Though it is commonly believed that rates of placebo response in trials of antidepressant medication have been increasing over the past few decades, the studies that have shown such trends may have been limited by the types of datasets or statistical methods they utilized. To clarify this issue, scientists from several international universities conducted a systematic review of double-blind, placebo-controlled randomized clinical trials that investigated the use of first and second generation antidepressants in adult patients with major depressive disorder (MDD). Their findings were published in Lancet Psychiatry.

In their review, the researchers aimed to explore links between placebo response rates and characteristics of the studies and participants. Previous studies, for instance, have found that the length of the clinical trial and the patients’ baseline depression severity may have influenced the rates of placebo response in earlier research.

The final analysis included 252 trials conducted between 1978 and 2015, which consisted of 26 324 patients who had been randomly assigned to placebo. The findings reveal that contrary to the belief that placebo response rates have been steadily rising in such trials, they have actually remained stable at 35-40% since 1991 (relative risk [RR] 1.00, 95% confidence interval (CI), 0.97-1.03, P=0.99, for every 5-year increase). These rates were consistent across various analyses of sensitivity.

Further analysis indicated that prior to the 1990’s, trials were more likely to be single-centered and of shorter duration than those conducted later. These characteristics were significant factors in the differences in average response rates before 1991 (RR 1.32, 95% CI, 1.11-1.57 for multicenter vs single-center trials; and RR 1.03, 95% CI, 1.01-1.05 for 1 additional week in trial length). These factors confounded results of studies conducted in the 1980’s and earlier, which showed especially low placebo response rates.

While the present findings negate the myth that the efficacy of antidepressant medications is declining, the 35-40% placebo response rate is still quite high. In addition to the need for innovation in drug development and clinical trial design, these results have immediate clinical implications.

“The expectation of improvement, classic conditioning, and the contact with a health-care environment with supportive and therapeutic features contribute to the objective response observed in patients with major depression who are randomly assigned to placebo,” the authors wrote. However, these factors are often not present in the real-world practice setting. “Clinicians should create a specific context and level of therapeutic contact, to enhance non-specific effects of treatment and gain greater treatment response,” they concluded.

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Furukawa TA, Cipriani A, Atkinson LZ, et al. Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies. Lancet Psychiatry. 2016; 3(11):1059-1066. doi:10.1016/S2215-0366(16)30307-8