Personalizing Addiction Medicine

Gene variants make anti-craving drugs a hit-or-miss affair.

Rather than taking on another broad hunt for the genes controlling the expression of alcoholism, noted addiction researcher Dr. Bankole Johnson and co-workers at the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia took a different tack. The researchers focused, instead, on investigating whether genetic variations among alcoholics might affect their responses to a specific anti-craving medication.

The result, according to Kenneth Warren, acting director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), is a study that represents “an important milestone in the search for personalized treatments for alcohol dependence.”

For any addiction, once it has been active for a sustained period, the first-line treatment of the future is likely to be biological. New addiction treatments will come—and in many cases already do come—in the form of drugs to treat drug addiction. Every day, addicts are quitting drugs and alcohol by availing themselves of drug treatments that did not exist fifteen years ago. As more of the biological substrate is teased out, the search for effective approaches narrows along avenues that are more fruitful. This is the most promising, and, without doubt, the most controversial development in the history of addiction treatment.

The researchers were interested in variations in the gene controlling the expression of a serotonin transporter protein. Dr. Johnson’s earlier work had centered on teasing out the influence the serotonin 5-HTT transporter exerts on the development of alcoholism. Previous research had focused attention on the so-called LL and TT variants of this transporter gene. After performing genetic analyses to determine which test subjects were carrying which versions of the gene in question, Dr. Johnson and his colleagues conducted a controlled trial of ondansetron on a randomized group of 283 alcoholics.
The findings were published in the American Journal of Psychiatry.

Ondansetron is an anti-emetic medication that has shown promise in treating addictions, particularly alcoholism. Ondansetron (trade name Zofran), helps block the nausea of chemotherapy by altering serotonin activity in the GI tract. (Vomiting is a serotonin-mediated reflex.) The scientists found that “individuals with the LL geno-type who received ondansetron had a lower mean number of drinks per day (-1.62) and a higher percentage of days abstinent (11.27%) than those who received placebo.”  This put the ondansetron drinkers under five drinks a day. All of the placebo drinkers continued to exceed the five drinks per day mark.

But the strongest difference was found in the group of alcoholics who possessed both the LL and TT genetic variants. The LL/TT alcoholics taking ondansetron “had a lower number of drinks per drinking day (-2.63) and a higher percentage of days abstinent (16.99%) than all other geno-type and treatment groups combined.” 

The goal here is straightforward. In an email exchange, Dr. Johnson told me: “I agree that it would be great if we could use a pharmacogenetic approach to study other anti-craving drugs. The idea of providing the right drug to the right person is definitely important for optimizing therapeutic effects and minimizing side-effects.” Here is a video of Dr. Johnson discussing the research, courtesy of the University of Virginia:

It won’t be easy. Such genetic testing is still in its infancy, and complications abound. For example, in an earlier study in the Journal of the American Medical Association, Dr. Johnson found that diagnosed patients who received ondansetron over an 11-week period increased their days of abstinence compared to alcoholics on placebo. However, in that study, “The researchers found no differences between ondansetron patients with late-onset alcoholism and those who received placebo.” This suggests that, along with genetic variations, ondansetron’s effectiveness with alcoholics may also depend on the type of alcoholism under consideration: early onset or late onset.

We have a long way to go, but individualized pharmaceutical assistance in the early stages of addiction recovery remains the Holy Grail for many addiction researchers. And hopes are running high.

Johnson, B., Ait-Daoud, N., Seneviratne, C., Roache, J., Javors, M., Wang, X., Liu, L., Penberthy, J., DiClemente, C., & Li, M. (2011). Pharmacogenetic Approach at the Serotonin Transporter Gene as a Method of Reducing the Severity of Alcohol Drinking American Journal of Psychiatry DOI: 10.1176/appi.ajp.2010.10050755

Graphics credit: Sergey Ivanov at http://pn.psychiatryonline.org/content/