Correlation Between Serum Concentrations of N-Desmethylclozapine and Granulocyte Levels in Patients with Schizophrenia: A Retrospective Observational Study
Clozapine is restricted to use in patients with treatment-refractory schizophrenia due to the risk of a serious drop in absolute neutrophil granulocyte count (ANC). The formation of reactive, unstable metabolites (adducts) has been suggested as a mechanism of clozapine-induced granulocyte decline. These adducts are not detectable in vivo, but stable clozapine metabolites could potentially be indirect pharmacokinetic measures of adduct formation.
The present retrospective observational study investigated the correlation between concentrations of N-desmethylclozapine, the major stable clozapine metabolite, and ANC in a real-life population of clozapine-treated patients.
Patients were included from a therapeutic drug monitoring service at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway, between March 2005 and December 2015. Information about clozapine and N-desmethylclozapine steady-state trough concentrations, as well as accompanying measurements of ANC, were collected from the laboratory database. Correlations of serum concentrations of N-desmethylclozapine and clozapine (and their respective ratios) with ANC were investigated by linear mixed-model analysis.
Overall, 129 patients with 855 measurements of clozapine/N-desmethylclozapine concentrations and ANC (range 0.9–19 × 109 cells/L, median 4.6) were included. Concentrations of N-desmethylclozapine, but not clozapine, correlated significantly and positively with ANC (estimated model slope 0.0011 × 109 cells/L/nM; p = 0.002), and the N-desmethylclozapine/clozapine ratio also positively correlated with ANC (p = 0.040).
N-Desmethylclozapine level and ANC significantly correlated in this real-life population of schizophrenia patients. The positive correlation, which was also present for the metabolic ratio, might reflect reduced clozapine availability for the formation of reactive metabolites potentially affecting granulocyte level. However, as our findings were based on ANC mainly within the reference range, this hypothesis should be studied further in clozapine-treated patients with neutropenia or agranulocytosis.
The authors would like to thank Kjersti Bjøntegård (user representative in the project) for valuable discussions during data analysis and manuscript preparation. We also thank Gro Jensen at the Department of Biochemistry, Diakonhjemmet Hospital, for providing methodological details on assays used for the determination of ANC.
Compliance with Ethical Standards
This project received funding from the South-Eastern Norway Regional Health Authority (Grant number 2016097).
Conflict of Interest
Ole A. Andreassen and Espen Molden have received speaker’s honoraria from Lundbeck, while Espen Molden has also received speaker’s honoraria from Lilly. Marja-Liisa Dahl received grants from the Swedish Research Council during the conduct of the study. Robert L. Smith, Tore Haslemo, Erik Eliasson, and Olav Spigset have no conflicts of interest to declare.
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