Intermittent Theta Burst for the Treatment of Alcohol Use Disorders in Veterans

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of intermittent theta burst repetitive transcranial magnetic stimulation (iTBS) as a treatment for Veterans with an alcohol use disorder (AUD) to decrease the exceedingly high rate of relapse associated with this condition. iTBS has demonstrated equivalent efficacy and safety to repetitive transcranial magnetic stimulation employing 10Hz stimulation protocols in treatment of depressive disorders. The advantage of iTBS is that it can be delivered in approximately 5 minutes where conventional 10Hz repetitive transcranial magnetic stimulation (rTMS) protocols are typically 20-25 minutes. It is hypothesized that Veterans with AUD who receive active iTBS applied to the left dorsolateral prefrontal cortex (DLPFC), compared to controls (i.e., Veterans with AUD who receive sham iTBS), will show significant decreases alcohol craving, depressive symptomatology and cigarette consumptions, as well as improved neurocognition, a longer period of abstinence, and a lower overall rate of relapse over 6 months following standard psychosocial treatment for AUD at VA substance treatment clinics. In exploratory analyses, it is also predicted that magnetic resonance measures of left DLPFC glutamate concentration, volume of anterior frontal cortical brain regions, and performance on fMRI tasks interrogating the function of the salience/reward circuits will serve as biomarkers of iTBS treatment response. The goal of this proposal is to implement treatment that effectively promotes sustained abstinence in Veterans with AUD, given long-term abstinence is related to optimal neurobiological, neuropsychological and psychosocial recovery and functioning.

Official Title
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Intermittent Theta Burst TMS for the Treatment of Alcohol Use Disorders in Veterans

Conditions
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Alcohol Use Disorder, Depressive Disorder, Cigarette Smoking

Intervention / Treatment
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* Device: Intermittent theta burst transcranial magnetic stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 21-65 years of age Meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for alcohol use disorder, and alcohol is self-identified as primary substance of misuse. Actively in treatment at VA Palo Alto HCS Addiction Treatment Service Able to read, verbalize understanding, and voluntarily sign the Informed Consent Form prior to participation in study procedures. Exclusion Criteria: History of Schizophrenia Spectrum Disorders, Bipolar Disorders, a Current substance use disorder that exceeds the severity of the AUD (based on DSM-5 diagnostic criteria) Current use of an FDA approved medication (i.e., disulfiram, acamprosate, and naltrexone) for treatment of AUD, Active current suicidal intent or plan (patients with a previous clinical flag for risk for suicide will be required to have an established safety plan involving their primary psychiatrist and the treatment team before entering the clinical trial), Any form of previous TMS or electroconvulsive treatment. Thyroid disease, Unstable congestive heart failure, angina, other severe cardiac illness as defined by treatment regimen changes in the prior 3 months Cerebrovascular accident Cancer if < 1 year since end of treatment Unstable diabetes COPD requiring oxygen supplementation Alzheimer's disease Parkinson's disease Any Biomedical implants with ferromagnetic content Neurostimulation devices, cardiac pacemakers or any magnetic resonance contraindications Traumatic brain injury with self-reported or observed loss of consciousness > 30 minutes Any primary or traumatically induced seizure disorder Lack of fluency in English, Wechsler Adult Reading Test below the 7th percentile (i.e., moderate or greater impairment in estimated general intelligence), Females who are pregnant or actively attempting pregnancy (conservative exclusion for magnetic resonance research), Current use of any medication or substance that is documented to lower seizure threshold or has been identified as a contraindication for TMS treatment.

Ages Eligible for Study
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Minimum Age: 21 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active iTBS<br>Participants will be randomized to active or sham iTBS. | Device: Intermittent theta burst transcranial magnetic stimulation<br>* 20 iTBS sessions (active or sham) administered over the course of 2 weeks<br>|
| Sham Comparator: Sham iTBS<br>Participants will be randomized to active or sham iTBS. | Device: Intermittent theta burst transcranial magnetic stimulation<br>* 20 iTBS sessions (active or sham) administered over the course of 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Were Abstinent Through Month 6 | Number of particiants in active vs. sham who maintained completed abstinence from alcohol/substance over 6 months post final rTMS session. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left Dorsolateral Prefrontal Region Glutamate/Creatine Ratio | Left dorsolateral prefrontal region glutamate/creatine ratio pre and post active/sham iTBS. Data were recorded in international units (IU) and converted to Z scores based on the entire sample (unit normal distribution, mean of 0, standard deviation of 1). Higher Z scores (standard deviation above the mean) indicate a greater metabolite concentration ratio and better functioning. | baseline and follow-up (approximately 2 weeks) | 
| Left Dorsolateral Prefrontal Cortex Thickness | Left dorsolateral prefrontal cortex thickness pre and post active/sham iTBS; hypothesized that increased thickness corresponds to improved cytoarchitectural integrity of the left dorsolateral prefrontal cortex. | baseline and follow-up (approximately 2 weeks) | 
| General Depressive Symptoms | Beck Depression Inventory-II score pre and post active/sham iTBS (score range, 0 to 63, higher scores indicate more severe symptoms). | baseline and follow-up (approximately 2 weeks) | 
| Anhedonic Depressive Symptoms | Anhedonic depressive symptoms from Mood and Anxiety Symptom Questionnaire (MASQ, 30-item version; score range: 10 to 50, high scores correspond to more severe symptoms). | baseline and follow-up (approximately 2 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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alcohol use disorder, intermittent theta burst, Veterans, depressive disorder, cigarette smoking