Gladys N. Pachas

Brain reactivity to smoking cues prior to smoking cessation predicts ability to maintain tobacco abstinence.

BACKGROUNDnDeveloping the means to identify smokers at high risk for relapse could advance relapse prevention therapy. We hypothesized that functional magnetic resonance imaging (fMRI) reactivity to smoking-related cues, measured before a quit attempt, could identify smokers with heightened relapse vulnerability.nnnMETHODSnBefore quitting smoking, 21 nicotine-dependent women underwent fMRI during which smoking-related and neutral images were shown. These smokers also were tested for possible attentional biases to smoking-related words using a computerized emotional Stroop (ES) task previously found to predict relapse. Smokers then made a quit attempt and were grouped based on outcomes (abstinence vs. slip: smoking > or = 1 cigarette after attaining abstinence). Prequit fMRI and ES measurements in these groups were compared.nnnRESULTSnSlip subjects had heightened fMRI reactivity to smoking-related images in brain regions implicated in emotion, interoceptive awareness, and motor planning and execution. Insula and dorsal anterior cingulate cortex (dACC) reactivity induced by smoking images correlated with an attentional bias to smoking-related words. A discriminant analysis of ES and fMRI data predicted outcomes with 79% accuracy. Additionally, smokers who slipped had decreased fMRI functional connectivity between an insula-containing network and brain regions involved in cognitive control, including the dACC and dorsal lateral prefrontal cortex, possibly reflecting reduced top-down control of cue-induced emotions.nnnCONCLUSIONSnThese findings suggest that the insula and dACC are important substrates of smoking relapse vulnerability. The data also suggest that relapse-vulnerable smokers can be identified before quit attempts, which could enable personalized treatment, improve tobacco-dependence treatment outcomes, and reduce smoking-related morbidity and mortality.

Maintenance Treatment With Varenicline for Smoking Cessation in Patients With Schizophrenia and Bipolar Disorder A Randomized Clinical Trial

IMPORTANCEnIt 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.nnnOBJECTIVEnTo determine whether smokers diagnosed with schizophrenia and bipolar disease have higher rates of prolonged tobacco abstinence with maintenance pharmacotherapy than with standard treatment.nnnDESIGN, SETTING, AND PARTICIPANTSnRandomized, 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.nnnINTERVENTIONSnParticipants 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.nnnMAIN OUTCOMES AND MEASURESnSeven-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.nnnRESULTSnSixty-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; Pu2009<u2009.001). 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; Pu2009=u2009.004), 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; Pu2009=u2009.03). There were no significant treatment effects on psychiatric symptom ratings or psychiatric adverse events.nnnCONCLUSIONS AND RELEVANCEnAmong 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.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00621777.

High-Dose Galantamine Augmentation Inferior to Placebo on Attention, Inhibitory Control and Working Memory Performance in Nonsmokers with Schizophrenia

Dysfunction in the neuronal nicotinic acetylcholine receptor (nAChR) system has been implicated in the pathophysiology of schizophrenia, and it has been postulated that treatments that increase nAChR activity may improve symptoms of the disorder. We investigated the effects of the acetylcholinesterase inhibitor and allosteric nAChR modulator, galantamine, on cognitive performance and clinical symptoms when added to a stable antipsychotic medication regimen in nonsmoking outpatients with schizophrenia in a double-blind, placebo-controlled, parallel-group design. Participants were randomized to receive either galantamine (n=10) up to 32 mg/day or identical placebo (n=10) for 8 weeks and completed a cognitive battery at baseline and week 8 and clinical scales at baseline, week 4 and week 8. The primary outcome measure was attentional performance as measured by the d measure in the Continuous Performance Test - Identical Pairs (CPT-IP) Version. Contrary to our hypothesis, galantamine treatment was associated with inferior performance on the CPT-IP, on the three-card Stroop task, and on the Letter-Number Span task without reordering. Galantamine had no effect on clinical symptoms. In summary, galantamine treatment, at a dose of 32 mg/day, was well tolerated but was not effective as an adjunctive treatment for cognitive deficits in stable nonsmokers with schizophrenia.

Varenicline for Smoking Cessation in Schizophrenia: Safety and Effectiveness in a 12-Week Open-Label Trial

Objective: 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 adults with stable, treated schizophrenia spectrum disorder and nicotine dependence. Methods: One-hundred twelve stable outpatients who smoked 10 or more 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 carbon monoxide 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 cognitive behavioral therapy in stable outpatients with schizophrenia, a group with high rates of smoking and smoking-attributable morbidity and mortality. This clinical trial is registered at www.clinicaltrials.gov as trial #NCT00621777.

Investigation of impulsivity in patients on dopamine agonist therapy for hyperprolactinemia: a pilot study

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 (nxa0=xa010) and a second group consisting of normoprolactinemic controls with pituitary lesions (nxa0=xa010). Measures of impulsivity included both self-report questionnaires as well as laboratory-based tasks. Hyperprolactinemic patients on DAs had a higher score (meanxa0±xa0SD) in one self-report measure of impulsivity, the attention subscale of the Barratt Impulsiveness Scale (16.2xa0±xa02.7), as compared to the hyperprolactinemic control group (12.3xa0±xa02.5) and the normoprolactinemic group (14.7xa0±xa04.4) (pxa0=xa00.04). 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 (r2xa0=xa00.49, pxa0=xa00.04). 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.

Anterior cingulate proton spectroscopy glutamate levels differ as a function of smoking cessation outcome

BACKGROUNDnCigarette 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.nnnMETHODSnProton 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).nnnRESULTSnSlip 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.nnnCONCLUSIONSnOur 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.

Single Dose Propranolol Does Not Affect Physiologic or Emotional Reactivity to Smoking Cues

BackgroundSmoking cue exposure reactivates salient smoking-related memories, triggering craving to smoke, a phenomenon associated with maintenance of smoking behavior and relapse after periods of abstinence. Acute β-adrenergic blockade with propranolol reduces physiologic reactivity during subsequent recollection of traumatic events by inhibiting reconsolidation of reactivated memories in a process called memory reconsolidation blockade.ObjectiveThe objective of this study is to determine whether a single dose of propranolol prior to retrieval of smoking-related memories reduces subsequent physiologic reactivity to personally salient smoking imagery scripts in current smokers.MethodsFifty-four overnight-abstinent, adult smokers received a single-dose propranolol or placebo prior to reactivation of smoking-related memories in a randomized, double-blind, placebo-controlled trial and resumed smoking afterward. One week later, skin conductance (SC), heart rate (HR), left corrugator electromyogram (EMG), self-reported emotional state, and craving were assessed following script-driven imagery with neutral and personalized smoking-related scripts.ResultsSmoking scripts were associated with increased physiologic activation (SC, HR, EMG), craving, and negative emotional state compared with neutral scripts. Propranolol did not moderate the effect of script type on any outcome.ConclusionPersonalized smoking script-driven imagery robustly increased physiologic activation, negative emotional state, and craving, and a single dose of propranolol prior to memory reactivation did not moderate this effect.

Achieving Smoking Cessation in Individuals with Schizophrenia: Special Considerations

Premature mortality due to cardiovascular disease in those with schizophrenia is the largest lifespan disparity in the US and is growing; adults in the US with schizophrenia die, on average, 28xa0years earlier than those in the general population. The rate of smoking prevalence among individuals with schizophrenia is estimated to be from 64 to 79%. Smokers with schizophrenia have historically been excluded from most large nicotine-dependence treatment studies. However, converging evidence indicates that a majority of smokers with schizophrenia want to quit smoking, and that available pharmacotherapeutic smoking cessation aids are well tolerated by this population of smokers and are effective when combined with behavioral treatment. The aim of this review is to present updated evidence for safety and efficacy of smoking cessation interventions for those with schizophrenia spectrum illness. We also highlight implications of the very low abstinence rates for smokers with schizophrenia who receive placebo plus behavioral treatment in randomized trials, and review treatment approaches to address the high rate of rapid relapse observed upon pharmacologic treatment discontinuation in this population. Recommendations for monitoring for treatment-emergent nicotine withdrawal symptoms, side effects, and effects of cessation on antipsychotic medication are also provided. Smokers with schizophrenia spectrum disorders should be encouraged to quit smoking and should receive varenicline, bupropion with or without nicotine replacement therapy (NRT), or NRT, all in combination with behavioral treatment for at least 12xa0weeks. Maintenance pharmacotherapy may reduce relapse and improve sustained abstinence rates. Controlled trials in smokers with schizophrenia consistently show no greater rate of neuropsychiatric adverse events with pharmacotherapeutic cessation aids than with placebo.

Weight Gain and 10-Year Cardiovascular Risk With Sustained Tobacco Abstinence in Smokers With Serious Mental Illness: A Subgroup Analysis of a Randomized Trial

OBJECTIVEnPeople with serious mental illness die earlier than those without mental illness, largely from cardiovascular disease due to high rates of smoking and obesity. The objective of this study was to determine whether the metabolic effects of postcessation weight gain among smokers with serious mental illness attenuated the cardiovascular benefit of tobacco abstinence.nnnMETHODnA subgroup analysis was conducted of 65 outpatient smokers with DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder from 10 community mental health centers in 6 states who enrolled between March 2008-April 2012 and completed a trial of varenicline for tobacco abstinence. The intervention included a 12-week open-label phase with varenicline followed by a 40-week randomized, placebo-controlled phase in 87 participants who achieved 12-week abstinence. Main outcome measures were smoking status and change from baseline in weight and 10-year Framingham cardiovascular risk score at end of intervention (week 52).nnnRESULTSnAt week 52, 65 participants completed follow-up (33 abstinent; 32 relapsed). At baseline, the 2 groups did not differ in body mass index (mean = 31 kg/m(2)), blood pressure, serum glucose, or diagnoses of diabetes (31%) and hypertension (34%). Abstinent participants were older and had a higher mean baseline Framingham risk score (14.2% vs 10.3%, P = .002). At week 52, abstinent participants gained more weight than relapsed participants (4.8 vs 1.2 kg, P = .048) and, as a result of quitting smoking, had a greater reduction in Framingham risk score (-7.6% vs 0.0%, P < .001). There was no effect of study drug assignment on weight or Framingham risk score.nnnCONCLUSIONSnSustained tobacco abstinence reduced 10-year cardiovascular risk in outpatients with serious mental illness despite significant postcessation weight gain and high prevalence of obesity, diabetes, and hypertension.nnnTRIAL REGISTRATIONnClinicaltrials.gov identifier: NCT00621777.

A double-blind, placebo-controlled trial of the NMDA glycine site antagonist, GW468816, for prevention of relapse to smoking in females.

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 (&khgr;2 [1, n = 96] = 0.168, P = 0.838), on the rates of relapse (&khgr;2 [1, n = 98] = 0.031, P = 1.000) or lapse (&khgr;2 [1, n = 62] = 0.802, P = 0.423), or on time to relapse (&khgr;2 [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.