This trial aims to investigate the effect of twice-daily 15 mA transcranial alternating current stimulation (tACS) through three conductive electrodes attached to the scalp in subjects with treatment-resistant depression (TRD). Two hundred adult subjects with TRD will be included in this randomized, double-blind, parallelized, multi-centre study. The primary outcome is the change of the Montgomery-Asberg Depression Rating Scale (MADRS) after four weeks of tACS.

This is an 8-week, multicenter, double-blind, sham-controlled, randomized, parallel-group trial.

TRD is defined as failure of response to at least two antidepressant medication trials based on the Massachusetts General Hospital antidepressant treatment response questionnaire (MGH-ATRQ). Patients will be randomized if they remain moderately ill, assessed by Hamilton Depression Scale-item 17 (HAMD-17) score ≥ 20. The primary outcome is a change in the MADRS total score after four weeks of tACS.

"Remission" is defined as MADRS total score ≤10 at Week 4 and Week 8. "Response" is a ≥50% reduction in MADRS total score from baseline to Week 4 and Week 8.

All participants will receive 40 sessions with stimulation at 77.5 Hz and 15 mA (Active group) or sham stimulation (Sham group).

Each session will last 40 minutes from Monday to Friday at a fixed daytime interval for four continuous weeks.

Inclusion Criteria:

1. 18-65 years old;
2. able to provide written informed consent;
3. had a diagnosis of major depression disorder (MDD) (recurrent episodes) without psychotic features in compliance with the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revised (DSM-IV-TR) and confirmed by the Mini-International Neuropsychiatric Interview Chinese version 5.0;
4. failure to respond to at least two antidepressant medication trials based on the MGH-ATRQ;
5. ongoing antidepressant(s) at a fixed dose for at least four weeks before baseline assessment;
6. scored≥20 on the Hamilton Depression Scale-item 17 (HAMD-17) at baseline.

Exclusion Criteria:

1. Axis I psychiatric disorders, including schizophrenia, bipolar disorder, manic episodes, anxiety disorders (panic disorder, generalized anxiety disorder, and social anxiety disorder), post-traumatic stress disorder, obsessive-compulsive disorder, anorexia nervosa, bulimia nervosa, psychosis over the previous six months, and any disorders in Axis II (borderline personality disorder, antisocial personality disorder, schizotypal personality disorder, and narcissistic personality disorder);
2. a treatment history of electroconvulsive therapy (ECT), modified ECT, transcranial direct current stimulation, tACS, deep brain stimulation, and transcranial magnetic stimulation (TMS);
3. risk for suicide (defined as a score of ≥ 3 on the suicide item of HAMD-17);
4. known allergy to electrode materials;
5. inability to communicate with researchers fluently;
6. traumatic brain injury;
7. cerebrovascular or cardiovascular stents;
8. substance use disorder (abuse or dependence, as defined by DSM-IV-TR) in the previous six months;
9. for females, pregnant or breastfeeding, or females of childbearing potential refused to use reliable contraceptive methods during the study;
10. dementia (as defined by Short Blessed > 10 and/or clinical evidence of dementia);
11. participated in other clinical research within three months before enrollment in this study.