Elevated homocysteine levels as a predictor of stress-associated anxiety and depressive disorders in war-affected Ukrainian adults

Introduction

Anxiety and depressive disorders (ADD) represent a leading psychiatric burden in war-affected populations. Full-scale armed aggression against Ukraine since February 2022 has resulted in a dramatic increase in stress-associated mental disorders, with prevalence rates reaching 19.6–54.8% among Ukrainian adults. Homocysteine, a key metabolite of one-carbon metabolism, is involved in DNA methylation, neurotransmitter synthesis, neuroplasticity, and hypothalamic-pituitary-adrenal axis regulation, suggesting its potential role in the pathogenesis of stress-associated ADD. Despite growing evidence linking hyperhomocysteinaemia to depression and anxiety, its role in war-related traumatic stress remains insufficiently studied.

Aims

To determine the role of elevated homocysteine in stress-associated ADD and evaluate its association with anxiety and depressive symptom severity in individuals exposed to prolonged war-related traumatic stress.

Methods

A prospective observational study was conducted in Ukraine. Ethics committee approval was obtained (Protocol No. 12, 15.09.2025); all participants provided written informed consent. A total of 131 adults (mean age 43.35±16.37 years; 54.2% women) permanently residing in Ukraine during active hostilities were enrolled. Of these, 56 (42.7%) met ICD-10 diagnostic criteria for clinically significant ADD, including generalized anxiety disorder (F41.1), mixed anxiety-depressive disorder (F41.2), adjustment disorder (F43.2), depressive episode (F32-F33) and dysthymia (F34.1). 75 (57.3%) presented with subclinical stress-related symptoms. Anxiety and depression were assessed using the Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9). А score of 10 or more defined clinically significant symptoms. Diagnoses were confirmed using the Structured Clinical Interview for DSM-5 Disorders. Serum homocysteine was quantified by liquid chromatography-mass spectrometry. Analyses included Mann-Whitney U test, odds ratio with 95% confidence intervals, and linear regression (p<0.05).

Results

Elevated homocysteine (≥10 μmol/L) was detected in 50.4% of participants (mean 9.89±4.79 μmol/L; median 10.0; IQR 7.0–12.0); severe hyperhomocysteinaemia (>15 μmol/L) was present in 11.5%. Mean homocysteine was approximately two-fold higher in individuals with clinically significant anxiety versus subclinical cases (13.98±4.50 vs 6.88±2.08 μmol/L; p<0.001), and similarly elevated for depression (13.92±4.43 vs 6.87±2.05 μmol/L; p<0.001), demonstrating a clear dose-dependent relationship. Elevated homocysteine was strongly associated with clinically significant anxiety (OR 157.5; 95% CI 33.4–741.7; p<0.001) and depression (OR 320.0; 95% CI 40.0–2557.9; p<0.001). Linear regression indicated a 58% increased probability of clinically significant anxiety and 64% for depression with elevated homocysteine. No significant associations with age or sex were identified, suggesting the observed relationships reflect neurobiological rather than demographic factors.

Conclusions

Hyperhomocysteinaemia was highly prevalent among Ukrainian adults exposed to prolonged war-related stress and demonstrated a robust, dose-dependent association with anxiety and depressive symptom severity, independent of age and sex. These findings support elevated homocysteine as a clinically relevant biomarker of risk and severity in stress-associated ADD, with potential value for patient stratification and personalized treatment planning. Further studies with larger samples are needed to clarify causal mechanisms and evaluate the therapeutic potential of homocysteine-targeted interventions.

References

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