Safety and efficacy of high-current tTIS targeting left sgACC for major depressive disorder: A randomized, double-blind, sham-controlled trial.

Major depressive disorder (MDD) is a leading cause of disability, and non-invasive stimulation of deep brain circuits such as the subgenual anterior cingulate cortex (sgACC) remains challenging. This randomized, double-blind, sham-controlled trial recruits 96 adults with moderate-to-severe MDD who received 10 sessions of 2 mA low-current, 15 mA high-current, or sham transcranial temporal interference stimulation (tTIS) targeting the left sgACC. The high-current group shows significantly greater reductions in depressive symptoms (17-item Hamilton Depression Rating Scale [HDRS-17] score) post-treatment and at 1-month follow-up compared with sham and outperforms the low-current group post-treatment. Exploratory Pittsburgh Sleep Quality Index (PSQI) analyses suggest improved sleep quality in both active groups, whereas anxiety outcomes show no intergroup differences. High-current tTIS is safe and well tolerated, with only transient tingling. These findings provide preliminary evidence that sgACC-targeted tTIS relieves depressive symptoms safely, with more robust short-to medium-term effects observed under the 15 mA protocol. This trial registers on Chictr.org.cn (ChiCTR2400094971).