Pharmacogenetics of alcohol use disorder treatments: an update

ABSTRACT

Introduction: Alcohol use disorder (AUD) is highly prevalent; costly economically, socially, and interpersonally; and grossly undertreated. The low rate of utilization of medications with demonstrated (albeit modest) efficacy is particularly noteworthy. One approach to increasing the utility and safety of available medications is to use a precision medicine approach, which seeks to identify patients for whom specific medications are likely to be most efficacious and have the fewest adverse effects.

Areas Covered: We review the literature on the pharmacogenetics of AUD treatment using both approved and off-label medications. We cover both laboratory studies and clinical trials, highlighting valuable mechanistic insights and underscoring the potential value of precision-based care for AUD.

Expert Opinion: Pharmacotherapy can be a useful component of AUD treatment. Currently, the evidence regarding genetic predictors of medication efficacy is very limited. Thus, a precision medicine approach is not yet ready for widespread clinical implementation. Further research is needed to identify candidate genetic variants that moderate the response to both established and novel medications. The growing availability of large-scale, longitudinal datasets that enable the synthesis of genetic and electronic health record data provides important opportunities to develop this area of research.

KEYWORDS:

• Alcohol use disorder
• pharmacogenetics
• precision medicine
• pharmacotherapy
• genetic moderators

Article highlights

• Alcohol use disorder (AUD) is highly prevalent, costly, and undertreated despite the availability of pharmacological treatments. Strategies to enhance treatment response to the various medications available include personalized treatment through the application of pharmacogenetics, which focuses on the genetic moderation of the pharmacokinetic and pharmacodynamic effects of a medication.

• Naltrexone, an opioid receptor antagonist, is the most extensively studied of the three FDA-approved medications. Although it has demonstrated efficacy in treating AUD, the pharmacogenetic analyses, aimed at enhancing treatment response, have yielded mixed findings.

• The response to topiramate, used off-label to treat AUD, may be moderated by a variant in GRIK1, a gene that encodes a kainate receptor subunit. Replication of this finding is required before the use of this variant can be recommended clinically.

• Thus, currently, the information available regarding the pharmacogenetics of AUD treatment is not adequate for clinical application. A host of methodological shortcomings in the limited number of trials in this field limit the interpretation of the findings. Future work will benefit from larger, more diverse, and better characterized samples. Elucidation of the pathophysiology of AUD and identifying valid endophenotypes will enhance the discovery of genetic moderators of AUD treatment and allow the targeting of genetic and biobehavioral mechanisms.

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Declaration of interest

H Kranzler is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which, in the last three years, was supported by AbbVie, Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer. H Kranzler is named as an inventor on PCT patent application #15/878,640 entitled: ‘Genotype-guided dosing of opioid agonists,’ filed 24 January 2018. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by support from the Mental Illness Research, Education, and Clinical Center of the Veterans Integrated Service Network 4, U.S. Department of Veterans Affairs provided to E Hartwell and H Kranzler and by the NIAAA grants R01 AA023192 and R01 AA021164 provided to H Kranzler.