Depression and Serum Bilirubin Levels among University Students in Aden, Yemen: A Cross-Sectional Study

Technical Summary: Depression and Serum Bilirubin Levels among University Students in Aden, Yemen

Problem Statement
Depression represents a significant mental health burden among university students globally, characterized by poor academic outcomes and elevated suicide rates. Recent literature suggests that the pathogenesis of depression involves complex interactions between genetic, psychological, and biological factors, specifically oxidative stress and a compromised antioxidant defense system. Bilirubin, traditionally viewed as a waste product of heme catabolism, has emerged as a potent endogenous antioxidant capable of scavenging reactive oxygen species and mitigating neuroinflammation. While epidemiological data from other regions (e.g., NHANES) and clinical studies have indicated an association between low serum bilirubin levels and depressive disorders, there is a paucity of data regarding this relationship within the specific context of Yemeni university students. This population faces unique psychosocial stressors, including prolonged instability, economic hardship, and limited access to psychiatric care, which may alter stress-related biological markers. This study addresses the gap in knowledge by evaluating the association between serum bilirubin levels and depression symptoms among students in Aden, Yemen.

Methodology
The research employed a cross-sectional, analytical design conducted over five months (January to May 2026) across public and private universities in Aden.

• Study Population: The sample consisted of 422 undergraduate students aged 18–25, selected via simple random sampling from various faculties.
• Inclusion/Exclusion Criteria: Participants were required to provide written consent. Exclusion criteria were strictly applied to eliminate confounding variables, including history of liver diseases (viral hepatitis, cirrhosis), hematological/genetic disorders affecting bilirubin metabolism (sickle cell, thalassemia, Gilbert's syndrome), prior psychiatric diagnoses, use of medications affecting bilirubin metabolism, recent infections, and pregnancy.
• Data Collection:
  • Depression Assessment: The Patient Health Questionnaire-9 (PHQ-9) was utilized to screen for depressive symptoms, with scores ranging from 0 to 27.
  • Sociodemographics & Lifestyle: A structured questionnaire captured data on age, gender, marital status, field of study, smoking, sleep quality, academic stress, and income.
  • Anthropometrics: Body Mass Index (BMI) was calculated using calibrated scales and stadiometers.
  • Laboratory Analysis: Fasting venous blood samples (8–12 hours) were collected between 8:00 and 10:00 a.m. to minimize diurnal and dietary variations. Total and direct bilirubin levels were quantified using a Roche cobas e 411 analyzer via electrochemiluminescence immunoassay (ECLIA). Samples were protected from light to prevent photodegradation.
• Statistical Analysis: Data were analyzed using descriptive statistics, Pearson correlation, one-way ANOVA (with Games-Howell post hoc tests), independent t-tests, and multiple linear regression. Regression models adjusted for confounders including age, gender, BMI, field of study, sleep quality, academic stress, and income.

Key Results

• Prevalence: The study identified a high prevalence of depressive symptoms, with 88.2% of participants reporting some level of depression. Mild depression was the most common category (32.0%), followed by severe (23.9%) and moderate (22.0%) depression. Only 11.8% of participants reported no depressive symptoms.
• Bilirubin Levels: The mean total bilirubin level was 0.510 ± 0.247 mg/dL, and the mean direct bilirubin level was 0.115 ± 0.056 mg/dL.
• Correlations: A statistically significant negative correlation was observed between PHQ-9 scores and both total bilirubin (r = −0.595, p < 0.001) and direct bilirubin (r = −0.452, p < 0.001).
• Severity Gradient: ANOVA results indicated that bilirubin levels decreased progressively as depression severity increased. Participants with no depression exhibited the highest mean total bilirubin (0.769 ± 0.274 mg/dL), while those with severe depression had the lowest (0.326 ± 0.082 mg/dL).
• Regression Analysis: Multiple linear regression confirmed that lower total and direct bilirubin levels were independent predictors of higher PHQ-9 scores, even after adjusting for demographic and lifestyle factors.
  • Total Bilirubin Model: Total bilirubin showed a strong inverse association with PHQ-9 scores (β = −0.569, p < 0.001). Other significant predictors included female gender, medical specialization, poor sleep quality, and higher academic stress.
  • Direct Bilirubin Model: Direct bilirubin also demonstrated a significant inverse relationship (β = −0.508, p < 0.001).
• Demographic Factors: Female gender, medical specialization, and financial dependence were significantly associated with higher depression scores, while independent income was associated with lower scores.

Significance and Claims
The authors posit that this study provides novel evidence linking low serum bilirubin levels to increased depression severity in a non-clinical university population, a demographic underrepresented in biomarker-based mental health research. The findings support the hypothesis that diminished endogenous antioxidant capacity, indicated by low bilirubin, contributes to the pathophysiology of depression through mechanisms involving oxidative stress and neuroinflammation.

The study claims that bilirubin may serve as a viable biomarker for depressive symptom burden in young adults. However, the authors maintain a modest stance regarding causality, explicitly acknowledging that the cross-sectional design precludes determining whether low bilirubin precedes the onset of depression or is a consequence of the physiological stress associated with the disorder. The paper concludes that while the association is robust and independent of confounders, further longitudinal studies are required to validate the causal relationship and explore the utility of bilirubin as a diagnostic or prognostic marker for depression in this population.