Detection of clinically significant drug-drug interactions in serotonin syndrome: a multisource real-world data and pharmacovigilance study.

内容摘要

Serotonin syndrome (SS) is a potentially life-threatening condition increasingly driven by complex drug-drug interactions (DDIs) as serotonergic agents expand beyond psychiatry into pain management and infectious disease treatment. Current clinical decision support tools often exhibit inconsistencies in detecting these risks, leading to potential under-recognition of severe interactions. This study aimed to detect and validate clinically significant DDIs associated with SS by integrating multisource real-world data. We sought to identify high-priority drug combinations, evaluate the concordance of major DDI checking tools, and highlight critical information gaps to improve patient safety strategies. A multisource, retrospective study combining a systematic literature review, a disproportionality analysis of spontaneous adverse event reports, and a comparative cross-sectional evaluation of online DDI databases. This study employed a multisource approach to detect and evaluate SS-related DDIs. We integrated findings from a systematic literature review (up to June 2025), a disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) with four frequency statistical models, and a comparative assessment of five major DDI checkers (Micromedex, Lexi-Interact, Epocrates, Medscape, and Drugs.com). The systematic review identified high-risk interactions involving not only antidepressants but also non-psychotropic drugs such as linezolid, fentanyl, and methylene blue. FAERS data revealed strong signals for combinations such as linezolid-sertraline and fentanyl-venlafaxine, indicating a rising trend in SS reporting over the past two decades. Evaluation of DDI checkers demonstrated significant discrepancies in sensitivity and severity grading. Notably, 10.16% were not indexed in any of the five databases, including several clinically documented DDIs (e.g., aripiprazole-paracetamol and trazodone-pantoprazole), highlighting critical information gaps. SS remains a significant clinical risk driven by increasingly complex polypharmacy. Relying on a single DDI checker may lead to an underestimation of risk due to inconsistent indexing and severity ratings. Hospital pharmacists should integrate multisource data and maintain high clinical vigilance, particularly for "hidden" serotonergic agents such as certain opioids and antibiotics, to ensure medication safety. Understanding the risks of serotonin syndrome: why checking drug interactions across multiple sources is vital for patient safety Serotonin syndrome is a rare but potentially life-threatening condition caused by an excessive buildup of serotonin—a chemical that helps transmit signals in the brain. This usually happens when a patient takes two or more medications that affect serotonin levels at the same time, leading to a dangerous drug-drug interaction. While these risks are well-known in psychiatry, many other common medications, such as certain painkillers and antibiotics, can also trigger this condition. This study was conducted to identify which drug combinations pose the highest risk and to see how well current digital tools (DDI checkers) warn doctors about them. We combined three types of evidence: a review of all existing medical research, an analysis of over 20 years of global safety reports from the FDA, and a comparison of five major drug-interaction databases used by healthcare professionals. Our findings show that reports of serotonin syndrome have been increasing. We identified several high-risk combinations, including interactions between antidepressants and “hidden” sources like the antibiotic linezolid or the painkiller fentanyl. Crucially, we discovered that no single digital tool is perfect; about 10% of the dangerous interactions we found in real-world reports were not listed in any of the five major databases. Furthermore, the databases often disagreed on how severe an interaction was. For patients and families, this research highlights that medication safety is complex. For healthcare providers, the results suggest that relying on just one computer system to check for drug risks may not be enough. We recommend that hospital pharmacists use multiple information sources and stay extra alert when patients are prescribed new types of antibiotics or painkillers alongside their regular medications. This proactive approach is essential to catching “hidden” risks and keeping patients safe.