Matching Genotypes and Serotonergic Medications for Alcoholism
Condition: Alcoholism
MeSH terms: Alcoholism
Study type: Interventional
Phase: Phase 1

Summary: 
      Sertraline, a serotonin-specific reuptake inhibitor (SSRI) that increases basal serotonin
      levels, was shown to reduce alcohol consumption in lower risk/severity and later onset (LOA)
      but not higher risk/severity earlier onset alcoholic individuals (EOA). By contrast,
      ondansetron, a 5-HT3 receptor reduced alcohol consumption in EOAs but not LOAs. To explain
      this contrast in clinical efficacy, one approach suggests that differential serotonergic
      response is based on a functional polymorphism of the 5-HTTLPR promoter region of the
      serotonin re-uptake transporter (SERT). These alleles have typically been classified as
      biallelic genotypes: LL, SS and SL. The LL variant is postulated to be associated with EOA
      and the SS/SL variants associated with LOA. To test this hypothesis the investigators
      therefore propose to match and mismatch serotonergic treatments to genetic polymorphic
      variants [in 132 non-treatment seeking alcohol dependent volunteers] in a double-blind
      placebo controlled 2 x 2 design human laboratory study. The investigators propose to
      randomize non-treatment-seeking alcohol dependent persons based on their 5'-HTTLPR variant
      genotype (LL or SS/SL) into one of two counterbalanced arms: participants in the first arm
      (LL) will first receive one drug (either 200mg/day of sertraline or ondansetron 0.5mg/day)
      for three weeks followed by an alcohol self-administration experiment (ASAE), [with a 1 week
      down-titration period if sertraline received first, during the first week of the "placebo
      period"] then receive placebo for two more weeks (this will be a single-blind portion to use
      as a comparison group and to wash out the pharmacodynamic effects of the first drug) followed
      by a second ASAE. Participants will then receive the second drug for three weeks followed by
      a third ASAE [all will receive medication for an additional 1 week period and those receiving
      sertraline last will be down-titrated]. Participants in the second arm (SS/SL) will receive
      the same medications in the same balanced design. Individuals in both arms will receive
      weekly medication management to enhance medication adherence. The long-term objective of this
      research is to prospectively examine serotonergic treatment matching for alcohol dependence
      based on genotyping. Of equal importance, the investigators also recognize the strong
      contribution of additional genetic and environmental influences on alcohol consumption.
    

Detailed description: 
      Medications and genetics have been identified as research priorities by NIAAA. The present
      application proposes to test two genetic-drug matching hypotheses to better understand
      heterogeneity among alcoholics. Previous basic science, treatment and genetic research
      suggests that active drinkers with the LL genetic variant of the serotonin transporter
      5'-HTTLPR (a hypothesized genetic risk factor for early onset alcoholism) will respond better
      to ondansetron than sertraline or placebo. Conversely, active drinkers with the SS or SL
      genetic variant of the serotonin transporter 5'-HTTLPR (a hypothesized genetic risk factor
      for late onset alcoholism) will respond better to sertraline than ondansetron or placebo. The
      objective of this research is to match and mismatch serotonergic treatments to genetic
      polymorphic variants in a double-blind placebo controlled 2 x 2 design laboratory study where
      the 2 arms will be counterbalanced. The specific aims are to investigate: (1) whether
      LL-carriers receiving ondansetron results in a significant reduction in alcohol consumption
      during an alcohol self-administration experiment (ASAE) and during the period of treatment;
      (2) whether SL and SS-carriers receiving sertraline will result in a significant reduction in
      alcohol consumption during an ASAE and during the period of treatment; (3) examine mechanism
      of action for craving and subjective effects during the ASAE sessions: (4) whether there is a
      reduction in alcohol consumption during the ASAEs in the presence of the LG, and LA 5-HTTLPR
      variants and when LL participants receive ondansetron or when LL participants receive
      sertraline; (5) if the primary aims are moderated by the presence of the C (-1019) G
      polymorphism of the 5-HT1A gene promoter. We propose to randomize 132 non-treatment-seeking
      alcohol dependent participants based on their 5'-HTTLPR variant genotype (LL or SS/SL) into
      one of two counterbalanced arms: e.g. subjects in the first arm will first receive one drug
      (either 200mg/day of sertraline or ondansetron 0.5mg/day) for three weeks followed by an
      ASAE, then receive placebo for three weeks (this will be a single-blind portion to use as a
      comparison group and to wash out the pharmacodynamic effects of the first drug) followed by a
      second ASAE. Finally, participants will receive the second drug for three weeks followed by a
      third ASAE. Volunteers in the second arm will receive the same medications in a
      counter-balanced fashion. There will be a 1-week down titration after the first and third
      segments for all subjects. The long-term objective of this proposed research is to examine
      serotonergic treatment matching for alcohol dependence based on genotyping, and begin to
      investigate patient variation when matched prospectively with one serotonergic treatment or
      the other.
    

Intervention name(s): Ondansetron and Sertraline
Intervention type(s): Drug
Intervention description(s): capsule 0.25mg twice a day for 21 days and capsule 100mg twice a day
Intervention MeSH terms: Ondansetron; Sertraline
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Diagnostic
Keywords: ondansetron; sertraline; lab studies; alcoholism; alcohol dependence