The International Journal of Neuropsychopharmacology


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

Stein Schalkwijka1a2a3, Juan Undurragaa2a4a6, Leonardo Tondoa1a2a5 and Ross J. Baldessarinia1a2 c1

a1 Department of Psychiatry, Harvard Medical School, Boston, MA, USA

a2 International Consortium for Research on Mood & Psychotic Disorders, McLean Hospital, Belmont, MA, USA

a3 Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Netherlands

a4 Bipolar Disorders Program, Institute of Neuroscience, Hospital Clínic Barcelona, IDIBAPS, CIBERSAM, University of Barcelona, Spain

a5 Lucio Bini Mood Disorders Centre, Cagliari and Rome, Italy

a6 Department of Psychiatry, Clinica Alemena, Universidad del Desarrollo, Santiago, Chile


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.

(Received December 05 2013)

(Reviewed December 17 2013)

(Revised January 08 2014)

(Accepted February 05 2014)

(Online publication March 13 2014)

Key words

  • Antidepressants;
  • efficacy;
  • placebo responses;
  • randomized controlled trials;
  • trends


c1 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: 1-617-855-3479 Email: