Abstract
I have read with great interest the article titled “β-blockers and risk of neuropsychiatric adverse events: An active-comparator restricted disproportionality on the FAERS” by Ez Eddin et al. (2025), recently published in the Journal of Psychopharmacology I would like to commend the authors on their thoughtful application of active-comparator restricted disproportionality methods to examine neuropsychiatric adverse events (AEs) related to β-blockers using the FAERS database. This work offers timely insights into the comparative safety profiles of commonly prescribed β-blockers and emphasizes a clinically significant issue often underexplored in pharmacovigilance literature.
The choice of lisinopril and losartan as active comparators is methodologically sound and enhances the internal validity by reducing confounding by indication. However, it would be valuable for the authors to further discuss the potential residual differences in comorbidity patterns between β-blocker users and those on RAAS inhibitors, especially considering propranolol’s broader off-label indications such as anxiety and migraine. Although the authors included a post hoc sensitivity analysis adjusting for such indications, elaboration on how frequently these were identifiable in the FAERS dataset would improve transparency regarding confounding control.
A key limitation inherent to spontaneous reporting systems like FAERS is the lack of precise clinical context (Goldman, 1998). Notably, the age distribution for propranolol users was considerably younger, likely due to non-cardiac indications. This heterogeneity may dilute or exaggerate associations depending on the neuropsychiatric outcome under evaluation. I encourage the authors to consider stratified analyses by presumed primary indication (e.g., anxiety vs. hypertension) in future studies or in sensitivity analyses, where feasible, to better understand whether the observed AEs are indication-specific or compound-specific.
The data revealing that propranolol—a highly lipophilic agent—was most strongly associated with neuropsychiatric events aligns with existing pharmacological theories. However, the observation that propranolol had lower odds for dizziness compared to atenolol and other β-blockers is intriguing. While the discussion offered plausible explanations (e.g., misattribution, therapeutic effect masking), this finding underscores the importance of incorporating clinical judgment or electronic health record linkage in future population-based studies to validate such signal-level discrepancies.
The study’s findings support more personalized selection of β-blockers, especially in patients with baseline psychiatric vulnerabilities. In light of the observed signal with propranolol, clinicians may benefit from enhanced pharmacovigilance or routine monitoring in high-risk populations. Furthermore, this study highlights the need for future longitudinal cohort studies or pragmatic trials to quantify the true incidence and severity of neuropsychiatric events associated with individual β-blockers across various clinical settings.
Overall, Ez Eddin et al. (2025) present a well-executed disproportionality analysis that contributes meaningfully to the literature on neuropsychiatric safety profiles of β-blockers. Their approach demonstrates methodological rigor, and their findings lay the groundwork for future hypothesis-driven pharmacoepidemiologic investigations. I appreciate the opportunity to comment on this important work and look forward to further developments from this research group.
