4A-02 - Clozapine use and risk of infections in schizophrenia: a population-based cohort study

Background: Infection is the leading natural cause of mortality in patients with schizophrenia and antipsychotic use may be associated with an increased risk of infections. This study aims to examine the association of clozapine use with a wide variety of infectious diseases.


Objectives: To quantify infection rates associated with clozapine use and evaluate their clinical significance relative to treatment resistance. We hypothesize that clozapine use may increase the incidence rate of infectious diseases.

Methods: •

Design: A retrospective cohort study.
• Setting: Using longitudinal population-wide electronic health records from the Hong Kong Hospital Authority, we identified individuals aged 18 years or older with schizophrenia who received at least 90 days of clozapine or olanzapine, alongside more than 2 prior antipsychotic prescriptions.
• Exposures or interventions: The prescription of clozapine was considered the exposure, with olanzapine used as the comparator due to its similar chemical structure and pharmacological profile with clozapine.
• Main outcome measures: The primary outcome was the incidence of any infectious disease diagnosis, with subgroup analysis classified by sex and age. A subgroup classification of infectious disease diagnoses was analyzed as a secondary outcome.
• Statistical analysis: Propensity score-based inverse probability of treatment weighting (IPTW) was applied to balance covariates (age, sex, prior prescriptions, comorbidities). Cox regression estimated Hazard ratios (HRs) of infections between clozapine and olanzapine users. The absolute rate difference (ARD) was also estimated. ‎

Results: Among 11,051 patients (1,450 clozapine users and 9,601 olanzapine users), clozapine users had a 25% higher overall infection risk compared to olanzapine users (hazard ratio [HR]= 1.25, 95% confidence interval [CI]: 1.13, 1.39). The absolute rate of infectious diseases was 1.27 per 1,000 person-years higher in clozapine users compared to olanzapine users (95% CI: 0.55, 2.04). The risk was notably higher in older age ranges, with adjusted HRs rising from 1.24 (95% CI: 1.08, 1.42) in those aged 18-44 years to 1.41 (95% CI: 1.15, 1.72) among those aged 45-54 years and 1.45 (95% CI: 1.14, 1.84) among those aged 55 years or older. The absolute rate differences were 2.23 per 1,000 person-years (95% CI: 0.82, 3.86) for those aged 45-54 years and 4.70 per 1,000 person-years (95% CI: 1.29, 8.45) for those aged 55 years or older. Secondary analyses identified upper and lower respiratory tract infections as well as gastrointestinal infections as primary contributors to the observed association.

Conclusions: Clozapine use is associated with a significantly higher risk of infectious diseases, particularly respiratory tract infections and gastrointestinal infections. This risk is more pronounced in older age ranges. Clinicians should balance the therapeutic benefits of clozapine with infection control measures, including regular monitoring and preventive strategies.