Post-marketing Safety Surveillance of Drug-induced Dementia: Utilizing Signal Detection and Mendelian Randomization in Spontaneous Reports

OBJECTIVE: Many medications associated with an increased risk of dementia do not have adequate warning labels, leading to a significant underestimation of their potential dangers. This study aims to leverage the FAERS database to identify drugs strongly linked to dementia and to examine the relationship between these drugs using Mendelian randomization techniques. The ultimate goal is to mitigate the risk of developing dementia. METHODS: We utilized the FAERS database to identify medications significantly associated with dementia cases. The DrugBank, OpenTargets, and STITCH databases were employed to pinpoint the target genes of these drugs. We then conducted Mendelian randomization analysis to explore the correlation between the expression of drug target genes and the incidence of dementia. Additionally, a time-to-onset analysis assessed the temporal relationships of drug ingestions. Furthermore, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction Network (PPI) analyses were performed to investigate the molecular pathways linked to target genes related to drugs associated with dementia. RESULTS: A total of 28,139 dementia events were recorded in the FAERS database. Our Mendelian randomization analysis revealed a significant association between the expression of all identified drug target genes and dementia in both blood and brain tissues. Specifically, we identified nine drug target genes with significant correlations, implicating quetiapine, clozapine, valproic acid, alendronate, and digoxin as being strongly associated with dementia, which could provide insight into areas of clinical concern regarding dementia occurrence. CONCLUSION: The adverse event data sourced from the FAERS database indicate that certain medications are associated with an increased risk of developing dementia, a finding corroborated by our Mendelian randomization analysis. Establishing a comprehensive monitoring and risk assessment program is crucial for identifying high-risk individuals and facilitating informed medication choices, thereby potentially reducing the incidence of dementia.