Efficacy of Transcranial Alternating Current Stimulation for Major Depressive Disorder and the Role of Intensity: A Systematic Review and Exploratory Meta-Analysis.

BACKGROUND: Current treatments for major depressive disorder (MDD) are limited by efficacy and adverse effects. Transcranial alternating current stimulation (tACS) has emerged as a promising alternative. However, there is still a lack of systematic evaluation of its effectiveness. Recent studies suggest that currents greater than 7 milliamperes (mA) may be necessary to significantly alter potentials in deep brain regions associated with depression. We conducted a systematic review and exploratory meta-analysis to assess the overall efficacy and safety of tACS for MDD and to explore potential associations regarding current intensity by comparing high-intensity tACS (HI-tACS) and low-intensity tACS (LI-tACS) protocols. METHODS: A systematic search of Embase, PubMed, Web of Science, the Cochrane Library, ClinicalTrials.gov, and WHO ICTRP was conducted from inception to January 5, 2026. Data were analyzed using a random-effects model, assessing changes in depressive scale scores, response and remission rates, discontinuation, and adverse events. RESULTS: Randomized controlled trials with 438 participants were included. Compared to sham stimulation, active tACS was associated with a significant reduction in depressive symptoms (moderate effect size). In an exploratory subgroup analysis, HI-tACS was associated with a larger effect size (large effect) than LI-tACS (small effect), with lower heterogeneity observed within subgroups. The HI-tACS group also showed significantly higher response and remission rates. No significant differences in adverse events or treatment discontinuations were observed between the two subgroups. CONCLUSIONS: Our results suggest that tACS may be a potentially effective treatment for MDD. Data from exploratory subgroup analyses provide preliminary, hypothesis-generating evidence that higher intensity may be associated with improved outcomes. However, given the limited evidence base and substantial heterogeneity, as well as the fact that intensity co-varied with stimulation frequency and other parameters in the included trials, these findings do not establish a sole causal link for intensity. Future large-scale, controlled, multi-arm trials are needed to disentangle these factors and confirm these preliminary observations. THE PROSPERO REGISTRATION: The study has been registered on https://www.crd.york.ac.uk/prospero/ (registration number: CRD42024589889; registration link: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024589889).