Abstract
Aim/background: The use of clozapine is restricted due to its serious side effects, particularly bone marrow suppression, which occurs at an average rate of 1%. These side effects are markedly related to blood concentrations of clozapine and its metabolite nor-clozapine. Therefore, therapeutic drug monitoring is recommended for clozapine. Currently, laboratory monitoring of bone marrow suppression includes neutrophil count follow-up. However, using early-changing biomarkers may be more effective in detecting and preventing this side effect before neutropenia develops. Therefore, we aimed to evaluate serum clozapine and nor-clozapine levels and their relationship with early parameters reflecting bone marrow activity in complete blood count (CBC), immature granulocyte (IG) for neutrophils, mean platelet volume (MPV) and platelet-to-large cell ratio (P-LCR) for platelets in patients with schizophrenia receiving clozapine.
Methods: Fifty-one patients with schizophrenia receiving clozapine were included in the study. Of these, 49% (n=25) were on a low dose (<300 mg/day), 49% (n=25) on a middle dose (300-600 mg/day), and one patient was on a high dose (>600 mg/day) clozapine. CBC parameters—especially IG, MPV and P-LCR—and serum clozapine/nor-clozapine levels along with clozapine doses were recorded on the same day. The relationship between serum drug concentrations and CBC parameters was evaluated separately for the total patients and dose groups.
Results: There was no correlation between clozapine dose and serum clozapine or nor-clozapine concentrations. None of the patients had neutropenia or agranulocytosis. Serum clozapine and nor-clozapine levels negatively correlated with P-LCR (r=-0.402, p=0.006 and r=-0.465, p=0.001, respectively) and MPV (r=-0.294, p=0.036 and r=-0.397, p=0.004, respectively); positively correlated with neutrophil (r=0.381, p=0.011 and r=0.387, p=0.009, respectively) and IG counts (r=0.346, p=0.018 and r=0.335, p=0.023, respectively); but not with other CBC sub-parameters. Although the clozapine dosing differed between the two groups, the serum levels of clozapine and nor-clozapine were not significantly different (p=0.078 and p=0.058, respectively). Furthermore, in the middle dose group, serum clozapine and nor-clozapine levels were negatively correlated with P-LCR (rho=-0.547, p=0.007 and rho=-0.636, p=0.001, respectively), consistent with the total group.
Conclusion: Monitoring early biomarkers reflecting bone marrow activity, such as P-LCR for platelets and IG for neutrophils, alongside serum clozapine and nor-clozapine levels, is promising for predicting and preventing bone marrow suppression in patients receiving clozapine, thereby protecting against this serious side effect. However, our findings need to be supported by further research.

Key words: Clozapine, Nor-clozapine, Therapeutic drug monitoring, Platelet large cell ratio, Immature granulocyte