Evaluating a Potential Link Between Alprazolam and Intracranial Aneurysm: A Pharmacovigilance and Bioinformatics Approach Through FAERS and Molecular Docking
Author(s)
SPOORTHI K R, Jr., MPH1, Eswaran Maheswari, Sr., PhD2, RAVINANDAN A P, PhD3, Sneha Anthony Zalki, Jr., MPH4, SHEETAL J, Jr., MPH5.
1Student, MSRUAS, Mysuru, India, 2Faculty, M S Ramaiah University Of Applied Sciences, Bangalore, India, 3Ph.D Scholar, MSRUAS, Bangalore, India, 4Student, MSRUAS, Bangalore, India, 5Student, MSRUAS, Bengalore, India.
1Student, MSRUAS, Mysuru, India, 2Faculty, M S Ramaiah University Of Applied Sciences, Bangalore, India, 3Ph.D Scholar, MSRUAS, Bangalore, India, 4Student, MSRUAS, Bangalore, India, 5Student, MSRUAS, Bengalore, India.
OBJECTIVES: Alprazolam, a commonly prescribed benzodiazepine for anxiety and panic disorders, has a well-established safety profile. However, rare but potentially life-threatening cerebrovascular events such as intracranial aneurysm remain critically underexplored in current pharmacovigilance literature. This study aimed to assess a potential link between alprazolam use and the occurrence of intracranial aneurysms using data from the US FDA Adverse Event Reporting System (FAERS) from 1998 to 2024.
METHODS: Adverse event data involving alprazolam were extractedthrough the OpenVigil platform. Disproportionality analysis using ProportionalReporting Ratio (PRR), Reporting Odds Ratio (ROR), and chi-square tests wasconducted to identify safety signals. Positive associations were defined by PRR≥ 2, ROR - 1.96SE > 2, and chi-square > 4, with a minimum of three reports.The genes were identified using gene cards, omim, huge navigator andpubmed database. The top 10 hub genes implicated in aneurysmpathophysiology were identified via STITCH, STRING, and HuGE Navigatordatabases. Molecular docking studies between alprazolam and these targetswere carried out using BIOVIA Discovery Studio.
RESULTS: Of the 28,655,483 adverse events reported in FAERS, 7,214 involvedalprazolam, with 14 cases linked to intracranial aneurysm. Disproportionalityanalysis yielded a PRR of 2.85 (95% CI: 1.67-4.89), ROR of 2.89 (95% CI:1.68-4.97), and a chi-square value of 18.73, indicating a positive signal.
Docking simulations showed strong binding affinities between alprazolam andselected protein structures (3OMO: -2.6; 6NJS: -6.2; 7X11: -9.4; 8F1X: -7.7),with key interactions involving residues PHE263, PHE236, PHE723, and LYS745.
CONCLUSIONS: The study provides preliminary evidence of a possible association betweenalprazolam and intracranial aneurysm, supported by both signal detection andin silico modeling. Further genetic and epidemiologic investigations areessential to validate these findings and assess their clinical relevance,particularly in high-risk patient populations and long-term users.
METHODS: Adverse event data involving alprazolam were extractedthrough the OpenVigil platform. Disproportionality analysis using ProportionalReporting Ratio (PRR), Reporting Odds Ratio (ROR), and chi-square tests wasconducted to identify safety signals. Positive associations were defined by PRR≥ 2, ROR - 1.96SE > 2, and chi-square > 4, with a minimum of three reports.The genes were identified using gene cards, omim, huge navigator andpubmed database. The top 10 hub genes implicated in aneurysmpathophysiology were identified via STITCH, STRING, and HuGE Navigatordatabases. Molecular docking studies between alprazolam and these targetswere carried out using BIOVIA Discovery Studio.
RESULTS: Of the 28,655,483 adverse events reported in FAERS, 7,214 involvedalprazolam, with 14 cases linked to intracranial aneurysm. Disproportionalityanalysis yielded a PRR of 2.85 (95% CI: 1.67-4.89), ROR of 2.89 (95% CI:1.68-4.97), and a chi-square value of 18.73, indicating a positive signal.
Docking simulations showed strong binding affinities between alprazolam andselected protein structures (3OMO: -2.6; 6NJS: -6.2; 7X11: -9.4; 8F1X: -7.7),with key interactions involving residues PHE263, PHE236, PHE723, and LYS745.
CONCLUSIONS: The study provides preliminary evidence of a possible association betweenalprazolam and intracranial aneurysm, supported by both signal detection andin silico modeling. Further genetic and epidemiologic investigations areessential to validate these findings and assess their clinical relevance,particularly in high-risk patient populations and long-term users.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
RWD77
Topic
Clinical Outcomes, Epidemiology & Public Health, Real World Data & Information Systems
Topic Subcategory
Distributed Data & Research Networks
Disease
Neurological Disorders