Intensive Transcranial Direct Current Stimulation in the Treatment of Major Depression: Feasibility Study
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)

 
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CLINICAL TRIAL PROTOCOL 
 
TITLE: Feasibility Study on the Use of an Intensive Transcranial Direct Current Stimulation 
Protocol for Major Depression 
 
CHUM project number: 2021-9546 
 
PRINCIPAL INVESTIGATOR: 
 
Jean-Philippe Miron, MD, PhD(c), FRCPC 
Unité de Neuromodulation Psychiatrique (UNP) 
Département de psychiatrie, CHUM 
Email : jean-philippe.miron.med@ssss.gouv.qc.ca 
  
CO-INVESTIGATOR: 
 
Paul Lespérance, MD, MSc, FRCPC 
Unité de Neuromodulation Psychiatrique (UNP) 
Département de psychiatrie, CHUM 
Email : paul.lesperance.med@ssss.gouv.qc.ca 
 
Chantal Bolduc, MD, FRCPC 
Département de dermatologie, CHUM 
Email : chantal.bolduc.med@ssss.gouv.qc.ca 
 
COLLABORATORS: 
 
Daniel Blumberger, MD, MSc, FRCPC 
Centre for Addiction and Mental Health (CAMH), Toronto 
Email: daniel.blumberger@camh.ca 
 
Prof. Michael Nitsche, MD 
IfADo Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund, 
Allemagne 
Email: nitsche@ifado.de 
 
 
 
 
 
 
 
 
 

 
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1.0 BACKGROUND AND RATIONALE 
 
Major depressive disorder (MDD) is estimated to currently affect over 280 million 
individuals around the globe and is now ranked as the leading cause of disability worldwide (1). 
First-line treatments include pharmaco- and psychotherapy 2. Even though these approaches are 
effective, a significant proportion of patients are left symptomatic and functionally impaired. 
Indeed, results from the Sequenced Treatment Alternatives to Relieve Depression Study have 
shown that after two (2) failed medication trials, remission rates with subsequent trials drop to 10-
15% (2). Additionally, up to 50% of patients experience a chronic or recurrent course, and 30 to 
40% develop treatment-resistant depression (TRD), having failed to respond to conventional 
treatments (3). TRD affects about 2% of the population and represents about 30 to 50% of the 
total treatment cost for MDD (4). Although antidepressants are convenient and simple to 
administer, discontinuation rates approach 50% after 3 months of use, due to concerns over side 
effects as much as non-response (5). Finally, intensive psychotherapy programs still achieve only 
20-25% remission rates in TRD (6). Novel therapeutic approaches are therefore needed.  
 
Non-invasive brain stimulation (NIBS) techniques, such as transcranial direct current 
stimulation (tDCS), have been gaining ground in the treatment of various psychiatric disorders. 
These non-pharmacological approaches possess an advantageous safety and tolerability profile 
over medication (16). Specific brain regions can be targeted using NIBS approaches, allowing 
modulation of the underlying dysfunctional brain networks common to various psychiatric 
conditions. 
 
tDCS is an easy-to-use NIBS technique with a well-established safety and tolerability 
profile (7)(8) and has been the subject of multiple studies in MDD, with mixed findings (9)(10) 
(11). It involves the use of small electrodes directly applied to the scalp to stimulate superficial 
cortical areas (12). tDCS has a well-established safety and tolerability profile and has the 
advantage to be low-cost, easy-to-use, and portable, with even the potential to do treatments at 
home (9)(13). So far, some evidence supports the use of tDCS for MDD, with two large 
randomized controlled trials (RCTs) having been carried out by the same group, with mixed 
results (14) (15). For example, the landmark tDCS trial by Brunoni et al. (14) (the largest to date) 
compared the use of tDCS to the antidepressant escitalopram for 10 weeks in a non-inferiority 
trial (N = 245). Even though participants received escitalopram daily for 10 weeks (70 times 
overall), only 22 sessions of tDCS were offered during this period. This was in part because tDCS 
was administered in-clinic during those 10 weeks; the number of sessions therefore had to be 
limited to maximize attendance and reduce attrition.  
 
This problem could be solved by intensive treatment. Indeed, a recent study by Michael 
Nitsche's group demonstrated that the effect of tDCS could be potentiated if two sessions were 
administered with a short break in-between, compared to a single session (16). In this study, 
cortical excitability induced by tDCS lasted only a few minutes when one single session was 
administered, while becoming prolonged up to more than 24 hours by the administration of two 
20 min sessions spaced by 20 min intervals. Our group has also piloted two intensive studies 
using a similar type of NIBS called transcranial magnetic stimulation (TMS), where we delivered 
6 (17) and 8 (18) daily sessions of TMS over a 5-day period. Treatments were safe and well-tolerated, 
with minimal side effects and dropout rates. Preliminary data also suggested increased clinical 
effects with more daily sessions. So far, this intensive approach has never been applied to tDCS. 
This could be due to potential concerns over adverse events (AEs) with such an intensive 
protocol, although the literature is limited on this issue. A recent review of the literature on the 

 
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therapeutic use of tDCS in humans reported no serious AEs over more than 33,200 sessions in 
N = 1,000 participants who received repeated sessions (≤ 40 min per session, ≤ 4 milliamps) (8). 
The most reported AE is a light rash under the stimulation electrode. Rare cases of mild and 
temporary skin lesions have also been reported (12),(19); however, this was not associated with any 
complication (20). In addition, a recent case study where 10 tDCS sessions were administered over 
2 days reported only a mild erythema which resolved quickly after the end of stimulation (21). 
Electrodes improperly soaked in saline can cause skin irritation, but this can be minimized using 
pre-packaged pre-soaked electrodes with an optimal amount of saline solution. Intensive tDCS 
protocols could be applied on a large scale given the low-cost, ease-of-use and portability of these 
devices. 
 
2.0 STUDY OBJECTIVES 
 
Primary objective: To assess the safety, tolerability, and feasibility of an intensive tDCS protocol 
for MDD. We hypothesize that our intensive tDCS protocol will be safe, well-tolerated and feasible. 
 
Secondary objective: To gather preliminary data on the clinical effects of the protocol. 
 
3.0 STUDY DESIGN 
 
This will be a prospective, open-label, single-arm feasibility study carried over an 24-month period 
starting in 2022. 
 
3.1 Study population 
 
Participants will be recruited through referrals to our treatment clinic. We will recruit 30 
outpatients 18 to 65 years of age with a diagnosis of unipolar MDD according to Diagnostic and 
Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria and confirmed by psychiatrists 
by means of the Mini-International Neuropsychiatric Interview (MINI) with a score of at least 17 
on the 17-item Hamilton Depression Rating Scale (HRSD-17) as well as a low risk of suicide 
(Blumberger et al. 2018). Participants will be required to have had no increase or initiation of any 
psychotropic medication in the 4 weeks prior to screening and have normal blood work (thyroid, 
complete blood count, electrolytes) in the past 6 months. Exclusion criteria will be bipolar disorder, 
substance use disorder within the last 3 months, dementia, personality disorder, brain injury, 
pregnancy, specific contraindications to tDCS (e.g., intracranial implants) or previous tDCS 
treatment. Antidepressant use will be permitted, but anticonvulsant medication or benzodiazepine 
use of more than 2 mg lorazepam equivalent will not be allowed. 
 
 
3.2 Intervention 
 
Treatments will take place over 10 days (Monday to Friday). Participants will receive 5 
tDCS sessions each day, for a total of 50 sessions. Each tDCS session will last 20 min at a 2 
milliamps intensity and will be spaced by 20 min intervals (3h treatment block). tDCS sessions 
will be administered through 1x1 tES mini-CT devices (Soterix, New York, USA) already acquired 
by the clinic (Fig. 1). These devices have been used in several large MDD trials and are Health 
Canada approved. They are equipped with a "SNAPstrap" fixing system to reliably position the 
two (2) electrodes (anode and cathode). The electrodes will be placed on the scalp according to 
the EEG 10-20 system, with the anode in F3 and the cathode in F4. Treatment will be 
administered by trained research personnel and single-use “SNAPpads” pre-saturated electrodes 

 
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will be provided to participants for each treatment. These electrodes contain just the right amount 
of saline solution to minimize any cutaneous side-effects. 
 
3.3 Outcomes 
 
Participants will be initially assessed at baseline one week before treatment, on every 
treatment day, at the end of the last treatment day, and one and four weeks following treatment. 
The complete schedule is presented in Fig. 2-3.  
 
Primary objective: participants will be systematically assessed every day of treatment and 
at follow-ups for potential AEs, and all AEs will be reported. At each treatment sessions, a safety 
check (i.e., visual skin examination) will be performed before and after each tDCS session, and 
pain levels will be assessed using a Verbal Rating Scale (VRS) of 0 to 10 (10 being the maximally 
tolerable amount of pain) (Fig. 4). Cognitive safety will also be assessed pre- and post-treatment 
using various tests, such as the Rey Auditory Verbal Learning Test, Rey-Osterrieth Complex 
Figure, Trail Making Test Parts A & B and verbal fluency test (Fig. 3). Completion and retention 
rates as well as the number of treatment sessions completed will be assessed. The following data 
will also be collected: number of potential participants referred to the study, number of patients 
screened, number of potential participants considered eligible, number of participants recruited, 
number of participants who initiated the intervention, number of treatment sessions completed, 
dropout rates and number of participants who completed treatment and assessments. Information 
on attendance in the intervention will also be measured. Regarding the secondary objective, 
depressive symptoms changes will be assessed through the HRSD-17, Montgomery-Asberg 
Depression Rating Scale (MADRS), Patient Health Questionnaire-9 (PHQ-9) and General Anxiety 
Disorder-7 (GAD-7) (Fig. 3). We will also use the 6-item HRSD (Fig. 3) before every treatment 
day and at the end of the last day, which is a highly sensitive depression scale that can be 
administered daily during treatment (22). 
 
3.4 Sample size justification 
 
No single guideline exists for pilot studies sample size calculations, with recommendations 
varying from 12 participants per group (23), 30 participants per group (24), 10 to 40 participants 
per group (25)(26) or at least 9% of the main trial's sample size (27). Using the non-central t-
distribution approach devised by Julious and Owen (28)(29) and a conservative effect size of 0.5 
(30), the required sample size would be of 24 participants. To account for potential dropouts, we 
choose a sample size of 30 participants. 
 
3.5 Statistical analysis 
 
Inferential statistics will be performed on baseline characteristics utilizing independent 
samples t-tests (two-tailed) for continuous variables and Chi-square tests for categorical variables 
and to summarise rates of consent, study retention, as well as data quality (completion of outcome 
measures and missing data). Treatment safety will be assessed by a line listing, frequency 
tabulations and 95% confidence intervals. We will also perform repeated measures analyses of 
variance (ANOVA) on mood scales score at diﬀerent timepoints to assess the eﬀect of the 
treatment through time. Planned repeated contrasts will be used to make comparisons between 
the diﬀerent evaluation times. To evaluate cognitive safety of the treatment in patients, we will 
use the reliable change index methodology to differentiate the possible effect of the treatment on 
cognitive functions and outcome results due to practice effects. 
 

 
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3.6 Safety and adverse events 
 
Hundreds of thousands of people have received tDCS over the last 25 years. Data 
available shows that tDCS is a very safe treatment with little or no side effects ((7), (8)). A recent 
review of the literature on the therapeutic use of tDCS in humans reported no serious AE over 
more than 33,200 sessions in N = 1,000 participants who received repeated sessions (≤ 40 min 
per session, ≤ 4 milliamps) (8). The most common of the reported side effects is simply a mild 
and temporary skin lesion under the electrode. A systematic review of 209 tDCS studies reported 
as side effects: itching (active treatment vs. placebo: 39.3% vs. 32.9%), tingling (22.2% vs. 
18.3%), headache (14.8% vs. 16.2%), burning sensation (8.7% vs. 10.0%) and discomfort (10.4% 
vs. 13.4%) (31). Rare cases of mild and temporary skin lesions have also been reported  (19), 
(12); however, the literature is reassuring to this effect (20). In addition, a recent case study 
where 10 tDCS sessions were administered over 2 days reported only a mild erythema 
which resolved quickly after the end of stimulation (21).  Rare cases of skin burn under the 
electrodes have been reported.  These cases were usually associated with incorrect 
application of the electrode or evaporation of the contact medium.   Most burns were superficial 
and healed without scarring.  As previously stated, the use of single-use “SNAPpads” pre-
saturated electrodes and application by trained personnel greatly minimizes the risk of skin 
reaction. Across the literature, only 11 cases of manic or hypomanic switches have been reported 
in bipolar patients, and it is not clear that these were actually related to tDCS. tDCS has never 
been shown to cause cerebral edema or changes in the blood-brain barrier. tDCS causes 
negligible temperature changes in the skin, making thermal damage to the brain very unlikely. 
Electrodes improperly soaked in saline can cause skin irritation, but this can be minimized by the 
use of bagged electrodes pre-soaked with the optimum amount of solution such as we will use in 
this study. In addition, reliable data from patients who received 100 to 1000 sessions of tDCS 
indicate no adverse effects due to cumulative exposure. Finally, no seizures were reported in 
association with the use of tDCS. 
 
Considering that very little data is available regarding intensive tDCS treatments, 
participants will be monitored by a dermatologist. An initial consultation will take place before the 
start of the treatment (Visite 2) and patients will be reassessed at the end of treatment session 
(visite 13). During the treatment week, high-resolution photographs of the skin will be taken daily 
before and after treatments and shared with the dermatologist, who will assess the treatment sites 
for skin lesions using a a global rating scale (0:absent to 3: severe). The dermatologist will advise 
the treatment team to continue or to stop treatment. 
  
Common side effects are expected and will be recorded separately from AEs. Participants 
will be asked to defer any medication changes for 4 weeks before and during the course of 
treatment to avoid confounding effects. All AEs reported during the study will be recorded in 
patients’ research file and include the following information: description and nature of event, onset 
time and date, duration, intensity, seriousness, relationship to treatment, action taken and 
evolution. In case of a serious adverse event, the aforementioned information will be collected in 
detail and will be reported to the CHUM IRB. Any AEs deemed to be related to the study by the 
Primary Investigator (PI), or that result in a participant’s withdrawal from the study, will be followed 
until its resolution or until the patient is considered stable. The decision as to whether or not an 
AE is sufficiently severe to warrant the termination of patient treatment will be left to the clinical 
judgment of the (PI). A participant may also voluntarily withdraw from treatment due to what 
he/she perceives as an intolerable AE. If either of these occurs, the participant will be required to 
undergo an end-of-study assessment and will be offered appropriate care under medical 
supervision until the condition becomes stable. 
  

 
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Procedures have been developed for researchers-developers and research staff involved 
in managing adverse incidents. One objective of these procedures is to describe the various 
processes surrounding management, documentation and tracking of serious or minor adverse 
effects that may arise during and after a clinical trial with or without a research product. They also 
define any reporting requirements that apply to the developer, regulatory bodies and Research 
Ethics Committee (REC). All serious AEs will be reported punctually to the CHUM’s Institutional 
Review Board. In the event of a SAE or UP, the PI implement the following procedures: 
 
1. When the study coordinator and/or PI become aware of a serious AE, reporting must be 
implemented in a timely manner 
2. The study coordinator will complete the required Quebec-government "Adverse Event 
Reporting Form" and submit the form to the PI. 
3. The event will be reviewed to determine whether it is a SAE or an AE. 
4. The serious AE form will then be submitted to the CHUM Institutional Review Board 
regarding these deadlines 
 
3.7 Attendance and Withdrawal Criteria 
 
Participants will be encouraged to attend all scheduled treatments. Those that do meet the 
following criteria will be excluded from the per protocol analysis if they:  
  
(1) Miss / Fail to attend more than 2 treatment days in the course overall.  
(2) Miss / Fail to attend more than 10 treatment sessions overall.  
(3) Cannot tolerate stimulation 
(4) Change their regimen of psychotropics during the treatment period.  
(5) Withdraw consent to participate. 
 
3.8 Clinical Trial Registration  
  
This study is registered on www.clinicaltrials.gov. NCT05194267. 
  
4.0 SUBJECT INCLUSION/EXCLUSION  
4.1 Inclusion Criteria 
 
4.1 Inclusion Criteria  
Patients will be included if they:  
(1) are outpatients  
(2) are voluntary and competent to consent to treatment 
(3) have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of MDD, 
single or recurrent  
(4) are between the ages of 18 and 65  
(5) have a score ≥ 17 on the HRSD-17 item  
(6) have had no increase or initiation of any psychotropic medication in the 4 weeks prior to 
screening  
(7) able to adhere to the treatment schedule  
(9) have normal blood work (thyroid, complete blood count, electrolytes) 
 
4.2 Exclusion Criteria  
Patients are excluded if they:  

 
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(1) have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of substance 
dependence or abuse within the last 3 months  
(2) have a concomitant major unstable medical illness, cardiac pacemaker or implanted 
medication pump  
(3) have active suicidal intent  
(4) are pregnant  
(5) have a lifetime Mini-International Neuropsychiatric Interview (MINI) diagnosis of bipolar I or II 
disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, 
or current psychotic symptoms  
(6) have a MINI diagnosis of obsessive compulsive disorder, post-traumatic stress disorder 
(current or within the last year), anxiety disorder (generalized anxiety disorder, social anxiety 
disorder, panic disorder), or dysthymia, that is assessed by a study investigator to be primary and 
causing greater impairment than MDD  
(7) have a diagnosis of any personality disorder, and assessed by a study investigator to be 
primary and causing greater impairment than MDD  
(8) have failed a course of ECT in the current episode or previous episode  
(9) have any significant neurological disorder or insult including, but not limited to: any condition 
likely to be associated with increased intracranial pressure, space occupying brain lesion, any 
history of seizure except those therapeutically induced by ECT or a febrile seizure of infancy, 
cerebral aneurysm, Parkinson’s disease, Huntington’s chorea, multiple sclerosis, significant head 
trauma with loss of consciousness for greater than 5 minutes  
(10) have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or 
electrodes) or any other metal object within or near the head, excluding the mouth, that cannot 
be safely removed  
(11) if participating in psychotherapy, must have been in stable treatment for at least 3 months 
prior to entry into the study, with no anticipation of change in the frequency of therapeutic 
sessions, or the therapeutic focus over the duration of the study  
(12) clinically significant laboratory abnormality, in the opinion of the one of the principal 
investigators or study physicians  
(13) currently take more than lorazepam 2 mg daily (or equivalent) or any dose of an 
anticonvulsant due to the potential to limit rTMS efficacy 
(14) non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to 
cooperate with the interview) 
(15) use of potentially irritant topical treatments (ex: retinoids, alpha hydroxy acids) 
(16) esthetic procedure on scalp or face within the last 6 months (laser, fillers, surgery, botulinic 
toxin,etc) 
(17) Active skin condition on face or scalp that would limit the application of the device or would 
unable the investigators to assess the skin following treatment  
  
5.0 DATA MANAGEMENT  
  
REDCap software will be used for data collection and overall study data management over the 
course of this project. REDCap is an open-source, web-based clinical data management and 
electronic data capture system and database. The system is developed and managed in 
compliance with HIPAA, PIPEDA, and FDA 21 CFR Part 11 regulations, providing functions such 
as defined user roles and privileges, user authentication and encryption, electronic signatures, 
de-identification of protected health information, comprehensive auditing features to record and 
monitor access and changes to data, and a validated software development lifecycle. This system 
will be used to design electronic case report forms (eCRFs), data entry, data monitoring and 
cleaning, and for the query and export of datasets for statistical analysis and predictive modeling. 
  

 
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6.0 CONSENT AND CONFIDENTIALITY 
  
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. All patients referred by a 
general physician or psychiatrist will undergo an extensive consultation with a brain stimulation 
psychiatrist, who will explain the research study to the patient and answer any questions that may 
arise. Patients will then be seen for eligibility screening by qualified research personnel. Research 
personnel will explain the trial in detail prior to obtaining consent. Consent forms describing in 
detail the study intervention, study procedures, and risks are given to the participant and written 
documentation of informed consent is required prior to starting the study. Once consent is 
obtained according to REB and GCP/Tri-Council guidelines, the research personnel will confirm 
inclusion/exclusion criteria is met before proceeding with baseline testing. Patients will be 
informed that they can withdraw participation at any point during the study and the rights and 
welfare of the participants will be protected by emphasizing that the quality of the participant’s 
medical care will not be adversely affected if they decline to participate in this study. A copy of 
the informed consent document will be given to the participants for their records.  
  
The confidentiality of the data collected and identity of the individuals participating in this study 
will be strictly maintained. All files pertaining to subjects in the study will be coded numerically. 
Subject names will not be supplied to anyone not directly involved in the study conduct. For this 
research study, required personal health information include name, address, date of birth, new or 
existing medical records that includes psychiatric or medical conditions, current and past 
medications, presence of surgical implants, and illnesses or psychiatric procedures that may 
influence the ability to participate in the study. In addition, a health card number will also be 
required for patient registration. Some personal health information such as consultation reports, 
medical history and blood test results may be kept as source documents. This information will be 
obtained from the subject, his/her physician, or his/her medical health record. Source documents 
will always be kept in a locked filing cabinet to limit access, and in the case of electronic source 
documents, files will be password-protected and saved in a secure server. However, our case 
report forms (CRF’s) will not contain any personal health information. Only the subject number 
will be recorded in the CRF, and if the subject name appears on any other document (e.g. 
laboratory report), it must be obliterated on the copy of the document retained in the Trial Master 
File or made available for audit. Study findings stored on a computer will be stored in accordance 
with data protection laws. Subjects will be informed that representatives of other parties (including 
pharmaceutical companies), ethics committee (IEC)/institutional review board (IRB) or regulatory 
authorities may inspect their records to verify the information collected, and that all personal 
information made available for inspection will be handled in the strictest confidence and in 
accordance with data protection laws. The investigator will maintain an encrypted and password 
protected personal subject identification list (subject numbers with the corresponding subject 
names) to enable records to be identified and retrieved. 
   
7.0 TIMELINE 
  
Fall 2021: Project submission to the research scientific and ethics boards 
Winter 2022 to Summer 2023: Recruitment  
Fall 2023: End of data collection, statistical analyses and redaction 
 
8.0 IMPACT 
 
If definite proof could be made that tDCS is effective for MDD, this would represent a major 
paradigm shift in the field. tDCS is a potentially highly scalable technology given its low-cost and 

 
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portability, and could revolutionize first-line MDD treatment; with patients having an alternative to 
medication. If our pilot project proves feasible, this could pave the way for a large-scale 
randomized controlled trial. Our tDCS approach could also be applied in other contexts, such as 
for relapse prevention after TMS, ketamine or ECT, as well as in other psychiatric pathologies 
(psychosis, bipolarity, obsessive-compulsive disorder). 
 
 
 
 

 
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