Study Suggests Gene May Predict Success of Therapies for Alcohol Dependence

Clinicians have come to recognize the wide variation among patients with alcohol dependence, and scientists are continuing to accumulate evidence suggesting that genetic differences may help explain these variations. Now studies are suggesting that targeting alcohol dependence therapies to an individual's genetic makeup may improve outcomes.

A growing body of data links variation in the μ-opioid receptors with an individual's response to alcohol. The findings also show a connection between such variation and a patient's response to treatment with naltrexone, a drug that targets these receptors. Additionally, basic studies have demonstrated that variations in the genes that encode serotonin transporters affect the response to alcohol. Now a randomized controlled trial has demonstrated that the latter variants can predict the response of alcohol-dependent patients to treatment with ondansetron, a drug used to treat chemotherapy-associated nausea that targets the serotonin receptors.

“Alcoholism is not one disease; it's many diseases,” explained Bankole Johnson, MD, PhD, chair of the department of psychiatry at the University of Virginia, in an interview. He said that the findings on the genetic basis of alcoholism may help scientists develop a better system for categorizing types of alcohol dependence and treating the disease, just as genetics and other techniques have enabled physicians to stage cancer and target therapies accordingly.

For example, clinical studies have demonstrated that patients with a certain profile of alcohol dependence (a strong family history, strong craving, and early age of onset) are more likely to respond to treatment with naltrexone. Scientists have also shown through retrospective studies of clinical trial results that individuals with alcohol dependence who carry the Asp40 allele of the μ-opioid receptor are more likely to respond to treatment with naltrexone (Oslin DW et al. Neuropsychopharmacology. 2003:28[8]:1546-1552; Anton RF et al. Arch Gen Psychiatry. 2008;65[2]:135-144). However, the finding remains controversial. A prospective randomized study that will compare the effects of the drug in patients with and without this variant is now under way and may help resolve the question.

Recent human and animal studies are helping to explain why such a relationship may exist. Markus Heilig, MD, PhD, clinical director of the National Institute on Alcohol Abuse and Alcoholism, and his colleagues have demonstrated using positron emission tomography that individuals who carry the Asp40 allele of the μ-opioid receptor release more dopamine in the brain in response to alcohol (Ramchandani VA et al. Mol Psychiatry. doi: 10.1038/mp.2010.56 [published ahead of print May 18, 2010]). Additionally, they showed that mice carrying the human opioid receptor variant have the same dopamine response to alcohol. The scientists conclude that the variant may make alcohol consumption more rewarding for individuals who carry it, which may place such individuals at risk of heavy drinking while also making them more likely to respond to treatment with naltrexone.

“It's confirming and providing a molecular explanation for what we’ve seen in the clinical trials,” Heilig said in an interview. He noted that such confirmation is necessary because retrospective studies may be biased.

Meanwhile, other scientists have identified a variant of the serotonin transporter that is associated with heavy drinking and that appears to predict the response of alcohol-dependent patients to a therapy targeting these transporters. Johnson and his colleagues categorized 283 patients with alcohol dependence involving heavy drinking by the variants they carried for the 5-HTT gene and randomized them to either treatment with 4 μg/kg twice daily of ondansetron or placebo (Johnson BA et al. Am J Psychiatry. doi: 10.1176/appi.ajp.2010.10050755 [published ahead of print January 19, 2011]). All participants received 11 weeks of the drug or placebo plus standardized cognitive behavioral therapy. They found that patients with the LL/TT variant of the gene who received ondansetron had a lower mean number of drinks per drinking day (−2.63) and a higher percentage of days abstinent (16.99%) than all other genotype and treatment groups combined. The authors concluded that these reductions are clinically significant because many of the patients started out with drinking behavior considered high risk, but at the end of the study were in the low-risk drinking category. Additionally, when patients with all variants who received ondansetron were compared, only those with the LL variant showed a substantial reduction in drinks per day and days abstinent; individuals carrying other variants had a similar response to both the drug and placebo.

Johnson cautioned that only about 35% of patients with alcohol dependence respond to ondansetron. However, if the findings are replicated, physicians could use genetic testing in the clinic to determine which patients are likely to respond to the therapy before treatment begins and cut out the current trial-and-error process.

“It will tell you who the drug won't work for, so you don't have to waste your time giving it to patients who won't respond,” he said.

But Heilig cautioned that confirmatory studies and basic research on the mechanisms involved are necessary. He explained that while studies have linked variations in serotonin transporters to heavy drinking and anxiety levels in humans, the mechanisms are complex, and “the neurobiology is not yet settled.”

“It's very promising,” he said. “It's a very interesting and sound study, but until other groups replicate it, we won't know for sure.”