Influence of placebo effect in mental disorders research: A systematic review and meta‐analysis

BACKGROUND: Randomized controlled trials (RCT) in mental disorders research commonly use active control groups including psychotherapeutic shams or inactive medication. This meta‐analysis assessed whether placebo conditions (active controls) had an effect compared to no treatment or usual care (passive controls). METHODS: PubMed, Scopus, PsycINFO, PsycARTICLES, Ovid, the Cochrane Central Register of Controlled Trials and Web of Science were searched from inception to April 2021 and reference lists of relevant articles. Three‐arm RCTs, including active and passive control groups, were selected. Where individual standardized mean difference (SMD) was calculable, random effects meta‐analyses were performed to estimate an overall effect size with 95% confidence intervals (CI) comparing active vs passive controls. Heterogeneity was assessed using I² statistic and meta‐regression. Funnel asymmetry was evaluated using Egger's test (Prospero registration: CRD42021242940). RESULTS: 24 articles with 25 relevant RCTs were included in the review, of which 11 studies were of high risk of bias. There was an improvement in outcomes favouring the placebo conditions, compared to passive controls, overall (25 studies, SMD 0.24, 95% CI 0.06–0.42, I² = 43%) and in subgroups with anxiety (SMD 0.45, 95% CI 0.07–0.84, I² = 59%) or depression (SMD 0.22, 95% CI 0.04–0.39, I² = 0%). Meta‐regression did not show a significant explanation for heterogeneity. Egger's test showed no asymmetry (p = .200). CONCLUSIONS: A small placebo effect was observed in mental disorders research overall, and in patients with anxiety or depression. These findings should be interpreted with caution in the light of heterogeneity and risk of bias.