Optimizing co-prescription of clozapine and antiseizure medications: a systematic review and expert recommendations for clinical practice

ABSTRACT

Introduction

Antiseizure medication (ASM) add-on to clozapine may be efficient to target clozapine-resistant mood or psychotic symptoms or clozapine-related adverse drug reactions (ADR) such as seizures. We aimed to synthesize the information relevant for clinical practice on the risks and benefits of clozapine-ASM co-prescription.

Areas covered

Articles were identified with MEDLINE, Web of Sciences and PsycINFO search from inception through October 2023. The review was restricted to ASM with mood-stabilizing properties or with potential efficacy for resistant psychotic symptoms (valproate (VPA), lamotrigine, topiramate, carbamazepine, oxcarbazepine).

Expert opinion

VPA add-on to clozapine is associated with a high risk of serious ADR (myocarditis, neutropenia, pneumonia) mostly explained by complex time-dependent drug-drug interactions. The initial inhibitory effects on clozapine metabolism require slow titration to avoid immuno-allergic reactions. After the titration period, VPA has mainly inductive effects on clozapine metabolism that are more marked in smokers requiring therapeutic drug monitoring. Lamotrigine and topiramate add-on may be recommended as the first-line treatment for clozapine-related seizures, but there is limited evidence regarding the efficacy of this strategy for clozapine-resistant psychotic symptoms. Carbamazepine should not be co-prescribed with clozapine because of its potential for agranulocytosis and for inducing clozapine metabolism.

KEYWORDS:

• Clozapine
• antiseizure medication
• adverse drug reaction
• drug-drug interaction
• therapeutic drug monitoring

Article highlights

• Lamotrigine and topiramate may be recommended as the first-line treatment for clozapine-related seizures.

• VPA add-on to clozapine should be avoided, as it is associated with a higher risk of serious ADR (myocarditis, neutropenia, pneumonia). Therapeutic drug monitoring is required because of complex time-dependent drug-drug interactions.

• Carbamazepine should not be co-prescribed with clozapine because of its potential for agranulocytosis and for inducing clozapine metabolism.

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 disclosure

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

Acknowledgments

The authors thank R Cooke for supervising the English of this manuscript.

Additional information

Funding

This paper was not funded.