This brief communication highlights the importance of genetic predictors and moderators of treatment research in the field of substance use.
The 25th annual meeting of the American Academy of Addiction Psychiatry (AAAP), will feature a symposium titled “Pharmacogenetically Driven Treatments Of Drug and Alcohol Dependence” on December 4, 2014. The symposium will highlight work of presenters: Dr Henry Kranzler (University of Pennsylvania, Perelman School of Medicine), Dr David Oslin (University of Pennsylvania), and Dr Thomas Kosten (Baylor College of Medicine).
This brief communication will focus on the recently completed randomized, controlled trials by Drs Kranzler and Oslin that studied the utility of pharmacogenetics in predicting treatment outcome for subjects with alcohol use disorders.
Dr Oslin presents the latest in his line of addiction research which has not been published yet. The research investigates usefulness of genetic variation in the gene encoding the µ-opioid receptor (OPRM1) in predicting treatment response to naltrexone among alcoholics. The research highlights a functional single-nucleotide polymorphism in exon 1 of the OPRM1 gene, rs1799971, also referred to as Asn40Asp (or A118G), which is one of the best-studied functional genetic variants relevant to alcoholism treatment.
The variant G allele is associated with a phenotype characterized by increased alcohol reward and reinforcement in healthy and heavy drinking subjects. In addition, this phenotype has a greater attenuation to alcohol-induced reward and reinforcement (including craving) with the administration of naltrexone. 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, though findings to date have been inconsistent.1
Another important gene associated with alcohol dependence is the glutamate receptor, ionotropic, kainate 1 (GRIK1) gene that encodes the Gluk1 (GluR5) subunit of the kainate glutamate receptor. One GRIK1 single nucleotide polymorphism (SNP), rs2832407, a C to A transition, was significantly associated with alcohol dependence, with the C allele being more common in subjects with the disorder.2
Building on the importance of this gene, Dr Kranzler presents findings of a published randomized controlled trial (RCT)3 in which a total of 138 heavy drinking participants (men > 24 drinks/week, women > 18 drinks/week) with an alcohol use disorder whose goal was not abstinence, rather to reduce the amount of drinking to safe levels. Subjects in this study were randomized to receiving a maximal topiramate dose of 200 mg or placebo.3 The primary outcome was heavy drinking days per week. Both groups received counseling to reduce drinking, and multiple assessments were done to monitor change in self-reported alcohol related problem, Beck Depression Inventory, and blood work (Kidney and liver functions including gamma-glutamyl transferase [GGT]).
The study found that the topiramate group had fewer heavy drinking days, and subjects in the topiramate group reduced drinking more rapidly compared with placebo. By the end of treatment weeks, subjects in placebo group were five times more likely to experience heavy drinking days compared to treatment group. Also subjects in the medication group had lower GGT levels compared to controls.
What adds to the merit of this study is the pharmacogenetics analysis that was done on the European American subsample, which represents the majority of the sample (83% of medication group, 93% of placebo group). Topiramate in Kranzler’s RCT was efficacious only in patients with CC allele of rs2832407, reducing heavy drinking days to on average one drinking day per week compared to three days per week in controls. There was no difference in response between medication and placebo among subjects with the A alleles. The authors conclude that studies with larger sample sizes and studies in samples different that European Americans are needed.
This brief communication highlights the importance of genetic predictors and moderators of treatment research in the field of substance use. The ability to predict response based on pharmacogenetic factors, among others, would allow for more efficacious personalized treatment plans for patients with substance use disorders. Much more translational research is needed before pharmacogentically guided treatments are a mainstay of regular clinical practice. Results to date have been promising, though there have been a number of inconsistent findings. Some of the discrepant findings to date may result from analyses focusing largely on single candidate genes, often only a single variant, while ignoring the effects of variation in other genes that could be affecting treatment response.
Dr Jefee-Bahloul is an Addiction Psychiatry fellow at Yale School of Medicine, Department of Psychiatry, in New Haven, Connecticut.
1. Arias AJ, Sewell RA. Pharmacogenetically driven treatments for alcoholism: are we there yet? CNS Drugs. 2012;26:461-476.
2. Kranzler HR, Gelernter J, Anton RF, et al. Association of markers in the 3' region of the GluR5 kainate receptor subunit gene to alcohol dependence. Alcohol Clin Exp Res. 2009;33:925-930.
3. Kranzler HR, Covault J, Feinn R, et al. Topiramate treatment for heavy drinkers: moderation by a GRIK1 polymorphism. Am J Psychiatry. 2014;171:445-452.