Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: Results from two randomized clinical trials of bupropion

Sean P. David; David R. Strong; Adam M. Leventhal; Molly A. Lancaster; John E. Mcgeary; Marcus R. Munafò; Andrew W. Bergen; Gary E. Swan; Neal L. Benowitz; Rachel F. Tyndale; David V. Conti; Richard A. Brown; Caryn Lerman; Raymond Niaura

doi:10.1111/add.12325

Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: Results from two randomized clinical trials of bupropion

Sean P. David, David R. Strong, Adam M. Leventhal, Molly A. Lancaster, John E. Mcgeary, Marcus R. Munafò, Andrew W. Bergen, Gary E. Swan, Neal L. Benowitz, Rachel F. Tyndale, David V. Conti, Richard A. Brown, Caryn Lerman, Raymond Niaura

Global Public Health

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Abstract

Aims: To evaluate the associations of treatment and an additive genetic efficacy score (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled into two randomized clinical trials of smoking cessation therapies. Design: Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support. Setting: Two hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2). Participants: A total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year. Measurements: Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1E713K], rs4680 [COMT V158M], DRD4 exon 3 variable number of tandem repeats polymorphism [DRD4VNTR], SLC6A3,3′VNTR) analyzed both separately and as part of an AGES, time to first lapse and point prevalence abstinence at end of treatment. Findings: Significant associations of the AGES (hazard ratio [HR]=1.10, 95% confidence interval [CI]=1.06-1.14, P=0.009) and of the DRD4VNTR (HR=1.29, 95% CI=1.17-1.41, P=0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β standard error=-0.18 [0.07], P=0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo. Conclusions: A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.

Original language	English (US)
Pages (from-to)	2202-2211
Number of pages	10
Journal	Addiction
Volume	108
Issue number	12
DOIs	https://doi.org/10.1111/add.12325
State	Published - Dec 2013

Keywords

Bupropion
First lapse
Genetic
Pharmacogenetic analysis
Randomized clinical trial

ASJC Scopus subject areas

Medicine (miscellaneous)
Psychiatry and Mental health

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10.1111/add.12325

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David, S. P., Strong, D. R., Leventhal, A. M., Lancaster, M. A., Mcgeary, J. E., Munafò, M. R., Bergen, A. W., Swan, G. E., Benowitz, N. L., Tyndale, R. F., Conti, D. V., Brown, R. A., Lerman, C., & Niaura, R. (2013). Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: Results from two randomized clinical trials of bupropion. Addiction, 108(12), 2202-2211. https://doi.org/10.1111/add.12325

David, SP, Strong, DR, Leventhal, AM, Lancaster, MA, Mcgeary, JE, Munafò, MR, Bergen, AW, Swan, GE, Benowitz, NL, Tyndale, RF, Conti, DV, Brown, RA, Lerman, C & Niaura, R 2013, 'Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: Results from two randomized clinical trials of bupropion', Addiction, vol. 108, no. 12, pp. 2202-2211. https://doi.org/10.1111/add.12325

@article{000d313749584236877c950cfeeb685d,

title = "Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: Results from two randomized clinical trials of bupropion",

abstract = "Aims: To evaluate the associations of treatment and an additive genetic efficacy score (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled into two randomized clinical trials of smoking cessation therapies. Design: Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support. Setting: Two hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2). Participants: A total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year. Measurements: Age, gender, Fagerstr{\"o}m Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1E713K], rs4680 [COMT V158M], DRD4 exon 3 variable number of tandem repeats polymorphism [DRD4VNTR], SLC6A3,3′VNTR) analyzed both separately and as part of an AGES, time to first lapse and point prevalence abstinence at end of treatment. Findings: Significant associations of the AGES (hazard ratio [HR]=1.10, 95% confidence interval [CI]=1.06-1.14, P=0.009) and of the DRD4VNTR (HR=1.29, 95% CI=1.17-1.41, P=0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β standard error=-0.18 [0.07], P=0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo. Conclusions: A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.",

keywords = "Bupropion, First lapse, Genetic, Pharmacogenetic analysis, Randomized clinical trial",

author = "David, {Sean P.} and Strong, {David R.} and Leventhal, {Adam M.} and Lancaster, {Molly A.} and Mcgeary, {John E.} and Munaf{\`o}, {Marcus R.} and Bergen, {Andrew W.} and Swan, {Gary E.} and Benowitz, {Neal L.} and Tyndale, {Rachel F.} and Conti, {David V.} and Brown, {Richard A.} and Caryn Lerman and Raymond Niaura",

year = "2013",

month = dec,

doi = "10.1111/add.12325",

language = "English (US)",

volume = "108",

pages = "2202--2211",

journal = "Addiction",

issn = "0965-2140",

publisher = "Wiley-Blackwell",

number = "12",

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T1 - Influence of a dopamine pathway additive genetic efficacy score on smoking cessation

T2 - Results from two randomized clinical trials of bupropion

AU - David, Sean P.

AU - Strong, David R.

AU - Leventhal, Adam M.

AU - Lancaster, Molly A.

AU - Mcgeary, John E.

AU - Munafò, Marcus R.

AU - Bergen, Andrew W.

AU - Swan, Gary E.

AU - Benowitz, Neal L.

AU - Tyndale, Rachel F.

AU - Conti, David V.

AU - Brown, Richard A.

AU - Lerman, Caryn

AU - Niaura, Raymond

PY - 2013/12

Y1 - 2013/12

N2 - Aims: To evaluate the associations of treatment and an additive genetic efficacy score (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled into two randomized clinical trials of smoking cessation therapies. Design: Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support. Setting: Two hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2). Participants: A total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year. Measurements: Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1E713K], rs4680 [COMT V158M], DRD4 exon 3 variable number of tandem repeats polymorphism [DRD4VNTR], SLC6A3,3′VNTR) analyzed both separately and as part of an AGES, time to first lapse and point prevalence abstinence at end of treatment. Findings: Significant associations of the AGES (hazard ratio [HR]=1.10, 95% confidence interval [CI]=1.06-1.14, P=0.009) and of the DRD4VNTR (HR=1.29, 95% CI=1.17-1.41, P=0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β standard error=-0.18 [0.07], P=0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo. Conclusions: A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.

AB - Aims: To evaluate the associations of treatment and an additive genetic efficacy score (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled into two randomized clinical trials of smoking cessation therapies. Design: Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support. Setting: Two hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2). Participants: A total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year. Measurements: Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1E713K], rs4680 [COMT V158M], DRD4 exon 3 variable number of tandem repeats polymorphism [DRD4VNTR], SLC6A3,3′VNTR) analyzed both separately and as part of an AGES, time to first lapse and point prevalence abstinence at end of treatment. Findings: Significant associations of the AGES (hazard ratio [HR]=1.10, 95% confidence interval [CI]=1.06-1.14, P=0.009) and of the DRD4VNTR (HR=1.29, 95% CI=1.17-1.41, P=0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β standard error=-0.18 [0.07], P=0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo. Conclusions: A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.

KW - Bupropion

KW - First lapse

KW - Genetic

KW - Pharmacogenetic analysis

KW - Randomized clinical trial

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Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: Results from two randomized clinical trials of bupropion

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