A placebo controlled trial of bupropion for smoking cessation in schizophrenia.

BACKGROUND: Schizophrenic patients have high rates of cigarette smoking compared with the general population. We compared sustained-release (SR) bupropion with placebo for smoking cessation in patients with schizophrenic disorders. We also examined how antipsychotic class predicts smoking cessation outcomes with bupropion. METHODS: Thirty-two subjects meeting DSM-IV criteria for schizophrenia or schizoaffective disorder and nicotine dependence were randomized to bupropion SR (BUP, 300 mg/day) or placebo (PLA). Outcomes included treatment retention, smoking abstinence rates, expired breath carbon monoxide (CO) levels, psychotic symptoms, and medication side effects. RESULTS: Bupropion significantly increased trial endpoint 7-day point prevalence smoking abstinence rates compared with placebo [BUP, 8/16 (50.0%), PLA, 2/16 (12.5%); chi(2) = 5.24, df = 1, p <.05], and reduced CO levels during the trial [Medication x Time interaction; Z = 3.09, p <.01]. Positive schizophrenia symptoms were not altered by BUP, but negative symptoms were significantly reduced. Atypical antipsychotic drug treatment enhanced smoking cessation responses to BUP. Major side effects were dry mouth, gastrointestinal symptoms, headache, and insomnia. CONCLUSIONS: Our results suggest that 1) BUP enhances smoking abstinence rates compared with PLA in nicotine-dependent schizophrenic smokers; 2) BUP is well-tolerated and safe for use in these patients; and 3) atypical antipsychotics may enhance smoking cessation outcomes with BUP.     

Varenicline in the treatment of tobacco dependence

Varenicline, a partial agonist of alpha(4)beta(2) nicotinic acetylcholine receptors, is the most recently approved drug for smoking cessation. This paper reviews the outcomes of Phase 2 and Phase 3 clinical trials that assess the efficacy of varenicline in comparison to placebo and other smoking cessation pharmacotherapies, ie, sustained-release bupropion (bupropion SR) and nicotine transdermal patch. Varenicline has higher abstinence rates than placebo and the alternative active treatments at the end of standard regimen treatment periods. Significantly higher abstinence rates were also found with varenicline in comparison to both placebo and bupropion SR at the end of a 40-week non-treatment follow-up period. Varenicline typically tripled the abstinence rates compared with placebo. In addition, varenicline reduced craving and withdrawal symptoms as well as some of the positive experiences associated with smoking to a greater extent than placebo, bupropion SR, and nicotine replacement therapy (NRT). These findings are consistent with the proposed agonist/antagonist effects of varenicline. Preliminary studies assessing individual variables such as smoking dependency level and smoking reinforcement types provide justification to examine further the effects of varenicline according to these individual factors. Outcomes from such research could improve our understanding of varenicline's mechanism of action and could ultimately help clinicians to develop individualized smoking cessation programs. Also, given varenicline's ability to reduce the reward from smoking, it might be helpful to use it before cessation to motivate or prepare smokers for a quit attempt.     

CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial.

BACKGROUND: CYP2B6 is the primary enzyme involved in bupropion (Zyban; GlaxoSmithKline, Research Triangle Park, North Carolina) metabolism. Genetic polymorphisms in CYP2B6, such as CYP2B6*6, can alter bupropion metabolism and may affect bupropion treatment outcome. METHODS: Subjects participated in a smoking cessation clinical trial of bupropion versus placebo. The main outcome was a 7-day point prevalence abstinence rate measured 10 weeks after the start of treatment (i.e., end of treatment) and at the 6-month follow-up; secondary outcomes were severity of adverse effects, withdrawal, and urge to smoke. Subjects were haplotyped for the CYP2B6*6 variants. RESULTS: Among smokers in the CYP2B6*6 group (CYP2B6*1/*6 or CYP2B6*6/*6 genotype, n = 147, 45% of the population), bupropion produced significantly higher abstinence rates than placebo at the end of treatment (32.5% vs. 14.3%, p = .01) and at the 6-month follow-up (31.2% vs. 12.9%, p = .008). In contrast, bupropion was no more effective than placebo for smokers in the CYP2B6*1 group (CYP2B6*1/*1, n = 179) at the end of treatment (31.0% vs. 31.6%, p = .93) or at the 6-month follow-up (22.0% vs. 21.5%, p = .94). There was a significant genotype by treatment interaction at the end of treatment (odds ratio [OR] = 2.97, confidence interval [CI] = 1.05-8.40, p = .04), which was similar at 6-month follow-up (OR = 2.98, CI = .98-9.06, p = .05). CONCLUSIONS: These data suggest that smokers with the CYP2B6*6 genotype have a higher liability to relapse on placebo and that they may be good candidates for bupropion treatment for smoking cessation.     

国产尼古丁舌下含片终止吸烟效果的随机双盲研究

目的 评价国产尼古丁舌下含片戒烟治疗的疗效及安全性。方法 采用随机双盲安慰剂对照研究方法，将230例符合入组条件并签署知情同意书的吸烟者分为尼古丁舌下含片组（治疗组；2mg／片）和安慰剂组，每组各115例，疗程12周；观察治疗期间不同时点戒烟成功率（吸烟量≤1支／d）、吸烟减少有效率（治疗期间吸烟量较治疗前减少≥50％的比例），并评定可视性渴求强度测评表；以尿可替宁和呼气一氧化碳浓度验证吸烟情况。结果 治疗后，治疗组和安慰剂组戒烟成功率分别为52．2％和19．1％，吸烟减少有效率分别为42．6％和14．8％，两组差异具有统计学意义（P〈0．01）；治疗第2～12周末治疗组渴求强度的得分、CO呼出量均小于安慰剂组（P〈0．01）；治疗组尿可替宁含量在第8周和第12周低于安慰剂组（P〈0．01）。治疗期间两组均无严重不良事件发生。结论 尼古丁舌下含片在12周内的戒烟疗效优于安慰剂，不良反应轻，耐受性好，适用于戒烟治疗。     

Two weeks of image-guided left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation improves smoking cessation: A double-blind,sham-controlled,randomized clinical trial

BackgroundPrevious studies have found that repetitive transcranial magnetic stimulation (rTMS) to the left dorsal lateral prefrontal cortex (LDLPFC) transiently reduces smoking craving, decreases cigarette consumption, and increases abstinence rates.ObjectiveWe investigated whether 10 daily MRI-guided rTMS sessions over two weeks to the LDLPFC paired with craving cues could reduce cigarette consumption and induce smoking cessation.MethodsWe enrolled 42 treatment-seeking nicotine-dependent smokers (≥10 cigarettes per day) in a randomized, double-blind, sham-controlled trial. Participants received 10 daily sessions over 2 weeks of either active or sham MRI-guided rTMS (10Hz, 3000 pulses each session) to the LDLPFC concurrently with video smoking cues. The primary outcome was a reduction in biochemically confirmed cigarette consumption with a secondary outcome of abstinence on the target quit date. We also recorded cue-induced craving and withdrawal symptoms.ResultsCompared to sham (n = 17), participants receiving active rTMS (n = 21) smoked significantly fewer cigarettes per day during the 2-week treatment (mean [SD], 13.73[9.18] vs. 11.06[9.29], P < .005) and at 1-month follow-up (12.78[9.53] vs. 7.93[7.24], P < .001). Active rTMS participants were also more likely to quit by their target quit rate (23.81%vs. 0%, OR 11.67, 90% CL, 0.96–141.32, x² = 4.66, P = .031). Furthermore, rTMS significantly reduced mean craving throughout the treatments and at follow-up (29.93[13.12] vs. 25.01[14.45], P < .001). Interestingly across the active treatment sample, more lateral coil location was associated with more success in quitting (−43.43[0.40] vs. −41.79[2.24], P < .013).ConclusionsDaily MRI-guided rTMS to the LDLPFC for 10 days reduces cigarette consumption and cued craving for up to one month and also increases the likelihood of smoking cessation.Trial registrationClinicalTrials.gov identifier: NCT02401672.     

Nicotine dependence in the United States: prevalence, trends, and smoking persistence.

BACKGROUND: The prevalence of smoking in the United States has been closely monitored. However, little is known about the epidemiology of nicotine dependence. We studied DSM-III-R nicotine dependence in the United States, trends across cohorts, and the role of nicotine dependence in smoking persistence. METHODS: The Tobacco Supplement to the National Comorbidity Survey was administered to a representative subset of 4414 persons aged 15 to 54 years. The World Health Organization's Composite International Diagnostic Interview was used to assess nicotine dependence. RESULTS: Lifetime prevalence of nicotine dependence was 24%, nearly half of those who had ever smoked daily for a month or more. The highest risk for nicotine dependence occurred in the first 16 years after daily smoking began, at which point the rate declined and continued at a slower pace for several years. Nicotine dependence increased the risk of smoking persistence, with an odds ratio (OR) of 2.2 (95% confidence interval [CI], 1.6-3.0). Members of the most recent cohort, who were 15 to 24 years of age at the time of the survey, were the least likely to smoke daily, but those who smoked had the highest risk of dependence: OR for daily smoking in the most recent vs earliest cohort was 0.7 (95% CI, 0.5-0.9), and for dependence among smokers, 7.2 (95% CI, 5.0-10.4). CONCLUSIONS: Despite evidence that nicotine dependence is the leading preventable cause of death and morbidity, it remains a common psychiatric disorder. Smoking cessation and the decline in uptake in recent years varied across subgroups of the population.     

Pharmacogenetic association of the galanin receptor (GALR1) SNP rs2717162 with smoking cessation

Galanin modulates dopaminergic neurotransmission in the mesolimbic dopamine system, thereby influencing the rewarding effects of nicotine. Variants in the galanin receptor 1 (GALR1) gene have been associated with retrospective craving severity and heaviness of smoking in prior research. We investigated pharmacogenetic associations of the previously studied GALR1 polymorphism, rs2717162, in 1217 smokers of European ancestry who participated in one of three pharmacogenetic smoking cessation clinical trials and were treated with nicotine patch (n=623), nicotine nasal spray (n=189), bupropion (n=213), or placebo (n=192). The primary endpoint was abstinence (7-day point prevalence, biochemically confirmed) at the end of treatment. Cravings to smoke were assessed on the target quit day (TQD). The longitudinal regression model revealed a significant genotype by treatment interaction (P=0.03). There was a reduced odds of quitting success with the presence of at least one minor (C) allele in the bupropion-treated group (OR=0.43; 95% CI=0.22-0.77; P=0.005) but equivalent quit rates by genotype in the nicotine-replacement therapy groups. This genotype by treatment interaction was reproduced in a Cox regression model of time to relapse (P=0.04). In the bupropion trial, smokers carrying the C allele also reported more severe TQD cravings. Further research to identify functional variants in GALR1 and to replicate pharmacogenetic associations is warranted.     

Response to nicotine dependence treatment in smokers with current and past alcohol problems

Smoking prevalence among alcoholics is high, and evidence indicates that smokers with a history of alcohol abuse may have more difficulty quitting cigarette smoking. This study is a post hoc analysis comparing the smoking cessation rates of smokers with active or past alcohol problems to the rates in smokers with no history of alcohol problems who were participants in a randomized, controlled trial of smoking cessation therapy. Subjects received either 44 mg/24 hour or 22 mg/24 hour nicotine patch for 4 or 6 weeks, respectively, followed by a tapering schedule to complete 8 weeks of therapy and a randomly assigned behavioral intervention (minimal, brief individual counseling, group therapy). The Self-Administered Alcoholism Screening Test (SAAST) score was used to determine alcohol group assignment (no alcohol problems <7; active alcohol problems ≥7 and still drinking; past alcohol problems if not drinking due to a past history of alcohol problems). Among 382 subjects (171 men and 211 women), 281 had no alcohol problems (74%), 53 had past alcohol problems (14%), and 48 had active alcohol problems (13%). Smoking cessation rates assessed at both weeks 4 and 8 were significantly different across groups (p=0.026 and 0.002 at weeks 4 and 8, respectively) with lower rates in the groups with past and active alcohol problems when compared to the “no problem” group. At week 26, subjects with past alcohol problems were less likely to be abstinent from smoking than no problem group subjects, but this was not statistically significant (odds ratio =0.49, 95% confidence interval 0.22→1.08). In the short term, smokers with past or active alcohol problems are less likely to quit smoking compared to those with no alcohol problems when treated with nicotine patch therapy for smoking cessation.     

Long-term effects of a combination of transdermal nicotine administration with behavior therapy for smoking cessation

Effects of a transdermal nicotine substitution on psychological smoking cessation were investigated in a double-blind prospective study. 131 smokers have been randomly assigned to three treatment conditions: All smokers underwent nine weeks of self-controlled smoking cessation. During 6 weeks one group was additionally treated with nicotine patches continuously releasing nicotine through the skin into the blood circuit. The second group received placebo patches; while the third group was treated with behavioral training alone. Treatment effects were measured by daily cigarette consumption. Follow-up investigations were performed 3, 6 and 12 months after therapy. Nicotine-treated subjects reached significantly higher abstinence rates during and at the end of treatment as well as during the follow-up period, than both placebo- and control-subjects. No severe side effects of plasters have been reported. The results thus indicate good therapeutic effectiveness of transdermal nicotine substitution.     

Association of functional COMT Val108/Met polymorphism with smoking cessation in a nicotine replacement therapy

Nicotine replacement treatment (NRT) can be efficacious for smoking cessation, but used by only a minority of smokers in China. Pharmacogenetic matching may improve treatment outcomes for NRT in subgroups of smokers. We evaluated the efficacy and safety of sublingual nicotine tablets (SNT) for smoking cessation and the association of catechol-O-methyltransferase (COMT) genotype with efficacy in this smoking cessation trial among Chinese smokers. We conducted a double-blind, placebo-controlled, 8-week trial of SNT with a follow-up at week 12 among 250 Chinese smokers. Efficacy and safety were evaluated at day 4 and weeks 2, 4, 6, 8, and 12. Abstinence was biochemically verified by exhaled carbon monoxide (CO) and urine cotinine. The COMT Val108Met genotype was determined as a restriction fragment length polymorphism. Our results showed that the success rates for complete abstinence were greater for active versus placebo treatments at 8?weeks (48 vs. 17?%) and 12?weeks (52 vs. 19?%) (both p?<?0.0001). Craving was significantly reduced from week 2 on active treatment compared to placebo. Adverse events were mild and tolerable. We found a genotype by treatment interaction at 12 weeks with greater abstinence rates in the COMT Val/Val (50 vs. 15?%) than the Met/Val?+?Met/Met genotypes (46 vs. 25?%). We found that SNT significantly increased smoking abstinence, reduced craving and was well tolerated, and the COMT Val/Val genotype was associated with a greater improvement in smoking cessation.     

Cigarette smoking, alcohol use, and subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage remains a devastating disease. Identification of etiologic risk factors would allow the possibility of prevention. METHODS: We conducted a population-based case-control study in King County, Washington. Patients whose bleeds originated from a source other than an aneurysm were excluded. Two age- and gender-matched control subjects were identified for each case through random digit telephone dialing. A standardized in-person interview was conducted with the patient whenever possible, a proxy respondent for the case in all instances, the two control subjects, and their proxies. Analyses involved conditional logistic regression taking into account matching on age, gender and respondent type. RESULTS: Over 2 years, 169 cases were identified, and 149 participated in the case-control study. Compared with those who never smoked, the odds ratio for current heavy smokers (greater than 20 cigarettes/day) was 11.1 (95% confidence interval [CI], 5.0-24.9); for current light smokers (less than or equal to 20 cigarettes/day), 4.1 (95% CI, 2.3-7.3); and for former smokers, 1.8 (95% CI, 1.0-3.2). The risk associated with smoking was greatest in the 3 hours after a cigarette (odds ratio [OR] = 7.0; 95% CI, 3.7-13.1) and then fell, not reaching the risk in those who had never smoked until more than 10 years had passed since the last cigarette. Heavy alcohol use (greater than 2 drinks/day) was also associated with bleeds (OR = 2.2; 95% CI, 0.9-5.1, after adjusting for smoking status). These associations were not substantially altered after adjusting for several possible confounding factors, including a history of hypertension. CONCLUSIONS: Cigarette smoking and heavy alcohol use are associated with the occurrence of subarachnoid hemorrhage.     

Memantine fails to facilitate partial cigarette deprivation in smokers – no role of Memantine in the treatment of nicotine dependency?

Summary. The efficacy of Memantine in the treatment of nicotine dependency in humans remained to be evaluated. The aims of our pilot study were to investigate (1) the effectiveness of Memantine in facilitating smoking reduction and (2) the influence of Memantine on the perception of nicotine. In order to achieve these aims we conducted a placebo controlled double-blind parallel group study in smokers (n = 20 per group). Before the beginning of the treatment-phase (10/20 mg Memantine per day) all participants were instructed to reduce smoking (partial deprivation). Before and during partial deprivation we registered the daily cigarette consumption and craving estimates. Following nasal stimulation with nicotine enantiomers hedonic and intensity estimates and the discrimination ability were assessed. Memantine failed to facilitate smoking reduction and did not influence the perception of nicotine with the exception of a weak reduction of olfactory intensity estimates reaching statistical significance for one nicotine enantiomer only.     

A preliminary study of the effects of cigarette smoking on prepulse inhibition in schizophrenia: involvement of nicotinic receptor mechanisms

BACKGROUND: Schizophrenics exhibit deficits in prepulse inhibition (PPI) of the startle response, and have high rates of cigarette smoking. We evaluated the effects of cigarette smoking on PPI deficits in schizophrenia, and the role of nicotinic acetylcholine receptors (nAChRs) in mediating cigarette smoking-related PPI enhancement. METHODS: PPI was assessed at baseline, after overnight abstinence, and after smoking reinstatement during three separate test weeks in nicotine-dependent schizophrenia (n=15) and control (n=14) smokers pre-treated with the nAChR antagonist mecamylamine (MEC; 0.0, 5.0 or 10.0 mg/day). RESULTS: PPI was comparable between schizophrenia and control smokers after ad lib cigarette smoking. Overnight smoking abstinence significantly reduced PPI, while smoking reinstatement reversed abstinence-induced worsening of PPI deficits in schizophrenia. However, acute abstinence and reinstatement did not alter PPI in controls. PPI enhancement by smoking reinstatement in schizophrenia was dose-dependently blocked by MEC, whereas MEC had no effect on PPI in control smokers. CONCLUSIONS: These results suggest that: 1) Non-deprived smokers with schizophrenia have comparable levels of PPI to non-deprived smoking controls; 2) In schizophrenia, PPI is impaired by smoking abstinence and improved by acute smoking reinstatement, and; 3) enhancement of PPI by cigarette smoking in schizophrenia is mediated by stimulation of central nAChRs. Our findings may contribute to understanding the increased vulnerability to nicotine dependence in schizophrenia, with implications for treatment of PPI deficits in this disorder.     

Sevrage tabagique chez les patients fumeurs VIH : expérience de la consultation de tabacologie de l’HEGP à Paris

Introduction

There is a particular need among HIV-infected patients to stop smoking because of the risk of smoking-related complications and the high prevalence of cigarette smoking among them. Only a few studies have focused on this population in real-world settings.

Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy.

BACKGROUND: Given that nicotine modulates amino acid neurotransmission, we sought to examine the impact of nicotine on cortical gamma-aminobutyric acid (GABA) levels in male and female smokers. METHODS: Healthy nicotine-dependent men (n = 10) and women (n = 6) underwent proton magnetic resonance spectroscopy (1H-MRS) to measure occipital cortex GABA concentrations. A subset of the smoking men (n = 5) underwent 1H-MRS scans before and after 48 hours of smoking abstinence, whereas each of the women were scheduled to undergo pre- and postabstinence scans during the follicular and luteal phases of one menstrual cycle. Healthy nonsmoking men (n = 7) and women (n = 13) underwent 1H-MRS for comparison. RESULTS: Short-term abstinence had no significant effect on cortical GABA concentrations in either men or women. There was, however, a significant effect of sex, diagnosis (smoker/nonsmoker), and menstrual cycle phase on cortical GABA levels, such that female smokers experienced a significant reduction in cortical GABA levels during the follicular phase and no cyclicity in GABA levels across the menstrual cycle, whereas cortical GABA levels were similar in smoking and nonsmoking men. CONCLUSIONS: Taken together with previous 1H-MRS data showing abnormalities in occipital cortex GABA concentrations in several affective disorders, our preliminary finding that nicotine modulation of GABA levels varies by sex provides a further rationale for investigating the impact of nicotine on central GABAergic function as a potential risk factor for women to experience depressive symptoms during smoking cessation.     

Association of smoking and nicotine dependence with trauma and posttraumatic stress disorder in a general population sample

This study is aimed at investigating the association between trauma, posttraumatic stress disorder (PTSD), smoking, and nicotine dependence. Data were collected in a representative population sample of 4075 adults aged 18 to 64 with the Composite International Diagnostic Interview. Findings show increased odds ratios (ORs) for smoking (OR: 1.28; 95% CI: 1.09-1.51) and nicotine dependence (OR: 1.52; 95% CI: 1.26-1.82) in traumatized persons, independent of PTSD. Persons with PTSD tended to have higher odds for smoking (OR: 2.12; 95% CI: 1.16-3.90) and nicotine dependence (OR: 2.70; 95% CI: 1.57-4.65), but also had lower rates for quitting smoking (OR: 0.38; 95% CI: 0.17-0.84) and for remission from nicotine dependence (OR: 0.18; CI: 0.05-0.63). We conclude that persons suffering from PTSD might need comprehensive aid in smoking cessation.     

Grey lungs and blue moods: smoking cessation in the context of lifetime depression history

OBJECTIVE: To present an overview of the relationship between depression and cigarette smoking and to provide recommendations for clinicians who wish to help patients with a history of depression to stop smoking. METHOD: English language journal articles published in the last 15 years on clinical material related to depression history, smoking cessation and related health issues were collected via MEDLINE, PsycINFO and Cochrane Library database searches. RESULTS: Nicotine dependence is associated with increased rates of depression prior to and after taking up smoking as well as increased rates of suicidal ideation. Depression history is associated with increased rates of nicotine dependence, problems with smoking cessation and depression after cessation. While nicotine replacement and counselling are effective for smoking cessation, standard smoking cessation strategies may not pay sufficient attention to the needs of smokers with a depression history. Some antidepressants (bupropion and nortriptyline) are particularly effective for those with a lifetime depression history as they appear to assist with dysphoria during withdrawal and prevent relapse. Psychological and lifestyle strategies, such as motivational interviewing, relaxation exercises and mood charts, assist in mood regulation over and above the standard smoking cessation treatments for smokers with a depression history, who require more attention to relapse of depression and smoking after quitting. CONCLUSIONS: There is a complex and circular relationship between depression, smoking and medical illness that complicates smoking cessation in those who have a history of depression. Depression-history smokers require a multimodal approach to assist with mood regulation and nicotine withdrawal. Further research is required to identify effective strategies to reduce smoking in this context.     

Acute reduction in secretory immunoglobulin A following smoking cessation

Smokers report an increase in upper respiratory infections in the early phase of stopping smoking. One possible cause is a depletion in secretory immunoglobulin A (S-IgA) which has been observed in one study. The present study sought to establish this finding in smokers using nicotine patches. Ninety-two smokers, trying to stop smoking, were assessed whilst smoking and for up to six weeks of abstinence. All smokers were prescribed 15 mg 16-h nicotine patches. Among abstinent smokers, changes in S-IgA and saliva volume were assessed. During the preliminary analyses, we observed that for the pre-smoking cessation measure a longer time since the last cigarette was significantly related to lower S-IgA levels (P=0.006). Consequently, the main analysis, of changes in S-IgA from pre-cessation to post-cessation, was confined to those who had smoked within 0.5–1.5 h of the pre-cessation measure (n=51). There was a significant decline in S-IgA, relative to pre-smoking abstinence levels, following abstinence of one day (P=0.027), but levels returned to pre-abstinence values after one week. There was no evidence of any significant changes in saliva volume following smoking cessation, relative to pre-cessation levels. Users of 15 mg patches are likely to experience a decline in S-IgA levels on the first day of smoking cessation, independent of saliva volumes, and this decline in S-IgA is likely to occur acutely, within the first few hours of smoking abstinence. This acute drop in S-IgA appears to stem from a factor other than depletion of nicotine from the body. The observed decrease in S-IgA may help to explain the increased susceptibility of smokers to upper respiratory tract infections in the immediate post-cessation period.     

Smoking cessation pharmacogenetics: analysis of varenicline and bupropion in placebo-controlled clinical trials

Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9-12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23-2.52) (p<0.005); for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27-2.50) (p<0.001). Incidence of nausea was associated with several nAChR subunit genes (OR=0.50; 95% CI: 0.36-0.70) (p<0.0001) and time to relapse after quitting was associated with HTR3B (HR=1.97; 95% CI: 1.45-2.68) (p<0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.     

Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms

BACKGROUND: Cigarette smoking rates in schizophrenia are higher than in the general population. OBJECTIVES: To determine whether cigarette smoking modifies cognitive deficits in schizophrenia and to establish the role of nicotinic acetylcholine receptors (nAChRs) in mediating cigarette smoking-related cognitive enhancement. DESIGN: Neuropsychological assessments were performed at smoking baseline, after overnight abstinence, and after smoking reinstatement across 3 separate test weeks during which subjects were pretreated in a counterbalanced manner with the nonselective nAChR antagonist mecamylamine hydrochloride (0, 5, or 10 mg/d). PARTICIPANTS: Twenty-five smokers with schizophrenia and 25 control smokers. SETTING: Outpatient mental health center. MAIN OUTCOME MEASURES: Visuospatial working memory (VSWM) and Continuous Performance Test (CPT) scores. RESULTS: In smokers with schizophrenia and control smokers, overnight abstinence led to undetectable plasma nicotine levels and an increase in tobacco craving. While abstinence reduced CPT hit rate in both groups, VSWM was only impaired in smokers with schizophrenia. Smoking reinstatement reversed abstinence-induced cognitive impairment. Enhancement of VSWM and CPT performance by smoking reinstatement in smokers with schizophrenia, but not the subjective effects of smoking, was blocked by mecamylamine treatment. CONCLUSIONS: Cigarette smoking may selectively enhance VSWM and attentional deficits in smokers with schizophrenia, which may depend on nAChR stimulation. These findings may have implications for understanding the high rates of smoking in schizophrenia and for developing pharmacotherapies for cognitive deficits and nicotine dependence in schizophrenia.