Genetic variants in the serotonin transporter influence the efficacy of bupropion and nortriptyline in smoking cessation

• Published in: Addiction (Abingdon, England) Vol. 107; no. 1; pp. 178 - 187
• Main Authors: Quaak, Marieke, van Schayck, Constant P., Postma, Dirkje S., Wagena, Edwin J., van Schooten, Frederik J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2012; Blackwell
• Subjects: 5-HTTLPR; Addiction; Addictive behaviors; Adult and adolescent clinical studies; Alleles; Antidepressants; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Biological and medical sciences; bupropion; Bupropion - pharmacology; Bupropion - therapeutic use; Clinical trials; Drugs; Female; Genes; Genetic Variation; Genotype; Humans; Logistic Models; Male; Medical care; Medical sciences; Medical treatment; Middle Aged; Netherlands; Neuropharmacology; nortriptyline; Nortriptyline - pharmacology; Nortriptyline - therapeutic use; Pharmaceuticals; pharmacogenetics; Pharmacology. Drug treatments; Placebos; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; rs25331; serotonin plasma membrane transport protein (5-HTT) gene (SLC6A4); Serotonin Plasma Membrane Transport Proteins - drug effects; Serotonin Plasma Membrane Transport Proteins - genetics; Serotonin Plasma Membrane Transport Proteins - metabolism; Smoking; Smoking - drug therapy; Smoking - metabolism; Smoking cessation; Smoking Cessation - methods; Smoking Cessation - statistics & numerical data; STin2 VNTR; Tobacco; Tobacco smoking; Tobacco, tobacco smoking; Toxicology; Treatment Outcome; Netherlands; Membrane protein; Psychotropic; Tobacco smoking; rs25331; Bupropion; Membrane transport; Genetics; Antidepressant agent; Human; STin2 VNTR; Nortriptyline; Drug addiction; Pharmacogenetics; Poison withdrawal; Serotonin; 5-HTTLPR; Genetic variant; Tricyclic compound; serotonin plasma membrane transport protein (5-HTT) gene (SLC6A4); Tobacco; Serotonin transporter; Addiction; Shutdown; smoking cessation; Plasma membrane; Neurotransmitter
• ISSN: 0965-2140; 1360-0443
• DOI: 10.1111/j.1360-0443.2011.03534.x

ABSTRACT Aims  We investigated whether variants in the serotonin transporter gene (SLC6A4) influence smoking cessation rates using antidepressant therapy (i.e. bupropion and nortriptyline). Design  Pharmacogenetic (secondary) analysis of a randomized, placebo‐controlled efficacy trial of bupropion and nortriptyline for smoking cessation. Setting  Single‐centre study, Maastricht University, the Netherlands. Participants  A total of 214 of 255 (84%) current daily smokers participating in a randomized controlled efficacy trial. Measurements  Subjects were genotyped for three functional variants in SLC6A4 (5‐HTTLPR, STin2, rs25531). Primary outcome measures were prolonged abstinence from weeks 4–12, 4–26 and 4–52. Secondary outcome measures included 7‐day point prevalence abstinence at weeks 4, 12, 26 and 52. Findings  Carriers of the 5‐HTTLPR high‐activity L‐variant had higher prolonged cessation rates with bupropion than placebo [odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.01–2.05, P = 0.04]. Combining the three variants resulted in increased prolonged cessation rates for both bupropion and nortriptyline among carriers of four to five high‐activity variants (bupropion: OR = 2.00, 95% CI = 1.21–3.29, P = 0.01; nortriptyline: OR = 1.91, 95% CI = 1.02–3.56, P = 0.04). Similar results were found for point prevalence abstinence. Conclusions  Bupropion and nortriptyline seem to be more effective in smoking cessation among SLC6A4 high‐activity variant carriers, probably by blocking the increased serotonin transporter activity, thereby increasing serotonin levels. Prospective studies have to assess if this can improve cessation rates when treatment is targeted at individuals based on their genotypes.