Ovide F. Pomerleau

Variants in Nicotinic Receptors and Risk for Nicotine Dependence

OBJECTIVE A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the alpha5 nicotinic cholinergic receptor (CHRNA5). The purpose of this study was to replicate these findings in an independent data set and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4, and the risk of smoking. METHOD Individuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid variant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influences receptor function. RESULTS A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This variant is within a highly conserved region across nonhuman species, but its frequency varied across human populations (0% in African populations to 37% in European populations). Furthermore, functional studies demonstrated that the risk allele decreased response to a nicotine agonist. A second independent finding was seen at rs578776 (p=0.003), and the functional significance of this association remains unknown. CONCLUSIONS This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.

Cigarette smoking in adult patients diagnosed with attention deficit hyperactivity disorder.

Previous work has shown that adolescent hyperactivity patients are significantly more likely to smoke than controls. To determine whether this pattern persists in adults, we studied a series of 71 patients (55 males, 16 females; mean age +/- SD: 33.9 +/- 11.4 years) diagnosed with ADHD. Of the males, 23 (42%) were current smokers, 7 (13%) were ex-smokers, and 25 (45%) were never smokers. Comparable figures for males in the general population in 1991, unselected for ADHD, were 28.1%, 29.1%, and 42.1%, respectively. Of the females, 6 (38%) were current smokers, 5 (31%) were ex-smokers, and 5 (31%) had never smoked, as compared with 23.5%, 19.0%, and 57.6%, respectively, in the general population. Quit ratio (percentage of ever-smokers who were ex-smokers) was 29% for ADHD patients, compared with 48.5% in the general population. The discrepancy was accounted for by the males, whose quit ratio was 23%, compared with 51.6% in the general population; the figure for ADHD females (45%) was similar to that in the general population (44.7%). Smokers recalled experiencing a significantly higher number of ADHD symptoms (11.5 +/- 1.7) as children than never smokers (9.9 +/- 2.3; p < .01) and scored significantly higher on several indices of childhood and adult comorbidity. Our findings suggest that ADHD patients overinclude smokers, and that these smokers find it extremely difficult to quit. For ADHD smokers, smoking may have begun as an attempt to manage deficits in attention and concentration, as suggested by greater childhood symptomatology in these patients.

Web-Based Smoking-Cessation Programs : Results of a Randomized Trial

BACKGROUND Initial trials of web-based smoking-cessation programs have generally been promising. The active components of these programs, however, are not well understood. This study aimed to (1) identify active psychosocial and communication components of a web-based smoking-cessation intervention and (2) examine the impact of increasing the tailoring depth on smoking cessation. DESIGN Randomized fractional factorial design. SETTING Two HMOs: Group Health in Washington State and Henry Ford Health System in Michigan. PARTICIPANTS 1866 smokers. INTERVENTION A web-based smoking-cessation program plus nicotine patch. Five components of the intervention were randomized using a fractional factorial design: high- versus low-depth tailored success story, outcome expectation, and efficacy expectation messages; high- versus low-personalized source; and multiple versus single exposure to the intervention components. MEASUREMENTS Primary outcome was 7 day point-prevalence abstinence at the 6-month follow-up. FINDINGS Abstinence was most influenced by high-depth tailored success stories and a high-personalized message source. The cumulative assignment of the three tailoring depth factors also resulted in increasing the rates of 6-month cessation, demonstrating an effect of tailoring depth. CONCLUSIONS The study identified relevant components of smoking-cessation interventions that should be generalizable to other cessation interventions. The study also demonstrated the importance of higher-depth tailoring in smoking-cessation programs. Finally, the use of a novel fractional factorial design allowed efficient examination of the study aims. The rapidly changing interfaces, software, and capabilities of eHealth are likely to require such dynamic experimental approaches to intervention discovery.

Individual Differences in Sensitivity to Nicotine: Implications for Genetic Research on Nicotine Dependence

Recent evidence suggests that cigarette smoking has a heritability index around 53%. While related research on underlying mechanisms also supports the idea that genetic factors contribute to nicotine dependence—as well as to cofactors such as substance use and mood disorders—the nature of the behavioral traits and biological capacity for reinforcement that constitutes vulnerability to nicotine dependence is not well understood. The present review explores the problem of why some people become highly nicotine dependent, others develop a pattern of occasional use, and still others avoid the drug entirely despite extensive exposure and widespread experimentation with tobacco in the population. Recent research—both infrahuman and human—suggests that vulnerability to nicotine dependence is related to high initial sensitivity to nicotine and that the development of tolerance is more rapid and self-administration more extensive in such individuals. Relevant findings from neuroscience and biobehavioral research are reviewed in order to identify variables and methodologies that might improve the reliability and validity of behavioral and molecular genetic studies on cigarette smoking. The integration of research in these areas may lead to new insights in the understanding of nicotine dependence as well as to improved techniques for prevention and treatment.

The role of engagement in a tailored web-based smoking cessation program: randomized controlled trial.

Background Web-based programs for health promotion, disease prevention, and disease management often experience high rates of attrition. There are 3 questions which are particularly relevant to this issue. First, does engagement with program content predict long-term outcomes? Second, which users are most likely to drop out or disengage from the program? Third, do particular intervention strategies enhance engagement? Objective To determine: (1) whether engagement (defined by the number of Web sections opened) in a Web-based smoking cessation intervention predicts 6-month abstinence, (2) whether particular sociodemographic and psychographic groups are more likely to have lower engagement, and (3) whether particular components of a Web-based smoking cessation program influence engagement. Methods A randomized trial of 1866 smokers was used to examine the efficacy of 5 different treatment components of a Web-based smoking cessation intervention. The components were: high- versus low-personalized message source, high- versus low-tailored outcome expectation, efficacy expectation, and success story messages. Moreover, the timing of exposure to these sections was manipulated, with participants randomized to either a single unified Web program with all sections available at once, or sequential exposure to each section over a 5-week period of time. Participants from 2 large health plans enrolled to receive the online behavioral smoking cessation program and a free course of nicotine replacement therapy (patch). The program included: an introduction section, a section focusing on outcome expectations, 2 sections focusing on efficacy expectations, and a section with a narrative success story (5 sections altogether, each with multiple screens). Most of the analyses were conducted with a stratification of the 2 exposure types. Measures included: sociodemographic and psychosocial characteristics, Web sections opened, perceived message relevance, and smoking cessation 6-months following quit date. Results The total number of Web sections opened was related to subsequent smoking cessation. Participants who were younger, were male, or had less formal education were more likely to disengage from the Web-based cessation program, particularly when the program sections were delivered sequentially over time. More personalized source and high-depth tailored self-efficacy components were related to a greater number of Web sections opened. A path analysis model suggested that the impact of high-depth message tailoring on engagement in the sequentially delivered Web program was mediated by perceived message relevance. Conclusions Results of this study suggest that one of the mechanisms underlying the impact of Web-based smoking cessation interventions is engagement with the program. The source of the message, the degree of message tailoring, and the timing of exposure appear to influence Web-based program engagement.

Nicotine may relieve symptoms of Parkinson's disease

Two elderly patients with Parkinsons disease were treated with nicotine gum and patch. Reliable changes in symptomatology were noted, using a single-subject, placebo-control reversal design. Improvement was associated with active nicotine dosing and involved diminished tremor and disorganized thinking in one patient and diminished bradykinesia and increased energy in the other.

Who gets what symptom? Effects of psychiatric cofactors and nicotine dependence on patterns of smoking withdrawal symptomatology

The present study used logistic regression techniques to examine the extent to which depression, anxiety, disordered eating, and nicotine dependence increased risk of experiencing craving and the eight DSM-IV withdrawal symptoms (depressed mood, insomnia, irritability, anxiety, difficulty concentrating, restlessness, decreased heart rate, increased appetite) during smoking abstinence, assessed retrospectively. Data were provided by a racially diverse sample of 365 male and female smokers recruited to participate in laboratory studies. Results indicate that variables known to be associated with smoking are risk factors for distinct and only somewhat overlapping patterns of symptomatology. Smokers scoring high on measures of anxiety, depression, or disordered eating were at increased risk primarily of experiencing withdrawal symptomatology pathognomonic to their particular disorder, whereas smokers scoring high on nicotine dependence appeared to be at increased risk of experiencing a syndromal pattern of withdrawal, encompassing craving and insomnia as well as cognitive/affective symptoms. Our results support the possibility that some individuals use smoking as a form of self-medication and suggest that elucidation of patterns of withdrawal symptomatology may contribute to improved specification of smoking phenotypes as well as facilitate treatment-matching.

Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with ‘pleasurable buzz’ during early experimentation with smoking

Aims To extend the previously identified association between a single nucleotide polymorphism (SNP) in neuronal acetylcholine receptor subunit alpha-5 (CHRNA5) and nicotine dependence to current smoking and initial smoking-experience phenotypes. Design, setting, participants Case–control association study with a community-based sample, comprising 363 Caucasians and 72 African Americans (203 cases, 232 controls). Measurements Cases had smoked ≥ five cigarettes/day for ≥ 5 years and had smoked at their current rate for the past 6 months. Controls had smoked between one and 100 cigarettes in their life-time, but never regularly. Participants also rated, retrospectively, pleasurable and displeasurable sensations experienced when they first smoked. We tested for associations between smoking phenotypes and the top 25 SNPs tested for association with nicotine dependence in a previous study. Findings A non-synonymous coding SNP in CHRNA5, rs16969968, was associated with case status [odds ratio (OR) = 1.5, P = 0.01] and, in Caucasians, with experiencing a pleasurable rush or buzz during the first cigarette (OR = 1.6, P = 0.01); these sensations were associated highly with current smoking (OR = 8.2, P = 0.0001). Conclusions We replicated the observation that the minor allele of rs16969968 affects smoking behavior, and extended these findings to sensitivity to smoking effects upon experimentation. While the ability to test genetic associations was limited by sample size, the polymorphism in the CHRNA5 subunit was shown to be associated significantly with enhanced pleasurable responses to initial cigarettes in regular smokers in an a priori test. The findings suggest that phenotypes related to subjective experiences upon smoking experimentation may mediate the development of nicotine dependence.

Relationship of tridimensional personality questionnaire scores and smoking variables in female and male smokers

The Tridimensional Personality Questionnaire (TPQ) was developed by Cloninger (1986) to measure heritable variation in three patterns of response to environmental stimuli: novelty seeking, harm avoidance, and reward dependence. Cloninger (1987) used the TPQ to identify two types of alcoholism: Type 1 (low novelty seeking, high harm avoidance and reward dependence; both male and female) and Type 2 (high novelty seeking, low harm avoidance and reward dependence; predominantly male). To determine whether characteristic patterns exist in smokers, we administered the TPQ to 119 female and 121 male smokers, along with the Fagerstrom Tolerance Questionnaire (FTQ, a measure of nicotine dependence), the Russell Motives for Smoking Questionnaire (RMSQ), and the Spielberger State-Trait Anxiety Inventory (STAI/trait). Compared with a normative sample, our sample exhibited elevated scores on the Novelty-Seeking scale; female smokers were somewhat overrepresented in the highest quartile of the Harm-Avoidance scale; both genders tended to be clustered in the lower quartiles of the Sentimentality-Attachment-Dependence subscale of the Reward-Dependence scale and in the highest quartile of the Persistence subscale. Female smokers showed a significant positive association between Harm Avoidance and FTQ scores, and Harm Avoidance was positively correlated with several RMSQ factors (including Additive smoking) in both genders. These findings suggest that the likelihood of becoming a smoker may be a function of novelty seeking and reward dependence, whereas degree of dependence or addiction once the habit is entrained may be linked to harm avoidance. Our observations establish the potential utility of the TPQ as a tool for examining environmental and heritable variation in smoking behavior and may contribute to improved strategies for prevention and treatment of smoking.

Nicotine Withdrawal and Psychiatric Symptoms in Cigarette Smokers with Schizophrenia

The prevalence of smoking is markedly elevated in schizophrenia. Low smoking cessation rates and reports that some smokers with schizophrenia experience an acute increase in symptoms during attempts to quit smoking, suggest a self-medication model. Alternatively, smoking may modulate medication side effects. The effects of treated and untreated smoking abstinence on psychotic symptoms and medication side effects were examined in this study. Nineteen outpatients with schizophrenia or schizoaffective disorder participated in a randomized, double-blind, balanced crossover study: 1 day of ad libitum smoking followed by 3 days of acute smoking abstinence while wearing 22 mg/day active or placebo transdermal nicotine patches, with a return to 3 days of smoking between patch conditions. Daily symptom and side-effect ratings, nicotine and cotinine blood levels were collected. Twelve subjects completed the study. Neither positive symptoms nor mood symptoms changed. An increase in negative symptoms during the first abstinent day occurred in both placebo and active patch conditions, but was not sustained over subsequent abstinent days. Despite physiological signs of withdrawal, completers did not endorse increased nicotine withdrawal symptoms. Dropouts reported higher withdrawal symptoms, but also had no increase in psychiatric symptoms in either phase of the study. Of note, dyskinesias decreased during abstinence and placebo patch treatment, but increased during abstinence and the active patch conditions. Acute exacerbation of psychiatric symptoms is an unlikely explanation for any difficulty smokers with schizophrenia have in early abstinence.