Adjunctive duration-doubled tDCS for the treatment of depressive patients with suicidal ideation: study protocol for a double-blind, randomized, sham-controlled trial

doi:10.21203/rs.3.rs-2240294/v1

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Adjunctive duration-doubled tDCS for the treatment of depressive patients with suicidal ideation: study protocol for a double-blind, randomized, sham-controlled trial

https://doi.org/10.21203/rs.3.rs-2240294/v1

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published 02 Jan, 2024

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Backgroud: The problem of suicide has become increasingly common in individuals with major depressive disorder (MDD). Transcranial direct current stimulation (tDCS) is an effective treatment for MDD with2 milliamperes (mA) for at least thirty minutes per day for two weeks. This study aims to investigate the efficacy of daily duration-doubled tDCS as an adjunctive intervention for rapidly reducing suicidal ideation and improving depression in MDD patients.

Methods and design: In this double-blind, randomized, sham-controlled study, 76 MDD patients with suicidal ideation are randomly assigned to either active (n=38) or sham (n=38) tDCS group. The anode and cathode are placed over the scalp areas corresponding to left and right dorsolateral prefrontal cortex (DLPFC), respectively, and each stimulation lasts for 60 minutes. The primary outcome is defined as change of Beck Scale for Suicide Ideation (BSI) after 10 sessions. The 17-item Hamilton Depression Rating Scale (HAMD-17), Wisconsin Card Sorting Test (WCST) and Stroop Color-Word Test (SCWT) are utilized to assess depressive symptoms, executive function. Blood biomarkers related to suicidal ideation are collected at baseline and after 10 sessions.

Discussion: This study suggest the adjunctive duration-doubled tDCS might be a novel method to rapidly reduce suicidal ideation and improve depressive symptom. The variation of biomarkers could be potential predictive models of suicide risk.

Trial registration: The trial protocol is registered with ClinicalTrials.gov under protocol registration number NCT05555927. Registered on September 25, 2022.

Transcranial direct current stimulation (tDCS)

Major depressive disorder (MDD)

Suicidal ideation

Randomized controlled trial (RCT)

Depression is a common mental disorer. Globally, it is estimated by World Health Organization that 5% of adults suffer from depression. During the last decade, the problem of suicide has become more serious in individuals with major depression disorder (MDD). It is important to track whether alternative or adjunct treatment strategies have the potential to rapidly and effectively reduce suicide risk. Among brain stimulations, transcranial direct current stimulation (tDCS) has been proposed as a possible interventional tool. Over the past decade, trials [1, 2] and meta-analyses [3, 4] have shown mixed, albeit positive, results for tDCS as a treatment for MDD. However, trials or meta-analyses that analysed the factor structure of depression, described as ‘suicide risk’, ‘suicide attempt’ or ‘suicidal ideation’ were rare.

On the other hand, until recently, the bulk of the literature into suicide-focused interventions centered around suicide attempts, particularly on preventing reattempt over the 6- to 12-month period after the index attempt [4]. In such trials, suicidal ideation is usually tracked as a secondary outcome measure. In contrast, evaluating rapid-acting interventions for suicidal ideation requires randomized clinical trials (RCTs) that focus on suicidal ideation as a primary outcome. Therefore, we highlight potential changes that could be made to clinical trials for suicidal ideation in the specific areas of participant selection, outcome measurement, and serum mechanisms of change.

Next, tDCS could be an effective method on depressive symptoms with a current of 2mA, 30 minutes per daily session and a therapeutic period of at least two weeks [5]. The excitement surrounding noninvasive neurostimulation as an adjunctive rapid-acting antidepressant with antisuicidal effects presents an important opportunity for framing studies in suicide research. In addition to offering an opportunity to evaluate the effects of tDCS as an adjunctive rapid-acting intervention on suicidal ideation and suicide risk, such initiatives could help researchers explore potential biomarkers of response and, ultimately, develop better treatments.

What’s more, in recent years, a wide range of possible biological risk factors for suicide have also been proposed. As some recent trials demonstrated, systematic inflammation, indicated by increased levels of white blood cell (WBC) count or serum C-reactive protein (CRP), was also associated with later risk of suicide [6, 7]. Two studies even suggested that neutrophil-to-lymphocyte ratio (NLR) may be a marker for suicide vulnerability in patients with MDD. NLR was substantially higher in suicidal depressed patients compared with nonsuicidal depressed patients and healthy controls. One logistic regression model included NLR and previous attempts as predictive variables for suicide status [8]. What’s more, NLR, monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cellline-derived neurotrophic factor (GDNF), interleukin (IL), soluble tumor necrosis factor receptor I (sTNFr1) and soluble tumor necrosis factor receptor II (sTNFr2) have been found to be associated with MDD [9, 10] as compared with healthy controls [11]. However, we are still far from having good biomarkers for either suicidal ideation or suicide attempt. Moreover, these possible biological risk factors were no more further investigated during or after certain antisuicidal treatment. And the possible association of their variation and suicide status change was not yet reported.

Therefore, any rapid-acting strategy for suicidal ideation has the potential to lead to new developments in clinical trial and to generate valuable clinical and research considerations for the field as a whole. While most tDCS research has focused on its antidepressive mechanisms, the field of preventing suicide is expanding to encompass important psychological considerations related to tDCS use that warrant discussion, including the best way to measure changes in suicidal ideation and the treatment of the suicidal individual. The present study will investigate the effects of daily duration-doubled tDCS as an adjunctive intervention for rapidly improving suicidal ideation and depression in MDD patients with antidepressants.

Objectives

The primary objective of this study is to investigate the acute efficacy on suicidal ideation, measured by the Beck scale for Suicidal Ideation (BSI) score. We hypothesis that a higher efficacy and larger reduction in suicidal ideation will be observed in tDCS group than sham group after one and two weeks when tDCS performed as an adjunctive treatment.

The secondary objectives include:

1. To investigate the acute improvement on depressive symptoms, measured by the 17-item Hamilton Depression Rating Scale (HAMD-17) score of the 2-week treatment of duration-doubled tDCS or sham tDCS, after one and two weeks.

2. To investigate the potential association among variation of WBC, CRP, NLR, MLR, PLR, NGF, BDNF, GDNF, IL, TNF-a, sTNFr1, sTNFr2 and suicidal ideation as well as depressive symptoms in MDD patients treated by adjunctive tDCS.

Trial design

We adopted a randomised allocation design to test sham-controlled antidepressant augmentation. MDD patients, who took no psychotropic drug at baseline or maintained actual pharmacotherapy for at least 2 weeks before the stimulation initiation and during the whole stimulation period. Groups will be randomized through a random code generator software (www.randomization.com) at ratio of 1:1 into one of the following two groups: tDCS group or sham group. The total study duration is 8 weeks (Figure 1).

(Figure 1 about here)

Figure 1 Trial flowchart. We plan to recruit 76 patients with MDD. For the patients who take no psychotropic drug at baseline or maintain actual pharmacotherapy for at least 2 weeks before the stimulation initiation and during the total stimulation period. The patients will be randomised (1:1) into one of the following two groups: tDCS group or sham group. Primary and secondary study parameters will be accessed at baseline (week 0), the 1^st week, 2^nd week, 4^th week, 6^th week and 8^th week.

Recruitment and eligibility criteria

We will approach patients at the Shanghai Mental Health Center outpatient and inpatient units. Our inpatient and outpatients’ care unit follows at least 10,000 patients with MMD each year. Considering the inclusion and exclusion criteria, we expect approaching 100 patients to recruit 76 patients. Usual clinical care will be maintained for all patients following completion of the trial at our care unit. A well-trained group is involved in the participant enrolment process, including one senior psychiatrist, one PhD student, one MD student, eight master students working full-time and ten psychiatrists who refer patients for scientific research. We provide the participants and their guardians with a thorough explanation to ensure that they fully understand the study.

Recruitment, pre-participation screening, allocation, intervention, and data collection will occur between september 2022 and march 2024. We plan that the study will be concluded, and the results will be available for analysis at the end of 2024. The present study protocol complies with the SPIRIT 2013 recommendations (Standard Protocol Items: Recommendations for International Trials) [12] (see Additional file 1). Figure 1 shows the schedule of enrollment, interventions, and assessments.

Eligibility criteria

Inclusion criteria

1. Ages are from 18 to 50;

2. Meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorder (DSM-5) for current unipolar MDD, which is assessed by at least one professional psychiatrist;

3. Han ethnicity;

4. Right handedness;

5. With a score≥17 on the HAMD-17 [13];

6. With a score≥6 on the BSI [14];

7. Without any pharmacotherapy at baseline or maintaining actual pharmacotherapy for at least 2 weeks before the stimulation initiation and during the total stimulation period.

Exclusion criteria

1.Assessed through applying the Mini-International Neuropsychiatric Interview (MINI) [15] by professional psychiatrists that diagnosed any other current or past psychiatric axis-I disorders (except MDD in the patients);

2. Severe liver and kidney diseases, active endocrine diseases or clinical symptoms. Severe cardiovascular disease, respiratory system disease, haematologic diseases and cancer;

3. Any clinically significant abnormal laboratory examination that may influence the health of participants;

4. A history of any aignificant medical illness such as neurological disorders (such as cerebral trauma, seizure disorder, etc);

5. Known current psychosis as determined by the DSM-5 or a history of a non-mood psychotic disorder;

6. Current alcohol and drug abuse;

7. Pregnancy or lactation;

8. Abnormal scalp such as open wounds;

9. HAMD-17 item 3 (suicide) score=4;

10. Receiving modified electroconvulsive therapy (MECT) or repetitive transcranial magnetic stimulation (rTMS) in the past 1 month;

11. Participation in another clinical trial concurrently or no more than 1 month prior to randomisation.

Interventions

There are two stimualtion types: tDCS group or sham group. For brain stimulation, tDCS-CT devices (Neuroelectrics, Starstim 8, USA) are used. The anode and cathode electrodes are inserted in saline-soaked sponges with diameter of 3.2cm and then positioned over the left and right dorsolateral prefrontal cortex (DLPFC) using specific headgear [16]. Each session uses a 2mA current and lasts 60 minutes. Ten sessions are daily performed. For sham, the current rapidly ramp up to 2mA over the first 30s and rapidly ramped down to 0mA over the next 30s automatically to allow participants to feel typical initial sensations of active tDCS. Trained psychiatrists and psychologists blind to group assignment administered the tDCS regimen. After completing ten sessions, no treatment is interdictory.

Participants can leave the study at any time for any of the following reasons:

1. If participants do not meet the inclusion criteria;

2. If participants or their guardians decide to leave the study;

3. If participants develop a serious physical disease whether or not it is related to tDCS;

4. If participants stop taking their medication for three consecutive days, stop effective contraception or become pregnant;

5. If participants use other treatments (including MECT, rTMS);

6. If other conditions occur, and the investigator decides to terminate the study;

7. Defaulting.

Outcomes

Primary outcome: The primary outcome is defined as reductive ratio of BSI after one and two weeks, as well as, after 5 and 10 sessions.

Secondary outcomes: The secondary outcome is defined as changes in other clinical assessments, such as HAMD-17, cognitive function, biomarkers representing potential mechanisms associated with suicidal ideation and depressive sumptoms.

Sample size

The sample size was calculated based on the data from Kalu et al. (2012) [17] and Boggio et al. (2008) [18]. In these studies, the active tDCS was assumed to be superior to sham tDCS in controlling depression with a conservative mean diference of 0.74 and standart deviation (SD)=25.8. We set the type 1 error, a (significance) , and the a power at 80%. We used G power software (V.3.1.9.4) to calculate the sample size. The result indicated that a minimum of 30 patients per group are needed (a total of 60 patients). Considering the 20% drop-out rate, 75 patients are needed in our experiment. Finally, we planned to enrol 38 patients per group for a total of 76 included patients.

Allocation

Patients are randomly assigned to either of two groups--the active tDCS group or the sham tDCS group based on a computer-generated randomization scheme stratified by the study staff, signed as group A or B. Subjects were not able to accurately guess what treatment they would receive. Clinician scales are administered by a trained and blinded study staff to ensure consistency. Moreover, we also checked the internal consistency for all psychiatrists involved in scale ratings with a kappa value of 0.89.

Two senior psychiatrists experienced with the MINI scale guarantee an accurate diagnosis. All patients who fulfil the inclusion criteria will be randomised. Randomisation will be requested by the psychiatrists who are responsible for recruitment and clinical interview.

Blinding

Staff responsible for the recruitment and symptom evaluation are blind to the information about group allocation. A staff member outside the research group will feed data into the computer.

Data collection methods

Primary study parameter/endpoint

BSI: The primary outcome criterion is the reductive ratio in BSI score after one and two weeks of the treatment. A treatment response is defined as a 50% reduction in the BSI score and remission is defined as score of 6 in the BSI at any point during the 8-week trial compared with the baseline.

Secondary study parameters

1. Mini International Neuropsychiatric Interview (MINI);

2. HAMD-17, Montgomery–Asberg Depression Rating Scale (MADRS) and Oxford Depression Questionnaire (ODQ);

3. Young Mania Rating Scale (YMRS);

4. Clinical Global Impression Scale (CGI);

5. Sheehan Disability Scale (SDS);

6. Wisconsin card sorting test (WCST) and Stroop color–word test (SCWT);

7. Peripheral venous blood: Biomarkers representing inflammatory mechanisms associated with suicidal ideation and MDD are assessed. (1) Routine tests: The routine tests include calculation of the WBC, CRP, neutrophils, lymphocytes, monocytes, platelets. (2) Specific tests: We collect the peripheral blood serum and store it at −80°C after centrifugation. We examine the NGF, BDNF, GDNF, IL, TNF-α, sTNFr1, sTNFr2. NLR, MLR, and PLR in serum using ELISA.

Participant timeline

All the time points for the physical examinations, scale assessments, medication use inventories and laboratory examinations are shown in Table 1.

Table 1 Data collection methods and clinical assessment time points

Data management

In the tDCS study, all data will be entered electronically. All of the data management work will be done at Shanghai Mental Health Center. A special database will be built to record all the data related to tDCS study. A complete back-up of the primary database will be performed once a month. A Data Monitoring Committee (DMC) has been established. The DMC is independent of the study organisers. We perform an interim analysis on the primary endpoint when 30% and 70% of patients have been randomised and have completed the 8-week follow-up.

The interim analysis is performed by an independent statistician. The statistician will report independently to the DMC.

Statistical methods

Descriptive analysis will consist of means and SD for continuous variables and percentages for categorical variables. Data normality will be tested with the results expressed as mean ± SD or percentage, whenever appropriate. Non-parametric tests will be used if data were not normally distributed. Baseline variables will be compared between the groups using either the Student t-test or chi-squared test (eg, sociodemographic data, cognitive function data, biomarkers representing inflammatory mechanisms associated with suicidal ideation and MDD, response and remission rates between groups). To compare primary endpoint, a two-way ANOVA will be used considering group (intervention and sham-control groups) and time points (pre and post-intervention), followed by the Bonferroni post hoc test, in case of significant F ratios. Using a mixed-effects model for repeated measures to analyse change from baseline of BSI scores, time and their interaction. We will also adopt pretreatment values (eg, age, gender, baseline BSI, HAMD-17, CRP and blood cells level) as covariates to correct the possible differences. An intention-to-treat analysis will be conducted, i.e., all participants, regardless of adherence to the intervention, will be included in the final analysis. No additional analyses are planned for the study. All calculations will be performed using the R-softawre, and the significance level will be set at P ≤ 0.05.

Harms

We record the possible side effects for each participant. Our trained team reports these data throughout the study using the serious adverse event reporting system. It is unlikely that the participants will be affected by a serious adverse event (SAEs) or a serious adverse reaction in this trial. Common adverse reactions include dizziness, headache, scalp tingling, etc. Only unexpected serious adverse events / reactions which are unrelated to these clinical procedures will be reported as SAEs.

Ethics and dissemination

Trained research psychiatrists will introduce the trial and information sheets to patients. Research psychiatrists will get written consent from patients and their supervisors. Additional serum and plasma samples will be obtained to be stored for future use. An informed consent will be obtained to specifically address the collection of these samples.

All study-related information and participant information will be stored in locked file cabinets in areas with limited access. All laboratory specimens and data reports will be accessed by a coded ID number. All records that contain names or other personal identifiers will be stored separately from study records.

All local databases will be accessed by password. Principal investigator (PI) will be given access to the cleaned data sets. All data will be password protected. To ensure confidentiality, project team members will be blinded to the data. Shanghai Mental Health Center has the insurance to cover all non-negligent harm associated with the protocol. Incidences from negligence (eg, major protocol violations) will not be covered by study insurance. The PI will review all publications and be considered for lead author derived from this study. No later than 5 years after the ending of recruitment, we will deliver the whole deidentified data set to an appropriate data archive. Any modifications to the protocol will require a formal amendment to the protocol.

In this double-blinded, randomized, sham-controlled trial, we aim to determine the acute effectiveness of duration-doubled tDCS on suicidal ideation in patients with MDD. In addition to their usual treatment, participants will be randomly assigned to receive either 10 weekday sessions of active (2 mA) or sham tDCS as an adjunctive treatment, with the anode over the left DLPFC and the cathode over the right DLPFC. We will regularly assess suicidal ideation, depression severity and functional impact using the BSI, HAMD-17, MADRS, ODQ, YMRS, CGI and SDS throughout the trial. We will assess cognitive changes using WCST and SCWT. We will also regularly assess treatment-related side effects using validated scales.

As suicidal ideation is regarded as one of the most important component in depression, the study will examine how suicidal ideation and depression change in participants with MDD throughout the trial period. Entrance and exit interviews will be recorded and analyzed by staffs in this research team in Shanghai Mental Health Center.

The study has numerous strengths and will follow the CONSORT (Consolidated Standards of Reporting Trials) 2010 statement on design and reporting [19]. Using REDCap to randomly assign participants to treatment groups will ensure that allocation is truly concealed, documented, and unchangeable. To minimize the placebo effect, both participants and treating investigators will be blinded. Primary and secondary outcomes were chosen to capture a range of subjective, objective, and functional measurements of suicidal ideation, depression severity, and the regular use of adverse event scales will ensure that treatment side effects are also adequately captured. Measurements will also be taken at multiple points during and after the trial to better describe the overall course and persistence of any treatment-related effects.

This study is unique for several reasons. It is the first of its kind to examine a MDD population with suicidal ideation, in which participants will have suffered from this mental disorder. The use of a relatively intensive tDCS regimen, in terms of session duration, is also unique among studies conducted with MDD. To our knowledge, this is also the first tDCS study for MDD that includes detailed measures of suicidal ideation. This may be useful in revealing the effect of this duration-doubled tDCS on suicidal ideation and in building a database of anonymized recordings for use in future analyses.

This study also has several practical limitations that may affect the results. With regard to treatment modality, delivering tDCS in a hospital setting will impose a minimal burden on inpatients, but outpatients will have to be functional enough to arrange for transport to the hospital on a daily basis. As such, there is a risk that the study population may miss outpatients with severe depression. The need for daily travel to the hospital can also pose problems with participant compliance. We may use home-based tDCS in future studies to mitigate this, although funding limitations prevented us from employing this approach in the this trial. Second, our blinding procedure follows that used in most other studies of tDCS, but recent evidence suggests that this may not sufficiently mitigate the placebo effect. Turi et al. (2019) [20] showed that healthy volunteers were able to distinguish the fade-in, short stimulation, fade-out method of sham stimulation, described above, from true active stimulation at a level significantly greater than chance. It is not yet known how generalizable these findings are to a population with depression, but there is a need for more research into alternative methods of blinding in tDCS studies.

In conclusion, this trial is a pragmatic, randomized, double-blinded, sham-controlled study that seeks to compare the impact of active versus sham duration-doubled tDCS in treating MDD patients with suicidal ideation. To our knowledge, this study is the first of its kind in this patient population and also the first to conjointly employ detailed measures of suicidal ideation, which will also be used in future analyses. Given the immense health, economic, and societal impacts of MDD, new and effective treatments beyond pharmacotherapy and psychotherapy are needed, and tDCS may prove useful in this regard.

BDNF: Brain-derived neurotrophic factor; BSI: Beck Scale for Suicide Ideation; CGI: Clinical Global Impression Scale; CONSORT: Consolidated Standards of Reporting Trials; CRP: C-reactive protein; DLPFC: Dorsolateral prefrontal cortex; DMC: Data Monitoring Committee; DSM-5: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; GDNF: Glial-cell line derived neurotrophic factor; HAMD-17: 17-item Hamilton Depression Rating Scale; MADRS: Montgomery–Asberg Depression Rating Scale; MECT: Modified electroconvulsive therapy; MLR: Monocyte-to-lymphocyte ratio; IL: Interleukins; MDD: Major depressive disorder; MINI: Mini International Neuropsychiatric Interview; NGF: Nerve growth factor; NLR: neutrophil-to-lymphocyte ratio; ODQ: Oxford Depression Questionnaire; PI: Principal investigator; PLR: platelet-to-lymphocyte ratio; RCTs: Randomized clinical trials; rTMS: Repetitive transcranial magnetic stimulation; sTNFr1: Soluble tumor necrosis factor receptor 1; sTNFr2: Soluble tumor necrosis factor receptor 2; t₁: after 5 sessions; t₂: after 10 sessions; t₃: at the end of 4 weeks; t₄: at the end of 6 weeks; t₅: at the end of 8 weeks; t₆: at the end of 12 weeks; tDCS: Transcranial direct current stimulation; TNF-a: Tumor necrosis factor-alpha; SAEs: Serious adverse events; SCWT: Stroop color–word test; SD: Standart deviation; SDS: Sheehan Disability Scale; WBC: White blood cell; WCST: Wisconsin card sorting test; YMRS: Young Mania Rating Scale.

Trial status

This trial is in the enrolment stage. The protocol was registered with ClinicalTrials.gov under protocol registration number NCT05555927 on September 25, 2022.

Protocol version 1.0

Recruitment began on October 10, 2022. Recruitment is expected to be completed in march 2024.

Ethics approval and consent to participate

The study protocol was approved by the Ethics committee of Shanghai Mental Health Center at Shanghai Jiao Tong University (Ethics approval number: 2021-72R). The aims and process of the trial, possible results, and risks will be explained to the participants. Written informed consent will be obtained from all participants, including a written informed consent for further use of biological specimens. This study is registered with ClinicalTrials.gov under protocol registration number NCT05555927.

Consent for publication

Not applicable.

Availability of data and materials

Data relevant for publications will be published on a suitable repository (e.g., Zenodo). On all datasets, documents and biological samples participants are only identified by a unique participant number. The raw data are available on request from the corresponding author, WH.

Competing interests

The authors declared no potential conflicts of interests with respect to the research, authorship, and/or publication of this article.

Funding

This study was supported by Shanghai “Science and Technology Innovation Action Plan” Medical Innovation Research (21Y11905600 and 21ZR1455100); National Key R&D Program of China (2016YFC0906300 and 2016YFC1307100); the ‘12th Five-year Plan’ of National Key Technologies R&D Program (2012BAI01B04); Shanghai Municipal Health Bureau (201740115); the Science and Technology Innovation Project of Shanghai Jiaotong University School of Medicine (Humanities and Social Sciences) (WK2017); the National Natural Science Foundation of China (81930033); the Key Project of Clinical Research Center of Shanghai Mental Health Center (CRC2018ZD02); and Research Proposal for the Capability Promotion Project for Research-Oriented Doctor at Shanghai Mental Health Center (2021-YJXYS-06) and was also supported by the Innovative Research Team of High-level Local Universities in Shanghai. The study protocol has undergone external peer review by the funding agency, as part of the peer review process. The funding agency had no role in the planning of the study design and will not be involved in data collection and analysis, decision to publish or preparation of the manuscript.

Authors' contributions

All the authors have read and approved the manuscript before submission. YC and WH drafted/revised the manuscript for its content, including medical writing, study concept, design, interpretation of data, acquisition of data and development of clinical algorithms. AD revised the manuscript for content, including medical writing and design.

Acknowledgements

We would like to thank all students and interns involved for their help with data collection, study management, the recruitment and screening of participants, as well as for their support in game development. Our special thanks go to all study participants for bringing up the time for participation in the study.

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Adjunctive duration-doubled tDCS for the treatment of depressive patients with suicidal ideation: study protocol for a double-blind, randomized, sham-controlled trial

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