The effects of the DRD2 polymorphism on smoking cessation and negative affect: evidence for a pharmacogenetic effect on mood

Nicotine Tob Res. 2004 Apr;6(2):229-39. doi: 10.1080/14622200410001676396.


This study evaluated the relationship between smoking cessation treatment outcome and the DRD2 polymorphism. Participants were 134 smokers who took part in a larger clinical trial evaluating the effects of an antidepressant medication (venlafaxine or placebo) plus standard care (brief counseling and nicotine replacement therapy). Venlafaxine is an antidepressant that inhibits the reuptake of serotonin and norepinephrine. A1 smokers were expected to quit significantly less often on placebo, although the abstinence rates between A1s and A2s on active drug were not expected to differ (i.e., an interaction between genotype and drug was hypothesized). In addition, antidepressant therapy was expected to have a similar genotype x treatment interaction on negative affect reduction. The results showed that smokers carrying the DRD2 A1 allele (A1/A1/A2) quit significantly less often than the homozygous A2s (OR=1.54, 95% CI=1.01-2.36). No interaction with treatment was observed. A significant pharmacogenetic effect of the drug on negative mood while quitting also was noted. Smokers absent the A1 allele (A2/A2) responded to the drug with a substantial reduction in negative affect, whereas those with the A1 allele showed no significant reduction in negative mood, F(1, 130)=5.95, p=.01. These results are contrary to expectations and suggest that although A1s may have more difficulty quitting, adding venlafaxine does not improve abstinence or mood. However, the results for the A2s provide evidence for a genotype-specific response to a pharmacological intervention, which could have implications for the development of future treatments.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Affect*
  • Antidepressive Agents, Second-Generation / pharmacology*
  • Counseling
  • Cyclohexanols / pharmacology*
  • Double-Blind Method
  • Female
  • Ganglionic Stimulants / administration & dosage
  • Ganglionic Stimulants / therapeutic use
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Nicotine / administration & dosage
  • Nicotine / therapeutic use
  • Placebos
  • Polymorphism, Genetic*
  • Receptors, Dopamine D2 / genetics*
  • Smoking Cessation / psychology*
  • Tobacco Use Disorder / drug therapy*
  • Tobacco Use Disorder / genetics*
  • Treatment Outcome
  • Venlafaxine Hydrochloride


  • Antidepressive Agents, Second-Generation
  • Cyclohexanols
  • Ganglionic Stimulants
  • Placebos
  • Receptors, Dopamine D2
  • Nicotine
  • Venlafaxine Hydrochloride