Temporal patterns of clozapine utilization and initiation timing in schizophrenia: a nationwide retrospective cohort study in south korea, 2010–2021

Introduction

Given the unique role of clozapine as the only antipsychotic with established efficacy for treatment-resistant schizophrenia [1], optimizing the timing of its initiation is a key component of schizophrenia care [2]. Accumulating evidence suggests that earlier clozapine initiation may be associated with more favorable clinical outcomes, whereas delayed initiation may be associated with poorer outcomes in patients with schizophrenia [3, 4]. Nevertheless, real-world studies examining the interval from schizophrenia diagnosis to clozapine initiation remain limited, and even fewer have investigated whether this interval differs by year of first recorded schizophrenia diagnosis. We therefore hypothesized that patients with a first recorded schizophrenia diagnosis in later years would have a shorter interval from diagnosis to clozapine initiation. Using nationwide real-world data, this study aimed to describe temporal patterns in clozapine utilization and initiation and to examine the association between year of first recorded schizophrenia diagnosis and time to first clozapine prescription.

Methods

This retrospective cohort study used nationwide claims data from the Korean Health Insurance Review and Assessment Service from 2010 to 2021. We estimated the annual numbers and proportions of patients receiving clozapine and those with a first clozapine prescription among all patients treated for schizophrenia. We used a Cox proportional hazards model to examine the association between the year of first recorded schizophrenia diagnosis and time from first recorded schizophrenia diagnosis to clozapine initiation.

Results

Between 2010 and 2021, the annual number of patients treated for schizophrenia increased from 275,024 to 366,185. Over the same period, the number of patients receiving clozapine increased from 9,890 to 17,611, with the corresponding proportion rising from 3.60% to 4.81%. The annual number of patients with a first recorded clozapine initiation ranged from 1,726 to 1,992, while the corresponding proportion showed no clear upward trend, changing from 0.63% in 2010 to 0.54% in 2021. In the time-to-event cohort of 153,803 patients with a first recorded schizophrenia diagnosis, 8,013 had a first recorded clozapine prescription. Later year of first recorded schizophrenia diagnosis was not significantly associated with shorter time to clozapine initiation (HR per 1-year later diagnosis = 1.002, 95% CI 0.994–1.009, p = 0.646).

Conclusions

This nationwide real-world analysis showed that clozapine utilization for schizophrenia increased between 2010 and 2021, but this growth was not accompanied by a marked proportional increase in new clozapine initiation. Moreover, we found no significant evidence of a shift toward earlier clozapine initiation among patients whose first recorded schizophrenia diagnosis occurred in more recent years. Taken together, these findings suggest that, despite growing recognition of the potential clinical benefits of earlier clozapine initiation, a clear shift toward earlier use was not observed in this nationwide real-world cohort. These findings underscore the need to better define and implement clinically appropriate timing of clozapine initiation in schizophrenia treatment.

References

1. Peraire, M., et al., Randomised controlled trial of clozapine in resistant schizophrenia and schizoaffective disorder. J Psychopharmacol, 2025. 39(11): p. 1284–1298.
2. Nielsen, J., et al., Geographical and temporal variations in clozapine prescription for schizophrenia. Eur Neuropsychopharmacol, 2012. 22(11): p. 818–24.
3. Hatano, M., et al., Long-term outcomes of delayed clozapine initiation in treatment-resistant schizophrenia: a multicenter retrospective cohort study. BMC Psychiatry, 2023. 23(1): p. 673.
4. Doyle, R., et al., Clozapine Use in a Cohort of First-Episode Psychosis. J Clin Psychopharmacol, 2017. 37(5): p. 512–517.