RATIONALE: Nicotinic acetylcholine receptors (nAChRs) have been implicated in the pathophysiology of cognitive deficits in the domains of attention and memory in schizophrenia. While nicotinic agonists and antagonists have been proposed as smoking cessation aids, few comparisons have been made of these agents on cognitive performance in individuals with schizophrenia. OBJECTIVES: This study investigated the acute effects of a nAChR antagonist, mecamylamine, and partial agonist, varenicline, on cognitive function in non-smokers with and without schizophrenia. METHODS: Single oral doses of mecamylamine 10 mg, varenicline 1 mg, and placebo were administered 1 week apart in random order to adults with schizophrenia (n = 30) and to healthy volunteers (n = 41) in a double-blind, crossover design. The primary outcome of interest was sustained attention as assessed with hit reaction time variability (HRT-SD) on the identical pairs continuous performance test (CPT-IP). RESULTS: Mecamylamine worsened performance on CPT-IP HRT-SD, a measure of attention, compared to varenicline in both groups. Performance on mecamylamine was worse than performance on both placebo and varenicline on several additional measures of attention, including CPT-IP hit reaction time (HRT) and random errors at various levels of task difficulty. There was a treatment by diagnosis interaction, such that mecamylamine worsened performance on CPT-IP 2-digit HRT, 3-digit random errors, and 4-digit hit rate compared to placebo and varenicline in participants with schizophrenia; effects not observed in controls. CONCLUSIONS: These findings support a role for nAChRs in attention and suggest that those with schizophrenia may be particularly sensitive to nAChR blockade.

Mindfulness training (MT) is an emerging therapeutic modality for addictive disorders. Nonjudgment of inner experience, a component of mindfulness, may influence addiction treatment response. To test whether this component influences smoking cessation, tobacco smokers (n = 85) in a randomized control trial of MT vs. Freedom from Smoking (FFS), a standard cognitive-behaviorally-oriented treatment, were divided into split-half subgroups based on baseline Five Facet Mindfulness Questionnaire nonjudgment subscale. Smokers who rarely judge inner experience (nonjudgment > 30.5) smoked less during follow-up when randomized to MT (3.9 cigs/d) vs. FFS (11.1 cigs/d), p < .01. Measuring trait nonjudgment may help personalize treatment assignments, improving outcomes.

The use of dopamine agonists (DAs) has been associated with increased impulsivity and impulse control disorders in several diseases, including Parkinson's disease. Such an effect of DAs on impulsivity has not been clearly characterized in hyperprolactinemic patients, where DAs are the mainstay of therapy. We studied the effects of DAs on impulsivity in hyperprolactinemic patients treated at a tertiary pituitary center, using validated psychometric tests. Cross-sectional study. Impulsivity was evaluated in 30 subjects, 10 hyperprolactinemic patients on DAs compared to two control groups; one comprising untreated hyperprolactinemic patients (n = 10) and a second group consisting of normoprolactinemic controls with pituitary lesions (n = 10). Measures of impulsivity included both self-report questionnaires as well as laboratory-based tasks. Hyperprolactinemic patients on DAs had a higher score (mean ± SD) in one self-report measure of impulsivity, the attention subscale of the Barratt Impulsiveness Scale (16.2 ± 2.7), as compared to the hyperprolactinemic control group (12.3 ± 2.5) and the normoprolactinemic group (14.7 ± 4.4) (p = 0.04). No statistically significant difference was found between groups with regards to the other impulsivity scales. In the DA-treated group, a correlation was observed between increased impulsivity (as assessed in the Experiential Discounting Task) and higher weekly cabergoline dose (r(2) = 0.49, p = 0.04). The use of DAs in hyperprolactinemic patients is associated with an increase in one aspect of impulsivity. This effect should be further characterized in larger, longitudinal studies.

IMPORTANCE: It is estimated that more than half of those with serious mental illness smoke tobacco regularly. Standard courses of pharmacotherapeutic cessation aids improve short-term abstinence, but most who attain abstinence relapse rapidly after discontinuation of pharmacotherapy. OBJECTIVE: To determine whether smokers diagnosed with schizophrenia and bipolar disease have higher rates of prolonged tobacco abstinence with maintenance pharmacotherapy than with standard treatment. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled, parallel-group, relapse-prevention clinical trial conducted in 10 community mental-health centers. Of 247 smokers with schizophrenia or bipolar disease recruited from March 2008-April 2012, 203 received 12-weeks' open-label varenicline and cognitive behavioral therapy and 87 met abstinence criteria to enter the relapse prevention intervention. INTERVENTIONS: Participants who had 2 weeks or more of continuous abstinence at week 12 of open treatment were randomly assigned to receive cognitive behavioral therapy and double-blind varenicline (1 mg, 2 per day) or placebo from weeks 12 to 52. Participants then discontinued study treatment and were followed up to week 76. MAIN OUTCOMES AND MEASURES: Seven-day rate of continuous abstinence at study week 52, the end of the relapse-prevention phase, confirmed by exhaled carbon monoxide. Secondary outcomes were continuous abstinence rates for weeks 12 through 64 based on biochemically verified abstinence and weeks 12 through 76, based on self-reported smoking behavior. RESULTS: Sixty-one participants completed the relapse-prevention phase; 26 discontinued participation (7 varenicline, 19 placebo) and were considered to have relapsed for the analyses; 18 of these had relapsed prior to dropout. At week 52, point-prevalence abstinence rates were 60% in the varenicline group (24 of 40) vs 19% (9 of 47) in the placebo group (odds ratio [OR], 6.2; 95% CI, 2.2-19.2; P < .001). From weeks 12 through 64, 45% (18 of 40) among those in the varenicline group vs 15% (7 of 47) in the placebo group were continuously abstinent (OR, 4.6; 95% CI, 1.5-15.7; P = .004), and from weeks 12 through 76, 30% (12 of 40) in the varenicline group vs 11% (5 of 47) in the placebo group were continuously abstinent (OR, 3.4; 95% CI, 1.02-13.6; P = .03). There were no significant treatment effects on psychiatric symptom ratings or psychiatric adverse events. CONCLUSIONS AND RELEVANCE: Among smokers with serious mental illness who attained initial abstinence with standard treatment, maintenance pharmacotherapy with varenicline and cognitive behavioral therapy improved prolonged tobacco abstinence rates compared with cognitive behavioral therapy alone after 1 year of treatment and at 6 months after treatment discontinuation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00621777.

OBJECTIVES: This meta-analysis sought to evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. Post-treatment abstinence was examined as a secondary outcome and effects on withdrawal symptoms, craving and reduced consumption were also explored. DESIGN: The search strategy for this meta-analysis included clinical trials (published and unpublished data) in the Cochrane Tobacco Addiction Group Specialized Register and MEDLINE. PARTICIPANTS: Adult smokers. INTERVENTIONS: We included randomised trials comparing opioid antagonists to placebo or an alternative therapy for smoking cessation and reported data on abstinence for a minimum of 6 months. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcomes included smoking abstinence at long-term follow-up (primary); abstinence at end of treatment (secondary); and effects on withdrawal, craving and smoking consumption (exploratory). RESULTS: 8 trials with a total of 1213 participants were included. Half the trials examined the benefit of adding naltrexone versus placebo to nicotine replacement therapy (NRT). There was no significant difference between naltrexone and placebo alone (relative risk (RR) 1.00; 95% CI 0.66 to 1.51) or as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30), with an overall pooled estimate of RR 0.97; 95% CI 0.76 to 1.24. Findings for naltrexone effects on withdrawal, craving and reduced smoking were equivocal. CONCLUSIONS: The findings indicate no beneficial effect of naltrexone alone or as an adjunct to NRT on short-term or long-term smoking abstinence. While further trials may narrow the confidence limits, they are unlikely to appreciably alter the conclusion.

As more US states and other countries consider legalizing marijuana, clinicians need to know the possible effects of this drug. Research has shown a connection between marijuana use and an increased risk for schizophrenia in young people who are vulnerable to developing psychosis. An international panel of experts addresses topics such as risk factors for schizophrenia, the potency and effects of cannabis use on adolescents, the effects of concurrent drug use with cannabis on schizophrenia risk, and current attitudes toward marijuana.

OBJECTIVE: Following successful smoking cessation, smokers with schizophrenia are vulnerable to relapse shortly after treatment discontinuation. Our objective was to assess the feasibility and effectiveness of a 12-month relapse prevention intervention in recently abstinent smokers with schizophrenia. METHOD: Adult outpatient smokers with schizophrenia received weekly cognitive behavioral therapy groups, bupropion slow release, transdermal nicotine patch, and nicotine gum or lozenge for three months. Subjects with seven-day point prevalence abstinence at month 3 received an additional 12 months (months 4-15) of therapy with bupropion, transdermal nicotine patch, and nicotine gum/lozenge in conjunction with relapse prevention-based cognitive behavioral therapy groups that were held weekly in month 4, biweekly in months 5-6, and monthly in months 7-15. RESULTS: Seventeen of 41 participants (41.5%) attained biochemically verified self-report of seven-day point prevalence abstinence at the end of three months of treatment and entered relapse prevention treatment. There was an 81% attendance rate at relapse prevention groups. At the end of the 12-month relapse prevention phase (month 15 overall), 11 of 17 (64.7%) demonstrated biochemically verified seven-day point prevalence abstinence, and 10 of 17 (58.8%) reported four-week continuous abstinence. Almost one quarter of the sample (23.5%) demonstrated long-term prolonged abstinence through the end of the trial. There were no clinically detected cases of psychiatric symptom exacerbation. One participant, who was managed as an outpatient, self-reported psychiatric symptom exacerbation in the interim period between study visits. CONCLUSIONS: Extended duration smoking cessation treatment is well-tolerated and may improve smoking outcomes for recently abstinent smokers with schizophrenia. Controlled trials are warranted.

BACKGROUND: The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking. OBJECTIVES: To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialised Register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using 'Narcotic antagonists' and smoking terms in April 2013. We also contacted investigators, when possible, for information on unpublished studies. SELECTION CRITERIA: We considered randomised controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. Abstinence at end of treatment was a secondary outcome. We extracted cotinine- or carbon monoxide-verified abstinence where available. Where appropriate, we performed meta-analysis, pooling risk ratios using a Mantel-Haenszel fixed-effect model. MAIN RESULTS: Eight trials of naltrexone met inclusion criteria for meta-analysis of long-term cessation. One trial used a factorial design so five trials compared naltrexone versus placebo and four trials compared naltrexone plus nicotine replacement therapy (NRT) versus placebo plus NRT. Results from 250 participants in one long-term trial remain unpublished. No significant difference was detected between naltrexone and placebo (risk ratio (RR) 1.00; 95% confidence interval (CI) 0.66 to 1.51, 445 participants), or between naltrexone and placebo as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30, 768 participants). The estimate was similar when all eight trials were pooled (RR 0.97; 95% CI 0.76 to 1.24, 1213 participants). In a secondary analysis of abstinence at end of treatment, there was also no evidence of any early treatment effect, (RR 1.03; 95% CI 0.88 to 1.22, 1213 participants). No trials of naloxone or buprenorphine reported abstinence outcomes. AUTHORS' CONCLUSIONS: Based on data from eight trials and over 1200 individuals, there was no evidence of an effect of naltrexone alone or as an adjunct to NRT on long-term smoking abstinence, with a point estimate strongly suggesting no effect and confidence intervals that make a clinically important effect of treatment unlikely. Although further trials might narrow the confidence intervals they are unlikely to be a good use of resources.

BACKGROUND: Tobacco smoking is the leading preventable cause of death in the developed world. Identifying risk factors for smoking may lead to more effective treatments. Genome wide association studies revealed a relationship between development of nicotine dependence and a single-nucleotide polymorphism (SNP, rs16969968) of the nicotine acetylcholine receptor (nAChR) alpha-5 subunit gene (CHRNA5). The relationship between this SNP and other factors contributing to smoking behavior such as smoking cue reactivity is unclear. METHODS: We assessed the role of rs16969968 on brain functional MRI (fMRI) reactivity to smoking cues by studying nicotine dependent women with the nicotine dependence 'risk' allele (A allele, N=14) and without the 'risk' allele (G/G smokers, N=10). Nicotine dependence severity, as assessed with the Fagerstrom test for nicotine dependence, smoking pack-years, and expired carbon monoxide levels, were equivalent in these groups. RESULTS: We observed a group difference in fMRI reactivity; women without the A allele (G/G smokers) showed greater fMRI reactivity to smoking images in brain areas related to memory and habitual behavior such as the hippocampus and dorsal striatum. CONCLUSIONS: Our finding suggests that nicotine-dependent smokers lacking the rs16969968 A allele are more likely to recall smoking-related memories and engage in habitual responding to smoking cues than A allele smokers. Although more studies are necessary to determine the mechanism underlying and significance of this cue reactivity difference, these data suggest that smokers may develop and remain nicotine dependent due to different factors including genetics and cue reactivity. This finding may have implications for personalizing smoking treatment.

OBJECTIVE: To clarify the efficacy and tolerability of bupropion sustained release (SR) for the treatment of cigarette smoking in people with schizophrenia. METHOD: The first study is a double-blind, placebo-controlled clinical trial with 32 outpatients from the Maryland Psychiatric Research Center. From May 2003 to July 2007, clinically stable people with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder who smoked at least 10 cigarettes per day and who were interested in quitting smoking or cutting down were recruited for participation. All participated in a 9-week support group and were randomly assigned to receive 12 weeks of bupropion SR or placebo. The primary outcome measure was 4 weeks' sustained abstinence over the last 4 study weeks. Secondary outcome measures included decrease in smoking behavior and change in symptoms, neuropsychological performance, and side effects. In the second study, we performed an electronic literature search of MEDLINE in September 2008. Articles in English published between 2003 and 2008 were searched for the terms schizophrenia, bupropion SR, and smoking. Bibliographies of studies identified through the MEDLINE search were also examined. Case reports, open-label studies, crossover studies, and studies using nonstandard dosing of bupropion SR were excluded. In this way, 4 studies similar in methodology to the currently presented clinical trial were identified and the individual data combined in a meta-analysis. A random effects meta-analysis using Comprehensive Meta-Analysis software was used to obtain a pooled estimate of the odds ratio for 4-week smoking abstinence between bupropion SR and placebo. RESULTS: There were no significant results on the primary or secondary smoking measures for the clinical trial, although a numeric advantage favored the bupropion SR group. There were no significant findings for secondary symptom or side effect measures and no significant change in neuropsychological performance. For the meta-analysis totaling 226 subjects, there were significant findings in favor of bupropion SR. The pooled estimate of the odds ratio for 4-week abstinence was 2.7 (95% CI, 1.3 to 5.7; P = .009), and clinically significant greater smoking reduction in the bupropion SR group, with pooled difference estimates increasing over time between groups, became statistically significant by week 5 of study medication (P < .02). CONCLUSIONS: New clinical trial data and a meta-analysis strongly support the tolerability and efficacy of bupropion SR for the treatment of cigarette smoking in people with schizophrenia TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00176449.

Evaluation of: Newhouse P, Kellar K, Aisen P et al. Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. Neurology 78(2), 91-101 (2012). There have been several drug trials in recent years investigating the efficacy of commonly used Alzheimer's disease therapies for symptoms of mild cognitive impairment (MCI). However, there are no US FDA-approved pharmacological treatments for MCI. As the incidence rates of MCI are considerable, it is clear that better treatments for MCI need to be developed. The reviewed paper presents new data on a pilot clinical trial which shows that transdermal nicotine treatment for 6 months improved cognitive performance in subjects with amnestic MCI. Further studies will possibly bring us wider usage of nicotine for individuals with cognitive dysfunction.

We sought to examine the efficacy and safety of acamprosate augmentation of escitalopram in patients with concurrent major depressive disorder (MDD) and alcohol use disorders. Twenty-three adults (43% female; mean ± SD age, 46 ± 14 years) were enrolled and received 12 weeks of treatment with psychosocial support; escitalopram, 10 to 30 mg/d; and either acamprosate, 2000 mg/d (n = 12), or identical placebo (n = 11). Outcomes included change in clinician ratings of depressive symptoms, MDD response and remission rates, changes in frequency and intensity of alcohol use, retention rates, and adverse events. Twelve subjects (acamprosate, n = 7; placebo, n = 5) completed the study. There was significant mean reduction in ratings of depressive symptoms from baseline in both treatment arms (P < 0.05), with no significant difference between the groups. Those in the acamprosate group had a 50% MDD response rate and a 42% remission rate, whereas those in the placebo arm had a 36% response and remission rate (not significant). Those assigned to acamprosate had significant reduction in number of drinks per week and drinks per month during the trial, whereas those assigned to placebo demonstrated no significant change in any alcohol use parameter, but the between-group difference was not significant. There were no significant associations between change in depressive symptoms and change in alcohol use. Attrition rates did not differ significantly between the 2 arms. Acamprosate added to escitalopram in adults with MDD and alcohol use disorders was associated with reduction in the frequency of alcohol use. The present study was not powered to detect superiority versus placebo. Further study in a larger sample is warranted.

RATIONALE: Smoking rates are up to five times higher in people with schizophrenia than in the general population, placing these individuals at high risk for smoking-related health problems. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, is a promising aid for smoking cessation in this population. To maximize treatment efficacy while minimizing risks, it is critical to identify reliable predictors of positive response to varenicline in smokers with schizophrenia. OBJECTIVES: Negative symptoms of schizophrenia are related to dysfunctions in the brain reward system, are associated with nicotine dependence, and may be improved by nicotine or nicotinic receptor agonists, suggesting that smoking cessation may be especially difficult for patients with substantial negative symptoms. The purpose of the study was to evaluate negative symptoms as predictors of response to varenicline. METHODS: Patients with schizophrenia (N = 53) completed a 12-week smoking cessation trial combining varenicline with cognitive behavioral therapy. Negative symptoms were assessed via the Scale for the Assessment of Negative Symptoms (Andreasen 1983). Outcomes included smoking abstinence as assessed by self-report and expired carbon monoxide. Change in performance on a probabilistic reward task was used as an index of change in reward sensitivity during treatment. RESULTS: At week 12, 32 participants met criteria for 14-day point-prevalence abstinence. Patients with lower baseline symptoms of affective flattening (more typical affect) were more likely to achieve smoking abstinence and demonstrated larger increases in reward sensitivity during treatment. CONCLUSIONS: These data suggest that affective flattening symptoms in smokers with schizophrenia may predict response to varenicline.

OBJECTIVES: Varenicline was approved by the FDA in 2006. In 2009, based largely on case reports, the FDA issued a warning of possible adverse neuropsychiatric effects including depression and suicidal thoughts and behavior for varenicline and bupropion. Prospective trials of varenicline have not reported increased incidence of psychiatric adverse events other than sleep disturbance, but smokers with major mental illness have been excluded from large prospective trials of varenicline to date. We sought to evaluate the effect of a standard open-label 12-week varenicline trial on prospectively assessed safety and smoking outcomes in stable, treated adults with schizophrenia spectrum disorder and nicotine dependence. METHODS: One-hundred-and-twelve stable outpatients who smoked >10 cigarettes/day participated in a 12-week, open-label, smoking cessation trial of varenicline and weekly group cognitive behavioral therapy. Participants took varenicline for 4 weeks before attempting cessation. Trained raters collected safety and smoking outcome data weekly. RESULTS: Participants demonstrated improved psychotic symptoms, depressive symptoms and nicotine withdrawal symptoms from baseline to week 12 or early termination. At the end of 12 weeks open label treatment, the 14- and 28-day continuous abstinence rates were 47.3 and 34%, respectively. Expired CO declined significantly during treatment in those who did not achieve abstinence. CONCLUSIONS: This prospective study suggests that varenicline may be well-tolerated and effective for smoking cessation in combination with group CBT in stable outpatients with schizophrenia, a group with high rates of smoking and smoking-attributable morbidity and mortality.

BACKGROUND: Cigarette smoking is the leading preventable cause of death. Unfortunately, the majority of smokers who attempt to quit smoking relapse within weeks. Abnormal dorsal anterior cingulate cortex (dACC) function may contribute to tobacco smoking relapse vulnerability. Growing evidence suggests that glutamate neurotransmission is involved in mediating nicotine dependence. We hypothesized that prior to a cessation attempt, dACC glutamate levels would be lower in relapse vulnerable smokers. METHODS: Proton magnetic resonance spectra (MRS) were obtained from dACC and a control region, the parieto-occipital cortex (POC), using two-dimensional J-resolved MRS at 4T and analyzed using LCModel. Nine nicotine-dependent women were scanned prior to making a quit attempt. Subjects then were divided into two groups; those able to maintain subsequent abstinence aided by nicotine replacement therapy (NRT) and those who slipped while on NRT (smoked any part of a cigarette after attaining at least 24h of abstinence). RESULTS: Slip subjects exhibited significantly reduced dACC MRS glutamate (Glu/Cr) levels (p<0.03) compared to abstinent subjects. This effect was not observed in the POC control region. CONCLUSIONS: Our preliminary findings suggest that dACC Glu levels as measured with MRS may help identify and/or be a biomarker for relapse vulnerable smokers. Future research following up on these findings may help clarify the role of dACC Glu in smoking dependence that may lead to new treatment strategies.

OBJECTIVE: Mood and alcohol use disorders are often co-occurring, each condition complicating the course and outcome of the other. The aim of this study was to examine the efficacy of antidepressants in patients with unipolar major depressive disorder (MDD) and/or dysthymic disorder with comorbid alcohol use disorders and to compare antidepressant and placebo response rates between depressed patients with or without comorbid alcohol use disorders. DATA SOURCES: MEDLINE/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for the acute-phase treatment of MDD and/or dysthymic disorder in patients with or without alcohol use disorders. The search term placebo was cross-referenced with each of the antidepressants approved by the US, Canadian, or European Union drug regulatory agencies for the treatment of MDD and/or dysthymic disorder. STUDY SELECTION: 195 articles were found eligible for inclusion in our analysis, 11 of which focused on the treatment of MDD/dysthymic disorder in patients with comorbid alcohol use disorders. The search was limited to articles published between January 1, 1980, and March 15, 2009 (inclusive). RESULTS: We found that antidepressant therapy was more effective than placebo in patients with comorbid alcohol use disorders (risk ratio of response = 1.336; P = .021). However, this was not the case when selective serotonin reuptake inhibitor (SSRI) antidepressants were examined alone (P > .05). There was no significant difference in the relative efficacy of antidepressants (versus placebo) when comparing studies in MDD/dysthymic disorder patients with or without alcohol use disorders (P = .973). Meta-regression analyses yielded no significant differences in the risk ratio of responding to antidepressants versus placebo in trials with comorbid alcohol use disorders, whether antidepressants were used alone or adjunctively to psychotherapy, whether they were used in patients actively drinking or recently sober, or whether they were used in pure MDD or in combined MDD and dysthymic disorder populations. CONCLUSIONS: These results support the utility of certain antidepressants (tricyclics, nefazodone) in treating depression in patients with comorbid alcohol use disorders. More data on the use of newer antidepressants, including the SSRIs, for this select patient population are needed.

Relapse to smoking is common after initial abstinence with pharmacotherapy and behavioral support and represents a major clinical challenge. Although mechanisms underlying relapse to smoking have not been elucidated, preclinical studies suggest that glutamate receptors may be involved. We sought to test a selective antagonist of the glycine coagonist site on the glutamate N-methyl-D-aspartate receptor, GW468816, for prevention of relapse in recently abstinent smokers. To do so, we enrolled 264 healthy female smokers in an open 8-week smoking cessation intervention with behavioral therapy and a standard dose of transdermal nicotine replacement therapy with taper and additional gum or lozenge as needed for nicotine withdrawal symptoms. Ninety-eight participants achieved 7-day point prevalence abstinence and were randomized into a 5-week double-blind, placebo-controlled, relapse-prevention trial of GW468816 (200 mg/d) and then followed for 60 days after randomization. There was no effect of treatment on abstinence rates at the end of treatment (χ² [1, n = 96] = 0.168, P = 0.838), on the rates of relapse (χ² [1, n = 98] = 0.031, P = 1.000) or lapse (χ² [1, n = 62] = 0.802, P = 0.423), or on time to relapse (χ² [1, n = 98) = 0.001, P = 0.972). No significant relationships were detected between plasma GW468816 concentrations and abstinence, time to relapse, or self-reported craving. In conclusion, despite promising preclinical data that support the use of a selective NMDA glycine site antagonist for prevention of relapse to smoking, we observed no effect of GW468816 on relapse or lapse rates, time to relapse, or craving compared to placebo.

Immune system abnormalities in schizophrenia include a shift from a Type 1 (cellular) to a Type 2 (humoral) immune response. To characterize the activation status of the immune system in schizophrenia, we examined the pattern of gene expression in peripheral blood cells for three Th1 cytokines (interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2)), and one Th2 cytokine (interleukin-10 (IL-10)). In a cross-sectional study, we used quantitative reverse-transcription polymerase chain reaction (RT-PCR) to compare the mRNA levels of IFN-gamma, TNF-alpha, IL-2, and IL-10 in peripheral blood mononuclear cells (PBMCs) between 15 schizophrenia patients and 15 matched healthy controls. Expression of IFN-gamma and TNF-alpha was significantly reduced in patients with schizophrenia compared with normal controls. No differences in IL-2 and IL-10 gene expression were observed. These results are consistent with impaired Type 1 cellular immunity in schizophrenia. While the data illustrate the potential utility of mRNA-based approaches for the identification and analysis of immune biomarkers for neuropsychiatric disorders, correlation of gene expression with direct measures of cytokine concentrations is required.