OBJECTIVES:

The current study aimed to investigate the novel signals associated with amitriptyline utilizing real-world data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.

METHODS: The data extracted from FAERS database was analysed to identify an unidentified adverse event of Amitriptyline. The disproportionality analysis was performed using OpenVigil 2 database for identifying the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). Positive signals were defined as values of PRR≥1, ROR-1.96SE>1 and chi-square > 4. The genes related with the identified adverse event was docked with the medication to determine the binding affinity using BIOVIA Discovery Studio, PyRx, Pymol and Swiss PDB viewer.

RESULTS: The FAERS database contained a total of 17,982 reported events associated with amitriptyline, which was approved for use in 1961. The database had events reported from 1969 to June 2024. The disproportionality analysis revealed 131 cases of cerebral microhaemorrhage, with 5 cases specifically attributed to amitriptyline. The calculated PRR was 10.415 (95% CI: 4.26-25.45) and ROR was 10.41 (95% CI: 4.26-25.46). The chi-squared value with Yates' correction was 32.34, indicating a statistically significant difference between the observed and expected frequencies. The proteins associated with cerebral microhaemorrhage are 1AAP, 6P25, and 8GRX, with the highest binding affinity for amitriptyline as -6.1, -7.8 and -7.2 respectively.

CONCLUSIONS: Amitriptyline induced cerebral microhaemorrhage was confirmed based on the disproportionality and bioinformatic analysis. Further pharmacoepidemiologic and pharmacogenetic investigations are warranted to elucidate the underlying mechanisms and establish the causal relationship between amitriptyline and cerebral microhaemorrhage. Clinicians should be aware of the potential risk and consider close monitoring and appropriate management strategies for patients on this medication.