Pharmacogenetics of Alcohol and Alcohol Dependence Treatment

In this article, we review studies of genetic moderators of the response to medications to treat alcohol dependence, the acute response to alcohol, and the response to the psychotherapeutic treatment of heavy drinking. We consider four neurotransmitter systems: opioidergic, dopaminergic, GABAergic, and glutamatergic and focus on one receptor protein in each: OPRM1 (the μ-opioid receptor gene), DRD4 (the D4 dopamine receptor gene), GABRA2 (GABAA receptor α-2 subunit gene), and GRIK1 (the kainate receptor GluR5 subunit gene). We conclude that because parallel developments in alcoholism treatment and the genetics of alcohol dependence are beginning to converge, using genotypic information, it may be possible to match patients with specific treatments. Of greatest clinical relevance is the finding that the presence of an Asp40 allele in OPRM1 modestly predicts a better response to naltrexone treatment. Promising findings include the observations that a polymorphism in GABRA2 predicts the response to specific psychotherapies; a polymorphism in DRD4 predicts the effects of the antipsychotic olanzapine on craving for alcohol and drinking behavior; and a polymorphism in GRIK1 predicts adverse events resulting from treatment with the anticonvulsant topiramate. Although variants in other genes have been associated with the risk for alcohol dependence, they have not been studied as moderators of the response either to treatment or acute alcohol administration. We recommend that, whenever possible, treatment trials include the collection of DNA samples to permit pharmacogenetic analyses, and that such analyses look broadly for relevant genetic variation.