A Preliminary Pharmacogenetic Investigation of Adverse Events From Topiramate in Heavy Drinkers

Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA.
Experimental and Clinical Psychopharmacology (Impact Factor: 2.71). 05/2009; 17(2):122-9. DOI: 10.1037/a0015700
Source: PubMed


Topiramate, an anticonvulsant medication, is an efficacious treatment for alcohol dependence. To date, little is known about genetic moderators of side effects from topiramate. The objective of this study was to examine 3 single nucleotide polymorphisms (SNPs) of the glutamate receptor GluR5 gene (GRIK1) as predictors of topiramate-induced side effects in the context of a laboratory study of topiramate. Heavy drinkers (n=51, 19 women and 32 men), 75% of whom met criteria for an alcohol use disorder, completed a 5-week dose escalation schedule to a target dose of either 200 or 300 mg or matched placebo. The combined medication groups were compared with placebo-treated individuals for side effects at target dose. Analyses revealed that an SNP in intron 9 of the GRIK1 gene (rs2832407) was associated with the severity of topiramate-induced side effects and with serum levels of topiramate. Genes underlying glutamatergic neurotransmission, such as the GRIK1 gene, may help predict heterogeneity in topiramate-induced side effects. Future studies in larger samples are needed to more fully establish these preliminary findings.

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    • "Such findings on safety and mechanisms are vital to deciding whether to invest resources for efficacy testing for a putative addiction medication . Our team has used human laboratory paradigms to test several medications for addiction, including naltrexone (Ray, Bujarski, Chin, & Miotto, 2012; Ray & Hutchison, 2007), topiramate (Miranda et al., 2008; Ray et al., 2009), quetiapine (Moallem & Ray, 2012; Ray, Chin, Heydari, & Miotto, 2011), and varenicline (Ray et al., 2014, 2013). Given the new opportunities presented by recent discoveries on the role of neuroinflammation in addiction as well as new advancements in the technology of medication development , including the refinement of powerful human laboratory models, the stage is set for the discovery of novel treatments for substance use disorders. "
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    • "In the subsample of European Americans (n = 122), topiramate was effective in reducing heavy drinking days only in rs2832407 C-allele homozygotes . In addition, a previous pharmacogenetic analysis of the human laboratory pilot study mentioned previously (Miranda et al., 2008) showed that rs2832407 was associated with the severity of topiramate-induced side effects (Ray et al., 2009). The RCT by Kranzler et al. (2014) did not find an effect of the SNP on adverse events, suggesting that the kainate receptor does not play a unique role in mediating topiramate-related adverse effects. "

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    • "The changes in mRNA levels do not directly address whether protein levels of glutamate receptors have changed but this could potentially be verified by Western blot analysis of protein expression. The data complement previous studies on the effects of alcohol on glutamate signaling (Wernicke et al., 2003; Petrakis et al., 2004; Rujescu et al., 2005; Kim et al., 2006; Preuss et al., 2006; Kranzler et al., 2009; Ray et al., 2009; Ridge et al., 2009) and provide further evidence for long-term changes of glutamate receptors in the central nervous system by chronic alcohol consumption. The hippocampus is important for learning and memory (Nicoll and Roche, 2013). "
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