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Principal Investigator: Milky Kohno
Organization: PORTLAND VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Effective treatments for alcohol-use disorder (AUD), especially for women veterans are critically needed, as
rates of AUD in women veterans have been steadily increasing. Sex differences in psychosocial and biological
risk factors, however, have not been systematically studied in clinical trials for AUD. Women veterans have a
higher prevalence of trauma and abuse than men, and
70% of women veterans experience military sexual
trauma and 36% report being victims of military sexual assault or rape. Abuse
and trauma
are significant
predictors for AUD in women veterans but not in men. Exposure to trauma and consequent impairments in
emotion regulation are significant risk factors for women with AUD and likely interact with immunological and
neurobiological pathways to promote greater addiction severity. Despite clear evidence that psychosocial
vulnerabilities, such as trauma and emotion regulation difficulties contribute to greater risk for relapse in
women
, there has been a paucity of studies that evaluate how these risk factors interact with sex-specific
differences in immunological and neurobiological systems to influence treatment outcome.
The primary objective of this study is to identify
the mechanistic link between sex-dependent risk factors and
treatment efficacy in a 12-week randomized placebo-controlled trial of naltrexone (NTX). This proposal will
extend and leverage previous studies of NTX to determine whether the neuromodulatory and anti-inflammatory
properties of NTX improve brain function, reduce inflammation and enhance emotion regulation in a sex-
dependent manner. Validated rating scales will comprehensively assess trauma history, including military
sexual trauma, combat exposure, physical or sexual assault, intimate partner violence and other traumatic life
events. Functional magnetic resonance imaging (fMRI) at rest and during an emotion regulation task will
assess limbic system connectivity and reactivity, respectively. Inflammation and neuronal integrity will be
assessed with magnetic resonance spectroscopy and a multiplex panel assay of peripheral inflammatory
markers. This project will first identify sex differences in the relationships between trauma and emotion
regulation, inflammation and limbic function deficits. The mechanism of NTX on biobehavioral interactions to
improve drinking behavior will then be assessed by testing whether reductions in alcohol use is moderated by
changes in or interactions between emotion regulation, inflammation or limbic function. Sex-dependent
mechanisms underlying NTX response will also be tested to examine if moderating effects on treatment
outcome differ between men and women veterans.
Findings from this project will identify psychosocial factors that influence immunological and neurobiological
systems and clarify how these risk factors manifest in emotion regulation deficits and alcohol use in a sex-
dependent manner. This systematic study of sex differences will provide a mechanistic understanding of NTX
on biobehavioral interactions and identify therapeutic targets by providing evidence for sex-specific biomarkers
that enhance treatment response. As women veterans have unique vulnerabilities that contribute to disease
severity, results from this study will have substantial impact in advancing the VA mission for precision medicine
by providing biomarkers for tailored treatment approaches, as well as, supporting a VA priority in addressing
the unique needs and improving health outcomes for female veterans.
Terms: <Address><Affect><Alcohol Drinking><Alcohol consumption><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Armed Forces Personnel><Assay><Attenuated><Behavioral><Bioassay><Biological><Biological Assay><Biological Markers><Brain><Brain Nervous System><Choline><Clinical Trials><Cognitive><Complex><Development><Differences between sexes><Differs between sexes><Effectiveness><Emotional Stress><Encephalon><EtOH drinking><EtOH use><Event><Exhibits><Exposure to><Forcible intercourse><Functional MRI><Functional Magnetic Resonance Imaging><Future><Health><High Prevalence><History><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Impairment><Inflammation><Life><Limbic System><Link><MR Spectroscopy><Magnetic Resonance Spectroscopy><Measures><Military><Military Personnel><Mission><N-acetyl aspartate><N-acetyl-L-aspartate><N-acetylaspartate><Nalorex><Naltrexone><Nemexin><Nerve Cells><Nerve Unit><Neural Cell><Neurobiology><Neurocyte><Neurons><Pathway interactions><Peripheral><Placebos><Prevalence><Property><Psychosocial Factor><Questionnaires><Rape><ReVia><Recording of previous events><Reporting><Rest><Risk Factors><Severities><Severity of illness><Sex Differences><Sexual differences><Sham Treatment><Substance abuse problem><System><Testing><Translating><Trauma><Treatment Efficacy><Treatment outcome><Veterans><Vivitrol><Woman><Work><abuse of substances><addiction><addictive disorder><alcohol abuse therapy><alcohol abuse treatment><alcohol ingestion><alcohol intake><alcohol product use><alcohol treatment><alcohol use><alcohol use disorder><alcoholic beverage consumption><alcoholic drink intake><assaulted sexually><attenuate><attenuates><binge alcohol consumption><binge drinking><bio-markers><biobehavior><biobehavioral><biologic><biologic marker><biomarker><brain abnormalities><combat><compare to control><comparing females and males><comparing women and men><comparison control><customized therapy><customized treatment><developmental><disease severity><drinking><drinking behavior><effective therapy><effective treatment><emotion regulation><emotional regulation><episodic drinking><ethanol consumption><ethanol drinking><ethanol ingestion><ethanol intake><ethanol product use><ethanol use><ethanol use disorder><experience><exposure to trauma><fMRI><female outcomes><females compared to males><females compared with males><females versus males><females vs males><forced sex><histories><improved><indexing><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><inflammation marker><inflammatory marker><insight><intervention efficacy><intimate partner violence><men><military population><negative affect><negative affectivity><neural control><neural regulation><neurobiological><neuroimaging biomarker><neuroimaging marker><neuromodulation><neuromodulatory><neuronal><neuroregulation><outcomes among females><outcomes among women><outcomes in females><outcomes in women><pathway><patient specific therapies><patient specific treatment><physical assault><physical attack><precision medicine><precision-based medicine><psychosocial><psychosocial variables><randomized placebo control trial><randomized placebo controlled trial><reduced alcohol use><relapse risk><response><response to therapy><response to treatment><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><sexual assault><sexual attack><sexual trauma><sham therapy><specific biomarkers><substance abuse><tailored medical treatment><tailored therapy><tailored treatment><therapeutic efficacy><therapeutic response><therapeutic target><therapy efficacy><therapy response><trauma exposure><traumatic event><treatment response><treatment responsiveness><unique treatment><women compared to men><women compared with men><women versus men><women vs men><women's outcomes>