Determination of Genotype Combinations That Can Predict the Outcome of the Treatment of Alcohol Dependence Using the 5-HT₃ Antagonist Ondansetron

The authors previously reported that the 5′-HTTLPR-LL and rs1042173-TT (SLC6A4-LL/TT) genotypes in the serotonin transporter gene predicted a significant reduction in the severity of alcohol consumption among alcoholics receiving the 5-HT₃ antagonist ondansetron. In this study, they explored additional markers of ondansetron treatment response in alcoholics by examining polymorphisms in the HTR3A and HTR3B genes, which regulate directly the function and binding of 5-HT₃ receptors to ondansetron.

The authors genotyped one rare and 18 common single-nucleotide polymorphisms in HTR3A and HTR3B in the same sample that they genotyped for SLC6A4-LL/TT in the previous randomized, double-blind, 11-week clinical trial. Participants were 283 European Americans who received oral ondansetron (4 µg/kg of body weight twice daily) or placebo along with weekly cognitive-behavioral therapy. Associations of individual and combined genotypes with treatment response on drinking outcomes were analyzed.

Individuals carrying one or more of genotypes rs1150226-AG and rs1176713-GG in HTR3A and rs17614942-AC in HTR3B showed a significant overall mean difference between ondansetron and placebo in drinks per drinking day (−2.50; effect size=0.867), percentage of heavy drinking days (−20.58%; effect size=0.780), and percentage of days abstinent (18.18%; effect size=0.683). Combining these HTR3A/HTR3B and SLC6A4-LL/TT genotypes increased the target cohort from approaching 20% (identified in the previous study) to 34%.

The authors present initial evidence suggesting that a combined five-marker genotype panel can be used to predict the outcome of treatment of alcohol dependence with ondansetron. Additional, larger pharmacogenetic studies would help to validate these results.