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

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 optimal dosing ranges. Methods We performed a systematic review and one-stage 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 modeled using restricted cubic spline models, and the maximum effective dose (EDmax) within the observed range was derived from the fitted model. Effect sizes were expressed as standardized mean differences and risk ratios with 95% confidence interval. 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. Peak efficacy for acute treatment was observed at 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 no additional benefit from higher doses across all parameters. Long-term analyses showed smaller and mostly linear associations: the best outcomes were 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 rTMS efficacy in MDE is maximized within a moderate dose range, beyond which additional stimulation yields minimal gain. Thus, sustained remission likely depends on maintenance strategies, not dose escalation.