Topiramate Treatment for Heavy Drinkers: Moderation by aGRIK1Polymorphism

Abstract

Objective: Topiramate has been shown to reduce drinking and heavy drinking in alcohol-dependent individuals whose goal was to stop drinking. The present study evaluated the efficacy and tolerability of topiramate in heavy drinkers whose treatment goal was to reduce drinking to safe levels. Method: We randomly assigned 138 individuals (62.3% male) to receive 12 weeks of treatment with topiramate (N=67), at a maximal daily dosage of 200 mg, or matching placebo (N=71), both groups receiving brief counseling to reduce drinking and increase abstinent days. We hypothesized that topiramate-treated patients would be better able to achieve these goals and predicted that, based on prior research, the effects would be moderated by a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the kainate GluK1 receptor subunit. Results: The rate of treatment completion was 84.9% and equal by treatment group. Topiramate treatment significantly reduced heavy drinking days (p<0.001) and increased abstinent days (p=0.032) relative to placebo. The topiramate group also had lower concentrations of the liver enzyme γ-glutamyltranspeptidase and lower scores on a measure of alcohol-related problems than the placebo group. In a European-American subsample (N=122), topiramate’s effect on heavy drinking days (p=0.004) was significantly greater than for placebo only in rs2832407 C-allele homozygotes. Conclusions: These findings support the use of topiramate 200 mg/day to reduce heavy drinking in problem drinkers. The moderator effect of rs2832407, if validated, would facilitate the identification of heavy drinkers who are likely to respond well to topiramate treatment and provide an important personalized treatment option. The pharmacogenetic findings also implicate the kainate receptor in the mechanism of topiramate’s effects on heavy drinking. www.clinicaltrials.gov registration: NCT00626925

Promising Pharmacogenetic Targets for Treating Alcohol Use Disorder: Evidence from Preclinical Models

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Underutilization of Pharmacotherapy for Treatment of Alcohol Use Disorders Part II-Results from a Survey of Practices among North Carolina Mental Health Providers and Brief Review of Efficacy of Available Pharmacotherapies

“…Most recent trials have demonstrated efficacy in decreasing heavy drinking to safer levels and also found certain genotypes that might benefit from treatment with Topiramate [36]. The slow dose titration required to achieve the reported ranges of 100-300 mg prevents benefit from being observed until the fourth week [37].…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…The kainate receptors (composed of GluK1-5) are inhibited by ethanol at low concentrations, but it is unclear whether this action involves direct effects on the receptor protein (Valenzuela et al, 1998a;Lack et al, 2008). The GluK1 receptors are especially interesting, because the presence of a polymorphism in GRIK1 gene correlated with a robust response to topiramate in reducing heavy drinking of alcoholdependent subjects (Kranzler et al, 2014). Taken together, inhibition of the iGluRs by ethanol decreases neuronal excitability and also inhibits synaptic plasticity that requires activation of iGluRs.…”