A systematic review and meta-analysis on placebo response to repetitive transcranial magnetic stimulation for depression trials

Background: Although several studies indicate that placebo response is large to antidepressant pharmacotherapy in major depressive disorder (MDD), no updated meta-analysis has quantified the magnitude of the placebo (sham) response to repetitive transcranial magnetic stimulation (rTMS) in MDD yet. Objective: To conduct a systematic review and meta-analysis on this issue in randomized controlled trials (RCTs) involving participants with MDD; and to explore potential moderators. Methodology: PubMed/MEDLINE, Embase, PsycINFO, and Web of Science electronic databases were searched from inception up to March 15, 2017 for RCTs that investigated the efficacy of any rTMS modality compared to sham intervention in participants with acute depressive episodes. Cochrane Risk of Bias Tool was used to estimate risks. We estimated the placebo effect size (Hedges's g, random-effects model) response using placebo groups baseline and endpoint depressive symptom scores. Meta-regressions have been employed to explore potential moderators of response. Results: Sixty-one studies met eligibility criteria (N = 1328; mean age, 47 years; 57% females). Placebo response was large (g = 0.8, 95% CI = 0.65-0.95, p < 0.01) regardless of the modality of intervention. Placebo response was directly associated with publication year and depression improvement of the active group, and inversely associated with higher levels of treatment-resistant depression. Other moderators, including gender, age, and stimulator type, were not associated with the outcome. Overall, 24.6%, 67.2%, and 8.2% of studies had an overall low, unclear, and high bias risk, respectively. Conclusion: Placebo response in rTMS depression trials was large and associated with depression improvement of the active treatment group. Such result suggests that excluding placebo responders with a run-in phase may not confer advantage since response to 'active' rTMS may decrease as well. Moreover, placebo response may be a component of therapeutic response to rTMS in MDD. In addition, placebo response increase over time could indicate improvement in rTMS trial designs, including better sham rTMS methods.