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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., Competing Interests: Declaration of competing interest The authors have no conflicts of interest concerning the subject of the study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Safe and effective administration of clozapine requires careful monitoring for inflammatory reactions during the initial titration. The concentration-to-dose (C/D) ratio must be taken into account, which may vary among ethnicities. In this retrospective study, 1408 Korean schizophrenia inpatients were examined for during the first 8 weeks of clozapine titration. The average doses of clozapine administered during weeks 1, 2, 4, and 8 were 77.37, 137.73, 193.20, and 212.83 mg/day, with significantly lower doses for females than males. The average C/D ratio was significantly higher in females (1.75 ± 1.04 and 1.11 ± 0.67 ng/mL per mg/day). Patients with higher C/D ratios were more likely to experience fever and were prescribed lower doses of clozapine starting from week 4. In total, 22.1 % of patients developed a fever at an average of 15.74 days after initiating clozapine. Patients who developed a fever were younger, used more antipsychotics at baseline, had a higher C/D ratio, and had a higher incidence of an elevated C-reactive protein level. A higher C/D ratio, use of a greater number of antipsychotics at baseline, and concomitant olanzapine use were risk factors for the development of inflammatory reactions. The incidence of pneumonia, agranulocytosis, and myocarditis within 8 weeks were 3.7 %, 0.3 %, and 0.1 %. In summary, the target dose of clozapine titration is lower for Korean schizophrenia patients, with a higher C/D ratio and more frequent fever compared to Western patients; however, myocarditis occurs rarely. Our findings may contribute to the titration methods for clozapine for the East Asian population., Competing Interests: Declaration of competing interest The authors have no conflicts of interest concerning the subject of the study., (Copyright © 2023 Elsevier B.V. All rights reserved.)