Efficacy, Effectiveness, and Safety of Transcranial Magnetic Stimulation for Bipolar Depression: A Systematic Review and Meta-Analysis.

BACKGROUND

Repetitive transcranial magnetic stimulation (rTMS) is cleared by the Food and Drug Administration for major depression, and recently received breakthrough status for bipolar depression (BDep). However, evidence on its efficacy and safety and optimal protocols for BDep remains limited. We conducted a systematic review to synthesize available data on rTMS for BDep.

METHODS

We systematically searched 4 literature databases for studies published between 1995 and 2025 treating participants with acute BDep (1097 articles). The primary outcome for the meta-analysis was change in mean depression severity scores from baseline. Determinants of treatment response were assessed using meta-regression and subgroup meta-analyses.

RESULTS

Fifty-six articles were included, representing a total of 1709 patients with BDep. Active TMS had superior antidepressant efficacy relative to sham in randomized controlled trials (RCTs) (Cohen's d = 0.40). Rates of treatment-emergent mania or hypomania were low and equivalent to those found for sham (odds ratio = 1.3; 95% CI, 0.7-2.4). A large effect size for antidepressant effectiveness was found when pooling active arms of RCTs with data from uncontrolled studies (Cohen's d = 1.4), with rates of response (46.81%) and remission (28.25%) similar to those described for MDD and preserved in subanalyses for high-frequency protocols, including intermittent theta burst stimulation (iTBS) delivered to the left dorsolateral prefrontal cortex (DLPFC) and low-frequency protocols delivered to the right DLPFC. Higher baseline illness severity and more treatment sessions were predictors of greater antidepressant effect.

CONCLUSIONS

TMS is efficacious and safe in BDep, with response and remission rates on par with rates for unipolar depression. High- and low-frequency protocols on the left and right DLPFC, respectively, are robustly associated with positive outcomes, with left DLPFC iTBS showing noninferiority to more widely used high-frequency rTMS protocols.