A 20-Year Population-Based Follow-Up Study on the Association Between Clozapine and Hospitalization in People With Treatment-Resistant Schizophrenia

BACKGROUND: Clozapine is the gold-standard treatment for treatment-resistant schizophrenia (TRS), but its real-world effectiveness compared with other antipsychotics, including long-acting injectable antipsychotics (LAIAs), remains underevaluated. We aimed to compare hospitalization risk of patients during periods receiving clozapine versus other antipsychotics. METHODS: In this population-based, self-controlled case series study, we analyzed data from the Hong Kong Clinical Data Analysis and Reporting System. We included all patients with schizophrenia who initiated clozapine treatment between 2003 and 2020. Periods of clozapine exposure (initial and subsequent) were compared with periods of use of other oral antipsychotics and LAIAs (first-generation and second-generation). The primary outcome was incidence rate ratio (IRR) for psychiatric hospitalization. RESULTS: The study included 4794 patients (52.5% female; mean [SD] age 39.3 [13.3] years). Compared with other antipsychotics, clozapine use was associated with a significantly reduced risk of psychiatric hospitalization (during initial exposure: IRR, 0.21; 95% CI, 0.19-0.22; during subsequent exposure: IRR, 0.27; 95% CI, 0.26-0.29). Use of LAIAs alone was associated with a nearly 4 times higher risk of psychiatric hospitalization compared with clozapine monotherapy (IRR, 3.90; 95% CI, 3.66-4.15). Clozapine combined with second-generation LAIAs was associated with a lower risk of any hospitalization compared with clozapine alone in female patients. CONCLUSIONS: Clozapine is associated with a substantially lower risk of hospitalization than other antipsychotics, including LAIAs, in patients with TRS, confirming its superior effectiveness in a real-world setting. The potential benefit of combining clozapine with second-generation LAIAs, particularly in female patients, suggests a role for stratified treatment strategies and warrants further prospective investigation.