Matching Genotypes and Serotonergic Medications for Alcoholism
| Status: | Archived |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 7/1/2011 |
| Start Date: | September 2008 |
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.
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.
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