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Declining efficacy in controlled trials of antidepressants: effects of placebo dropout

Stein Schalkwijk, Juan Undurraga, Leonardo Tondo, Ross J. Baldessarini
DOI: http://dx.doi.org/10.1017/S1461145714000224 1343-1352 First published online: 1 August 2014


Drug-placebo differences (effect-sizes) in controlled trials of antidepressants for major depressive episodes have declined for several decades, in association with selectively increasing clinical improvement associated with placebo-treatment. As these trends require adequate explanation, we tested the hypothesis that decreasing trial-dropout rates may be an important contributor. We gathered reports of peer-reviewed, placebo-controlled trials of antidepressants (1980–2011) by computerized literature searching, and applied meta-analysis, meta-regression and multiple linear regression methods to evaluate associations of dropout rates and other factors of interest, to reporting year and reported efficacy [standardized mean drug-placebo difference (SMD) as Hedges' g-statistic]. In 56 trials meeting inclusion and exclusion criteria, we confirmed significant overall efficacy of antidepressants but declining drug-placebo contrasts over the past three decades. Among other changes, there was a corresponding increase in placebo-associated improvement with a decline in placebo-dropout rate, mainly for lack of efficacy. These effects were found only when last-observation-carried-forward (LOCF) analyses were used. Other trial-design and subject factors, including drug-responses and drug-dropout rates, were much less associated with efficacy. We propose that declining placebo-dropout rates ascribed to inefficacy combined with use of LOCF analyses led to increasing improvement in placebo-arms that contributed to declining antidepressant–placebo contrasts in controlled treatment trials since the 1980s.

Key words
  • Antidepressants
  • efficacy
  • placebo responses
  • randomized controlled trials
  • trends
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