Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials.
Although bupropion and nicotine replacement therapy (NRT) are efficacious tobacco dependence treatments, there is substantial interindividual variability in therapeutic response and most smokers relapse. Pharmacogenetics research may improve treatment outcomes by identifying genetic variants predictive of therapeutic response. We investigated the roles of two functional genetic variants in the dopamine D2 receptor (DRD2) gene in response to pharmacotherapy for tobacco dependence among participants in two randomized clinical trials with a 6-month follow-up period: a double-blind placebo-controlled trial of bupropion (n=414) and an open label trial of transdermal nicotine vs nicotine nasal spray (n=368). At the end of the treatment phase, a statistically significant (p=0.01) interaction between the DRD2 - 141C Ins/Del genotype and treatment indicated a more favorable response to bupropion among smokers homozygous for the Ins C allele compared to those carrying a Del C allele. By contrast, smokers carrying the Del C allele had statistically significantly (p=0.006) higher quit rates on NRT compared to those homozygous for the Ins C allele, independent of NRT type. The C957T variant was also associated (p=0.03) with abstinence following NRT. These results suggest that bupropion may be the preferred pharmacologic treatment for smokers homozygous for the DRD2 - 141 Ins C allele, while NRT may be more beneficial for those who carry the Del C allele. Study findings require confirmation in additional larger samples before they are applied in practice.
Lerman
Caryn
C
Department of Psychiatry and Abramson Cancer Center, Tobacco Use Research Center, University of Pennsylvania, Philadelphia, PA 19104, USA. clerman@mail.med.upenn.edu
Jepson
Christopher
C
Wileyto
E Paul
EP
Epstein
Leonard H
LH
Rukstalis
Margaret
M
Patterson
Freda
F
Kaufmann
Vyga
V
Restine
Stephanie
S
Hawk
Larry
L
Niaura
Ray
R
Berrettini
Wade
W
D000281:Administration, Intranasal; D000328:Adult; D000483:Alleles; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects / Q000627:therapeutic use*; D016642:Bupropion / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D016540:Smoking Cessation / Q000379:methods*; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000235:genetics*; D016896:Treatment Outcome
D018687:Antidepressive Agents, Second-Generation; D018722:Nicotinic Agonists; D017448:Receptors, Dopamine D2; D016642:Bupropion; D009538:Nicotine