Angelo Termine

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.

Effects of Smoking Abstinence on Visuospatial Working Memory Function in Schizophrenia

Schizophrenic patients have impairments in cognitive function, including deficits in visuospatial working memory (VSWM). VSWM is mediated, in part, by prefrontal cortical dopamine (DA) function, and dysregulation of prefrontal cortical DA systems may contribute to the pathophysiology of schizophrenia. Nicotine has complex effects on spatial working memory (SWM) in animal studies, with most studies demonstrating enhancement of SWM. Cigarette smoking is highly prevalent in schizophrenia, and these patients may smoke cigarettes to remediate cognitive deficits. The present study examined the effects of acute (<1 week) and prolonged (8–10 weeks) smoking abstinence on VSWM in schizophrenic (n = 23) and control (n = 29) nicotine-dependent cigarette smokers during placebo-controlled smoking cessation trials. Schizophrenic and control smoking patients had significant impairments in VSWM compared to non-smoking controls, after adjusting for differences in age, education and depressive symptoms. Schizophrenic smokers who quit smoking had further impairments in VSWM, and control quitters had improvements in VSWM. Abstinence-induced changes in VSWM varied as a function of gender in controls, but not in schizophrenics. These changes in VSWM appeared to be independent of study medications, and smoking abstinence did not significantly alter performance on the Stroop Color Word Test in either group. These results suggest that smoking abstinence differentially alters VSWM in schizophrenic vs. control smokers, and that cigarette smoking has beneficial effects on VSWM in schizophrenic, but not control, smokers.

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.

A preliminary placebo-controlled trial of selegiline hydrochloride for smoking cessation

BACKGROUND Since dopaminergic mechanisms appear to be involved in nicotine dependence, we studied the safety and efficacy of the monoamine oxidase B inhibitor selegiline hydrochloride compared with placebo for smoking cessation in nicotine-dependent cigarette smokers. METHODS Forty subjects with DSM-IV nicotine dependence were randomized to: 1) selegiline hydrochloride (5 mg p.o. twice daily) or 2) placebo in an 8-week trial. Outcome measures included smoking cessation rates, treatment retention, and medication side effects. RESULTS Selegiline hydrochloride increased trial end point (week 8) 7-day point prevalence smoking cessation rates (selegiline hydrochloride, 9/20 [45.0%]; placebo, 3/20 [15.0%], odds ratio = 4.64, 95% CI, 1.02-21.00, p <.05), and smoking cessation rates during the last 4 weeks of the trial (selegiline hydrochloride, 6/20 [30.0%]; placebo, 1/20 [5.0%], odds ratio = 8.14, 95% CI, 0.88-75.48, p =.07) in comparison with placebo. Six-month follow-up 7-day point prevalence smoking cessation rates were reduced compared with trial end point (selegiline hydrochloride, 4/20 [20.0%]; placebo, 1/20 [5.0%], odds ratio = 4.75, 95% CI, 0.48-46.91, p =.18). Treatment retention was similar between drug and placebo groups (p =.13), and selegiline hydrochloride was well tolerated in cigarette smokers. CONCLUSION This preliminary study suggests that selegiline (10 mg/day) is safe for use and enhances smoking cessation rates compared with placebo in nicotine-dependent cigarette smokers.

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.

Smoking Cue Reactivity in Schizophrenia: Effects of a Nicotinic Receptor Antagonist

BACKGROUND Rates of cigarette smoking in schizophrenia are higher than in the general population. To investigate differences in sensitivity to smoking cues between schizophrenia and control subjects, we compared smoking cue reactivity (CR) in schizophrenia versus control smokers with and without pretreatment with the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (MEC). METHODS Smoking CR in schizophrenia (n = 22) and nonpsychiatric control (n = 20) smokers was determined using exposure to smoking pictures. Three doses of MEC (0, 5, and 10 mg/day) were administered during the 3 test weeks to determine the role of nAChRs in mediating the smoking CR response. RESULTS Eleven of 22 (50%) schizophrenia and 10 of 20 (50%) control smokers displayed smoking CR. Smoking CR was not significantly different between schizophrenia and control smokers in the placebo (0 mg/day) condition. However, MEC pretreatment produced a dose-dependent reduction of CR in schizophrenia smokers compared with placebo. There was no significant effect of MEC on CR in control smokers. CONCLUSIONS Our findings suggest that blockade of CR by MEC may be more robust in schizophrenia versus control smokers, possibly due to reduced nAChR levels in the brains of patients with schizophrenia.

Neuropsychological deficits in nonsmokers with schizophrenia: Effects of a nicotinic antagonist

BACKGROUND Biochemical, physiological and genetic evidence suggests dysregulation of central nicotinic acetylcholine receptor (nAChR) systems in schizophrenia, which may contribute to neuropsychological dysfunction and the high rates of smoking in this disorder. To evaluate the effects of nAChR blockade on neuropsychological performance in schizophrenia without the confounding effects of cigarette smoking, we compared neuropsychological performance in schizophrenia and healthy control nonsmokers after pre-treatment with the centrally-acting nAChR antagonist mecamylamine (MEC). METHODS Using a within-subjects, counterbalanced design, schizophrenia (n = 14) and control (n = 15) nonsmokers were pre-treated for 3 days with MEC (0.0, 5.0, and 10.0 mg/day). Subjects performed repeated neuropsychological assessments including visuospatial working memory (VSWM), Continuous Performance Test (CPT), Wisconsin Card Sorting Test (WCST), Word Serial Position Test (WSPT) and Stroop Color Word Test (SCWT) during three sequential test sessions per week over three test weeks. RESULTS We found significant main effects of schizophrenia diagnosis on: VSWM 30 and 60 delays (ps < 0.01), CPT (% Hit Rate, Reaction Time, Variability Index; p < 0.01 for all outcomes), WCST (p < 0.01 for all outcomes) and Word Serial Position Test (p < 0.01). However, there were no main effects of repeated test administration (Session) or MEC dose on any of these outcomes, and no significant 3-way (DiagnosisxSessionxMEC dose) interactions. CONCLUSIONS Our results suggest that there are a broad range of neuropsychological deficits in nonsmokers with schizophrenia. Furthermore, pretreatment with a centrally-acting nAChR antagonist did not alter neuropsychological performance in either nonsmoking patients with schizophrenia or controls.