Association between initial clozapine titration and pneumonia risk among patients with schizophrenia in a Korean tertiary hospital

Pneumonia is a significant adverse drug reaction (ADR) associated with clozapine, characterized by high mortality and potential linkage with other inflammatory responses. Despite the critical nature, research regarding the development of pneumonia during initial clozapine titration remains limited. This retrospective study included 1408 Korean inpatients with schizophrenia spectrum disorders. Data were collected from January 2000 to January 2023. Pneumonia developed in 3.5 % of patients within 8 weeks of clozapine initiation. Patients who developed pneumonia were taking a greater number and higher dose of antipsychotics at baseline (2.14 vs. 1.58, p < 0.001; 25.64 vs. 19.34, p = 0.012). The average onset occurred 17.24 days after initiation, on an average dose of 151.28 mg/day. Titration was either paused or slowed in most of these patients, with no reported fatalities. The types of pneumonia included aspiration pneumonia, mycoplasma pneumonia, bronchopneumonia, and COVID-19 pneumonia. Myocarditis, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, and urinary tract infections were also identified. Logistic regression analysis revealed that a greater number of concomitant antipsychotics (odds ratio [OR] = 1.59, p = 0.027) and concomitant benzodiazepine use (OR = 2.33, p = 0.005) at baseline were associated with an increased risk of pneumonia. Overall, pneumonia development during clozapine titration is linked with other inflammatory ADRs, suggesting a shared immunological mechanism. Close monitoring is recommended, especially for patients taking multiple antipsychotics and benzodiazepines. Further studies involving repeated measures of clozapine concentrations at trough and steady state, along with a more detailed description of pneumonia types, are warranted.