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Association Between Serum Bilirubin Levels and Depressive Symptoms Among University Students in Aden, Yemen: A Cross-Sectional Study

This cross-sectional study of 422 university students in Aden, Yemen, reveals a significant inverse association between serum bilirubin levels (particularly total bilirubin) and the severity of depressive symptoms, suggesting that lower bilirubin concentrations are linked to higher depression scores.

Original authors: Hanan A. A. Mohammed, Ali N. M. Gubran

Published 2026-07-15

📖 4 min read☕ Coffee break read

CC BY 4.0

Original authors: Hanan A. A. Mohammed, Ali N. M. Gubran

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

Imagine your body is a bustling city, and inside every cell, there's a tiny, invisible battle happening. Sometimes, the city gets attacked by "rust" (scientists call this oxidative stress), which can make the whole system feel grumpy, tired, and down. To fight this rust, the city produces a special superhero shield called bilirubin. Think of bilirubin as a golden, glowing force field that neutralizes the rust and keeps the city's lights bright.

Now, picture a group of 422 university students in Aden, Yemen. These are young people juggling classes, exams, and life, just like you might. The researchers wanted to see if the strength of this "golden shield" in their blood had anything to do with how sad or stressed they felt. They used a famous mood-checker called the PHQ-9, which asks nine questions to see if someone is feeling down.

Here is the big discovery: The students who felt the most depressed had the weakest golden shields.

The study found a clear, straight-line connection: as the sadness got heavier, the amount of bilirubin in their blood got lower. It's like a seesaw. On one side, you have the sadness score; on the other, the bilirubin level. When the sadness went up, the bilirubin went down.

The Numbers: The researchers measured the bilirubin in milligrams per deciliter (mg/dL). The average amount of total bilirubin in the group was 0.510 ± 0.247 mg/dL, and the direct bilirubin was 0.115 ± 0.056 mg/dL.
The Seesaw Effect: Students with no depression had the highest shields, with an average total bilirubin of 0.769 ± 0.274 mg/dL. But for those with severe depression, the shield dropped to just 0.326 ± 0.082 mg/dL.
The Strength of the Link: The connection was so strong that the researchers could say with high confidence that lower bilirubin levels are linked to more severe symptoms. In fact, the "total bilirubin" shield was a better predictor of sadness than the "direct bilirubin" part.

But wait, did the researchers prove that low bilirubin causes the sadness? No. And this is a very important part of the story.

The paper explicitly rules out the idea that they have solved the mystery of why this happens. They are careful to say this is a cross-sectional study, which is like taking a single snapshot in time. They can see that the shield is low and the sadness is high at the exact same moment, but they cannot tell which came first. Did the sadness eat up the shield? Or did the lack of a shield let the sadness in? The paper says we don't know yet. It's a "chicken or the egg" situation that needs more time to figure out.

The researchers also checked to make sure other things weren't the real culprits. They looked at age, gender, how much money the students had, what they studied, and even their sleep. Even after adjusting for all these factors, the link between the low bilirubin shield and high sadness scores remained strong.

So, what's the takeaway for our curious teenager?
This study suggests that in this group of students, a weaker internal antioxidant shield (bilirubin) travels hand-in-hand with heavier feelings of depression. It's a fascinating clue that our body's chemistry and our mood are deeply connected. However, the paper stops short of saying, "Give everyone bilirubin to cure depression!" That would be jumping the gun. Instead, the authors suggest we need more studies—specifically ones that follow students over time—to see if fixing the shield helps fix the mood, or if the mood fix helps the shield.

For now, we know the pattern: Lower bilirubin, higher sadness. It's a clue, not a conclusion, but it's a pretty cool clue in the mystery of how our bodies and minds talk to each other.

Technical Summary: Association Between Serum Bilirubin Levels and Depressive Symptoms Among University Students in Aden, Yemen

Problem Statement
Depressive symptoms are a prevalent mental health issue among university students globally, linked to poor academic performance and increased suicide risk. While the pathogenesis of depression is multifactorial, growing evidence implicates oxidative stress and impaired antioxidant defense mechanisms. Bilirubin, traditionally viewed as a liver function marker, is increasingly recognized as an endogenous antioxidant with anti-inflammatory properties that may protect neural tissues. Although previous studies have explored the link between serum bilirubin and depression in general or clinical populations, evidence remains inconsistent. Crucially, no published research had specifically examined this association within the university student population, a group exposed to unique psychosocial stressors, particularly in resource-limited settings like Yemen.

Methodology
This study employed a cross-sectional, analytical design involving 422 undergraduate university students (aged 18–25) recruited from public and private universities in Aden, Yemen.

Participants: Inclusion criteria required written consent and enrollment in undergraduate programs. Exclusion criteria were strict, eliminating individuals with a history of liver conditions (e.g., hepatitis, cirrhosis), hematological/genetic disorders affecting bilirubin metabolism (e.g., Gilbert's syndrome, sickle cell disease), prior psychiatric diagnoses, current use of medications affecting bilirubin metabolism, recent infections, or pregnancy.
Data Collection: Sociodemographic and lifestyle data were gathered via structured questionnaires. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), a validated tool based on DSM criteria, with scores ranging from 0 to 27.
Laboratory Procedures: Fasting venous blood samples (10–12 hours) were collected between 8:00 and 10:00 a.m. to minimize diurnal and dietary variations. Serum total and direct bilirubin concentrations were measured using a cobas c 311 clinical chemistry analyzer (Roche Diagnostics) via a diazo-based colorimetric method. Hemolyzed samples were excluded.
Statistical Analysis: Data were analyzed using IBM SPSS Statistics (v25). Descriptive statistics, Pearson's and Spearman's correlation analyses, and one-way ANOVA (with Games–Howell post hoc tests) were used. Multiple linear regression analyses were conducted to determine independent associations between bilirubin levels and PHQ-9 scores, adjusting for age, sex, marital status, field of study, income, and academic stress.

Key Results

Prevalence: Depressive symptoms were identified in 88.2% of participants. The distribution was: mild (32.0%), severe (23.9%), moderate (22.0%), and moderately severe (10.2%). Only 11.8% reported no depressive symptoms.
Bilirubin Levels: The mean serum total bilirubin was 0.510 ± 0.247 mg/dL, and mean direct bilirubin was 0.115 ± 0.056 mg/dL.
Correlations: A significant inverse 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: One-way ANOVA revealed that bilirubin levels decreased progressively as depression severity increased. Participants with no depression had the highest total bilirubin (0.769 ± 0.274 mg/dL), while those with severe depression had the lowest (0.326 ± 0.082 mg/dL).
Regression Analysis: After adjusting for confounders, both total bilirubin ( $\beta = -0.568, p < 0.001$ ) and direct bilirubin ( $\beta = -0.431, p < 0.001$ ) remained significantly associated with PHQ-9 scores. The model including total bilirubin explained a greater proportion of variance in depressive symptom scores (Adjusted $R^2 = 0.417$ ) compared to the model with direct bilirubin (Adjusted $R^2 = 0.287$ ).
Other Factors: In the adjusted models, female sex, non-medical specialization, and independent income were also significantly associated with PHQ-9 scores.

Significance and Claims
The study concludes that lower serum bilirubin levels are significantly associated with greater severity of depressive symptoms among university students in Aden. The authors assert that total bilirubin demonstrates a stronger association with depressive symptoms than direct bilirubin.

The paper positions these findings as evidence supporting an association between endogenous antioxidant status (specifically bilirubin) and depressive symptoms, rather than establishing a causal relationship. The authors highlight that this study provides novel data from a young, non-clinical population in a resource-limited setting, an area previously underrepresented in biomarker-based mental health research.

The authors explicitly state that their findings support the hypothesis linking oxidative stress and antioxidant status to depression. However, they maintain a modest stance regarding clinical utility, noting that prospective longitudinal studies are required to determine the temporal direction of this association and to evaluate whether serum bilirubin can serve as a reliable biomarker for depressive symptoms in this demographic. The study does not propose immediate clinical interventions but suggests that these findings underscore the need for strengthened mental health screening and support services for university students.

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