Janet Audrain

DEPRESSION AND SELF-MEDICATION WITH NICOTINE : THE MODIFYING INFLUENCE OF THE DOPAMINE D4 RECEPTOR GENE

This study evaluated whether there are genetic subgroups of depressed individuals who are more or less predisposed to engage in self-medication smoking practices. Smokers (N = 231) completed self-report questionnaires of depression and smoking practices and were genotyped for the dopamine D4 receptor (DRD4) gene. A significant interaction (DRD4 Genotype x Depression) was found for stimulation smoking and negative-affect reduction smoking. Specifically, these smoking practices were significantly heightened in depressed smokers homozygous for the short alleles of DRD4 but not in those heterozygous or homozygous for the long alleles of DRD4. These preliminary results suggest that the rewarding effects of smoking and the beneficial effects of nicotine replacement therapy for depressed smokers may depend, in part, on genetic factors involved in dopamine transmission.

Pharmacogenetic investigation of smoking cessation treatment.

Despite the efficacy of bupropion for smoking cessation, smokers exhibit variability in treatment outcome. The CYP2B6 gene has been implicated in bupropion kinetics and nicotine metabolism, and is a plausible candidate for pharmacogenetic studies of treatment response. We investigated whether a functional genetic polymorphism in the CYP2B6 gene predicts smoking outcomes in a placebo-controlled randomized trial. Four hundred and twenty-six smokers of European Caucasian ancestry provided blood samples and received bupropion (300 mg/day for 10 weeks) or placebo, plus counseling. Smoking status, abstinence symptoms and side-effects were recorded weekly, and smoking status was verified at the end of treatment and at 6-month follow-up. Smokers with a decreased activity variant of CYP2B6 reported greater increases in cravings for cigarettes following the target quit date and had higher relapse rates. These effects were modified by a significant gender x genotype x treatment interaction, suggesting that bupropion attenuated the effects of genotype among female smokers. We conclude that smokers with the CYP2B6 variant may be more vulnerable to abstinence symptoms and relapse. Bupropion may attenuate these effects, especially among females. Additional trials are warranted to confirm these results, as are studies to explore the neurobiological mechanisms. Such research could ultimately enable practitioners to select the optimal type and dose of medication for individual smokers.

Association of Attention-Deficit/Hyperactivity Disorder Symptoms With Levels of Cigarette Smoking in a Community Sample of Adolescents

OBJECTIVE Research on the association of attention-deficit/hyperactivity disorder (ADHD) with cigarette smoking has primarily occurred within samples of clinically referred youths. This paper reports the association of ADHD symptoms with smoking practices in a community sample of adolescents. METHOD Confidential self-report surveys were completed by 1,066 tenth-grade students enrolled in five public high schools who were taking part in a longitudinal study of biobehavioral predictors of adolescent smoking adoption. A well-standardized measure of ADHD inattention and hyperactivity-impulsivity symptoms, as well as demographic and social risk factors, were examined in relation to three levels of cigarette smoking: (1) never having smoked, (2) ever having smoked, and (3) current smoking (having smoked a cigarette within the past 30 days). RESULTS Regarding lifetime cigarette use, approximately 43% of students had ever smoked. Among those who had ever smoked, approximately 31% of students were current smokers. Ever having smoked was associated with family (odds ratio [OR] = 2.49, confidence interval [CI] = 1.85, 3.36) and peer smoking (OR = 4.05, CI = 3.07, 5.33) and clinically significant ADHD inattention symptoms (OR = 3.39, CI = 1.53, 7.54). Current smoking was also associated with peer smoking (OR = 2.99, CI = 1.72, 5.20) and clinically significant ADHD inattention symptoms (OR = 2.80, CI = 1.20, 6.56). CONCLUSION Clinically significant ADHD symptoms should be taken into account when identifying adolescents at risk to smoke, since those with problematic inattention may be more likely to experiment with smoking and to become regular tobacco users.

Effects of dopamine transporter and receptor polymorphisms on smoking cessation in a bupropion clinical trial.

This study examined the role of dopaminergic genes in prospective smoking cessation and response to bupropion treatment in a placebo-controlled clinical trial. Smokers of European ancestry (N=418) provided blood samples for genetic analysis and received either bupropion or placebo (10 weeks) plus counseling. Assessments included the dopamine D2 receptor (DRD2) genotype, dopamine transporter (SLC6A3) genotype, demographic factors, and nicotine dependence. Smoking status was verified at the end of treatment (EOT) and at 6-month follow-up. The results provided evidence for a significant DRD2 * SLC6A3 interaction effect on prolonged smoking abstinence and time to relapse at EOT, independent of treatment condition. Such effects were no longer significant at 6-month follow-up, however. These results provide the first evidence from a prospective clinical trial that genes that alter dopamine function may influence smoking cessation and relapse during the treatment phase.

Incorporating biomarkers of exposure and genetic susceptibility into smoking cessation treatment: effects on smoking-related cognitions, emotions, and behavior change.

In this article the authors report on the short-term impact of incorporating biomarker feedback about exposure and genetic susceptibility into minimal-contact quit-smoking counseling (QSC). Four hundred and twenty-seven smokers were randomized to 1 of 3 treatments: (a) QSC, (b) QSC + exposure biomarker feedback (EBF) about carbon monoxide in exhaled breath, or (b) QSC + EBF + biomarker feedback about genetic susceptibility to lung cancer (SBF). We observed significant immediate positive effects of SBF, compared with EBF and QSC on perceived risk, perceived quitting benefits, and fear arousal. However, at the 2-month follow-up, there were no group differences in quit rates. SBF did lead to significant reductions in the number of cigarettes smoked for smokers who were in the preparation stage. Smokers in the EBF and QSC conditions showed reductions in depressive symptoms by 2 months, but smokers in the SBF condition did not. In the context of QSC, genetic feedback may heighten vulnerability and possibly promote distress, but may not immediately enhance quitting in most smokers.

Mediating mechanisms for the impact of bupropion in smoking cessation treatment

Several studies have documented the effectiveness of bupropion for smoking cessation, yet little is known about the mechanisms by which it facilitates abstinence. In this placebo-controlled randomized trial. We examined whether bupropions effects on cessation were mediated by changes in withdrawal and/or negative or positive affect (PA). Two hundred and fifty-one smokers received 10-week treatment with bupropion or placebo, plus behavioral counseling. Changes in affect and withdrawal symptoms from pre-quit to 1 week post quit were examined as mediating variables in structural equation models. Cotinine-verified 7-day point prevalence cessation rates at the end of treatment (8-weeks post quit date) were 48% for bupropion and 29% for placebo (P=0.001). There were significant treatment effects on withdrawal and negative affect (NA); however, only change in NA predicted cessation. In a path model, change in NA was a significant mediator of bupropions effects on cessation. However, the proportion of variance accounted for by this mediator was small, suggesting that other unmeasured factors play an important role. Laboratory-based paradigms may be useful to identify other mediators of bupropions effects, thereby pointing to mechanisms of effect that can be bolstered in future treatment studies.

Interacting effects of the serotonin transporter gene and neuroticism in smoking practices and nicotine dependence

Individual differences in propensity to nicotine dependence appear to be mediated, in part, by genetic factors.1 The serotonin transporter gene has a functional polymorphism (5-HTTLPR) which modulates gene transcription and reuptake.2, 3 A possible role in nicotine dependence is suggested by a link between 5-HTTLPR and neuroticism,4 a personality trait which has been related to smoking practices.5 In a cross-sectional study of 185 smokers, we utilized multiple linear regression modeling to examine the interacting effects of the 5-HTTLPR and neuroticism on smoking practices and nicotine dependence. Genotype was classified according to the presence or absence of the short (s) allele vs the long (l) allele of 5-HTTLPR (ie, s/s or s/l vs l/l). Models controlled for gender, age, race, and alcohol use. The 5-HTTLPR by neuroticism interaction effect was statistically significant in the models of nicotine intake (P = 0.05), nicotine dependence (P = 0.001), and smoking motivations (smoking to reduce negative mood (P = 0.01); smoking for stimulation (P = 0.01)). The results suggested that neuroticism was positively associated with these smoking practices among smokers with 5-HTTLPR S genotypes (s/s or s/l), but not among smokers with the L genotype (l/l). The 5-HTTLPR may modify the effects of neuroticism on smoking motivations and nicotine dependence. Assessment of 5-HTTLPR genotype and neuroticism may help to identify smokers who are more responsive to psychotropic medications, such as selective serotonin reuptake inhibitors (SSRIs), which are being used in smoking cessation treatment.

Psychological distress in women seeking genetic counseling for breast-ovarian cancer risk: The contributions of personality and appraisal

The purpose of the present study was two-fold: (a) to characterize the psychological status of women with a family history of breast or ovarian cancer who self-refer for genetic counseling and BRCA1 testing; and (b) to identify specific demographic, personality, and appraisal factors that contribute to cancer-specific distress and general distress in this group of women. Participants were 256 women ages 18 and older who had at least one first-degree relative (FDR) with breast and/or ovarian cancer. Participants were recruited through breast cancer clinics and obstetrics/gynecology departments at two medical centers by responding to program information described in a brochure. The results revealed moderate distress levels in this population. The results of a hierarchical regression of general distress indicated that women with higher levels of general distress were less likely to be married, less optimistic, and had heightened breast cancer risk perceptions accompanied by feelings of low perceptions of control over the development of breast cancer (R2=.44, p=.0001). Women with higher levels of cancer-specific distress tended to be younger and non-White and had low perceptions of control over developing breast cancer (R2=.15, p=.0002). These findings suggest that self-referred genetic counseling participants may be psychologically vulnerable and may benefit from interventions designed to decrease distress and the perceived absence of control over developing breast cancer.

Genetic testing for colon cancer susceptibility : Anticipated reactions of patients and challenges to providers

The commercial availability of genetic tests for colon cancer susceptibility is creating new opportunities and challenges for both patients and providers. To provide information useful in the education and counseling of individuals considering genetic testing, we conducted structured interviews with 45 male and female first‐degree relatives of colorectal cancer patients. Fifty‐one percent of respondents indicated that they definitely would want to obtain a genetic test for colon cancer susceptibility when it is available and 31% said that they probably would want to be tested. Interest in genetic testing was significantly higher among persons with less formal education and those with a Catholic religious preference. Motivations for genetic testing included the following: to know if more screening tests are needed, to learn if ones children are at risk and to be reassured. Barriers to testing included concerns about insurance, test accuracy and how ones family would react emotionally. Most participants anticipated that they would become depressed and anxious if they tested positive for a mutation, while many would feel guilty and still worry if they tested negative. Of note, about one‐half of respondents expected that they would decrease their use of screening tests and make fewer attempts to reduce dietary fat if they tested negative. These preliminary results underscore the importance of educating patients about the potential risks, benefits and limitations of genetic testing, with particular emphasis on the possibility of adverse psychological effects and implications for health insurance. The potential for false reassurance following a negative test result should be addressed by emphasizing the residual risks of cancer among non‐carriers of predisposing mutations.

Genetic susceptibility testing in smoking-cessation treatment: One-year outcomes of a randomized trial☆☆☆

This study evaluated the long-term impact of genetic susceptibility biomarker feedback on smoking behavior change and symptoms of depression in 426 male and female smokers. Smokers were randomized to one of three smoking-cessation interventions: minimal contact quit-smoking counseling (QSC), QSC + exposure biomarker feedback (EBF), and QSC + EBF + biomarker feedback about genetic susceptibility to lung cancer (SBF). The logistic regression model for quit attempt revealed a significant main effect for treatment such that participants in the SBF group were more than two times more likely to make a quit attempt than participants in the QSC group. There was not a significant difference between EBF and QSC participants. The results also revealed a significant effect for baseline stage of change. Those smokers in the preparation stage at baseline were more than three times more likely to make a quit attempt over the 12 months following treatment. The models for 30-day cessation and follow-up smoking rate revealed no significant main or interacting effects for treatment. A repeated measures analysis of variance revealed a significant main effect for time, indicating that an initial increase in depression in the genetic susceptibility group was not maintained over time. Genetic susceptibility feedback has the intended effects on motivation to quit, but it may need to be delivered within a more intensive smoking-cessation treatment for the heightened motivation to translate into smoking cessation.