Pharmacology of N-desmethylclozapine

Abstract

Currently available treatments for schizophrenia have limited efficacy and are generally poorly tolerated. However, among these antipsychotic agents, clozapine stands apart in having generally superior motoric tolerability and efficacy. One intriguing possibility, based on clinical correlations, receptor activity profiles and studies with animal models predictive of antipsychotic or cognitive action is that the activity of N-desmethylclozapine (NDMC), a major metabolite of clozapine, may, at least in part, underlie the unique efficacy of clozapine. In this review we compare the pharmacological properties of NDMC to those of clozapine and consider how they may contribute to the overall clinical properties of clozapine. We also consider whether NDMC, in its own right, might be a superior antipsychotic drug.

Introduction

Schizophrenia is a debilitating neuropsychiatric disorder that is characterized by hallucinations and delusions (positive symptoms), flattened affect, anhedonia, and anergia (negative symptoms), and cognitive disturbances (Wong & Tol, 2003). To date, over 50 chemically distinct antipsychotic agents have been administered to schizophrenia patients worldwide, yet for nearly all patients therapeutic outcome is unsatisfactory. With current treatment regimens approximately 30% of patients continue to have severe and persistent symptoms and more than 60% of patients fail to achieve full alleviation of symptoms (Kane et al., 1988, Lieberman et al., 2005, Stroup et al., 2006a, Stroup et al., 2006b). Moreover, for many patients, intolerable side effects, coupled with limited efficacy, results in premature discontinuation of therapy (Kane et al., 1988, Stroup et al., 2006a). One symptom domain that is especially poorly addressed by current therapies is the cognitive deficits associated with the disease. This is a significant shortcoming because cognitive impairment is a major determinant of functional outcome in schizophrenia (Green, 1996, Green et al., 2000). Thus, there is a tremendous unmet need for new antipsychotic medications that effectively treat all aspects of the disease, while possessing a side-effect profile that poses little challenge to compliance.

Of the currently available medications, there has been a long standing perception that clozapine, the first atypical antipsychotic agent, has efficacy and tolerability features that clinically discriminate it from other antipsychotic drugs (APDs) (Leucht et al., 2003). Clozapine displays superior efficacy against positive and negative symptoms, while producing minimal extrapyramidal motoric effects. Moreover, clozapine is effective in treatment-resistant schizophrenia patients (Kane et al., 1988), reduces the incidence of suicide (Meltzer, 1999, Meltzer, 2003, Wagstaff and Perry, 2003), and, by some reports, improves cognitive function (The Parkinson's Study Group, 1999, Lee et al., 1999, McGurk, 1999). Recent clinical studies further support clozapine's superior clinical profile inasmuch as the average length of therapy prior to discontinuation by the patient was significantly longer for clozapine than for other antipsychotic agents investigated (Jones et al., 2006, McEnvoy et al., 2006).

One challenge facing investigators attempting to elucidate the basis of clozapine's unique clinical profile is the possible role of a predominant active metabolite, N-desmethylclozapine (NDMC). High plasma levels of NDMC (ranging from 1200–4230 ng/ml), approaching those of clozapine itself, have been observed in humans given clozapine (Bondesson and Lindstrom, 1988, Hasegawa et al., 1994, Weigmann et al., 1997, Dumortier et al., 1998, Flanagan et al., 2003). Moreover, several investigators have shown that the degree to which clozapine is converted to NDMC predicts clinical outcome on multiple measures of cognition, negative and positive symptoms, as well as quality of life (Frazier et al., 2003, Mauri et al., 2003, Weiner et al., 2004, Shaw et al., 2006, Sporn et al., in press). It is noteworthy that the ratio of NDMC to clozapine, rather than absolute levels of either clozapine or NDMC, was found to be the best predictor of a positive clinical outcome (Weiner et al., 2004, Sporn et al., in press). This observation suggests that certain pharmacological properties of clozapine may actually counteract beneficial pharmacology of NDMC. However, contrary to these findings, other investigators have found no relationship between the conversion of clozapine to NDMC and clinical outcome and indeed have suggested that NDMC fails to enter the brain and thus is unlikely to contribute to the therapeutic actions of clozapine (Weigmann et al., 1999). These widely divergent views underscore the need for a complete appraisal of the pharmacological properties of NDMC.