Abstract
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.
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Data availability
The data that support the findings of this study are available on request from the corresponding author Bomin Sun and Xin Lv. Raw data are protected and are not publicly available due to data privacy laws. Access to the data is restricted to psychiatry or neurology specialists, with a response timeframe of one month and a validity period of six months. The datasets will be distributed by email upon reasonable request.
Code availability
Statistical analysis in this study was performed using SPSS (version 27.0, IBM Corp.) and R (version 4.3.0, R Foundation for Statistical Computing). SPSS is a commercial software, while R is an open-source platform publicly available from its official website (https://www.r-project.org/). The specific R scripts, data analysis pipelines, and custom functions used to generate the reported results are available from the corresponding author Bomin Sun and Xin Lv for non-commercial, academic research purposes.
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Acknowledgements
This study was funded by the National Natural Science Foundation of China (32571273, 82271515, 82401813, T2293730, T2293734), the Scientific and technological innovation action plan of Shanghai (KY20211478), the Shanghai Municipal Science and Technology Major Project (2021SHZDZX), the Nursing Development Program of Shanghai Jiao Tong University School of Medicine (SJTUHLXK2022), 2024 Shanghai Ruijin Hospital Nursing Research Fund (RJHK-2024-001), and 2024 Shanghai Nursing Association Research Fund (2024MS-B13).
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L.X. and W.Y.H. designed this study and developed the methodology; Y.K.H., W.Y.H., G.H.H., L.D.B., M.Y., S.Z.Y., H.P., P.Y.X. performed the experiments and collected the data. L.X., W.Y.H., and N.C.B. conducted the statistical analysis. L.X., S.B.M., W.J.J., C.Y., S.L., Q.X. supervised the project; W.Y.H., S.B.M. acquired the funding; All authors participated in writing, reviewing, and editing the manuscript.
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Wu, Y., Ning, C., Shi, L. et al. A multicenter randomized clinical trial of portable transcranial alternating current stimulation for major depressive disorder. npj Digit. Med. (2026). https://doi.org/10.1038/s41746-026-02575-9
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DOI: https://doi.org/10.1038/s41746-026-02575-9
