2026 ECNP Congress

PS01-1081

Allostatic load and pain-depression comorbidity: a mediation analysis of bilirubin

Haoyun Tang — J. Chen · Shanghai Mental Health Center- Shanghai Jiao Tong University School of Medicine, Department of Mood Disorders, Shanghai, China

2026 ECNP Congress

Introduction

Chronic pain and depression are highly comorbid in clinical settings. These conditions mutually reinforce each other, leading to more severe symptoms, poorer prognosis and higher healthcare costs compared to either condition alone[1]. Accumulating evidence suggests that these two diseases may share multiple underlying biological pathways, making it difficult to explain them through a single mechanism. The allostatic load index (ALI) integrates biomarkers from cardiovascular, metabolic, and immune systems to quantify cumulative multisystem physiological dysregulation caused by chronic stress, providing an integrative perspective for elucidating comorbidity mechanisms[2]. Elevated ALI may reflect poorer health status state and greater susceptibility to pain-depression comorbidity[3]. Bilirubin has recently been recognized for its antioxidant and anti-inflammatory properties[4]. Indeed, clinical and animal studies have demonstrated associations between bilirubin levels and both depression and pain sensitivity, suggesting its potential mediating role in the pathogenesis of pain-depression comorbidity[5]. However, the association between ALI and comorbidity, as well as the mediating role of bilirubin, remain unexplored.

Aims

To investigate the association between ALI and pain-depression comorbidity and to examine whether bilirubin mediates this relationship.

Methods

This study included 3,891 U.S. adults from the National Health and Nutrition Examination Survey (NHANES) 2009–2010 cycle. Participants were categorized into four groups: healthy, pain without depression, depression without pain, and pain-depression comorbidity. ALI was derived from ten biomarkers across cardiovascular, metabolic, and immune domains. Weighted multinomial logistic regression, restricted cubic splines (RCS), mediation analyses, and XGBoost machine learning were conducted.

Results

The comorbidity group showed the highest ALI (median 3.00 [IQR 2.50–4.00]) and the greatest socioeconomic disadvantage. ALI significantly increased the risk of pain-depression comorbidity (adjusted odds ratio [aOR]=1.31, 95% confidence interval [CI]: 1.16-1.47), followed by pain without depression (aOR=1.09, 95%CI: 1.03-1.16), showing linear trends (both P-overall<0.05) with no evidence of nonlinearity. In contrast, no significant association was observed between ALI and depression without comorbid pain (aOR=1.03, 95%CI: 0.92-1.17). Bilirubin partially mediated the ALI-comorbidity association (mediation proportion: 11.8%, 95%CI: 2.3%-25.5%). Subgroup analyses revealed that the ALI-comorbidity association was consistent across most strata (OR range: 1.24-1.88), with effect modification by race, marital status, and alcohol consumption (all P for interaction < 0.05). The ALI-pain association was stable across subgroups, whereas the ALI-depression association was highly heterogeneous. XGBoost identified PIR (29.2%), age (26.2%), and ALI (15.6%) as the top predictors of comorbidity.

Conclusions

This study demonstrated the association between ALI and pain-depression comorbidity, with bilirubin serving as a partial mediator, highlighting the substantial disease burden of chronic stress and oxidative stress. From the perspective of cumulative physiological dysfunction, this study deepens our understanding of the pathogenesis of chronic pain and depression, and provides a practical tool for risk identification, prevention and efficacy prediction. Our mediation and machine learning analyses support interventions targeting both stress management and oxidative balance, with precision public health strategies aimed at lower-income and elderly populations. Future intervention studies are crucial for verifying and expanding these findings.

References

  1. Armbrecht E, Shah A, Schepman P, et al. Economic and humanistic burden associated with noncommunicable diseases among adults with depression and anxiety in the United States. J Med Econ 2020;23:1032–42. https://doi.org/10.1080/13696998.2020.1776297.
  2. McEWEN BS. Stress, adaptation, and disease: allostasis and allostatic load. Ann N Y Acad Sci 1998;840:33–44. https://doi.org/10.1111/j.1749-6632.1998.tb09546.x.
  3. Finlay S, Rudd D, McDermott B, et al. Allostatic load and systemic comorbidities in psychiatric disorders. Psychoneuroendocrinology 2022;140:105726. https://doi.org/10.1016/j.psyneuen.2022.105726.
  4. Zhang Y, Luan H, Song P. Bilirubin metabolism and its application in disease prevention: mechanisms and research advances. Inflamm Res 2025;74:81. https://doi.org/10.1007/s00011-025-02049-w.
  5. Kong S, Niu Z, Lyu D, et al. Analysis of seasonal clinical characteristics in patients with bipolar or unipolar depression. Front Psychiatry 2022;13:847485. https://doi.org/10.3389/fpsyt.2022.847485.