Investigators at the University of Texas Health Science Center at San Antonio report in the lead article in today's Journal of the American Medical Association (Volume 284, Number 8) that the medication ondansetron may be an effective therapy for patients with early-onset alcohol dependence (alcoholism). Ondasetron appears to work by acting on serotonin, one of the brain's many neurotransmitters. The study was supported by the National Institute on Alcohol Abuse and Alcoholism and led by Bankole A. Johnson, M.D., Ph.D., chief of the Division of Alcohol and Drug Addiction, Department of Psychiatry, UTHSC.
"Dr. Johnson's findings are consistent with a lengthy literature on serotonin dysfunction among early-onset alcoholics," said NIAAA Director Enoch Gordis, M.D. "If confirmed in future studies, they may predict new treatments for a subgroup of patients who often are resistant to behavioral therapies alone."
Early-onset (< age 25) alcoholism is a clinical alcoholism subtype, or typology, in which patients have a greater family history of alcoholism, increased propensity for antisocial behaviors, and a more stable and severe disease state than those with late-onset alcoholism. First devised in Europe and the United States more than a century ago and more recently posited by E.M. Jellinek in 1961, C. Robert Cloninger in 1987, and Thomas F. Babor in 1992, among others, typologies are used in research to categorize the empirical contributions of various biological and environmental influences on alcoholism. In clinical settings, typologies may guide treatment decisions; treatment responses in turn may provide clues to the neurochemical factors that mediate different behavioral aspects of the disease.
Today's report is based on a study conducted between 1995 and 1999, in which 271 patients with diagnosed alcoholism were randomized to receive one of three different doses of either ondansetron or placebo for 11 weeks. Compared with those who received the placebo, all groups of ondansetron patients with early-onset alcoholism had fewer drinks per day and drinks per drinking day. Early-onset patients in the most successful ondansetron group (patients who received 4mg/kg twice daily) also reported a significant increase in the percentage of days abstinent and total days abstinent per study week. The researchers found no differences between ondansetron patients with late-onset alcoholism and those who received placebo.
Patients in the UTHSC study also participated in weekly group cognitive behavioral psychotherapy. NIAAA research published in 1996 (see "NIAAA Reports Project MATCH Main Findings," December 1996, at http://www.niaaa.nih.gov news releases) showed that three forms of behavioral treatment--cognitive-behavioral, motivational enhancement, and 12-step facilitationcontribute to sustained abstinence and reduced drinking. "Future research-based treatments for alcoholism will involve various combinations of behavioral and pharmacological treatments," according to Richard Fuller, M.D., Director of NIAAA's Division of Clinical and Prevention Research.
In recent years, NIAAA researchers have mounted a concerted effort to identify medications that modify the activities of multiple brain neurotransmitter systems (including the opioid, glutamate, dopamine, and serotonin systems) implicated in the actual mechanisms of alcoholism. Medications to ameliorate biochemical abnormalities that may underlie inherited risk are one focus of this medications development effort.
In 1995, the U.S. Food and Drug Administration approved the opioid antagonist naltrexone, the first medication shown to prevent relapse and help maintain abstinence, probably by blocking alcohol-induced release of another neurotransmitter, dopamine. A 1999 study reported that nalmefene, another opioid antagonist, was similarly effective. In addition, acamprosate, believed to work on the glutamate neurotransmitter system, has demonstrated success in European studies in reducing the intensity of craving following drinking cessation. Of these mechanistic agents, the FDA has approved only naltrexone specifically for the use in alcoholism treatment. (The aversive medication disulfiram [AntabuseTM], approved in 1948, is still in use.)
Today's report on ondansetron is the most promising to date on the use of a serotonergic agent to address alcoholism. Earlier research on general serotonergic agents, including the selective serotonin reuptake inhibitor fluoxetine (ProzacTM), produced mixed results. Medications that differentially affect some of the 15 specific serotonin-receptor subtypes, including the 5HT3 receptor targeted by ondansetron, are more promising, according to recent studies.
Dr. Johnson and his team based their research on animal studies in which antagonists at the 5HT3 receptor reduced alcohol intake in animals. The Johnson team found in humans in 1993 that ondansetron reduced some of alcohol's positive subjective effects. The present study found positive effects only in early-onset alcoholics, leading the researchers to conclude that ondansetron may ameliorate an inherited serotonergic abnormality in that alcoholic subtype.
Ondansetron is FDA-approved for the treatment of chemotherapy-induced nausea at doses much larger than those used in the alcoholism study. It is likely to remain an investigational tool in alcoholism research until today's findings are replicated.
For interviews with Dr. Johnson, please telephone 210-567-2570. For interviews with Drs. Gordis and Fuller, please telephone NIAAA Press (301-443-3860). For additional information about alcohol research, please visit http://www.niaaa.nih.gov.
Journal
JAMA