Accelerated High-dose Sequential Bilateral Theta Burst Stimulation for Treatment Resistant Depression

Study Overview
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Brief Summary
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Repetitive transcranial magnetic stimulation (rTMS) and Theta burst stimulation (TBS) are approved by the US. Food and Drug administration (FDA) for the treatment of refractory major depression. TBS is more efficient than rTMS as it requires shorter stimulation time.Studies suggest that the efficacy of TBS could be enhanced and expedited by accelerated protocols (more than once daily sessions) with higher doses of stimulation (>600 TBS pulses up to 3600 pulses per session) and shorter duration of treatment (4-10days). The main objective of this study is to determine the clinical efficacy and safety of accelerated high dose bilateral TBS treatment for patients with treatment resistant depression in comparison to sham stimulation using a randomized double blind clinical trial design.

Detailed Description
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Major depressive disorder (MDD) accounts for the highest global burden of all mental health disorders, and approximately 50% of depressed patients meet criteria for treatment resistant of depression. Stimulation based therapies have recently become a promising alternative for patients with treatment resistant depression. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) is approved by the US. Food and Drug administration (FDA) and has been recommended as a viable treatment option for major depression. Recently, a newer form of rTMS called Theta burst stimulation (TBS) is approved by FDA as it has shown comparable clinical efficacy and safety to rTMS in the treatment of depression. TBS is more efficient than rTMS as it requires shorter stimulation time of ≤ 6min compared to 20-40 min required in conventional rTMS protocol and produces equivalent antidepressant responses. Studies suggest that the efficacy of TBS could be enhanced and expedited by accelerated protocols (more than once daily sessions ranging from 2-10 sessions/day) higher doses of stimulation (>600 TBS pulses up to 3600 pulses per session) with shorter duration of treatment (4-10days). Recently, an accelerated Stanford Neuromodulation Therapy protocol (10 sessions of iTBS a day for 5 days) with high dose stimulation (90,000 pulses in total) was found to be more effective than sham for severe TRD. This protocol yielded robust results with 69.2% response rates compared to 13% in sham during the 4-week outcome period . The main goal of this project is to determine the clinical efficacy and safety of accelerated high dose bilateral TBS treatment for TRD in comparison to sham stimulation using a randomized double blind clinical trial design. The second objective is to examine the durability of antidepressant effect of this treatment protocol. Our initial open label study of accelerated high dose bilateral TBS demonstrated efficacy in a small cohort of participants with TRD. This proposed study builds on our initial findings whether the antidepressant efficacy of accelerated high dose bilateral TBS would be significantly greater than an identical schedule of sham stimulation. This pilot study will help to examine the feasibility, acceptability, and tolerability of treatment protocol, and estimate the sample size for the next pivotal trial. Hypotheses: Accounting this is a pilot study using small sample size without power size calculations, it is not designed for hypothesis testing. However, it is predicted that the accelerated bilateral TBS would be clinically effective and safe in the treatment of patients with TRD compared to sham stimulation. Additionally, it is anticipated that the antidepressant effects of this treatment may be durable.

Official Title
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Accelerated High-dose Sequential Bilateral Theta Burst Stimulation for Treatment Resistant Depression: A Randomized Double-Blind Sham-controlled Pilot Study

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Device: Sequential bilateral theta burst stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of MDD (DSM-V) Adults in the age range of 18 - 65 Both sex HAMD-17 score of ≥20 TRD - failure to two antidepressant trial Stage II (Thase and Rush classification) Exclusion Criteria: Post traumatic stress disorder, Obsessive compulsive disorder, Psychosis Bipolar disorder, substance abuse disorder, autistic spectrum disorder, active suicidal behavior Epilepsy Dementia, Movement disorders severe head injury Brain metallic implants, cardiac pacemakers Pregnancy . Non-response to prior rTMS, Electroconvulsive treatment, Vagal nerve or Deep brain stimulation or a history of psychosurgery. Borderline personality disorder, Schizotypal, schizoid & paranoid personality disorder Current treatment with anticonvulsants or benzodiazepines

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This will be a randomized, sham-controlled, double-blind single centre study using a 1:1 ratio parallel design. We aim to recruit 40 participants (active=20; sham =20) for this pilot study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active stimulation<br>Bilateral real TBS | Device: Sequential bilateral theta burst stimulation<br>* Three sessions of active or sham bilateral TBS will be delivered daily for 10 days in 2 weeks (no session on weekend) with a total of 30 sessions for each patient. Daily low intensity (90% resting motor threshold) bilateral sequential continousTBS ( cTBI) will be applied first on the right DLPFC (1800 pulses) and then intermittent TBS (iTBS)on the left DLPFC (1800 pulses) with an intersession interval of 60 minutes. We will adopt 1800 pulse per session based on the previous studies. Patients will receive a stimulation of 3600 pulses a session, 10,800 pulses a day and 108,000 pulses in total. After the study, sham group will receive active stimulation following the same protocol<br>|
| Sham Comparator: Sham stimulation<br>Bilateral Sham stimulation | Device: Sequential bilateral theta burst stimulation<br>* Three sessions of active or sham bilateral TBS will be delivered daily for 10 days in 2 weeks (no session on weekend) with a total of 30 sessions for each patient. Daily low intensity (90% resting motor threshold) bilateral sequential continousTBS ( cTBI) will be applied first on the right DLPFC (1800 pulses) and then intermittent TBS (iTBS)on the left DLPFC (1800 pulses) with an intersession interval of 60 minutes. We will adopt 1800 pulse per session based on the previous studies. Patients will receive a stimulation of 3600 pulses a session, 10,800 pulses a day and 108,000 pulses in total. After the study, sham group will receive active stimulation following the same protocol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery Asberg Depression Rating Scale (MADRS) | Mean change in Montgomery Asberg Depression Rating Scale (MADRS) scores (0-60) from baseline to week 4 post treatment. Higher scores mean worse outcome. | Baseline to week 4 post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Depression Rating Scale-17(HDRS-17) | Mean change in Hamilton Depression Rating Scale-17(HDRS-17) scores (0-52) from baseline to week 4 post treatment. Higher scores mean worse outcome | Baseline to week 4 post treatment | 
| Quick Inventory of Depressive Symptomatology- Self Report (QIDS-SR) | Mean change in Quick Inventory of Depressive Symptomatology- Self Report (QIDS-SR) scores (0-27) from baseline to week 4 post treatment. Higher scores mean worse outcome. | Baseline to week 4 post treatment | 
| Columbia scale of suicidal behavior (CSS) | Mean change in Columbia scale of suicidal behavior (CSS) scores (2-25) from baseline to week 4 post treatment. Higher scores mean worse outcome. | Baseline to week 4 post treatment | 
| World Health Organization Quality of Life ( WHOQOL) BREF | Mean change in Quality of Life- ( WHOQOL) BREF - scores ( 0-100) from baseline to week 4 post treatment. Higher scores mean better outcome. | Baseline to week 4 post treatment | 
| Clinical Global Impression Scale (CGI) | Mean change from Clinical Global Impression Scale (CGI) ( 1-7) baseline to week 4 post treatment. Higher scores mean worse outcome | Baseline to week 4 post treatment | 
| Categorical outcomes | Response (a reduction ≥ 50% in MADRS from the baseline to 4 weekend point) and remission (MADRS score ≤ 10) rates for each group | At 4 week post treatment |