Anxiety, Depression, Schizophrenia, and Bipolar Disorder in Eosinophilic Esophagitis Patients: A Global Federated Cohort Analysis of Bidirectional Risks

Eosinophilic esophagitis (EoE) impairs quality of life through persistent symptoms and long-term dietary management [1]. Emerging studies suggest EoE is associated with increased psychiatric morbidity, but evidence is mostly limited to anxiety and depression in single-country cohorts, with little data on broader outcomes globally [2-4]. We therefore conducted a large, multinational cohort study to evaluate psychiatric risks associated with EoE. This retrospective cohort study was derived from the TriNetX Global Collaborative Network, an electronic health record platform utilized in many epidemiological studies [5]. Adults aged ≥ 18 years with at least two visits between January 2005 and December 2023 were eligible. Patients with EoE were identified using ICD-10-CM codes (Table S1), and individuals without a diagnosis of EoE served as controls; those with prior death, malignancy, or pre-existing psychiatric disorders were excluded. Propensity score matching (1:1) was applied to balance age, sex, race, body mass index, atopic comorbidities, cardiometabolic diseases, substance use disorders, healthcare utilization, and socioeconomic indicators. The primary outcomes were incident generalized anxiety disorder, major depressive disorder (MDD), bipolar disorder, and schizophrenia occurring ≥ 3 months after the index date. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Sensitivity analytic models were reported in Table S2. Bidirectional analyses assessing the risk of EoE following psychiatric disorders were also performed. After matching, 39,331 well-balanced patients were included in each cohort (Table 1; Figure S1). During follow-up, EoE was associated with a higher risk of generalized anxiety disorder (HR 1.34, 95% CI 1.20–1.50) and MDD (HR 1.67, 95% CI 1.44–1.93) compared with controls (Figure S2). These associations were generally consistent across sex and age subgroups and robust in sensitivity analyses. When compared with patients with gastroesophageal reflux disease, the risk estimates for anxiety and MDD were attenuated (Figure 1). No consistent association was found between EoE and schizophrenia, with low event rates and wide confidence intervals. For bipolar disorder, an elevated risk in crude analyses was attenuated after comprehensive matching and varied across analytic strategies. In bidirectional analyses, prior generalized anxiety disorder (HR 1.23, 95% CI 1.05–1.44) and MDD (HR 1.57, 95% CI 1.31–1.89) were associated with an increased subsequent risk of EoE, whereas bipolar disorder was not (Figure S3). We report that EoE was associated with an increased risk of common mood and anxiety disorders. Associations with schizophrenia were not robust, and estimates for bipolar disorder varied across analytic strategies, likely reflecting low event counts and limited statistical power. These findings extend prior single-country studies and suggest that psychiatric burden in EoE predominantly involves anxiety-depressive domains [3]. From a real-world perspective, severe mental illnesses such as schizophrenia are less clearly related to atopic or inflammatory conditions [6]; however, these negative findings should be interpreted with caution, as they may largely reflect low event counts rather than a true absence of association. Potential mechanisms may involve persistent disease-related burden and lifestyle constraints, which may preferentially predispose patients to anxiety and depressive disorders rather than severe psychiatric conditions. Though the bidirectional design and multinational scope provide a more integrated real-world perspective on the psychiatric burden associated with EoE, several limitations should be acknowledged. As an observational analysis based on administrative codes, causal inference cannot be established, and residual confounding related to disease severity, symptom burden, dietary restriction, and psychosocial stress may persist. Subclinical or undiagnosed psychiatric conditions before cohort entry may also be incompletely captured. Moreover, although data were drawn from multiple countries, findings may not be fully generalizable beyond healthcare-engaged populations. These findings highlight the importance of heightened awareness and timely screening for anxiety and depressive disorders in patients with EoE as part of comprehensive disease management. All the authors involved in drafting or revising the article approved of the submitted version. Study conception and design: Shuo-Yan Gau, Hui-Chin Chang, Meng-Che Wu, and Torsten Zuberbier. Data acquisition: Hui-Chin Chang and Shuo-Yan Gau. Data analysis and demonstration: Shuo-Yan Gau, Hui-Chin Chang, Meng-Che Wu, and Torsten Zuberbier. Original draft preparation: Shuo-Yan Gau, Hui-Chin Chang, Meng-Che Wu, and Torsten Zuberbier. Open Access funding enabled and organized by Projekt DEAL. This study was partially supported by the funding from Chung Shan Medical University Hospital (CSH-2025-C-007) and the Taiwan Global Pathfinders Initiative (Program No: 190). This research has been approved by the Institutional Review Board of Chung Shan Medical University Hospital (IRB No. CS1-25002) and the need of informed consent is exempted by the Institutional Review Board. Trial registry is not applicable as the current study is not a clinical trial. The authors have nothing to report. The authors declare no conflicts of interest. Data in this study were retrieved from TriNetX Research Network. All data available in the database were administered by the TriNetX platform. Detailed information can be retrieved at the official website of the research network (https://trinetx.com). Table S1: Utilized proxy codes a. Table S2: Description of all applied sensitivity analysis models in Figures 2–6. Figure S1: Patient selection flowchart. Figure S2: Cumulative probability of generalized anxiety disorder, major depressive disorder, schizophrenia and bipolar disorder risk in EoE patients. Figure S3: Risk of eosinophilic esophagitis in generalized anxiety disorder, major depressive disorder, bipolar disorder and schizophrenia. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.