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. 2026 Jan 16;52(1):sbae213.
doi: 10.1093/schbul/sbae213.

Relationship Between Clozapine-Induced Inflammation and Eosinophilia: A Retrospective Cohort Study

Yuki Kikuchi  1   2 , Yuji Otsuka  3 , Fumiaki Ito  4 , Yuji Yada  5 , Hiroaki Tanifuji  6 , Hiroshi Komatsu  7 , Hiroaki Tomita  1   7
Affiliations

Relationship Between Clozapine-Induced Inflammation and Eosinophilia: A Retrospective Cohort Study

Yuki Kikuchi et al. Schizophr Bull. .

Abstract

Background and hypothesis: Eosinophilia has not been highlighted in clozapine-induced adverse inflammatory events, as it is often asymptomatic and self-limiting, while drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome occurs rarely. This study aimed to reveal the temporal relationships between eosinophilia and other inflammatory events during clozapine initiation.

Study design: The temporal relationships between eosinophilia and other inflammatory events were evaluated among 241 patients with schizophrenia treated with clozapine for the first time at 7 hospitals. Risk factors for eosinophilia were investigated among preceding inflammatory events and other clinical characteristics. Furthermore, patients with eosinophilia were stratified by the severity of adverse inflammatory events and their clinical characteristics were compared.

Study results: Of the 54 patients who experienced inflammatory adverse events, 27 (50%) developed eosinophilia. In all but 1 patient, clinical symptoms of inflammatory adverse events preceded eosinophilia. In contrast, of the 187 patients without inflammatory events, 21 (11%) developed eosinophilia. Multivariate analysis revealed that more severe preceding inflammatory adverse events were associated with a greater risk of eosinophilia. The median time to the first detection of eosinophilia and peak eosinophil count occurred significantly earlier in patients with severe adverse events than in asymptomatic patients.

Conclusions: In most cases, eosinophilia developed after the onset of inflammatory symptoms. Preceding inflammation was associated with the development of clozapine-induced eosinophilia. Eosinophilia may not be suitable as an early detection marker of severe inflammatory adverse effects. These findings enhanced our understanding of the involvement of eosinophilia in clozapine-induced inflammatory events.

Keywords: C-reactive protein; DRESS; fever; myocarditis; pneumonia.

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Conflict of interest statement

Y.Y. received speaker fees from Otsuka and Sumitomo Pharma. H.To. received research funding, directed to Tohoku University, from Daiichi Sankyo Company, Limited; Eisai Co., Ltd; Otsuka Pharmaceutical Co., Ltd; and Sumitomo Dainippon Pharma Co., Ltd. H.To. also received personal honoraria from Daiichi Sankyo Company, Limited; EA Pharma Co., Ltd; Eisai Co., Ltd; Janssen Pharmaceutical K.K.; Lundbeck; Meiji Seika Pharma Co., Ltd; Mochida Pharmaceutical Co., Ltd; MSD K.K.; Mylan EPD G.K.; Otsuka Pharmaceutical Co., Ltd; Pfizer Japan Inc.; Sumitomo Pharma Co., Ltd; Takeda Pharmaceutical Company Limited; and Viatris Inc.

Figures

Figure 1.
Figure 1.
Relationship between the onset date of inflammatory adverse events and the onset date of the first detection of eosinophilia in 27 patients with both eosinophilia and inflammatory adverse events.
Figure 2.
Figure 2.
Time course of 8 patients who experienced severe adverse reactions associated with eosinophilia, leading to the discontinuation of clozapine. The left axis represents C-reactive protein (CRP) levels (mg/dL), while the right axis indicates eosinophil count (EOS; /mm³). The horizontal axis shows the number of days since the initiation of clozapine treatment. The “Onset” marker denotes the date when the patient first developed clinical symptoms. Shaded areas indicate the period after clozapine discontinuation.
See this image and copyright information in PMC

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