GRIK1

Literature Summary: Glutamate Receptor Kainate 1 (GRIK1)

GRIK1 C/C Genotype is associated with improved response to topiramate in reducing heavy drinking

https://www.ncbi.nlm.nih.gov/pubmed/26891181 [139]

The number needed to treat (NNT) “…for topiramate was 5.29, the NNT for patients with moderate adverse events was 7.52, and the NNT for patients with severe adverse events was 6.12. Among European Americans with the rs2832407*CC genotype, the NNT was 2.28, the NNT for patients with moderate adverse events was 2.63, and the NNT for patients with severe adverse events was 2.56. In

contrast, for rs2832407*A-allele carriers, the NNT was 180.00, the NNT for patients with moderate adverse events was 322.16, and the NNT for patients with severe adverse events was 217.45…In this

sample of heavy drinkers, topiramate had a clinically important treatment effect that was most evident in European Americans with the rs2832407*CC genotype. In that group, in particular, it had a robust

treatment effect, even when adjusted for adverse events.” [139] 

Topiramate treatment for heavy drinkers: moderation by a GRIK1 polymorphism.

http://www.ncbi.nlm.nih.gov/pubmed/24525690 [140]

“Topiramate has been shown to reduce drinking and heavy drinking in individuals with alcohol dependence whose goal was to stop drinking. The authors evaluated the efficacy and tolerability of

topiramate in heavy drinkers whose treatment goal was to reduce drinking to safe levels… Topiramate treatment significantly reduced heavy drinking days and increased abstinent days relative to placebo. In

a European American subsample (N=122), topiramate's effect on heavy drinking days was significantly greater than that for placebo only in rs2832407 C-allele homozygotes. These findings support the use of topiramate at a daily dose of 200 mg to reduce heavy drinking in problem drinkers. The moderator effect of rs2832407, if validated, would facilitate the identification of heavy drinkers who are likely to respond well to topiramate treatment and provide an important personalized treatment option. Thepharmacogenetic findings also implicate the kainate receptor in the mechanism of topiramate's effects on heavy drinking.” [140] 

Posttreatment effects of topiramate treatment for heavy drinking.

http://www.ncbi.nlm.nih.gov/pubmed/25581656 [141]

“We examined whether the effects of topiramate and a single nucleotide polymorphism (rs2832407) in GRIK1, which encodes a kainate receptor subunit, persisted following a 12-week, placebo-controlled trial in 138 heavy drinkers with a treatment goal of reduced drinking. During treatment, topiramate 200 mg/d significantly reduced heavy drinking days and increased the frequency of abstinent days (Am J Psychiatry, 2014, 171:445). In the European-American (EA) subsample (n = 122), rs2832407 moderated the treatment effect on heavy drinking…In the full sample, the lower PHDD and higher PDA seen with topiramate treatment were no longer significant during follow-up. Nonetheless, the topiramate-treated patients had lower alcohol-related problem scores during treatment and both follow-up periods. Further, in the EA subsample, the greater reduction in PHDD seen with topiramate treatment in rs2832407*C-allele homozygotes persisted throughout follow-up, with no significant effects in A-allele carriers. A reduction in GGTP concentration was consistent with the reduction in heavy drinking, but did not reach statistical significance.” [141]

GRIK1 genotype moderates topiramate's effects on daily drinking level, expectations of alcohol's

positive effects and desire to drink.

http://www.ncbi.nlm.nih.gov/pubmed/24786948 [142]

“We found that rs2832407*C allele homozygotes treated with topiramate drank less overall during treatment than those receiving placebo, validating our earlier findings for heavy drinking days There was

also a study day × medication group × genotype group interaction that predicted both positive alcohol expectancies and desire to drink, with rs2832407 C-allele homozygotes treated with topiramate showing

the largest decreases in these outcomes during the study period. Changes in positive alcohol expectancies or desire to drink did not mediate the effects on drinking. These findings validate and

extend our previous pharmacogenetic findings with topiramate.” [142]

Self-efficacy mediates the effects of topiramate and GRIK1 genotype on drinking.

http://www.ncbi.nlm.nih.gov/pubmed/25496338 [143]

“In a 12-week, placebo-controlled trial of topiramate, we used daily interactive voice response technology to measure self-efficacy (i.e. confidence in avoiding heavy drinking later in the day) and

drinking behavior in 122 European-American heavy drinkers. Topiramate's effects on both self-efficacy and drinking level were moderated by rs2832407. C-allele homozygotes treated with topiramate showed

higher levels of self-efficacy and lower levels of nighttime drinking across the 12-week trial. Further, the interactive effect of topiramate and genotype on mean nighttime drinking levels was mediated by mean levels of self-efficacy. By modeling topiramate's effects on nighttime drinking across multiple levels of analysis, we found that self-efficacy, a key psychologic construct, mediated the effect of topiramate, which was moderated by rs2832407 genotype. Thus, it may be possible to use an individualized assessment (i.e. genotype) to select treatment to optimize the reduction in heavy drinking and thereby provide a personalized treatment approach.” [143]