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Student, Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht, Netherlands
Student, Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences
Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Associate Professor, Faculty of Pharmacy, Department of Clinical Pharmacology, Faculty of Medicine, University of Toronto
Reprints: Thomas R Einarson PhD, Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, Ontario M5S 2S2, Canada, FAX 416/978-8511, t.einarson{at}utoronto.ca
BACKGROUND: Placebo effects in major depressive disorder (MDD) have received much interest in the medical literature. However, few quantitative analyses have been done in homogeneous populations.
OBJECTIVE: To determine efficacy rates for placebo in patients with MDD; to quantify the correlation between efficacy and publication year, as well as between placebo and drug response rates.
DESIGN: Searching MEDLINE (1966–December 2000),
EMBASE (1998–February 2001), HealthSTAR (1975–December 2000), and
Cochrane (1980–December 2000) databases, randomized, placebo-controlled
trials were retrieved including patients with MDD as defined by Diagnostic
and Statistical Manual of Mental Disorders, 3rd and 4th editions
criteria, Hamilton Rating Scale for Depression score 
18 or
Montgomery–Asberg Depression Rating Scale score 16, reporting
successes as 50% decreases in scores after 6–8 weeks of treatment.
Response rates were summarized using a random effects meta-analysis for per
protocol (PP) and intent-to-treat (ITT) results.
RESULTS: We included 24 of 134 potential studies examining 4459 patients, 1786 on placebo and 2673 on an antidepressant. Placebo response rates were 45.5% (PP) and 26.9% (ITT). Correlations were significant between year and rates (PP rho 0.448, p = 0.042; ITT rho 0.557; p = 0.006), but not for active drugs. Placebo and drug rates were correlated (PP r 0.397, p = 0.020; ITT r 0.539; p = 0.002).
CONCLUSIONS: These placebo rates confirm those reported previously, but were from a homogeneous population. Although statistically significant, the correlation between drug and placebo rates was lower than others reported. During the study period, placebo rates increased linearly; active drugs did not. Correlations between placebo and drug response rates reflected moderate to strong effect sizes. We suggest that current methodology has been unsuccessful in achieving unbiased double-blind conditions not influenced by extra-trial factors, including time.
Key Words: depression, major depressive disorder, meta-analysis, placebo, randomized controlled trials
Published Online, October 10, 2003. www.theannals.com, DOI 10.1345/aph.1D172
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