Gene Combo May Predict Alcohol Treatment Outcomes

Deborah Brauser

August 08, 2013

Specific gene combinations may predict the success or failure of an experimental medication for the treatment of alcohol dependence, new research suggests.

A study of nearly 300 alcohol-dependent participants showed that the effectiveness of ondansetron for treating their disorder, including a reduction in severe drinking and an increase in abstinence, was strongly associated with whether they had 1 of 3 specific HTR3 gene variants. Ondansetron is a serotonin-3 (5-HT3) antagonist that is commonly used to treat postchemotherapy nausea and vomiting.

These results extend prior research done by Bankole A. Johnson, MD, DSc, professor of medicine and of neuroscience at the University of Virginia in Charlottesville, and colleagues that analyzed variants of genes that regulate the function and binding of serotonin.

"Taken together, these studies implicate a collective effect of serotonin receptor and transporter gene combinations, defined by a 5-marker genotype panel, on the response to treatment with ondansetron for a genetically defined subpopulation of individuals with alcohol dependence," said Dr. Johnson in a release.

The investigators note that this means this combination of genotypes can eventually be used to better screen for patients for whom this medication will be successful.

"This study is another important step toward personalized treatments for alcohol dependence," Kenneth R. Warren, PhD, acting director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), said in a release.

"A personalized approach based on a person's genetic makeup is increasingly being investigated for delivering optimum treatment to the 'right' patient," added Dr. Warren.

The study was published online July 30 in the American Journal of Psychiatry.

Blocking Serotonin

According to the researchers, ondansetron "works by blocking serotonin-3 receptors, and has shown potential" as a treatment for alcohol dependence.

A total of 283 alcohol-dependent participants between the ages of 20 and 78 years (73% male; 85% white, 15% Hispanic; mean age, 44.7 years) were enrolled in a phase 2, 11-week randomized controlled trial. All received a score of 8 or higher on the Alcohol Use Disorders Identification Test.

Dr. Bankole Johnson

The participants were randomly assigned to receive either ondansetron (4 μg/kg of body weight given orally twice daily, n = 140) or matching placebo (n = 143). Both groups also received weekly sessions of cognitive-behavioral therapy.

As reported by Medscape Medical News, the investigative team previously found that SLC6A4-LL/TT variants in these patients were associated with efficacious treatment.

In the current analysis, 19 single-nucleotide polymorphisms in HTR3A and HTR3B were analyzed from blood samples.

Information on drinks per day, percentage of days abstinent, and percentage of heavy drinking days was collected and assessed as to effect from any genotype. Information concerning daily alcohol intake for the 90 days prior to the study's start was also collected.

Significant Predictor

Results showed that 3 HTR3 variants were significantly associated with treatment effectiveness.

The participants who carried the HTR3A genotypes rs1150226-AG or rs1176713-GG and/or the HTR3B genotype rs17614942-AC had a significant 1.5-drink reduction per day in response to receiving ondansetron (P < .05).

Those with these genotypes who were treated with ondansetron also had significantly fewer drinks per day on average than those with any of the genotypes who were treated with placebo (mean difference, -2.50; P = .0006).

They also had a significantly lower percentage of heavy drinking days (mean difference, -20.58%; P = .002) and a higher percentage of abstinent days (mean difference, 18.18%; P = .006).

Fatigue was the only treatment-related adverse event reported by significantly more of the ondansetron group than by the placebo group (P = .019). There were no differences in adverse events between those with and those without the specific genotypes.

"In conclusion, we have shown that polymorphisms in [these] genes are predictors of reduced drinking in response to ondansetron," write the investigators.

They note that additional pharmacogenetic studies are now needed to help validate the results.

"Multisite, larger studies are about to begin to progress this work," added Dr. Johnson.

The study was funded by grants from the NIAAA and the National Institute on Drug Abuse. Dr. Johnson reports having served as a consultant and chairman for ADial Pharmaceuticals and as a consultant for D&A Pharma, Eli Lilly, Organon, and the Psychological Education Publishing Company. One other study author reports having served as a consultant and board member for ADial. The other 3 study authors have disclosed no relevant financial relationships.

Am J Psychiatry. Published online July 30, 2013. Abstract

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