Henry R Kranzler1, Emily E Hartwell2, Richard Feinn3, Timothy Pond2, Katie Witkiewitz4, Joel Gelernter5, Richard C Crist6. 1. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, United States; Mental Illness Research, Education and Clinical Center, Crescenz VAMC, United States. Electronic address: kranzler@pennmedicine.upenn.edu. 2. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, United States; Mental Illness Research, Education and Clinical Center, Crescenz VAMC, United States. 3. Department of Medical Sciences, Frank H. Netter School of Medicine at Quinnipiac University, North Haven, CT, 06473, United States. 4. Department of Psychology, Center on Alcoholism, Substance Abuse, and Addictions, University of New Mexico, Albuquerque, NM, 87131, United States. 5. Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, CT, 06516, United States. 6. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, United States.
Abstract
BACKGROUND: In an initial study, we reported that topiramate reduced heavy drinking among individuals who sought to reduce their drinking and that the effect was moderated by a single nucleotide polymorphism (SNP; rs2832407) in GRIK1, which encodes the kainate GluK1 receptor subunit (Kranzler et al., 2014). In a subsequent study that prospectively randomized patients to medication group based on their rs2832407 genotype, we replicated the main effect of topiramate but not the moderating effect of the SNP (Kranzler et al., 2021). Given the similar design of the two studies, here we combined the findings to provide greater statistical power to test the pharmacogenetic effect. MATERIAL AND METHODS: This secondary analysis of two 12-week, randomized controlled trials of topiramate included a total of 292 European-ancestry individuals (67.1 % male; topiramate: 48.3 %, placebo: 51.7 %) with problematic alcohol use. Using MANOVA, we examined changes in self-reported alcohol consumption, problems resulting from alcohol use, and quality of life, and the biomarker γ-glutamyltransferase. To test the pharmacogenetic hypothesis, all patients were genotyped for rs2832407. RESULTS: There was a significant overall effect of topiramate on the alcohol-related outcomes (partial η2 = 0.134, p < 0.001), with follow-up analyses showing significant reductions in percent heavy drinking days (Cohen's d = 0.49), percent days abstinent (d = 0.23), drinks/day (d = 0.29) and alcohol-related problems (d = 0.45). Overall, the moderating effect of the SNP was non-significant (partial η² = 0.026, p = 0.37). CONCLUSIONS: Although topiramate is an efficacious medication for reducing drinking and alcohol-related problems among patients with problematic alcohol use, rs2832407 does not appear to moderate its therapeutic effects. www.clinicaltrials.gov registrations: NCT00626925 and NCT02371889.
BACKGROUND: In an initial study, we reported that topiramate reduced heavy drinking among individuals who sought to reduce their drinking and that the effect was moderated by a single nucleotide polymorphism (SNP; rs2832407) in GRIK1, which encodes the kainate GluK1 receptor subunit (Kranzler et al., 2014). In a subsequent study that prospectively randomized patients to medication group based on their rs2832407 genotype, we replicated the main effect of topiramate but not the moderating effect of the SNP (Kranzler et al., 2021). Given the similar design of the two studies, here we combined the findings to provide greater statistical power to test the pharmacogenetic effect. MATERIAL AND METHODS: This secondary analysis of two 12-week, randomized controlled trials of topiramate included a total of 292 European-ancestry individuals (67.1 % male; topiramate: 48.3 %, placebo: 51.7 %) with problematic alcohol use. Using MANOVA, we examined changes in self-reported alcohol consumption, problems resulting from alcohol use, and quality of life, and the biomarker γ-glutamyltransferase. To test the pharmacogenetic hypothesis, all patients were genotyped for rs2832407. RESULTS: There was a significant overall effect of topiramate on the alcohol-related outcomes (partial η2 = 0.134, p < 0.001), with follow-up analyses showing significant reductions in percent heavy drinking days (Cohen's d = 0.49), percent days abstinent (d = 0.23), drinks/day (d = 0.29) and alcohol-related problems (d = 0.45). Overall, the moderating effect of the SNP was non-significant (partial η² = 0.026, p = 0.37). CONCLUSIONS: Although topiramate is an efficacious medication for reducing drinking and alcohol-related problems among patients with problematic alcohol use, rs2832407 does not appear to moderate its therapeutic effects. www.clinicaltrials.gov registrations: NCT00626925 and NCT02371889.
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