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author:("Lerman, carya")
1.  Drug Metabolizing Enzyme and Transporter Gene Variation, Nicotine Metabolism, Prospective Abstinence, and Cigarette Consumption 
PLoS ONE  2015;10(7):e0126113.
The Nicotine Metabolite Ratio (NMR, ratio of trans-3’-hydroxycotinine and cotinine), has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 PACT=4.1E-7, rs4803381 PACT=4.5E-5, rs1137115, PACT=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.
PMCID: PMC4488893  PMID: 26132489
2.  Lack of Associations of CHRNA5-A3-B4 Genetic Variants with Smoking Cessation Treatment Outcomes in Caucasian Smokers despite Associations with Baseline Smoking 
PLoS ONE  2015;10(5):e0128109.
CHRNA5-A3-B4 variants, rs16969968, rs588765 and rs578776, are consistently associated with tobacco consumption among smokers, but the association with smoking cessation is less consistent. Among the studies that reported significant associations with cessation, the effects were observed in smokers treated with placebo treatment in some studies and conversely in those receiving active pharmacological therapy (bupropion and nicotine replacement therapies) in others. Thus, it remains unclear whether CHRNA5-A3-B4 is a useful marker for optimizing smoking cessation. Using data from 654 Caucasian smokers treated with placebo, nicotine patch or varenicline, we investigated whether CHRNA5-A3-B4 variants were associated with smoking cessation outcomes, and whether there were significant genotype-by-treatment or haplotype-by-treatment interactions. We observed no significant associations between CHRNA5-A3-B4 variants and smoking cessation, despite replicating previous associations with baseline tobacco consumption. At end of treatment the effect size on smoking cessation in the placebo, patch and varenicline groups for rs16969968 [GG vs. GA+AA] was OR = 0.66 (P = 0.23), OR = 1.01 (P = 0.99), and OR = 1.30 (P = 0.36) respectively, of rs588765 [CC vs. CT+TT] was OR = 0.96 (P = 0.90), OR = 0.84 (P = 0.58), and OR = 0.74 (P = 0.29) respectively, and for rs578776 [GG vs. GA+AA] on smoking cessation was OR = 1.02 (P = 0.95), OR = 0.75 (P = 0.35), and OR = 1.20 (P = 0.51) respectively. Furthermore, we observed no associations with cessation using the CHRNA5-A3-B4 haplotype (constructed using rs16969968 and rs588765), nor did we observe any significant genotype-by-treatment interactions, with or without adjusting for the rate of nicotine metabolism (all P>0.05). We also observed no significant genetic associations with 6 month or 12 month smoking abstinence. In conclusion, we found no association between CHRNA5-A3-B4 variants and smoking cessation rates in this clinical trial; however, as expected, significant associations with baseline tobacco consumption were replicated. Our data suggest that CHRNA5-A3-B4 gene variants do not exhibit a robust association with smoking cessation and are unlikely to be useful for clinically optimizing smoking cessation pharmacotherapy for Caucasian smokers.
PMCID: PMC4444267  PMID: 26010901
3.  Genetic variation in the serotonin pathway and smoking cessation with nicotine replacement therapy: New data from the Patch in Practice trial and pooled analyses 
Drug and alcohol dependence  2008;98(0):77-85.
The serotonin pathway has been implicated in nicotine dependence and may influence smoking cessation. Therefore, 792 cigarette smokers from the Patch in Practice trial were genotyped for the tryptophan hydroxylase (TPH1 A779C), serotonin transporter (SLC6A4 5-HTTLPR), and 5-HT1A (HTR1A C-1019G) polymorphisms. Cox regression analysis did not demonstrate significant effects of any of the three genotypes on relapse to smoking: TPH1 (Reference AA; AC: hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.78, 1.24, p = 0.90; CC: HR 0.93, 95% CI 0.73, 1.18, p = 0.55); 5-HTTLPR (Reference LL; SL: HR 1.01, 95% CI 0.85, 1.20, p = 0.90; SS: HR 1.13, 95% CI 0.91, 1.39, p = 0.27); HTR1A (Reference CC; CG: HR 1.04, 95% CI 0.86, 1.25, p = 0.70; GG: HR 1.01, 95% CI 0.82, 1.24, p = 0.93). Moreover, pooled analyses of data from all three extant pharmacogenetic NRT trials (N= 1398) found no significant effect of 5-HTTLPR genotype on continuous abstinence at 12-week (Reference LL; SL: odds ratio (OR) = 1.25, 95% CI 0.89, 1.74, p = 0.19; SS: OR= 1.31, 95% CI 0.86, 1.98, p = 0.21) or 26-week follow-up (Reference LL; SL: OR= 0.93, 95% CI 0.64, 1.33, p = 0.68; SS: OR= 1.00, 95% CI 0.63, 1.58, p = 1.00). These data do not support a statistically or clinically significant moderating effect of these specific 5-HT pathway genetic variants on smoking cessation. However, the possibility remains that other variants in these or other 5-HT genes may influence NRT efficacy for smoking cessation in treatment seeking smokers.
PMCID: PMC4439462  PMID: 18562131
Smoking cessation; Tryptophan hydroxylase; Serotonin transporter; 5-HT1A receptor; Nicotine replacement therapy; Pharmacogenetics
4.  Nicotine dependence as a moderator of genetic influences on smoking cessation treatment outcome☆ 
Drug and alcohol dependence  2014;138:109-117.
Genetic influences on smoking cessation treatment outcome may be affected by pretreatment patient characteristics. Nicotine dependence is arguably the most salient clinical factor in smoking cessation.
In this secondary analysis of clinical trial data (N = 793), we examined nicotine dependence severity as a moderator of the effects of 1198 single nucleotide polymorphisms (SNPs) in 53 biologically-relevant gene regions on smoking cessation outcomes. P-values were adjusted to account for multiple correlated SNPs within a gene region; corrected system-wide significance was 5 × 10−4.
SNP × nicotine dependence interactions reached region-wide significance for several SNPs in the Dopamine Beta Hydroxylase (DBH) locus (0.0005 < Adjusted-P < 0.05), including rs1541333, which reached system-wide significance for predicting end of treatment (EOT) abstinence (Adjusted-P = 0.0004). A haplotype including 6 DBH SNPs predicted abstinence at EOT (OR = 1.7, P = 0.001) and 6-month follow-up (OR = 1.6, P = 0.008) in those with high nicotine dependence (n = 526) but not in those with low dependence (n = 227). The DBH signal observed here may be distinct from a previously reported genome-wide significant signal for former smoking status and from the principal haplotype associated with plasma dopamine beta-hydroxylase activity. A haplotype within the Chromosome 15 Nicotinic Acetylcholine Receptor gene region predicted abstinence at EOT in those with high (OR = 2.0, P = 0.0004) but not low (P = 0.6) dependence in post hoc analyses.
Considering pre-treatment nicotine dependence level may optimize the prediction of genetic influences on cessation outcomes. If replicated, results like these may inform prognosticative genomic screening panels designed to identify smokers at high risk of relapse when coupled with severe nicotine dependence.
PMCID: PMC4095777  PMID: 24667010
Genetics; Smoking cessation; Nicotine dependence; Dopamine
5.  A Measure of Perceived Argument Strength: Reliability and Validity 
Studies of the content of persuasive messages in which the central arguments of the message are scrutinized have traditionally relied on the technique of thought-listing to assess argument strength. Although the validity of the thought-listing procedure is well documented, its utility can be limited in situations involving non-adult populations and sensitive topics. In this paper we present a self-reported scale that can be used to assess perceived argument strength in contexts where thought-listing may be less appropriate. This scale taps into perceived argument strength from multiple points of view, including but also extending beyond the potential of the argument to elicit positive and negative thoughts. Reliability and validity of this scale were assessed in health communication contexts involving anti-drug PSAs directed at adolescents and anti-smoking PSAs targeting adults. Evidence of convergence between this scale and the thought-listing technique was also obtained using the classical comprehensive exam arguments.
PMCID: PMC4283835  PMID: 25568663
Psychopharmacology  2013;231(1):1-11.
Initial screening of new medications for potential efficacy (i.e. FDA early Phase 2), such as in aiding smoking cessation, should be efficient in identifying which drugs do, or do not, warrant more extensive (and expensive) clinical testing.
This focused review outlines our research on development, evaluation, and validation of an efficient crossover procedure for sensitivity in detecting medication efficacy for smoking cessation. First-line FDA-approved medications of nicotine patch, varenicline, and bupropion were tested, as model drugs, in 3 separate placebo-controlled studies. We also tested specificity of our procedure in identifying a drug that lacks efficacy, using modafinil.
This crossover procedure showed sensitivity (increased days of abstinence) during week-long “practice” quit attempts with each of the active cessation medications (positive controls) vs. placebo, but not with modafinil (negative control) vs. placebo, as hypothesized. Sensitivity to medication efficacy signal was observed only in smokers high in intrinsic quit motivation (i.e. already preparing to quit soon) and not smokers low in intrinsic quit motivation, even if monetarily reinforced for abstinence (i.e., given extrinsic motivation).
A crossover procedure requiring less time and fewer subjects than formal trials may provide an efficient strategy for a go/no-go decision whether to advance to subsequent Phase 2 randomized clinical trials with a novel drug. Future research is needed to replicate our results and evaluate this procedure with novel compounds, identify factors that may limit its utility, and evaluate its applicability to testing efficacy of compounds for treating other forms of addiction.
PMCID: PMC3910509  PMID: 24297304
Medication screening; Pharmacotherapy; Nicotine dependence; Addiction
7.  Cognitive Function During Nicotine Withdrawal: Implications for Nicotine Dependence Treatment 
Neuropharmacology  2013;76(0 0):10.1016/j.neuropharm.2013.04.034.
Nicotine withdrawal is associated with deficits in neurocognitive function including sustained attention, working memory, and response inhibition. Several convergent lines of evidence suggest that these deficits may represent a core dependence phenotype and a target for treatment development efforts. A better understanding of the mechanisms underlying withdrawal-related cognitive deficits may lead to improve nicotine dependence treatment. We begin with an overview of the neurocognitive effects of withdrawal in rodent and human models, followed by discussion of the neurobehavioral mechanisms that are thought to underlie these effects. We then review individual differences in withdrawal-related neurocognitive effects including genetics, gender, and psychiatric comorbidity. We conclude with a discussion of the implications of this research for developing improved therapies, both pharmacotherapy and behavioral treatments, that target cognitive symptoms of nicotine withdrawal.
PMCID: PMC3779499  PMID: 23639437
nicotine; withdrawal; cognition; attention; working memory; smoking cessation
8.  Evidence from Mouse and Man for a Role of Neuregulin 3 in Nicotine Dependence 
Molecular psychiatry  2013;19(7):801-810.
Addiction to nicotine and ability to quit smoking are influenced by genetic factors. We used functional genomic approaches (chromatin immunoprecipitation (ChIP) and whole genome sequencing) to identify CREB targets following chronic nicotine administration and withdrawal in rodents. fWe found that chronic nicotine and withdrawal differentially modulate CREB binding to the gene for Neuregulin 3 (NRG3). Quantitative analysis of saline, nicotine, and nicotine withdrawal in two biological replicates corroborate this finding, with NRG3 increases in both mRNA and protein following withdrawal from chronic nicotine treatment. To translate these data for human relevance, single nucleotide polymorphisms (SNPs) across NRG3 were examined for association with prospective smoking cessation among smokers of European ancestry treated with transdermal nicotine in two independent cohorts. Individual SNP and haplotype analysis support association of NRG3 SNPs and smoking cessation success. NRG3 is a neural-enriched member of the EGF family, and a specific ligand for the receptor tyrosine kinase ErbB4, which is also up-regulated following nicotine treatment and withdrawal. Mice with significantly reduced levels of NRG3 or pharmacological inhibition of ErbB4 show similar reductions in anxiety following nicotine withdrawal compared to control animals, suggesting a role for NRG3 in nicotine dependence. While the function of the SNP in NRG3 in humans is not known, these data suggest that Nrg3/ErbB4 signaling may be an important factor in nicotine dependence.
PMCID: PMC3877725  PMID: 23999525
mouse; human; single nucleotide polymorphism (SNP); ChIP-Seq; neuregulin 3 (NRG3); nicotine; smoking cessation
9.  Effects of tolcapone on working memory and brain activity in abstinent smokers: A proof-of-concept study 
Drug and alcohol dependence  2013;133(3):852-856.
Dopamine levels in the prefrontal cortex (PFC) are thought to play an important role in cognitive function and nicotine dependence. The catechol-O-methyltransferase (COMT) inhibitor tolcapone, an FDA-approved treatment for Parkinson’s disease, increases prefrontal dopamine levels, with cognitive benefits that may vary by COMT genotype. We tested whether tolcapone alters working memory-related brain activity and performance in abstinent smokers.
In this double-blind crossover study, 20 smokers completed 8 days of treatment with tolcapone and placebo. In both medication periods, smokers completed blood oxygen level-dependent (BOLD) fMRI scans while performing a working memory N-back task after 24 h of abstinence. Smokers were genotyped prospectively for the COMT val158met polymorphism for exploratory analysis.
Compared to placebo, tolcapone modestly improved accuracy (p = 0.017) and enhanced suppression of activation in the ventromedial prefrontal cortex (vmPFC) (p = 0.002). There were no effects of medication in other a priori regions of interest (dorsolateral PFC, dorsal cingulate/medial prefrontal cortex, or posterior cingulate cortex). Exploratory analyses suggested that tolcapone led to a decrease in BOLD signal in several regions among smokers with val/val genotypes, but increased or remained unchanged among met allele carriers. Tolcapone did not attenuate craving, mood, or withdrawal symptoms compared to placebo.
Data from this proof-of-concept study do not provide strong support for further evaluation of COMT inhibitors as smoking cessation aids.
PMCID: PMC3960598  PMID: 24095246
Smoking; Nicotine; COMT; Tolcapone; fMRI; Working memory
10.  Influence of a Dopamine Pathway Additive Genetic Efficacy Score on Smoking Cessation: Results from Two Randomized Clinical Trials of Bupropion 
Addiction (Abingdon, England)  2013;108(12):10.1111/add.12325.
To evaluate 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 in two randomized clinical trials of smoking cessation therapies.
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.
Two Hospital-affiliated clinics (Study 1), and two University-affiliated clinics (Study 2).
N=792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.
Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 Variable Number of Tandem Repeats polymorphism [DRD4 VNTR], SLC6A3 3' VNTR) analyzed both separately and as part of an AGES, time to first lapse, and point prevalence abstinence at end of treatment.
Significant associations of the AGES (hazard ratio = 1.10, 95% Confidence Interval [CI] = 1.06–1.14], p=0.0099) and of the DRD4 VNTR (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 [SE]=−0.18 [0.07], p=0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo.
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.
PMCID: PMC3834197  PMID: 23941313
Bupropion; genetic; pharmacogenetic analysis; randomized clinical trial; first lapse
11.  Association of abstinence-induced alterations in working memory function and COMT genotype in smokers 
Psychopharmacology  2013;230(4):10.1007/s00213-013-3197-3.
The common val158met polymorphism in the catechol-O-methyltransferase (COMT) gene has been associated with nicotine dependence, alterations in executive cognitive function, and abstinence-induced working memory deficits in smokers.
We sought to replicate the association of the COMT val allele with abstinence-induced alterations in working memory-related activity in task-positive (executive control) and task-negative (default mode network) regions.
Forty smokers (20 val/val and 20 met/met) performed an N-back task while undergoing blood oxygen level-dependent (BOLD) fMRI on two separate occasions: following 72 hours of confirmed abstinence and during smoking as usual. An independent sample of 48 smokers who completed the identical N-back task during fMRI in smoking versus abstinence for another study was used as a validation sample.
Contrary to expectations, genotype by session interactions on BOLD signal in executive control regions (dorsolateral prefrontal cortex (DLPFC) and dorsal cingulate/medial prefrontal cortex (MF/CG)) revealed significant abstinence-induced reductions in the met/met group, but not the val/val group. Results also revealed that val/val smokers may exhibit less suppression of activation in task-negative regions such as the posterior cingulate cortex during abstinence (versus smoking). These patterns were confirmed in the validation sample and in the whole-brain analysis, though the regions differed from the apriori ROIs (e.g., precuneus, insula).
The COMT val158met polymorphism was associated with abstinence-related working memory deficits in two independent samples of smokers. However, inconsistencies compared to prior findings and across methods (ROI vs. whole-brain analysis) highlight the challenges inherent in reproducing results of imaging genetic studies in addiction.
PMCID: PMC3840089  PMID: 23828159
Smoking; nicotine; COMT; genetic; fMRI; cognition; working memory
12.  Applying Quantitative Approaches to the Formative Evaluation of Antismoking Campaign Messages 
Social marketing quarterly  2013;19(4):242-264.
This article shares an in-depth summary of a formative evaluation that used quantitative data to inform the development and selection of promotional ads for the antismoking communication component of a social marketing campaign. A foundational survey provided cross-sectional data to identify beliefs about quitting smoking that campaign messages should target, as well as beliefs to avoid. Pretesting draft ads against quantitative indicators of message effectiveness further facilitated the selection and rejection of final campaign ads. Finally, we consider lessons learned from the process of balancing quantitative methods and judgment to make formative decisions about more and less promising persuasive messages for campaigns.
PMCID: PMC4012855  PMID: 24817829
Tobacco Cessation; Monitoring and Evaluation; Formative Evaluation
13.  A Novel Recruitment Message to Increase Enrollment into a Smoking Cessation Treatment Program: Preliminary Results from a Randomized Triala 
Health communication  2011;26(8):735-742.
Most smokers do not utilize approved interventions for nicotine dependence, reducing the probability of cessation. Smoking cessation programs typically use recruitment messages emphasizing the health threats of smoking. Augmenting this threat message by describing the genetic aspects of nicotine addiction may enhance enrollment into a cessation program. During telephone recruitment, 125 treatment-seeking smokers were randomized to receive by phone either a standard threat message or a threat plus genetic prime message and were offered open-label varenicline and counseling. There was a greater rate of enrollment into the cessation program for the threat plus genetic prime participants (51.7%) vs. the threat-only participants (37.7%; p = .03). Smokers who self-identified from racial/ethnic minority groups were less likely to enroll in the cessation program (p = .01) vs. smokers who self-identified as Caucasian. These preliminary data suggest that a simple, affordable, and transportable communication approach enhances enrollment of smokers into a smoking cessation program. A larger clinical trial to evaluate a genetic prime message for improving recruitment into smoking cessation programs is warranted.
PMCID: PMC4243839  PMID: 21667366
14.  Neuroimaging in Psychiatric Pharmacogenetics Research: The Promise and Pitfalls 
Neuropsychopharmacology  2013;38(12):2327-2337.
The integration of research on neuroimaging and pharmacogenetics holds promise for improving treatment for neuropsychiatric conditions. Neuroimaging may provide a more sensitive early measure of treatment response in genetically defined patient groups, and could facilitate development of novel therapies based on an improved understanding of pathogenic mechanisms underlying pharmacogenetic associations. This review summarizes progress in efforts to incorporate neuroimaging into genetics and treatment research on major psychiatric disorders, such as schizophrenia, major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, and addiction. Methodological challenges include: performing genetic analyses in small study populations used in imaging studies; inclusion of patients with psychiatric comorbidities; and the extensive variability across studies in neuroimaging protocols, neurobehavioral task probes, and analytic strategies. Moreover, few studies use pharmacogenetic designs that permit testing of genotype × drug effects. As a result of these limitations, few findings have been fully replicated. Future studies that pre-screen participants for genetic variants selected a priori based on drug metabolism and targets have the greatest potential to advance the science and practice of psychiatric treatment.
PMCID: PMC3799069  PMID: 23793356
imaging; clinical or preclinical; neurogenetics; neuroimaging; neuropharmacology; pharmacogenetics/pharmacogenomics; psychiatry; treatment; neuroimaging; pharmacogenetics; psychiatry; treatment
Drug and alcohol dependence  2013;133(1):283-286.
Bupropion may aid tobacco abstinence by quickly relieving symptoms of nicotine withdrawal, perhaps including impaired cognitive performance. We examined whether bupropion would attenuate abstinence-induced cognitive deficits on the first day of a brief quit attempt, when smokers are most likely to relapse.
Smokers (N=24) with high quit interest were recruited for a within-subjects cross-over test of bupropion vs placebo on ability to abstain during separate short-term practice quit smoking attempts. After introduction to working memory (N-back) and sustained attention (continuous performance task; CPT) tasks during the pre-quit smoking baseline, performance on these tasks was assessed after abstaining overnight (CO<10 ppm) on the first day of each quit attempt, while on bupropion and on placebo.
Compared to placebo, bupropion after abstinence improved correct response times for working memory (p=.01 for medication by memory load interaction) and for one measure of sustained attention (numbers, but not letters; p<.05).
Bupropion may attenuate some features of impaired cognitive performance due to withdrawal on the first day of a quit attempt. Future studies could examine whether this effect of bupropion contributes to its efficacy for longer-term smoking cessation.
PMCID: PMC3786016  PMID: 23726977
cognition; working memory; attention; tobacco dependence; smoking cessation; bupropion
16.  No Untoward Effects of Smoking Cues in Anti-smoking Public Service Announcements* 
Drug and alcohol dependence  2013;133(1):279-282.
Anti-smoking public service announcements (PSAs) often include smoking-related cues; however, visual drug cues can trigger acute cravings that may impede cognitive processing of the anti-smoking message. This experiment evaluated effects of smoking cues in PSAs on smoking urges, immediate smoking behavior, and persuasion measures in daily smokers.
Three-hundred eighteen non-treatment seeking smokers completed a single laboratory session during which they viewed sets of PSAs differentiated by presence of smoking cues (central to the PSA’s argument, peripheral, or no cues) and argument strength (high versus low). After viewing the PSAs, participants completed self-report measures of smoking urges, attitudes toward quitting, self-efficacy, and intentions to quit smoking. Smoking behavior was recorded during a one-hour ad-libitum smoking period immediately following PSA viewing and assessment.
There was a significant positive effect of argument strength on attitudes toward quitting smoking (p = 0.012). There were no main effects of smoking cues or smoking cue by argument strength interactions on any of the outcome measures.
Visual smoking cues in PSAs do not increase urges to smoke, nor is there evidence that the inclusion of such cues impede the recall or persuasive effects of anti-smoking arguments.
PMCID: PMC3786034  PMID: 23742844
smoking; tobacco; public service announcements; smoking cues; health communication
Addiction (Abingdon, England)  2013;108(11):1962-1968.
Background and aim
It is important to find economical methods in early Phase 2 studies to screen drugs potentially useful to aid smoking cessation. A method has been developed that detects efficacy of varenicline and nicotine patch. This study aimed to evaluate whether the method would detect efficacy of bupropion and correctly identify lack of efficacy of modafinil.
Using a within-subject double crossover design, smokers attempted to quit during each treatment, with bupropion (150 mg b.i.d.), modafinil (100 mg b.i.d.), or placebo (double-blind, counter-balanced order). In each of three medication periods, all smoked with no drug on week 1 (baseline or washout), began dose run-up on week 2, and tried to quit every day during week 3.
A university research center in the United States.
Forty-five adult smokers high in quit interest.
Abstinence was verified daily each quit week by self-report of no smoking over the prior 24 hr and CO<5 ppm.
Compared with placebo, bupropion did (F(1,44)=6.98, p=.01), but modafinil did not (F(1,44)=.29, p=.60), increase the number of abstinent days. Also, bupropion (versus placebo) significantly increased the number of those able to maintain continuous abstinence on all 5 days throughout the quit week (11 vs 4), Z= 2.11, p <.05, while modafinil did not (6).
Assessing days abstinent during 1 week of use of medication versus placebo in a cross-over design could be a useful early Phase 2 study design for discriminating between medications useful vs not useful in aiding smoking cessation.
PMCID: PMC3797155  PMID: 23773319
18.  Large-Scale Brain Network Coupling Predicts Acute Nicotine Abstinence Effects on Craving and Cognitive Function 
JAMA psychiatry  2014;71(5):523-530.
Interactions of large-scale brain networks may underlie cognitive dysfunctions in psychiatric and addictive disorders.
To test the hypothesis that the strength of coupling among 3 large-scale brain networks–salience, executive control, and default mode–will reflect the state of nicotine withdrawal (vs smoking satiety) and will predict abstinence-induced craving and cognitive deficits and to develop a resource allocation index (RAI) that reflects the combined strength of interactions among the 3 large-scale networks.
A within-subject functional magnetic resonance imaging study in an academic medical center compared resting-state functional connectivity coherence strength after 24 hours of abstinence and after smoking satiety. We examined the relationship of abstinence-induced changes in the RAI with alterations in subjective, behavioral, and neural functions. We included 37 healthy smoking volunteers, aged 19 to 61 years, for analyses.
Twenty-four hours of abstinence vs smoking satiety.
Inter-network connectivity strength (primary) and the relationship with subjective, behavioral, and neural measures of nicotine withdrawal during abstinence vs smoking satiety states (secondary).
The RAI was significantly lower in the abstinent compared with the smoking satiety states (left RAI, P = .002; right RAI, P = .04), suggesting weaker inhibition between the default mode and salience networks. Weaker inter-network connectivity (reduced RAI) predicted abstinence-induced cravings to smoke (r = −0.59; P = .007) and less suppression of default mode activity during performance of a subsequent working memory task (ventromedial prefrontal cortex, r = −0.66, P = .003; posterior cingulate cortex, r = −0.65, P = .001).
Alterations in coupling of the salience and default mode networks and the inability to disengage from the default mode network may be critical in cognitive/affective alterations that underlie nicotine dependence.
PMCID: PMC4097018  PMID: 24622915
19.  The DRD4 Exon III VNTR, Bupropion, and Associations With Prospective Abstinence 
Nicotine & Tobacco Research  2012;15(7):1190-1200.
DRD4 Exon III Variable Number of Tandem Repeat (VNTR) variation was found to interact with bupropion to influence prospective smoking abstinence, in a recently published longitudinal analyses of N = 331 individuals from a randomized double-blind placebo-controlled trial of bupropion and intensive cognitive–behavioral mood management therapy.
We used univariate, multivariate, and longitudinal logistic regression to evaluate gene, treatment, time, and interaction effects on point prevalence and continuous abstinence at end of treatment, 6 months, and 12 months, respectively, in N = 416 European ancestry participants in a double-blind pharmacogenetic efficacy trial randomizing participants to active or placebo bupropion. Participants received 10 weeks of pharmacotherapy and 7 sessions of behavioral therapy, with a target quit date 2 weeks after initiating both therapies. VNTR genotypes were coded with the long allele dominant resulting in 4 analysis categories. Covariates included demographics, dependence measures, depressive symptoms, and genetic ancestry. We also performed genotype-stratified secondary analyses.
We observed significant effects of time in longitudinal analyses of both abstinence outcomes, of treatment in individuals with VNTR long allele genotypes for both abstinence outcomes, and of covariates in some analyses. We observed non-significantly larger differences in active versus placebo effect sizes in individuals with VNTR long allele genotypes than in individuals without the VNTR long allele, in the directions previously reported.
VNTR by treatment interaction differences between these and previous analyses may be attributable to insufficient size of the replication sample. Analyses of multiple randomized clinical trials will enable identification and validation of factors mediating treatment response.
PMCID: PMC3682839  PMID: 23212438
20.  APOE ε4, an Alzheimer’s disease susceptibility allele, and smoking cessation 
The pharmacogenomics journal  2012;13(6):10.1038/tpj.2012.49.
Possessing an APOE ε4 allele, advanced age, and smoking are risk factors for Alzheimer’s disease and cognitive decline. Deficits in cognitive function also increase risk for smoking relapse. Data from 917 adult smokers of European ancestry were pooled across three randomized trials of smoking cessation. We examined whether smokers who carry at least one ε4 allele (n=252) have more difficulty quitting smoking compared to noncarriers (n=665), and whether age moderated this association. The genotype by age interaction was significant for 7-day point-prevalence abstinence rates (p=0.04) and time to 7-day failure (p=0.03). Among smokers over age 60, ε4 carriers were less likely to quit (OR=0.27, p=0.018) and relapsed more quickly (HR=3.38, p=0.001) compared to noncarriers. The genotype association with relapse was non-significant among younger smokers. An increased understanding of the underlying pathophysiological mechanisms of this association could facilitate the development of targeted therapies for smokers with increased risk for cognitive decline.
PMCID: PMC3604077  PMID: 23247396
smoking; smoking cessation; relapse; nicotine; cognition; APOE
21.  Association of BDNF and COMT genotypes with cognitive processing of anti-smoking PSAs 
Genes, brain, and behavior  2011;10(8):862-867.
Anti-smoking public service announcements (PSAs) often use persuasive arguments to attempt to influence attitudes about smoking. The persuasiveness of a PSA has previously been associated with factors that influence the cognitive processing of its message. Genetic factors that influence cognitive processing might thus affect individuals' responses to the persuasive arguments presented in PSAs. In the current study, we examined polymorphisms in the genes encoding brain-derived neurotrophic factor (BDNF Val66Met) and catechol-O-methyltransferase (COMT Val158Met), which affect cognitive processing in the prefrontal cortex, to identify genetic factors associated with self-reported outcomes of message processing, perceived effectiveness, and quitting intentions among smokers viewing PSAs. 120 smokers viewed sets of 4 PSAs which varied with respect to features of argument strength and message sensation value. We observed significant associations of BDNF genotype with central processing, narrative processing, perceived effectiveness of the anti-smoking PSAs, and participant quitting intentions; the BDNF Met allele was associated with lower scores on all these measures. Central processing acted as a mediator of the association of genotype with quitting intentions and perceived effectiveness. There was a significant interaction of COMT genotype by argument strength in the model of narrative processing, such that individuals homozygous for the COMT Val allele reported higher narrative processing in the high argument strength condition, but not in the low argument strength condition. To our knowledge, this is the first study to identify genetic factors associated with cognitive processing of anti-smoking public service announcements.
PMCID: PMC4000094  PMID: 21883922
BDNF; COMT; genetics; cognitive processing; public service announcements
22.  The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race and sex 
Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine and carcinogen exposure. However a given cotinine level may not represent the same tobacco exposure; for example, African Americans have higher cotinine levels than Caucasians after controlling for exposure.
Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal which are both mediated by the enzyme CYP2A6. Since CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal were measured in non-smoking Caucasians (Study 1, n=181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n=163).
Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P=0.01), or 1.39 and 1.12 in males and females (P=0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by ≥25% in CYP2A6 reduced metabolizers (≈2 fold between some genotypes) and in males.
In people with slower, relative to faster, CYP2A6 activity cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure.
Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e. African Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels) or between the sexes.
PMCID: PMC3617060  PMID: 23371292
Tobacco; Cotinine; CYP2A6; Polycyclic aromatic hydrocarbons; NNAL
23.  Effects of Smoking Cues and Argument Strength of Antismoking Advertisements on Former Smokers’ Self-efficacy, Attitude, and Intention to Refrain From Smoking 
Nicotine & Tobacco Research  2012;15(2):527-533.
This study examines the impact of smoking cues employed in antismoking advertisements on former smokers. Previous findings indicate that visual smoking cues in antismoking advertisements with weak antismoking arguments can elicit smoking urges in smokers and undermine message effectiveness. This study extends these observations to former smokers asking whether smoking cues in antismoking advertisements influence former smokers’ self-efficacy, attitudes, and intention to refrain from smoking, along with smoking urges and perceived message effectiveness.
The study was a mixed 2 (smoking cues; present vs. absent) × 2 (argument strength [AS]; high vs. low) design where smoking cue was a between-subject factor and AS was a within-subject factor. Potential participants recruited via online ads were screened in a phone interview for their eligibility. A total of 105 former smokers (aged 21–65) participated in the study, which was conducted in a laboratory setting. Repeated measure ANOVA and MANOVA were used for the analyses.
The results showed that the presence of smoking cues in antismoking ads undermines former smokers’ behavioral self-efficacy, attitude, and intention about smoking abstinence, which increased as AS for the ads increased. Former smokers’ reports of smoking urge were not affected by smoking cues or AS. However, consistent with previous findings for smokers, the presence of cues weakened perceived message effectiveness of antismoking ads rated by former smokers.
The effect of smoking cues on former smokers’ self-efficacy, attitude, and intention to refrain from smoking is problematic. Inclusion of smoking cues in antismoking ads should be undertaken only when accompanied by strong arguments.
PMCID: PMC3545718  PMID: 22949578
24.  Nicotinic Acetylcholine Receptor Variation and Response to Smoking Cessation Therapies 
Pharmacogenetics and genomics  2013;23(2):94-103.
Evaluate nicotinic acetycholine receptor (nAChR) single nucleotide polymorphism (SNP) association with seven day point prevalence abstinence (abstinence) in randomized clinical trials of smoking cessation therapies (RCTs) in individuals grouped by pharmacotherapy randomization to inform the development of personalized smoking cessation therapy.
We quantified association of four SNPs at three nAChRs with abstinence in eight RCTs. Participants were 2,633 outpatient treatment-seeking, self-identified European ancestry individuals smoking ≥10 cigarettes per day, recruited via advertisement, prescribed pharmacotherapy, and provided with behavioral therapy. Interventions included nicotine replacement therapy (NRT), bupropion, varenicline, placebo or combined NRT and bupropion, and five modes of group and individual behavioral therapy. Outcome measures tested in multivariate logistic regression were end of treatment (EOT) and six month (6MO) abstinence, with demographic, behavioral and genetic covariates.
“Risk” alleles previously associated with smoking heaviness were significantly (P<0.05) associated with reduced abstinence in the placebo pharmacotherapy group (PG) at 6MO [for rs588765 OR (95%CI) 0.41 (0.17–0.99)], and at EOT and at 6MO [for rs1051730, 0.42 (0.19–0.93) and 0.31 (0.12–0.80)], and with increased abstinence in the NRT PG at 6MO [for rs588765 2.07 (1.11–3.87) and for rs1051730 2.54 (1.29–4.99)]. We observed significant heterogeneity in rs1051730 effects (F=2.48, P=0.021) between PGs.
chr15q25.1 nAChR SNP risk alleles for smoking heaviness significantly increase relapse with placebo treatment and significantly increase abstinence with NRT. These SNP-PG associations require replication in independent samples for validation, and testing in larger sample sizes to evaluate whether similar effects occur in other PGs.
PMCID: PMC3563676  PMID: 23249876
logistic regression; mediation analysis; nAChR variation; nicotine dependence; pharmacotherapy; randomized clinical trials
25.  Pharmacogenetics of smoking cessation: role of nicotine target and metabolism genes 
Human genetics  2012;10.1007/s00439-012-1143-9.
Many smokers attempt to quit smoking but few are successful in the long term. The heritability of nicotine addiction and smoking relapse have been documented, and research is focused on identifying specific genetic influences on the ability to quit smoking and response to specific medications. Research in genetically modified cell lines and mice has identified nicotine acetylcholine receptor subtypes that mediate the pharmacological and behavioral effects of nicotine sensitivity and withdrawal. Human genetic association studies have identified single nucleotide polymorphisms (SNPs) in genes encoding nicotine acetylcholine receptor subunits and nicotine metabolizing enzymes that influence smoking cessation phenotypes. There is initial promising evidence for a role in smoking cessation for SNPs in the β2 and α5/α3/β4 nAChR subunit genes; however, effects are small and not consistently replicated. There are reproducible and clinically significant associations of genotypic and phenotypic measures of CYP2A6 enzyme activity and nicotine metabolic rate with smoking cessation as well as response to nicotine replacement therapies and bupropion. Prospective clinical trials to identify associations of genetic variants and gene–gene interactions on smoking cessation are needed to generate the evidence base for both medication development and targeted therapy approaches based on genotype.
PMCID: PMC3864572  PMID: 22290489

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