Response to Transdermal Selegiline Smoking Cessation Therapy and Markers in the 15q24 Chromosomal Region

Abstract

Introduction: Current treatments for smoking cessation have limited efficacy. A potential pharmaceutical treatment for smoking cessation is selegiline, a selective and irreversible monoamine oxidase B inhibitor. A few clinical trials have been carried out using selegiline but the results have been mixed. We sought to determine if genetic markers in cholinergic loci in the 15q24 chromosomal region predict response to smoking cessation therapy with selegiline.

Methods: We performed an 8-week double-blind, placebo-controlled clinical trial of the selegiline transdermal system in heavy smokers, with follow-up at weeks 25 and 52. Eight single nucleotide polymorphisms (SNPs) in the 15q24 region, which contains the genes for the nicotinic acetylcholine receptor subunits CHRNA5, CHRNA3, and CHRNB4, were investigated for association with treatment response.

Results: The CHRNB4 promoter SNP rs3813567 was associated with both point prevalence abstinence and post-quit craving. Carriers of the minor C allele treated with selegiline showed lower rates of abstinence and higher levels of craving than selegiline-treated non-carriers, indicating that the rs3813567 C allele adversely affects abstinence in selegiline-treated smokers. This effect was not present among placebo-treated smokers. Selegiline-treated smokers with the CHRNA5 rs680244 GG genotype had lower post-quit craving, and unlike placebo-treated GG-carrying smokers, did not experience a post-quit increase in depressive symptoms.

Conclusions: Variants in genes encoding cholinergic receptors affect abstinence, craving and mood in selegiline-treated smokers. Selegiline primarily affects dopamine levels in the brain, but cholinergic input affects nicotine-induced dopaminergic activity. These markers may have value in identifying those likely to respond to selegiline for smoking cessation.

Figure 1.

Linkage disequilibrium (LD) map of the 15q24 region showing the position of the genotyped single nucleotide polymorphisms. LD is expressed as r ² values. Map is based on the full sample.

Figure 2.

Effect of rs3813567 and rs680244 genotype on mean scores for craving (top, middle panels) and of rs680244 genotype on Center for Epidemiological Studies Depression Scale (CES-D) (bottom panels) over the 8-week treatment period. Results for selegiline and placebo are presented separately. Lines represent scores for individual genotype groups. The first point in each graph represents baseline assessment, whereas the second point represents 24hr after quitting. Subsequent points represent weekly assessments. Full sample.