The Clinical Trial of Transcranial Alternating Current Stimulation in the Treatment of Treatment-Resistant Depression

Study Overview
=================
Brief Summary
-----------------
The goal of this clinical trial is to investigate the effectiveness and safety of twice-daily 15 mA transcranial alternating current stimulation though three Nexalin conductive electrodes attached to the scalp in subjects with treatment-resistant major depression (TRD). Two hundreds adult subjects with TRD will be included in this randomized, double-blind, parallelized, multi-center clinical trial. The primary outcome measure will be the change in the Montgomery-Asberg Depression Rating Scale (MADRS) four weeks after the commencement of stimulation.

Detailed Description
-----------------
This was a multicenter, double-blind, sham-controlled, randomized, parallel-group (2 groups), 4-week, tACS trial. TRD was 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 were randomized if they remained moderately ill, assessed by Hamilton Depression Scale-item 17 (HAMD-17) score ≥ 20. Change in the MADRS total score after four weeks of tACS was the primary efficacy outcome measure. Remission was defined as MADRS total score ≤10 at Week 4. Response was defined as a ≥50% reduction in MADRS total score from baseline to Week 4 and Week 8. All participants will be treated for a total of 20 sessions with stimulation at 77.5 Hz and 15 mA (Active group) or sham stimulation (Sham group). From Monday to Friday, each session will last 40 min at a fixed daytime interval for four weeks.

Official Title
-----------------
The Clinical Trial of Transcranial Alternating Current Stimulation in the Treatment of Treatment-Resistant Depression

Conditions
-----------------
Treatment-Resistant Depression

Intervention / Treatment
-----------------
* Device: transcranial alternating current stimulation (tACS)
* Device: Sham tACS


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: (i) male or female, 18-65 years old; (ii) able to provide written informed consent voluntarily; (iii) 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; (iv) failure of response to at least two antidepressant medication trials based on the Massachusetts General Hospital antidepressant treatment response questionnaire (MGH-ATRQ); (v) ongoing antidepressant(s) at a fixed dose for at least four weeks prior to baseline assessment; (vi) had a score of ≥20 on the Hamilton Depression Scale- item 17 (HAMD-17) at baseline. Exclusion Criteria: (i) 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); (ii) a treatment history of electroconvulsive therapy (ECT), modified ECT, transcranial direct current stimulation, transcranial alternating current stimulation, deep brain stimulation, and transcranial magnetic stimulation (TMS); (iii) risk for suicide (defined as a score of ≥ 3 on the suicide item of HAMD-17); (iv) known allergy to electrode materials; (v) inability to communicate with researchers fluently; (vi) traumatic brain injury; (vii) cerebrovascular or cardiovascular stents; (viii) substance use disorder (abuse or dependence, as defined by DSM-IV-TR) in the previous six months; (ix) for females, pregnant or breastfeeding, or females of childbearing potential refused to use reliable contraceptive methods during the study; (x) dementia (as defined by Short Blessed > 10 and/or clinical evidence of dementia); (xi) participated in other clinical research within three months before enrollment in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: transcranial alternating current stimulation (tACS)<br>Three Nexalin conductive electrodes will be placed overhead. In the 10/20 international placement system, a 4.45 times 9.53 cm electrode is placed on the forehead corresponding to Fpz, Fp1, and Fp2. Two 3.18 times 3.81 cm electrodes are placed on the mastoid region of each side. The tACS stimulation waveform includes ramp-up and ramp-down periods of 180 and 12 s, respectively. It is a square-wave with an average amplitude of 15 mA and is equally distributed from the frontal region to the mastoid areas (amplitudes are reported as zero-to-peak). All participants will be treated for a total of 20 sessions with stimulation at 77.5 Hz and 15 mA. From Monday to Friday, each session will last 40 min at a fixed daytime interval. | Device: transcranial alternating current stimulation (tACS)<br>* Three Nexalin conductive electrodes will be placed overhead. In the 10/20 international placement system, a 4.45 times 9.53 cm electrode is placed on the forehead corresponding to Fpz, Fp1 and Fp2. Two 3.18 times 3.81 cm electrodes are placed on the mastoid region of each side. The tACS stimulation waveform includes ramp-up and ramp-down periods of 180 and 12 s, respectively. It is a square-wave with an average amplitude of 15 mA and is equally distributed from the frontal region to the mastoid areas (amplitudes are reported as zero-to-peak). All participants will be treated for a total of 20 sessions with stimulation at 77.5 Hz and 15 mA. From Monday to Friday, each session will last 40 min at a fixed daytime interval.<br>|
| Sham Comparator: Sham tACS<br>no active stimulation | Device: Sham tACS<br>* Sham tACS<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MADRS | the change from baseline to 4 weeks in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| remission rate | the remission rate (defined as MADRS total score ≤10) at Week 4; | 4 weeks | 
| response rates | the response rates defined as a ≥50% reduction in MADRS total score from baseline to Week 4 and Week 8; | week 4-week 8 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Treatment-Resistant Depression; tACS