Blood-brain barrier permeability as a determinant of depression risk in long-term beta-blocker users: a real-world TriNetX cohort study

Background Beta-blockers (BBs) remain a cornerstone in the management of hypertension and cardiovascular disease. While early literature suggested a "depressogenic" effect, recent meta-analyses have largely refuted a general association between BBs and depression. However, these aggregated analyses may overlook a critical pharmacokinetic variable: the ability of the drug to cross the blood-brain barrier (BBB). We hypothesized that the risk of depression is not a class effect but is dependent on BBB permeability. Aims & Objectives To evaluate the differential risk of incident depression associated with beta-blockers of varying blood-brain barrier permeability using large-scale real-world data, and to inform clinical prescribing strategies for patients requiring long-term antihypertensive therapy. Method We conducted a retrospective cohort study using the TriNetX global health research network. We identified adult patients (≥18 years) with hypertension treated with BBs for at least 5 years. Patients with prior history of psychiatric disorders (including mood, anxiety, and psychotic disorders), dementia, stroke, or other central nervous system conditions were strictly excluded to ensure a clean incidence analysis. BBs were categorized into three groups based on BBB permeability: High (e.g., Propranolol), Moderate (e.g., Metoprolol), and Low (e.g., Atenolol). Propensity score matching (PSM) was utilized to balance cohorts for demographics, comorbidities, and comedications. The primary outcome was incident depression occurring between 6 months and 5 years post-index. Hazard Ratios (HR) were calculated using Kaplan-Meier analysis. To ensure robustness, we performed subgroup analyses stratified by age (adults 18–64 vs. elderly ≥65) and implemented three specific negative control outcomes to detect unmeasured confounding: Herpes Zoster (acute healthcare accessibility), Trigger Finger (chronic healthcare engagement), and Ganglion Cyst (surveillance/reporting bias). Results The analysis revealed a distinct risk stratification based on permeability. Patients receiving High-permeability BBs showed a significantly increased risk of depression compared to the Low-permeability group (HR = 1.474 [1.327-1.636], log-rank test p < 0.0001). Notably, the Moderate-permeability group also demonstrated a significantly higher risk of depression compared to the Low-permeability group (HR = 1.351 [1.257-1.452], p < 0.0001). There was no statistically significant difference in depression risk between the High and Moderate groups (HR = 1.041 [0.949-1.143], p = 0.3922). This pattern was consistent across both the adult (18–64) and elderly (≥65) subgroups, ruling out age-related confounders such as pseudodementia or frailty. Furthermore, all three negative outcome controls (Herpes Zoster, Trigger Finger, Ganglion Cyst) yielded non-significant results across all comparisons, validating that the observed depression risk was not driven by differential healthcare access, surveillance bias, or general medical engagement. Discussion & Conclusions BBB permeability is a key predictor of depression risk in patients treated with beta-blockers. Contrary to the prevailing clinical view that moderate-permeability agents (such as Metoprolol) are safer than high-permeability agents (such as Propranolol), our findings suggest they carry a similar neuropsychiatric risk profile compared to low-permeability agents. Clinicians should remain vigilant for depressive symptoms in patients treated with both high- and moderate-permeability beta-blockers, regardless of patient age.