¹Taichung Veterans General Hospital, Department of Psychiatry, Taichung, Taiwan

Background: Allergic rhinitis is highly prevalent among children and adolescents and has been increasingly linked to elevated risks of depression. Parallel observational findings also suggest that antihistamines themselves may correlate with mood symptoms, although the underlying mechanisms remain unclear. A key pharmacological difference between antihistamine classes is their ability to cross the blood–brain barrier (BBB). First-generation antihistamines are lipophilic and readily penetrate the central nervous system, whereas second-generation agents exhibit minimal BBB permeability. Whether this pharmacokinetic property contributes to differential psychiatric risk in pediatric populations has never been systematically examined.

Aims & Objectives: The primary aim of this study was to evaluate whether BBB permeability of antihistamines is associated with differing risks of incident depression in children and adolescents with allergic rhinitis. A secondary objective was to assess the internal validity of the findings through negative-control outcomes that lack any plausible mechanistic relationship with antihistamine pharmacodynamics.

Method: This retrospective new-user cohort study was conducted using the TriNetX Global Collaborative Network. Eligible participants were aged 8–17 years, carried a diagnosis of allergic rhinitis, and had at least one year of baseline clinical activity. Individuals with any prior psychiatric diagnosis were excluded. Exposure groups were defined by antihistamine BBB permeability: the low-BBB cohort (fexofenadine, bilastine, ebastine, olopatadine, acrivastine) and the high-BBB cohort (diphenhydramine, chlorpheniramine, hydroxyzine, promethazine, doxylamine, triprolidine, pheniramine). Sustained antihistamine use was ensured through repeated prescriptions across multiple post-index intervals. Before matching, 1,091 low-BBB and 3,728 high-BBB users met inclusion criteria. Propensity score matching (1:1) produced two balanced cohorts of 1,066 patients each. The primary outcome was incident depression recorded after the index prescription. Viral warts and acne were included as negative-control outcomes.

Results: High-BBB antihistamines were associated with a substantially increased risk of depression compared with low-BBB agents. The hazard ratio for depression in the low-BBB cohort was 0.453, corresponding to an approximately 2.2-fold higher hazard in the high-BBB cohort. Kaplan–Meier curves diverged significantly (log-rank χ² = 23.076, p < 0.0001). In contrast, negative-control outcomes demonstrated no significant between-group differences. Viral warts showed a hazard ratio of 1.24 (p = 0.92), and acne showed a hazard ratio of 1.24 (p = 0.37). These null associations reinforce that the observed relationship is specific to psychiatric outcomes rather than a reflection of systematic bias or residual confounding.

Discussion & Conclusions: This large-scale, real-world analysis suggests that high-BBB-penetrant antihistamines may confer an elevated risk of depression in children and adolescents with allergic rhinitis. The absence of associations for negative-control outcomes supports the internal validity of this finding and implicates BBB permeability as a plausible factor influencing psychiatric vulnerability. Clinically, these results highlight the importance of considering BBB penetrability when selecting antihistamines for pediatric patients, particularly those with emotional or behavioral risk factors. Further mechanistic and prospective studies are warranted to elucidate causal pathways and inform safer prescribing practices.