de Leon Jose, Arrojo-Romero Manuel, Verdoux Hélène, Ruan Can-Jun, Schoretsanitis Georgios, Rohde Christopher, Cohen Dan, Schulte Peter F J, Kim Se Hyun, Cotes Robert O, Leung Jonathan G, Otsuka Yuji, Kirilochev Oleg O, Baptista Trino, Grover Sandeep, Every-Palmer Susanna, Clark Scott R, McGrane Ian R, Motuca Mariano, Olmos Ismael, Wilkowska Alina, Sagud Marina, Anil Yağcioğlu A Elif, Ristic Dragana Ignjatovic, Lazary Judit, Sanz Emilio J, De Las Cuevas Carlos
Department of Psychiatry, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain.
Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France.
J Clin Psychopharmacol. 2023;43(3):239-245. doi: 10.1097/JCP.0000000000001678.
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.
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.
目的/背景：本期刊最近发表的一篇文章从美国视角探讨了氯氮平处方的现代化问题，并提议摆脱粒细胞缺乏症所带来的长期阴影。
在此，一个国际合作团队通过关注氯氮平使用的全球结果来讨论与美国观点互补的观点，这些结果在氯氮平药物不良反应发生频率方面可能存在不均衡性。
发现/结果：来自斯堪的纳维亚国家注册系统（芬兰和丹麦）的研究未发现氯氮平治疗患者死亡率增加，也未发现氯氮平所谓毒性的明确证据。氯氮平相关致命结果的数据来自最近发表的两项药物警戒研究以及英国药物警戒数据库。一项专注于医生报告以评估2010年至2019年全球药物致死率的药物警戒研究发现，英国有968例与氯氮平相关的致命结果。此外，英国占全球氯氮平相关致命结果的55%（1761例中的968例），占欧洲氯氮平相关致命结果的90%（1073例中的968例）。在一项来自英国数据库（2008年至2017年）的药物警戒研究中，氯氮平每年与383例致命结果相关，包括来自医生和非医生的所有报告。从2018年到2021年，英国氯氮平相关致命结果增加到每年440例。
启示/结论：利用药物警戒数据库对每个国家的致命结果进行解读是有限的，仅能进行大致比较；即便存在这些局限性，英国的数据似乎令人担忧。在解释氯氮平治疗患者各国间致命结果分布不均的问题上，肺炎和心肌炎可能比粒细胞缺乏症更为重要。
