Clozapine-Associated Myocarditis and Cardiomyopathy: Investigating a Metabolic Basis of Toxicity

Abstract

Clozapine is an antipsychotic drug indicated for treatment-resistant schizophrenia. However, its use is severely restricted due to its ability to cause potentially-fatal agranulocytosis. Whilst this problem has been overcome to some extent by mandatory intensive monitoring of white blood cells during initiation of therapy, clozapine therapy is also associated with myocarditis and cardiomyopathy. If detected early enough, these adverse reactions may result in drug withdrawal; if not, they may be fatal. However, despite the fact that these adverse events are recognised as problematic, neither the true incidence of myocarditis and cardiomyopathy nor the underlying mechanism for these toxicities has been determined. The catastrophic nature of the cardiac damage means that psychiatrists often withhold this life-changing drug because they cannot predict who will have problems with it. The main aims of this thesis were to determine the incidence of clozapine-associated myocarditis and cardiomyopathy in the Auckland area and to undertake a multidisciplinary approach to investigate whether aberrant clozapine concentrations and the biotransformation product profile associates with clozapine-associated cardiotoxicity. A systematic review of clozapine-associated myocarditis identified over 350 case reports in the literature. The review highlighted the heterogeneity of the clinical investigations used to monitor and diagnose patients with myocarditis. The findings from the review also served as the basis for the updated clozapine guidelines for the Auckland District Health Board. A retrospective review of the clinical records of patients taking clozapine determined the incidence of clozapine-associated myocarditis and cardiomyopathy in the Auckland District Health Board is 3.8% and 1% respectively. The incidence of clozapine-associated myocarditis reported here is approximately 20-fold greater than indicated by the New Zealand Medicines and Medical Devices Safety Authority. A robust analytical assay was developed to quantitate clozapine and its two plasma metabolites, N-desmethyl clozapine and clozapine N-oxide. The N-oxide metabolite is not measured in clinical settings. Clozapine disposition was investigated in post-mortem samples of patients who died whilst taking clozapine and in patients who were followed from initiation to determine if there was a temporal relationship between clozapine and metabolite exposure and clozapine-associated cardiotoxicity. The post-mortem study established a legal process to obtain tissue taken for the purpose of coronial autopsy in New Zealand. The findings from this study led to the formation of a formal review panel at the request of the Chief Coroner. This review resulted in the change in the manner of death from suicide to natural causes in two patients who died whilst taking clozapine and a six month pilot study into the way clozapine related deaths are investigated in New Zealand. The prospective longitudinal study identified that in cases of myocarditis versus no myocarditis with a similar elevation in C-reactive protein, formation of the N-oxide metabolite appeared greater and the N-desmethyl/N-oxide ratio was perturbed significantly. This has not been previously reported. If alternate routes play a role in clozapine-associated toxicity it is subtle.