Ondansetron for Reduction of Drinking Among Biologically Predisposed Alcoholic Patients

Department of Psychiatry, University of Texas Health Science Center, 7703 Floyd Curl Dr, Mail Stop 7792, San Antonio, TX 78229-3900, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 08/2000; 284(8):963-71. DOI: 10.1001/jama.284.8.963
Source: PubMed


Early-onset alcoholism differs from late-onset alcoholism by its association with greater serotonergic abnormality and antisocial behaviors. Thus, individuals with early-onset alcoholism may be responsive to treatment with a selective serotonergic agent.
To test the hypothesis that drinking outcomes associated with early vs late-onset alcoholism are differentially improved by the selective 5-HT(3) (serotonin) antagonist ondansetron.
Double-blind, randomized, placebo-controlled clinical trial.
University of Texas Health Science Center in Houston (April 1995-June 1998) and University of Texas Health Science Center in San Antonio (July 1998-December 1999).
A total of 321 patients with diagnosed alcoholism (mean age, 40.6 years; 70.5% male; 78.6% white) were enrolled, 271 of whom proceeded to randomization.
After 1 lead-in week of single-blind placebo, patients were randomly assigned to receive 11 weeks of treatment with ondansetron, 1 microg/kg (n = 67), 4 microg/kg (n = 77), or 16 microg/kg (n = 71) twice per day; or identical placebo (n = 56). All patients also participated in weekly standardized group cognitive behavioral therapy.
Self-reported alcohol consumption (drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent per study week); and plasma carbohydrate deficient transferrin (CDT) level, an objective and sensitive marker of transient alcohol consumption.
Patients with early-onset alcoholism who received ondansetron (1, 4, and 16 microg/kg twice per day) compared with those who were administered placebo, had fewer drinks per day (1.89, 1.56, and 1.87 vs 3.30; P =.03, P =.01, and P =.02, respectively) and drinks per drinking day (4.75, 4.28, and 5.18 vs 6.90; P =.03, P =.004, and P =.03, respectively). Ondansetron, 4 microg/kg twice per day, was superior to placebo in increasing percentage of days abstinent (70.10 vs 50.20; P =.02) and total days abstinent per study week (6.74 vs 5.92; P =.03). Among patients with early-onset alcoholism, there was a significant difference in the mean log CDT ratio between those who received ondansetron (1 and 4 microg/kg twice per day) compared with those who received the placebo (-0.17 and -0.19 vs 0.12; P =.03 and P =.01, respectively).
Our results suggest that ondansetron (particularly the 4 microg/kg twice per day dosage) is an effective treatment for patients with early-onset alcoholism, presumably by ameliorating an underlying serotonergic abnormality. JAMA. 2000;284:963-971

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    • "It is well tolerated and has a relatively safe side-effect profile. Ondansetron has been evaluated in different psychiatric disorders (Romach et al., 1998; Toren et al., 1999; Johnson et al., 2000; Ye et al., 2001; Akhondzadeh et al., 2009). Soltani et al. (2010) reported significantly greater improvement in symptoms of OCD Clinical Trial registry name and registration number: Iranian registry of clinical trials. "
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    ABSTRACT: The aim of this study was to investigate the efficacy and safety of ondansetron as an augmentative agent to fluvoxamine in the treatment of patients with obsessive-compulsive disorder (OCD). Forty-six men and women, aged 18-60 years, who fulfilled the diagnostic criteria of OCD on the basis of the DSM-IV-TR and had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of at least 21 were recruited into the study. The patients randomly received either ondansetron (8 mg/day) or placebo for 8 weeks. All patients received fluvoxamine (100 mg/day) for the first 4 weeks, followed by 200 mg/day for the rest of the trial. The patients were assessed using the Y-BOCS and the adverse event checklists at baseline, and the second, fourth, sixth, and eighth week. Forty-four patients completed the study. The Y-BOCS total score as well as the Y-BOCS obsession subscale score and compulsion subscale score showed significantly greater reduction in the ondansetron group than in the placebo group. There was no significant difference in adverse events between the two groups. In this 8-week double-blind randomized-controlled trial, ondansetron showed significant beneficial effect as an augmentative agent with fluvoxamine in patients with moderate to severe OCD and it was generally well tolerated.
    International Clinical Psychopharmacology 05/2014; 29(6). DOI:10.1097/YIC.0000000000000043 · 2.46 Impact Factor
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    • "No benefit was seen in heavy drinkers (>10 drinks/day).121 Additional studies using weight-based dosing found benefits in craving,122 abstinence, and total drinks.123 One study showed increase in craving but reduced drinks per day. "
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    ABSTRACT: Alcohol use disorders (AUD) continue to be a concerning health issue worldwide. Harmful alcohol use leads to 2.5 million deaths annually worldwide. Multiple options exist for the management of dependence on alcohol, not all of which are approved by drug-regulating agencies. Current practice in treating AUD does not reflect the diversity of pharmacologic options that have potential to provide benefit, and guidance for clinicians is limited. Few medications are approved for treatment of AUD, and these have exhibited small and/or inconsistent effects in broad patient populations with diverse drinking patterns. The need for continued research into the treatment of this disease is evident in order to provide patients with more specific and effective options. This review describes the neurobiological mechanisms of AUD that are amenable to treatment and drug therapies that target pathophysiological conditions of AUD to reduce drinking. In addition, current literature on pharmacologic (both approved and non-approved) treatment options for AUD offered in the United States and elsewhere are reviewed. The aim is to inform clinicians regarding the options for alcohol abuse treatment, keeping in mind that not all treatments are completely successful in reducing craving or heavy drinking or increasing abstinence.
    01/2014; 5:1-12. DOI:10.2147/SAR.S37907
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    • "In other words, the in silico experiments with alcohol dependence treatment use behavioral and social parameters that serve as generators of metabolic disturbances to the system (person), which are then processed through an individualized metabolic model, thereby allowing the formal decomposition and reconstruction of the patterns of drinking behavior and their modulation by placebo or medication treatment. We illustrate our proposed approach by re-analyzing data from a study of ondansetron for the treatment of alcohol dependence (Johnson et al., 2000) and include in the model the non-specific placebo effects that occurred before the active treatment phase of the study (Penberthy et al., 2007), with a special emphasis on the highly significant differences between heavy and non-heavy drinkers observed during the study. Such a quantitative approach has several potential advantages. "
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    ABSTRACT: In this paper we view alcohol dependence and the response to treatment as a recurrent bio-behavioral process developing in time and propose formal models of this process combining behavior and biology in silico. The behavioral components of alcohol dependence and treatment are formally described by a stochastic process of human behavior, which serves as an event generator challenging the metabolic system. The biological component is driven by the biochemistry of alcohol intoxication described by deterministic models of ethanol pharmacodynamics and pharmacokinetics to enable simulation of drinking addiction in humans. Derived from the known physiology of ethanol and the literature of both ethanol intoxication and ethanol absorption, the different models are distilled into a minimal model (as simple as the complexity of the data allows) that can represent any specific patient. We use these modeling and simulation techniques to explain responses to placebo and ondansetron treatment observed in clinical studies. Specifically, the response to placebo was explained by a reduction of the probability of environmental reinforcement, while the effect of ondansetron was explained by a gradual decline in the degree of ethanol-induced neuromodulation. Further, we use in silico experiments to study critical transitions in blood alcohol levels after specific average number of drinks per day, and propose the existence of two critical thresholds in the human - one at 5 and another at 11 drinks/day - at which the system shifts from stable to critical and to super critical state indicating a state of alcohol addiction. The advantages of such a model-based investigation are that (1) the process of instigation of alcohol dependence and its treatment can be deconstructed into meaningful steps, which allow for individualized treatment tailoring, and (2) physiology and behavior can be quantified in different (animal or human) studies and then the results can be integrated in silico.
    Frontiers in Psychiatry 02/2012; 3:4. DOI:10.3389/fpsyt.2012.00004
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