Analysis of the relationship between histamine H1 receptor antagonists and broad dementia events using the FAERS, JADER, and CVAR databases

Recent studies suggest histamine H1 receptor antagonists (H1RAs) may elevate broad dementia events risk, though real-world data remain scarce. This pharmacovigilance study analyzed FDA Adverse Event Reporting System (FAERS), Japanese Adverse Drug Event Report (JADER), and Canada Vigilance Adverse Reaction (CVAR) databases from January 2004 to June 2024. Using disproportionality analyses such as the reporting odds ratio (ROR) and proportion reporting ratio (PRR), time-to-onset analysis, propensity score matching, and multivariate regression, we compared broad dementia event signals among first-generation H1RAs (FG-H1RAs), second-generation H1RAs (SG-H1RAs), and benzodiazepines (BDs). According to the FAERS database, FG-H1RAs (ROR = 3.33, 95%CI 3.22–3.44; PRR = 3.11, χ2 = 5426.01), SG-H1RAs (ROR = 2.03, 95%CI 1.98–2.07; PRR = 1.97, χ2 = 3706.58), and BDs (ROR = 2.74, 95%CI 2.68–2.80; PRR = 2.6, χ2 = 8338.34) were significantly associated with broad dementia events, with FG-H1RAs having a stronger association with broad dementia events compared to SG-H1RAs (aROR = 0.60, 95%CI 0.54–0.67, <i>p</i> &lt; 0.001). Analysis of the JADER and CVAR databases yielded similar results. FG-H1RAs exhibited immediate broad dementia events reporting (median = 0 days), while SG-H1RAs showed delayed onset (median = 1 day), both with early risk decay. This study provides evidence for the association between H1RAs treatment and broad dementia events, highlighting signaling differences among H1RAs. However, large-scale, high-quality epidemiological studies are still needed for validation.