=0.04 ) among patients treated with morning BLT when compared to placebo group . It should be noted that in the population of drug-resistant patients , BLT was more efficacious than placebo . There were no statistically significant differences between unipolar and bipolar disorders ( p=0.4 ) . CONCLUSION Although overall improvement in HDRS-21 scores were not superior in the BLT group , both response and remission rates were significantly higher among patients treated with BLT relative to those receiving the sham intervention . BLT was also more efficacious than placebo in the population of patients with drug-resistant depression . Further studies to define the sub population of patients with non-seasonal depression who may benefit the most from BLT are needed BACKGROUND It has not been examined trialed whether obsessive compulsive symptoms in patients with bipolar disorder respond to topiramate as an adjuvant treatment . METHODS This 4-month double-blind placebo-controlled r and omized clinical trial examined the efficacy and safety of augmentation with topiramat for treating the patients with bipolar disorder , manic phase type-I , and obsessive compulsive disorder symptoms . Both groups received lithium+olanzapine+clonazepam . However , one group received topiramate and the other group placebo as adjuvant medications . Yale Brown obsessive compulsive behavior scale was used to assess the outcome . Adverse effects were also recorded . RESULTS A total of 32 patients completed this trial . The mean score decreased from 24.2(4.8 ) to 17.6(8.7 ) in the topiramate group ( P<0.003 ) and from 20.9(2.9 ) to 9.6(3.5 ) in the placebo group during this trial ( P<0.0001 ) . Additionally , 9(52.9 % ) out of 17 patients in the topiramate group and 2(12.5 % ) out of 16 patients in the placebo group showed more than 34 % decline in YBOC score ( x2=6.0 , df=1 , P<0.01 ) . No serious adverse effects were detected . LIMITATIONS The limitations of the present study were its small sample size and the fact that it was conducted in a single center . CONCLUSIONS The combination of lithium+olanzapine+clonazepam decreased the symptoms of obsessive compulsive disorder in the patients with bipolar disorder type I. However , topiramate had a more significant effect than placebo on improvement of the patients with bipolar disorder and obsessive compulsive symptoms . This combination seems to be without serious adverse effects In their interesting paper , Khan and Brown ( 1 ) sought to summarize the factors contributing to the trend of continuously decreasing drug-placebo differences in antidepressant r and omized controlled trials ( RCTs ) ( 2 ) . This trend conveys the impression that the newer marketed antidepressants are less efficacious than the older ones , or even that the older and well-established antidepressants have lost efficacy over time . Thus , recognizing the method ological reasons for the decline in antidepressant-placebo separation within RCTs is highly relevant in order to appraise the clinical value of an antidepressant for psychiatric routine care . This is especially meaningful with regard to newly developed and newly introduced antidepressants . In our opinion , the constant increase in placebo response over the last decades is the main factor accounting for the mitigation of the drug-placebo differences in antidepressant RCTs . Due to the larger symptom improvement of study participants r and omized to placebo , it is much more difficult for an antidepressant to outperform placebo at a statistically significant level . This could be the beginning of an ominous cascade . The diminishing drug-placebo contrast leads to a higher probability of so-called inconclusive or even negative trials . As a consequence , the risk for a newly developed compound to fail the market approval because of negative phase III studies increases . As such late failure is associated with enormous costs for the pharmaceutical industry , this could result in a slowdown of research efforts for new antidepressant agents . An often cited reason for the continuously increasing placebo response is the fact that placebo administration represents in itself a non-specific treatment ( 3 ) . Study participants in the placebo groups of RCTs receive enormous clinical attention . Indeed , parallel to the raising placebo response in RCTs , the requirements concerning the accomplishment of RCTs have become more stringent , for instance through the need of an increasingly closer monitoring of participants ( 4 ) . The intensive contact with the clinical staff can produce positive effects in terms of symptom improvement , particularly in not severely ill participants , who are nowadays increasingly included in RCTs , because the enrollment of more severely ill patients is often not possible due to ethical concerns ( a phenomenon called “ baseline inflation ” ) . Another element contributing to the magnitude of placebo response in RCTs is the hope of participants in the placebo groups to receive an active , efficacious treatment ( a phenomenon called “ hope induction ” or “ expectation bias ” ) . A number of systematic evaluations corroborate this assumption : the more study arms an RCT comprised ( i.e. , the lower the probability to receive placebo ) , the higher was the placebo response . On the other h and , the highest antidepressant response was found in direct drug comparisons ( head-to-head trials ) , where participants were certain to receive active drug treatment ( 5 ) . Furthermore , in many antidepressant RCTs , the enrolled subjects are not representative of clinical practice , in which a number of depressive patients suffer from severe comorbidities or suicidal ideation . Exactly those severely ill patients who are excluded from RCTs might particularly benefit from antidepressant pharmacotherapy . However , it must be noted that , in some analyses , a higher symptom severity at baseline was associated with a higher placebo response ( 6 ) , a phenomenon which is not fully understood as yet . There is a large body of evidence suggesting that clinical studies carried out in the U.S. are characterized by a larger placebo response compared to non-U.S. trials . This phenomenon could be observed , to provide a recent example , in RCTs of vortioxetine ( 7 ) . The inclusion of so-called professional research participants in U.S. studies may account for this finding . These subjects are mainly recruited by advertisements , and their motivation is often the prospect for free medication or other financial compensation . Therefore , they often aim to please the investigators in order to be invited again for participation in a clinical study . It appears meaningful to emphasize that the drug-placebo contrast in long-term , relapse-prevention studies is usually higher compared to acute-phase trials ( 8) . Interestingly , in a double-blind , long-term citalopram RCT , responders to acute-phase treatment were r and omized to either placebo or continuing citalopram , while placebo responders of the acute phase continued the placebo administration under double-blind conditions . Both placebo responders and citalopram responders receiving placebo in the long-term study exhibited a higher relapse rate compared to the participants in the citalopram continuation arm ( 9 ) , suggesting that the underlying biological abnormality is not sensitive to placebo . In summary , the reasons contributing to the raising placebo response over time and the subsequent decreasing drug-placebo separation should be critically considered in the interpretation of antidepressant clinical trial results . Expectation bias and increased clinical attention are often called “ unspecific effects ” of placebo administration , and these effects are not present in routine clinical care ( 10 ) . Therefore , it can be assumed that the effectiveness of an antidepressant in the routine care is higher than the antidepressant-placebo difference of RCTs indicates . The increase over time of  placebo response should also be considered in meta-analyses ( 11 ) , in which data are pooled from trials carried out in different periods OBJECTIVE There has been concern about a high rate of placebo response and a substantial failure rate in recent clinical trials in major depressive disorder ( MDD ) . This report explores differences in efficacy data from placebo-controlled MDD trials su bmi tted in support of new drug applications ( NDAs ) over a 25-year period . METHOD We compiled efficacy data from 81 r and omized , double-blind clinical trials , with 21,611 evaluable patients , that were su bmi tted to the US Food and Drug Administration as part of NDAs for an antidepressant cl aim between 1983 and 2008 . Trial data were limited to completed , r and omized , multicenter , double-blind , placebo-controlled clinical trials in adult patients diagnosed with MDD according to DSM-III or DSM-IV criteria . The data base was further limited to patients who were involved in clinical trials for drugs widely viewed as effective antidepressants and for doses of these drugs also viewed as effective doses . Trials were rated as successful if they showed statistical superiority vs placebo for the investigational drug on change in Hamilton Depression Rating Scale ( HDRS ) score ( last-observation-carried-forward data ) . ( Trials with multiple investigational drug groups were successful if there was superiority in at least 1 drug group after adjustment for multiplicity . ) In particular , we explored differences in effect size and success rate of these trials , based on when the studies were conducted , geographic location of the study sites ( US vs non-US ) , trial duration , dosing regimen , study size , and baseline disease characteristics . RESULTS Eighty-one percent of MDD patients were enrolled in US sites . Although the observed placebo and drug responses at non-US sites tended to be larger than at US sites , the treatment effect ( drug-placebo difference ) was similar ( mean change from baseline of about -2.5 units in HDRS total score ) in US and non-US trials . In both US and non-US trials , the placebo response showed a modest increase over the observation period ( 1983 - 2008 ) . Treatment effect clearly diminished over this same period , at a similar rate for both US and non-US trials despite a marked increase in the sample size of the trials . Our analysis showed that 53 % of all MDD trials in the last 25 years were successful . US trials had a higher success rate than non-US trials ( 58 % vs 33 % ) . Before 1995 , the overall success rate was 55 % , compared to 50 % for trials in 1995 or later , and , in general , 6-week trials had a higher success rate than 8-week trials ( 55 % vs 42 % ) . It should be noted that the earlier trials were mostly 6 weeks , and the 6-week trials had higher mean baseline HDRS scores than the 8-week trials . Study size did not seem to influence trial success rates . Mean baseline HDRS total scores declined over the 25-year observation period for patients in both US and non-US trials , as did treatment effect in these trials , again , regardless of region . Fixed-dose trials had a numerically slightly greater success rate than flexible-dose trials ( 57 % vs 51 % ) , although on average treatment effect was numerically larger in the flexible-dose trials than in fixed-dose trials ( mean of -2.9 vs -2.0 on HDRS units ) . CONCLUSIONS Treatment effect has declined over time in MDD trials , and there has been a high failure rate for these trials during the entire period , but the reasons for these findings remain elusive . Baseline disease severity seems to be a more important factor in study outcome than study duration , dosing regimen , sample size , time when studies were conducted , and regions where data were generated . Close attention is needed to a variety of factors in the design and conduct of these studies , including patient population , diagnostic considerations , patient assessment , and clinical practice differences . These considerations become increasingly important as globalization of clinical trials continues to increase ABSTRACT Objective : To evaluate the efficacy and safety of quetiapine monotherapy for mania in bipolar disorder by an a priori defined combined analysis of data from two placebo-controlled studies . Method : The intent-to-treat ( ITT ) population s from two studies of patients with DSM-IV bipolar I disorder , manic episode , r and omised to 12 weeks of double-blind treatment with quetiapine ( up to 800 mg/day ) or placebo were combined . The primary efficacy endpoint was change in Young Mania Rating Scale ( YMRS ) score from baseline to Day 21 . Secondary endpoints included change from baseline in YMRS to Day 84 , YMRS response and remission rates and change from baseline to Days 21 and 84 in the Montgomery – Asberg Depression Rating Scale ( MADRS ) , Clinical Global Impressions ( CGI ) , Clinical Global Impressions – Bipolar ( CGI-BP ) and the Positive and Negative Syndrome Scale ( PANSS ) . These endpoints were analysed as continuous variables , using an analysis of covariance ( ANCOVA ) , with the baseline as covariate . In order to account for any difference in response between studies , the analyses were stratified by study as a fixed effect , and centre as a r and om effect . The Cochran – Mantel – Haenszel test was used to analyse binary variables . A chi square test was used to compare the frequency of adverse events between the treatment groups . Results : The combined analysis included a total of 403 patients from two quetiapine monotherapy studies in patients with bipolar I disorder . A significant improvement in YMRS score was observed from Day 4 ( p = 0.021 ) onward in the quetiapine group compared with placebo . The treatment advantage of quetiapine over placebo continued to increase to Day 21 ( p < 0.001 ) and Day 84 ( p < 0.001 ) . Significantly more quetiapine-treated than placebo-treated patients achieved a response ( p < 0.001 ) . The average quetiapine dose in responders was approximately 600 mg daily . Of adverse events occurring in ≥ 5 % of patients , quetiapine-treated patients had a significantly greater incidence versus placebo of somnolence ( 16.3 % vs. 4.0 % ) , dry mouth ( 15.8 % vs. 3 % ) , weight gain ( 9.1 % vs. 1.5 % ) and dizziness ( 6.7 % vs. 2.5 % ) . Conclusions : The data from this combined analysis support the results from the individual studies and indicate that quetiapine monotherapy is effective across a broad range of mood symptoms , fast-acting and well tolerated in the treatment of mania BACKGROUND The anticonvulsant lamotrigine was previously shown to be effective for bipolar depression . This study assessed the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of mood episodes in bipolar disorder . METHOD During an 8- to 16-week open-label phase , lamotrigine ( titrated to 200 mg/day ) was added to current therapy for currently or recently depressed DSM-IV-defined bipolar I out patients ( N = 966 ) and concomitant drugs were gradually withdrawn . Patients stabilized on open-label treatment ( N = 463 ) were then r and omly assigned to lamotrigine ( 50 , 200 , or 400 mg/day ; N = 221 ) , lithium ( 0.8 - 1.1 mEq/L ; N = 121 ) , or placebo ( N = 121 ) monotherapy for up to 18 months . The primary outcome measure was time from r and omization to intervention ( addition of pharmacotherapy ) for any mood episode ( depressive , manic , hypomanic , or mixed ) . Data were gathered from September 1997 to August 2001 . RESULTS Time to intervention for any mood episode was statistically superior ( p = .029 ) for both lamotrigine and lithium compared with placebo-median  survival times were 200 , 170 , and 93 days , respectively . Intervention for depression was more frequent than for mania by a factor of nearly 3:1 . Lamotrigine was statistically superior to placebo at prolonging the time to intervention for a depressive episode ( p = .047 ) . The proportions of patients who were intervention-free for depression at 1 year were lamotrigine 57 % , lithium 46 % , and placebo 45 % . Lithium was statistically superior to placebo at prolonging the time to intervention for a manic or hypomanic episode ( p = .026 ) . The proportions of patients who were intervention-free for mania at 1 year were lamotrigine 77 % , lithium 86 % , and placebo 72 % . Headache was the most frequent adverse event for all 3 treatment groups . CONCLUSION Lamotrigine and lithium were superior to placebo for the prevention of mood episodes in bipolar I patients , with lamotrigine predominantly effective against depression and lithium predominantly effective against mania OBJECTIVE To investigate the efficacy and safety of topiramate versus placebo as adjunctive therapy for the outpatient management of bipolar I disorder . METHOD In this 12-week , r and omized , double-blind , placebo-controlled trial , adults with bipolar I disorder ( DSM-IV criteria ) experiencing a manic or mixed episode with a Young Mania Rating Scale ( YMRS ) score of > or= 18 while taking therapeutic levels of valproate or lithium received adjunctive topiramate or placebo . Topiramate was titrated from 25 to 400 mg/day over 8 weeks and was continued for 4 additional weeks . The study was conducted from October 2001 through October 2003 . The primary outcome measure was the change in YMRS score from baseline to last study visit during the double-blind phase . RESULTS The mean + /- SD change in YMRS score from baseline was -10.1 + /- 8.7 ( -40.1 % ) in the topiramate group ( N = 143 ) and -9.6 + /- 8.2 ( -40.2 % ) in the placebo group ( N = 144 , p = .797 ) . Greater than 50 % reduction in YMRS was achieved by 39 % of the topiramate group and 38 % of the placebo group ( p = .914 ) . No significant treatment differences were observed for secondary efficacy measures . Compared with adjunctive placebo , adjunctive topiramate did not worsen mania or induce depression . Paresthesia , diarrhea , and anorexia were more common in the topiramate group . The topiramate group achieved greater reductions than the placebo group in body weight ( -2.5 vs. 0.2 kg , p < .001 ) and body mass index ( -0.84 vs. 0.07 kg/m(2 ) , p < .001 ) . CONCLUSION In patients treated with lithium or valproate , there was no difference in the reduction of YMRS score in the topiramate and placebo groups . Both groups showed declines of 40 % . Topiramate reduced body weight significantly relative to placebo without worsening depressive or manic symptoms In the early 1980s , the National Institute of Mental Health supported a multicenter , r and omized , controlled , clinical trial on unipolar and bipolar disorder to evaluate the comparative efficacies of lithium carbonate , imipramine hydrochloride , a lithium-imipramine combination , and placebo in preventing the recurrence of affective disorders . The objective of this report is to present a re analysis of the relative efficacies of these treatments in patients with unipolar disorder to focus attention on general issues related to the design and conduct of maintenance therapy trials . We show that the earlier conclusions of that study that imipramine and the combination therapy are more effective than lithium and placebo in preventing the recurrence of depression in unipolar patients can be accounted for by alternative explanations that are a consequence of the design of the study . Our findings have important implication s for the design , conduct , and interpretation of results of maintenance therapy clinical trials in general OBJECTIVE The therapeutics for bipolar disorders are still far from adequate , and new options with improved effectiveness , safety , and tolerability in a wide range of patients are necessary . Preliminary data have suggested a role for dysfunctions targeting the purinergic system in mood disorders . This study aim ed to evaluate the efficacy and tolerability of the purinergic agents allopurinol and dipyridamole combined with lithium in bipolar mania . METHOD A r and omized , placebo-controlled , double-blind study was performed in adult in patients ( N = 180 ) with a DSM-IV-TR diagnosis of bipolar I disorder , current episode manic with or without psychotic features ( rapid cyclers and mixed episodes were not included ) . No antipsychotic agent was used during the study . Subjects were given fixed oral doses of either allopurinol 600 mg/day ( N = 60 ) , dipyridamole 200 mg/day ( N = 60 ) , or placebo ( N = 60 ) added to lithium for 4 weeks . Subjects were rated at baseline and days 7 , 14 , 21 , and 28 using the Young Mania Rating Scale ( YMRS ) as the primary efficacy measure . The study was conducted between September 2003 and September 2006 . RESULTS Allopurinol result ed in greater mean reductions in YMRS scores from baseline to day 21 ( p < .001 ) and day 28 ( p = .003 ) compared with placebo using a linear model analysis ( d = 0.32 , 95 % CI = 0.07 to 0.57 ) . Remission rates were significantly higher for allopurinol compared with dipyridamole and placebo ( p = .008 ) . Lithium showed a significant antimanic efficacy even in the placebo group . Decrease in plasma uric acid levels showed a significant positive association with antimanic effects in the allopurinol group ( p < .001 ) . CONCLUSION Allopurinol is clinical ly effective and well-tolerated adjunctively with lithium in manic episodes and may represent an alternative approach in the treatment of acute mania , especially for those presenting tolerability and safety issues with antipsychotics . The present results strongly support the involvement of the purinergic system in the pathophysiology and therapeutics of bipolar disorder . Further placebo-controlled studies with allo-purinol compared with st and ard mood stabilizers in mania and maintenance are warranted . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00560079 The gold st and ard for evidence in psychiatry , as elsewhere in medicine , is often considered to be the r and omized , placebo-controlled , double-blind study . The use of blinding or masking plays a key role in these design s by addressing the problem of expectancy . First , if participants anticipate greater benefit from a particular treatment , they may be more likely to respond to it , which is considered a component of placebo response . Not surprisingly , participants have been found to report greater anticipated benefits when they were r and omized to enter an active-comparator , versus a placebo-comparator , study ( 1 ) . Likewise , raters may anticipate greater benefit from active drug and thus favor it in their ratings , whether consciously or unconsciously . Greater response rates in both active and placebo arms occur when a greater proportion of participants receive active treatment — that is , when patients ( 1 ) or raters ( 2 ) expect more participants to benefit . Double-blinding , typically by providing drug and placebo in identical capsules , is intended to minimize the impact of expectancy and the related concept of credibility . The blind may be compromised in a variety of ways , however , beginning with differences in medication taste or smell . Of particular concern may be the emergence of adverse effects , particularly when those adverse effects are known to be associated with a specific medication . The requirement that informed consent forms delineate common adverse effects may increase this risk ( 3 ) . Indeed , when the degree of unblinding is assessed in antidepressant trials , multiple reports suggest that it is extensive : at least three-quarters of patients are typically able to correctly guess at their treatment assignment ( 4 , 5 ) . Moreover , even the sudden absence of adverse effects may contribute to unblinding , as might occur when a participant stabilized on a sedating medication is abruptly switched to placebo at r and omization in a relapse-prevention study . If such unblinding occurs , does it meaningfully affect trial results ? A meta- analysis of antidepressant trials using active placebos , such as those with antihistaminergic or anticholinergic effects , suggested smaller effect sizes than those observed in the presumably less blinded trials with inert placebo ( 6 ) . Estimating the potential impact in published studies is difficult , but certain findings when results are stratified by potentially unblinding adverse effects raise concern . In a trial of quetiapine in bipolar depression ( 7 ) , for example , when investigators examined only the groups reporting sedation , mean change in the Montgomery-Åsberg Depression Rating Scale total score at week 8 was -18.8 in the quetiapine groups ( N=195 ) and -18.9 in the placebo group ( N=24 ) . Conversely , when the subset of participants without sedation were examined , the mean change in the Montgomery-Åsberg Depression Rating Scale total score was -19.3 and -11.7 in the quetiapine and placebo groups , respectively . While only a small subset of patients were in the placebo/sedation arm , the disparity in placebo response might suggest that clinical raters were attempting to “ guess ” at treatment assignment . Unfortunately , for psychotropic drugs , CNS side effects may be inevitable . Therefore , we call for more uniform application of st and ards in the design , reporting , and review of clinical trials . 1 . Consistent with CONSORT ( 8) and international guidelines ( 9 ) , participants and raters should be asked to guess treatment assignment , and the degree of true and false unblinding should be reported in the primary publication of results . Statistical
Placebo response in bipolar disorder trials is more likely to occur in patients who are mildly ill , bipolar II , mixed-episode , first-episode , rapid cycling , atypical , non-psychotic , substance abusers and medically ill .
The use of concomitant medication such as benzodiazepines , a high frequency of visits , a high number of treatment groups and sites , fixed-dose design s , and the concomitant use of psychotherapy are likely to increase placebo response .
There are a number of clinical and method ological variables that are associated with placebo response
Background :  Placebo response is high in bipolar disorder trials .
This is a challenge for research ers and an enigma for clinicians .
This article will attempt to aid in the comprehension of the ethical questions and method ologies related to the use of placebo in bipolar disorder .
Results : Placebo has a very important role in the study of bipolar disorders .
From a method ological point of view , and given the limitations of non-inferiority design s , the use of placebo is necessary to evaluate the sensitivity of the study and ensure that the drug under investigation is really effective .