Clozapine is the antipsychotic of choice for people with treatment-resistant schizophrenia (TRS) but is associated with the uncommon but potentially life-threatening adverse effect of myocarditis. However, there are no criteria for diagnosing clozapine-associated myocarditis (CAM) or global guidelines on detection and risk reduction, or for restarting clozapine after CAM.

To develop criteria for CAM and algorithms for clozapine initiation and clozapine rechallenge after CAM in a multiprofessional consensus process.

We conducted a systematic literature search for cases of clozapine rechallenge following CAM using the PubMed, EMBASE, CINAHL and PsycINFO databases, followed by a multidisciplinary international two-step Delphi consensus process in July and October 2024. The Delphi panel comprised psychiatrists, cardiologists, pharmacists, psychopharmacologists and nurses with expertise on clozapine or myocarditis.

Ninety-three clinicians and academics with experience in prescribing clozapine from six continents participated in the Delphi process. A consensus was reached on a definition of CAM according to modified clinical criteria from the European Society of Cardiology for myocarditis associated with immune checkpoint inhibitors. Titration schemes slower than those given in the Summary of Product Characteristics for clozapine were recommended to minimise CAM risk. Minimum and enhanced requirements for screening and monitoring were developed to account for global perspectives and limited resources in certain healthcare systems, and an approach to clozapine rechallenge was elaborated.

This multidisciplinary project represents the first guidance for CAM and will inform clinicians, other caregivers and patients, as well as facilitating the development of national guidelines on CAM prevention, screening and monitoring and rechallenge after an index episode of myocarditis in individuals taking clozapine.