Magazine article Clinical Psychiatry News

Smoking Cessation: Physicians Urged to Lead

Magazine article Clinical Psychiatry News

Smoking Cessation: Physicians Urged to Lead

Article excerpt

ORLANDO, FLA. -- Pharmacogenetics will play a major role in the war on tobacco, Sean P. David, M.D., predicted at Wonca 2004, the conference of the World Organization of Family Doctors.

It's already possible in research settings to significantly improve upon the traditional and rather unspectacular quit rates of existing first-line smoking cessation therapies by tailoring treatment to patients' individual genetic variation in relevant brain neurotransmitters, said Dr. David, who is director of research in family medicine at Brown University, Providence, R.I.

Twin studies indicate roughly half of the variation in smoking behavior is caused by genetic factors. The dopamine and serotonin systems are logical places to search for genes governing individual differences in the addictive potential of nicotine. These neurotransmitter systems are richly represented in the nucleus accumbens and other pleasure centers of the brain. Dr. David's own recent work has focused on two candidate genes: the dopamine DRD2 receptor and the serotonin transporter gene.

Polymorphisms in the dopamine DRD2 receptor have been shown in case-control studies to be associated with nicotine dependence, obesity, and alcohol abuse. A 44-base pair deletion/insertion polymorphism of the serotonin transporter gene has similarly been associated with smoking behavior, depression, and neuroticism.

Dr. David performed a study in which he randomized 30 smokers to bupropion or placebo and conducted detailed interviews regarding nicotine withdrawal symptoms at baseline and after 14 days of treatment. He found that only in the subgroup having the DRD2-Taq1 A2/A2 genotype was bupropion associated with decreased nicotine craving, irritability, and anxiety in response to environmental smoking cues. In the A1/A1 and A1/A2 groups, bupropion wasn't significantly better than placebo at curbing specific symptoms of nicotine withdrawal.

Next, Dr. David analyzed DNA from blood samples belonging to 292 participants in the Zyban Collaborative Study, a multicenter prospective placebo-controlled trial of bupropion for smoking cessation. In his retrospective secondary analysis, patients with the DRD2-Taq1 A1/A1 or A1/A2 genotypes had a 23% successful quit rate 6 months after attempting to quit, regardless of whether they'd been assigned to bupropion or placebo.

In contrast, patients with the A2/A2 polymorphism had a 34% quit rate on bupropion and a mere 13% quit rate on placebo. After adjusting for potential confounders, this worked out to a 3.3-fold greater likelihood of successfully quitting smoking with bupropion as compared with placebo in patients with the A2/A2 genotype.

"This is just one study and it requires replication, but I know there are colleagues at University of Pennsylvania and SRI International who are seeing the same thing," he said.

In a brain MRI study he conducted in collaboration with investigators at University of Oxford (England), Dr. David determined that healthy volunteers having at least one copy of the S allele of the serotonin transporter gene--indicative of a deletion in the gene's promoter region--had lower levels of serotonin binding in every one of 21 different examined regions of the brain.

Dr. David then gained access to blood samples that had been collected as part of a randomized placebo-controlled trial of nicotine patch therapy conducted at Oxford a decade ago. …

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