A Review of the Effects of Nicotine on Schizophrenia and Antipsychotic Medications

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1 A Review of the Effects of Nicotine on Schizophrenia and Antipsychotic Medications Edward R. Lyon, M.S., Ed.D. Objective: Research on the impact of nicotine on schizophrenia and antipsychotic medications was reviewed to determine ways to improve treatment planning for patients with schizophrenia who smoke and to evaluate smoking cessation programs for this population. Methods: All major research databases were searched. The review focuses on reports published since Results: Smoking improves processing of auditory stimuli (sensory gating) by patients with schizophrenia and may lessen negative symptoms by increasing dopamine in the nucleus accumbens and the prefrontal and frontal cortex. Use of traditional antipsychotics may result in patients smoking more, whereas patients taking atypical antipsychotics may smoke less. Patients who smoke metabolize antipsychotics faster than nonsmoking patients. Smoking cessation programs for outpatients with schizophrenia report a success rate of about 12 percent after six months. No studies of cessation programs for chronically ill inpatients with schizophrenia have been published. Several hospitals have implemented smoking bans with equivocal results. Conclusions: Nicotine affects both schizophrenia and antipsychotic medications. Neurobiological and psychosocial factors reinforce the high use of nicotine by patients with schizophrenia (Psychiatric Services 50: , 1999) Many patients in psychiatric hospitals would smoke two, three, or even four packs of cigarettes a day if an unlimited supply of cigarettes were available. However, most patients do not have an unlimited supply, mainly because of the cost. When patients smoke all of their cigarettes, some may resort to stealing, begging, prostitution, intimidation, and similar behaviors to obtain more. During the past few years, considerable interest and research has been focused on the high use of cigarettes in psychiatric populations. Before the mid-1980s, most studies focused on depression and anxiety. Patients with major depression and anxiety are more likely to smoke than patients without these disorders, and they experience more problems when they attempt to quit smoking (1 6). Several other diagnostic groups have higher rates of nicotine use. They include patients with alcohol abuse and dependence, panic disorder, and personality and adjustment disorders (2). Studies have consistently reported that patients with schizophrenia have the highest rate of nicotine use (2,7,8). Compared with other diagnostic groups, patients with schizophrenia are more likely to be heavy smokers, defined as those who smoke more than one and a half packs a day. Reports from hospitals suggest that chronically ill inpatients Dr. Lyon is director of psychology at the G. Pierce Wood Memorial Hospital, 5847 Southeast Highway 31, Arcadia, Florida ( , edward_lyon@dcf.state.fl.us). with schizophrenia have even higher rates of smoking than other patients with this disorder, and research supports this observation. For example, in a British study of 100 institutionalized patients, Masterson and O Shea (9) found that 92 percent of the men and 82 percent of the women smoked. In 1990 about a quarter of the general U.S. population were smokers 28 percent of men and 22 percent of women (10). The rate of smoking among inpatients with schizophrenia has been found to be between three and four times the rate in the general population. If the average patient with schizophrenia smokes one and a half packs of cigarettes each day, then each year in the United States this patient population smokes more than 10 billion packs of cigarettes, or about $20 billion worth of cigarettes (8). Patients with schizophrenia are also more likely to smoke high-tar cigarettes. One study found that nearly 59 percent of patients with schizophrenia smoked high-tar cigarettes, compared with less than one percent of the general public (11). Patients with schizophrenia also have smoked for longer periods compared with other groups (12,13). Lohr and Flynn (8) point out that these patients prefer cigarettes high in nicotine and frequently smoke them down to the very end. This practice leaves cigarette burns and yellow stains on their fingers, a condition often observed at institutions with chronic psychiatric patients. Although allowing cigarettes to burn to the very end is sometimes attributed to patients forgetfulness or to their psychotic state, another factor may 1346

2 be involved. The highest level of nicotine is found at the very end of the cigarette, and thus this behavior may be reinforcing (9). Until recently the high rate of smoking among patients with schizophrenia was poorly understood. Current research suggests a link between nicotine, schizophrenia, and antipsychotic medication. This link has direct implications for treatment, as well as for the therapeutic milieu in psychiatric hospitals. This paper examines neurobiological and psychosocial factors that contribute to the high rate of smoking among patients with schizophrenia and describes the interaction of nicotine and antipsychotic medications. The effectiveness of smoking cessation programs is reviewed, and recommendations are made for improving treatment of patients with schizophrenia who smoke. Methods The keywords nicotine, schizophrenia, and antipsychotics were used to search all major research databases. All studies located were examined, although not all are reviewed here. For example, several studies related to neuroleptic-induced movement disorders and nicotine were excluded to stay within the word limitations for publication. The review focuses on studies published since Nicotine s stimulation of dopamine could help explain the high use of nicotine by patients with schizophrenia as a form of self-medication to reduce negative symptoms. Results Neurobiology of nicotine and schizophrenia Although several factors are involved in the high rate of smoking among patients with schizophrenia, the area of neurobiology is the most interesting. Neurobiological factors provide the strongest explanation for the link between smoking and schizophrenia because a direct neurochemical interaction can be demonstrated. Nicotine is involved with several neurotransmitters, including glutamate, acetylcholine, serotonin, and norepinephrine, but its effects on dopamine are likely the most relevant in understanding the high use of nicotine by patients with schizophrenia (14,15). Research has shown that nicotine increases mesolimbicocorticol dopaminergic activity in the nucleus accumbens and the prefrontal cortex (16,17). This stimulation of dopamine could help explain the high use of nicotine as a form of selfmedication to reduce negative symptoms (18). Hypofrontality, a reduction in neuronal activity in the frontal and prefrontal section of the brain, is believed responsible for the negative symptoms of schizophrenia (19 21). These symptoms include social withdrawal, apathy, anhedonia, and lack of motivation. Dopamine release in the nucleus accumbens and the prefrontal areas is associated with several pleasurable and reinforcing activities, such as eating and sex, as well as the use of drugs such as cocaine and amphetamines (22). By increasing the release of dopamine, nicotine is believed to produce similar results for patients with schizophrenia. Research reports by Svensson and associates (20) and Grenhoff and colleagues (23) further suggest that this dopamine increase may partially and temporarily reverse symptoms of hypofrontality. Although traditional antipsychotics appear to have a greater impact on positive symptoms than on negative symptoms (8), the newer agents have been shown to reduce negative symptoms (24 26). At least two of the newer antipsychotics have been shown to reduce nicotine use (27,28). These newer drugs are believed to be better than nicotine in reversing hypofrontality (23,25). Thus the atypicals may benefit patients by reducing both nicotine use and negative symptoms. Psychosocial aspects of nicotine and schizophrenia Besides the neurobiological link between nicotine and schizophrenia, psychosocial factors are involved (29). People in the general population report that nicotine use induces relaxation and pleasurable feelings and reduces anxiety, anger, and depression. These effects may have greater importance among patients with a major mental illness because their sources of pleasure and satisfaction are likely diminished. Glynn and Sussman (30) found that most patients with schizophrenia felt more relaxed and less anxious after smoking. Reduction of the negative symptoms of schizophrenia, such as social and emotional withdrawal, through either psychosocial or neurochemical actions, might increase patients interaction with others. Increased social contact may reduce feelings of isolation and thus reinforce nicotine use. The depressive symptoms that are often experienced by patients with schizophrenia also influence the rate of smoking. Studies have shown that depression is associated with increased smoking, more difficulty withdrawing from nicotine, and a greater relapse rate after quitting (31,32). Interaction of nicotine and antipsychotics No evidence links metabolism of medications directly to nicotine. However, polycyclic hydrocarbons in cigarette smoke stimulate the hepatic microsomal system, inducing liver enzymes to increase the metabolism of psychotropic medications (33). Nemeroff and colleagues (34) suggest that the induction of the cytochrome P450 1A2 isoform may explain the increased metabolism. The cytochrome P450 isoenzymes are involved in the oxidative metabolism of 1347

3 several different types of drugs including the majority of antidepressants and antipsychotics. Several studies have reported that smokers require higher levels of antipsychotics than nonsmokers (7,31, 35). Smoking can lower the blood levels of some antipsychotics by as much as 50 percent, requiring a corresponding increase in dosage to achieve therapeutic blood levels. For example, Ziedonis and associates (29) found that the average antipsychotic dosage for smokers in their sample was 590 mg in chlorpromazine equivalents compared with 375 mg for nonsmokers. Other studies have investigated the connection between specific antipsychotics and the rate of smoking among patients with schizophrenia. McEvoy and colleagues (27) found that patients who started haloperidol treatment smoked more, as measured by their expired-air carbon monoxide and plasma nicotine and cotinine levels, than they did at baseline when they were free of antipsychotic medications. The same researchers studied smoking rates among patients switched from haloperidol to clozapine (36). Patients switched to clozapine at therapeutically effective dosages decreased their smoking, while those whose dosages were below therapeutic ranges showed no change in smoking behavior. George and associates (28) found a similar reduction in smoking when patients were placed on clozapine. Albanese and coworkers (37) reported that patients with schizophrenia who were treated with clozapine showed a reduction in alcohol, cocaine, and heroin abuse. This finding is interesting because several of the atypicals clozapine, risperidone, and olanzapine may increase cortical dopamine release in a manner similar to that of nicotine (25,26). Besides clozapine, amperozide, another atypical antipsychotic, also has been reported to reduce negative symptoms of schizophrenia (19,23,24). This finding strengthens the position that the newer antipsychotics may reduce hypofrontality and thus reduce nicotine dependence among patients with schizophrenia. Effects of smoking on auditory physiology Among persons who do not have schizophrenia, the auditory evoked response to the second of two paired auditory stimuli is significantly lower than the response to the first. Patients with schizophrenia have a deficit in this sensory gating function so that their response to the second stimulus is significantly greater than normal. This defect is one of several auditory sensory gating deficits in schizophrenia. Patients impaired ability to filter out background noise in the environment would interfere with attention and with processing sensory stimuli. Patients who were switched to clozapine at therapeutically effective dosages decreased their smoking, while those whose dosages were below therapeutic ranges showed no change in smoking behavior. Adler and associates (38,39) found that subjects with schizophrenia had a marked improvement in auditory gating immediately after smoking, whereas subjects without schizophrenia showed a slight impairment. This finding suggests that nicotine can temporarily normalize the impairment of auditory gating in subjects with schizophrenia. Smoking cessation programs and schizophrenia Patients with schizophrenia not only smoke at high rates but are less likely to stop smoking than persons in the general population (31). One reason may be that patients with this disorder have less motivation to stop smoking (40). More research is needed to compare patients with schizophrenia with other patient groups to determine whether they have less motivation to quit and whether a larger proportion of patients with schizophrenia are unable to stop smoking. Research on smoking cessation programs for patients with schizophrenia is limited. Ziedonis and George (33) conducted a ten-week smoking cessation program for 24 volunteer outpatients with schizophrenia. Patients continued to receive their usual psychiatric treatment. The average patient had smoked for 27 years and at the time of the study smoked about one and a half packs a day. At the end of six months, three patients remained smoke free with nicotine replacement. Traditional smoking cessation treatment may not work for patients with schizophrenia because of their illness. Addington (41) described an eight-week smoking cessation program modified for patients with schizophrenia. To test this approach, 50 patients with schizophrenia participated in one of five smoking cessation groups. Forty-two percent were smoke free for four weeks, 16 percent stopped smoking for three months, and 12 percent were smoke free at six months. Some research indicates that patients with schizophrenia may experience more problems when they attempt to quit smoking. Ziedonis and George (33) found that 71 percent of their sample of patients with schizophrenia reported substantial withdrawal symptoms, which resulted in a smoking relapse. These symptoms included craving, anxiety, concentration problems, irritability, increased appetite, and restlessness. No studies have examined smoking cessation programs for chronic inpatients with schizophrenia. Because of the severity of psychosis in this patient group, it would be difficult to develop and promote such treatment approaches. These patients have 1348

4 marked affective, cognitive, and social disturbances that would make the educational approaches of traditional smoking cessation programs questionable. Clearly, the motivational and cognitive skills necessary to comprehend the need to reduce or eliminate the use of nicotine are compromised among chronic inpatients. Several psychiatric hospitals have attempted a smoking ban, but the results are inconclusive. Velasco and associates (42) reported the effects of a ban on smoking on a 25-bed psychiatric inpatient unit. Immediately after the smoking ban and for two years, they found no increase in calls for security assistance, physical assaults, restraints, or seclusion. Verbal assaults and as-needed medications for anxiety increased immediately after the ban but were not a problem two years later. Haller and colleagues (43) also found little impact on ward milieu after a complete smoking ban was initiated on a locked ward where the median length of stay was two weeks. Although staff anticipated problems before the ban, the majority voted to keep the ban after it was implemented. Patients views were negative both before and after the ban. Greeman and McClellan s study (44) found many problems with a smoking ban at a Veterans Affairs medical center. They reported that 20 to 25 percent of patients experienced significant problems, some of which caused major disruption to their treatment. The authors speculated that problems associated with smoke-free inpatient settings were underreported in the literature. Conclusions and recommendations Nicotine and the polycyclic hydrocarbons in cigarettes have significant implications for patients with schizophrenia who take antipsychotic medications. Research studies cited here suggest that these chemicals may increase dopamine in the nucleus accumbens and the prefrontal cortex. Research further indicates that an increase in dopamine in these areas of the brain has an impact on hypofrontality, a condition believed to be related to the negative symptoms of schizophrenia. The use of nicotine also temporarily improves sensory gating among patients with schizophrenia, which may increase patients ability to interact with their environment. The interaction between nicotine and antipsychotic medications should be considered in clinical decisions. Among patients who smoke, typical antipsychotics are likely to increase smoking, whereas the atypical medications may decrease this behavior. Heavy smoking may decrease the blood levels of antipsychotic medications by as much as 50 percent. Smoking cessation programs for outpatients with schizophrenia have resulted in small reductions in smoking. No reports of smoking cessation programs for chronic inpatients have been published, perhaps reflecting the difficulty of designing such programs for severely ill patients. Several hospitals have experimented with a smoking ban for staff and patients. The results are inconclusive. Some hospitals report few problems, but one research team speculated that problems related to smoking restrictions are underreported. More research on smoking bans is needed. The following recommendations are based on the studies reviewed here. Clinicians conducting psychiatric evaluations of patients with schizophrenia should determine whether and how much patients smoke. Smoking alters the metabolism of psychotropic drugs, a factor that clinicians should consider when prescribing these medications. Patients with schizophrenia who are dependent on nicotine should not be denied smoking opportunities without being provided alternatives. To reduce the distress of patients who cannot monitor their use of cigarettes and thus use up their supply, treatment teams should consider monitoring the use of cigarettes by such patients. Patients who cannot obtain their own supply of cigarettes should be provided the means to acquire them so that they will not resort to prostitution, trafficking, assault, and similar disruptive behaviors. Although atypical antipsychotics may reduce smoking among patients with schizophrenia, other interventions, such as specialized smoking cessation programs, should be developed, especially for chronic inpatients. References 1. Glassman H: Cigarette smoking: implications for psychiatric illness. American Journal of Psychiatry 150: , Hughes JR, Hatsukami DK, Mitchell JE, et al: Prevalence of smoking among psychiatric outpatients. American Journal of Psychiatry 143: , Breslau N, Kilbey MM, Andreski P: Nicotine dependence and major depression: new evidence from a prospective investigation. Archives of General Psychiatry 50:31 35, Paulson GW: Addiction to nicotine is due to high intrinsic levels of dopamine. 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Hospital and Community Psychiatry 42: , 1991 Psychiatric Services seeks expert reviewers in the following areas: Cost-effectivness of drug and alcohol treatment Work with the police Psychiatry in other countries Experiences of patients and former patients Telemedicine and telecommunications Outcome and clinical measurement scales Depot medications Length of stay Quality of life Reviewers should be familiar with the literature in their areas of expertise, should have published in peerreviewed journals, and should be familiar with the content and focus of Psychiatric Services. Prospective reviewers should send a curriculum vitae, specifying areas of interest, to John A. Talbott, M.D., Editor, Psychiatric Services, APA, 1400 K Street, N.W., Washington, D.C ( , psjournal@psych.org).