Therapeutic drug monitoring of clozapine in adults with schizophrenia: a review of challenges and strategies

Abstract

ABSTRACT Introduction Clozapine (CLZ) is the superior drug in treatment of schizophrenia. Serum concentration of CLZ is associated with clinical response and dose-dependents side effects, where generalized tonic-clonic seizures are most critical. Thus, therapeutic drug monitoring (TDM) of CLZ may guide individual dosing to reach target exposure and prevent dose-dependent side effects. However, current TDM methods are not capable of predicting the risk of agranulocytosis, which is a dose-independent side effect restricting use of CLZ to treatment-resistant schizophrenia (TRS). Areas covered The article provides an overview of clinical, pharmacological, and toxicological aspects of CLZ, and the role of TDM as a tool for dose titration and follow-up in patients with TRS. Main focus is on current challenges and strategies in CLZ TDM, including future perspectives on potential identification/analysis of CLZ metabolite biomarkers reflecting the risk of granulocyte toxicity. Expert opinion The association between CLZ serum concentration, clinical response and risk of seizures is indisputable. TDM should therefore always guide CLZ dose titration. Development of advanced TDM methods, including biomarkers predicting the risk of granulocyte toxicity might extend TDM to be a tool for deciding which patients that can be treated safely with CLZ, potentially increasing its utility beyond TRS.