Cardiac Safety Profile of Ziprasidone: A Real-World PharmacovigilanceStudy Using FAERS and Network Toxicology

Background: Schizophrenia is a chronic psychiatric disorder affecting 1% of the global population and is associated with substantial morbidity and mortality. Ziprasidone, a secondgeneration antipsychotic widely used in the treatment of schizophrenia, has been linked to several cardiovascular adverse events in post-marketing surveillance. The present study aimed to systematically evaluate the association between ziprasidone use and cardiac adverse events, and to explore the potential molecular mechanisms. Methods: Adverse event reports associated with ziprasidone were extracted from the FAERS database (covering the period from 2001 to Q4 2024). Disproportionality analyses, including ROR, PRR, MGPS, BCPNN, and TTO, were conducted to detect safety signals and evaluate onset times. The ChEMBL and SwissTargetPrediction databases were used to identify potential ziprasidonerelated targets, while the GeneCards, TTD, and OMIM databases were queried for genes associated with Ziprasidone-induced cardiac toxicity. The STRING database was used to identify the network of selected candidate genes, and GO and KEGG pathway enrichment analyses were conducted. results: 15,685 adverse events were associated with ziprasidone, 1,609 were classified as cardiac disorders. Females accounted for 50.14%, 51.35% were between 18 and 64 years old, 7.90% resulted in death. Significant signals were detected across multiple SOCs. 180 overlapping targets were confirmed between the two sets and 5 genes were identified as the core target genes. KEGG pathway enrichment analysis identified the Calcium signaling pathway was the underlying mechanisms. The results of binding affinities were less than zero, indicating strong binding effect between ziprasidone and these core targets. Results: A total of 15,685 adverse events were associated with ziprasidone, of which 1,609 were classified as cardiac disorders. Females accounted for 50.14%, 51.35% were between 18 and 64 years old, and 7.90% of events resulted in death. Significant signals were detected across multiple SOCs. 180 overlapping targets were confirmed between the two sets, and 5 genes were identified as core target genes. KEGG pathway enrichment analysis identified the calcium signaling pathway as the underlying mechanism. All binding affinity values were negative, indicating strong binding of ziprasidone to these core targets. Discussion: The findings of this study suggest a potential association between ziprasidone exposure and cardiac adverse events in real-world pharmacovigilance data. The integration of pharmacovigilance analysis with network toxicology provides mechanistic insights into the molecular pathways potentially involved in ziprasidone-induced cardiac injury. In particular, dysregulation of calcium signaling pathways may contribute to arrhythmogenic and cardiotoxic effects associated with antipsychotic therapy. Conclusion: The findings from FAERS pharmacovigilance analysis suggest a potential association between ziprasidone exposure and cardiac adverse events. Toxicological network analysis further indicated that the calcium signaling pathway may be involved in the underlying molecular mechanisms.