Matching Genotypes and Serotonergic Medications for Alcoholism

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.

Conditions

• Alcoholism

Interventions

DRUG

Ondansetron and Sertraline

capsule 0.25mg twice a day for 21 days and capsule 100mg twice a day

Sponsors & Collaborators

• National Institute on Alcohol Abuse and Alcoholism (NIAAA)

  collaborator NIH

• Brown University

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

DIAGNOSTIC

Masking

TRIPLE

Model

SINGLE_GROUP

Eligibility

Min Age

21 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2008-09-30

Primary Completion

2012-02-29

Completion

2012-02-29

Countries

• United States

Study Locations