International trends in clozapine utilisation prevalence in adults, adolescents and older people: An observational study in 42 countries between 2015 and 2024

Importance: Clozapine is the only evidence-based treatment for treatment-resistant schizophrenia (TRS), yet substantial international variation in its use has been reported. Objective: To provide a comprehensive and updated assessment of international clozapine utilisation by estimating prevalence across countries using a standardised methodology and examining factors associated with variation in use. Design, Setting, and Participants: Repeated cross-sectional study using population-based data from 2015 to 2024. Individual-level data were obtained from 36 countries and 1 special administrative region, supplemented by national clozapine consumption data from 5 additional countries. Analyses were conducted separately for adults (20-64 years; primary analysis), adolescents (10-19 years), and older adults (≥65 years). Main Outcomes and Measures: Annual outpatient clozapine utilisation prevalence per 100,000 population by age group, sex, country and calendar year. Associations between clozapine utilisation prevalence and country-level health system, demographic, and socioeconomic indicators were also examined. Results: We analysed data from more than 1.1 billion people across all inhabited continents. In 2024, crude adult clozapine use prevalence was highest in Croatia (415.3 per 100,000 population) and Finland (302.0 per 100,000), and lowest in Oman (0.5 per 100,000) and Ethiopia (0.3 per 100,000), representing a 1,384-fold difference. Across most countries, utilisation peaked among individuals aged 50 to 59 years. The male-to-female prevalence ratio ranged from 0.4 in the United Arab Emirates to 2.8 in Colombia. Among adolescents, prevalence was highest in Colombia (42.7 per 100,000) and Croatia (24.4 per 100,000), while among older adults it was highest in Croatia (406.9 per 100,000) and Iceland (339.7 per 100,000). Across all countries, adult clozapine utilisation increased by 17% (95% CI, 16%-18%), from 44.7 per 100,000 population (95% CI, 44.5-44.9) to 52.2 per 100,000 population (95% CI, 51.1-52.4). Country-specific trends ranged from a 71% decrease to a 342% increase. None of the examined indicators explained variation in clozapine utilisation across countries. Conclusion and relevance: Clozapine use increased modestly over the past decade but remained highly variable between countries. This variation was not explained by national socioeconomic, healthcare-system, or monitoring-related factors, suggesting an important role for clinical and service-level barriers. The concentration of clozapine use in later adulthood is consistent with delayed initiation and highlights opportunities to improve timely access to evidence-based treatment for TRS.