Pharmacogenetically Driven Treatments for Drug and Alcohol Dependence

Applied pharmacogenetic science — the study of how genetic variation affects medication response and can be used to enhance it — is emerging as an important component of personalized medicine. 

Commercial services for clinical genotyping are already widely available, with companies focused on general psychiatric and pain medicine markets. The use of pharmacogenetic in psychiatry and addiction treatment services, although not clinically feasible at the moment, is promising.

Addictive disorders are highly heritable, so that they are likely to be amenable to a pharmacogenetic approach to treatment.

Some genetic variants are linked to behavioral phenotypes that are not exclusively related to substance abuse, but also probably to other disordered behaviors (e.g. attention-deficit/hyperactivity disorder, eating disorders). These are often referred to as “translational phenotypes.”

Translational phenotypes have readily characterized features, such as increased impulsive and risk-taking behaviors, or an altered response to environmental stressors.

There are two main types of pharmacogenetic interaction that can affect medication response clinically: pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body).  Either of these factors can influence the extent of the subjective response to a substance of abuse. 

There is also the potential for more complex gene-environment-medication interactions to occur. A gene-environment interaction could increase or decrease treatment response to a medication.

For example, a medication that decreases anxiety and drinking could be especially useful in patients genetically predisposed to greater amounts of stress-induced craving and subsequent relapse.

One of the first genetic variants to be explored in addiction treatment is a single nucleotide polymorphism in the OPRM1 gene, which encodes the mu-opioid receptor. Referred to as A118G, Asn40Asp, or rs1799971, it is a functional polymorphism, with the less common G allele having been associated with greater alcohol-induced reward in healthy and heavy drinking humans.

Individuals with the variant G allele also experience a greater attenuation of alcohol reward and craving with naltrexone in a human laboratory setting. 

Alchohol-Dependence Treatments

Dr. David Oslin, an associate professor of psychiatry at the Philadelphia Veterans Affairs Medical Center, and colleagues first reported a preferential response to naltrexone treatment in individuals with the G allele in a retrospective pooled analysis of three clinical trials.¹ Since then, multiple studies of the effects of rs1799971 on naltrexone treatment response for alcoholism have been published.  

The findings from these studies have been inconsistent. The mixed findings to date for this polymorphism as a predictor of opioid antagonist treatment of alcohol dependence may be explained by the effects of other variants, either in the mu-opioid receptor gene (OPRM1) or in dopaminergic system genes that may affect naltrexone response, or interact with OPRM1 variants.

Oslin will present results at the 2014 Meeting of the American Academy of Addiction Psychiatry (AAAP 2014) from a naltrexone study that he and colleagues recently completed using a prospective design with stratification and enrichment of the sample based to include G-allele carriers.² This was a 12-week placebo-controlled trial in 221 alcohol dependent subjects, the results of which will be published in a forthcoming edition of JAMA Psychiatry. 

In another presentation at AAAP 2014, Henry Kranzler, MD, of the Perelman School of Medicine at the University of Pennsylvania explained the pharmacogenetic findings from a clinical trial of topiramate 200 mg daily for treating heavy drinkers.

The prospective, randomized, placebo-controlled, 12-week trial assessed the efficacy and tolerability of the medication in 138 patients, who did not want to quit drinking, but sought to reduce their drinking to non-hazardous levels.³

The researchers selected rs2832407, a variant in the GRIK1 gene that encodes the GluK1 subunit of the kainate glutamatergic ionotropic receptor, as a predictor topiramate response.⁴  The GluK1 kainate subunit has previously been associated with risk for alcohol dependence and is also a prime candidate for interacting with topiramate response, as it is thought to bind topiramate preferentially.

Topiramate was superior to placebo on all primary and major drinking outcomes including the percentage of subjects with no relapse to heavy drinking and reduction in gamma-glutamyltranspeptidase concentrations, a biomarker of alcohol consumption.