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. 2022 Jul;36(7):659-679.
doi: 10.1007/s40263-022-00932-2. Epub 2022 Jun 27.

A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia

C U Correll  1   2   3 , Ofer Agid  4 , Benedicto Crespo-Facorro  5 , Andrea de Bartolomeis  6 , Andrea Fagiolini  7 , Niko Seppälä  8 , Oliver D Howes  9
Affiliations

A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia

C U Correll et al. CNS Drugs. 2022 Jul.

Erratum in

Abstract

Treatment-resistant schizophrenia (TRS) will affect about one in three patients with schizophrenia. Clozapine is the only treatment approved for TRS, and patients should be treated as soon as possible to improve their chances of achieving remission. Despite its effectiveness, concern over side effects, monitoring requirements, and inexperience with prescribing often result in long delays that can expose patients to unnecessary risks and compromise their chances of achieving favorable long-term outcomes. We critically reviewed the literature on clozapine use in TRS, focusing on guidelines, systematic reviews, and algorithms to identify strategies for improving clozapine safety and tolerability. Based on this, we have provided an overview of strategies to support early initiation of clozapine in patients with TRS based on the latest evidence and our clinical experience, and have summarized the key elements in a practical, evidence-based checklist for identifying and managing patients with TRS, with the aim of increasing confidence in prescribing and monitoring clozapine therapy.

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Conflict of interest statement

Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Cardio Diagnostics, Compass, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Pharmabrain, Recordati, Relmada, Reviva, Rovi, Seqirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and holds stock options for Cardio Diagnostics, Mindpax, and LB Pharma. Dr. Agid has been a consultant and/or advisor to or has received honoraria as follows: Advisory Board/Consultant: Janssen-Ortho (Johnson & Johnson); Otsuka; Lundbeck; Allergan/Abbvie; Speaker: Janssen-Ortho (Johnson & Johnson); Lundbeck, Otsuka, Mylan Pharmaceuticals; HLS Therapeutics; Research Contracts: Janssen-Ortho (Johnson & Johnson); Otsuka; Boehringer Ingelheim; Neurocrine Bioscience; DiaMentis. Prof. Crespo-Facorro has received honoraria as a consultant and/or advisor to Angelini, Janssen/J&J, Lundbeck, Otsuka and Viatris. Dr. de Bartolomeis has participated in advisory boards, lectures and unrestricted presentations sponsored by Trivia- Mylan. Dr. Fagiolini is /has been a consultant and/or a speaker and/or has received research grants from: Angelini, Apsen, Boehringer Ingelheim, Lundbeck, Janssen, Viatris, Otsuka, Recordati, Sanofi Aventis, Sunovion, Glaxo Smith Kline. Dr. Seppala is a part-time employee of Viatris Finland as a Consultant counselling doctors on clozapine-related problems. He has participated as advisor/speaker in meetings organized by Viatris, Recordati, and Janssen-Cilag. Dr. Howes is a part-time employee of H. Lundbeck A/S and has received investigator-initiated research funding from and/or participated in advisory/ speaker meetings organized by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche and Viatris/ Mylan.

Figures

Fig. 1
Fig. 1
Definition and identification of treatment-resistant schizophrenia. TRS treatment-resistant schizophrenia, CRS clozapine-resistant schizophrenia [7]; BPRS Brief Psychiatric Rating Scale, CGI-S-TRS Clinical Global Impressions-Severity TRS Scale, PANSS Positive and Negative Syndrome Scale, SANS Scale for the Assessment of Negative Symptoms, SAPS Scale for the Assessment of Positive Symptoms (adapted from reference [4], permission not required)
Fig. 2
Fig. 2
Algorithm for initial schizophrenia treatment and determination of treatment-resistance schizophrenia (TRS) [, –71] (drawn from published information, permission not required)
Fig. 3
Fig. 3
Provisional protocol for discontinuation of clozapine ( adapted from reference [102], permission not required)
Fig. 4
Fig. 4
The typical evolution of clozapine-induced myocarditis. bpm beats per minute, CRP C-reactive protein, HR heart rate, LV left ventricular, ULN upper limit of normal [131] (reprinted by permission of SAGE Publications)
Fig. 5
Fig. 5
Monitoring for clozapine-induced cardiotoxicity [, –133]. Less or more frequent monitoring may be appropriate depending on the clinical situation and local guidelines. aSymptoms may include chest pain, edema, shortness of breath, and other signs associated with heart failure. If signs or symptoms develop, or cardio markers are elevated, increase the frequency of troponin and C-reactive protein tests until normalized
See this image and copyright information in PMC

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