Investigating Potential Clinical Biomarkers of Clozapine-Induced Myocarditis

Abstract

Clozapine is an effective antipsychotic used in treatment resistant schizophrenia. However, its use is associated with, and limited by, a rare but potentially fatal myocarditis. It is possible that clozapine administration, along with an obesity-related pro-inflammatory state, may alter fatty acid utilisation in the heart sensitising an individual to developing myocarditis. The aim of this thesis was to investigate the feasibility of testing samples collected prospectively from patients initiating clozapine therapy for an association between the composition of free fatty acids, other lipids, inflammatory markers and the development of clozapine induced myocarditis. Patients who were initiating or reinitiating clozapine treatment within the Auckland District Health Board were eligible for this study, and where possible an extra blood sample was collected at the time a sample was taken for mandated blood cell counts. Lipid profiles and total free fatty acids were analysed for trends. An HPLC method was successfully developed with acceptable precision and accuracy. Finally, a 10-plex cytokine kit was used to measure temporal levels of inflammatory markers. In this study, one patient developed myocarditis. In this patient the percentage content of linoleic, oleic, stearic and palmitic acids increased by 24%, 11%, 13% and 34%, respectively upon the advent of myocarditis. There was an apparent positive association between clozapineinduced myocarditis and the level of total free fatty acids and the cytokines IL-6, TNF-α and INF-γ. There are currently no selective biomarkers for the diagnosis of clozapine-induced myocarditis. The pilot data presented in this thesis reports the first instance of an increase in specific free fatty acids with the development of clozapine-induced myocarditis. Future work with a larger cohort is required to evaluate the potential for cytokines and free fatty acids to be used as a biomarker for clozapine related myocarditis.