A Population-Based Study on Long-Term Mortality Risk Associated With Clozapine Use Among Patients With Schizophrenia

Background Patients with schizophrenia had significant elevated mortality risk. Clozapine is effective for treatment-resistant schizophrenia, but its use is limited because of side effects. Understanding its association with mortality risk in schizophrenia population is crucial. Though meta-analysis reported clozapine use is associated with a significant reduction in all-cause mortality mainly for patients who are continuously treated with clozapine, inconsistent results were reported in more recent studies. Furthermore, few studies reported on relationship of clozapine use and specific cause of mortality including suicide. Aims & Objectives To investigate the association of clozapine with all-cause and cause-specific mortality risk in patients with schizophrenia. Method This 18-year population-based cohort study retrieved records of schizophrenia patients from the electronic clinical records of all public hospitals in Hong Kong. Clozapine users (ClozUs) comprised schizophrenia patients who initiated clozapine treatment between 2003 and 2012, with the index date set at clozapine initiation. Comparators were non-clozapine antipsychotic users (Non-ClozUs) of the same diagnosis without a clozapine prescription ever. They were 1:2 propensity-score matched with demographic characteristics and physical and psychiatric comorbidities. ClozUs were further defined according to the continuation of clozapine use and co-prescribed with other antipsychotics (polypharmacy). Accelerated failure time (AFT) models were applied to estimate the risk of all-cause and cause-specific mortalities (i.e., suicide, cardiovascular disease, infection, and cancer). Results This study included 9,456 individuals, with 2,020 continuous ClozUs (mean [SD] age at the index date, 37.54 [12.42] years; 49.6% females; median [IQR] follow-up time, 12.30 [9.72–15.10] years), 1,132 discontinuous users (40.67 [13.01] years; 53.45% females; 12.61 [10.05–15.45] years), and 6,304 Non-ClozUs (39.37 [13.01] years; 50.6% females; 12.36 [9.73–15.19] years). Using adjusted AFT models accounted for Bonferroni Correction, continuous ClozUs exhibited a lower risk of suicide mortality (AF, 3.01, 99% CI, 1.41–6.44) compared to continuous Non-ClozUs. Continuous clozapine polypharmacy exhibited a lower risk of suicide mortality (3.67; 1.41–9.60) and all-cause mortality (1.42; 1.07–1.88) compared to continuous Non-ClozUs. Discussion & Conclusions These results add to the existing evidence on clozapine’s effectiveness, particularly its anti-suicide effects, and emphasize the need for continuous clozapine use for suitable patients and the possible benefit of clozapine polypharmacy.