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Excerpts from: Genes May Determine Effect of Anti-Smoking Therapy

By Andrew Holtz  Reuters Health  [04/2301]
 
(Reuters Health) - Genes appear to influence the response of cigarette smokers to smoking cessation
therapy with an antidepressant drug, researchers have found.

Smokers carrying one form of a gene that affects brain cell receptors to the neurochemical dopamine responded to an
antidepressant medicine, the researchers explain, while smokers with another form of the gene did not. The findings were
reported here Sunday at the American Cancer Society Science Writers Seminar.

Dopamine is a brain chemical that helps produce feelings of pleasure and satisfaction. Abnormalities in dopamine activity in the
brain have been linked to addiction.

``What we were all excited about in this study was that this was a demonstration of a pharmacogenetic effect,'' said Dr. Paul
Cinciripini of the University of Texas MD Anderson Cancer Center in Houston, the study's lead author. ``That is, we were able
to give a particular drug to a group of people who were characterized on the basis of their genetic profile, and show that this
drug could work better for them than it could work for others.''

The researchers ran genetic tests on 134 smokers to determine whether they carried the A1 or A2 form of the DRD2 gene.

Individuals with at least one copy of the A1 version of the gene have fewer and less sensitive D2 dopamine receptors than do
individuals with two copies of the A2 allele, the researchers explained. This means they have a weaker response to dopamine's
effects. The A1 version of the gene has been linked to smoking and other forms of substance abuse.

As part of a smoking cessation program, half the smokers were given the antidepressant venlafaxine (Effexor). The other half
received a placebo. All the smokers were offered standard smoking cessation counseling and nicotine patches.

People with the A1 gene were more than twice as likely to relapse, both at one week after first trying to kick the habit, and 10
weeks later, Cinciripini and his colleagues found. The patients with the A2 gene who were taking venlafaxine experienced a
steady reduction in depressive feelings for the 18 weeks that they were taking the drug, while the patients with the A1 gene had
a more variable mood response.

``It's the first demonstration of a pharmacogenetic effect,'' said Dr. Dileep Bal, president of the American Cancer Society. ''The
implications are that if we show genetics plays a role in nicotine dependence, we can develop drugs for people with specific
(genetic) profiles.''

Cinciripini was cautiously optimistic about the practical applications of his findings. It may one day be possible to perform the
gene test used in the study cheaply. ``As to whether or not you'd be able to tailor the drugs specifically by genotype,'' he added,
``that'll remain to be seen.''

But he argues that genotyping may well come to play an important role in guiding addiction-treatment decisions. ``Up until very
recently it's been 'one size fits all,' and what we're trying to say over on the behavioral end as well as on the pharmacological
end is that may that's not such a good idea.''

The research was supported by the National Cancer Institute, with Wyeth-Ayerst supplying the Venlafaxine.