# A pharmacogenetic human laboratory investigation of brexpiprazole in Alcohol Use Disorder

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $489,925

## Abstract

ABSTRACT
Only three medications are FDA-approved to treat Alcohol Use Disorder (AUD), and replicable patient-level
predictors of medication response remain elusive. Thus, evaluation of novel medications in a precision medicine
framework is needed to advance AUD treatment. At its most severe stage, AUD is characterized by dysregulated
cortical inhibition of striatal reward signaling, leading to preoccupation with alcohol and loss of control over
drinking. This phenomenon is accompanied by changes in multiple neurotransmitter systems, including
dopamine (DA) and serotonin (5-HT). Several serotonin/dopamine activity modulators (SDAMs), which act at D2,
D3, 5-HT1A, and 5-HT2A receptors, have been explored as AUD treatments. Of these compounds, aripiprazole
(APZ) has displayed the most promise, but variable efficacy and concerns about its tolerability have reduced
enthusiasm for further study. In our preliminary data, we conducted a human lab study of APZ in which we
demonstrated that variation at a variable number tandem repeat (VNTR) polymorphism in the gene encoding the
DA transporter (DAT), DAT1/SLC6A3, moderated APZ effects on alcohol cue-elicited brain activation and
drinking in a bar-lab paradigm. Specifically, APZ reduced these outcomes only among DAT1 9R carriers (i.e.,
those predisposed to higher basal DA tone). However, interpretation of findings was limited because participants
were lower severity non-treatment-seekers, DAT1 genotype was not used for prospective randomization, and
APZ effects on cortical processing were not tested. Further, APZ caused increased adverse effects despite the
use of a lower dose than previously tested.
This project aims to build upon our preliminary data by testing the effects of a novel SDAM, brexpiprazole
(BREX), in a pharmacogenetic human laboratory paradigm. BREX is an FDA-approved SDAM with similar
molecular targets as APZ (D2, D3, and 5-HT1A agonism and 5-HT2A antagonism) but enhanced serotonergic and
noradrenergic effects and an improved adverse effect profile. A group of non-treatment-seeking individuals with
higher severity AUD will be recruited and prospectively randomized, on the basis of their DAT1 VNTR genotype,
to one of two doses of BREX, or matched placebo, for fourteen days. Our primary aims are to evaluate the effect
of BREX on 1) brain activation associated with response inhibition and alcohol cue reactivity and 2) drinking in
the natural environment and in a bar-lab paradigm, and to determine whether DAT1 genotype predicts these
effects. Secondarily, we will explore whether BREX effects on inhibition-related cortical activation or cue-elicited
VS activation mediate its effects on drinking. Achievement of these aims will potentially advance BREX as a new
treatment option for AUD, indicate a subgroup for whom it may be most effective, and/or offer information about
BREX’s potential mechanism of action in reducing drinking.

## Key facts

- **NIH application ID:** 10022084
- **Project number:** 5R01AA027765-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** JOSEPH P. SCHACHT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $489,925
- **Award type:** 5
- **Project period:** 2019-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10022084

## Citation

> US National Institutes of Health, RePORTER application 10022084, A pharmacogenetic human laboratory investigation of brexpiprazole in Alcohol Use Disorder (5R01AA027765-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10022084. Licensed CC0.

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