Initial evidence suggests that a five-marker genotype panel can effectively predict which patients will have a more favorable treatment response with an experimental drug for alcohol addiction, according to a study published in theAmerican Journal of Psychiatry. While additional validation is needed, the authors say that the identification of these genetic variants represents a step forward toward personalized pharmacogenomic treatment of addiction. The researchers had previously identified that the SLC6A4-LL/TT genotypes in the 5-HTT serotonin transporter gene predicted a significantly greater effectiveness of the experimental drug ondansetron. Without patient stratification by genotype, there was no difference between treatment effect in the ondansetron and placebo groups. Since the drug works by blocking certain serotonin receptors (as opposed to binding with the transporter molecules regulated by the 5-HTT gene), the scientists speculated that additional genetic variations affecting the binding receptor might further determine the effectiveness of ondansetron. In the current study, genotyping was performed on one rare and 18 common single-nucleotide polymorphisms in HTR3A, HTR3B, and SLC6A4 genes utilizing samples from the same cohort previously studied. The 283 patients were participating in a randomized, double-blind, 11-week clinical trial in which they received oral ondansetron or placebo along with weekly counseling. The researchers […]
Initial evidence suggests that a five-marker genotype panel can effectively predict which patients will have a more favorable treatment response with an experimental drug for alcohol addiction, according to a study published in theAmerican Journal of Psychiatry. While additional validation is needed, the authors say that the identification of these genetic variants represents a step forward toward personalized pharmacogenomic treatment of addiction.
The researchers had previously identified that the SLC6A4-LL/TT genotypes in the 5-HTT serotonin transporter gene predicted a significantly greater effectiveness of the experimental drug ondansetron. Without patient stratification by genotype, there was no difference between treatment effect in the ondansetron and placebo groups. Since the drug works by blocking certain serotonin receptors (as opposed to binding with the transporter molecules regulated by the 5-HTT gene), the scientists speculated that additional genetic variations affecting the binding receptor might further determine the effectiveness of ondansetron.
In the current study, genotyping was performed on one rare and 18 common single-nucleotide polymorphisms in HTR3A, HTR3B, and SLC6A4 genes utilizing samples from the same cohort previously studied. The 283 patients were participating in a randomized, double-blind, 11-week clinical trial in which they received oral ondansetron or placebo along with weekly counseling.
The researchers found that individuals carrying one or more of genotypes rs1150226-AG and rs1176713-GG in HTR3A and rs17614942-AC in HTR3B showed significant overall mean differences (comparing ondansetron and placebo) in drinks per drinking day, percentage of heavy drinking days, and percentage of days abstinent. When the HTR3A/HTR3B variants were combined with the previously identified SLC6A4-LL/TT genotypes, the target cohort of patients likely to benefit from the drug increased from 20 percent (identified in the previous study) to 34 percent. A subset of these carriers (totaling approximately 25 percent of the cohort) may constitue a group of “super-responders” as they had more than a fivefold increase in percentage of participants with no heavy drinking days when taking the drug.
“These initial statistical trends generally [support] a molecular basis for the use of ondansetron as a treatment for a particular cohort of alcohol-dependent individuals,” write the authors, led by Bankole Johnson, D.Sc., M.D., from the University of Virginia (Charlottesville). “Perhaps because of [alcoholism’s] heterogeneity, the therapeutic effect sizes of the approved medications for the treatment of alcohol dependence have been relatively small. A personalized approach based on the patient’s genetic makeup is increasingly being investigated for delivering optimum treatment to suitable patients.”
Johnson reports financial ties to the pharmaceutical industry, including ADial Pharmaceutical, which is developing and testing an ondansetron product for addiction.
Takeaway: The identification of genetic variants that predict the success of drug treatment for alcohol dependence is another step toward the clinical practice of personalized medicine. Ondansetron provides another example of how patient stratification, based on genetics, can play a crucial role in drug trials.
