The goal of this clinical trial is to identify sex-specific biomarkers that confer greater susceptibility for Alcohol Use Disorder (AUD) and differentiate how treatment response varies by sex in people with Alcohol Use Disorder.
The main questions it aims to answer are:
* How does trauma affect emotion regulation, inflammation, and limbic function, and what are the sex-dependent effects of NTX (Naltrexone) on these aspects? * What is the mechanism of Naltrexone (NTX), and how does it potentially moderate reductions in alcohol use through changes in or interactions between emotion regulation, inflammation, or limbic system function?
Participants will
* Be consented and will undergo comprehensive screening for eligibility criteria * Complete behavioral assessments and neuropsychological assessments, as well as neurocognitive assessments and neuroimaging measures * Provide urine samples for a urine drug screen (UDS) and urine pregnancy test (for women), and have blood and a cheek swab collected and stored in the repository * Take a study drug once daily for 12 weeks and track drug usage and effects in a study journal * Undergo weekly assessment calls and bi-weekly medical follow-up safety exams
Researchers will compare naltrexone to placebo in AUD to see if naltrexone is effective in reducing alcohol cravings and promoting abstinence.
Researchers will also compare baseline measures between AUD and Healthy Controls.
18-60 years old
Veteran enrolled in VHA healthcare
must meet diagnosis for recent alcohol-use disorder (DSM-V)
willing to return for follow-up visits and can participate for 12-weeks
Clinically significant neurological, endocrine, hepatic, or systemic disease that would compromise safe participation or confound outcomes
Left-handedness
Axis-1 psychiatric diagnoses other than anxiety, depression or post-traumatic stress disorder
Recreational or prescriptive use of psychotropic medications
Parallel
Naltrexone
Drug12-week randomized double blinded placebo-controlled drug trial titrating drug/placebo dose after 1 week.
Change from baseline in alcohol use (number of drinking days, amount used per day)
Drinking days and average number of weekly standard drinks will be measured at baseline and at follow-up
Changes from baseline in peripheral immune biomarkers associated with inflammation
Plasma samples will be analyzed using a customized, high-sensitivity magnetic bead multiplex assay Luminex system. Samples will be prepared and analyzed to measure peripheral immune markers: interleukin (IL)-1-beta, IL-6, IL-10, tumor necrosis factor (TNF)-alpha, brain-derived neurotrophic factor (BDNF), monocyte chemotactic protein (MCP)-1 and neural cell adhesion molecule (NCAM). Intra-and inter-assay coefficients of variation, as indices of within-and between-assay precision, respectively, will be calculated to examine the reliability of cytokine measurements.
Changes in limbic functional connectivity
Resting-state functional magnetic resonance imaging (rs-fMRI) will be used to assess changes in limbic system connectivity. Correlation coefficients of low-frequency oscillations in the fMRI blood oxygenation level dependent (BOLD) signal between regions and between large-scale resting-state networks in the brain will be z-score transformed. A score of 0 indicates no change while higher or lower scores indicate increased or decreased connectivity, respectively.
Changes from baseline in BOLD signal brain activation during an emotion regulation fMRI task
The task will assess emotional reactivity and regulation to negative and stressful images. Each event (cue, neutral-look, negative-look, negative-reappraise and rating scale of negative affect) will be modeled using a canonical hemodynamic response function with a time derivative. The contrasts of interest will be Negative-look vs Neutral-look and Negative-look vs Negative-reappraise. Amygdala BOLD signal estimates will be extracted to calculate percent-change.
Change from baseline in craving (include craving measures/questionnaires)
The Brief Alcohol Craving Scale, a 10-item self-report assessment of craving, will be used. Participants will be prompted with a statement regarding alcohol cravings and will choose an answer ranging between "strongly disagree" and "strongly agree."
Differences in baseline trauma exposure (composite score)
Department of Veterans Affairs Military Sexual Trauma Screening consists of two questions used nationally within the Veterans Heath Administration (VHA) to screen for MST. Response options are yes, no, or decline to respond. Trauma Assessment for Adults (TAA) is a 17-item self-report on combat exposure, physical or sexual assault, surviving serious accidents and other threatening life events. Life Stressor Checklist-Revised (LSC-R) includes self-report measures relevant to women such as abortion or caregiver duties, in addition to 30 life events related to natural disasters, physical or sexual assault, death of a relative, incarceration and financial hardships. Childhood Maltreatment questionnaire is 70 items in five dimensions: emotional, physical, and sexual abuse, and physical and emotional neglect. A 7-point scale will be used to indicate level of trauma
Change from baseline in neuropsychological testing scores
The Standard Neuropsychological Battery will be used
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Milky Kohno
Lead sponsor
Oregon Health and Science University
Sponsor institution
Portland VA Medical Center
Collaborator
