Kristi A. Sacco

Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders

Cigarette smoking rates in the American population are approximately 23%, whereas rates of smoking in clinical and population studies of individuals with neuropsychiatric disorders are typically two- to four-fold higher. Studies conducted in a variety of neuropsychiatric populations [e.g. attention-deficit hyperactivity disorder (ADHD), Alzheimer’s disease, schizophrenia] have collectively suggested that nicotine may be efficacious in remediating selected cognitive deficits associated with these disorders, thus providing a framework for understanding the specific vulnerability of these patients to smoking initiation and maintenance. However, the specific gain in cognitive performance produced by nicotine administration in healthy subjects with normal cognitive function is less clear. This article reviews our current understanding of central nicotinic acetylcholine receptor (nAChRs) systems in normal and neuropsychiatric disease states and, specifically, their role with respect to cognitive dysfunction and clinical symptoms in several specific neuropsychiatric populations, including ADHD, Alzheimer’s disease, Parkinson’s disease, Tourette’s Disorder, schizophrenia and affective disorders. The potential benefits of nicotinic agents for therapeutic use in neuropsychiatric disorders is discussed, as well as directions for further research in this area.

A Placebo-Controlled Trial of Bupropion Combined with Nicotine Patch for Smoking Cessation in Schizophrenia

BACKGROUND Individuals with schizophrenia smoke at higher rates (58%-88%) than the general population (approximately 22%), and have difficulty quitting. We determined whether the combination of sustained-release (SR) bupropion (BUP) with the transdermal nicotine patch (TNP) was well-tolerated and superior to placebo (PLO)+TNP for smoking cessation in schizophrenia. METHODS A 10-week, double-blind, placebo-controlled trial of BUP (300 mg/day) in combination with TNP (21 mg/24h) for 58 outpatient smokers with schizophrenia was conducted. Primary outcome measures were continuous smoking abstinence in the last 4 weeks of the trial (Days 43-70) and 7-day point prevalence abstinence at 6 months post-target quit date (TQD) (week 26). RESULTS Smokers assigned to the BUP+TNP group (n = 29) were more likely to achieve continuous smoking abstinence (8/29, 27.6%) than the PLO+TNP group (n = 29, 1/29, 3.4%) [Fishers Exact Test, p < .05]; at 6-months post-TQD, 4/29 (13.8%) versus 0/29 (0.0%) achieved 7-day point prevalence smoking abstinence (p = .11). Neither bupropion SR nor smoking abstinence significantly altered the positive or negative symptoms of schizophrenia. The combination was well-tolerated in smokers with schizophrenia. CONCLUSIONS Combination therapy with bupropion SR+TNP versus placebo+TNP is well-tolerated and significantly improved short-term smoking abstinence in smokers with schizophrenia.

Nicotinic antagonist augmentation of selective serotonin reuptake inhibitor-refractory major depressive disorder: a preliminary study.

Background: There is evidence for nicotinic hypercholinergic mechanisms in depression. Clinical relationships between tobacco use and depression suggest important effects of nicotine in major depressive disorder (MDD). It has been hypothesized that cigarette smoking may exert antidepressant effects, presumably mediated through stimulation of nicotinic acetylcholine receptor systems. We compared the nicotinic antagonist, mecamylamine hydrochloride (MEC), with placebo as an augmentation strategy for patients with MDD who were refractory to selective serotonin reuptake inhibitor (SSRI) treatment. Methods: Twenty-one SSRI-treated subjects with MDD were randomized to MEC (up to 10 mg/d; n = 11) or placebo (PLO group; n = 10) during an 8-week trial. The primary outcome measure was the change in depressive symptoms assessed using the 17-item Hamilton Depression Rating Scale during the 8-week trial. Results: There was a significant reduction in 17-item Hamilton Depression Rating Scale scores in the MEC versus PLO groups, as evidenced by a significant medication × time interaction (F1,19 = 6.47, P < 0.05). Five (45.5%) of 11 subjects in the active study medication group demonstrated a 50% or more decrease in depressive symptoms from baseline as compared with 1 (10%) of 10 subjects assigned to placebo medication, but this difference was not significant (P = 0.15; Fisher exact test). The primary side effects of MEC were constipation and orthostatic hypotension. Conclusions: These preliminary findings suggest that the nicotinic acetylcholine receptor antagonist, MEC, may have utility as an augmentation strategy for patients with SSRI-refractory MDD.

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.

Neuropsychological deficits are associated with smoking cessation treatment failure in patients with schizophrenia.

Schizophrenics have deficits in neuropsychological performance, some of which are modified by cigarette smoking. These patients also have high rates of smoking and resistance to smoking cessation interventions. We examined whether the presence of neuropsychological deficits prior to smoking cessation treatment was associated with smoking cessation treatment failure in schizophrenic as compared to non-psychiatric control smokers. Neuropsychological assessments were performed prior to treatment with pharmacological agents during the course of placebo-controlled trials in schizophrenic and non-psychiatric control smokers, and included the Wisconsin Card Sorting Test (WCST), a Visuospatial Working Memory (VSWM) task, the Stroop Color Word Test (SCWT) and the Continuous Performance Test (CPT). In schizophrenics (n=32), subjects who had greater deficits in VSWM and WCST performance were significantly less likely to quit smoking, but this association was not observed in controls (n=40). Differences between quitters and non-quitters were not likely related to atypical antipsychotic treatment or differences in depressive symptoms. No associations between baseline performance on CPT or SCWT and quit status were found in either group. These preliminary data suggest that in schizophrenics, neuropsychological deficits are associated with smoking cessation treatment failure.

Risk/reward decision-making in schizophrenia: A preliminary examination of the influence of tobacco smoking and relationship to Wisconsin Card Sorting Task performance

BACKGROUND Individuals with schizophrenia show deficits in cognitive functioning, as evidenced by deficits on neurocognitive tasks such as the Wisconsin Card Sorting Task (WCST). Studies of risk/reward decision-making in individuals with schizophrenia have yielded mixed results, and few studies have examined systematically the relationship between these domains and their relationship with clinical factors. METHOD Thirty-two smokers with schizophrenia, ten non-smokers with schizophrenia, nine non-psychiatric non-smokers and ten non-psychiatric smokers were administered computerized versions of the Iowa Gambling Task (IGT) and the WCST. Smokers were allowed to smoke adlibitum during designated breaks in order to prevent deprivation. RESULTS Subjects with schizophrenia performed significantly worse than non-psychiatric controls on both the IGT and the WCST, and performance on these tasks was significantly correlated across subject groups. Among women with schizophrenia, smokers performed significantly better than non-smokers on the IGT. CONCLUSIONS Individuals with schizophrenia perform worse than controls on the IGT, suggesting impairments in risk/reward decision-making. Correlations between IGT and WCST performance suggest a shared element underlying task performance, such as a deficit in set-shifting or perseverance. Further research is needed to establish the relationship between cigarette smoking and IGT performance in schizophrenia.

Neuropsychological performance in patients with schizophrenia and controls as a function of cigarette smoking status

Schizophrenia is associated with many neurocognitive deficits, some of which are improved by nicotine and cigarette smoking. To better understand the relationship between smoking and cognitive function in schizophrenia, cross-sectional assessment of neuropsychological performance as a function of smoking status (smoker or non-smoker) and smoking history (current, former or never-smoker) in clinically stable outpatients with schizophrenia and controls was evaluated. Subjects (n=140) were divided into subgroups on the basis of self-report and biochemical verification of smoking history. Current smokers with schizophrenia (n=38), former smokers with schizophrenia (n=17), never-smokers with schizophrenia (n=12), control smokers (n=31), control former smokers (n=16), and control never-smokers (n=26) were administered a comprehensive neuropsychological battery. Smokers were studied under non-deprivation conditions. Comparison of neuropsychological performance in schizophrenia and control subjects revealed significant main effects of diagnosis. Analysis of the data as a function of smoking history demonstrated that never-smokers with schizophrenia performed the poorest on measures of sustained attention, processing speed and response inhibition, when compared to the other schizophrenia subgroups. Cigarette smoking did not alter neuropsychological performance in controls. Our findings suggest that smoking status and history differentially alters neuropsychological outcomes in schizophrenia compared to non-psychiatric controls, and that never-smokers may present with more severe neurocognitive impairments.

Prefrontal cognitive dysfunction is associated with tobacco dependence treatment failure in smokers with schizophrenia

BACKGROUND Patients with schizophrenia have higher rates of smoking (58-88%) than in the general population ( approximately 22%), and are more refractory to smoking cessation. These patients also exhibit numerous neurocognitive deficits, some of which may be ameliorated by cigarette smoking. The neurocognitive benefits derived from nicotine may, in turn, contribute to elevated rates of smoking and smoking persistence in schizophrenia. The present study examined the relationship between neurocognitive function and smoking cessation in schizophrenia. METHODS Treatment-seeking smokers with schizophrenia (N=58) participated in a 10-week placebo-controlled trial of sustained-release (SR) bupropion plus transdermal nicotine patch. Neuropsychological performance was evaluated in a subset of patients (n=31), prior to pharmacological treatment, using a neurocognitive battery. RESULTS Subjects were compared as a function of endpoint smoking status (Quit versus Not Quit), assessed by end of trial 7-day point prevalence abstinence, confirmed by CO level (< 10 ppm) on demographic traits, smoking, and clinical outcomes. While there were no significant baseline differences between quitters and non-quitters, non-quitters exhibited significantly greater deficits in performance on Trail Making Test, Part B (p=0.01) and on Digit Span backwards (p=0.04) compared to quitters. No associations were found between quit status and performance on other neuropsychological measures. CONCLUSIONS Our findings extend results of previous studies which suggest deficits in frontal executive function are associated with smoking cessation failure in schizophrenia. This may have implications for the development of tailored smoking cessation treatments in this population.

Effects of acute abstinence, reinstatement, and mecamylamine on biochemical and behavioral measures of cigarette smoking in schizophrenia.

BACKGROUND Schizophrenics have higher rates of smoking than the general population, and more difficulty with smoking cessation. However, there has been little study of differences between schizophrenics and controls with respect to biochemical and behavioral indices of smoking. We compared smokers with schizophrenia (SS; n=27) and control smokers (CS; n=26) on smoking and psychiatric outcomes at baseline, during acute smoking abstinence and reinstatement, and with pre-treatment using the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (MEC) in a human laboratory setting. METHODS Biochemical (e.g., plasma nicotine) and behavioral (e.g., craving, withdrawal) outcomes were assessed at baseline, after overnight abstinence, and after smoking reinstatement during three consecutive test weeks. Each week, participants received one of three doses of MEC (0.0, 5.0, or 10.0 mg/dayx3 days) in a randomized, counterbalanced manner. RESULTS Compared to CS, SS displayed similar levels of craving and withdrawal, but higher plasma nicotine and cotinine levels, and cotinine/CPD ratio. During reinstatement, SS consumed significantly more cigarettes than CS, but MEC did not significantly alter indices of smoking, psychiatric symptoms, or cigarette consumption during reinstatement. CONCLUSIONS 1) The reinforcing effects of smoking may be increased in SS versus CS after overnight abstinence; 2) the lack of effects of nAChR antagonism may suggest that non-nicotinic components of cigarettes may contribute to the behavioral effects of smoking in both SS and CS; and 3) consistent with previous studies, SS may exhibit higher baseline levels of nicotine and cotinine, and greater extraction of nicotine per cigarette than CS.

Prepulse inhibition deficits in schizophrenia are modified by smoking status

BACKGROUND Schizophrenia is associated with high rates of cigarette smoking and deficits in sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle response. However, the relationship between PPI deficits and smoking status is unclear. We examined whether smoking status modifies PPI deficits in schizophrenia. METHODS We studied PPI as a function of smoking status and schizophrenia diagnosis in four groups using a cross-sectional design: Smokers with schizophrenia (SS; n=14), non-smokers with schizophrenia (SNS; n=15), control smokers (CS; n=11), and control non-smokers (CNS; n=10). PPI in smokers was recorded under conditions of smoking satiation, and smoking status was verified biochemically. RESULTS The Diagnosis x Smoking Status x Prepulse Interval interaction was significant (F(11,140)=5.01, p<0.001). At all prepulse to pulse intervals (PPTPIs; 30, 60 and 120 ms), we found that SNS had reductions (~50%; p<0.01) in PPI compared to CNS. However, when SS were compared to CS under conditions of smoking satiation, SS had comparable levels of PPI to CS, and significantly higher levels of PPI than SNS. CONCLUSIONS Our findings suggest that PPI deficits are present in nonsmokers with schizophrenia, and may be modified by smoking status. Acute smoking in schizophrenia is associated with an elevation of PPI to the levels in non-psychiatric control smokers. These findings have significant implications for understanding vulnerability to tobacco dependence in schizophrenia, which may lead to the development of more effective treatments for PPI deficits and tobacco dependence in this population.