Causes of death and mortality patterns in clozapine-treated patients: 17-year retrospective cohort study

Clozapine reduces overall mortality and suicide risk in schizophrenia, but the specific causes and clinical contexts of death among clozapine-treated patients remain less well characterised.

We aimed to characterise causes of death in clozapine-treated patients within a defined UK catchment area over 17 years (2009-2025); compare features across predefined mortality clusters (suicide, expected, unexpected); compare unexpected death cases with a clozapine-treated comparison cohort alive in 2019 and examine temporal mortality patterns.

We conducted a retrospective, descriptive cohort study of all deaths among clozapine-treated patients within a UK mental health National Health Service Trust between 1 January 2009 and 31 December 2025. Deaths were classified into suicide, expected and non-intentional unexpected, using a previously established framework. Variables were compared across clusters and between unexpected death cases and a clozapine-treated comparison cohort alive in 2019.

Of 87 deaths, 11 (12.6%) were suicides, 29 (33.3%) were expected and 47 (54.0%) were non-intentional unexpected. Malignancy was the most common cause (21/87, 24.1%), followed by cardiovascular (13/87, 14.9%) and respiratory or infective causes (9/87, 10.3%). Age differed across clusters (p = 0.005), with suicides at younger ages. Compared with the 2019 cohort, patients who died unexpectedly were older (55.0 v. 48.6 years, p = 0.006) and more likely to smoke (75.0 v. 34.6%, p < 0.001). Annual mortality peaked in 2021 and was not fully explained by direct COVID-19 deaths.

Mortality in clozapine-treated patients arises across diverse clinical contexts, with more than half classified as non-intentional unexpected. Findings support sustained physical health monitoring, closer attention to smoking and other modifiable risks, and continuity of care.