Ondansetron reduces mood disturbance among biologically predisposed, alcohol-dependent individuals

Background: Early-onset alcoholics (EOA) differ from late-onset alcoholics (LOA) by developing problem drinking during youth, experiencing severe behavioral problems, having a familial disease history, and possessing a tendency toward subsyndromal mood disturbance, including symptoms of depression, anxiety, and hostility. Subsyndromal mood disturbance is, therefore, an important component of the early-onset syndrome and may be mediated by serotonin dysfunction. Therefore, the serotonin-3 antagonist ondansetron, which has been shown to be effective at improving drinking outcomes and promoting abstinence among EOA, presumably by ameliorating serotonin dysfunction, also may exert its beneficial effects by alleviating mood disturbance among EOA. Methods: After one lead-in week of single-blind placebo administration, subjects underwent 11 weeks of double-blind outpatient treatment using a 2 X 4 factorial design that examined age of onset (EOA versus LOA) and medication dose (placebo, or ondansetron 1, 4, or 16 mug/kg twice daily) combined with weekly standardized group cognitive-behavioral therapy. The placebo lead-in week was used to adjust for study entrance effects but not for excluding subjects. Assessments of mood were performed by using the overall score and subscales of the Profile of Mood States both at screening and at weekly intervals during the study. Results: Subsyndromal mood disturbance was shown to be an important component of early-onset alcoholism. Ondansetron (16 mug/kg twice daily) showed greater therapeutic efficacy at alleviating symptoms of overall mood disturbance, fatigue, vigor, confusion/bewilderment, and depression among EOA compared with LOA. EOA-associated improvements in mood disturbance seemed to be independent of drinking behavior. Conclusions: Ondansetron has been shown to be an effective treatment for early-onset alcoholism. Ondansetron's ability to improve symptoms of depression, anxiety, and hostility among EOA may make an additional contribution to its therapeutic effect. Mechanistic studies are needed to delineate more clearly the relationship between serotonin dysfunction and pathophysiology among various subtypes of alcohol-dependent individuals.