title: Ondansetron and sertraline may interact with 5-HTTLPR and DRD4 polymorphisms to reduce drinking in non-treatment seeking alcohol-dependent women: exploratory findings.
abstract: The purpose of this exploratory study was to examine the interaction of 5-HTTLPR and DRD4 exon III polymorphisms with gender in non-treatment seeking alcohol-dependent (AD) individuals while alternately taking ondansetron and sertraline. Evidence suggests that alcohol dependence may be influenced by a genetic interaction that may be gender-specific with temporal changes making pharmacological treatment with serotonergic drugs complex. The main trial was a within-subject double-blind placebo-controlled human laboratory study with 77 non-treatment-seeking AD individuals randomized (55 completed, 49 complete data) to receive 200 mg/day of sertraline or 0.5 mg/day of ondansetron for 3 weeks followed by an alcohol self-administration experiment (ASAE), then placebo for 3 weeks followed by a second ASAE, then receive the alternate drug, in a counterbalanced order, for 3 weeks followed by a third ASAE. Results for men were not significant. Women with the LL 5-HTTLPR genotype receiving ondansetron and SS/SL 5-HTTLPR genotype receiving sertraline (matched), drank significantly fewer drinks per drinking day (DDD) during the 7 days prior to the first and third ASAEs than women receiving the mismatched medication (i.e., sertraline to LL and ondansetron to SS/SL). In a 3-way interaction, 5-HTTLPR alleles by DRD4 alleles by medications, women with the LL genotype who received ondansetron and had DRD4≥7 exon III repeats drank significantly fewer DDD as did SS/SL women who received sertraline but conversely had DRD4<7 repeats in the 7-day period leading up to the first and third ASAEs. Consistent with these data was a significant reduction of milliliters consumed ad libitum during these same ASAEs. These exploratory findings add possible support to gender and genetic differences among AD individuals in response to serotonergic pharmacotherapies. Future trials should be powerful enough to take into account that endophenotypes and a targeting of serotonergic interactions may be essential to successfully treat alcohol dependence.
authors.affiliation: Department of Psychiatry and Human Behavior, Brown University, Providence, RI, USA; Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA. Electronic address: George_Kenna@Brown.edu.
authors.forename: George A
authors.initials: GA
authors.lastname: Kenna
authors.affiliation: Department of Psychiatry and Human Behavior, Brown University, Providence, RI, USA; Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA; Decision Scientific Institute, Pacific Institute for Research and Evaluation, Pawtucket, RI, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Zywiak
authors.affiliation: Department of Psychiatry and Human Behavior, Brown University, Providence, RI, USA; Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA; Providence VA Medical Center, Providence, RI, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Swift
authors.affiliation: Department of Psychiatry and Human Behavior, Brown University, Providence, RI, USA; Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA; Providence VA Medical Center, Providence, RI, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: McGeary
authors.affiliation: Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Clifford
authors.affiliation: Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Shoaff
authors.affiliation: Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Fricchione
authors.affiliation: Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Brickley
authors.affiliation: Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA.
authors.forename: Kayla
authors.initials: K
authors.lastname: Beaucage
authors.affiliation: Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA.
authors.forename: Carolina L
authors.initials: CL
authors.lastname: Haass-Koffler
authors.affiliation: Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA; Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA; Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Leggio
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D017294:Ondansetron / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D020280:Sertraline / Q000494:pharmacology*
chemical_list: C493599:DRD4 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D050638:Receptors, Dopamine D4; D017294:Ondansetron; D020280:Sertraline
keywords: 5-HTTLPR; Alcohol; DRD4; Gender; Ondansetron; Sertraline