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

Disclosures

Brain. 2022;145(1):83-91.

Abstract and Introduction

Abstract

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.

Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Baseline demographics and historical characteristics
Characteristics	All (n = 100)	Active (n = 50)	Sham (n = 50)	P-value^a
Age at the enrolment, years, mean (SD)	40.0 (12.6)	38.3 (12.2)	41.6 (12.8)	0.10
Sex, n (%)				0.36
Male	26 (26.0)	11 (22.0)	15 (30.0)
Female	74 (74.0)	39 (78.0)	35 (70.0)
Marital status, n (%)				0.26
Married	27 (27.0)	11 (22.0)	16 (32.0)
Single	73 (73.0)	39 (78.0)	34 (68.0)
Educational level, n (%)				1.00
Had high school education	93 (93.0)	47 (94.0)	46 (92.0)
Over high school education	7 (7.0)	3 (6.0)	4 (8.0)
Occupational status, n (%)				0.44
Unemployed or retired	7 (7.0)	2 (4.0)	5 (10.0)
Employed	93 (93.0)	48 (96.0)	45 (90.0)
BMI, kg/m², mean (SD)	23.5 (2.4)	23.8 (2.5)	23.3 (2.3)	0.48
Duration, months, mean (SD)	9.0 (4.0)	9.6 (3.8)	8.5 (4.3)	0.08
HDRS-17 total score, mean (SD)	27.0 (3.3)	27.3 (3.7)	26.6 (2.9)	0.09
CGI-S, mean (SD)	5.1 (0.6)	5.1 (0.6)	5.1 (0.7)	0.95
YMRS, mean (SD),	0.4 (0.6)	0.5 (0.7)	0.4 (0.5)	0.58
Family history of depression, n (%)	0 (0)	0 (0)	0 (0)	–
History of alcohol, smoking, drug, n (%)	0 (0)	0 (0)	0 (0)	–
History of neurological disorder, n (%)	0 (0)	0 (0)	0 (0)	–
History of other psychiatric disorder, n (%)	0 (0)	0 (0)	0 (0)	–
History of traumatic brain injury, n (%)	0 (0)	0 (0)	0 (0)	–

BMI = body mass index; SD = standard deviation.
^a P-values were obtained using chi-square tests or Fisher's exact tests for categorical variables, and Mann-Whitney U-tests for continuous variables.

Table 2. Differences between active and sham treatments in primary and secondary outcome measures at Week 4 and Week 8 in the ITT sample
Outcomes	Baseline		Week 4				Week 8				P-value^b
Outcomes	Active (n = 50)	Sham (n = 50)	Active (n = 49)	Sham (n = 46)	Effect size^a (95% CI)	P-value	Active (n = 49)	Sham (n = 46)	Effect size^a 95% CI)	P-value	P-value^b
Remission rate, n (%)^c,d
Risk ratio	NA	NA	31 (62.0)	13 (26.0)	1.95 (1.32, 2.88)	<0.01	27 (54.0)	9 (18.0)	1.78 (1.29, 2.47)	<0.01	NA
Risk difference	NA	NA	31 (62.0)	13 (26.0)	0.36 (0.18, 0.54)	<0.01	27 (54.0)	9 (18.0)	0.36 (0.19, 0.53)	<0.01	NA
Response rate, n (%)^d,e
Risk ratio	NA	NA	35 (70.0)	21 (42.0)	2.63 (1.29, 5.36)	<0.01	37 (74.0)	19 (38.0)	3.00 (1.40, 6.42)	<0.01	NA
Risk difference	NA	NA	35 (70.0)	21 (42.0)	0.28 (0.09, 0.47)	<0.01	37 (74.0)	19 (38.0)	0.36 (0.18, 0.54)	<0.01	NA
HDRS-17 total score, mean (SD)	27.3 (3.7)	26.6 (2.9)	9.0 (5.8)	15.2 (6.6)	−6.81 (−9.53, −4.09)	<0.01	10.0 (6.6)	15.7 (5.5)	−6.35 (−9.21, −3.49)	<0.01	<0.01
Subscales of HDRS-17
Somatic anxiety^f, mean (SD)	11.4 (1.9)	11.1 (1.7)	3.8 (3.3)	6.6 (3.1)	−3.09 (−4.48, −1.70)	<0.01	4.3 (3.3)	7.3 (2.5)	−3.38 (−4.80, −1.97)	<0.01	<0.01
Psychic anxiety^g, mean (SD)	4.8 (1.1)	4.6 (1.0)	1.6 (1.5)	2.3 (1.4)	−0.90 (−1.56, −0.24)	0.01	1.6 (1.8)	2.3 (1.5)	−0.94 (−1.69, −0.19)	0.01	0.03
Core depressive symptoms^h, mean(SD)	6.4 (0.9)	6.4 (0.7)	3.0 (1.6)	4.4 (2.1)	−1.45 (−2.33, −0.66)	<0.01	3.0 (1.9)	4.2 (1.7)	−1.19 (−1.97, −0.41)	<0.01	0.01
Anorexiaⁱ, mean (SD)	3.4 (0.8)	3.3 (0.7)	0.2 (0.4)	1.1 (1.3)	−0.99 (−1.46, −0.51)	<0.01	0.4 (1.0)	1.0 (1.1)	−0.59 (−1.12, −0.06)	0.03	0.02
Genital symptoms^j, mean (SD)	1.5 (0.5)	1.4 (0.5)	0.2 (0.6)	0.8 (0.9)	−0.66 (−1.02, −0.30)	<0.01	0.5 (0.7)	0.8 (0.8)	−0.38 (−0.41, −0.002)	0.05	0.58
Suicide^k, mean (SD)	1.4 (0.5)	1.5 (0.5)	0.5 (0.7)	0.8 (0.8)	−0.20 (−0.57, 0.17)	0.28	0.4 (0.6)	0.6 (0.6)	−0.11 (−0.45, 0.23)	0.53	0.52
CGI-S, mean (SD)	5.1 (0.6)	5.1 (0.7)	1.1 (1.4)	2.7 (1.1)	−1.63 (−2.20, −1.06)	<0.01	1.8 (1.3)	4.5 (1.0)	−2.74 (−3.25, −2.23)	<0.01	<0.01
CGI-I^d, n (%)											NA
Not improved	NA	NA	2 (4.0)	15 (32.6)	1.00		3 (6.0)	40 (80.0)	1.00
Much or very much improved	NA	NA	48 (96.0)	35 (70.0)	7.50 (1.81, 31.10)	<0.01	47 (94.0)	10 (20.0)	13.33 (4.41, 40.29)	<0.01
YMRS, mean (SD)	0.5 (0.7)	0.4 (0.5)	1.0 (0.8)	0.8 (1.0)	0.14 (−0.17, 0.45)	0.37	0.5 (0.6)	0.4 (0.5)	−0.01 (−0.26, 0.24)	0.96	0.80
Adverse reaction^l, n (%)											NA
Risk ratio	NA	NA	10 (20.0)	6 (12.0)	1.10 (0.93, 1.31)	0.28	10 (20.0)	6 (12.0)	1.10 (0.93, 1.31)	0.28
Risk difference	NA	NA	10 (20.0)	6 (12.0)	0.08 (−0.06, 0.22)	0.28	10 (20.0)	6 (12.0)	0.08 (−0.06, 0.22)	0.28
Rate of epileptiform activities, n (%)	0	0	0	0	NA	NA	0	0	NA	NA	NA

NA = not applicable.
^aEffect size was defined as risk ratio or risk difference for categorical outcomes and mean difference from baseline for continuous outcomes (if baseline data were available) between two groups.
^b P-value for an interaction effect between group (active versus sham) and time (baseline, Week 4, Week 8) in the linear mixed-effects models.
^cRemission rate was defined as an HDRS-17 score ≤7.
^dCalculated based on 100 randomized participants using worst-case imputation.
^eResponse rate was defined as a ≥ 50% reduction of HDRS-17 from baseline.
^fSomatic anxiety using seven items from HDRS-17 (Early insomnia, Middle insomnia, Late insomnia, Somatic anxiety, Gastrointestinal symptoms, General somatic symptoms and Hypochondria).
^gPsychic anxiety symptoms using four items from HDRS-17 (Guilt, Agitation, Psychic anxiety and Insight).
^hCore depressive symptoms using three items from HDRS-17 (Depressed mood, Work and interests and Retardation).
ⁱAnorexia using two items from HDRS-17 (Gastrointestinal symptoms and Weight loss).
^jGenital symptoms using one item from HDRS-17 (Genital symptoms).
^kSuicide using one item from HDRS-17 (Suicide).
^lAll adverse reactions occurred during treatment.

Table 3. Summary of the most common non-serious adverse events and duration experienced by participants in both groups
Participant ID	Group	Type of adverse event	Duration
5	Sham group	Headache	1 day
15	Sham group	Tinnitus cerebri	1 day
35	Sham group	Aurium tinnitus	2 days
36	Sham group	Discomfort	3 days
50	Sham group	Itches	4 days
90	Sham group	Tinnitus cerebri	2 days
3	Active group	Aurium tinnitus	2 days
4	Active group	Tinnitus cerebri	1 day
13	Active group	Discomfort	2 days
33	Active group	Headache	2 days
43	Active group	Aurium tinnitus	3 days
52	Active group	Aurium tinnitus	2 days
59	Active group	Tinnitus cerebri	2 days
62	Active group	Aurium tinnitus	2 days
71	Active group	Itches	3 days
74	Active group	Discomfort	3 days

Authors and Disclosures

Hongxing Wang^1,2, Kun Wang^1,3, Qing Xue¹, Mao Peng¹, Lu Yin⁴, Xuecun Gu³, Haixia Leng¹, Juan Lu³, Hongzhi Liu³, Di Wang³, Jin Xiao³, Zhichao Sun¹, Ning Li¹, Kai Dong¹, Qian Zhang¹, Shuqin Zhan¹, Chunqiu Fan¹, Baoquan Min¹, Aihong Zhou¹, Yunyan Xie¹, Haiqing Song¹, Jing Ye¹, Aihua Liu¹, Ran Gao¹, Liyuan Huang¹, Lidong Jiao¹, Yang Song¹, Huiqing Dong¹, Zichen Tian⁵, Tianmei Si⁶, Xiangyang Zhang⁷, Xinmin Li⁸, Atsushi Kamiya⁹, Fiammetta Cosci¹⁰, Keming Gao¹¹ and Yuping Wang¹

1 Division of Neuropsychiatry and Psychosomatics, Department of Neurology, Beijing Psychosomatic Disease Consultation Center, Xuanwu Hospital, National Center for Neurological Disorders, National Clinical Research Center for Geriatric Diseases, Capital Medical University, Beijing 100053, China
2 Institute of Sleep and Consciousness Disorders, Center of Epilepsy, Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100053, China
3 Department of Neurology, Beijing Puren Hospital, Beijing 100062, China
4 Medical Research & Biometrics Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
5 Department of Biology, Carleton College, Northfield, MN 55057, USA
6 Key Laboratory of Mental Health, Ministry of Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University Sixth Hospital and Peking University Institute of Mental Health, Beijing 100191, China
7 CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China
8 Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Albert T6G 2B7, Canada
9 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore MD 21287, USA
10 Department of Health Sciences, University of Florence, Florence 50135, Italy
11 Department of Psychiatry, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA

Correspondence to
Hongxing Wang, MD, PhD Division of Neuropsychiatry and Psychosomatics, Department of Neurology, Beijing Psychosomatic Disease Consultation Center, Xuanwu Hospital, National Center for Neurological Disorders National Clinical Research Center for Geriatric Diseases, Capital Medical University 45 Changchun Street, Beijing 100053, China E-mail: wanghongxing@xwh.ccmu.edu.cn

Correspondence may also be addressed to
Yuping Wang, MD, PhD E-mail: wangyuping01@sina.cn

Competing interests
The authors report no competing interests.