Original ArticlesSmoking and therapeutic response to clozapine in patients with schizophrenia
Introduction
Patients with schizophrenia smoke at prevalence rates of 70 to 80%, i.e., approximately three times that of the general population Hughes et al 1986, Goff et al 1992, de Leon 1995. Although conventional antipsychotic drugs may increase how much a smoker smokes Dawe et al 1995, McEvoy et al 1995a, patients with schizophrenia smoke at these prevalence rates even before their first exposure to antipsychotics (McEvoy and Brown in press). Nicotine may have “therapeutic” effects in patients with schizophrenia; for example, nicotine normalizes a deficit in auditory sensory gating found in many patients with schizophrenia and in approximately 50% of their first-degree relatives (Adler et al 1992). An inability to filter out unimportant sounds could distract and disorganize patients, and provide a substrate for delusional misinterpretations (Adler et al 1998). This sensory gating deficit is not corrected by conventional antipsychotic drugs. However, this sensory gating deficit is corrected by clozapine in those patients who show a favorable therapeutic response to clozapine (Nagamoto et al 1996). Previous studies have suggested that smoking decreases when patients with schizophrenia switch treatments from conventional antipsychotics to clozapine George et al 1995, McEvoy et al 1995b. Nicotine also correct eye-tracking abnormalities (Olincy et al 1998) and haloperidol-induced cognitive psychomotor slowing (Levin et al 1996) in patients with schizophrenia.
We appended measures of smoking to a study primarily designed to prospectively compare the therapeutic efficacy of clozapine treatment within three nonoverlapping clozapine serum level ranges VanderZwaag et al 1996, Freudenreich et al 1996, Freudenreich et al 1997. The medium (200 to 300 ng/mL) and high (350 to 450 ng/mL) ranges proved significantly more therapeutically effective than the low (50 to 150 ng/mL) serum level range (VanderZwaag et al 1996). In this report we examine: 1) whether being a smoker predicts therapeutic response to clozapine; 2) whether switching from a conventional antipsychotic to clozapine decreases how much patients smoke; and 3) whether therapeutic (medium or high) serum clozapine levels affect smoking differently than subtherapeutic (low) levels.
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Methods and materials
Given the considerable financial burden clozapine places on the limited resources of our state hospital, candidates for clozapine treatment must be reviewed and approved by a clozapine committee whose mandate is to ensure that those most in need receive treatment. We approached patients consecutively approved by this committee for informed consent.
Fifteen women and 55 men who met the DSM-III-R criteria for schizophrenia participated in this study. Their mean age was 36.5 years (range = 21 to
Results
Sixty-six of the 70 patients who entered completed the 12-week trial. The other four patients were removed from the trial early because of inadequate response to treatment. All four were assigned to the low clozapine serum level group, and three were nonsmokers. Their last observed values (week 6) were carried forward for the analyses.
Fifty-five of these 70 patients with schizophrenia smoked, a prevalence rate (79%) similar to that reported by others. Table 1demonstrates that smokers and
Discussion
Seventy-nine percent of these treatment-refractory patients with schizophrenia smoked. Being a smoker was associated with having a more favorable therapeutic response to clozapine. This suggests two possibilities: 1) nicotine augments clozapine’s efficacy and the limited therapeutic response to clozapine in nonsmokers could be enhanced by administering nicotine (this “additive” hypothesis is easily testable); or 2) certain patients with schizophrenia have contributing pathophysiologic
Acknowledgements
Financial support: NIDA 08434, NARSAD Independent Investigator Award (JPM).
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