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Transcranial direct current stimulation (tDCS), with advantages such as affordability, home-use application, and mild side effects, has been proposed for treating depression. Yet, its clinical efficacy is not established. Optimizing tDCS interventions for more effective and feasible clinical application is a need and topic of ongoing research. This randomized, sham\u2011controlled trial compares the efficacy of computationally optimized multichannel tDCS (4\u2009mA), a less source-demanding alternative for personalized tDCS, vs conventional tDCS (2\u2009mA) for treating unipolar depression. Seventy-one\u00a0patients were randomly assigned to the optimized multichannel tDCS, conventional tDCS, and sham tDCS arms, of whom 60 provided\u00a0endpoint data. In the optimized multichannel tDCS, electrical current was delivered via 7 small electrodes (max 1.65\u2009mA per electrode; total injected current per polarity \u2248\u00a04\u2009mA [precisely 3.99\u2009mA]) while in the conventional (2\u2009mA per electrode) and sham tDCS, two 35\u2009cm\u00b2 sponge electrodes were used. Intervention efficacy and treatment response were evaluated before the intervention, at weeks 2, 4, 6, and 1- and 3-month post-intervention, and cognitive functions and brain connectivity changes were assessed before and\u00a0after the intervention. Both active tDCS interventions significantly reduced depressive symptoms compared to the sham group after the intervention. The optimized multichannel tDCS demonstrated earlier and stronger symptom alleviation than conventional tDCS. It additionally improved cognitive control and modulated functional connectivity markers associated with depression pathophysiology. The mean change in the primary clinical outcome from baseline to the study endpoint was 6.30 in the sham group and 13.50 and 21.50 in the conventional and multichannel tDCS groups, with corresponding response rate (\u226550% symptom reduction) of 20% (4\/20), 45% (9\/20), and 75% (15\/20), respectively. Blinding was unsuccessful only in the optimized multichannel arm, likely due to more intense stimulation-related sensations, however, this did not impact clinical outcomes. The optimized multichannel 4\u2009mA tDCS shows clinical efficacy for treating depression, warranting further investigations in the future. Trial Registration Identifier:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT06165445\" ext-link-type=\"uri\">NCT06165445<\/jats:ext-link>\n                    \/ IRCT20210517051330N1.\n                  <\/jats:p>","DOI":"10.1038\/s41380-026-03560-0","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T18:06:32Z","timestamp":1775153192000},"page":"4632-4644","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Optimized multichannel 4\u2009mA vs conventional transcranial direct current stimulation for major depressive disorder: A randomized sham-controlled trial"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1913-4677","authenticated-orcid":false,"given":"Mohammad Ali","family":"Salehinejad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzieh","family":"Abdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsen","family":"Dadashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Habibi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir-Homayun","family":"Hallajian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiomars","family":"Sharifi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Khadem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Salvador","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Ruffini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2207-5965","authenticated-orcid":false,"given":"Michael A.","family":"Nitsche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"3560_CR1","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1016\/S0140-6736(24)00757-8","volume":"403","author":"AJ Ferrari","year":"2024","unstructured":"Ferrari AJ, Santomauro DF, Aali A, Abate YH, Abbafati C, Abbastabar H, et al. 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