Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

Abstract

PURPOSE/BACKGROUND:

A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis.

METHODS:

Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions.

FINDINGS/RESULTS:

Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year.

IMPLICATIONS/CONCLUSIONS:

The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

• Authors: Jose de Leon, Manuel Arrojo-Romero, Hélène Verdoux, Can-Jun Ruan, Georgios Schoretsanitis, Christopher Rohde, Dan Cohen, Peter F J Schulte, Se Hyun Kim, Robert O Cotes, Jonathan G Leung, Yuji Otsuka, Oleg O Kirilochev, Trino Baptista, Sandeep Grover, Susanna Every-Palmer, Scott R Clark, Ian R McGrane, Mariano Motuca, Ismael Olmos, Alina Wilkowska, Marina Sagud, A Elif Anil Yağcioğlu, Dragana Ignjatovic Ristic, Judit Lazary, Emilio J Sanz, Carlos De Las Cuevas
• Journal: Journal of clinical psychopharmacology (J Clin Psychopharmacol) 2023 May-Jun 01 Vol. 43 Issue 3 Pg. 239-245 ISSN: 1533-712X [Electronic] United States
• PMID: 37068034 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

Chemical References

• Clozapine
• Antipsychotic Agents

Topics

• Humans
• Clozapine (adverse effects)
• Antipsychotic Agents (adverse effects)
• Pharmacovigilance
• Agranulocytosis (chemically induced)
• United Kingdom