title: Efficacy of drug treatment for acute mania differs across geographic regions: An individual patient data meta-analysis of placebo-controlled studies.
abstract: Given globalization trends in the conduct of clinical trials, the external validity of trial results across geographic regions is questioned. The objective of this study was to examine the efficacy of treatment in acute mania in bipolar disorder across regions and to explain potential differences by differences in patient characteristics. We performed a meta-analysis of individual patient data from 12 registration studies for the indication acute manic episode of bipolar disorder. Patients (n = 3207) were classified into one of three geographic regions: Europe (n = 981), USA (n = 1270), and other regions (n = 956). Primary outcome measures were mean symptom change score on the Young Mania Rating Scale (YMRS) from baseline to endpoint and responder status (50% improvement form baseline). Effect sizes were significantly smaller in the USA (g = 0.203, 95% confidence interval (CI) 0.062-0.344; odds ratio (OR) 1.406, 95% CI 0.998-1.980) than in Europe (g = 0.476, 95% CI 0.200-0.672; OR 2.380, 95% CI 1.682-3.368) or other regions (g = 0.533, 95% CI 0.399-0.667; OR 2.300, 95% CI 1.800-2.941). Regional differences in age, gender, initial severity, body mass index, placebo response, discontinuation rate, and type of compound could not explain the geographic differences in effect. Less severe symptoms at baseline in the US patients did explain some of the difference in responder status between patients in Europe and the USA. These findings suggest that the results of studies involving patients with acute mania cannot be extrapolated across geographic regions. Similar findings have been identified in schizophrenia, contraceptive, and in cardiovascular trials. Therefore, this finding may indicate a more general problem regarding the generalizability of pharmacological trials over geographic regions.
authors.affiliation: Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Medicines Evaluation Board, Utrecht, the Netherlands c.c.welten@amc.uva.nl.
authors.forename: Carlijn C M
authors.initials: CC
authors.lastname: Welten
authors.affiliation: Department 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 D
authors.initials: TD
authors.lastname: Wohlfarth
authors.affiliation: Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: J G
authors.initials: JG
authors.lastname: Storosum
authors.affiliation: Department 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: Department 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; D000349:Africa; D001208:Asia; D001315:Australia; D001714:Bipolar Disorder / Q000188:drug therapy*; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D017063:Outcome Assessment, Health Care / Q000706:statistics & numerical data*; D013020:South America; D014481:United States
keywords: Mania; bipolar disorder; efficacy; geographic region; treatment