title: Declining efficacy in controlled trials of antidepressants: effects of placebo dropout.
abstract: 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.
authors.affiliation: Department of Psychiatry,Harvard Medical School,Boston, MA,USA.
authors.forename: Stein
authors.initials: S
authors.lastname: Schalkwijk
authors.affiliation: International Consortium for Research on Mood & Psychotic Disorders, McLean Hospital,Belmont, MA,USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Undurraga
authors.affiliation: Department of Psychiatry,Harvard Medical School,Boston, MA,USA.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Tondo
authors.affiliation: Department of Psychiatry,Harvard Medical School,Boston, MA,USA.
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Baldessarini
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D018849:Controlled Clinical Trials as Topic / Q000706:statistics & numerical data* / Q000639:trends*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D016014:Linear Models; D010352:Patient Dropouts / Q000706:statistics & numerical data*; D015990:Placebo Effect; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents