Abstract
BACKGROUND: Topiramate has shown efficacy in reducing alcohol consumption and is increasingly used off-label for individuals with harmful alcohol use. However, findings regarding the moderating effect of the GRIK1 rs2832407 single nucleotide polymorphism (SNP) on treatment outcomes remain inconsistent, highlighting the need for a review of the current evidence. We evaluated whether the GRIK1 rs2832407 SNP moderates the efficacy and safety of topiramate treatment for alcohol use. METHODS: We searched multiple databases including MEDLINE, Cochrane Library, ClinicalTrials.gov, and the International Clinical Trials Registry Platform up to December 1, 2024. Randomized controlled trials (RCTs) comparing treatment outcomes of topiramate in patients with alcohol use who were homozygous for the C allele at rs2832407 with those carrying one or more A alleles at rs2832407 were included. Primary outcomes were heavy drinking days (HDDs) and percentage of days abstinent (PDA), and the secondary outcome was side effects. Each outcome was evaluated using version 2 of the Cochrane Risk of Bias tool. RESULTS: Our analysis included four RCTs. Among three studies evaluating HDDs, only one study demonstrated genotype effects, demonstrating a reduction in HDDs among CC carriers. Of two studies examining PDA, only one revealed genotype effects, indicating an increase in PDA. Side effects were evaluated in two studies, both of which assessed the severity of side effects, but with conflicting results regarding the effect of genotype. CONCLUSIONS: This systematic review highlights the current lack of sufficient evidence to confirm the pharmacogenetic effect of the GRIK1 rs2832407 SNP on the efficacy or safety of topiramate treatment in individuals with harmful alcohol use. TRIAL REGISTRATION: This research was prospectively registered with the Open Science Framework ( https://osf.io/z2awu/ ).