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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).<\/jats:p>","DOI":"10.31083\/ap47383","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:23:51Z","timestamp":1788438231000},"source":"Crossref","is-referenced-by-count":0,"title":["Efficacy of Transcranial Alternating Current Stimulation for Major Depressive Disorder and the Role of Intensity: A Systematic Review and Exploratory Meta-Analysis"],"prefix":"10.31083","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8617-4420","authenticated-orcid":true,"given":"Li","family":"Qi","sequence":"first","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China"},{"name":"Department of Psychology and Sleep Medicine, The Second Affiliated Hospital of Anhui Medical University, 230601 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhishun","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital of Anhui Medical University, 230601 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6197-914X","authenticated-orcid":true,"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China"},{"name":"Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, 230088 Hefei, Anhui, China"},{"name":"Anhui Province Key Laboratory of Cognition and Neuropsychiatric Disorders, 230032 Hefei, Anhui, China"},{"name":"Collaborative Innovation Center of Neuropsychiatric Disorders and Mental Health, 230032 Hefei, Anhui, China"},{"name":"Anhui Institute of Translational Medicine, 230032 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Psychology and Sleep Medicine, The Second Affiliated Hospital of Anhui Medical University, 230601 Hefei, Anhui, China"},{"name":"Anhui Province Key Laboratory of Cognition and Neuropsychiatric Disorders, 230032 Hefei, Anhui, China"},{"name":"Collaborative Innovation Center of Neuropsychiatric Disorders and Mental Health, 230032 Hefei, Anhui, China"},{"name":"Anhui Institute of Translational Medicine, 230032 Hefei, Anhui, China"},{"name":"The School of Mental Health and Psychological Sciences, Anhui Medical University, 230032 Hefei, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongjian","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Anhui Medical University, 230022 Hefei, Anhui, China"},{"name":"Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, 230088 Hefei, Anhui, China"},{"name":"Anhui Province Key Laboratory of Cognition and Neuropsychiatric Disorders, 230032 Hefei, Anhui, China"},{"name":"Collaborative Innovation Center of Neuropsychiatric Disorders and Mental Health, 230032 Hefei, Anhui, China"},{"name":"Anhui Institute of Translational Medicine, 230032 Hefei, Anhui, 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