Transcranial Alternating Current Stimulation for Treating Depression

A Randomized Controlled Trial

Hongxing Wang; Kun Wang; Qing Xue; Mao Peng; Lu Yin; Xuecun Gu; Haixia Leng; Juan Lu; Hongzhi Liu; Di Wang; Jin Xiao; Zhichao Sun; Ning Li; Kai Dong; Qian Zhang; Shuqin Zhan; Chunqiu Fan; Baoquan Min; Aihong Zhou; Yunyan Xie; Haiqing Song; Jing Ye; Aihua Liu; Ran Gao; Liyuan Huang; Lidong Jiao; Yang Song; Huiqing Dong; Zichen Tian; Tianmei Si; Xiangyang Zhang; Xinmin Li; Atsushi Kamiya; Fiammetta Cosci; Keming Gao; Yuping Wang


Brain. 2022;145(1):83-91. 

In This Article

Abstract and Introduction


Treatment of depression with antidepressants is partly effective. Transcranial alternating current stimulation can provide a non-pharmacological alternative for adult patients with major depressive disorder. However, no study has used the stimulation to treat first-episode and drug-naïve patients with major depressive disorder.

We used a randomized, double-blind, sham-controlled design to examine the clinical efficacy and safety of the stimulation in treating first-episode drug-naïve patients in a Chinese Han population. From 4 June 2018 to 30 December 2019, 100 patients were recruited and randomly assigned to receive 20 daily 40-min, 77.5 Hz, 15 mA, one forehead and two mastoid sessions of active or sham stimulation (n = 50 for each group) in four consecutive weeks (Week 4), and were followed for additional 4-week efficacy/safety assessment without stimulation (Week 8). The primary outcome was a remission rate defined as the 17-item Hamilton Depression Rating Scale (HDRS-17) score ≤ 7 at Week 8. Secondary analyses were response rates (defined as a reduction of ≥ 50% in the HDRS-17), changes in depressive symptoms and severity from baseline to Week 4 and Week 8, and rates of adverse events. Data were analysed in an intention-to-treat sample.

Forty-nine in the active and 46 in the sham completed the study. Twenty-seven of 50 (54%) in the active treatment group and 9 of 50 (18%) in the sham group achieved remission at the end of Week 8. The remission rate was significantly higher in the active group compared to that in the sham group with a risk ratio of 1.78 (95% confidence interval, 1.29, 2.47). Compared with the sham, the active group had a significantly higher remission rate at Week 4, response rates at Weeks 4 and 8, and a larger reduction in depressive symptoms from baseline to Weeks 4 and 8. Adverse events were similar between the groups.

In conclusion, the stimulation on the frontal cortex and two mastoids significantly improved symptoms in first-episode drug-naïve patients with major depressive disorder and may be considered as a non-pharmacological intervention for them in an outpatient setting.


Depression is a highly prevalent mental disorder that places a heavy burden on society and increases the risk of suicide.[1] Despite antidepressants and psychotherapies being available, they are only partially effective in treating depression,[2,3] and >20% of patients fail to respond to antidepressants and psychotherapy interventions.[4–6] Transcranial magnetic stimulation (TMS), as level A evidence (definite efficacy),[7,8] has recently received attention as a non-pharmaceutical treatment for patients with depression who have failed antidepressant treatment.[9] However, the findings of the TMS procedure in different trials have shown inconsistent results,[7,10] and the risk of seizure has been reported to be small.[11] Another widely used non-invasive cranial electrotherapy stimulation, transcranial direct current stimulation (tDCS), as a level B of evidence (probable efficacy),[12,13] showed a better effect than placebo in reducing depressive symptoms in patients with unipolar depression, but also produced 3% (2 in 72) new-onset mania/hypomania.[14] Both TMS and tDCS may have the potential for cognitive improvements.[15]

Transcranial alternating current stimulation (tACS) is another method of cranial electrotherapy stimulation, which provides brain stimulation by applying changing intensity electrical currents to the scalp to regulate cortical excitability and spontaneous brain activity.[16–20] Compared with tDCS, tACS appears to have an advantage because it involves less sensory experience[21] and has fewer known adverse effects.[22] Although tACS is regarded as a promising method for treating patients with depression,[23] the evidence for the effectiveness of tACS in depression remains limited.[24] A few studies have assessed tACS as a treatment for depression, but provided uncertain interpretations due to lack of methodological rigour.[25,26] Through electrodes placed on the forehead and mastoid regions, tACS (with a frequency of 77.5 Hz) has an antinociceptive effect by increasing the levels of beta-endorphin and neurotransmitters (including serotonin) in the CSF, brainstem, hypothalamus and cortex.[27,28] Some of these changes are believed to be the neurobiological mechanisms for improving depressive symptoms.[29,30] Therefore, we think that tACS with a frequency of 77.5 Hz may have a therapeutic effect on adults with major depression.

Our pilot study with a frequency of 77.5 Hz and 15 mA current over the frontal region and both mastoid regions (n = 30 in the sham and active groups) showed that tACS had good feasibility and acceptability in patients with first-episode drug-naïve major depressive disorder (MDD).[20] To the best of our knowledge, no other clinical studies have tested the efficacy of tACS in patients with first-episode drug-naïve MDD. Moreover, depressive patients have different illness courses, such as a first-episode versus recurrent episode, acute versus chronic illness and treatment response versus treatment-resistance. Each different group of patients have different treatment responses and distinct prognoses.[31,32] Therefore, our current study aimed to use a larger sample size of patients with first-episode drug-naïve MDD in a Chinese Han population to examine the efficacy and safety of tACS, with a frequency of 77.5 Hz and a current of 15 mA over the frontal region and both mastoid regions. We hypothesized that active tACS would have significantly more antidepressive effects than sham tACS. We also posited that there was no significant difference in the incidence of adverse events between the two groups.