Genetic variants in the serotonin transporter influence the efficacy of bupropion and nortriptyline in smoking cessation.

AIMS: We investigated whether variants in the serotonin transporter gene (SLC6A4) influence smoking cessation rates using antidepressant therapy (i.e. bupropion and nortriptyline). DESIGN: Pharmacogenetic (secondary) analysis of a randomized, placebo-controlled efficacy trial of bupropion and nortriptyline for smoking cessation. SETTING: Single-centre study, Maastricht University, the Netherlands. PARTICIPANTS: A total of 214 of 255 (84%) current daily smokers participating in a randomized controlled efficacy trial. MEASUREMENTS: Subjects were genotyped for three functional variants in SLC6A4 (5-HTTLPR, STin2, rs25531). Primary outcome measures were prolonged abstinence from weeks 4-12, 4-26 and 4-52. Secondary outcome measures included 7-day point prevalence abstinence at weeks 4, 12, 26 and 52. FINDINGS: Carriers of the 5-HTTLPR high-activity L-variant had higher prolonged cessation rates with bupropion than placebo [odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.01-2.05, P = 0.04]. Combining the three variants resulted in increased prolonged cessation rates for both bupropion and nortriptyline among carriers of four to five high-activity variants (bupropion: OR = 2.00, 95% CI =1.21-3.29, P = 0.01; nortriptyline: OR = 1.91, 95% CI = 1.02-3.56, P = 0.04). Similar results were found for point prevalence abstinence. CONCLUSIONS: Bupropion and nortriptyline seem to be more effective in smoking cessation among SLC6A4 high-activity variant carriers, probably by blocking the increased serotonin transporter activity, thereby increasing serotonin levels. Prospective studies have to assess if this can improve cessation rates when treatment is targeted at individuals based on their genotypes.

The cost-effectiveness of antidepressants for smoking cessation in chronic obstructive pulmonary disease (COPD) patients.

OBJECTIVES: In healthy smokers, antidepressants can double the odds of cessation. Because of its four times lower costs and comparable efficacy in healthy smokers, nortriptyline appears to be favourable compared to bupropion. We assessed which of both drugs was most effective and cost-effective in stopping smoking after 1 year compared with placebo among smokers at risk or with existing chronic obstructive pulmonary disease (COPD). METHODS: A total of 255 participants, aged 30-70 years, received smoking cessation counselling and were assigned bupropion, nortriptyline or placebo randomly for 12 weeks. Prolonged abstinence from smoking was defined as a participant's report of no cigarettes from week 4 to week 52, validated by urinary cotinine. Costs were calculated using a societal perspective and uncertainty was assessed using the bootstrap method. RESULTS: The prolonged abstinence rate was 20.9% with bupropion, 20.0% with nortriptyline and 13.5% with placebo. The differences between bupropion and placebo [relative risk (RR) = 1.6; 95% confidence interval (CI) 0.8-3.0] and between nortriptyline and placebo (RR = 1.5; 95% CI 0.8-2.9) were not significant. Severity of airway obstruction did not influence abstinence significantly. Societal costs were 1368 euros (2.5th-97.5th percentile 193-5260) with bupropion, 1906 euros (2.5th-97.5th 120-17 761) with nortriptyline and 1212 euros (2.5th-97.5th 96-6602) with placebo. Were society willing to pay more than 2000 euros for a quitter, bupropion was most likely to be cost-effective. CONCLUSIONS: Bupropion and nortriptyline seem to be equally effective, but bupropion appears to be more cost-effective when compared to placebo and nortriptyline. This impression holds using only health care costs. As the cost-effectiveness analyses concern some uncertainties, the results should be interpreted with care and future studies are needed to replicate the findings.

The immunogenicity and safety of a nicotine vaccine in smokers and nonsmokers: results of a randomized, placebo-controlled phase 1/2 trial.

This randomized, placebo-controlled phase 1/2 trial evaluated the safety and immunogenicity of four doses of a nicotine vaccine in smokers and nonsmokers. Subjects were 21 smokers and 9 nonsmokers in good physical and mental health. They were aged 24-60 years, were recruited from the general public using newspaper advertisements, and were evaluated at University Hospital Maastricht. Each volunteer received four spaced intramuscular injections of 100 microg of purified 3'-aminomethylnicotine conjugated to detoxified Pseudomonas aeruginosa r-exoprotein A or placebo both adsorbed to 800 microg aluminum into the deltoid muscle of alternating arms. Clinical safety was determined by vital signs, reactogenicity, and adverse events, and immunogenicity was measured by enzyme-linked immunosorbent assay. Intensive follow-up for 266 days revealed the vaccine to be well tolerated. We found no significant differences in adverse events between the vaccine and placebo groups. Significant increases in the geometric mean titer (GMT) levels of nicotine-specific antibodies were observed from 7 days after the second vaccination (day 21), reaching nicotine-specific antibody levels of at least 8 microg/ml in half of the subjects (50%) at day 49. A fourth dose administered at day 182 significantly boosted waning antibody levels to a GMT of 10.8 microg/ml at day 217 (95% CI 6.0-19.3). Results showed that the immunogenicity of the vaccine was not impeded by the presence of nicotine. These observations provide evidence in humans that the vaccine we used may represent a feasible strategy for evoking type-specific antibodies against nicotine.

Smoking cessation practices of Dutch general practitioners, cardiologists, and lung physicians.

STUDY OBJECTIVES: To assess and compare the smoking cessation practices and smoking behavior of Dutch general practitioners (GPs), cardiologists, and lung physicians. METHODS: We conducted questionnaire surveys among a random sample of 2000 Dutch GPs, all Dutch cardiologists (N=594), and all Dutch lung physicians (N=375). RESULTS: In total, 834 GPs (41.7%), 300 cardiologists (50.5%), and 258 lung physicians (68.8%) filled out and returned the questionnaire. The prevalence of current smokers was 8.2% among GPs, 4.3% among cardiologists, and 3.5% among lung physicians. Of the pharmacological aids for smoking cessation, physicians recommended bupropion most frequently, followed by nicotine patches and nicotine gum. More lung physicians recommended the use of these three aids (67.0%, 36.3% and 18.2%, respectively) than GPs (65.7%, 18.7% and 9.8%, respectively), and than cardiologists (31.6%, 19.7% and 13.2%, respectively). A higher proportion of lung physicians (69.3%) had referred at least one smoker to a nurse for smoking cessation treatment than cardiologists (25%), and than GPs (11.3%). CONCLUSIONS: Based on this national survey, one may conclude that the prevalence of current smoking among Dutch physicians is relatively low and has further decreased since 1988. Dutch GPs, cardiologists, and lung physicians mainly use interventions for smoking cessation that are easy to administer and are not very time consuming. Furthermore, more lung physicians than GPs and cardiologists recommend the use of bupropion, nicotine patch, and nicotine gum. When designing interventions for smoking cessation, one should take into account that physicians are often reluctant to provide interventions which demand much time. Therefore, intensive counseling of smokers who want to quit smoking may be more feasible for trained non-physicians, such as nurses.

Encouraging smokers to quit: the cost effectiveness of reimbursing the costs of smoking cessation treatment.

BACKGROUND: Smoking cessation should be encouraged in order to increase life expectancy and reduce smoking-related healthcare costs. Results of a randomised trial suggested that reimbursing the costs of smoking cessation treatment (SCT) may lead to an increased use of SCT and an increased number of quitters versus no reimbursement. OBJECTIVE: To assess whether reimbursement for SCT is a cost-effective intervention (from the Dutch societal perspective), we calculated the incremental costs per quitter and extrapolated this outcome to incremental costs per QALY saved versus no reimbursement. METHODS: In the reimbursement trial, 1266 Dutch smokers were randomly assigned to the intervention or control group using a randomised double consent design. Reimbursement for SCT was offered to the intervention group for a period of 6 months. No reimbursement was offered to the control group. Prolonged abstinence from smoking was determined 6 months after the end of the reimbursement period. The QALYs gained from quitting were calculated until 80 years of age using data from the US. Costs (year 2002 values) were determined from the societal perspective during the reimbursement period (May-November 2002). Benefits were discounted at 4% per annum. The uncertainty of the incremental cost-effectiveness ratios was estimated using non-parametric bootstrapping. RESULTS: Eighteen participants in the control group (2.8%) and 35 participants in the intervention group (5.5%) successfully quit smoking. The costs per participant were 291 euro and 322 euro, respectively. If society is willing to pay 1000 euro or 10,000 euro for an additional 12-month quitter, the probability that reimbursement for SCT would be cost effective was 50% or 95%, respectively. If society is willing to pay 18,000 euro for a QALY, the probability that reimbursement for SCT would be cost effective was 95%. However, the external validity of the extrapolation from quitters to QALYs is uncertain and several assumptions had to be made. CONCLUSION: Reimbursement for SCT may be cost effective if Dutch society is willing to pay 10,000 euro for an additional quitter or 18,000 euro for a QALY.

Chronic bronchitis, cigarette smoking, and the subsequent onset of depression and anxiety: results from a prospective population-based cohort study.

OBJECTIVE: The authors used data from a prospective, population-based cohort study to examine: (a) whether the presence of chronic bronchitis predicts the subsequent onset of depression or anxiety, and (b) if the incidence of depressed or anxious cases was different for smokers compared with nonsmokers. MATERIALS AND METHODS: For studying the relation between chronic bronchitis and anxiety or depression, we used data from respectively 4468 and 4520 respondents. RESULTS: The number of incident anxious (19.1%, n = 17) and depressed (14.0%, n = 13) cases was highest in employees with chronic bronchitis compared with employees without respiratory complaints (4.3%, n = 189 and 3.3%, n = 145, respectively). The presence of chronic bronchitis was associated with a significant increase in anxious and depressed cases (odds ratio (OR) for anxiety = 5.09, 95% confidence interval (CI) 2.91, 8.89; OR for depression = 4.38, 95% CI 2.35, 8.16). The incidence of anxiety as well as depression was strongest in the smokers group (OR for anxiety = 8.94, 95% CI 4.08, 19.59; OR for depression = 7.56, 95% CI 3.37, 16.96). CONCLUSIONS: This prospective study shows significantly higher levels of anxiety as well as depression in employees with chronic bronchitis. Results also seem to indicate that smoking cigarettes modifies this association, resulting in an increased risk of depression and anxiety in employees with chronic bronchitis who smoke.

Risk of depression and anxiety in employees with chronic bronchitis: the modifying effect of cigarette smoking.

OBJECTIVE: The present study evaluates whether smoking status modifies the association between chronic bronchitis and depression or anxiety in a population-based sample. Furthermore, we tested whether these associations are different in people without any respiratory complaints and those with asthma. METHODS: For this study, we used cross-sectional data form the Maastricht Cohort Study, a population-based cohort study among Dutch employees. RESULTS: In total, 7482 employees completed and returned the questionnaire (92.7%). In employees with chronic bronchitis, the prevalence of depression and anxiety was significantly higher compared with healthy employees and employees with asthma. Results indicate that the odds of having comorbid depression or anxiety for employees with chronic bronchitis compared with healthy employees is highest in current and past smokers, indicating that smoking status modifies this association. CONCLUSION: Chronic bronchitis is strongly associated with depression and anxiety. Because depression and/or anxiety may not only interfere with an attempt to stop smoking but also contribute significantly to experiencing low quality of life, it is important to consider these disorders and chronic bronchitis as different disease entities. Prospective longitudinal studies are needed to elucidate the mechanisms underlying the association among chronic bronchitis, psychiatric disorders, and cigarette smoking.