HK data: Clozapine may increase infection risk in schizophrenia | Multidisciplinary

Clozapine is associated with a moderately increased risk of infection vs olanzapine in patients with schizophrenia in Hong Kong, with the association being notably stronger in older age groups, according to researchers from the Department of Family Medicine and Primary Care at the University of Hong Kong (HKU).

Infection is the leading natural cause of mortality in patients with schizophrenia. Recent hypotheses suggest that clozapine use may be associated with an increased risk of infection. [Lancet Psychiatry 2025;12:628-637]

Using territory-wide electronic health records from the Hong Kong Hospital Authority, the HKU researchers conducted a population-based cohort study of patients with schizophrenia who used clozapine (n=1,450; mean age, 45,33 years; male, 45.1 percent) or olanzapine (n=9,601; mean age, 40.59 years; male, 47.7 percent) between 1 January 2004 and 31 December 2023.

The overall incidence of infection was increased with clozapine vs olanzapine use (weighted incidence rate, 7.26 vs 6.00 per 100 person-years; weighted hazard ratio [HR], 1.25; 95 percent confidence interval [CI],1.13–1.39).

“Clozapine use may weaken the overall immune response to pathogens and increase the risk of infections,” explained the researchers.

The risk of infection was notably higher in older age groups. The weighted HRs increased from 1.24 (95 percent CI, 1.08–1.42) in patients aged 18–44 years to 1.41 (95 percent CI, 1.15–1.72) in those aged 45–54 years, and 1.45 (95 percent CI, 1.14–1.84) in those aged ≥55 years. Similarly, weighted absolute differences in incidence rate rose with age, from 0.81 per 100 person-years in those 18–44 years of age, to 2.23 per 100 person-years in those 45–54 years of age, and 4.70 per 100 person-years in those aged ≥ 55 years.

“The age-stratified subgroup analysis showing larger association and rate difference among the older groups pinpoints a specific risk group for further research to examine,” pointed out the researchers. “It also showed that risk of infection is not likely to be a substantial concern for patients aged <45 years.”

“To the best of our knowledge, the current study represents the first population-based cohort analysis to assess infection risk associated with clozapine across a comprehensive variety of infectious disease categories,” noted the researchers.

Secondary analyses identified upper respiratory tract infections (weight HR, 1.50; 95 percent CI, 1.26–1.77), lower respiratory tract infections (HR, 1.71; 95 percent CI, 1.43–2.05), and gastrointestinal infections (HR,1.90; 95 percent CI, 1.37–2.64) as primary contributors to the observed increased incidence associated with clozapine vs olanzapine use. “These results aligned with a recent cohort study and other evidence on the potential effect of clozapine on respiratory, gastrointestinal, and other infections,” commented the researchers.

Clozapine has been the only medication approved by the US FDA for treatment-resistant schizophrenia in the past decades, demonstrating nearly unparalleled effectiveness in alleviating symptom and reducing rehospitalization and mortality rates. Recent initiatives call for expanding clozapine’s indications to earlier stages of schizophrenia. Results of the current study suggest that clinicians should balance the therapeutic benefits and risk of clozapine use, and follow risk mitigation strategies such as proactive vaccination and regular screening for respiratory symptoms (eg, cough, fever), especially in patients aged ≥45 years.