Acute and long-term effects of repetitive transcranial magnetic stimulation in major depressive episodes: a systematic review and dose-response meta-analysis of randomized sham-controlled trials

Abstract Background To characterize the dose-response relationships between key repetitive transcranial magnetic stimulation (rTMS) dosing parameters and clinical outcomes in major depressive episodes (MDE), and to identify group-level dose ranges at which predicted benefits plateaued for each dosing dimension separately. Methods We performed a systematic review and dose-response meta-analysis of randomized sham-controlled trials investigating rTMS for adults with MDE. Outcomes were symptom severity, response, and remission, assessed acutely and in follow-up (> 7 days). Four key dosing dimensions (total pulses, pulses/session, sessions, duration) were examined separately using restricted cubic spline models, and the dose associated with the highest predicted group-level benefit within the observed range was derived from the fitted model. Effect sizes were expressed as standardized mean differences and risk ratios with 95% confidence intervals. Results Across 108 trials (134 active arms; n = 5,621), total pulses, pulses per session, total sessions and treatment duration showed significant non-linear associations with acute efficacy in separate univariable models. For each dosing dimension considered separately, the highest predicted group-level acute benefits were observed at approximately 30,000–39,000 total pulses, 1,800–2,200 pulses per session, 14–16 sessions, and 2.7–3.1 weeks of treatment, with limited additional benefit from higher exposures. Follow-up analyses showed smaller and mostly linear associations, with the most favorable group-level estimates generally observed at 26,000–33,000 total pulses, 1,300–1,800 pulses per session, 10–14 sessions, and 2.8–3.3 weeks of treatment. Sensitivity analyses confirmed the stability of these estimates, and publication bias was minimal. Conclusions In separate univariable models, rTMS efficacy in MDE appeared to plateau within moderate dose ranges for each dosing dimension. These findings provide descriptive group-level reference points rather than an individualized dosing rule or a single optimal treatment protocol. Sustained benefit may depend more on maintenance strategies than on further dose escalation alone.