Clozapine/norclozapine plasma concentrations and their ratio in treatment resistant, early psychosis patients

Treatment-resistant schizophrenia affects approximately 30% of schizophrenia patients, and clozapine is the antipsychotic of choice for their treatment. Despite its effectiveness, clozapine is considerably under-prescribed for the aforementioned patients' group, probably due to its severe side effects. Measurement of plasma concentrations of clozapine and its active metabolite, norclozapine, in plasma could help clinicians to monitor compliance to treatment and reduce the possibility of severe side effects. Such measurements are currently not included in routine clinical practice, although clozapine plasma concentrations seem to be influenced by many different factors and do not usually reflect the prescribed dose. The aim of the present study was to measure clozapine and norclozapine plasma concentrations and their ratio in a group of early psychosis, treatment-resistant, schizophrenia patients and to investigate possible associations among the prescribed clozapine daily dose and socio- demographic variables. Thirty-eight patients were included in the study, and 342 blood samples were collected. Clozapine and norclozapine plasma concentration measurements were performed by UHPLC-MS/MS. Mixed-effects linear regression models were performed to associate blood clozapine and norclozapine levels and their ratio to clozapine dose. The median clozapine dose, clozapine, norclozapine plasma concentrations, and their ratio at first and last measurement were as follows: 400mg/day (IQR = 350mg/day to 500mg/day) and 425mg/day (IQR = 350mg/day to 600mg/day), 335 ng/ml (IQR = 191 ng/ml to 427 ng/ml) and 389 ng/ml (IQR = 276 ng/ml to 523 ng/ml), 129 ng/ml (IQR = 62 ng/ml to 218 ng/ml) and 135 ng/ml (IQR = 82 ng/ml to 209 ng/ml), 2.5 (IQR = 1.6 to 4.8) and 2.9 (IQR = 1.7 to 4.4). An increase of clozapine dose by 50mg/day was associated with higher blood clozapine and norclozapine levels but with lower clozapine/norclozapine ratio. Clozapine dose was positively associated with blood clozapine and norclozapine levels and negatively with the clozapine/norclozapine ratio.