Protocol on Transcranial Alternating Current Stimulation for the Treatment of Major Depressive Disorder: A Randomized Controlled Trial
Major depressive disorder (MDD) is a prevalent and debilitating mental health condition that imposes a significant burden on individuals and society. Despite the availability of pharmacological and psychotherapeutic interventions, many patients do not achieve full remission, and the side effects of antidepressants can be problematic. This has led to the exploration of non-pharmacological treatments, including neuromodulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). However, these methods have limitations, including paradoxical outcomes and risks such as seizures or new-onset mania. Transcranial alternating current stimulation (tACS) has emerged as a promising alternative, offering potential benefits with fewer side effects. This article provides a comprehensive overview of a randomized controlled trial (RCT) investigating the efficacy and safety of tACS in treating MDD.
Introduction
MDD is a leading cause of disability worldwide, contributing to significant economic and social burdens. Current treatments, including antidepressants and psychotherapy, are only partially effective, and many patients experience adverse effects. Non-pharmacological interventions such as TMS and tDCS have shown promise but are associated with risks and inconsistent outcomes. tACS, a newer neuromodulation technique, delivers weak electrical currents to the scalp to modulate cortical excitability and spontaneous brain activity. Unlike tDCS, tACS is associated with fewer sensations and adverse responses, making it a potentially safer and more tolerable option. Preclinical studies have suggested that tACS at a frequency of 77.5 Hz and a current of 15 mA may have therapeutic effects on depression by targeting the forehead and mastoid areas. This RCT aims to evaluate the efficacy and safety of tACS in treating MDD.
Methods
The study is an 8-week, double-blind, randomized, placebo-controlled trial conducted at a single center. Ninety-two drug-naive patients with MDD, aged 18 to 65 years, are randomized to either active or sham tACS groups in a 1:1 ratio. The intervention consists of 20 daily 40-minute sessions of tACS at 77.5 Hz and 15 mA, delivered on weekdays for four consecutive weeks, followed by a four-week observation period. The primary outcome is the remission rate, defined as a score of ≤7 on the 17-item Hamilton Depression Rating Scale (HDRS-17) at week 8. Secondary outcomes include response rates at weeks 4 and 8, remission rates at week 4, improvements in the Clinical Global Impression-Improvement (CGI-I) scale, changes in HDRS-17 scores, and variations in brain imaging and neurocognitive function from baseline to week 4. Safety is assessed through vital signs and adverse event monitoring throughout the study.
Study Design and Randomization
The study employs a permuted block randomization method, with blocks of four, to ensure balanced allocation between the active and sham groups. A computer-generated random number sequence is used, and the allocation is concealed using sealed, opaque envelopes. Twelve tACS devices (six active and six sham) are used, with two devices reserved as backups. The devices are identical in appearance, weight, and odor to maintain blinding. Participants, investigators, and raters are blinded to the treatment assignment until the end of the study. Blinding is only broken in emergencies.
Participant Selection
Participants are recruited from a university hospital through referrals and advertisements. Inclusion criteria include being aged 18 to 65 years, having a diagnosis of unipolar, non-psychotic MDD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), and scoring >17 on the HDRS-17 at baseline. Exclusion criteria include a history of other DSM-IV-TR axis I or II disorders, previous use of antipsychotics, antidepressants, or anxiolytics, severe physical or neurological illnesses, and contraindications for tACS (e.g., cochlear implants or cardiac pacemakers). Participants are also excluded if they have active suicidal intent or plan, impaired skin integrity at electrode sites, or are pregnant or lactating.
Intervention Protocol
Participants receive either active or sham tACS using FDA-cleared devices. The active tACS involves a 77.5 Hz frequency and 15 mA current, while the sham treatment involves no stimulation. Three electrodes are placed on the scalp: one on the forehead and two on the mastoid areas. Each session lasts 40 minutes, and participants are instructed to relax and avoid using smartphones during the procedure. Compliance is monitored, and participants are encouraged to complete all sessions. No additional antidepressant treatments are allowed during the study.
Outcome Measures
The primary outcome is the remission rate at week 8, defined as an HDRS-17 score of ≤7. Secondary outcomes include response rates (≥50% reduction in HDRS-17 scores) at weeks 4 and 8, remission rates at week 4, and improvements in the CGI-I scale. Exploratory outcomes include changes in cognitive function, brain connectivity, and metabolism, assessed using neurocognitive tools and brain imaging techniques such as resting-state magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI), and positron emission tomography/magnetic resonance (PET/MR). Safety is evaluated through vital signs, adverse event monitoring, and electroencephalography (EEG) to detect potential seizures.
Data Management and Analysis
Data are collected in paper-based case report forms (CRFs) and entered into the EpiData system by two independent investigators. Double-entry verification is performed to ensure accuracy. Statistical analysis is conducted using SAS software, with a significance level of P < 0.05. Continuous variables are summarized as means and standard deviations, while categorical variables are described as frequencies and percentages. Between-group comparisons are made using the Mann-Whitney U test for continuous variables and the Chi-square or Fisher’s exact test for categorical variables. The primary outcome is analyzed using intention-to-treat analysis with worst-case imputation. Mixed linear models are used for repeated continuous outcomes.
Discussion
MDD is a significant public health issue, and current treatments are often inadequate. This RCT aims to evaluate the efficacy and safety of tACS as a non-pharmacological intervention for MDD. The study design addresses several limitations of previous research, including the use of a double-blind, randomized, placebo-controlled protocol and comprehensive outcome measures. The inclusion of brain imaging and neurocognitive assessments provides insights into the mechanisms underlying tACS effects.
The study has some limitations, including its single-center design and short intervention duration. The generalizability of the results to other populations or regions may be limited. Additionally, the optimal number of tACS sessions and long-term effects remain unknown. Future research should explore these questions and investigate potential moderators of treatment response.
Conclusion
This RCT represents a significant step forward in the development of non-pharmacological treatments for MDD. If tACS is shown to be effective and safe, it could provide a valuable alternative or adjunct to existing therapies, particularly for patients who do not respond to or cannot tolerate antidepressants. The study’s findings will contribute to the growing body of evidence on neuromodulation techniques and may pave the way for broader clinical application of tACS in the treatment of depression.
doi.org/10.1097/CM9.0000000000000589
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