Effects of Nicotine and Smoking on Clinical and Cognitive Deficits Associated With Schizophrenia

Several cross-sectional studies have examined the effects of cigarette smoking on psychotic symptoms in schizophrenic patients (Goff et al. 1992; Hall et al. 1995; Ziedonis et al. 1994). Goff and colleagues found that schizophrenic smokers had higher Brief Psychiatric Rating Scale (BPRS) total scores than schizophrenic nonsmokers, and higher subscale scores for both positive and negative symptoms. Ziedonis and colleagues found increased positive symptom scores and reduced negative symptom scores in smoking versus nonsmoking schizophrenic patients, with heavy smokers having the highest positive and lowest negative symptom scores. Hall and colleagues noted that schizophrenic patients who were former smokers had fewer negative symptoms than current schizophrenic smokers, yet a recent study by our group found that schizophrenic former smokers had more negative symptoms than current smokers after adjustment for differences in age, depressive symptoms, and education (George et al. 2002a). Interestingly, one report suggested that smoking was reduced in schizophrenic patients reporting an exacerbation of psychotic symptoms (Ham-era et al. 1995), whereas Dalack and colleagues (Dalack and Meador-Woodruff 1996) observed exacerbation of positive symptoms during smoking cessation or reduction.

There have been few direct studies of the effects of smoking or nicotine administration on clinical symptoms in patients with schizophrenia. In contrast to results from cross-sectional studies, controlled laboratory studies of smoking abstinence (Dalack et al. 1999; George et al. 2002a) and nicotine patch administration (Dalack and Meador-Woodruff 1999) have not shown significant effects on these clinical symptoms of schizophrenia. Furthermore, two recent smoking cessation trials (Addington et al. 1998; George et al. 2000a), in which all subjects used the nicotine patch, found no evidence of significant changes in psychotic symptoms with smoking abstinence in schizophrenic patients. Thus, the effects of cigarette smoking and smoking abstinence on schizophrenia symptoms are not clear. There may be some trait differences in psychotic symptoms in schizophrenic smokers versus nonsmokers (e.g., more refractory symptoms in nonsmok-ers) that could explain these findings, independent of smoking status (George et al. 2002a).

Cigarette smoking has been reported to reduce neuroleptic-induced parkinsonism (Decina et al. 1990; Goff et al. 1992; Sandyk 1993; Ziedonis et al. 1994), and may worsen symptoms of tardive dyskinesia (Yassa et al. 1987), but these effects have not been observed consistently in other studies (Dalack et al. 1998; Goff et al. 1992; Menza et al. 1991). Those properties leading to reduction in extrapyramidal side effects may relate to nicotine's enhancement of subcortical dopamine systems, but other transmitter systems, such as GABA and glutamate, are likely involved (Dalack et al. 1998).

Several human laboratory studies have suggested that schizophrenic subjects possess deficits in auditory information processing (P50 event-related potentials), which can be transiently normalized by cigarette smoking or administration of nicotine gum (Adler et al. 1993, 1998). In addition, these deficits in P50 responses in schizophrenics are improved by treatment with the atypical agent clozapine (Nagamoto et al. 1996) and other atypical antipsychotic agents (Light et al. 2000). Recent evidence has suggested that these P50 response deficits may be linked to a locus on chromosome 15 (q14) near the coding region for the a7 nAChR (Freed-man et al. 1997). This subtype of nAChR has been strongly implicated in

P50 responses, leading to speculation that if some schizophrenic patients possess defective a7 nAChR-mediated neurotransmission, they may smoke heavily to overcome the related neurophysiological deficits. In addition, schizophrenic patients have abnormalities in another auditory information-processing response known as prepulse inhibition (PPI) of the acoustic startle reflex (Parwani et al. 2000; Swerdlow et al. 1992). The neural substrates mediating this response appear to be distinct from those mediating P50 responses (Swerdlow et al. 1992), and a recent study found that clozapine, but not typical antipsychotic drugs, appears to normalize deficits in PPI in schizophrenic patients (Kumari et al. 1999). Cigarette smoking may improve PPI, whereas acute smoking abstinence may impair it (George et al. 2001; Kumari et al. 1996). Thus, schizophrenic patients may be using cigarette smoking to ameliorate defects in cognitive function, further supporting the self-medication hypothesis of cigarette smoking in schizophrenia. This assertion is supported by 1) studies by Levin and colleagues demonstrating that the nicotine patch could dose-dependently reverse cognitive deficits associated with haloperidol administration in persons with schizophrenia (Levin et al. 1996) and 2) recent data on the effects of smoking abstinence on cognitive function in schizophrenic versus control smokers (George et al. 2002a).

The Yale Program for Research in Smokers with Mental Illness has studied cognitive function in schizophrenic and nonpsychiatric control subjects as a function of smoking status (George et al. 2002a). Although schizophrenic subjects compared with control subjects had deficits in visuo-spatial working memory (VSWM) function, a task dependent in part on prefrontal cortical dopamine function (Williams and Goldman-Rakic 1995), smoking appeared to improve these deficits in schizophrenic subjects and impair them in control subjects after adjustment for differences in age, educational attainment, and depressive symptoms between the four comparison groups. However, when schizophrenic smokers quit smoking during the course of a 10-week smoking cessation trial using bu-propion hydrochloride (or placebo), deficits in VSWM were further impaired to the level of deficit in schizophrenic nonsmokers. In contrast, healthy control smokers who quit smoking in a smoking cessation trial with selegiline hydrochloride or placebo demonstrated improvements in VSWM function. These abstinence-induced changes in VSWM in both schizophrenic and control smokers appeared to be independent of the study medications used to facilitate smoking cessation (George et al. 2002a).

These preliminary results in schizophrenic versus control smokers, coupled with data on the effects of nicotine on the cortical dopamine system in animal studies (George et al. 1998, 2000c), allow one to propose a model

Nicotine Cognitive Effects

Cortical dopamine activity

Figure 5-1. Relationship between cortical dopamine function and spatial working memory: effects of schizophrenia and cigarette smoking.

Cortical dopamine activity

Figure 5-1. Relationship between cortical dopamine function and spatial working memory: effects of schizophrenia and cigarette smoking.

to explain the relationship between nicotine/smoking, cortical dopamine (and norepinephrine) function, and spatial working memory (Figure 5-1) (George et al. 1998, 2000b; Williams and Goldman-Rakic 1995).

Normal cortical dopamine function is associated with optimal levels of VSWM performance (Arnsten 2000; Williams and Goldman-Rakic 1995; Zahrt et al. 1997). In schizophrenic patients who have cortical dopamine hypofunction, VSWM is impaired, and nicotine administration through cigarette smoking leads to increases in cortical dopamine and improvements in VSWM (see Figure 5-1, Schizophrenia ^ Normal), whereas abstinence in the schizophrenic smoker impairs (Normal ^ Schizophrenia) VSWM, presumably in association with reductions in cortical dopamine activity as discussed previously. In control smokers, excessive cortical dopamine stimulation by cigarette smoking (see Figure 5-1, Normal ^ Stress) impairs VSWM (Park et al. 2000), similar to the effects of acute stress (George et al. 1998), and smoking abstinence in control subjects improves VSWM (Stress ^ Normal). Hence, the results from the Yale group are consistent with previous models that postulate an "inverted-U" relationship between cortical dopamine and spatial working memory, which is likely mediated by postsynaptic Dx dopamine receptor stimulation (Arnsten 2000; Williams and Goldman-Rakic 1995; Zahrt et al. 1997). That is, too little (e.g., schizophrenia) or too much (e.g., produced by stress or smoking) cortical dopamine function impairs spatial working memory, and moderate levels of cortical dopamine activity are required for optimal spatial working memory function. In schizophrenic subjects, cigarette smoking (nicotine) augments VSWM (and cortical dopamine), and in control smokers, cigarette smoking impairs VSWM by producing cortical dopamine hyperfunction. This model may thus have important implications for the development of treatments for schizophrenia, and for nicotine addiction in these patients, possibly with the use of nonaddictive nicotinic receptor agonists.

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