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

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.

KEYWORDS:

• Clozapine
• therapeutic drug monitoring
• tdm
• side effects
• seizure
• agranulocytosis

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

∙ Clozapine (CLZ) is superior other drugs in the treatment of schizophrenia.

∙ Therapeutic drugs monitoring (TDM) should always guide CLZ dosing to ensure satisfactory symptom control and prevent generalized tonic-clonic seizures and other severe concentration-dependent side effects, e.g. hypersalivation.

∙ The risk of potentially life-threatening CLZ-induced agranulocytosis (CIA) is not concentration-dependent and cannot be prevented by current TDM methods; instead the risk of CIA is managed by mandatory, rigorous haematological monitoring, which represents a barrier against CLZ use.

∙ A future goal should be to identify metabolite biomarkers predicting the risk of CIA, which then can be integrated in TDM methods for early assessment of potential granulocyte toxicity as a tool for both safe use and increased utility of CLZ beyond treatment-resistant schizophrenia.

This box summarizes key points contained in the article.

Additional information

Funding

This paper was not funded.