ArticleToxicological sciences : an official journal of the Society of Toxicology2022
Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 2 of them syntheses that pooled it.
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Who cites it
19 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Risk factors associated with blood dyscrasia during clozapine treatment: a systematic review and meta-analysis.Psychological medicine · 2026Pooled it
- Clozapine and Pneumonia: Synthesizing the Link by Reviewing Existing Reports-A Systematic Review and Meta-Analysis.Medicina (Kaunas, Lithuania) · 2024Pooled it
- Hepatic responses as potential biomarkers of idiosyncratic drug reaction risk.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- Risk of Long-Term Clozapine Medication over Decades for Cardiac Adverse Events Including Heart Failure and Its Pathophysiology: A Japan and China Retrospective Cohort Analysis.Medical sciences (Basel, Switzerland) · 2026Article
- Clozapine-induced inflammation: a case report.Frontiers in psychiatry · 2026Article
- The adverse effects of clozapine on blood markers and electrocardiographic findings in patients with schizophrenia.BioMedicine · 2026Article
- Longitudinal trends in blood concentrations of clozapine and norclozapine, inflammatory markers, and clinical outcomes in Japanese patients: a 12-week prospective study.Frontiers in psychiatry · 2026Article
- Association between endogenous lactate accumulation and dysregulated activation of the NLRP3 inflammasome pathway in schizophrenia.Scientific reports · 2025Observational
- TAK-994 mechanistic investigation into drug-induced liver injury.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Disproportionality analysis of flutamide- or bicalutamide-induced liver injury with and without steroids by using the Japanese Adverse Drug Event Report database.International journal of clinical pharmacy · 2025Article
- Clozapine Induces Agranulocytosis via Inflammatory and Hematopoietic Cytokine Induction of the JAK-STAT Signaling Pathway: Evidence From Network Pharmacology and Molecular Docking.CNS neuroscience & therapeutics · 2025Article
- COVID-19 disease outcomes in patients receiving clozapine versus other antipsychotics: a national study in Qatar.Frontiers in psychiatry · 2025Article
- Review
- The Association Between Clozapine Plasma Concentration, CYP2D6 (*10, *2) Polymorphisms and Risk of Adverse Reactions.Psychiatry and clinical psychopharmacology · 2023Article
- Association of Peripheral Inflammatory Biomarkers and Growth Factors Levels with Sex, Therapy and Other Clinical Factors in Schizophrenia and Patient Stratification Based on These Data.Brain sciences · 2023Article
- Characterization of Drug-Specific CD4Chemical research in toxicology · 2023Article
- The Role of Myeloperoxidase in Clozapine-Induced Inflammation: A Mechanistic Update for Idiosyncratic Drug-Induced Agranulocytosis.International journal of molecular sciences · 2023Article
- Inflammatory markers in outpatients with schizophrenia diagnosis in regular use of clozapine: a cross-sectional study.Frontiers in psychiatry · 2023Article
- The role of hypothalamic endoplasmic reticulum stress in schizophrenia and antipsychotic-induced weight gain: A narrative review.Frontiers in neuroscience · 2022Review
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
Although clozapine is a highly efficacious schizophrenia treatment, it is under-prescribed due to the risk of idiosyncratic drug-induced agranulocytosis (IDIAG). Clinical data indicate that most patients starting clozapine experience a transient immune response early in treatment and a similar response has been observed in clozapine-treated rats, but the mechanism by which clozapine triggers this transient inflammation remains unclear. Therefore, the aim of this study was to characterize the role of inflammasome activation during the early immune response to clozapine using in vitro and in vivo models. In both differentiated and nondifferentiated human monocytic THP-1 cells, clozapine, but not its structural analogues fluperlapine and olanzapine, caused inflammasome-dependent caspase-1 activation and IL-1β release that was inhibited using the caspase-1 inhibitor yVAD-cmk. In Sprague Dawley rats, a single dose of clozapine caused an increase in circulating neutrophils and a decrease in lymphocytes within hours of drug administration along with transient spikes in the proinflammatory mediators IL-1β, CXCL1, and TNF-α in the blood, spleen, and bone marrow. Blockade of inflammasome signaling using the caspase-1 inhibitor VX-765 or the IL-1 receptor antagonist anakinra attenuated this inflammatory response. These data indicate that caspase-1-dependent IL-1β production is fundamental for the induction of the early immune response to clozapine and, furthermore, support the general hypothesis that inflammasome activation is a common mechanism by which drugs associated with the risk of idiosyncratic reactions trigger early immune system activation. Ultimately, inhibition of inflammasome signaling may reduce the risk of IDIAG, enabling safer, more frequent use of clozapine in patients.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.