Serum Copper, Zinc, Iron, and Superoxide Dismutase Levels as Biomarkers in Depression
DOI:
https://doi.org/10.66984/jsmdc.v12.i01.oa.07Keywords:
Depressive disorder, Copper, Zinc, Superoxide dismutase, Oxidative stressAbstract
Objective: To assess levels of hemoglobin, serum copper (Cu), zinc (Zn), iron (Fe), and superoxide dismutase (SOD) levels in individuals with depressive disorder and to evaluate their diagnostic utility as biomarkers using receiver operating characteristic (ROC) curve analysis.
Methodology: This cross-sectional comparative study was conducted at the University of Health Sciences, Lahore from September 2025 to March 2026 and serum samples were collected from Combined Military Hospital, Muzaffarabad. After obtaining institutional ethical approval, 30 healthy controls and 60 patients with depressive disorder diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria were included. Study participants were recruited using non-probability consecutive sampling technique. After obtaining informed written consent, blood samples were analyzed for hemoglobin, copper, zinc, iron, and SOD levels using standard laboratory methods. Statistical Package for the Social Sciences (SPSS) version 25.0 was used for data analysis and a p-value <0.05 was considered statistically significant.
Results: Patients with depression had significantly higher serum copper levels (129.31±45.81 vs. 101.32±14.14 µg/dL, p=0.001) and Cu/Zn ratio (1.71±1.05 vs. 1.15±0.44, p=0.001), but lower hemoglobin levels (10.89±0.92 vs. 11.35±1.01 g/dL, p=0.040) and SOD activity (54.14±44.66 vs. 84.02±28.72 U/mL, p=0.001) compared to healthy controls. In the depression group, serum copper showed significant inverse correlations with zinc (r=-0.38, p=0.004) and SOD activity (r=-0.41, p=0.002). Regarding diagnostic performance, serum copper demonstrated fair discriminatory ability [area under the curve (AUC)=0.70, 95% confidence interval (CI):0.58-0.82], while a combined model of serum copper and Cu/Zn ratio showed improved performance (AUC=0.82, 95% CI:0.71-0.90), indicating good discriminatory ability.
Conclusion: The depression group showed significantly elevated serum copper, increased Cu/Zn ratio, reduced SOD activity, and lower hemoglobin levels as compared to healthy controls. Serum copper was inversely correlated with zinc and SOD in the depression group. Serum copper and the Cu/Zn ratio combined showed good diagnostic performance on ROC analysis. Serum zinc and iron levels were not significantly different between groups.
References
1. Ait Tayeb AEK, Poinsignon V, Chappell K, Bouligand J, Becquemont L, Verstuyft C. Major depressive disorder and oxidative stress: a review of peripheral and genetic biomarkers according to clinical characteristics and disease stages. Antioxidants (Basel). 2023; 12(4):942. doi:10.3390/ antiox12040942.
2. An Y, Li S, Huang X, Chen X, Shan H, Zhang M. The role of copper homeostasis in brain disease. Int J Mol Sci. 2022; 23(22):13850. doi:10.3390/ijms232213850.
3. Zielinska M, Luszczki E, Deren K. Dietary nutrient deficiencies and risk of depression (review article 2018-2023). Nutrients. 2023; 15(11):2433. doi:10.3390/nu 15112433.
4. Swiadro M, Ordon K, Herman M, Dudek D, Wietecha-Posluszny R. Copper and zinc as potential biomarkers of mood disorders and pandemic syndrome. Molecules. 2021; 27(1):91. doi:10.3390/molecules27010091.
5. Fiani D, Engler S, Ni Y, Fields S, Calarge C. Iron deficiency and internalizing symptoms among adolescents in the national health and nutrition examination survey. Nutrients. 2024; 16(21):3643. doi:10.3390/nu16213643.
6. Rajkumar RP. Iron deficiency and depression: evidence of critical risk periods. Front Psychiatry. 2026; 17:1770460. doi:10.3389/fpsyt.2026.1770460.
7. Chidambaram SB, Anand N, Varma SR, Ramamurthy S, Vichitra C, Sharma A, et al. Superoxide dismutase and neurological disorders. IBRO Neurosci Rep. 2024; 16:373-94. doi:10.1016/j.ibneur.2023.11.007.
8. Liu X, Lin C, Wang S, Yu X, Jia Y, Chen J. Effects of high levels of copper on the depression-related memory disorders. J Gerontol A Biol Sci Med Sci. 2023; 78(4):611-8. doi:10.1093/gerona/glac222.
9. Kim BR, Hur JW, Park DS, Moon HR, Choi SW. Increased neural responses to negative facial emotions and their relationship with dysfunctional attitudes among unmedicated individuals with major depressive disorder. Curr Psychol. 2023; 42: 20409-20. doi:10.1007/s12144-022-03144-5.
10. Farinde A, Teruya J. Lab values, normal adult: laboratory reference ranges in healthy adults. Medscape. 2025. Available from: https://emedicine.medscape.com/article/ 2172316-overview.
11. Corbacıoglu SK, Aksel G. Receiver operating characteristic curve analysis in diagnostic accuracy studies: a guide to interpreting the area under the curve value. Turk J Emerg Med. 2023; 23(4):195-8. doi:10.4103/tjem.tjem_182_23.
12. Huang D, Lai S, Zhong S, Jia Y. Association between serum copper, zinc, and selenium concentrations and depressive symptoms in the US adult population, NHANES (2011-2016). BMC Psychiatry. 2023; 23(1):498. doi:10. 1186/s12888-023-04953-z.
13. Davarinejad O, Nasseri Z, Mansouri B. Association between serum levels of essential elements (copper, zinc, and iron) and major depressive disorder: a systematic review and meta-analysis. Rev Environ Health. 2025; 41(1):43-55. doi:10.1515/reveh-2025-0116.
14. Squitti R, Ventriglia M, Simonelli I, Bonvicini C, Crescenti D, Borroni B, et al. Copper dysregulation in major depression: a systematic review and meta-analytic evidence for a putative trait marker. Int J Mol Sci. 2025; 26(18):9247. doi:10.3390/ijms26189247.
15. Gromadzka G, Antos A, Sorysz Z, Litwin T. Psychiatric symptoms in wilson's disease-consequence of ATP7B gene mutations or just coincidence?-possible causal cascades and molecular pathways. Int J Mol Sci. 2024; 25(22):12354. doi:10.3390/ijms252212354.
16. Yosaee S, Clark CCT, Keshtkaran Z, Ashourpour M, Keshani P, Soltani S. Zinc in depression: from development to treatment: a comparative/dose response meta-analysis of observational studies and randomized controlled trials. Gen Hosp Psychiatry. 2022; 74:110-7. doi:10.1016/j. genhosppsych.2020.08.001.
17. Lopez-Alonso M, Rivas I, Miranda M. Trace mineral imbalances in global health: challenges, biomarkers, and the role of serum analysis. Nutrients. 2025; 17(13):2241. doi:10.3390/nu17132241.
18. Al-Hakeim HK, Al-Fadhel SZ, Al-Dujaili AH. Correlation of serum Cu and Zn with some cytokines in major depressive disorder. JGPT. 2020; 12(6):115-21. Available from https://jgpt.co.in/index.php/jgpt/article/view/3503/2711.
19. Leung CY, Kyung M. Associations of iron deficiency and depressive symptoms among young adult males and Females: NHANES 2017 to 2020. Prev Med Rep. 2023; 37:102549. doi:10.1016/j.pmedr.2023.102549.
20. Peng RJ, Sun C, Fan Y, Li J, Gao J, Sun WX, et al. Oxidative stress and cognitive function in Chinese patients with major depressive disorder: the mediating role of depression severity. BMC Psychiatry. 2025; 25(1):1012. doi:10.1186/s12888-025-07478-9.
21. Abd Elmoneim LA, Mohamed SS, Raslan EI, Al-Azayem SA, Hussein HA, Elsayed IT. A case control study of oxidative stress in a sample of patients with major depressive disorder. Front Health Inform. 2024; 13(8):2453-61. Available from: https://healthinformatics journal.com/index.php/IJMI/article/view/1881/1775.
22. Zhu Z, Song M, Ren J, Liang L, Mao G, Chen M. Copper homeostasis and cuproptosis in central nervous system diseases. Cell Death Dis. 2024; 15(11):850. doi:10.1038/ s41419-024-07206-3.
23. Trebaticka J, Vatral M, Katrencikova B, Muchova J, Durackova Z. Current insight into biological markers of depressive disorder in children and adolescents: a narrative review. Antioxidants (Basel). 2025; 14(6):699. doi:10. 3390/antiox14060699.
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