title: An analysis of moderators in the COMBINE study: Identifying subgroups of patients who benefit from acamprosate.
abstract: The goal of the current study was to use tree-based methods to identify moderators of acamprosate effect on abstinence from heavy drinking in COMBINE, the largest study of pharmacotherapy for alcoholism in the United States to date. We used three different tree-based methods for identification of subgroups with enhanced treatment response on acamprosate based on over 100 predictors measured at baseline in COMBINE. No heavy drinking during the last two months of treatment was the considered outcome. All three methods identified consecutive days of abstinence prior to treatment as the most important moderator of treatment effect. Acamprosate was beneficial for participants with shorter abstinence (1 week or less) especially when body mass index was low or normal. In this group, 46% of participants receiving active acamprosate abstained from heavy drinking compared to 23% of those receiving placebo acamprosate. Prior treatment, age, drinking goal and cognitive inefficiency were identified as moderators of acamprosate effects by one of the three methods. In conclusion, acamprosate may be beneficial for participants with shorter abstinence who are not overweight or obese. One hypothesis for this finding is that this subgroup may have greater glutamatergic hyperactivity, a target of acamprosate, and may achieve better drug plasma levels based on their lower BMI. In contrast, those with extended pretreatment abstinence who have an otherwise good prognosis did not benefit from acamprosate. Further validation of the results in independent data sets is necessary.
authors.affiliation: Department of Biostatistics, Yale University School of Public Health and School of Medicine, New Haven, CT 06520, USA. Electronic address: ralitza.gueorguieva@yale.edu.
authors.forename: Ralitza
authors.initials: R
authors.lastname: Gueorguieva
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Biostatistics, Yale University School of Public Health and School of Medicine, New Haven, CT 06520, USA.
authors.forename: Wan-Min
authors.initials: WM
authors.lastname: Tsai
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: O'Connor
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Fucito
authors.affiliation: Department of Biostatistics, Yale University School of Public Health and School of Medicine, New Haven, CT 06520, USA.
authors.forename: Heping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: O'Malley
mesh_terms: D000077443:Acamprosate; D000328:Adult; D000427:Alcohol Deterrents / Q000627:therapeutic use*; D000437:Alcoholism / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology / Q000503:physiopathology; D015992:Body Mass Index; D003663:Decision Trees; D004311:Double-Blind Method; D006801:Humans; D008875:Middle Aged; D013654:Taurine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome; D014481:United States
chemical_list: D000427:Alcohol Deterrents; D013654:Taurine; D000077443:Acamprosate
keywords: Alcohol dependence; Classification and regression trees; Clinical trials; Moderator effects; Subgroups with enhanced treatment effect