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1.  Pharmacogenetic Smoking Cessation Intervention in a Health Care Setting: A Pilot Feasibility Study 
Nicotine & Tobacco Research  2012;15(2):518-526.
Introduction:
There is increasing evidence that response to pharmacological treatment for nicotine dependence may be moderated by genetic polymorphisms. However, the feasibility, acceptability, and impact of genetically tailoring treatment in real-world clinical settings are unknown.
Methods:
We conducted a multiphased, mixed-methods feasibility study with current smokers to develop and evaluate a patient-centered, theoretically grounded personalized medicine treatment protocol. The initial research phase included formative work to develop intervention materials. The second phase included a randomized pilot trial to evaluate the intervention. Trial participants (n = 36) were genotyped for ANKK1 rs1800497 and were randomized to receive genetic feedback (GF) plus standard behavioral counseling (BC) for smoking cessation or BC without GF. All participants received genetically tailored pharmacotherapy (nicotine patch or bupropion).
Results:
The intervention was feasible to implement and was acceptable to participants based on satisfaction ratings and objective measures of participation. There was no evidence that the GF resulted in adverse psychological outcomes (e.g., depression, fatalism, reduced perceived control over quitting, differential motivation for quitting) based on quantitative or qualitative outcomes.
Conclusions:
Study results suggest that it is feasible to offer treatment within a health care setting that includes genetically tailored pharmacotherapy and doing so had no apparent adverse psychological impacts. Further evaluation of pharmacogenetically tailored smoking cessation interventions appears warranted.
doi:10.1093/ntr/nts173
PMCID: PMC3611995  PMID: 22949583
2.  A recall-by-genotype study of CHRNA5-A3-B4 genotype, cotinine and smoking topography: study protocol 
BMC Medical Genetics  2014;15:13.
Background
Genome-wide association studies have revealed an association between several loci in the nicotinic acetylcholine receptor gene cluster CHRNA5-A3-B4 and daily cigarette consumption. Recent studies have sought to refine this phenotype, and have shown that a locus within this cluster, marked primarily by rs1051730 and rs16969968, is also associated with levels of cotinine, the primary metabolite of nicotine. This association remains after adjustment for self-reported smoking, which suggests that even amongst people who smoke the same number of cigarettes there is still genetically-influenced variation in nicotine consumption. This is likely to be due to differences in smoking topography, that is, how a cigarette is smoked (e.g., volume of smoke inhaled per puff, number of puffs taken per cigarette). The aim of this study is to determine potential mediation of the relationship between the rs1051730 locus and cotinine levels by smoking topography.
Methods/Design
Adopting a recall-by-genotype design, we will recruit 200 adults from the Avon Longitudinal Study of Parents and Children on the basis of minor or major homozygote status at rs1051730 (100 in each genotype group). All participants will be current, daily smokers. Our primary study outcome measures will be measures of smoking topography: total volume of smoke (ml) inhaled per cigarette, total volume of smoke (ml) inhaled over of the course of one day, and salivary cotinine level (ng/ml).
Discussion
This study will extend our understanding of the biological basis of inter-individual variability in heaviness of smoking, and therefore in exposure to smoking-related toxins. The novel recall-by-genotype approach we will use is efficient, maximising statistical power, and enables the collection of extremely precise phenotypic data that are impractical to collect in a larger sample. The methods described within this protocol also hold the potential for wider application in the field of molecular genetics.
doi:10.1186/1471-2350-15-13
PMCID: PMC3900674  PMID: 24451018
Smoking; Cotinine; Genetics; CHRNA3; CHRNA5; Smoking topography
3.  Attentional bias retraining in cigarette smokers attempting smoking cessation (ARTS): Study protocol for a double blind randomised controlled trial 
BMC Public Health  2013;13:1176.
Background
Smokers attend preferentially to cigarettes and other smoking-related cues in the environment, in what is known as an attentional bias. There is evidence that attentional bias may contribute to craving and failure to stop smoking. Attentional retraining procedures have been used in laboratory studies to train smokers to reduce attentional bias, although these procedures have not been applied in smoking cessation programmes. This trial will examine the efficacy of multiple sessions of attentional retraining on attentional bias, craving, and abstinence in smokers attempting cessation.
Methods/Design
This is a double-blind randomised controlled trial. Adult smokers attending a 7-session weekly stop smoking clinic will be randomised to either a modified visual probe task with attentional retraining or placebo training. Training will start 1 week prior to quit day and be given weekly for 5 sessions. Both groups will receive 21 mg transdermal nicotine patches for 8–12 weeks and withdrawal-orientated behavioural support for 7 sessions. Primary outcome measures are the change in attentional bias reaction time and urge to smoke on the Mood and Physical Symptoms Scale at 4 weeks post-quit. Secondary outcome measures include differences in withdrawal, time to first lapse and prolonged abstinence at 4 weeks post-quit, which will be biochemically validated at each clinic visit. Follow-up will take place at 8 weeks, 3 months and 6 months post-quit.
Discussion
This is the first randomised controlled trial of attentional retraining in smokers attempting cessation. This trial could provide proof of principle for a treatment aimed at a fundamental cause of addiction.
Trial registration
Current Controlled Trials: ISRCTN54375405.
doi:10.1186/1471-2458-13-1176
PMCID: PMC3890623  PMID: 24330656
4.  Systematic review and meta-analysis of serotonin transporter genotype and discontinuation from antidepressant treatment 
European Neuropsychopharmacology  2013;23(10):1143-1150.
There is evidence that 5-HTTLPR is associated with response following treatment from selective serotonin reuptake inhibitors (SSRIs). The short (S) allele has reduced serotonin transporter expression, compared to the long (L) allele, and has been reported to be associated with poorer response in Europeans, with the effect in other populations unclear. However the published literature is inconsistent. A systematic review and meta-analysis was performed to investigate the effect of 5-HTTLPR on discontinuation from antidepressant treatment. Data were obtained from 17 studies including 4309 participants. The principal outcome measure was the allelic odds ratio (OR) for the 5-HTTLPR S allele and discontinuation status. A random effects meta-analysis provided no evidence that the S allele was associated with increased odds of discontinuation from SSRIs in Europeans (OR 1.09, 95% CI 0.83–1.42, p=0.53; 10 studies, n=2504) but in East Asians there was evidence of a reduced odds of discontinuation (OR 0.28, 95% CI 0.12–0.64, p=0.002; 2 studies, n=136). There was a suggestion of small study bias (p=0.05). This meta-analysis provides no evidence of an association between 5-HTTLPR and discontinuation from antidepressant treatment in Europeans. The low number of studies in East Asian samples using SSRIs reduces confidence in our evidence that the S allele decreases the odds of discontinuation in this population. At present, there is no evidence of an association between 5-HTTLPR and discontinuation from SSRI treatment in a European population with further studies required to investigate its effects in different populations.
doi:10.1016/j.euroneuro.2012.12.001
PMCID: PMC3791403  PMID: 23265954
5-HTTLPR; Antidepressant; SSRI; Meta-analysis; Discontinuation
5.  Weekly versus basic smoking cessation support in primary care: a randomised controlled trial 
Thorax  2007;62(10):898-903.
Background
There is insufficient and conflicting evidence about whether more intensive behavioural support is more effective than basic behavioural support for smoking cessation and whether primary care nurses can deliver effective behavioural support.
Methods
A randomised controlled trial was performed in 26 UK general practices. 925 smokers of ⩾10 cigarettes per day were randomly allocated to basic or weekly support. All participants were seen before quitting, telephoned around quit day, and seen 1 and 4 weeks after the initial appointment (basic support). Participants receiving weekly support had an additional telephone call at 10 days and 3 weeks after the initial appointment and an additional visit at 2 weeks to motivate adherence to nicotine replacement and renew quit attempts. 15 mg/16 h nicotine patches were given to all participants. The outcome was assessed by intention to treat analyses of the percentage confirmed sustained abstinence at 4, 12, 26 and 52 weeks after quit day.
Results
Of the 469 and 456 participants in the basic and weekly arms, the numbers (%) who quit and the percentage difference were 105 (22.4%) vs 102 (22.4%), 0.1% (95% CI −5.3% to 5.5%) at 4 weeks, 66 (14.1%) vs 52 (11.4%), −2.6% (95% CI −6.9% to 1.7%) at 12 weeks, 50 (10.7%) vs 40 (8.8%), −1.9% (95% CI −5.7% to 2.0%) at 26 weeks and 36 (7.7%) vs 30 (6.6%), −1.1% (95% CI −4.4% to 2.3%) at 52 weeks.
Conclusions
The absolute quit rates achieved are those expected from nicotine replacement alone, implying that neither basic nor weekly support were effective. Primary care smoking cessation treatment should provide pharmacotherapy with sufficient support only to ensure it is used appropriately, and those in need of support should be referred to specialists.
doi:10.1136/thx.2006.071837
PMCID: PMC2094265  PMID: 17483139
6.  Amphetamine as a social drug: Effects of d-amphetamine on social processing and behavior 
Psychopharmacology  2012;223(2):199-210.
Rationale
Drug users often report using drugs to enhance social situations, and empirical studies support the idea that drugs increase both social behavior and the value of social interactions. One way drugs may affect social behavior is by altering social processing, for example by decreasing perceptions of negative emotion in others.
Objectives
We examined effects of d-amphetamine on processing of emotional facial expressions, and on the social behavior of talking. We predicted amphetamine would enhance attention, identification and responsivity to positive expressions, and that this in turn would predict increased talkativeness.
Methods
Over three sessions, 36 healthy normal adults received placebo, 10mg, and 20mg d-amphetamine under counterbalanced double-blind conditions. At each session we measured processing of happy, fearful, sad and angry expressions using an attentional visual probe task, a dynamic emotion identification task, and measures of facial muscle activity. We also measured talking.
Results
Amphetamine decreased the threshold for identifying all emotions, increased negative facial responses to sad expressions, and increased talkativeness. Contrary to our hypotheses, amphetamine did not alter attention to, identification of or facial responses to positive emotions specifically. Interestingly, the drug decreased the threshold to identify all emotions, and this effect was uniquely related to increased talkativeness, even after controlling for overall sensitivity to amphetamine.
Conclusions
The results suggest that amphetamine may encourage sociability by increasing sensitivity to subtle emotional expressions. These findings suggest novel social mechanisms that may contribute to the rewarding effects of amphetamine.
doi:10.1007/s00213-012-2708-y
PMCID: PMC3422595  PMID: 22526538
amphetamine; emotional faces; attentional bias; social interaction; psychophysiology
7.  The endophenotype concept in psychiatric genetics 
Psychological Medicine  2006;37(2):163-180.
The idea that some phenotypes bear a closer relationship to the biological processes that give rise to psychiatric illness than diagnostic categories has attracted considerable interest. Much effort has been devoted to finding such endophenotypes, partly because it is believed that the genetic basis of endophenotypes will be easier to analyse than that of psychiatric disease. This belief depends in part on the assumption that the effect sizes of genetic loci contributing to endophenotypes are larger than those contributing to disease susceptibility, hence increasing the chance that genetic linkage and association tests will detect them. We examine this assumption by applying meta-analytical techniques to genetic association studies of endophenotypes. We find that the genetic effect sizes of the loci examined to date are no larger than those reported for other phenotypes. A review of the genetic architecture of traits in model organisms also provides no support for the view that the effect sizes of loci contributing to phenotypes closer to the biological basis of disease is any larger than those contributing to disease itself. While endophenotype measures may afford greater reliability, it should not be assumed that they will also demonstrate simpler genetic architecture.
doi:10.1017/S0033291706008750
PMCID: PMC2829981  PMID: 16978446
8.  Association of the DRD2 gene Taq1A polymorphism and smoking behavior: A meta-analysis and new data 
Nicotine & Tobacco Research  2009;11(1):64-76.
Introduction:
Many studies have investigated the association of the dopamine type-2 receptor (DRD2) Taq1A polymorphism with tobacco use and cigarette smoking behaviors, but findings remain equivocal. There is a biological basis for considering that this association differs by sex, and differences in subpopulations might explain some of the contradictory evidence.
Methods:
Our a priori hypothesis was that the association of the DRD2 Taq1A polymorphism with smoking behavior would be more prominent in females than males. We therefore investigated the strength of evidence for an association between the DRD2 Taq1A polymorphism and smoking behavior in a large sample of females and used meta-analytic techniques to synthesize existing published data and explore the role of sex in explaining any heterogeneity between studies.
Results:
We did not observe any strong evidence of association between the DRD2 Taq1A polymorphism and smoking behavior, including smoking initiation, smoking persistence, and smoking rate, either in our female sample or in our meta-analysis of 29 studies, comprising 28 published studies and the data from the present study. Metaregression suggested an association between the proportion of male participants in a study and the individual study effect size, indicating a larger effect size with a greater proportion of male participants for smoking initiation and smoking persistence. This effect did not appear to be due to the inclusion of the data from the present study.
Discussion:
Available evidence does not support an association between the DRD2 Taq1A polymorphism and smoking behavior. Contrary to our a priori hypothesis, we found evidence of a stronger association in males than in females.
doi:10.1093/ntr/ntn012
PMCID: PMC3203402  PMID: 19246443
9.  A Translational Rodent Assay of Affective Biases in Depression and Antidepressant Therapy 
Neuropsychopharmacology  2013;38(9):1625-1635.
The subjective measures used to study mood disorders in humans cannot be replicated in animals; however, the increasing application of objective neuropsychological methods provides opportunities to develop translational animal tasks. Here we describe a novel behavioral approach, which has enabled us to investigate similar affective biases in rodents. In our affective bias test (ABT), rats encounter two independent positive experiences—the association between food reward and specific digging substrate—during discrimination learning sessions. These are performed on separate days under either neutral conditions or during a pharmacological or affective state manipulation. Affective bias is then quantified using a preference test where both previously rewarded substrates are presented together and the rat's choices recorded. The absolute value of the experience is kept consistent and all other factors are counterbalanced so that any bias at recall can be attributed to treatment. Replicating previous findings from studies in healthy volunteers, we observe significant positive affective biases following acute treatment with typical (fluoxetine, citalopram, reboxetine, venlafaxine, clomipramine) and atypical antidepressants (agomelatine, mirtazapine), and significant negative affective biases following treatment with drugs associated with inducing negative affective states in humans (FG7142, rimonabant, 13-cis retinoic acid). We also observed that acute psychosocial stress and environmental enrichment induce significant negative and positive affective biases, respectively, and provide evidence that these affective biases involve memory consolidation. The positive and negative affective biases induced in our test also mirror the antidepressant and pro-depressant effects of these drugs in patients suggesting our test has both translational and predictive validity. Our results suggest that cognitive affective biases could contribute to drug- or stress-induced mood changes in people and support the hypothesis that a cognitive neuropsychological mechanism contributes to antidepressant drug efficacy.
doi:10.1038/npp.2013.69
PMCID: PMC3717539  PMID: 23503126
affective bias; animal models; antidepressant; behavioral Science; mood/anxiety/stress disorders; pro-depressant; psychopharmacology; translational; depression; antidepressant; pro-depressant; affective bias; animal model
10.  Credible genetic associations? 
The proliferation in genetic association studies, and the recurring failure of initially promising findings to robustly replicate, demonstrates the need for stringent standards to ensure the identification of credible associations. The Human Genome Epidemiology Network has recently published intermin guideliness on evidential criteria for genetic association studies. These are reviewed, and their value and importance discussed, as well as the impact these guidelines will have on the conduct of genetic association studies.
PMCID: PMC3076746  PMID: 21537450
Genetic association; replication; HuGENet; Meta-Analysis
11.  Serotonin Transporter (5-HTTLPR) Genotype and Amygdala Activation: A Meta-Analysis 
Biological psychiatry  2007;63(9):852-857.
Background:
We evaluated the magnitude of the reported associations between amygdala activation and the serotonin transporter gene linked polymorphic region (5-HTTLPR) and the likely effect size of this relationship.
Methods:
We used meta-analytic techniques to combine data from existing published and unpublished studies. We also tested for possible publication bias and explored possible moderating influences on any association, such as sample ancestry.
Results:
Our results provide support for the association of the 5-HTTLPR polymorphism and amygdala activation and suggest that this locus may account for up to 10% of phenotypic variance. Although we did not observe evidence for potential publication bias in our main analysis, this was due in part to efforts to obtain unpublished data pertinent to this meta-analysis, and when three unpublished data sets were excluded we did observe evidence of such bias. We also observed evidence that the first published study may provide an overestimate of the true effect size, which is consistent with findings from genetic association studies of other phenotypes.
Conclusions:
Although our analysis provides support for the association of the 5-HTTLPR polymorphism and amygdala activation, it also suggests that most studies to date are nevertheless lacking in statistical power. Increasing the sample sizes of future imaging genetics studies will allow a more accurate characterization of any true effect size and afford adequate power to examine the impact of multiple polymorphisms that likely work in concert to affect gene function and, in turn, bias neural processes mediating dispositional traits such as temperament and personality.
doi:10.1016/j.biopsych.2007.08.016
PMCID: PMC2755289  PMID: 17949693
5-HTTLPR; amygdala; fMRI; meta-analysis; serotonin transporter gene
12.  Association of Maternal Smoking With Child Cotinine Levels 
Nicotine & Tobacco Research  2013;15(12):2029-2036.
Introduction:
Our aim was to understand the strength of association between parental smoking and child environmental tobacco smoke (ETS) exposure in order to inform the development of future tobacco control policies. ETS was measured using child cotinine levels below the active smoking threshold.
Methods:
Participants were drawn from the Avon Longitudinal Study of Parents and Children and included 3,128 participants at age 7 years and 1,868 participants at age 15 years. The primary outcome was cotinine levels of nonsmoking children, to investigate the relationship between maternal smoking and child cotinine levels. The secondary outcome was cotinine levels of all individuals to investigate the relationship between child smoking and child cotinine levels. Maternal and child smoking behavior was assessed by self-report questionnaire. We adjusted for several sociodemographic variables.
Results:
We found an association between maternal smoking and child cotinine at age 7 years (mean cotinine = 1.16ng/ml serum, ratio of geometric means = 3.94, 95% CI = 2.86–5.42) and at age 15 years (mean cotinine = 0.94ng/ml serum, ratio of geometric means = 5.26, 95% CI = 3.06–9.03), after adjustment for potential confounders.
Conclusions:
The magnitude of this association for children whose mothers were heavy smokers was comparable with the quantity of half the levels of cotinine observed among children who were irregular (i.e., nonweekly) active smokers, and it was greater than five times higher than that seen in nonsmoking children whose mothers didn’t smoke. This provides further evidence for the importance of public health interventions to reduce smoking exposure in the home.
doi:10.1093/ntr/ntt094
PMCID: PMC3819976  PMID: 23880896
13.  A cost-effectiveness analysis of genetic testing of the DRD2 Taq1A polymorphism to aid treatment choice for smoking cessation 
We conducted a cost-effectiveness analysis of genetic testing for smoking cessation, based on data available from the published pharmacogenetic studies of nicotine replacement therapy and bupropion, and a previous cost-effectiveness analysis of smoking cessation treatments. We use multiparameter evidence synthesis methods to combine evidence on cessation by genotype with evidence on cessation irrespective of genotype (which can be written as a function of genotype-specific parameters). Our intention was to explore the most cost-effective approach to prescribing smoking cessation pharmacotherapy, given the hypothetical availability of a test based on a single-gene variant that has been reported to predict treatment response. We considered four types of treatment: nicotine replacement therapy (NRT) pharmacotherapy, bupropion SR pharmacotherapy, combination NRT and bupropion, and standard care as the control. Two scenarios were investigated, one in which the control represented brief advice and the other in which the control represented individual counseling. Strategies that either do not test for dopamine D2 receptor (DRD2) genotype (each individual receives the same treatment), or do test for DRD2 genotype (treatment allocated according to genotype), were evaluated. Our results indicated that the most cost-effective strategy in our hypothetical example of a single-gene test to aid prescription of smoking cessation pharmacotherapy is to prescribe both NRT and bupropion regardless of genotype, as a first-line treatment for smoking cessation. We conclude that it should not be assumed that genetic tailoring will necessarily be more cost-effective than applying the current “one-size-fits-all” model of pharmacotherapy for smoking cessation. In addition, single-gene tests are unlikely to be cost-effective, partly because the predictive value of these tests is likely to be modest.
doi:10.1080/14622200701767761
PMCID: PMC2257987  PMID: 18188764
14.  Lack of Association Between COMT and Working Memory in a Population-Based Cohort of Healthy Young Adults 
Neuropsychopharmacology  2013;38(7):1253-1263.
The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is an important regulator of dopamine in the prefrontal cortex, an area critical to working memory. Working memory deficits are present in several psychiatric disorders, and there is wide variation in working memory capacity in the normal population. Association studies of COMT and working memory in healthy volunteers have yielded inconsistent results, possibly because of small sample sizes. Here we examine COMT in relation to N-Back working memory task performance in a large population-based cohort of young adults. We predicted individuals with one or two copies of the Met allele would perform better, and that this relationship would be more evident in males than females. Participants (N=1857–2659) tested at 18 years of age, were enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). We used multiple regression to examine effects of sex and COMT genotype on N-Back hits, false positives, discriminability (d'), and reaction time while controlling for important covariates. COMT genotype did not predict hits or d'. There was a nominally significant interaction between COMT and sex on false positives, but this was not in the predicted direction, and was not significant after controlling for covariates. COMT genotype was not related to working memory in this large population-based cohort. It is possible COMT is not meaningfully associated with working memory in healthy young adults, or that COMT effects are detectable only in assessments reflecting neural processes underlying cognition, such as fMRI, rather than in behavioral performance.
doi:10.1038/npp.2013.24
PMCID: PMC3656369  PMID: 23337869
dopamine; cognition; learning & memory; neurogenetics; COMT genotype; executive functioning; ALSPAC; COMT genotype; executive functioning; working memory; genetics; ALSPAC
15.  Effects of emotion recognition training on mood among individuals with high levels of depressive symptoms: study protocol for a randomised controlled trial 
Trials  2013;14:161.
Background
We have developed a new paradigm that targets the recognition of facial expression of emotions. Here we report the protocol of a randomised controlled trial of the effects of emotion recognition training on mood in a sample of individuals with depressive symptoms over a 6-week follow-up period.
Methods/Design
We will recruit 190 adults from the general population who report high levels of depressive symptoms (defined as a score ≥ 14 on the Beck Depression Inventory-II). Participants will attend a screening session and will be randomised to intervention or control procedures, repeated five times over consecutive days (Monday to Friday). A follow-up session will take place at end-of -treatment, 2-weeks and 6-weeks after training. Our primary study outcome will be depressive symptoms, Beck Depression Inventory- II (rated over the past two weeks). Our secondary outcomes are: depressive symptoms, Hamilton Rating Scale for Depression; anxiety symptoms, Beck Anxiety Inventory (rated over the past month); positive affect, Positive and Negative Affect Schedule (rated as ‘how you feel right now’); negative affect, Positive and Negative Affect Schedule (rated as ‘how you feel right now’); emotion sensitivity, Emotion Recognition Task (test phase); approach motivation and persistence, the Fishing Game; and depressive interpretation bias, Scrambled Sentences Test.
Discussion
This study is of a novel cognitive bias modification technique that targets biases in emotional processing characteristic of depression, and can be delivered automatically via computer, Internet or Smartphone. It therefore has potential to be a valuable cost-effective adjunctive treatment for depression which may be used together with more traditional psychotherapy, cognitive-behavioural therapy and pharmacotherapy.
Trial registration
Current Controlled Trials: ISRCTN17767674
doi:10.1186/1745-6215-14-161
PMCID: PMC3686600  PMID: 23725208
Emotion recognition training; Mood; Depression
16.  Candidate and non-candidate genes in behavior genetics 
Highlights
► Common variants of small effect contribute to psychiatric disease. ► Rare de novo mutations occur in the exons of patients with schizophrenia and autism. ► Effect sizes of loci influencing brain size are comparable to those of other phenotypes. ► The literature of imaging genetic studies contains many false positives. ► Studies on gene by environment interaction are mostly underpowered.
In this review we discuss recent developments in psychiatric genetics: on the one hand, studies using whole genome approaches (genome-wide association studies (GWAS) and exome sequencing) are coming close to finding genes and molecular variants that contribute to disease susceptibility; on the other candidate genes, such as the serotonin transporter, continue to dominate in genetic studies of brain imaging phenotypes and in protracted searches for gene by environment interactions. These two areas intersect, in that new information about genetic effects from whole genome approaches, should (but does not always) inform the single locus analyses.
doi:10.1016/j.conb.2012.07.005
PMCID: PMC3752971  PMID: 22878161
17.  Characterizing Patterns of Smoking Initiation in Adolescence: Comparison of Methods for Dealing With Missing Data 
Nicotine & Tobacco Research  2011;13(12):1266-1275.
Introduction:
Tobacco use is common and remains one of the leading causes of preventable death in developed countries. Smoking commonly begins in adolescence, and hence, it is important to understand how smoking behavior develops during this period.
Methods:
In a U.K.-based birth cohort, we analyzed repeated measures of smoking frequency in a sample of 7,322 young adolescents. Latent class analysis was used to summarize the data, and the resulting classes of behavior were related to a range of smoking risk factors. Results from a complete case analysis were compared with estimation using full-information maximum likelihood (FIML) and estimation using multiple imputation (MI).
Results:
Fifty-three percent of the sample reported having smoked a whole cigarette by age 16 years. The longitudinal data were summarized by 4 distinct patterns of smoking initiation: nonsmokers (79.7%), experimenters (10.3%), late-onset regular smokers (5.5%), and early-onset regular smokers (4.5%). Social disadvantage, other substance use, conduct problems, and female sex were strongly related to being a regular smoker; however, no risk factors studied showed any strong or consistent association with experimentation. In the complete case sample, smoking prevalence was lower, and in addition, the association between different smoking patterns and covariates was often inconsistent with those obtained through FIML/MI.
Conclusions:
Most young people have experimented with tobacco smoking by age 16 years, and regular smoking is established in a substantial minority characterized by social disadvantage, other substance, use and conduct disorder. Prevention strategies should focus on this subgroup as most children who experiment with tobacco do not progress to regular smoking.
doi:10.1093/ntr/ntr161
PMCID: PMC3223580  PMID: 21994336
18.  Effect of social stress during acute nicotine abstinence 
Psychopharmacology  2011;218(1):39-48.
Rationale
Relapse to smoking is often precipitated by stress, yet little is known about the effects of nicotine withdrawal on responses to acute stress, or whether nicotine replacement reverses withdrawal-induced changes in stress response.
Objectives
The aim of the present study is to use an effective social stressor, the Trier Social Stress Test (TSST), to study subjective, cardiovascular and hormonal responses to stress during withdrawal, and examine whether nicotine replacement moderates responses to stress during withdrawal.
Methods
Forty-nine current regular smokers were randomly assigned to smoke as normal (SM), 12-h abstention with placebo patch (PL), or 12-h abstention with nicotine patch (NIC). They participated in a single session using the TSST, during which subjective affect, heart rate (HR), mean arterial blood pressure (MAP) and salivary cortisol were measured.
Results
The TSST produced expected increases in subjective negative affect, HR, MAP, and cortisol. Groups did not differ in subjective or cardiovascular responses, but the PL group exhibited larger stress-induced increase in cortisol than the other groups.
Conclusions
The increased cortisol response might indicate a greater hormonal stress response during nicotine withdrawal. Alternatively, considering that cortisol also provides negative feedback to the stress system, and blunted cortisol responses are predictive of smoking relapse, the lower cortisol responses in the NIC and SM groups might indicate chronic dysregulation of the stress system. In this case, restoration of cortisol response by nicotine treatment to the lower levels seen during regular smoking may actually represent an undesired side effect of nicotine replacement.
doi:10.1007/s00213-010-2150-y
PMCID: PMC3094594  PMID: 21234550
Nicotine withdrawal; Stress; Nicotine replacement; Cortisol
19.  CHRNA3 rs1051730 Genotype and Short-Term Smoking Cessation 
Nicotine & Tobacco Research  2011;13(10):982-988.
Introduction:
The rs1051730 genetic variant within the CHRNA5-A3-B4 gene cluster is associated with heaviness of smoking and has recently been reported to be associated with likelihood of stopping smoking. We investigated the potential association of rs1051730 genotype with reduced likelihood of smoking cessation in 2 cohorts of treatment-seeking smokers in primary care in the United Kingdom.
Methods:
Data were drawn from 2 clinical trials on which DNA was available. One sample was a randomized placebo-controlled trial of nicotine transdermal patch and the other sample an open-label trial where all participants received nicotine transdermal patch. Smoking status was biochemically verified. Logistic regression was used to assess evidence for association in each sample, and data were combined within a meta-analysis.
Results:
There was evidence of association of rs1051730 genotype with short-term (4-week) cessation in our open-label trial sample but not our placebo-controlled trial sample. When combined in a meta-analysis, this effect remained. There was no evidence of association at later follow-up intervals. Adjustment for cigarette consumption and tobacco dependence did not alter these results substantially.
Conclusions:
Our data, taken together with previous recent studies, provide some support for a weak association between this variant and short-term smoking cessation in treatment-seeking smokers, which does not seem to operate only among those receiving nicotine replacement therapy. Moreover, the rs1051730 variant may not merely operate as a marker for dependence or heaviness of smoking.
doi:10.1093/ntr/ntr106
PMCID: PMC3179672  PMID: 21690317
20.  Glass Shape Influences Consumption Rate for Alcoholic Beverages 
PLoS ONE  2012;7(8):e43007.
Background
High levels of alcohol consumption and increases in heavy episodic drinking (binge drinking) are a growing public concern, due to their association with increased risk of personal and societal harm. Alcohol consumption has been shown to be sensitive to factors such as price and availability. The aim of this study was to explore the influence of glass shape on the rate of consumption of alcoholic and non-alcoholic beverages.
Methods
This was an experimental design with beverage (lager, soft drink), glass (straight, curved) and quantity (6 fl oz, 12 fl oz) as between-subjects factors. Social male and female alcohol consumers (n = 159) attended two experimental sessions, and were randomised to drink either lager or a soft drink from either a curved or straight-sided glass, and complete a computerised task identifying perceived midpoint of the two glasses (order counterbalanced). Ethical approval was granted by the Faculty of Science Research Ethics Committee at the University of Bristol. The primary outcome measures were total drinking time of an alcoholic or non-alcoholic beverage, and perceptual judgement of the half-way point of a straight and curved glass.
Results
Participants were 60% slower to consume an alcoholic beverage from a straight glass compared to a curved glass. This effect was only observed for a full glass and not a half-full glass, and was not observed for a non-alcoholic beverage. Participants also misjudged the half-way point of a curved glass to a greater degree than that of a straight glass, and there was a trend towards a positive association between the degree of error and total drinking time.
Conclusions
Glass shape appears to influence the rate of drinking of alcoholic beverages. This may represent a modifiable target for public health interventions.
doi:10.1371/journal.pone.0043007
PMCID: PMC3422221  PMID: 22912776
21.  Delayed reward discounting and addictive behavior: a meta-analysis 
Psychopharmacology  2011;216(3):305-321.
Rationale
Delayed reward discounting (DRD) is a behavioral economic index of impulsivity and numerous studies have examined DRD in relation to addictive behavior. To synthesize the findings across the literature, the current review is a meta-analysis of studies comparing DRD between criterion groups exhibiting addictive behavior and control groups.
Objectives
The meta-analysis sought to characterize the overall patterns of findings, systematic variability by sample and study type, and possible small study (publication) bias.
Methods
Literature reviews identified 310 candidate articles from which 46 studies reporting 64 comparisons were identified (total N=56,013).
Results
From the total comparisons identified, a small magnitude effect was evident (d=.15; p<.00001) with very high heterogeneity of effect size. Based on systematic observed differences, large studies assessing DRD with a small number of self-report items were removed and an analysis of 57 comparisons (n=3,329) using equivalent methods and exhibiting acceptable heterogeneity revealed a medium magnitude effect (d=.58; p<.00001). Further analyses revealed significantly larger effect sizes for studies using clinical samples (d=.61) compared with studies using nonclinical samples (d=.45). Indices of small study bias among the various comparisons suggested varying levels of influence by unpublished findings, ranging from minimal to moderate.
Conclusions
These results provide strong evidence of greater DRD in individuals exhibiting addictive behavior in general and particularly in individuals who meet criteria for an addictive disorder. Implications for the assessment of DRD and research priorities are discussed.
doi:10.1007/s00213-011-2229-0
PMCID: PMC3201846  PMID: 21373791
Delay discounting; Impulsivity; Addiction; Substance dependence; Alcohol; Tobacco; Nicotine; Stimulant; Opiate; Gambling; Meta-analysis
22.  Inhalation of 7.5% Carbon Dioxide Increases Threat Processing in Humans 
Neuropsychopharmacology  2011;36(8):1557-1562.
Inhalation of 7.5% CO2 increases anxiety and autonomic arousal in humans, and elicits fear behavior in animals. However, it is not known whether CO2 challenge in humans induces dysfunction in neurocognitive processes that characterize generalized anxiety, notably selective attention to environmental threat. Healthy volunteers completed an emotional antisaccade task in which they looked toward or away from (inhibited) negative and neutral stimuli during inhalation of 7.5% CO2 and air. CO2 inhalation increased anxiety, autonomic arousal, and erroneous eye movements toward threat on antisaccade trials. Autonomic response to CO2 correlated with hypervigilance to threat (speed to initiate prosaccades) and reduced threat inhibition (increased orienting toward and slower orienting away from threat on antisaccade trials) independent of change in mood. Findings extend evidence that CO2 triggers fear behavior in animals via direct innervation of a distributed fear network that mobilizes the detection of and allocation of processing resources toward environmental threat in humans.
doi:10.1038/npp.2011.15
PMCID: PMC3138667  PMID: 21490591
CO2; anxiety; cognition; attention; emotion processing; antisaccade; cognition; biological psychiatry; mood; anxiety; stress disorders; psychopharmacology
23.  From Men to Mice: CHRNA5/CHRNA3, Smoking Behavior and Disease 
Nicotine & Tobacco Research  2012;14(11):1291-1299.
Introduction:
The nicotinic acetylcholine receptor (nAChR) gene cluster CHRNA5-A3-B4 on chromosome 15 has been the subject of a considerable body of research over recent years. Two highly correlated single nucleotide polymorphisms (SNPs) within this region—rs16969968 in CHRNA5 and rs1051730 in CHRNA3—have generated particular interest.
Methods:
We reviewed the literature relating to SNPs rs16969968 and rs1051730 and smoking-related phenotypes, and clinical and preclinical studies, which shed light on the mechanisms underlying these associations.
Results:
Following the initial discovery of an association between this locus and smoking behavior, further associations with numerous phenotypes have been subsequently identified, including smoking-related behaviors, diseases, and cognitive phenotypes. Potential mechanisms thought to underlie these have also been described, as well as possible gene × environment interaction effects.
Conclusions:
Perhaps counter to the usual route of scientific inquiry, these initial findings, based exclusively on human samples and strengthened by their identification through agnostic genome-wide methods, have led to preclinical research focused on determining the mechanism underlying these associations. Progress has been made using knockout mouse models, highlighting the importance of α5 nAChR subunits in regulating nicotine intake, particularly those localized to the habenula–interpeduncular nucleus pathway. Translational research seeking to evaluate the effect of nicotine challenge on brain activation as a function of rs16969968 genotype using neuroimaging technologies is now called for, which may point to new targets for novel smoking cessation therapies.
doi:10.1093/ntr/nts106
PMCID: PMC3482013  PMID: 22544838
24.  Association Between Genetic Variants on Chromosome 15q25 Locus and Objective Measures of Tobacco Exposure 
Background
Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure.
Methods
We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730–rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730–rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided.
Results
Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730–rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10−6) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10−11). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730–rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42).
Conclusions
Our data show a stronger association of rs1051730–rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.
doi:10.1093/jnci/djs191
PMCID: PMC3352832  PMID: 22534784
25.  Effect on Adherence to Nicotine Replacement Therapy of Informing Smokers Their Dose Is Determined by Their Genotype: A Randomised Controlled Trial 
PLoS ONE  2012;7(4):e35249.
Background
The behavioural impact of pharmacogenomics is untested. We tested two hypotheses concerning the behavioural impact of informing smokers their oral dose of NRT is tailored to analysis of DNA.
Methods and Findings
We conducted an RCT with smokers in smoking cessation clinics (N = 633). In combination with NRT patch, participants were informed that their doses of oral NRT were based either on their mu-opioid receptor (OPRM1) genotype, or their nicotine dependence questionnaire score (phenotype). The proportion of prescribed NRT consumed in the first 28 days following quitting was not significantly different between groups: (68.5% of prescribed NRT consumed in genotype vs 63.6%, phenotype group, difference  =  5.0%, 95% CI −0.9,10.8, p  =  0.098). Motivation to make another quit attempt among those (n  =  331) not abstinent at six months was not significantly different between groups (p  =  0.23). Abstinence at 28 days was not different between groups (p = 0.67); at six months was greater in genotype than phenotype group (13.7% vs 7.9%, difference  =  5.8%, 95% CI 1.0,10.7, p  =  0.018).
Conclusions
Informing smokers their oral dose of NRT was tailored to genotype not phenotype had a small, statistically non-significant effect on 28-day adherence to NRT. Among those still smoking at six months, there was no evidence that saying NRT was tailored to genotype adversely affected motivation to make another quit attempt. Higher abstinence rate at six months in the genotype arm requires investigation.
Trial registration
Controlled-Trials.com ISRCTN14352545.
doi:10.1371/journal.pone.0035249
PMCID: PMC3324463  PMID: 22509402

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