The Role of Neuroinflammation and Inflammatory Biomarkers in Major Depressive Disorder
Main Article Content
Abstract
Neuroinflammation plays a significant role in the pathophysiology and progression of major depressive disorder. Elevated levels of inflammatory markers are associated with treatment resistance to conventional antidepressants and poor prognosis. Targeting inflammation with alternative anti-inflammatory treatments might be a promising treatment strategy for patients suffering from depression with underlying immune dysfunction. The use of inflammatory biomarkers is very useful to identify patients with inflammatory abnormalities at risk to develop treatment resistance and to select the appropriate treatment option from the beginning. The aim of the present review is to elucidate the impact of neuroinflammation on the pathogenesis and progression of major depressive disorder. It provides insight into alternative therapies targeting inflammatory pathways, such as electroconvulsive therapy and ketamine, and illustrates the role of potential inflammatory biomarkers to improve prevention of treatment resistance and treatment strategies.
Keywords:
Major depressive disorder, neuroinflammation, treatment resistance, immune dysfunction, inflammatory biomarkers
Article Details
How to Cite
BREIT, Sigrid.
The Role of Neuroinflammation and Inflammatory Biomarkers in Major Depressive Disorder.
Medical Research Archives, [S.l.], v. 13, n. 7, july 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6743>. Date accessed: 05 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i7.6743.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Reutfors J, Andersson TM, Tanskanen A, et al. Risk Factors for Suicide and Suicide Attempts Among Patients With Treatment-Resistant Depression: Nested Case-Control Study. Arch Suicide Res. 2021;25(3):424-438.
4. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446-457.
5. Liu Y, Ho RC, Mak A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-alpha) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord. 2012;139(3):230-239.
6. Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimaki M. Cumulative meta-analysis of interleukins 6 and 1beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder. Brain Behav Immun. 2015;49:206-215.
7. Kohler CA, Freitas TH, Maes M, et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand. 2017;135(5):373-387.
8. Yang C, Tiemessen KM, Bosker FJ, Wardenaar KJ, Lie J, Schoevers RA. Interleukin, tumor necrosis factor-alpha and C-reactive protein profiles in melancholic and non-melancholic depression: A systematic review. J Psychosom Res. 2018;111:58-68.
9. Reus GZ, Manosso LM, Quevedo J, Carvalho AF. Major depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities. Neurosci Biobehav Rev. 2023;155:105425.
10. Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ. Inflammation and clinical response to treatment in depression: A meta-analysis. Eur Neuropsychopharmacol. 2015;25(10):1532-1543.
11. Liu JJ, Wei YB, Strawbridge R, et al. Peripheral cytokine levels and response to antidepressant treatment in depression: a systematic review and meta-analysis. Mol Psychiatry. 2020;25(2):339-350.
12. Hassamal S. Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories. Front Psychiatry. 2023;14:1130989.
13. Streit WJ, Walter SA, Pennell NA. Reactive microgliosis. Prog Neurobiol. 1999;57(6):563-581.
14. Sugama S, Takenouchi T, Fujita M, Conti B, Hashimoto M. Differential microglial activation between acute stress and lipopolysaccharide treatment. J Neuroimmunol. 2009;207(1-2):24-31.
15. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56.
16. Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R. The new '5-HT' hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):702-721.
17. Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012;37(1):137-162.
18. Mulla A, Buckingham JC. Regulation of the hypothalamo-pituitary-adrenal axis by cytokines. Baillieres Best Pract Res Clin Endocrinol Metab. 1999;13(4):503-521.
19. Silverman MN, Pearce BD, Biron CA, Miller AH. Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol. 2005;18(1):41-78.
20. Leonard BE. The HPA and immune axes in stress: the involvement of the serotonergic system. Eur Psychiatry. 2005;20 Suppl 3:S302-306.
21. Rutters F, Nieuwenhuizen AG, Lemmens SG, Born JM, Westerterp-Plantenga MS. Hypothalamic-pituitary-adrenal (HPA) axis functioning in relation to body fat distribution. Clin Endocrinol (Oxf). 2010;72(6):738-743.
22. Benedetti F, Poletti S, Vai B, et al. Higher baseline interleukin-1beta and TNF-alpha hamper antidepressant response in major depressive disorder. Eur Neuropsychopharmacol. 2021;42:35-44.
23. Lei AA, Phang VWX, Lee YZ, et al. Chronic Stress-Associated Depressive Disorders: The Impact of HPA Axis Dysregulation and Neuroinflammation on the Hippocampus-A Mini Review. Int J Mol Sci. 2025;26(7).
24. Bertollo AG, Mingoti MED, Ignacio ZM. Neurobiological mechanisms in the kynurenine pathway and major depressive disorder. Rev Neurosci. 2025;36(2):169-187.
25. Han KM, Ham BJ. How Inflammation Affects the Brain in Depression: A Review of Functional and Structural MRI Studies. J Clin Neurol. 2021;17(4):503-515.
26. MacQueen G, Frodl T. The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research? Mol Psychiatry. 2011;16(3):252-264.
27. Troubat R, Barone P, Leman S, et al. Neuroinflammation and depression: A review. Eur J Neurosci. 2021;53(1):151-171.
28. Yang C, Wardenaar KJ, Bosker FJ, Li J, Schoevers RA. Inflammatory markers and treatment outcome in treatment resistant depression: A systematic review. J Affect Disord. 2019;257:640-649.
29. Yin M, Zhou H, Li J, et al. The change of inflammatory cytokines after antidepressant treatment and correlation with depressive symptoms. J Psychiatr Res. 2025;184:418-423.
30. Ma K, Zhang H, Baloch Z. Pathogenetic and Therapeutic Applications of Tumor Necrosis Factor-alpha (TNF-alpha) in Major Depressive Disorder: A Systematic Review. Int J Mol Sci. 2016;17(5).
31. Yao L, Pan L, Qian M, et al. Tumor Necrosis Factor-alpha Variations in Patients With Major Depressive Disorder Before and After Antidepressant Treatment. Front Psychiatry. 2020;11:518837.
32. Amitai M, Taler M, Carmel M, et al. The Relationship Between Plasma Cytokine Levels and Response to Selective Serotonin Reuptake Inhibitor Treatment in Children and Adolescents with Depression and/or Anxiety Disorders. J Child Adolesc Psychopharmacol. 2016;26(8):727-732.
33. Nobile B, Durand M, Olie E, et al. The Anti-inflammatory Effect of the Tricyclic Antidepressant Clomipramine and Its High Penetration in the Brain Might Be Useful to Prevent the Psychiatric Consequences of SARS-CoV-2 Infection. Front Pharmacol. 2021;12:615695.
34. Eslami M, Monemi M, Nazari MA, et al. The Anti-Inflammatory Potential of Tricyclic Antidepressants (TCAs): A Novel Therapeutic Approach to Atherosclerosis Pathophysiology. Pharmaceuticals (Basel). 2025;18(2).
35. Xiang JJ, Hong S, Ran LY, et al. [Effect of Sertraline on Serum Cytokine Levels in Adolescents With First-Episode Major Depressive Disorder]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2023;54(2):310-315.
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