Gene Modifies Response to Topiramate in Heavy Drinkers

Henry R. Kranzler, MD Professor, Department of Psychiatry Director of the Center for Studies of Addiction. University of Pennsylvania Perelman School of Medicine, PhiladelphiaMedicalResearch.com Interview with:
Henry R. Kranzler, MD
Professor, Department of Psychiatry
Director of the Center for Studies of Addiction.
University of Pennsylvania Perelman School of Medicine, Philadelphia

MedicalResearch.com: What are the main findings of the study?

Dr. Kranzler: The study had two main findings:

  • First, topiramate, at a maximal dosage of 200 mg/day, which is lower than the 300 mg/day used in prior treatment trials, substantially reduced the frequency of heavy drinking and increased the frequency of abstinent days more than placebo. The lower dosage was well tolerated.
  • Second, a variant in a gene that encodes a receptor subunit that binds topiramate moderated the response to topiramate. That is, C-allele homozygotes in the single nucleotide polymorphism rs2832407 in GRIK1, the gene encoding the GluK1 subunit of the kainate receptor, were the subgroup that accounted for the effects of topiramate on heavy drinking. This has important implications for the personalized treatment of alcohol use disorder, in that 40% of people of European ancestry have this genotype and, if confirmed, these findings would make it possible to screen people genetically to select an effective treatment.


MedicalResearch.com: Were any of the findings unexpected?

Dr. Kranzler: Although the moderating effect of rs2832407 was hypothesized beforehand, the magnitude of the effect was surprisingly large.

MedicalResearch.com: What should clinicians and patients take away from your report?

Dr. Kranzler: Topiramate can be used to reduce heavy drinking in people whose goal is sensible drinking, rather than only those with a goal of abstinence. This is consistent with prior studies. Although it requires replication before it can be widely recommended, the finding of genetic moderation could make it possible to select patients for whom topiramate would be the medication of choice to treat alcohol use disorder.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. Kranzler: The findings of moderation require replication. We are planning a study in which patients are selected in advance based on genotype and then treated with topiramate to validate our initial findings. I am also working with investigators in Australia on a plan to replicate the findings there.

Citation:

Topiramate Treatment for Heavy Drinkers: Moderation by a GRIK1 Polymorphism

Henry R. Kranzler, M.D.; Jonathan Covault, M.D., Ph.D.; Richard Feinn, Ph.D.; Stephen Armeli, Ph.D.; Howard Tennen, Ph.D.; Albert J. Arias, M.D.; Joel Gelernter, M.D.; Timothy Pond, M.P.H.; Cheryl Oncken, M.D., M.P.H.; Kyle M. Kampman, M.D. Am J Psychiatry 2014;:. doi:10.1176/appi.ajp.2013.13081014