Clozapine metabolism is associated with Absolute Neutrophil Count in individuals with treatment-resistant schizophrenia

Willcocks, I. R.; Legge, S. E.; Nalmpanti, M.; Mazzeo, L.; King, A.; Jansen, J.; Helthuis, M.; Owen, M. J.; O'Donovan, M. C.; Walters, J. T. R.; Pardinas, A. F.

AIM: To investigate the relationship between clozapine concentration and neutrophils in a European cohort of long-term clozapine users. METHODS: Pearson's Correlation and Linear Regression analyses were applied to a subset of the CLOZUK2 dataset (N=208) to assess the association between Absolute Neutrophil Count (ANC) and plasma clozapine concentration. Norclozapine and the metabolic ratio between clozapine and norclozapine were also investigated, along with SNPs associated with clozapine metabolism. RESULTS: Association between ANC and plasma clozapine concentration was found to be significant in a linear regression model (beta=-1.41, p=0.009), with a decrease in ANC of approximately 141 cells/mm3 for every 0.1 mg/litre increase in clozapine concentration. This association was attenuated by the addition of the metabolic ratio, which was significantly negatively correlated with ANC (beta=-0.69, p=0.021). In a further regression model, three SNPs previously associated with norclozapine plasma concentrations and clozapine/norclozapine ratio were also found to be significantly associated with ANC: rs61750900 (beta=-0.410, p=0.048), rs2011425 (beta=0.450, p=0.026) and rs1126545 (beta=0.330, p=0.039). CONCLUSION: ANC was found to be significantly negatively associated with plasma clozapine concentration. Further investigation has suggested that the relationship is mediated by the clozapine/norclozapine ratio, and potentially moderated by genetic variants with effects on clozapine metabolism.