Manic switching is seldom observed during rTMS therapy for unipolar depression: Implications for antidepressant mechanisms

Recent Japanese real ‐ world studies may provide an informative context for considering mood switching during repetitive transcranial magnetic stimulation (rTMS) for depression. In both studies, treat-ment under the Japanese public health insurance system was delivered using the NeuroStar TMS Therapy System, with the left dorsolateral prefrontal cortex target defined as 5.5 cm anterior to the site used to determine the motor threshold. Stimulation was delivered at a frequency of 10 Hz and an intensity of 120% of the standard motor threshold. Each session comprised 75 trains, each lasting 4 s stimulation, yielding a total of 3000 pulses. Treatment was administered once daily, generally 5 days per week, for up to 30 sessions. 1,2 In a registry ‐ based report from the Kansai TMS network, Imazu et al. 1 described 102 consecutive patients treated with rTMS within the Japanese public health insurance system and reported no serious adverse events (0/102; 0%); manic or hypomanic events were not separately reported. In our subsequent nationwide observational report, Matsuda et al. 2 retrospectively collected clinical data from 21 institutes between June 2019 and December 2023; 497 patients with treatment ‐ resistant depression were candidates for analysis, dropout due to adverse effects was 4.2%, and no convulsive seizures or manic changes were observed (0/497; 0%). In light of these observations, treatment ‐ emergent mania or hypomania appears to be seldom observed during standard rTMS for appropriately selected patients with unipolar depression. This observation is relevant not only to the safety profile of rTMS but also to the possibility that different antidepressant interventions differ in switch liability. This impression is broadly consistent with the wider literature (Table S1). A review of rTMS ‐ associated mania and hypomania suggests that such events are rare overall, and that many published cases occurred in clinical contexts that differ from present ‐