High-definition transcranial direct current stimulation (HD-tDCS) in major depressive disorder with anxious distress—a study protocol for a double-blinded randomized sham-controlled trial

To emphasize the importance and impact of the concurrence of anxiety and depressive disorders, the Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5) has added the anxious distress specifier (ADS) [1]. The diagnostic criteria for ADS require the presence of at least two of the following symptoms: (1) feeling keyed up or tense, (2) restlessness, (3) difficulty concentrating due to worry, (4) feeling that something awful may happen, and (5) feeling that one may lose control of oneself. Data suggests that ADS criteria are met by 50–65% of individuals diagnosed with major depressive disorder (MDD), and the specifier is more effective than comorbid anxiety diagnoses in predicting significant clinical outcomes such as chronicity, remission, and disability [2‐5]. This underscores its presumed clinical relevance. Greater severity of illness was observed

in adults with ADS, as evidenced by a higher frequency of hospitalizations, increased rates of suicidal ideation, greater severity of depressive symptoms, more significant workplace impairment, reduced quality of life, and self-reported cognitive decline [6]. Therefore, there is an urgent need for a novel treatment option that can effectively and tolerably address the needs of these subjects.

A main drawback of traditional transcranial direct current stimulation (tDCS) is the spatial crudity of its effect. The highest cortical current density may not occur directly under the target electrode [7], which probably alters the effects of tDCS and contributes to the inconsistent results of existing tDCS studies [8, 9]. HD-tDCS was developed as a solution to tackle this issue with high precision and accuracy. Similar to conventional tDCS, which utilizes an anode and a cathode placed on the scalp to establish a unidirectional current flow, HD-tDCS also involves the use of both anode and cathode electrodes, typically consisting of more than two smaller electrodes. In the latter, precise delivery of current to the intended target site is its primary advantage. Although various montages can be explored, the “4X1 ring” montage is by far the most commonly used. It utilizes a center anode electrode surrounded by four return cathode electrodes and confers HD-tDCS with the ability to achieve a single desired activity without inducing cortical stimulation due to opposite polarity [10, 11]. The density of the cortical field and spatial focality can be modulated by changing the diameter of the ring of electrodes [12]. In addition to enhancing the spatial focality of stimulation, the augmented effects of neuroplasticity may also manifest in longer-lasting after-effects, as demonstrated in a previous study on HD-tDCS [10]. At the same time, the tolerability was found to be comparable to that of conventional tDCS [13]. No HD-tDCS study of MDD with ADS has yet been performed. Therefore, our team conducted a pilot study to test the effects and tolerability of HD-tDCS on MDD patients with ADS [14].

A pilot study [14] was conducted by our team in 39 adults who have MDD with ADS received five consecutive daily sessions of 20-min active or sham HD-tDCS interventions weekly for 2 weeks. The results revealed that the HD-tDCS has significant efficacy in the treatment among MDD patients with anxious distress. The rate of adverse events(e.g., itching, tingling and headache) showed no significant differences between the two groups. Additionally, no severe adverse events or mania was reported. Nevertheless, it should be noted that the trial was of short duration, limited to hospitalized patients, and did not include an evaluation of cognitive or daily functioning. A double-blinded randomized controlled trial (RCT) with an adequate sample size and adequate study periods is warranted to confirm the efficacy of HD-tDCS as an augmentation therapy with antidepressants in MDD patients with ADS.

This study proposes a RCT with parallel group design, in which participants are randomly allocated to the experimental group or the sham group in a 1:1 ratio. This trial intends to investigate the superiority of HD-tDCS treatment over sham stimulation. It is hypothesized that MDD patients with ADS receiving ten consecutive sessions of HD-tDCS will report a positive effect on the impact of on depressive symptom and confirm the findings of our pilot investigation, compared to patients receiving sham stimulation.

The study is being conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee of Zhenjiang Mental Health Center (ethics approval number: 2023Y01) on April 26, 2023; then, the ethics committee’s phone, email, and address are as follows: 0086-0511-88773868, zjwyllwyh@163.com, and No.199, Tuanshan Road, Runzhou District, Zhenjiang 212000, China. Investigators will obtain signed informed consent forms from participants prior to their enrollment in the study. Following the study, all patients will continue to receive ongoing medical care from the investigators. The findings of this research will be disseminated through scholarly articles and presentations at national and international conferences. Therefore, this study will make a valuable contribution to the current treatment options for patients with MDD and offer a non-pharmacological intervention approach that will be readily available in the near future.

The study described in this protocol is a RCT to evaluate the superiority of an active HD-tDCS program for MDD patients with ADS compared with the sham HD-tDCS program. MDD patients with ADS will undergo at least 2 weeks of maintenance pharmacotherapy prior to stimulation initiation and continue such treatment throughout the entire stimulation period. Fifty-eight MDD patients with ADS will be randomized (1:1) in the active HD-tDCS group or the sham HD-tDCS group.

We will approach patients in the Zhenjiang Mental Health Center outpatient and inpatient units. Our inpatient and outpatient care units follow up at least 5000 patients with MDD each year. We will ensure the completion of the study schedule in accordance with the current protocol. Standard clinical care will continue to be provided to all participants upon completion of the trial at our healthcare facility. Recruitment, pre-participation screening, allocation, intervention, and data collection will be conducted between Jun 2023 and November 2025. Our plan is to conclude the study by the end of 2026 and make the results available for analysis. The current study protocol adheres to the SPIRIT 2013 recommendations (Standard Protocol Items: Recommendations for International Trials) [15]. Figure 1 shows the schedule of enrollment, interventions, and assessments.

The inclusion criteria are as follows:

The exclusion criteria are as follows:

The eligibility participants will be randomly assigned to either active or sham HD-tDCS group with a 1:1 allocation. This study will use the Statistical Analysis Software (version 9.3, SAS Institute Inc., Cary, NC, USA) to generate the random allocation sequence. The randomization list will be enclosed in computer-generated opaque envelopes, each labeled with a sequence number on the outside. After the eligible patients have been screened, the researchers will proceed to open the envelopes. The unblinded researchers will create the randomization sequence and allocate participants to treatments. The trained operators responsible for administering HD-tDCS will not be blinded to allocation and, as a result, will be excluded from assessments and data processing. The participants, statisticians, and evaluators will be kept blinded to the treatment allocation. The unblinding process should only be initiated in the event of an emergency, such as the occurrence of any serious adverse events.

The sample size will be determined using G*Power 3.1, based on the findings of a a tDCS meta-analysis of adult patients with MDD [17]. In this study, active tDCS was found to be significantly more effective than sham tDCS for the reduction of depression severity (Hedges’ g = 0.743). For a power of 80% and an alpha level of 5%, a total sample size of 48 patients (24 in each group) is required to detect significant differences between the groups. To account for a 20% drop-out rate, a total of 58 patients (29 in each arm) will be recruited.

Trained nurses will administer the intervention and provide instructions for participants to receive either active or sham HD-tDCS treatment (Soterix medical, Inc., Woodbridge, NJ, USA) under the same instructions during all sessions for 2 weeks. All participants will be treated using the same device model. The HD-tDCS device is capable of being portable and wirelessly controlled through computer software developed by the manufacturer. The montages will be arranged in a “4 × 1 ring set-up,” which is the most commonly utilized HD-tDCS setting. The center anode electrode is surrounded by four return cathode electrodes. The anode will be positioned over the left DLPFC, which is located at F3 according to the 10/20 electroencephalogram system. The four cathodal electrodes will be placed at FC1, AF3, F7, and FC5 (Additional file 1). The designated electrode stimulation areas on the scalp will be coated with conductive electrode gel. The electrodes will be secured in place by using caps that are appropriate for the head size of each participant. Impedance checks will be performed prior to each treatment session. A 2-mA stimulation will be administered for a duration of 20 min, with the current gradually ramping up and down over a period of 30 s. The patients will be instructed to maintain a relaxed and immobile state throughout the intervention. The administrator will closely monitor the impedance levels throughout each session and document any adverse reactions reported by the participants. The participants will be granted a 5-min rest period following the intervention and will be actively queried regarding any discomfort they may experience. Each session will have a duration of approximately 30 min, and there will be a total of 10 sessions (consisting of two consecutive weeks of treatment, with 5 days per week).

The procedure for sham stimulation will be identical, with the exception that the electrical current will gradually decrease to zero after 30 s, thereby producing an equivalent initial sensation of HD-tDCS. The stimulator will be programmed to automatically control the current, eliminating the need for operator intervention. The computer will be positioned posterior to the subjects’ craniums, thereby obstructing their visual access to the readout.

The diagnoses will be confirmed through a semi-structured psychiatric diagnostic assessment, conducted by an experienced psychiatrist using the validated Chinese-bilingual version of the Structured Clinical Interview for DSM Mental Disorders in accordance with DSM-5.

The participants’ fundamental demographic information, encompassing age, gender, educational attainment, birthplace, marital status, offspring count, financial standing, family history of affective disorders, and household income will be obtained upon enrollment into the study. Details of the subjects’ psychiatric history, including the age at onset of their initial depressive episode, number of relapse episodes, and current medication and dosage, will be documented during the baseline assessment. The medical history and treatment of patients will be evaluated through direct inquiry and confirmed with their electronic health records in the hospital authority.

The primary outcome will be the change of depressive symptoms. The clinical response rate and remission rate, as assessed by the HDRS-17 (17-item Hamilton Depression Rating Scale) at 6 weeks post-intervention were measured. The Chinese version of HDRS-17 has been validated for its psychometric properties and is commonly used to evaluate depressive severity in Chinese patients with depression symptoms [18]. The clinical response is defined as a ≥ 50% reduction from the baseline [19], and a score of 7 or less will be used as an indicator of remission [20].

The visit schedule for all assessments is presented in Table 1.

The hypotheses will be tested using unpaired, two-tailed tests at a significance level of 0.05. The software SAS, v.9.4 (SAS Institute Inc.), was utilized.

A research management group, consisting of the trial investigators, will be established to oversee the project’s governance and day-to-day operations. The group will meet on a monthly basis to assess progress and ensure that the study is being conducted in accordance with the requirements of research ethics approval. While the importance of a trial steering committee in upholding study conduct quality is recognized, financial limitations have prevented the establishment of such a committee. Nevertheless, this research will be carried out under the auspices of Zhenjiang Mental Health Center, where stringent research governance structures are in place to ensure the quality of study conduct.

The research management group will take on the responsibility of data monitoring. Although we acknowledge that an independent committee would be optimal for this role, financial constraints have made it unfeasible to appoint one. However, as mentioned earlier, stringent research governance procedures are in place at Zhenjiang Mental Health Center to ensure the quality of study conduct.

tDCS is considered to be a safe technique, but some small risks are recognized. A checklist of potential adverse effects associated with t-DCS administration will be generated with reference to the available literature [28, 29]. All potential risks will be fully disclosed to the participants, along with instructions on how to handle any side effects they may experience. Furthermore, participants will receive a debriefing at the conclusion of each session and will be instructed to contact the principal investigator in the event of any adverse effects resulting from their involvement in the study. In the event of a serious adverse reaction during treatment sessions, local staff (clinic, hospital, institutional) will be promptly notified and emergency protocols will be implemented. We do not expect any adverse events, whether serious or otherwise. However, in the event that one does occur, it will be documented and reported to the local ethics committee of Zhenjiang Mental Health Center.

The local ethics committee of Zhenjiang Mental Health Center will be consulted for approval of significant protocol modifications, such as changes to eligibility criteria, outcomes, and analyses. Upon receipt of approval, the modifications will be formally communicated in written form to relevant stakeholders (such as investigators and trial participants), and the trial record on chictr.org.cn will be appropriately updated.

The principal investigator (PI) ST shall assume responsibility for the ongoing management of the study. The sponsor shall oversee and perform audits on a subset of studies within its clinical research portfolio. The monitoring and auditing activities will be carried out in accordance with the sponsor’s established procedures for monitoring and audit.