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  • The International Journal of Neuropsychopharmacology, Volume 17, Issue 8
  • August 2014, pp. 1343-1352

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

  • Stein Schalkwijk (a1) (a2) (a3), Juan Undurraga (a2) (a4) (a5), Leonardo Tondo (a1) (a2) (a6) and Ross J. Baldessarini (a1) (a2)
  • DOI:
  • Published online: 13 March 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.

Corresponding author
Address for correspondence: Dr R. J. Baldessarini, Mailman Research Centre, McLean Hospital, 115 Mill Street, Belmont, MA 02478-9106, USA. Tel.: 1-617-855-3203 Fax: 1-617-855-3479Email:
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Schalkwijk Supplementary Material
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