Is placebo response in antidepressant trials rising or not? A reanalysis of datasets to conclude this long-lasting controversy.

It had long been believed that placebo response rates in antidepressant trials have been increasing and that they were responsible for rising numbers of so-called failed antidepressant trials. Two recent systematic reviews examined this issue and reached completely opposite findings. Furukawa and colleagues in a paper published in 2016 found that the placebo response rates are stable since 1991 and the apparent increase up to 2000 was confounded by changes in trial design features. By contrast, Khan and colleagues more recently concluded that placebo response rates had grown steadily in the past 30 years. The two reviews differed in the datasets they used, definitions of placebo response and statistical analyses. In this perspective article, we examined if such differences were responsible for the two reviews' contrasting conclusions. Our reanalyses confirmed our previous results. We found that in any dataset and for any placebo response definition, there was no increase in placebo response over the years when the analysis was adjusted for the confounders related to study design features or when it was limited to studies published after 1990s. We conclude that placebo response in antidepressant trials has remained stable for the past 25 years, during which time the large majority of the studies have come to share similar design features.