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Grant Details

Grant Number: 5R01CA063562-10 Interpret this number
Primary Investigator: Lerman, Caryn
Organization: University Of Pennsylvania
Project Title: Biobehavioral Lung Cancer Prevention Program
Fiscal Year: 2004


Abstract

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.



Publications

Assessing the fit of parametric cure models.
Authors: Wileyto E.P. , Li Y. , Chen J. , Heitjan D.F. .
Source: Biostatistics (oxford, England), 2013 Apr; 14(2), p. 340-50.
PMID: 23197383
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Nicotinic acetylcholine receptor variation and response to smoking cessation therapies.
Authors: Bergen A.W. , Javitz H.S. , Krasnow R. , Nishita D. , Michel M. , Conti D.V. , Liu J. , Lee W. , Edlund C.K. , Hall S. , et al. .
Source: Pharmacogenetics And Genomics, 2013 Feb; 23(2), p. 94-103.
PMID: 23249876
Related Citations

Comparative dynamics of four smoking withdrawal symptom scales.
Authors: Javitz H.S. , Lerman C. , Swan G.E. .
Source: Addiction (abingdon, England), 2012 Aug; 107(8), p. 1501-11.
PMID: 22321019
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Statistical Analysis Of Daily Smoking Status In Smoking Cessation Clinical Trials
Authors: Li Y. , Wileyto E.P. , Heitjan D.F. .
Source: Addiction (abingdon, England), 2011 Nov; 106(11), p. 2039-46.
PMID: 21631623
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The dynamics of the urge-to-smoke following smoking cessation via pharmacotherapy.
Authors: Javitz H.S. , Swan G.E. , Lerman C. .
Source: Addiction (abingdon, England), 2011 Oct; 106(10), p. 1835-45.
PMID: 21561501
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Multiplicity-calibrated Bayesian Hypothesis Tests
Authors: Guo M. , Heitjan D.F. .
Source: Biostatistics (oxford, England), 2010 Jul; 11(3), p. 473-83.
PMID: 20212321
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Modeling Smoking Cessation Data With Alternating States And A Cure Fraction Using Frailty Models
Authors: Li Y. , Wileyto E.P. , Heitjan D.F. .
Source: Statistics In Medicine, 2010-03-15 00:00:00.0; 29(6), p. 627-38.
PMID: 20077505
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Dopamine genes and nicotine dependence in treatment-seeking and community smokers.
Authors: Bergen A.W. , Conti D.V. , Van Den Berg D. , Lee W. , Liu J. , Li D. , Guo N. , Mi H. , Thomas P.D. , Lessov-Schlaggar C.N. , et al. .
Source: Neuropsychopharmacology : Official Publication Of The American College Of Neuropsychopharmacology, 2009 Sep; 34(10), p. 2252-64.
PMID: 19494806
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Cost-effectiveness Of Pharmacogenetic Testing To Tailor Smoking-cessation Treatment
Authors: Heitjan D.F. , Asch D.A. , Ray R. , Rukstalis M. , Patterson F. , Lerman C. .
Source: The Pharmacogenomics Journal, 2008 Dec; 8(6), p. 391-9.
PMID: 18347612
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Molecular Genetics Of Addiction And Related Heritable Phenotypes: Genome-wide Association Approaches Identify "connectivity Constellation" And Drug Target Genes With Pleiotropic Effects
Authors: Uhl G.R. , Drgon T. , Johnson C. , Li C.Y. , Contoreggi C. , Hess J. , Naiman D. , Liu Q.R. .
Source: Annals Of The New York Academy Of Sciences, 2008 Oct; 1141, p. 318-81.
PMID: 18991966
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Identification Of Pharmacogenetic Markers In Smoking Cessation Therapy
Authors: Heitjan D.F. , Guo M. , Ray R. , Wileyto E.P. , Epstein L.H. , Lerman C. .
Source: American Journal Of Medical Genetics. Part B, Neuropsychiatric Genetics : The Official Publication Of The International Society Of Psychiatric Genetics, 2008-09-05 00:00:00.0; 147B(6), p. 712-9.
PMID: 18165968
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Toward Personalized Therapy For Smoking Cessation: A Randomized Placebo-controlled Trial Of Bupropion
Authors: Patterson F. , Schnoll R.A. , Wileyto E.P. , Pinto A. , Epstein L.H. , Shields P.G. , Hawk L.W. , Tyndale R.F. , Benowitz N. , Lerman C. .
Source: Clinical Pharmacology And Therapeutics, 2008 Sep; 84(3), p. 320-5.
PMID: 18388868
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Molecular Genetics Of Successful Smoking Cessation: Convergent Genome-wide Association Study Results
Authors: Uhl G.R. , Liu Q.R. , Drgon T. , Johnson C. , Walther D. , Rose J.E. , David S.P. , Niaura R. , Lerman C. .
Source: Archives Of General Psychiatry, 2008 Jun; 65(6), p. 683-93.
PMID: 18519826
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Can The Blind See? Participant Guess About Treatment Arm Assignment May Influence Outcome In A Clinical Trial Of Bupropion For Smoking Cessation
Authors: Schnoll R.A. , Epstein L. , Audrain J. , Niaura R. , Hawk L. , Shields P.G. , Lerman C. , Wileyto E.P. .
Source: Journal Of Substance Abuse Treatment, 2008 Mar; 34(2), p. 234-41.
PMID: 17600649
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Genetics and smoking cessation improving outcomes in smokers at risk.
Authors: Lerman C.E. , Schnoll R.A. , Munafò M.R. .
Source: American Journal Of Preventive Medicine, 2007 Dec; 33(6 Suppl), p. S398-405.
PMID: 18021915
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Bupropion efficacy for smoking cessation is influenced by the DRD2 Taq1A polymorphism: analysis of pooled data from two clinical trials.
Authors: David S.P. , Strong D.R. , Munafò M.R. , Brown R.A. , Lloyd-Richardson E.E. , Wileyto P.E. , Evins E.A. , Shields P.G. , Lerman C. , Niaura R. .
Source: Nicotine & Tobacco Research : Official Journal Of The Society For Research On Nicotine And Tobacco, 2007 Dec; 9(12), p. 1251-7.
PMID: 18058343
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Translating Basic Science To Improve Pharmacotherapy For Nicotine Dependence
Authors: Phillips J.M. , Siegel S.J. , Shields A.E. , Patterson F. , Gould T.J. , Strasser A.A. , Ray R. , Pinto A. , Audrain-McGovern J. , Rukstalis M. , et al. .
Source: Nicotine & Tobacco Research : Official Journal Of The Society For Research On Nicotine And Tobacco, 2007 Nov; 9 Suppl 4, p. S583-98.
PMID: 18067034
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Cyp2b6 Genotype Alters Abstinence Rates In A Bupropion Smoking Cessation Trial
Authors: Lee A.M. , Jepson C. , Hoffmann E. , Epstein L. , Hawk L.W. , Lerman C. , Tyndale R.F. .
Source: Biological Psychiatry, 2007-09-15 00:00:00.0; 62(6), p. 635-41.
PMID: 17223085
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Catechol-o-methyltransferase (comt) Gene Variants Predict Response To Bupropion Therapy For Tobacco Dependence
Authors: Berrettini W.H. , Wileyto E.P. , Epstein L. , Restine S. , Hawk L. , Shields P. , Niaura R. , Lerman C. .
Source: Biological Psychiatry, 2007-01-01 00:00:00.0; 61(1), p. 111-8.
PMID: 16876132
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Helping Smokers Quit Through Pharmacogenetics
Authors: Lerman C. .
Source: Ldi Issue Brief, 2006 May-Jun; 11(6), p. 1-4.
PMID: 16827222
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Role Of Functional Genetic Variation In The Dopamine D2 Receptor (drd2) In Response To Bupropion And Nicotine Replacement Therapy For Tobacco Dependence: Results Of Two Randomized Clinical Trials
Authors: Lerman C. , Jepson C. , Wileyto E.P. , Epstein L.H. , Rukstalis M. , Patterson F. , Kaufmann V. , Restine S. , Hawk L. , Niaura R. , et al. .
Source: Neuropsychopharmacology : Official Publication Of The American College Of Neuropsychopharmacology, 2006 Jan; 31(1), p. 231-42.
PMID: 16123753
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Catechol-o-methyl-transferase Functional Polymorphism And Nicotine Dependence: An Evaluation Of Nonreplicated Results
Authors: Redden D.T. , Shields P.G. , Epstein L. , Wileyto E.P. , Zakharkin S.O. , Allison D.B. , Lerman C. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2005 Jun; 14(6), p. 1384-9.
PMID: 15941945
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Recurrent event analysis of lapse and recovery in a smoking cessation clinical trial using bupropion.
Authors: Wileyto E.P. , Patterson F. , Niaura R. , Epstein L.H. , Brown R.A. , Audrain-McGovern J. , Hawk L.W. , Lerman C. .
Source: Nicotine & Tobacco Research : Official Journal Of The Society For Research On Nicotine And Tobacco, 2005 Apr; 7(2), p. 257-68.
PMID: 16036283
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Effect Of Bupropion On Depression Symptoms In A Smoking Cessation Clinical Trial
Authors: Lerman C. , Niaura R. , Collins B.N. , Wileyto P. , Audrain-McGovern J. , Pinto A. , Hawk L. , Epstein L.H. .
Source: Psychology Of Addictive Behaviors : Journal Of The Society Of Psychologists In Addictive Behaviors, 2004 Dec; 18(4), p. 362-6.
PMID: 15631608
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Changes In Food Reward Following Smoking Cessation: A Pharmacogenetic Investigation
Authors: Lerman C. , Berrettini W. , Pinto A. , Patterson F. , Crystal-Mansour S. , Wileyto E.P. , Restine S.L. , Leonard D.G. , Shields P.G. , Epstein L.H. .
Source: Psychopharmacology, 2004 Aug; 174(4), p. 571-7.
PMID: 15138759
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Relationship Between Education And Delay Discounting In Smokers
Authors: Jaroni J.L. , Wright S.M. , Lerman C. , Epstein L.H. .
Source: Addictive Behaviors, 2004 Aug; 29(6), p. 1171-5.
PMID: 15236819
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Relation Between Food Reinforcement And Dopamine Genotypes And Its Effect On Food Intake In Smokers
Authors: Epstein L.H. , Wright S.M. , Paluch R.A. , Leddy J.J. , Hawk L.W. , Jaroni J.L. , Saad F.G. , Crystal-Mansour S. , Shields P.G. , Lerman C. .
Source: The American Journal Of Clinical Nutrition, 2004 Jul; 80(1), p. 82-8.
PMID: 15213032
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Food Hedonics And Reinforcement As Determinants Of Laboratory Food Intake In Smokers
Authors: Epstein L.H. , Wright S.M. , Paluch R.A. , Leddy J. , Hawk L.W. , Jaroni J.L. , Saad F.G. , Crystal-Mansour S. , Lerman C. .
Source: Physiology & Behavior, 2004 May; 81(3), p. 511-7.
PMID: 15135024
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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 & Tobacco Research : Official Journal Of The Society For Research On Nicotine And Tobacco, 2004 Apr; 6(2), p. 357-66.
PMID: 15203809
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Influence of methylphenidate on eating in obese men.
Authors: Leddy J.J. , Epstein L.H. , Jaroni J.L. , Roemmich J.N. , Paluch R.A. , Goldfield G.S. , Lerman C. .
Source: Obesity Research, 2004 Feb; 12(2), p. 224-32.
PMID: 14981214
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Transdisciplinary science applied to the evaluation of treatments for tobacco use.
Authors: Baker T.B. , Hatsukami D.K. , Lerman C. , O'Malley S.S. , Shields A.E. , Fiore M.C. .
Source: Nicotine & Tobacco Research : Official Journal Of The Society For Research On Nicotine And Tobacco, 2003 Dec; 5 Suppl 1, p. S89-99.
PMID: 14668089
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Effects Of Dopamine Transporter And Receptor Polymorphisms On Smoking Cessation In A Bupropion Clinical Trial
Authors: Lerman C. , Shields P.G. , Wileyto E.P. , Audrain J. , Hawk L.H. , Pinto A. , Kucharski S. , Krishnan S. , Niaura R. , Epstein L.H. .
Source: Health Psychology : Official Journal Of The Division Of Health Psychology, American Psychological Association, 2003 Sep; 22(5), p. 541-8.
PMID: 14570538
Related Citations

Comparison between two measures of delay discounting in smokers.
Authors: Epstein L.H. , Richards J.B. , Saad F.G. , Paluch R.A. , Roemmich J.N. , Lerman C. .
Source: Experimental And Clinical Psychopharmacology, 2003 May; 11(2), p. 131-8.
PMID: 12755457
Related Citations

Dopamine Transporter Genotype As A Risk Factor For Obesity In African-american Smokers
Authors: Epstein L.H. , Jaroni J.L. , Paluch R.A. , Leddy J.J. , Vahue H.E. , Hawk L. , Wileyto E.P. , Shields P.G. , Lerman C. .
Source: Obesity Research, 2002 Dec; 10(12), p. 1232-40.
PMID: 12490667
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Applying genetic approaches to the treatment of nicotine dependence.
Authors: Lerman C. , Niaura R. .
Source: Oncogene, 2002-10-21 00:00:00.0; 21(48), p. 7412-20.
PMID: 12379882
Related Citations

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 And Alcohol Dependence, 2002-07-01 00:00:00.0; 67(2), p. 219-23.
PMID: 12095672
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Attention-deficit Hyperactivity Disorder (adhd) Symptoms And Smoking Patterns Among Participants In A Smoking-cessation Program
Authors: Lerman C. , Audrain J. , Tercyak K. , Hawk L.W. , Bush A. , Crystal-Mansour S. , Rose C. , Niaura R. , Epstein L.H. .
Source: Nicotine & Tobacco Research : Official Journal Of The Society For Research On Nicotine And Tobacco, 2001 Nov; 3(4), p. 353-9.
PMID: 11694203
Related Citations

Interacting Effects Of The Serotonin Transporter Gene And Neuroticism In Smoking Practices And Nicotine Dependence
Authors: Lerman C. , Caporaso N.E. , Audrain J. , Main D. , Boyd N.R. , Shields P.G. .
Source: Molecular Psychiatry, 2000 Mar; 5(2), p. 189-92.
PMID: 10822347
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Evidence Suggesting The Role Of Specific Genetic Factors In Cigarette Smoking
Authors: Lerman C. , Caporaso N.E. , Audrain J. , Main D. , Bowman E.D. , Lockshin B. , Boyd N.R. , Shields P.G. .
Source: Health Psychology : Official Journal Of The Division Of Health Psychology, American Psychological Association, 1999 Jan; 18(1), p. 14-20.
PMID: 9925041
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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 N.R. , Bowman E.D. , Shields P.G. .
Source: Health Psychology : Official Journal Of The Division Of Health Psychology, American Psychological Association, 1998 Jan; 17(1), p. 56-62.
PMID: 9459071
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Genetic Susceptibility Testing In Smoking-cessation Treatment: One-year Outcomes Of A Randomized Trial
Authors: Audrain J. , Boyd N.R. , Roth J. , Main D. , Caporaso N.F. , Lerman C. .
Source: Addictive Behaviors, 1997 Nov-Dec; 22(6), p. 741-51.
PMID: 9426791
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Gender And Ethnic Differences In Readiness To Change Smoking Behavior
Authors: Audrain J. , Gomez-Caminero A. , Robertson A.R. , Boyd R. , Orleans C.T. , Lerman C. .
Source: Women's Health (hillsdale, N.j.), 1997 Summer; 3(2), p. 139-50.
PMID: 9332155
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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 T.H. , Boyd N.R. , Orleans C.T. , Wilfond B. , Louben G. , Caporaso N. .
Source: Health Psychology : Official Journal Of The Division Of Health Psychology, American Psychological Association, 1997 Jan; 16(1), p. 87-99.
PMID: 9028818
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Investigation Of Mechanisms Linking Depressed Mood To Nicotine Dependence
Authors: Lerman C. , Audrain J. , Orleans C.T. , Boyd R. , Gold K. , Main D. , Caporaso N. .
Source: Addictive Behaviors, 1996 Jan-Feb; 21(1), p. 9-19.
PMID: 8729703
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