THE IMPACT OF ELEVATED HOMOCYSTEINE LEVELS ON THE DEVELOPMENT OF STRESS-ASSOCIATED ANXIETY AND DEPRESSIVE DISORDERS
DOI:
https://doi.org/10.32782/2226-2008-2026-1-9Keywords:
homocysteine, stress-associated disorders, anxiety depression, methylation, one-carbon metabolismAbstract
Methods. A prospective observational study included 131 adults (mean age 43.35 ± 16.37 years; 54.2 % women). Anxiety and depression were assessed using the GAD-7 and PHQ-9 scales. Homocysteine levels were quantified by LC-MS. Group comparisons and odds ratios (OR, 95 % CI) were calculated; p < 0.05 was considered statistically significant. Results. Elevated homocysteine levels (≥ 10 μmol/L) were detected in 50.4 % of participants, while concentrations > 15 μmol/L were observed in 11.5 %. Homocysteine levels were approximately two-fold higher in individuals with clinically significant symptoms compared with those with subclinical manifestations (anxiety: 13.98 ± 4.50 vs 6.88 ± 2.08; depression: 13.92 ± 4.43 vs 6.87 ± 2.05; p < 0.001). Homocysteine ≥ 10 μmol/L was strongly associated with clinically significant anxiety (OR = 157.5; 95 % CI 33.4–741.6; p < 0.001) and depression (OR = 320.0; 95 % CI 40.0–2557.8; p < 0.001). Conclusions. Hyperhomocysteinemia was common among individuals exposed to prolonged war-related stress and closely associated with the severity of anxiety and depression. Elevated homocysteine levels were identified in 50.4 % of the examined participants with ADDs, indicating a high prevalence of disturbances in one-carbon metabolism. A dose-dependent relationship between homocysteine concentration and ADDs severity was observed. Increased homocysteine levels were associated with a higher probability of clinically significant anxiety (58 %) and depressive disorders (64 %). These findings support the pathogenetic role of hyperhomocysteinemia in stress-associated ADDs and justify the use of homocysteine as a biomarker of risk, severity, and prognosis of anxiety-phobic and affective disorders.
References
Hohls JK, Konig HH, Quirke E, Hajek A. Anxiety, depression and quality of life – a systematic review of evidence from longitudinal observational studies. International Journal of Environmental Research and Public Health. 2021;18(22):12022. DOI: https://doi.org/10.3390/ijerph182212022.
Chernenko II, Markova MV. Comparative analysis of depressive, anxiety and post-traumatic symptoms in patients with a history of combat traumatic brain injury depending on its severity and duration. Psychiatry, Neurology and Medical Psychology. 2025;12(1(27):7–21. https://doi.org/10.26565/2312-5675-2025-27-01.
Kozhyna HM, Sukharieva VA. Evaluation of the effectiveness of a comprehensive personalized treatment program for warrelated mental disorders in combatants. Ukrainian Bulletin of Psychoneurology. 2025;33(1):32–38. DOI: https://doi.org/10.36927/2079-0325-V33-is1-2025-5.
Georgescu MF, Beydoun MA, Maino Vieytes CA, et al. Longitudinal association of homocysteine with depressive and anxiety symptoms among urban adults: healthy aging in neighborhoods of diversity across the life span study. Translational Psychiatry. 2024;14(1):444. DOI: https://doi.org/10.1038/s41398-024-03111-7.
Nikonenko OS, Nikonenko AO, Chmul KO, Osaulenko VV. Study of the influence of homocysteine and vitamin D metabolism on the development of destructive vascular wall processes. Ukrainskyi Zhurnal Sertsevo-sudynnoi Khirurhii. 2020;3(40):22–27. https://doi.org/10.30702/ujcvs/20.4009/050022-027/11.9.
Krawczyk M, Burzynska-Pedziwiatr I, Wozniak LA, Bukowiecka-Matusiak M. The Implication of a Polymorphism in the Methylenetetrahydrofolate Reductase Gene in Homocysteine Metabolism and Related Civilisation Diseases. International Journal of Molecular Sciences. 2024;25(1):193. DOI: https://doi.org/10.3390/ijms25010193.
Kaur G, Gaur R, Yadav S, Saraswathy KN. Association of vitamin B12 mediated hyperhomocysteinemia and methylenetetrafolate reductase (C677T) gene polymorphism with cognitive impairment: A population based study from North India. Psychiatry Research. 2018;270:123–125. DOI: https://doi.org/10.1016/j.psychres.2018.08.103.
Zhang A, Qin Y, Wang H, et al. Serum folate and homocysteine as biomarkers for suicide risk in major depressive disorder: insights in males and younger patients. BMC Psychiatry. 2025;25(1):745. DOI: https://doi.org/10.1186/s12888-025-07183-7.
Lyon P, Strippoli V, Fang B, Cimmino L. B vitamins and one-carbon metabolism: implications in human health and disease. Nutrients. 2020;12(9):2867. DOI: https://doi.org/10.3390/nu12092867.
Liwinski T, Lang UE. Folate and Its Significance in Depressive Disorders and Suicidality: A Comprehensive Narrative Review. Nutrients. 2023;15(17):3859. DOI: https://doi.org/10.3390/nu15173859.
Ulloque-Badaracco JR, Hernandez-Bustamante EA, Alarcon-Braga EA, et al. Vitamin B12, folate, and homocysteine in metabolic syndrome: a systematic review and meta-analysis. Frontiers in Endocrinology. 2023;14:1221259. DOI: https://doi.org/10.3389/fendo.2023.1221259.
Elstgeest LEM, Brouwer IA, Penninx BWJH, van Schoor NM, Visser M. Vitamin B12, homocysteine and depressive symptoms: a longitudinal study among older adults. European Journal of Clinical Nutrition. 2017;71(4):468–475. DOI: https://doi.org/10.1038/ejcn.2016.224.
Altaf R, Gonzalez I, Rubino K, Nemec EC. Folate as adjunct therapy to SSRI/SNRI for major depressive disorder: systematic review and meta-analysis. Complementary Therapies in Medicine. 2021;61:102770. DOI: https://doi.org/10.1016/j.ctim.2021.102770.
Gao S, Khalid A, Amini-Salehi E, Radkhah N, Jamilian P, Badpeyma M, Zarezadeh M. Folate supplementation as a beneficial add-on treatment in relieving depressive symptoms: A meta-analysis of meta-analyses. Food Science & Nutrition. 2024;12(6):3806–3818. DOI: https://doi.org/10.1002/fsn3.4073.
Mech AW, Farah A. Correlation of clinical response with homocysteine reduction during therapy with reduced B vitamins in patients with major depressive disorder who are positive for MTHFR C677T or A1298C polymorphism: a randomized, double-blind, placebo-controlled study. The Journal of Clinical Psychiatry. 2016;77(5):668–671. DOI: https://doi.org/10.4088/JCP.15m10166.
Maletic V, Shelton R, Holmes V. A review of L-methylfolate as adjunctive therapy in the treatment of major depressive disorder. Primary Care Companion for CNS Disorders. 2023;25(3):22nr03361. DOI: https://doi.org/10.4088/PCC.22nr03361.
Saraswathy KN, Ansari SN, Kaur G, Joshi PC, Chandel S. Association of vitamin B12 mediated hyperhomocysteinemia with depression and anxiety disorder: a cross-sectional study among Bhil indigenous population of India. Clinical Nutrition ESPEN. 2019;30:199–203. DOI: https://doi.org/10.1016/j.clnesp.2019.01.009.
Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Archives of Internal Medicine. 2006;166(10):1092–1097. DOI: https://doi.org/10.1001/archinte.166.10.1092.
Chae D, Lee J, Lee EH. Internal structure of the Patient Health Questionnaire-9: a systematic review and meta-analysis. Asian Nursing Research. 2025;19(1):1–12. DOI: https://doi.org/10.1016/j.anr.2024.12.005.
Lushchak O, Orru M, Strilbytska O, et al. Metabolic and immune dysfunctions in post-traumatic stress disorder: what can we learn from animal models? EXCLI Journal. 2023;22:928–945. DOI: https://doi.org/10.17179/excli2023-6391.
