DANA POINT, CALIF—The A1 allele of the D2 dopamine receptor (DRD2) gene, which is associated with elevated smoking prevalence, has now also been linked to poorer outcome for attempts at smoking cessation. According to a recent study, the antidepressant venlafaxine is also less effective at reducing negative affect during smoking cessation in individuals with at least one copy of the A1 allele than in those without the allele.[1]

Paul Cinciripini, PhD, of University of Texas M. D. Anderson Cancer Research Center, Houston, and colleagues presented preliminary results at the American Cancer Society’s 43rd Science Writers Seminar. Their findings may help identify genetic factors that are likely to determine which drugs are most effective in assisting a smoker to quit.

After genotyping 134 smokers for the DRD2 receptor, the investigators entered them into a smoking cessation program. Subjects received brief behavioral counseling, either venlafaxine or placebo (beginning one week before quitting and continuing for 21 weeks), and transdermal nicotine replacement patches (for six weeks beginning on the first day of smoking cessation).

Venlafaxine, like bupropion, significantly improved abstinence rates among subjects as a whole. “So far, the antidepressant bupropion is the only FDA-approved psychotropic for use in facilitating smoking cessation,” noted Dr. Cinciripini, Associate Professor of Behavioral Science at University of Texas M. D. Anderson.

In the patients given venlafaxine and in those receiving placebo, the presence of one or two A1 alleles was associated with smoking relapse during both the first week and the first 10 weeks after the quit date. The data did not reveal a significant interaction between genotype and antidepressant use on abstinence rates. “However, if you looked at negative affect scores, there was an effect of genotype on drug efficacy,” Dr. Cinciripini pointed out. While those with only A2 alleles showed “a significant and consistent effect of the drug on affect,” responses among bearers of the A1 allele were much more variable.

Dr. Cinciripini cited evidence that serotonin reuptake inhibitors like venlafaxine can affect dopamine availability in the brain: “PET [positron emission tomography] imaging and [11C]raclopride used to study dopamine binding showed a general decrease in unoccupied sites—it looked like it was affecting dopamine metabolism downstream.”[2] He hypothesized, “People with the A1 allele may have lower receptor number or lower binding affinity for dopamine; those with the A1 genotype might be less affected by changes in dopamine availability.” Dr. Cinciripini also extended this explanation to the elevated smoking prevalence found among those with the A1 allele: “If A1 people have deficits in their responsiveness to dopamine, they might compensate for this by using nicotine and other substances more.”

Although no significant interaction between genotype and drug treatment on smoking cessation has emerged from the research yet, Dr. Cinciripini thinks that linking the A1 allele and inconsistent affective responsiveness may point up subtle pharmacological variations that could help explain genetic differences in ability to quit. “Antidepressant efficacy often depends on individual differences,” said Dr. Cinciripini. “The hope is that … we could somehow tailor drugs to a particular genotype.”

—Mimi Zucker, PhD