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Kranzler HR1, Perez E,1 De Biasi M1

1Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

Topiramate has a variety of pharmacological effects, one of which is to block kainate receptors containing GluK1 and GluK2 subunits, which are encoded by the GRIK1 and GRIK2 genes, respectively. Based on this pharmacology, we found an association with alcohol dependence of a single nucleotide polymorphism (SNP; rs2832407) in GRIK1, with the C allele overrepresented in AD individuals (Kranzler et al. 2009). We examined the moderating effect of rs2832407 on the response to topiramate (at a maximal dosage of 200 mg/day) in a 12-week treatment study in 138 heavy drinkers whose goal was to reduce their drinking. This was followed by 3- and 6-month post-treatment follow-up visits. The rate of treatment completion and follow-ups was >80% and equal by treatment group. During treatment, 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 gamma-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. The number needed to prevent heavy drinking in the last month of treatment, after adjustment for adverse effects, was also highly favorable for this genotype responsive group that received topiramate. Further, among topiramate-treated patients with the responsive genotype, the reduction in heavy drinking days persisted for 6 months after treatment. To identify a more specific medication for use in reducing heavy drinking, we have begun to examine a GluK1-specific antagonist (LY466196) in a mouse model of drinking, early results of which are promising.