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Review Articles

Correlation Between Different Levels of Placebo Response Rate and Clinical Trial Outcome in Major Depressive Disorder: A Meta-Analysis

Nadia Iovieno, MD, PhD, and George I. Papakostas, MD

Published: October 15, 2012

Article Abstract

Objective: To investigate the relationship between specific levels of placebo response rates and the drug response rate and the relative risk of response to drug versus placebo in clinical trials of antidepressant monotherapy and adjunctive polypharmacy for MDD.

Data Sources: MEDLINE/PubMed databases were searched for studies published in the English language between January 1980 and March 2011 by using the search terms depression, placebo, augmentation, adjunct, adjunctive, and each of the antidepressant agents identified. The search was supplemented by manual bibliographic review and examination of relevant review articles.

Study Selection: The analysis included randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for MDD, 4 weeks or longer, and of augmentation/combination treatments for antidepressant partial responders/nonresponders with MDD, 1 week or longer. 169 antidepressant monotherapy studies and 35 adjunctive polypharmacy studies were found eligible for inclusion in our analysis.

Data Extraction: Data extracted included number of patients enrolled, patient characteristics, drug dosages and scheme (fixed vs flexible dosing), duration of the trial, and response rates.

Results: In antidepressant monotherapy studies, a higher placebo response rate correlated with a lower risk ratio of responding to antidepressant versus placebo (P<.001) and correlated with higher antidepressant response rates (P<.001); the number needed to treat (NNT) for response was approximately 4, 6, and 9 in trials with placebo response rates <30%, ≥30% and <40%, and ≥40%, respectively. In adjunctive trials, a higher placebo response rate correlated with a lower risk ratio of responding to the adjunctive drug versus placebo (P<.001) and correlated with a trend toward statistical significance with higher response rates to the adjunctive drug (P=.050); the NNT was approximately 6, 7, 11, and 17 in trials with placebo response rates <20%, ≥20% and <30%, ≥30% and <40%, and ≥40%, respectively.

Conclusions: These results suggest that the relative efficacy of the active drug compared to placebo in clinical trials for MDD is highly heterogeneous across studies with different placebo response rates, with a worse performance in showing a superiority of the drug versus placebo for studies with placebo response rates ≥30% and ≥40%, respectively, for monotherapy and adjunctive trials. It is important to maintain placebo response rates below this critical threshold, since this is one of the most challenging obstacles for new treatment development in MDD.

‘ ‹J Clin Psychiatry 2012;73(10):1300-1306

Submitted: October 24, 2011; accepted August 7, 2012 (doi:10.4088/JCP.11r07485).

Corresponding author: Nadia Iovieno, MD, PhD, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 1 Bowdoin Sq, Boston, MA 02114 (

Volume: 73

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