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Background <p>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.</p> Methods <p>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<sub>025</sub> &gt; 0 and ROR<sub>025</sub> &gt; 1. Time-to-onset (TTO) patterns were modeled via Weibull distribution, with co-medication interactions assessed through Ω shrinkage analysis (positive interaction threshold Ω<sub>025</sub> &gt; 0). Fluorouracil and olanzapine served as positive and negative controls, respectively. Bioinformatics analysis explored pathway overlaps between clozapine and co-medications.</p> Results <p>Among 97,101 clozapine reports, 8021 involved gastrointestinal ADRs, with GSO showing strong disproportionality signals (ROR<sub>025</sub> = 3.03; IC<sub>025</sub> = 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&#xa0;days), indicating cumulative risk with prolonged use. Co-medications (e.g., anticholinergics and β-blockers) synergistically increased GSO risk (Ω<sub>025</sub> &gt; 0), particularly via neuroactive ligand-receptor and calcium signaling pathways.</p> Conclusion <p>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.</p> Graphical Abstract <p>This graphical abstract summarizes a pharmacovigilance study analyzing clozapine-associated gastrointestinal adverse drug reactions (ADRs) using FAERS data (2013–2024). Key findings include: Visualized trends highlight the need for long-term GSO monitoring in clozapine users. Time-to-onset analysis reveals delayed GSO risk (median 395&#xa0;days), showing cumulative toxicity. Disproportionality signals confirm clozapine’s strong association with GSO. Drug interactions exacerbate GSO via shared off-target effects pathways. GSO, gastrointestinal stenosis and obstruction.</p> <p></p>

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Higher risk of gastrointestinal stenosis and obstruction in clozapine-treated individuals with schizophrenia: a pharmacovigilance study based on the FDA adverse event reporting system database

  • 期刊论文

  • 发表日期：

    2025年7月30日

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  • Dandan Li,
  • Zilong Zhao,
  • Zhenhui Chen,
  • Zhenzhen Qiao,
  • Yao He,
  • Jianxing Zhou,
  • Xiaoyuan Zheng

摘要

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 IC025 > 0 and ROR025 > 1. Time-to-onset (TTO) patterns were modeled via Weibull distribution, with co-medication interactions assessed through Ω shrinkage analysis (positive interaction threshold Ω025 > 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 (ROR025 = 3.03; IC025 = 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 β-blockers) synergistically increased GSO risk (Ω025 > 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.

Graphical Abstract

This graphical abstract summarizes a pharmacovigilance study analyzing clozapine-associated gastrointestinal adverse drug reactions (ADRs) using FAERS data (2013–2024). Key findings include: Visualized trends highlight the need for long-term GSO monitoring in clozapine users. Time-to-onset analysis reveals delayed GSO risk (median 395 days), showing cumulative toxicity. Disproportionality signals confirm clozapine’s strong association with GSO. Drug interactions exacerbate GSO via shared off-target effects pathways. GSO, gastrointestinal stenosis and obstruction.