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.

Abstract

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.