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

Abstract

Objective Previously, we 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, we 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. Method We genotyped 1 rare and 18 common single-nucleotide polymorphisms in HTR3A and HTR3B in the same sample that we had 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 twice daily) or placebo along with weekly cognitive behavioral therapy. Associations of individual and combined genotypes with treatment response on drinking outcomes were analyzed. Results 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 (ES)=0.867), percentage of heavy drinking days (−20.58%; ES=0.780), and percentage of days abstinent (18.18%; ES=0.683). Combining these HTR3A/HTR3B and SLC6A4-LL/TT genotypes increased the target cohort from approaching 20% (identified in our previous study) to 34%. Conclusions We present initial evidence suggesting that a combined 5-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 our results.

Attention-Deficit/Hyperactivity Disorder and Risk for Substance Use Disorders in Relatives

“…Also, further exploration of genetic underpinnings of both disorders is important to individualize and optimize future psychosocial and pharmacological treatment. Theoretically, individuals with a genetic susceptibility for ADHD and SUD might benefit from different treatment options than individuals without such hereditary risk factors (34).…”

Pharmacological treatment options for alcohol use disorder

“…Studies with ondansetron have shown a reduction in the amount of alcohol used and a longer remission in persons with early-onset AUD (108). In addition, a polymorphism in the starting region of the serotonin carrier gene has been shown to affect the response to ondansetron, and in carriers of the long LL allele, ondansetron reduced the amount of alcohol used (109). Another experimental study reported that ondansetron might reduce alcohol consumption in women with the LL 5-HTTLPR genotype, while it was not effective in women with the SS/SL 5-HTTLPR genotype (110).…”

Pharmacotherapy of Alcohol and Drug Dependence

“…A more recent study demonstrated ondansetron's efficacy in patients with variants in genes encoding the serotonin transporter or serotonin-3 receptors [66].…”