Matching Genotypes and Serotonergic Medications for Alcoholism
Status:
Completed
Trial end date:
2012-02-01
Target enrollment:
Participant gender:
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.
Phase:
Phase 1
Details
Lead Sponsor:
Brown University
Collaborator:
National Institute on Alcohol Abuse and Alcoholism (NIAAA)