Genes May Determine Drug’s Alcohol-Treatment Success

Taking a more personalized approach, several studies are investigating whether patients’ genetic makeup can help physicians more effectively treat chronic illnesses, including substance use disorders.

Bankole Johnson, M.D., D.Sc., a professor of psychiatry and neurobehavioral sciences at the University of Virginia, headed a pharmacogenetic study published in the July 2011 American Journal of Psychiatry showing that individuals treated for alcohol addiction with ondansetron—a drug that is approved by the Food and Drug Administration to treat nausea in chemotherapy patients—were more likely to abstain from drinking when they expressed both length (LL) and nucleotide (TT) variances in the serotonin transporter gene, SLC6A4, than were those who did not carry the SLC6A4-TT/LL genotype.

Now Johnson and colleagues have reported in the September American Journal of Psychiatry that possessing polymorphisms within the HTR3A and HTR3B genes—subunits of serontonin-3 receptors (5-HT3)—may result in even greater benefits for individuals being treating for alcohol dependency with ondansetron.

“The [recently published] paper builds upon earlier work showing that alcohol-dependent individuals vary in genetic profile with respect to the serotonin transporter receptor and 5-HT3 subclasses,” Johnson told Psychiatric News. He explained that because ondansetron is a selective inhibitor for the A subunit of the 5-HT3 receptor, it was logical to direct attention toward HTR3A—the gene that encodes the A subunit. The HTR3B gene was studied by default because A and B subunits of 5-HT3 receptors form a complex.

Studies conducted by other researchers have shown that genetic deletion of HTR3A in animals is associated with increased alcohol consumption, while human studies have shown that specific variances in the both HTR3A and HTR3B were associated with a higher incidence for combined heroin, cocaine, and alcohol addiction.

In their recent study, Johnson and his team conducted an 11-week double-blind study to assess how allelic variances in the HTR3A and HTR3B genes affect ondansetron efficacy in treating alcoholism.

Using the same 283 alcohol-dependent subjects from their 2011 AJP report, the researchers divided the subjects into two groups—ondansetron and placebo. Ondansetron was administered orally twice daily at 4ug/kg of body weight. Participants were tested for 21 polymorphisms for the HTR3A and HTR3B genes, in addition to the SLC6A4-TT/LL genotype from previous studies. The researchers also assessed the effects of drinking outcomes in the presence of multiple variances.

Results showed that individuals possessing one or more genotypes for rs1150226-AG and rs1176713-GG in the HTR3A gene and rs1714942-AC in HTR3B exhibited a reduction of two drinks per drinking day in response to ondansetron as compared with trait carriers who were given placebo.

Ondansetron participants with allelic variances had a 20 percent lower incidence of heavy drinking days and were twice as likely to abstain from alcohol as were those with the same allelic variants taking placebo. In addition, a subpopulation of individuals carrying a combined genotype for SLC6A4-TT/LL and HTR3A/HTR3B polymorphisms were able to reduce drinking days by 34 percent while taking ondansetron, while individuals expressing SLC6A4-TT/LL alone reduced drinking days by 20 percent compared with the control group.

“The era of personalized medicine by which we can target subpopulations of those with alcohol dependence for optimum treatment effect has arrived,” said Johnson, explaining that having variances in both the presynaptic serotonin transporter gene and postsynaptic 5-HT3 suggest a greater response to ondansetron in lowering alcohol consumption.

Ondansetron has yet to be FDA-approved to treat alcoholism, but phase 3 clinical trials for alcoholism are underway, Johnson told Psychiatric News.

According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), millions of U.S. alcohol abusers are not diagnosed and treated until late stages of the disease when there has been much damage—often irreversible.

NIAAA is conducting studies to reproduce the results of Johnson and colleagues. According to Raye Litten, Ph.D., associate director of the Division of Treatment and Recovery Research at NIAAA, the pharmacogenetic aspect of ondansetron “is not ready for primetime just yet” for the field is fairly new. “If we can reproduce Johnson’s results it will be very promising for the future of medicine in treating alcohol dependency, which is such a complex disorder” said Litten.

The study was funded by NIAAA. ■

“Determination of Genotype Combinations That Can Predict the Outcome of the Treatment of Alcohol Dependence Using the 5-HT3 Antagonist Ondansetron“ is posted at http://ajp.psychiatryonline.org/article.aspx?articleID=1722045.