A multicenter randomized clinical trial of portable transcranial alternating current stimulation for major depressive disorder.

High-definition transcranial alternating current stimulation (HD-tACS) is an emerging neuromodulatory intervention for major depressive disorder (MDD). Here, we evaluate the efficacy and safety of a portable, low-intensity (1.6 mA), 10 Hz HD-tACS protocol targeting the bilateral dorsolateral prefrontal cortex (DLPFC) in adults with MDD. This randomized clinical trial was conducted including 120 adult MDD participants. Participants underwent 20 sessions (5 sessions/week for 4 weeks) of either active 10 Hz HD-tACS (1.6 mA) or sham stimulation a ratio of 1:1 and were followed for an additional 4 weeks. The primary outcome was the percentage reduction in 17-item Hamilton Depression Rating Scale scores at week 4. The active group showed significantly greater improvement in depression than the sham group (48% ± 14% vs 24% ± 13%, p < 0.001), sustained through the 4-week follow-up period. Additionally, significant improvements in the active group were also found in anxiety, sleep efficiency, quality of life components of physical, vitality, social functioning, and mental health. Adverse events including two cases of new-onset hypomania occurred, but no serious adverse events were observed. Thus, this trial supported the efficacy and good tolerability of 10 Hz HD-tACS for patients with MDD. Further research requires more focus on the underlying neural mechanisms and the optimized stimulation protocols. Trial Registration: China Clinical Trial Registry Identifier: ChiCTR2500103570. ClinicalTrials.gov Identifier: NCT06891326.