Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking.
OBJECTIVE
Severe drinking can cause serious morbidity and death. Because the serotonin transporter (5-HTT) is an important regulator of neuronal 5-HT function, allelic differences at that gene may modulate the severity of alcohol consumption and predict therapeutic response to the 5-HT(3) receptor antagonist, ondansetron.


METHODS
The authors randomized 283 alcoholics by genotype in the 5'-regulatory region of the 5-HTT gene (LL/LS/SS), with additional genotyping for another functional single-nucleotide polymorphism (T/G), rs1042173, in the 3'-untranslated region, in a double-blind controlled trial. Participants received either ondansetron (4 μg/kg twice daily) or placebo for 11 weeks, plus standardized cognitive-behavioral therapy.


RESULTS
Individuals with the LL genotype who received ondansetron had a lower mean number of drinks per drinking day (-1.62) and a higher percentage of days abstinent (11.27%) than those who received placebo. Among ondansetron recipients, the number of drinks per drinking day was lower (-1.53) and the percentage of days abstinent higher (9.73%) in LL compared with LS/SS individuals. LL individuals in the ondansetron group also had a lower number of drinks per drinking day (-1.45) and a higher percentage of days abstinent (9.65%) than all other genotype and treatment groups combined. For both number of drinks per drinking day and percentage of days abstinent, 5'-HTTLPR and rs1042173 variants interacted significantly. LL/TT individuals in the ondansetron group had a lower number of drinks per drinking day (-2.63) and a higher percentage of days abstinent (16.99%) than all other genotype and treatment groups combined.


CONCLUSIONS
The authors propose a new pharmacogenetic approach using ondansetron to treat severe drinking and improve abstinence in alcoholics.
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22908-0623, USA. bankolejohnson@virginia.edu
Bankole A
BA
Johnson
Nassima
N
Ait-Daoud
Chamindi
C
Seneviratne
John D
JD
Roache
Martin A
MA
Javors
Xin-Qun
XQ
Wang
Lei
L
Liu
J Kim
JK
Penberthy
Carlo C
CC
DiClemente
Ming D
MD
Li
D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000188:drug therapy* / Q000235:genetics* / Q000628:therapy; D000437:Alcoholism / Q000188:drug therapy* / Q000235:genetics* / Q000628:therapy; D015928:Cognitive Behavioral Therapy / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D017294:Ondansetron / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*
D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017294:Ondansetron
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