title: Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation.
abstract: This randomized, double-blinded, placebo-controlled trial examined genetic influences on treatment response to sustained-release bupropion for smoking cessation. Smokers of European ancestry (N = 291), who were randomized to receive bupropion or placebo (12 weeks) plus counseling, were genotyped for the dopamine D2 receptor (DRD2-Taq1A), dopamine transporter (SLC6A3 3' VNTR), and cytochrome P450 2B6 (CYP2B6 1459 CT) polymorphisms. Main outcome measures were cotinine-verified point prevalence of abstinence at end of treatment and at 2-, 6-, and 12-month follow-ups post quit date. Using generalized estimating equations, we found that bupropion, compared with placebo, was associated with significantly greater odds of abstinence at all time points (all p values<.01). We found a significant DRD2 x bupropion interaction (B = 1.49, SE = 0.59, p = .012) [corrected] and a three-way DRD2 x bupropion x craving interaction on 6-month smoking cessation outcomes (B = -0.45, SE = 0.22, p = .038), such that smokers with the A2/A2 genotype demonstrated the greatest craving reduction and the highest abstinence rates with bupropion. Furthermore, there was a significant DRD2 x CYP2B6 interaction (B = 1.43, SE = 0.56, p = .01), such that individuals with the DRD2-Taq1 A2/A2 genotype demonstrated a higher odds of abstinence only if they possessed the CYP2B6 1459 T/T or C/T genotype. Because the sample size of this study was modest for pharmacogenetic investigations, the results should be interpreted with caution. Although these results require replication, the data suggest preliminarily that the DRD2-Taq1A polymorphism may influence treatment response to bupropion for smoking cessation and, further, that exploration of gene x gene and gene x craving interactions in future, larger studies may provide mechanistic insights into the complex pharmacodynamics of bupropion.
authors.affiliation: Brown University Center for Primary Care and Prevention, Providence, RI 02860, USA. sean_david@brown.edu
authors.forename: Sean P
authors.initials: SP
authors.lastname: David
authors.forename: Richard A
authors.initials: RA
authors.lastname: Brown
authors.forename: George D
authors.initials: GD
authors.lastname: Papandonatos
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Kahler
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Lloyd-Richardson
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Munafò
authors.forename: Peter G
authors.initials: PG
authors.lastname: Shields
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
authors.forename: David
authors.initials: D
authors.lastname: Strong
authors.forename: Jeanne
authors.initials: J
authors.lastname: McCaffery
authors.forename: Raymond
authors.initials: R
authors.lastname: Niaura
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D016642:Bupropion / Q000627:therapeutic use*; D065702:Cytochrome P-450 CYP2B6; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D011110:Polymorphism, Genetic; D017448:Receptors, Dopamine D2 / Q000235:genetics; D012907:Smoking / Q000188:drug therapy / Q000235:genetics; D016540:Smoking Cessation / Q000379:methods; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000235:genetics*; D016896:Treatment Outcome; D044465:White People / Q000235:genetics*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D017448:Receptors, Dopamine D2; D016642:Bupropion; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating