NESBID: Neuro-Stimulation of the Brain in Depression

Study Overview
=================
Brief Summary
-----------------
In Canada, approximately 20% of patients with Major Depressive Disorder (MDD) have treatment-resistance and fail to respond to trials of pharmacotherapy or psychotherapy. Although the treatment of choice has historically consisted of electroconvulsive therapy (ECT), this is not always feasible or practical, and carries a risk of side-effects that may be unacceptable to certain patients. In this pragmatic, multi-site, placebo-controlled and double-blinded clinical trial, participants with ultra treatment-resistant MDD will be randomized to receive either active or sham transcranial direct current stimulation in addition to their usual treatment. Ultra treatment-resistant depression will be operationally defined as MDD that has failed to respond to at least five previous trials of antidepressants at sufficient doses, or ECT, or ketamine. Patients will receive a total of 30 active or sham treatment sessions (5 per week), for 30 minutes per session. In both groups, the anode will be placed over the left dorsolateral prefrontal cortex (position F3), and the cathode over the right dorsolateral prefrontal cortex (position F4). Patients in the sham group will receive electrical stimulation at 2 mA for less than 30 seconds, whereas patients in the active group will receive that level of stimulation for the entire duration of treatment. The study's primary outcome is the change in score on a clinician-graded depression inventory (the Montgomery-Asberg Depression Rating Scales). Secondary outcomes include change in scores on a self-administered depression rating scale and measurement of function scale. Information on language ability will also be collected, as will data on side-effects of treatment. Scores will be collected before the trial start, after every 10 sessions, and one month after trial completion.

Official Title
-----------------
NESBID: Neuro-Stimulation of the Brain in Depression. A Randomized, Controlled Clinical Trial of Transcranial Direct Current Stimulation Augmentation, as Compared to Sham Therapy, in the Treatment of Ultra-resistant Major Depressive Disorder

Conditions
-----------------
Electric Stimulation Therapy, Depressive Disorder, Major, Depressive Disorder, Treatment-Resistant, Transcranial Direct Current Stimulation

Intervention / Treatment
-----------------
* Device: Transcranial direct current stimulation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Currently suffering from an MDE with a score on the Montgomery-Åsberg Depression Rating Scale (MADRS) greater than 34 (signifying severe depression) Have ultra treatment resistant MDD (defined as failure to remit despite adequate trials with five antidepressants, or failure to remit with ECT, or failure to remit with ketamine) Exclusion Criteria: Have been diagnosed with psychosis, an addiction disorder (other than nicotine), borderline personality disorder, or antisocial personality disorder, as these conditions could interfere with adherence to the study protocol Are currently using a herbal compound or known NMDA-modulating agent, as these substances could interfere with the induction of LTP and thereby limit the effectiveness of tDCS Are pregnant, as tDCS has not been adequately studied in this population Have an electronic implant, cardiac dysrhythmia, seizure disorder, neurological disorder, or neurosurgical history, as the safety of electrical stimulation with tDCS cannot be assured given these comorbidities

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active transcranial direct current stimulation<br>Active transcranial direct current stimulation (tDCS), delivered at 2 mA and for 30 minutes, on sequential weekdays, for a total of 30 sessions. Participants will continue to receive their usual pharmacotherapy and psychotherapy. | Device: Transcranial direct current stimulation<br>* A Sooma transcranial direct current stimulator, using carbon electrodes, a reusable cap (to promote reproducible electrode placement), and disposable sponges that will be soaked in normal saline. The anode will be positioned over the left dorsolateral prefrontal cortex (position F3 on the 10-20 the International EEG system), and the cathode will be positioned over the right dorsolateral prefrontal cortex (position F4).<br>* Other names: Sooma tDCS;|
| Sham Comparator: Sham transcranial direct current stimulation<br>Sham transcranial direct current stimulation (tDCS), which will ramp up to 2 mA over 17 s, and then ramp down to and remain at 0.3 mA for the remainder of the 30 minute session. The short period of active stimulation is included to stimulate the somatic sensations of active therapy. The trickle current at 0.3 mA is necessary to measure electrode contact and prevent investigators from deducing that the device is no longer active. Participants will receive the sham therapy on sequential weekdays for a total of 30 sessions. Participants will continue to receive their usual pharmacotherapy and psychotherapy. | Device: Transcranial direct current stimulation<br>* A Sooma transcranial direct current stimulator, using carbon electrodes, a reusable cap (to promote reproducible electrode placement), and disposable sponges that will be soaked in normal saline. The anode will be positioned over the left dorsolateral prefrontal cortex (position F3 on the 10-20 the International EEG system), and the cathode will be positioned over the right dorsolateral prefrontal cortex (position F4).<br>* Other names: Sooma tDCS;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery-Asberg Depression Rating Scale (MADRS) | An observer-assessed score of depression severity. The total is scored from 0 to 60, with higher scores representing greater depression severity | Baseline, after 2 weeks, after 4 weeks, after 6 weeks/trial completion, and 1 month after trial completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR16) | A participant-assessed measurement of depression severity. The total is scored from 0 to 27, with higher scores indicating greater depression severity. | Baseline, after 2 weeks, after 4 weeks, after 6 weeks/trial completion, and 1 month after trial completion | 
| World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) | Change in the World Health Organization Disability Assessment Schedule score | Baseline, after 2 weeks, after 4 weeks, after 6 weeks/trial completion, and 1 month after trial completion | 
| Exploratory language analysis | Change in language characteristics, based on recorded interviews | Baseline and after 6 weeks/trial completion | 
| Lexical decision making task | Performance on a task in which patients much distinguish real from fictitious words as quickly as possible | Baseline and after 6 weeks/trial completion | 
| tDCS adverse events scale | Adverse events as assessed on a scale derived from a systematic review on side effects that may be associated with tDCS | Baseline, after 2 weeks, after 4 weeks, after 6 weeks/trial completion, and 1 month after trial completion | 
| FIBSER | Frequency, Intensity, and Burden of Side-Effects Rating Scale | Baseline, after 2 weeks, after 4 weeks, after 6 weeks/trial completion, and 1 month after trial completion | 
| PRISE | Patient-Rated Inventory of Side-Effects Scale | Baseline, after 2 weeks, after 4 weeks, after 6 weeks/trial completion, and 1 month after trial completion | 
| YMRS | Young Mania Rating Scale, included to capture treatment-related manic or hypomanic switches | Baseline, after 2 weeks, after 4 weeks, after 6 weeks/trial completion, and 1 month after trial completion |