Biomarkers of Theta Burst Stimulation in Major Depressive Disorder

Study Overview
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Brief Summary
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This study investigates the brain-based biomarkers of treatment response to accelerated theta burst stimulation (aTBS) in patients with Major Depressive Disorder resistant to pharmacological treatment(MDD) in an open label design.

Detailed Description
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Theta burst stimulation (TBS) is a newer form of rTMS which requires less stimulation time and produces longer lasting post-stimulation effects in the cerebral cortex (4). It has been shown to be effective in inducing synaptic plasticity and has similar or better efficacy in treating depression compared to rTMS (4).Newer accelerated TBS (aTBS) protocols that condense stimulation sessions down to several days rather than weeks have shown similar response rates when compared to prolonged TBS protocols, also with similar tolerability and safety. In order to develop aTBS as an effective treatment for MDD, future research should focus on identification of reliable predictors for better outcome to TBS. The main objectives were: 1) To directly compare multiple different brain-based measures (neuroimaging and electrophysiology) to identify which has the most power in accurately predicting response to TBS compared to sham. 2) To track both short and long-term longitudinal electrophysiological (EEG) changes related to the therapeutic effects of TBS.

Official Title
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Using Multiple Brain-based Biomarkers to Validate and Predict Response to Theta Burst Stimulation as a New Treatment for Major Depressive Disorder

Conditions
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Depressive Disorder, Treatment-Resistant

Intervention / Treatment
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* Device: Theta Burst Stimulation ( Transcranial Magnetic Stimulation)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must meet the DSM-5 diagnostic criteria for single-episode Major Depressive Disorder (MDD). Participant must have failed to respond to >1 but <4 classes of oral antidepressant treatments in the current episode of depression. Participant must have a HAMD total score of at least 18 Exclusion Criteria: The participant's depressive symptoms have previously demonstrated nonresponse to: An adequate course of rTMS/TBS over DLPFC in the current major depressive episode, defined as at least 3 weeks of treatment, 5 times weekly An adequate course of treatment with electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral/bilateral ECT. Participant has received vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depression. Participant has a current or prior DSM-5 diagnosis of Axis I comorbidities, including psychosis, bipolar disorder, obsessive compulsive disorder, based upon clinical assessment and confirmed by the MINI. Participant has a current or prior DSM-5 diagnosis of Axis II comorbidities, including severe borderline personality disorders, antisocial, schizotypal, schizoid personality disorders based upon clinical assessment and confirmed by the MINI. Participant has severe suicidal ideation/plan/ intent. Participant has a history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria. Participant has a current or past history of seizures and neurological problems, e.g. head injury, stroke, progressive neurological disorder and complicated and unstable medical disorders, e.g. cardiovascular-related conditions, diabetes.

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
Intervention Model: Single Group Assignment
Interventional Model Description: Open label study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active TBS-DLPFC<br>There is only one arm. All participants will receive Theta Burst Stimulation (transcranial magnetic stimulation) of the dorsolateral prefrontal cortex. | Device: Theta Burst Stimulation ( Transcranial Magnetic Stimulation)<br>* Participants will receive bilateral TBS, 5 times daily (15 minutes between), over 5 consecutive days (25 sessions total). In each session they will receive intermittent TBS (iTBS) over left dorsolateral prefrontal cortex (DLPFC), followed by continuous TBS (cTBS) over right DLPFC. Stimulation sites will be targeted with the Localite neuronavigation system and Visor2 software, and according to Talairach coordinates in relation to individual MRIs. Intensity will be standardized at 120% of RMT. The MagPro stimulator will deliver iTBS over left DLPFC with 1620 pulses in 54 triplet bursts (5Hz) with train duration of 2 seconds, and intertrain interval of 8 seconds. cTBS over right DLPFC will consist of 1620 pulses in 54 triplet bursts, train duration of 2 seconds, with no intertrain interval.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Depression Rating Scale | Clinician administered questionnaire to asses clinical improvement and classify response and remission | Change from baseline at 5 days of TBS treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. Montgomery-Åsberg Depression Rating Scale (MADRS) | A ten item clinician administered questionnaire to measure the severity of depressive symptoms on a 0 to 6 severity scale with higher scores indicating more severe depressive symptoms. Cut-off points include: 0 to 6 - symptom absent, 7 to 19 - mild depression, 30 to 34 - moderate, 35 to 60 - severe depression. | Change from baseline at 5 days of TBS treatment | 
| 2. Hamilton Anxiety rating Scale (HAM-A) | A rating scale to measure the severity of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. | Change from baseline at 5 days of TBS treatment | 
| 2. Columbia Suicide Severity Rating Scale ( CSSRS) | A suicidal rating scale devised by researchers at Columbia University. The presence of suicidal ideation score ranges from 1-5 and the intensity of the suicidal ideation ranges from 0-25 with higher scores indicating higher levels of intensity. | Change from baseline at 5 days of TBS treatment | 
| MGH Rumination questionnaire | Self administered 9 items scale to measure the severity of rumination. Each item is measured from 0-4 with a total score range of 0-36. Higher scores indicate more severe rumination. | Change from baseline at 5 days of TBS treatment | 
| Snaith-Hamilton Pleasure scale-Clinician administered (SHAP-C) | This is to evaluate the ability to enjoy/experience pleasure. Each item can score 0 or 1 with a total score possibility of 0-14. Higher scores represent higher anhedonia and 3 or over is considered abnormal. | Change from baseline at 5 days of TBS treatment | 
| 36 item short form survey (SF-36) | This is to evaluate physical and emotional health. | Change from baseline at 5 days of TBS treatment | 
| Global Assessment of Functioning (GAF) | This is to evaluate psychological, social and occupational functioning | Change from baseline at 5 days of TBS treatment | 
| Resting state functional connectivity-Functional magnetic resonance imaging (rsfMRI) | Temporal correlation of brain signals as measured by BOLD signals | Pretreatment baseline | 
| Magnetic resonance spectroscopy (MRS) | To measure glutathione and glutamate concentration in DLPFC and ACC | Pretreatment baseline | 
| Electroencephalogram | To measure neuronal oscillations | Change from baseline at 5 days of TBS treatment |