Pharmacogenetically Driven Treatments for Alcoholism

Abstract

Pharmacogenetic analyses of treatments for alcohol dependence attempt to predict treatment response and side-effect risk for specific medications. We review the literature on pharmacogenetics relevant to alcohol dependence treatment, and describe state-of-the-art methods of pharmacogenetic research in this area. Two main pharmacogenetic study designs predominate: challenge studies and treatment-trial analyses. Medications studied include US FDA-approved naltrexone and acamprosate, both indicated for treating alcohol dependence, as well as several investigational (and off-label) treatments such as sertraline, olanzapine and ondansetron. The best-studied functional genetic variant relevant to alcoholism treatment is rs1799971, a single-nucleotide polymorphism in exon 1 of the OPRM1 gene that encodes the μ-opioid receptor. Evidence from clinical trials suggests that the presence of the variant G allele of rs1799971 may predict better treatment response to opioid receptor antagonists such as naltrexone. Evidence from clinical trials also suggests that several medications interact pharmacogenetically with variation in genes that encode proteins involved in dopaminergic and serotonergic neurotransmission. Variation in the DRD4 gene, which encodes the dopamine D4 receptor, may predict better response to naltrexone and olanzapine. A polymorphism in the serotonin transporter gene SLC6A4 promoter region appears related to differential treatment response to sertraline depending on the subject’s age of onset of alcoholism. Genetic variation in SLC6A4 may also be associated with better treatment response to ondansetron. Initial pharmacogenetic efforts in alcohol research have identified functional variants with potential clinical utility, but more research is needed to further elucidate the mechanism of these pharmacogenetic interactions and their moderators in order to translate them into clinical practice.

Biomarkers in mood disorders research: developing new and improved therapeutics

“…While an a priori stratification approach has not been extensively performed in neuropsychiatric research, it is a rational conceptual framework for additional biomarker research in this field. One notable example is that the OPRM1A118G single nucleotide polymorphism (SNP) predicted antidepressant response to the opioid receptor antagonist naltrexone in alcohol use disorders 21 .…”

Targeted Opioid Receptor Antagonists in the Treatment of Alcohol Use Disorders

“…A single nucleotide polymorphism (SNP) in OPRM1 (A118G → Asn40Asp amino acid substitution) has drawn particular attention. OPRM1 A118G has demonstrated pharmacogenetic effects in preclinical studies, but the results of pharmacogenetic analyses of treatment trials have unfortunately yielded inconsistent results (for a review of pharmacogenetic treatment studies in AUDs, see Arias and Sewell [67]). A total of 158 problem drinkers were randomized to receive either daily or targeted naltrexone 50 mg ( n = 81) or matching placebo ( n = 77) for 12 weeks.…”

Developing Biomarkers in Mood Disorders Research Through the Use of Rapid-Acting Antidepressants

“…HER2 monoclonal antibody trastuzumab therapy for over-expressing tumors in breast cancer, cetuximab use in epidermal growth factor receptor-overexpressing KRAS wild-type metastatic colorectal cancer, [31; 32] and in autoimmune diseases. [33; 34] A priori subject stratification has also been successfully used in alcohol use disorder research – the OPRM1A118G single nucleotide polymorphism predicts a positive response to naltrexone [35]. …”