|Grant Number:||5R01CA063562-10 Interpret this number|
|Primary Investigator:||Lerman, Caryn|
|Organization:||University Of Pennsylvania|
|Project Title:||Biobehavioral Lung Cancer Prevention Program|
ABSTRACT=In our original grant (R01CA63562), we evaluated the impact of a smoking cessation treatment which incorporated motivational feedback about genetic susceptibility to lung cancer. We found strong positive effects of genetic feedback on perceived risk, perceived quitting benefits, and fear arousal. While smokers receiving genetic feedback made more quit attempts, they were no more likely to quit than were smokers receiving standard minimal contact cessation treatment. Observing that the vast majority of smokers were unable to quit, even in the face of perceived vulnerability and heightened motivation, we became interested in the genetic basis of nicotine dependence and smoking cessation. The strongest evidence (by our group and others) supports the role of the dopamine transporter gene (SLC6A3) which regulates reuptake of dopamine at the synapse. This is consistent with a large body of data suggesting that the reinforcing effects of nicotine are due to its impact on the neurotransmitter dopamine. Thus, in this competitive renewal, we propose to extend our research by evaluating the role of SLC6A3 in the response of smokers to pharmacological smoking cessation treatment (bupropion/Zyban). We have selected bupropion because: (a) initial data from randomized clinical trials provide strong support for its efficacy as a smoking cessation treatment, and (b) bupropion has inhibitory effects of dopamine transport (the protein product of the SLC6A3 gene). The specific aims of the proposed research are: (1) to evaluate the role of genetic factors in response to standard smoking cessation treatment; (2) to evaluate the role of genetic factors in response to bupropion treatment; and (3) to evaluate the psychobiological mechanisms by which genotype and bupropion influence smoking cessation. The study will be a double blind randomized placebo-controlled clinical trial of bupropion in 600 adult male and female smokers. The factorial design includes one treatment factor (bupropion plus standard treatment (with nicotine patch) vs. placebo plus standard treatment with patch) and one subject factor (SLC6A3 genotype, genetically predisposed vs. genetically protected). Bupropion or placebo will be delivered over a 10-week treatment period. All subjects will receive standard minimal contact cessation treatment, which includes two in-person sessions plus five brief structured phone-counseling sessions. A major innovation of this study is that we will use a behavioral economics computer paradigm to evaluate the reinforcing value of nicotine at pre-treatment and during bupropion therapy. Other mediating outcomes (mood, withdrawal) will be assessed at pre-treatment and at multiple points during treatment. The primary smoking cessation outcomes will be assessed at 1-, 6- and 12- months post-treatment. The proposed research will be the first to examine the role of specific genetic factors in response to pharmacological therapy for smoking cessation and to evaluate novel mediating mechanisms. The long-term objective is to provide information necessary to match smoking cessation treatments to individuals, based on their genetic predispositions.
Dopamine genes and nicotine dependence in treatment-seeking and community smokers.
Authors: Bergen AW, Conti DV, Van Den Berg D, Lee W, Liu J, Li D, Guo N, Mi H, Thomas PD, Lessov-Schlaggar CN, Krasnow R, He Y, Nishita D, Jiang R, McClure JB, Tildesley E, Hops H, Tyndale RF, Benowitz NL, Lerman C, Swan GE
Source: Neuropsychopharmacology, 2009 Sep;34(10), p. 2252-64.
EPub date: 2009 Jun 3.
Molecular genetics of addiction and related heritable phenotypes: genome-wide association approaches identify "connectivity constellation" and drug target genes with pleiotropic effects.
Authors: Uhl GR, Drgon T, Johnson C, Li CY, Contoreggi C, Hess J, Naiman D, Liu QR
Source: Ann N Y Acad Sci, 2008 Oct;1141, p. 318-81.
Translating basic science to improve pharmacotherapy for nicotine dependence.
Authors: Phillips JM, Siegel SJ, Shields AE, Patterson F, Gould TJ, Strasser AA, Ray R, Pinto A, Audrain-McGovern J, Rukstalis M, Perkins KA, Blendy JA, Lerman C
Source: Nicotine Tob Res, 2007 Nov;9 Suppl 4, p. S583-98.
Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: analysis of pooled data from two clinical trials.
Authors: David SP, Strong DR, Munaf˛ MR, Brown RA, Lloyd-Richardson EE, Wileyto PE, Evins EA, Shields PG, Lerman C, Niaura R
Source: Nicotine Tob Res, 2007 Dec;9(12), p. 1251-7.
Genetics and smoking cessation improving outcomes in smokers at risk.
Authors: Lerman CE, Schnoll RA, Munaf˛ MR
Source: Am J Prev Med, 2007 Dec;33(6 Suppl), p. S398-405.
Can the blind see? Participant guess about treatment arm assignment may influence outcome in a clinical trial of bupropion for smoking cessation.
Authors: Schnoll RA, Epstein L, Audrain J, Niaura R, Hawk L, Shields PG, Lerman C, Wileyto EP
Source: J Subst Abuse Treat, 2008 Mar;34(2), p. 234-41.
EPub date: 2007 Jun 27.
Recurrent event analysis of lapse and recovery in a smoking cessation clinical trial using bupropion.
Authors: Wileyto EP, Patterson F, Niaura R, Epstein LH, Brown RA, Audrain-McGovern J, Hawk LW Jr, Lerman C
Source: Nicotine Tob Res, 2005 Apr;7(2), p. 257-68.
Catechol-O-methyl-transferase functional polymorphism and nicotine dependence: an evaluation of nonreplicated results.
Authors: Redden DT, Shields PG, Epstein L, Wileyto EP, Zakharkin SO, Allison DB, Lerman C
Source: Cancer Epidemiol Biomarkers Prev, 2005 Jun;14(6), p. 1384-9.
Effect of bupropion on depression symptoms in a smoking cessation clinical trial.
Authors: Lerman C, Niaura R, Collins BN, Wileyto P, Audrain-McGovern J, Pinto A, Hawk L, Epstein LH
Source: Psychol Addict Behav, 2004 Dec;18(4), p. 362-6.
Relationship between education and delay discounting in smokers.
Authors: Jaroni JL, Wright SM, Lerman C, Epstein LH
Source: Addict Behav, 2004 Aug;29(6), p. 1171-5.
Relation between food reinforcement and dopamine genotypes and its effect on food intake in smokers.
Authors: Epstein LH, Wright SM, Paluch RA, Leddy JJ, Hawk LW Jr, Jaroni JL, Saad FG, Crystal-Mansour S, Shields PG, Lerman C
Source: Am J Clin Nutr, 2004 Jul;80(1), p. 82-8.
Do small lapses predict relapse to smoking behavior under bupropion treatment?
Authors: Wileyto P, Patterson F, Niaura R, Epstein L, Brown R, Audrain-McGovern J, Hawk L, Lerman C, Patterson F
Source: Nicotine Tob Res, 2004 Apr;6(2), p. 357-66.
Food hedonics and reinforcement as determinants of laboratory food intake in smokers.
Authors: Epstein LH, Wright SM, Paluch RA, Leddy J, Hawk LW Jr, Jaroni JL, Saad FG, Crystal-Mansour S, Lerman C
Source: Physiol Behav, 2004 May;81(3), p. 511-7.
Influence of methylphenidate on eating in obese men.
Authors: Leddy JJ, Epstein LH, Jaroni JL, Roemmich JN, Paluch RA, Goldfield GS, Lerman C
Source: Obes Res, 2004 Feb;12(2), p. 224-32.
Transdisciplinary science applied to the evaluation of treatments for tobacco use.
Authors: Baker TB, Hatsukami DK, Lerman C, O'Malley SS, Shields AE, Fiore MC
Source: Nicotine Tob Res, 2003 Dec;5 Suppl 1, p. S89-99.
Effects of dopamine transporter and receptor polymorphisms on smoking cessation in a bupropion clinical trial.
Authors: Lerman C, Shields PG, Wileyto EP, Audrain J, Hawk LH Jr, Pinto A, Kucharski S, Krishnan S, Niaura R, Epstein LH
Source: Health Psychol, 2003 Sep;22(5), p. 541-8.
Comparison between two measures of delay discounting in smokers.
Authors: Epstein LH, Richards JB, Saad FG, Paluch RA, Roemmich JN, Lerman C
Source: Exp Clin Psychopharmacol, 2003 May;11(2), p. 131-8.
Dopamine transporter genotype as a risk factor for obesity in African-American smokers.
Authors: Epstein LH, Jaroni JL, Paluch RA, Leddy JJ, Vahue HE, Hawk L, Wileyto EP, Shields PG, Lerman C
Source: Obes Res, 2002 Dec;10(12), p. 1232-40.
Applying genetic approaches to the treatment of nicotine dependence.
Authors: Lerman C, Niaura R
Source: Oncogene, 2002 Oct 21;21(48), p. 7412-20.
Mediating mechanisms for the impact of bupropion in smoking cessation treatment.
Authors: Lerman C, Roth D, Kaufmann V, Audrain J, Hawk L, Liu A, Niaura R, Epstein L
Source: Drug Alcohol Depend, 2002 Jul 1;67(2), p. 219-23.
Attention-Deficit Hyperactivity Disorder (ADHD) symptoms and smoking patterns among participants in a smoking-cessation program.
Authors: Lerman C, Audrain J, Tercyak K, Hawk LW Jr, Bush A, Crystal-Mansour S, Rose C, Niaura R, Epstein LH
Source: Nicotine Tob Res, 2001 Nov;3(4), p. 353-9.
Interacting effects of the serotonin transporter gene and neuroticism in smoking practices and nicotine dependence.
Authors: Lerman C, Caporaso NE, Audrain J, Main D, Boyd NR, Shields PG
Source: Mol Psychiatry, 2000 Mar;5(2), p. 189-92.
Evidence suggesting the role of specific genetic factors in cigarette smoking.
Authors: Lerman C, Caporaso NE, Audrain J, Main D, Bowman ED, Lockshin B, Boyd NR, Shields PG
Source: Health Psychol, 1999 Jan;18(1), p. 14-20.
Depression and self-medication with nicotine: the modifying influence of the dopamine D4 receptor gene.
Authors: Lerman C, Caporaso N, Main D, Audrain J, Boyd NR, Bowman ED, Shields PG
Source: Health Psychol, 1998 Jan;17(1), p. 56-62.
Genetic susceptibility testing in smoking-cessation treatment: one-year outcomes of a randomized trial.
Authors: Audrain J, Boyd NR, Roth J, Main D, Caporaso NF, Lerman C
Source: Addict Behav, 1997 Nov-Dec;22(6), p. 741-51.
Gender and ethnic differences in readiness to change smoking behavior.
Authors: Audrain J, Gomez-Caminero A, Robertson AR, Boyd R, Orleans CT, Lerman C
Source: Womens Health, 1997 Summer;3(2), p. 139-50.
Incorporating biomarkers of exposure and genetic susceptibility into smoking cessation treatment: effects on smoking-related cognitions, emotions, and behavior change.
Authors: Lerman C, Gold K, Audrain J, Lin TH, Boyd NR, Orleans CT, Wilfond B, Louben G, Caporaso N
Source: Health Psychol, 1997 Jan;16(1), p. 87-99.
Investigation of mechanisms linking depressed mood to nicotine dependence.
Authors: Lerman C, Audrain J, Orleans CT, Boyd R, Gold K, Main D, Caporaso N
Source: Addict Behav, 1996 Jan-Feb;21(1), p. 9-19.