Alcohol Use Disorder, Cigarette Smoking, Depressive Disorder
Conditions
Keywords
alcohol use disorder, intermittent theta burst, Veterans, depressive disorder, cigarette smoking
Brief summary
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.
Interventions
DEVICEIntermittent theta burst transcranial magnetic stimulation
20 iTBS sessions (active or sham) administered over the course of 2 weeks
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Were Abstinent Through Month 6 | 6 months | Number of particiants in active vs. sham who maintained completed abstinence from alcohol/substance over 6 months post final rTMS session. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Left Dorsolateral Prefrontal Region Glutamate/Creatine Ratio | baseline and follow-up (approximately 2 weeks) | 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. |
| Left Dorsolateral Prefrontal Cortex Thickness | baseline and follow-up (approximately 2 weeks) | 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. |
| General Depressive Symptoms | baseline and follow-up (approximately 2 weeks) | Beck Depression Inventory-II score pre and post active/sham iTBS (score range, 0 to 63, higher scores indicate more severe symptoms). |
| Anhedonic Depressive Symptoms | baseline and follow-up (approximately 2 weeks) | 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). |
Countries
United States
Participant flow
Recruitment details
From 20MAR20-31AUG21 no participants were recruited due the mandatory hiatus of recruitment of human participants (forced by the COVID-19 pandemic) and the Principal Investigator's mobilization to active military service. The PI discussed the recruitment issues with the Stanford NeuroChoice Initiative funding agency, and it was decided to discontinue recruitment in JUL21.
Participants by arm
| Arm | Count |
|---|---|
| Active iTBS Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks | 8 |
| Sham iTBS Intermittent theta burst transcranial magnetic stimulation: Participants will be randomized to active or sham iTBS conditions, and receive 20 iTBS sessions over the course of 2 weeks | 9 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Participant self-discharged against medical advice from treatment program during active study phase | 1 | 0 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Residential treatment team requested participant withdraw due to multiple conflicting appointments. | 0 | 1 |
Baseline characteristics
| Characteristic | Active iTBS | Sham iTBS | Total |
|---|---|---|---|
| Age, Continuous | 32.0 years STANDARD_DEVIATION 9.8 | 48.5 years STANDARD_DEVIATION 12.4 | 42.3 years STANDARD_DEVIATION 11.1 |
| Education | 13.5 years STANDARD_DEVIATION 1.5 | 13.3 years STANDARD_DEVIATION 1.8 | 13.4 years STANDARD_DEVIATION 1.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 7 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 6 Participants | 11 Participants |
| Region of Enrollment United States | 8 Participants | 9 Participants | 17 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 9 |
| other Total, other adverse events | 0 / 8 | 0 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 9 |
Outcome results
Primary
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.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active iTBS | Number of Participants Who Were Abstinent Through Month 6 | 5 Participants |
| Sham iTBS | Number of Participants Who Were Abstinent Through Month 6 | 7 Participants |
p-value: 0.99Chi-squared
Secondary
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).
Time frame: baseline and follow-up (approximately 2 weeks)
Population: Participants with available data are included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active iTBS | Anhedonic Depressive Symptoms | baseline | 29.1 score on a scale | Standard Error 2.8 |
| Active iTBS | Anhedonic Depressive Symptoms | Follow-up | 22.5 score on a scale | Standard Error 3.3 |
| Sham iTBS | Anhedonic Depressive Symptoms | baseline | 32.7 score on a scale | Standard Error 2.6 |
| Sham iTBS | Anhedonic Depressive Symptoms | Follow-up | 30.5 score on a scale | Standard Error 2.4 |
Comparison: Linear mixed modelingp-value: 0.11Mixed Models Analysis
Secondary
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).
Time frame: baseline and follow-up (approximately 2 weeks)
Population: Participants with available data are included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active iTBS | General Depressive Symptoms | Baseline | 18.4 score on a scale | Standard Error 3.4 |
| Active iTBS | General Depressive Symptoms | Follow-up | 10.0 score on a scale | Standard Error 4 |
| Sham iTBS | General Depressive Symptoms | Follow-up | 11.9 score on a scale | Standard Error 2.9 |
| Sham iTBS | General Depressive Symptoms | Baseline | 18.0 score on a scale | Standard Error 3.1 |
p-value: 0.7Mixed Models Analysis
Secondary
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.
Time frame: baseline and follow-up (approximately 2 weeks)
Population: Participants with data available at each respective assessment point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active iTBS | Left Dorsolateral Prefrontal Cortex Thickness | Baseline | 2.34 mm | Standard Deviation 0.14 |
| Active iTBS | Left Dorsolateral Prefrontal Cortex Thickness | Follow-up | 2.39 mm | Standard Deviation 0.17 |
| Sham iTBS | Left Dorsolateral Prefrontal Cortex Thickness | Baseline | 2.36 mm | Standard Deviation 0.15 |
| Sham iTBS | Left Dorsolateral Prefrontal Cortex Thickness | Follow-up | 2.37 mm | Standard Deviation 0.19 |
p-value: 0.34Mixed Models Analysis
Secondary
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.
Time frame: baseline and follow-up (approximately 2 weeks)
Population: Participants with available data are included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active iTBS | Left Dorsolateral Prefrontal Region Glutamate/Creatine Ratio | baseline | 0.31 z-score | Standard Error 0.29 |
| Active iTBS | Left Dorsolateral Prefrontal Region Glutamate/Creatine Ratio | week 2 | 0.25 z-score | Standard Error 0.29 |
| Sham iTBS | Left Dorsolateral Prefrontal Region Glutamate/Creatine Ratio | baseline | 0.02 z-score | Standard Error 0.3 |
| Sham iTBS | Left Dorsolateral Prefrontal Region Glutamate/Creatine Ratio | week 2 | 0.29 z-score | Standard Error 0.22 |
Comparison: Linear mixed modelingp-value: 0.68Mixed Models Analysis