Each year more than 440,000 people in the United States die of smoking-related illness, and nearly half a billion dollars in health-related economic losses are directly attributable to smoking.1,2 Cigarette smoking has been the single largest source of preventable morbidity and mortality in the United States for the past 29 years, and the global mortality toll of smoking, 5 million annually, is on the rise.3 Smokers die on average 10 years earlier than lifelong nonsmokers, and smoking cessation clearly reduces morbidity and mortality. For example, although cigarette smoking from early adult life triples age-specific mortality rates at middle age (43% vs 15%), cessation at age 50 halves the hazard, and cessation at age 40 nearly abrogates the elevated risk.4 An estimated 45% of all cigarettes sold in the United States are sold to people with a mental illness: those with a major mental illness are more likely than those without psychiatric illness to be heavy smokers.5
In an epidemiological study in a state hospital, 79% of patients were smokers and 37% were considered to be heavy smokers. Patients with schizophrenia smoked more than those with a diagnosis other than schizophrenia (85% vs 67%, respectively).6 The presence of psychiatric beds had a negative effect on the response rate for the Joint Commission on Accreditation of Health Care Organization standard requiring acute care hospitals to be smoke-free.7
Between 72% and 90% of schizophrenic patients smoke cigarettes compared with 24% of the general population.8 Patients with schizophrenia smoke many more cigarettes on average per day9 and often spend one third of their weekly income on cigarettes.10 In addition, some studies have found that these patients have higher serum levels of cotinine, the primary metabolite of nicotine.11 Mortality from smoking-related diseases, such as pulmonary and cardiovascular diseases, is 2 to 6 times higher in patients with schizophrenia than in age-matched nonpsychiatric controls.12
Evidence for shared neurobiological pathways
It has been speculated that the high rate of nicotine dependence in persons with schizophrenia represents an adaptive behavior to minimize adverse effects of conventional antipsychotic medications. In behavioral studies, smokers with and without schizophrenia smoked more cigarettes during ad lib periods following a single dose of haloperidol than after placebo.13 Smoking, but not nicotine, induces hepatic microsomal enzyme activity, particularly that of cytochrome P-450 1A2 (CYP1A2), and thus reduces blood levels of many antipsychotic medications, particularly clozapine and olanzapine.14 Consistent with this, smokers with schizophrenia receive significantly higher doses of conventional antipsychotics than nonsmokers but do not show higher rates of, or more severe, tardive dyskinesia or parkinsonism.15 Haloperidol is associated with dose-dependent impairment in cognitive functioning in humans, an effect that is partially reversed by nicotine patch application, perhaps through increased dopamine release.16 In animals, nicotine administration reverses impairments in attentional performance caused by haloperidol, risperidone, and clozapine.17
Although reduction of adverse effects of antipsychotic medication may partly explain elevated rates of smoking and heavy smoking in patients with schizophrenia, reports of increased smoking rates in healthy adolescents in whom schizophrenia later develops18 and among a cohort with first-episode psychosis with little or no exposure to antipsychotic medications suggests that the amelioration of adverse medication effects does not entirely account for this phenomenon.19
Nicotinic cholinergic receptor abnormalities
Multiple lines of evidence have converged to implicate the nicotinic cholinergic system in the pathophysiology of schizophrenia. Independent of smoking behavior, postmortem studies find decreased numbers of both high- (a4b2) and low-affinity (a7) nicotinic acetylcholine receptors (nAChRs) in the hippocampus and other brain regions of schizophrenic patients compared with controls.20,21 Polymorphisms in the promoter regions of the a7 nAChR gene that result in reduced nAChR transcription have been identified, which may partly explain the finding of reduced a7 nAChR expression in schizophrenia.22
A functional nAChR abnormality consistent with abnormally rapid receptor desensitization related to sensory gating hypofunction has been described by Griffith and coworkers.23 Abnormal auditory CYP-evoked potentials and smooth pursuit eye movements that have been described in individuals with schizophrenia and their first-degree relatives are associated with the gene that codes for the a7 nAChR and are transiently normalized by nicotine patch or smoking, which suggests that nicotine at least briefly improves the ability to filter irrelevant sensory information.24-26 Schizophrenia is associated with both an abnormally low expression of nAChRs and their rapid desensitization, hence the receptors may be unavailable for stimulation much of the time. Sensory deficits characteristic of a neurobiological vulnerability to schizophrenia are to some extent reversed by nicotine administration.
Heavy smoking in schizophrenia is consistent with a need for high nicotine concentrations to compensate for the decrease in receptor effectiveness and/or number. Nicotinic receptors interact with dopamine, glutamate, norepinephrine, serotonin, g-aminobutyric acid, and other systems, which suggests that nicotine may have broad-spectrum effects on a number of brain regions. For example, hippocampal hyperactivity has been identified in schizophrenic patients during smooth pursuit eye movements,27 and nicotine may improve sensory gating via its effects in diminishing hippocampal activation.28 Furthermore, nicotine administration has been found to improve perception and attention to moving stimuli in patients with schizophrenia, effects that are correlated with reduced hippocampal activation and consistent with diminished nicotinic neurotransmission as mediating inhibitory neuronal dysfunction in patients with schizophrenia.27
Nicotinic receptors modulate activity in frontoparietal-thalamic regions—brain regions known to mediate visual attention, arousal, and motor activity—and nicotine administration elicits improvements in attentional performance concomitant with this increased activity.29 Subjective craving is mediated by thalamocortical circuitry and the anterior cingulate cortex,30 and these areas are differentially activated by nicotine replacement therapy (NRT), in persons with schizophrenia compared with controls.31
Negative symptoms of schizophrenia are linked to N-methyl d-aspartate (NMDA) receptor hypofunction.32 Chronic nicotine use increases NMDA receptor density in the hippocampus33 and further increases glutamatergic activity through stimulation of presynaptic nAChRs on limbic glutamatergic neurons.34 Activation of nAChRs stimulates central dopamine release and turnover,35 which may be another mechanism by which nicotine may improve cognitive deficits, negative affect, and reward responsivity.
Several studies have shown the benefits of NRT in persons with schizophrenia. In their investigation of schizophrenic patients who did not smoke, Harris and colleagues36 found that NRT gum improved performance on attentional tasks. Findings from a study by Barr and colleagues37 indicate that consistent with nAChR hypofunction in schizophrenia, a single-dose 14-mg NRT patch elicits greater improvement in impulsive response on attentional tasks in nonsmokers with schizophrenia than in controls.
In minimally deprived smokers with schizophrenia, the NRT patch improves reaction time on attentional and spatial rotation tasks.17 NRT nasal spray improves spatial organization, some measures of verbal memory, and 2-choice reaction time.38 Myers and colleagues39 have reported that 1 mg of NRT by nasal spray normalized memory in a delayed spatial recognition task, an effect mediated by reduced false alarms (enhanced inhibition). Furthermore, a high-dose NRT patch normalized working memory performance in patients with schizophrenia and worsened performance in normal controls. The high-dose patch also increased anterior cingulate cortex, right thalamus, and hippocampus activity during attentional tasks in schizophrenic patients significantly more than in controls.31
Nicotine thus facilitates patient performance on tasks involving high cognitive load, activates brain areas that facilitate attention, and increases inhibition of impulsive responses. Some investigators have postulated that such effects are limited by tachyphylaxis and are not clinically significant.36 However, while low-affinity nAChR subtypes desensitize rapidly, the positive effects of nicotine treatment on attention and memory nevertheless appear to persist and may become more robust over time.23,40
Both smoking and nicotine ad-ministration increase nicotinic transmission by providing exogenous agonists and by increasing the nAChR number.41 The atypical antipsychotic, clozapine, while not a direct nicotinic agonist, indirectly increases release of acetylcholine in the hippocampus, a property not shared by older dopamine D2 receptor antagonists.42 Findings from a study by Adler and colleagues18 indicate that clozapine increases inhibition of the P50 auditory evoked response in schizophrenia. In animal models, this effect is mediated by stimulation of the a7 nAChR.43
Of interest, clinical response to clozapine may be greater in patients with schizophrenia who smoke, perhaps because of an increased nAChR number in smokers. In addition, clozapine treatment is associated with decreased smoking, consistent with nicotinic cholinergic agonism as a mechanism of its therapeutic effect.44,45 In an animal model of schizophrenia, acute administration of nicotine and clozapine significantly improved attention and working memory; the effects were of equal magnitude and not additive, again implying a common mechanism.46 An exploratory analysis in one study suggested that patients with schizophrenia who are treated with atypical antipsychotics are more likely to quit smoking with NRT and cognitive-behavioral therapy (CBT), although it is not known whether atypical antipsychotic treatment in general or clozapine treatment specifically reduces smoking relapse in schizophrenic patients.47
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