Growing placebo response in TMS treatment for depression: a meta-analysis of 27-year randomized sham-controlled trials

This meta-analysis investigated placebo responses in repetitive transcranial magnetic stimulation treatment for depression, an area with limited systematic analysis. The initial literature search yielded 2,783 relevant records from the past 27 years, leading to the analysis of 52 randomized controlled trials encompassing 54 placebo arms with 2,122 sham participants. Placebo responses were large (d = 1.016) and increasing yearly (Z = 2.18, P = 0.029), irrespective of sham methods, assessment scales or age. Nevertheless, the trial location, number of sites, sample size, sponsor, sex ratio, study quality and medication status had an influence on the active or sham effect and consequently the outcome. Notably, the placebo and active effects increased in parallel (rs = 0.738, P < 0.001), resulting in a time-independent trial outcome. These findings reveal significant placebo responses from 1996 to 2022 but with minimal impact on the trial outcomes, as placebo and active effects demonstrated parallel growth. These results could inform the design of further clinical trials, especially for repetitive transcranial magnetic stimulation in the treatment of depression. The authors conducted a systematic review and meta-analysis to identify predictors of placebo response in repetitive transcranial magnetic stimulation treatment for depression.