LAUSR

National drug agencies send reports of adverse drug reactions (ADRs) to the World Health Organization's (WHO) pharmacovigilance database, used by Montastruc et al. for an extremely important contribution regarding fatal outcomes of clozapine ADRs. The comparison of transnational fatal outcomes in this database is limited by lack of knowledge of: (1) ADRs occurring versus those reported, (2) reports of fatal versus non-fatal outcomes, and (3) the number of patients taking clozapine corrected by population size. Thus, only “gross” transnational comparisons can be made. Even with its limitations, Montastruc et al. has published the only comparison of fatal outcomes presumably explained by clozapine ADRs in various countries. Over a 10-year period (2010–2019), physicians worldwide reported in the WHO database 1761 fatal outcomes associated with clozapine, according to Montastruc et al. Clozapine was the third most lethal drug in the world overall, but was the most lethal drug among non-geriatric adults worldwide. The distribution was uneven since physicians in the United Kingdom (UK) reported 968 fatal outcomes versus 892 in the rest of the world, including only 105 fatal outcomes reported by physicians in the other European countries. Clozapine was the most lethal drug in the UK, explaining 52% (968/1869) of fatal outcomes. In the UK, clozapine is mainly used for treatment-resistant schizophrenia (TRS); however, the same is true in most countries, so mortality associated with TRS cannot explain the UK's overrepresentation in clozapine lethal outcomes. The UK has a clozapine national registry for haematological monitoring, as do many countries. In a review of clozapine regulations in eight countries besides the UK, Nielsen et al. described the existence of national registries in four other countries: Ireland, the United States, Japan and New Zealand. A prior article provided the causes of worldwide fatal outcomes in clozapine including all reports from physicians and non-physicians in the WHO database. From inception through 2019, the four largest causes of fatal outcomes in clozapine patients were pneumonia, sudden death, agranulocytosis and myocarditis. Through 2019, pneumonia explained 2077 clozapine fatal outcomes worldwide (30% relative lethality; 2077/6983). Therefore, it is likely that a good number of the 968 fatal UK outcomes in that 10-year period may be associated with pneumonia. Using the Danish registry, it has been estimated that approximately two-thirds of the risk of pneumonia in clozapine patients is due to TRS and only one-third due to clozapine treatment, but there is no similar estimate of the contribution of TRS vs. clozapine in fatal outcomes during pneumonia. Sudden death/cardiac arrest was the second leading cause of death worldwide in clozapine patients with 1449 fatal outcomes. It is not easy to interpret sudden deaths reported to pharmacovigilance databases since they may be explained by clozapine, co-medications or comorbidities such as a sudden myocardial infarct. Almost all deaths associated with agranulocytosis in clozapine patients are probably explained by clozapine since other drugs with that potential are usually not administered in clozapine patients. Through 2019 there were only 550 agranulocytosis deaths in clozapine patients worldwide, comprising very low relative lethality of 2% (550/34 931). Thus, it is not likely that agranulocytosis explains many of the 968 fatal outcomes in the UK described by Montastruc et al. Moreover, a recent British article by Taylor et al. proposes that in one area of London a significant proportion of cases of agranulocytosis identified in patients who were prescribed clozapine are not life-threatening and may not even be clozapine-related. The WHO database's fourth leading cause of death worldwide from inception through 2019 was myocarditis with 539 deaths (12% relative lethality; 539/4586). Myocarditis may be explained by too-rapid titration for the clozapine metabolism of specific patients. In a more recent WHO database review focused on clozapine-induced myocarditis (excluding myocardiopathy) until early 2021, Australia ranked first with 1813 cases and the UK second with 590 cases. In fatal outcomes, Australia had 53 and the UK 25. Thus, only a maximum of 25 of 986 fatal UK outcomes from 2010 through 2019 may be explained by myocarditis. In summary, this letter proposes that many of the 986 lethal outcomes in UK clozapine patients from 2010 through 2019 reported by physicians may be associated with pneumonia or sudden death, the two leading causes of fatal outcomes associated with clozapine in the WHO database. More importantly, it is urgent that the UK's national drug agency and clozapine experts in the UK explore the causes associated with so many fatal outcomes in UK clozapine patients. It is urgent because 968 UK fatal outcomes mean that around 97 patients die every year in ways that their treating physicians consider important enough to report to the UK drug agency. Furthermore, UK reports from all sources indicated 383 mean clozapine fatal outcomes every year (3828 in the last 10 years). Received: 22 July 2022 Revised: 17 August 2022 Accepted: 31 August 2022