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Relaxation of the criteria for entry to the UK Clozapine Central Non-Rechallenge Database: a modelling study

Oloyede, Ebenezer, Whiskey, Eromona, Casetta, Cecilia, Dzahini, Olubanke, Dunnett, Danielle, Gandhi, Shreyans, Gaughran, Fiona, Shergill, Sukhi S., McGuire, Philip, MacCabe, James H., and others. (2022) Relaxation of the criteria for entry to the UK Clozapine Central Non-Rechallenge Database: a modelling study. The Lancet Psychiatry, 9 (8). pp. 636-644. ISSN 2215-0366. (doi:10.1016/S2215-0366(22)00188-2) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:96356)

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Background: Clozapine is uniquely effective in treatment-resistant psychosis. In the UK, patients must discontinue clozapine indefinitely if they are placed on the Central Non-Rechallenge Database (CNRD) after their haematological parameters fall below particular thresholds. Under exceptional circumstances, patients can be rechallenged on clozapine under an off-licence agreement. In the USA in 2015, restrictive practice was discontinued to allow greater flexibility for clozapine maintenance. The absolute neutrophil count leading to treatment interruption was lowered from less than 1·5 × 109/L to less than 1·0 × 109/L and platelet and white cell count monitoring were ceased. We aimed to investigate the implications of a similar policy change on clozapine use in the UK.

Methods: This was a modelling study of all patients registered on the UK CNRD. First, we determined the proportion of patients placed on the database in the UK who would have had to discontinue clozapine treatment under the US Food and Drug Administration (FDA) criteria. Second, we compared the haematological characteristics of patients who did or did not meet FDA criteria for discontinuing clozapine, including the time to registration from clozapine initiation and the proportion of cases of severe neutropenia at registration. Third, we investigated the success rates of clozapine re-challenge for patients that had been placed on the CNRD. Successful rechallenge was defined as no recurrence of CNRD registration.

Findings: Between May 2, 2002 and March 1, 2021, 3731 patients were placed on the CNRD, with a mean age of 47 years (SD 15), including 1420 (38%) women and 2311 (62%) men, of whom 3089 (83%) were White, 360 (10%) were Black, 190 (5%) were Asian, and 92 (2%) were classified as other. 566 (15%) of 3731 patients met the equivalent criteria for clozapine discontinuation under the FDA guidelines. The median time to CNRD registration from clozapine initiation was 1·6 years (IQR 0·2–4·9). Data for 519 rechallenged patients were examined; 419 (81%) were successful. Clozapine rechallenge success rates were broadly similar between individuals who did not meet the US CNRD registration criteria (36 [78%] of 46) and those who did meet the criteria (383 [81%] of 473).

Interpretation: Implementing the revised FDA monitoring criteria in the UK would substantially reduce clozapine discontinuation for haematological reasons, which would greatly improve the mental health outcomes of these patients without having a major effect on their physical health.

Item Type: Article
DOI/Identification number: 10.1016/S2215-0366(22)00188-2
Additional information: Funding Information: We would like to thank Britannia Pharmaceuticals, Leyden Delta BV, and Viatris for allowing access to anonymised data and their (non-financial) support for this study. We would also like to thank the SLaM Psychosis Clinical Academic Group Service user advisory group for reviewing and critically appraising the manuscript. The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health and Care Excellence, or the Department of Health and Social Care. Funding Information: DT has received speaker honoraria and research funding from Janssen, Recordati, and Sunovion, and has stock in Psychiatric Genetic Testing outside the submitted work. JHM has received research funding from Lundbeck outside the submitted work. All other authors declare no competing interests. EO is part funded by the Maudsley Charity. JHM, FG, and PM are part funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. FG is part supported by the Maudsley Charity and the NIHR Applied Research Collaboration South London at King's College Hospital NHS Foundation Trust. Publisher Copyright: © 2022 Elsevier Ltd
Subjects: R Medicine
Divisions: Divisions > Division of Natural Sciences > Kent and Medway Medical School
Funders: King's College London (
Depositing User: Rachael Heller
Date Deposited: 22 Sep 2022 13:52 UTC
Last Modified: 04 Mar 2024 15:16 UTC
Resource URI: (The current URI for this page, for reference purposes)

University of Kent Author Information

Shergill, Sukhi S..

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