This randomized, double-blind, sham-controlled pilot study will evaluate the feasibility, acceptability, safety, and preliminary clinical effects of transcranial alternating current stimulation as an adjunctive treatment for adolescents with major depressive disorder. It will also examine changes in depressive symptoms and related clinical outcomes, while exploring potential effects on emotional regulation, cognitive function, and brain function following the intervention.
This randomized, double-blind, sham-controlled pilot trial will evaluate transcranial alternating current stimulation (tACS) as an adjunct to stable pharmacotherapy in adolescents with major depressive disorder (MDD). Eligible participants will be aged 12-18 years, meet DSM-5 criteria for a current depressive episode, have a Children's Depression Rating Scale-Revised (CDRS-R) score of at least 40, and have received stable antidepressant treatment for at least 4 weeks. Thirty participants will be randomized 1:1 to active or sham stimulation while continuing their current medication. The active group will receive 20 sessions over 4 weeks using the NEXALIN ADI device (77.5 Hz, 15 mA, approximately 40 minutes per session). The sham device will be identical in appearance but will deliver no current. Participants and operators will remain blinded. Primary outcomes will include feasibility, acceptability, safety, and preliminary clinical efficacy. These will be examined through recruitment, treatment completion, follow-up retention, adverse events, and CDRS-R-defined response and remission. Secondary outcomes will assess depressive and anxiety symptoms, suicidality, sleep quality, global clinical status and improvement, rumination, and pediatric health-related quality of life. Exploratory outcomes will include THINC-it cognitive performance, magnetic resonance imaging, electroencephalography, functional near-infrared spectroscopy, eye tracking, facial expression features, and acoustic features.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
30
This intervention uses the NEXALIN ADI alternating current stimulation device from Beijing Naisilin Technology Co., Ltd., to deliver targeted stimulation to the prefrontal cortex and bilateral mastoid regions. The prefrontal cortex electrode directly stimulates the cerebral cortex, while the mastoid electrodes ensure the synchronized activation of bilateral neural pathways. Stimulation is applied at a frequency of 77.5 Hz and a current intensity of 15 mA, aiming to optimize brainwave synchronization and modulate brain activity. Participants will undergo daily sessions lasting approximately 40 minutes each, for a total of 20 sessions over 4 weeks. The non-invasive nature of the intervention, combined with its precise targeting of specific brain regions, distinguishes it from other neuromodulation therapies. The treatment aims to enhance neural synchronization, promote neuroplasticity, and provide a non-pharmacological therapeutic alternative for patients.
In the sham stimulation group, participants will receive intervention using a sham device that is identical in appearance, operation, and stimulation protocol to the real tACS device, but does not deliver any current. Both participants and operators will be unable to distinguish between real and sham stimulation based on the device's appearance, sound, or tactile feedback. Device allocation will follow a randomized code generated in advance to ensure blinding and proper group assignment.
The First Affiliated Hospital of Chongqing Medical University
Chongqing, Chongqing Municipality, China
RECRUITINGRecruitment Feasibility (Number of Participants Enrolled)
The total number of participants successfully enrolled in this study will be recorded to assess recruitment feasibility. The goal is to recruit 30 participants (15 in each of the two groups) over a 2-year period.
Time frame: From the start of recruitment to completion of enrollment, up to 2 years
Intervention adherence (number of participants who completed the full 20 treatment sessions)
This outcome measure will assess participants' adherence to the 20 sessions of transcranial alternating current stimulation. Adherence is defined as completing all 20 sessions. Adherence is calculated by dividing the number of participants who met this criterion by the total number of participants.
Time frame: End of treatment at Week 4
Retention Rate (Number of Participants Remaining at 16-Week Follow-up)
This outcome measure will assess the proportion of participants still enrolled in the study at the 16-week follow-up assessment. Retention rate is calculated as the number of participants who completed the 16-Week assessment divided by the number of participants enrolled at baseline.
Time frame: From randomization through the final follow-up assessment at Week 16
Response rate and remission rate of depressive symptoms
Preliminary clinical efficacy will be assessed by change in the Children's Depression Rating Scale-Revised (CDRS-R) total score from baseline. CDRS-R is a clinician-rated scale used to assess the severity of depressive symptoms in children and adolescents. It consists of 17 items, and the total score ranges from 17 to 113. Higher scores indicate more severe depressive symptoms. Changes in CDRS-R total score from baseline will be assessed at the end of treatment and at follow-up visits. Response rate of depressive symptoms will be defined as a ≥50% reduction in CDRS-R total score from baseline, and remission rate of depressive symptoms will be defined as a CDRS-R total score ≤28.
Time frame: Baseline, throughout the 4-week treatment period, and during follow-up through Week 16
Incidence of Adverse Events and Serious Adverse Events
Adverse events, abbreviated as AEs, and serious adverse events, abbreviated as SAEs, will be assessed to evaluate the safety and tolerability of the intervention. An AE is defined as any unfavorable medical occurrence in a participant during the study period, regardless of whether it is considered related to the intervention. An SAE is defined as any adverse event that results in death, is life-threatening, requires hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, or is otherwise considered medically significant. The number and proportion of participants experiencing at least one AE or SAE will be recorded throughout the study period. The severity, outcome, and relationship to the intervention will also be documented.
Time frame: From the first stimulation session through the final follow-up assessment at Week 16
Change in BDI-II (Beck Depression Inventory-II) scores from baseline
The Beck Depression Inventory-II, abbreviated as BDI-II, is a 21-item self-report scale used to measure the severity of depressive symptoms. Each item is scored from 0 to 3, and the total score ranges from 0 to 63. Higher scores indicate more severe depressive symptoms. Changes in BDI-II total score from baseline will be assessed at the end of treatment and at follow-up visits.
Time frame: Baseline, Week 4, Week 8, and Week 16
Change in HAMA score from baseline
The Hamilton Anxiety Rating Scale, abbreviated as HAMA, is a clinician-rated scale used to assess the severity of anxiety symptoms. It consists of 14 items covering both psychic anxiety and somatic anxiety symptoms. Each item is scored from 0 to 4, and the total score ranges from 0 to 56. Higher scores indicate more severe anxiety symptoms. Changes in HAMA total score from baseline will be assessed at the end of treatment and at follow-up visits.
Time frame: Baseline, Week 4, Week 8, and Week 16
Change in SCARED (The Screen for Child Anxiety-Related Emotional Disorders) scores from baseline
The Screen for Child Anxiety Related Emotional Disorders, abbreviated as SCARED, is a self-report scale used to assess anxiety symptoms in children and adolescents. The total score ranges from 0 to 82, with higher scores indicating more severe anxiety symptoms. The change in SCARED total score from baseline will be calculated at each post-baseline assessment time point.
Time frame: Baseline, Week 4, Week 8, and Week 16
Change in suicide risk from baseline on the C-SSRS (Columbia Suicide Severity Rating Scale)
The Columbia-Suicide Severity Rating Scale, abbreviated as C-SSRS, is a clinician-administered scale used to assess suicidal ideation and suicidal behavior. The C-SSRS Suicidal Ideation Severity Score ranges from 0 to 5, where 0 indicates no suicidal ideation and higher scores indicate more severe suicidal ideation. The change in C-SSRS Suicidal Ideation Severity Score from baseline will be calculated at each post-baseline assessment time point.
Time frame: Baseline, Week 4, Week 8, and Week 16
Change in PSQI (Pittsburgh Sleep Quality Index) scores from baseline
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The Pittsburgh Sleep Quality Index, abbreviated as PSQI, is a self-report questionnaire used to assess sleep quality and sleep disturbances over the past month. The 19 self-rated items are used to generate seven component scores, including subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Each component score ranges from 0 to 3, and the global PSQI score ranges from 0 to 21. Higher scores indicate poorer sleep quality. Changes in the global PSQI score from baseline will be assessed at the end of treatment and at follow-up visits.
Time frame: Baseline, Week 4, Week 8, and Week 16
Change in PedsQL 4.0 score from baseline
The Pediatric Quality of Life Inventory Version 4.0 Generic Core Scales, abbreviated as PedsQL 4.0, is a standardized questionnaire used to assess health-related quality of life in children and adolescents. It consists of 23 items covering four domains: physical functioning, emotional functioning, social functioning, and school functioning. Raw item scores are reverse-scored and linearly transformed to a 0 to 100 scale, with 0=100, 1=75, 2=50, 3=25, and 4=0. The total scale score is calculated as the mean of all answered items, with higher scores indicating better health-related quality of life. Changes in PedsQL 4.0 total score from baseline will be assessed at the end of treatment and at follow-up visits.
Time frame: Baseline, Week 4, Week 8, and Week 16
Change in CGI-S (Clinical Global Impressions-Severity Scales) scores from baseline
The Clinical Global Impression-Severity scale, abbreviated as CGI-S, is a clinician-rated scale used to assess the overall severity of illness at the time of evaluation. It is rated on a 7-point scale, ranging from 1 = normal, not at all ill to 7 = among the most extremely ill patients. Higher scores indicate greater illness severity. Changes in CGI-S score from baseline will be assessed at the end of treatment and at follow-up visits.
Time frame: Baseline, Week 4, Week 8, and Week 16
Change in CGI-I (Clinical Global Impressions-Improvement Scales) scores from baseline
The Clinical Global Impression-Improvement scale, abbreviated as CGI-I, is a clinician-rated scale used to assess the overall change in a participant's clinical condition compared with baseline. It is rated on a 7-point scale, ranging from 1 = very much improved to 7 = very much worse. Lower scores indicate greater clinical improvement. CGI-I scores will be assessed at the end of treatment and at follow-up visits.
Time frame: Week 4, Week 8, and Week 16
Change in RRS (Ruminative Responses Scale)
The Ruminative Responses Scale, abbreviated as RRS, is a self-report scale used to assess the tendency to engage in ruminative thinking in response to depressed mood. The full version consists of 22 items, and each item is rated on a 4-point scale, ranging from 1 to 4. The total score ranges from 22 to 88. Higher scores indicate greater levels of rumination. Changes in RRS total score from baseline will be assessed at the end of treatment and at follow-up visits.
Time frame: Baseline, Week 4, Week 8, and Week 16