A. Eden Evins, MD, MPH

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.

 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.

 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.

 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.

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).

 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.

Between 72% and 90% of schizophrenic patients smoke cigarettes compared with 24% of the general population.

 Patients with schizophrenia smoke many more cigarettes on average per day

 and often spend one third of their weekly income on cigarettes.

 In addition, some studies have found that these patients have higher serum levels of cotinine, the primary metabolite of nicotine.

 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.

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.

 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.

 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.

 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.

 In animals, nicotine administration reverses impairments in attentional performance caused by haloperidol, risperidone, and clozapine.

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 develops

 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.

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.

 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.

A functional nAChR abnormality consistent with abnormally rapid receptor desensitization related to sensory gating hypofunction has been described by Griffith and coworkers.

 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.

 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,

 and nicotine may improve sensory gating via its effects in diminishing hippocampal activation.

 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.

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.

 Subjective craving is mediated by thalamocortical circuitry and the anterior cingulate cortex,

 and these areas are differentially activated by nicotine replacement therapy (NRT), in persons with schizophrenia compared with controls.

Negative symptoms of schizophrenia are linked to 

-methyl d-aspartate (NMDA) receptor hypofunction.

 Chronic nicotine use increases NMDA receptor density in the hippocampus

 and further increases glutamatergic activity through stimulation of presynaptic nAChRs on limbic glutamatergic neurons.

 Activation of nAChRs stimulates central dopamine release and turnover,

 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 colleagues

 found that NRT gum improved performance on attentional tasks. Findings from a study by Barr and colleagues

 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.

 NRT nasal spray improves spatial organization, some measures of verbal memory, and 2-choice reaction time.

 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.

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.

 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.

Both smoking and nicotine ad-ministration increase nicotinic transmission by providing exogenous agonists and by increasing the nAChR number.

 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 D

 Findings from a study by Adler and colleagues

 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.

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.

 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.

 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.

Persons with schizophrenia are often highly motivated and persistent in their attempts to quit smoking despite having long histories of smoking and high levels of nicotine dependence.

 In a sample of smokers with schizophrenia with a mean age of 57 years and a mean smoking history of 20 years, 70% reported a history of at least one serious attempt to quit smoking.

Conventional treatment regimens of 8 to 12 weeks with bupropion

 added to CBT were well tolerated and moderately effective in persons with schizophrenia. However, relapse rates were high after discontinuation of bupropion, NRT, and CBT. Abstinence rates have been 4% to 19% at 3- to 6-month follow-up with bupropion, NRT, and CBT, and 0% to 6% with placebo and CBT.

 For example, in a 12-week trial of bupropion 300 mg/d for smoking cessation in 53 schizophrenic patients, the abstinence rates at the end of treatment were 16% in the bupropion with CBT group and 0% in the placebo with CBT group. The relapse rate was 50% within 2 weeks of discontinuation of bupropion and 75% at the 3-month follow-up.

Tailored nicotine dependence therapy with higher-dose NRT and longer-duration pharmacotherapy may improve abstinence rates and reduce relapse rates in schizophrenic patients. Combined treatment with bupropion and NRT has shown promise in both general and psychiatric populations. The combination of bupropion sustained-release (SR) and NRT was superior to placebo and to NRT alone but not to bupropion alone for smoking cessation in a nonpsychiatric population.

In an open, nonrandomized smoking cessation study of 115 smokers with comorbid psychiatric and substance use disorders, patients randomized to receive a combination of bupropion SR, NRT, and CBT had significantly greater smoking reduction than those treated with the combinations of bupropion SR and CBT, NRT and CBT, or CBT alone.

 Patients tolerated the combined treatment, and there were significantly fewer dropouts in the combined bupropion and NRT group.

Treatment with a nicotine patch combined with nicotine gum or nasal spray has shown superiority over single-form NRT (

 In a study of 51 smokers with schizophrenia randomly assigned to receive bupropion SR or placebo added to high-dose combination NRT patch and gum, 60% of those who received combination pharmacotherapy had significant reduction or abstinence compared with 31% of those who were assigned to placebo and NRT.

 Those who received combination pharmacotherapy had significantly lower expired carbon monoxide levels than those receiving a combination of placebo and 2 forms of NRT. They also demonstrated higher rates of continuous abstinence before the NRT taper. However, as in previous studies, the relapse rate was quite high during and after discontinuation of nicotine dependence treatment: 31% of those who had quit relapsed during the NRT taper and 77% had relapsed by 12 months, which suggests a role for maintenance nicotine dependence treatment to reduce relapse rates.

In the general population, relapse rates are 41% to 58% at 1 year if pharmacological treatment is discontinued following treatment for 7 to 12 weeks.

 In patients with schizophrenia, relapse rates of 70% to 83% have been reported 6 to 12 months after discontinuation of 8 to 12 weeks of treatment.

 Thus, relapse rates are approximately 25% higher in patients with schizophrenia who quit smoking than in persons in the general population who quit. Longer-duration pharmacotherapy may be necessary to reduce relapse in patients with schizophrenia who are able to achieve abstinence.

Longer-duration pharmacotherapy has been associated with higher rates of sustained smoking abstinence in the general population. Continuation treatment for 1 year in those who achieved abstinence with bupropion was well tolerated, and in these patients, the relapse rate at 12 months was lower than it was in those who received placebo (45% vs 58%, respectively), perhaps through reduction in craving.

 Similarly, 1 year of treatment with combination CBT, NRT, and either active treatment or placebo resulted in significantly lower relapse rates compared with the same intervention over the more standard 12-week duration (

 Trials of longer-duration pharmacotherapy are under way in patients with schizophrenia.

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A. Eden Evins, MD, MPH

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Nicotine Dependence in Schizophrenia: Prevalence, Mechanisms, and Implications for Treatment