Efficacy and Safety of Transcranial Alternating Current Stimulation (tACS) Combined With Stable Medication in Adolescents With Depression

This randomized, double-blind, sham-controlled pilot trial will evaluate transcranial alternating current stimulation (tACS) as an adjunct to stable pharmacotherapy in adolescents with major depressive disorder (MDD). Eligible participants will be aged 12-18 years, meet DSM-5 criteria for a current depressive episode, have a Children's Depression Rating Scale-Revised (CDRS-R) score of at least 40, and have received stable antidepressant treatment for at least 4 weeks. Thirty participants will be randomized 1:1 to active or sham stimulation while continuing their current medication. The active group will receive 20 sessions over 4 weeks using the NEXALIN ADI device (77.5 Hz, 15 mA, approximately 40 minutes per session). The sham device will be identical in appearance but will deliver no current. Participants and operators will remain blinded. Primary outcomes will assess recruitment feasibility, intervention adherence, follow-up retention, and safety and tolerability. These will be evaluated through the number of participants enrolled over a recruitment period of up to 2 years, the number and proportion completing all 20 treatment sessions by Week 4, the number and proportion completing the Week 16 assessment, and the number and proportion experiencing adverse events or serious adverse events from the first stimulation session through Week 16. Pre-specified exploratory outcomes will assess changes in CDRS-R total scores and CDRS-R-defined response and remission rates, as well as changes in depressive and anxiety symptoms, suicidal ideation severity, overall illness severity, sleep quality, rumination, and pediatric health-related quality of life using the BDI-II, SCARED, HAMA, C-SSRS, CGI-S, PSQI, RRS, and PedsQL 4.0. Overall clinical improvement will be assessed using the CGI-I. Additional exploratory outcomes will include THINC-it cognitive performance, magnetic resonance imaging, electroencephalography, functional near-infrared spectroscopy, eye tracking, facial expression features, and acoustic features.