Comparing Uni- and Bi-lateral TBS in Major Depression

Not Applicable

Recruiting

• Conditions: Major Depressive Episode
• Interventions: Device: Theta burst stimulation

• Registration Number: NCT04142996
• Lead Sponsor: The Royal Ottawa Mental Health Centre

Brief Summary

Repetitive transcranial magnetic stimulation (rTMS) is a Health Canada approved treatment for major depression. Theta burst stimulation (TBS) is a very promising new treatment for major depression that allows a 15-fold reduction in duration of daily sessions. However, no large scale naturalistic study has assessed the superiority of bilateral TBS in comparison with unilateral left TBS. In fact, no TBS study thus far has included both unipolar and bipolar depression, or other psychiatric comorbidities such as anxiety. Maintenance has yet to be studied with TBS, along with an effective maintenance protocol to prevent relapse. Our study aims to explore and address these gaps.

Detailed Description

Repetitive transcranial magnetic stimulation (rTMS) is a Health Canada approved treatment for major depression. Typical treatments involve 30 to 45 minutes daily session delivered over 4 to 6 weeks. Recent technical advances allowed the development of theta burst stimulation (TBS), a novel rTMS paradigm which reduces daily sessions to 3 to 4 minutes while maintaining the same clinical efficacy. However, it remains to be determined if applying TBS to both sides of the frontal cortex (i.e. bilateral TBS) is more efficient than delivering it to only one side (i.e. unilateral TBS). In addition, it is difficult to predict treatment response as there is a lack of tools to identify potential responders early on in the treatment phase. Finally, the effects of rTMS are known to last up to 12 months after the treatment. To avoid relapse, a maintenance phase is typically introduced after treatment in which treatment sessions are delivered at a gradually decreasing rate. This study proposes to bridge these gaps by conducting a randomized double-blinded naturalistic superiority trial in which the efficacy of bilateral and unilateral TBS will be compared in individuals with a diagnosis of major depressive episodes. Neurobiological markers of response will be assessed at different time points. In people that respond to treatment, a 6-month maintenance phase will be conducted using a flexible schedule.

The study has four primary aims:

1. To compare the efficacy of bilateral and unilateral TBS on symptoms of depression, as well as rates of remission and response

2. To investigate how unilateral and bilateral TBS modulates brain activity in the dorsolateral prefrontal cortex (DLPFC) using interleaved TMS-EEG

3. To investigate neural predictors of the clinical response to TBS.

4. To assess the efficacy of a flexible schedule of maintenance on a period of 6 months on symptoms of depression and rate of relapse.

TREATMENT PHASE TBS treatment will be administered 5 days/week (on weekdays) over a first phase of 4 weeks (20 sessions). If remission is achieved (Hamilton Rating Scale for Depression-17 score \< 8), treatment will cease and the patient will move on to the maintenance phase. Non-remitters will receive a second phase of treatment, consisting of an additional 2 weeks (10 sessions, for a total of 30). After 6 weeks, all responders may move on to the maintenance phase.

MAINTENANCE PHASE The maintenance phase will be of 6 months duration from the end of the randomized treatment. For each TBS condition, responders will be assigned to a flexible maintenance protocol based on symptom emergence. Participants will receive a fixed 2x/week schedule for the month 1. For month 2 and 3, a brief weekly assessment (Hamilton Rating Scale for Depression-17 score) will be conducted in which it will be determined if they will receive 0, 1 or 2 sessions in the week. For month 4 and 5, a bimonthly assessment (Hamilton Rating Scale for Depression-17 score) will be conducted in which it will be determined if they will receive 0, 1 or 2 sessions over the two weeks. For month 6, one brief assessment (Hamilton Rating Scale for Depression-17 score) will be conducted in which it will be determined if they will receive 0, 1 or 2 sessions in the month.

Study Timeline

• Study First Submitted: 2019-10-15
• Study First Submitted QC: 2019-10-25
• Study First Posted: 2019-10-29
• Study Start: 2019-12-12
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-28
• Last Update Posted: 2023-12-04
• Primary Completion: 2026-09
• Study Completion: 2026-09

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 256

Inclusion Criteria

1. voluntary and competent to consent to study,
2. female or male aged 18 years old or older,
3. can speak and read English and/or French
4. primary and/or predominant diagnosis of major depressive episode without psychotic features in the current depressive episode (confirmed by a Mini-International Neuropsychiatric Interview),
5. depressive symptoms have not improved after ≥ 1 adequate dose of antidepressant trial in the current depressive episode,
6. moderate symptoms in the current depressive episode as indexed by a score of at least 15 at the 17-item Hamilton Rating Scale for Depression (HRSD-17),
7. have been referred to rTMS treatment by their treating physician, and took a free and informed decision to follow this treatment,
8. are able to adhere to treatment schedule,
9. have received a stable psychiatric medication (including prescribed cannabis) or psychotherapy regimen for at least four weeks prior to entering the trial,
10. have an education-adjusted score of ≥ 24 at the Mini-Mental State Evaluation (MMSE) if are aged ≥ 65.

Exclusion Criteria

1. current or past (< 3 months) substance (excluding caffeine or nicotine) or alcohol abuse/dependence, as defined in the Diagnostic and Statistical Manual 5th Edition (DSM-5) criteria. Based on the DSM-5 criteria, mild cannabis or alcohol use would be permissible in the past 3 months, moderate to severe would be an exclusion
2. current use of illegal substances or recreational cannabis
3. have a concomitant major unstable medical or neurologic illness (e.g. uncontrolled diabetes or renal dysfunction),
4. organic cause to the depressive symptoms (e.g. thyroid dysfunctions), determined by the referring physician
5. acute suicidality or threat to life from self-neglect,
6. are pregnant or breastfeeding, or thinking of becoming pregnant during course of treatment,
7. have a specific contraindication for TMS (e.g., personal history of epilepsy or seizure, metallic head implant, pacemaker),
8. unwilling to maintain current antidepressant regimen,
9. are taking more than 1 mg of lorazepam or equivalent,
10. any other condition that, in the opinion of the investigators, would adversely affect the participant's ability to complete the study,
11. have failed a course of electroconvulsive therapy (ECT) within the current depressive episode due to the lower likelihood of response to rTMS.If they have had failed ECT in the past, this does not exclude them

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Unilateral TBS	Theta burst stimulation	Intermittent Theta Burst Stimulation (iTBS) will be applied to the left DLPFC. Realistic sham continuous TBS (cTBS-sham) will be applied to the right DLPFC. Participants will receive daily sessions (Mon-Fri) for 4 to 6 weeks (stop at 4 weeks if remission is achieved).
Maintenance Phase: Flexible	Theta burst stimulation	The flexible maintenance protocol will be based on symptom emergence. Participants will receive a fixed TBS (2x/week) schedule for the first month. For the following months (2-6), they will come in for an assessment (HRSD-17) to determine how many TBS sessions (0, 1, or 2) they receive on a flexible basis.
Bilateral TBS	Theta burst stimulation	Intermittent Theta Burst Stimulation (iTBS) will be applied to the left DLPFC and continuous TBS (cTBS) will be applied to the right DLPFC. Participants will receive daily sessions (Mon-Fri) for 4 to 6 weeks (stop at 4 weeks if remission is achieved).

Primary Outcome Measures

Name	Time	Method
Response - Maintenance Phase (Hamilton Rating Scale for Depression-17 score)	6 months	Response to treatment will be defined as a \> 50% reduction in pre-treatment symptoms severity as measured by the mean Hamilton Rating Scale for Depression-17 score. The minimum value is 0 and the maximum value is 53. A higher score indicates a negative outcome
Response - Treatment Phase (Hamilton Rating Scale for Depression-17 score)	Week 6	Response to treatment will be defined as a \> 50% reduction in pre-treatment symptoms severity as measured by the mean Hamilton Rating Scale for Depression-17 score. The minimum value is 0 and the maximum value is 53. A higher score indicates a negative outcome.
Remission - Treatment Phase (Hamilton Rating Scale for Depression-17 Score)	End of treatment phase (week 4 or 6)	Remission will be defined as a Hamilton Rating Scale for Depression-17 score ≤ 8 The minimum value is 0 and the maximum value is 53. A higher score indicates a negative outcome.
Remission - Maintenance Phase (Hamilton Rating Scale for Depression-17 Score)	6 months	Remission will be defined as a Hamilton Rating Scale for Depression-17 score ≤ 8 The minimum value is 0 and the maximum value is 53. A higher score indicates a negative outcome.

Secondary Outcome Measures

Name	Time	Method
Response - Treatment Phase (Quick Inventory of Depression Symptomology-Self Report)	Week 6	Response to treatment will be defined as a \> 50% reduction in pre-treatment symptoms severity as measured by the mean the Quick Inventory of Depression Symptomology-Self Report score. The minimum value is 0 and the maximum value is 48. A higher score indicates a negative outcome.
Remission - Treatment Phase (Quick Inventory of Depression Symptomology-Self Report)	End of treatment phase (week 4 or 6)	Remission will be defined as a Quick Inventory of Depression Symptomology-Self Report score ≤ 6. The minimum value is 0 and the maximum value is 48. A higher score indicates a negative outcome
Remission - Maintenance Phase Quick Inventory of Depression Symptomology-Self Report)	6 months	Remission will be defined as a Quick Inventory of Depression Symptomology-Self Report score ≤ 6. The minimum value is 0 and the maximum value is 48. A higher score indicates a negative outcome.
Response - Maintenance Phase (Quick Inventory of Depression Symptomology-Self Report)	6 months	Response to treatment will be defined as a \> 50% reduction in pre-treatment symptoms severity as measured by the mean the Quick Inventory of Depression Symptomology-Self Report score. The minimum value is 0 and the maximum value is 48. A higher score indicates a negative outcome.

Trial Locations

Locations (1)

The Royal Ottawa Mental Health Centre; 🇨🇦 Ottawa, Ontario, Canada