Protocol-level moderators of antidepressant efficacy in prefrontal rTMS: A sham-controlled meta-analysis of randomized trials.

BACKGROUND

Prefrontal repetitive transcranial magnetic stimulation (rTMS) is an established treatment for major depressive disorder (MDD), yet heterogeneity in stimulation protocols has led to debate regarding optimal parameters. Whether higher intensity, pulse dose, or session density translates into superior efficacy remains unclear. We conducted a sham-controlled meta-analysis to examine protocol-level moderators of antidepressant response.

METHODS

PubMed, Web of Science, and CENTRAL were searched to January 2026. Randomized sham-controlled trials evaluating prefrontal rTMS or theta burst stimulation in adults with MDD or treatment-resistant depression (TRD) were included. Random-effects meta-analyses using restricted maximum likelihood estimation with Hartung-Knapp adjustment were performed. Meta-regressions examined dose-response relationships across frequency, intensity, total pulses, session number, and treatment duration. Risk of bias was assessed using ROB 2.0; certainty of evidence with GRADE.

RESULTS

Thirty comparisons (N = 1850) were included. Active rTMS reduced depressive symptoms versus sham (Hedges' g = -1.056, 95% CI -1.407 to -0.704; p < 0.001), with high heterogeneity (I2 = 84.6%; 95% PI -2.42 to +0.31). Binary outcomes showed robust effects: response OR = 4.78 (95% CI 3.08-7.41; NNT = 2.9; I2 = 21.9%) and remission OR = 3.55 (95% CI 2.06-6.13; NNT = 4.4; I2 = 34.5%), both high-certainty by GRADE. Meta-regression identified no significant linear dose-response relationships. Effect sizes were larger in single-blind versus double-blind trials (Q p < 0.001).

CONCLUSIONS

Prefrontal rTMS robustly increases response and remission probability in MDD. Greater dose or intensity does not confer proportional benefit linearly, suggesting dose-escalation strategies require reconsideration in favor of precision-oriented approaches.