| アブストラクト | BACKGROUND: Clozapine, the most effective antipsychotic for treatment-resistant schizophrenia, is associated with severe adverse drug reactions (ADRs), including gastrointestinal stenosis and obstruction (GSO). Despite its efficacy, clozapine's anticholinergic properties impair gastrointestinal motility, leading to underrecognized yet life-threatening complications. This study investigates the risk of GSO in clozapine-treated individuals using real-world pharmacovigilance data. METHODS: A retrospective analysis of the FDA Adverse Event Reporting System database (2013-2024) identified clozapine-related GSO cases. Disproportionality analysis used Reporting Odds Ratio (ROR) and Information Component (IC), with positive signals requiring both IC(025) > 0 and ROR(025) > 1. Time-to-onset (TTO) patterns were modeled via Weibull distribution, with co-medication interactions assessed through Omega shrinkage analysis (positive interaction threshold Omega(025) > 0). Fluorouracil and olanzapine served as positive and negative controls, respectively. Bioinformatics analysis explored pathway overlaps between clozapine and co-medications. RESULTS: Among 97,101 clozapine reports, 8021 involved gastrointestinal ADRs, with GSO showing strong disproportionality signals (ROR(025) = 3.03; IC(025) = 1.59). GSO cases had high rates of serious outcomes (96.15% classified as Important Medical Events), including hospitalization (61.16%) and death (14.46%). GSO exhibited a wear-out failure pattern (median TTO = 395.5 days), indicating cumulative risk with prolonged use. Co-medications (e.g., anticholinergics and beta-blockers) synergistically increased GSO risk (Omega(025) > 0), particularly via neuroactive ligand-receptor and calcium signaling pathways. CONCLUSION: Clozapine significantly elevates GSO risk, with delayed onset and polypharmacy exacerbating toxicity. Findings underscore the need for enhanced gastrointestinal monitoring in long-term clozapine users and reevaluation of co-prescribing practices to mitigate this underprioritized ADR. |
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| ジャーナル名 | Naunyn-Schmiedeberg's archives of pharmacology |
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| Pubmed追加日 | 2025/7/30 |
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| 投稿者 | Li, Dandan; Zhao, Zilong; Chen, Zhenhui; Qiao, Zhenzhen; He, Yao; Zhou, Jianxing; Zheng, Xiaoyuan |
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| 組織名 | Pharmacy Department, Chongqing Emergency Medical Center, Chongqing University;Central Hospital, Medical College, Chongqing University, Chongqing, China.;Department of Pharmacy, Zhongshan Hospital (Xiamen), Fudan University, Xiamen,;Fujian, China.;Department of Pharmacy, The First Affiliated Hospital of Fujian Medical;University, Fuzhou, China. zhoujianxing@fjmu.edu.cn.;Department of Pharmacy, National Regional Medical Center, Binhai Campus of the;First Affiliated Hospital, Fujian Medical University, Fuzhou, China.;zhoujianxing@fjmu.edu.cn.;XiaoyuanZheng20@126.com. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/40736538/ |
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