title: Placebo response in antipsychotic trials of patients with acute mania: Results of an individual patient data meta-analysis.
abstract: We examined the role of placebo response in acute mania trials. Specifically, whether placebo response: (1) predicts treatment effect, (2) can be predicted by patient and study characteristics, and (3) can be predicted by a parsimonious model. We performed a meta-analysis of individual patient data from 10 registration studies (n=1019) for the indication acute manic episode of bipolar disorder. We assessed the effect of 14 determinants on placebo response. Primary outcome measures were mean symptom change score (MCS) on the Young Mania Rating Scale (YMRS) and response rate (RR), defined as ≥ 50% YMRS symptom improvement from baseline to endpoint. The overall placebo response was 8.5 points improvement on the YMRS (=27.9%) with a RR of 32.8%. Placebo response was significantly associated with the overall treatment response. Five determinants significantly (p<0.05) predicted the placebo response. The multivariate prediction model, which consisted of baseline severity, psychotic features at baseline, number of geographic regions, and region, explained 10.4% and 5.5% of the variance in MSC and RR, respectively. Our findings showed that the placebo response in efficacy trials of antipsychotics for acute mania is substantial and an important determinant of treatment effect. Placebo response is influenced by patient characteristics (illness severity and presence of psychotic features) and by study characteristics (study year, number of geographic regions and region). However, the prediction model could only explain the placebo response to a limited extent. Therefore, limiting trials to certain patients in certain geographic regions seems not a viable strategy to improve assay sensitivity.
authors.affiliation: Dept. of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Medicines Evaluation Board, Utrecht, The Netherlands. Electronic address: c.c.welten@amc.uva.nl.
authors.forename: C C M
authors.initials: CC
authors.lastname: Welten
authors.affiliation: Dept. of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M W J
authors.initials: MW
authors.lastname: Koeter
authors.affiliation: Medicines Evaluation Board, Utrecht, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Wohlfarth
authors.affiliation: Dept. of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: J G
authors.initials: JG
authors.lastname: Storosum
authors.affiliation: Dept. of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: van den Brink
authors.affiliation: Medicines Evaluation Board, Utrecht, The Netherlands.
authors.forename: C C
authors.initials: CC
authors.lastname: Gispen-de Wied
authors.affiliation: Medicines Evaluation Board, Utrecht, The Netherlands.
authors.forename: H G M
authors.initials: HG
authors.lastname: Leufkens
authors.affiliation: Dept. of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.
authors.forename: D A J P
authors.initials: DA
authors.lastname: Denys
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy*; D016208:Databases, Factual / Q000706:statistics & numerical data; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D015990:Placebo Effect; D011237:Predictive Value of Tests; D011569:Psychiatric Status Rating Scales
chemical_list: D014150:Antipsychotic Agents
keywords: Antipsychotics; Bipolar mania; Placebo response; Predictors