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.

Biomarkers of Response to Smoking Cessation Pharmacotherapies: Progress to Date

“…SNP or haplotype (two or more SNPs) hypothesis-driven [82-87] studies of the chr15q25.1 nAChR locus [88-93] have included analyses of one to eight RCTs. In 400 participants from two RCTs randomizing participants to bupropion or placebo treatment [94, 95], Baker [88] identified a significant association by haplotype, comprised of alleles from five SNPs (rs680244, rs569207, rs16969968, rs578776, rs1051730), previously associated with increased smoking heaviness [85], with reduced abstinence from baseline to end-of-treatment (EOT), with no difference in association by treatment.…”

The Value of Control Conditions for Evaluating Pharmacogenetic Effects

“…The genetic effect of CHRNA5 on smoking cessation has been demonstrated in some research studies [3,7,[9][10][11][12][13][14][15], but not in several other important studies [16][17][18][19]. We believe that such variability reflects the actions of important moderators related to treatment and sample characteristics.…”

New Pharmacological Agents to Aid Smoking Cessation and Tobacco Harm Reduction: What Has Been Investigated, and What Is in the Pipeline?

“…However, genetic markers in cholinergic loci in the 15q24 chromosomal region have been proposed to affect response and thus it may be possible to identify those likely to benefit from treatment [305].…”

“…Selegiline is well tolerated by smokers [307], and does not have any serious adverse effects [305,307]. In a recent double bind parallel group trial with over two hundred smokers, selegiline compliance was high and there was no evidence of an effect on depressive symptoms [308].…”

“…A transdermal form of selegiline, approved for the treatment of depression by the Food and Drug Administration, may be appropriate for those adverse to oral formulations [305]. Similar dosing profiles are required as for the other antidepressants, including bupropion [86].…”