A Comprehensive Study of Inflammation's Contribution to the Pathophysiology of Major Depressive Syndrome
DOI:
https://doi.org/10.56294/hl2025615Keywords:
Chronic inflammation, proinflammatory cytokines, HPA axis, oxidative stress, neurodegeneration, tryptophan-kynurenine pathway, immunomodulation, antidepressant therapyAbstract
Objective: The research aims to summaries the data demonstrating the connection between persistent low-grade inflammation and the pathophysiology of severe depression, and the effects of chronic low-grade inflammation on the immune system, neurodegeneration, and the neuroendocrine system.
Materials and methods: The research examining the connection between severe depression and inflammation. The hypothalamic-pituitary-adrenal (HPA) axis is highlighted, as are the functions of proinflammatory cytokines and the tryptophan-kynurenine pathway in neurotoxicity and oxidative stress.
Results: The HPA axis is activated, and cortisol production is enhanced in severe depression, characterized by chronic low-grade inflammation. The tryptophan-kynurenine pathway is also triggered by proinflammatory cytokines, which produce neurotoxic substances such as quinolinic acid and 3-hydroxykynurenine. Particularly in cases of late-life depression, these mechanisms lead to oxidative stress and neurodegeneration.
Conclusion: Antidepressant drugs exhibit some mitigation of the immunological and endocrine alterations brought on by inflammation. Not all potent antidepressants, however, focus on these systems. To be more successful, the research advises that innovative antidepressant research should take into account medications specifically targeting the immunological, endocrine, and neurotransmitter systems.
References
1. Pitsillou E, Bresnehan SM, Kagarakis EA, Wijoyo SJ, Liang J, Hung A, Karagiannis TC. Thecellular and molecular basisofmajordepressivedisorder: towards a unifiedmodelforunderstandingclinicaldepression. Molecular biologyreports. 2020 Jan;47:753-70.
2. Opel N, Cearns M, Clark S, Toben C, Grotegerd D, Heindel W, Kugel H, Teuber A, Minnerup H, Berger K, Dannlowski U. Large-scaleevidenceforanassociationbetweenlow-grade peripheralinflammation and brainstructuralalterations in majordepression in theBiDirectstudy. JournalofPsychiatry and Neuroscience. 2019 Nov 1;44(6):423-31.
3. Chan KL, Cathomas F, Russo SJ. Central and peripheralinflammation link metabolicsyndrome and majordepressivedisorder. Physiology. 2019 Mar 1;34(2):123-33.
4. Knuesel T, Mohajeri MH. The role ofthegutmicrobiota in thedevelopment and progressionofmajordepressive and bipolar disorder. Nutrients. 2021 Dec 23;14(1):37.
5. Arteaga-Henríquez G, Simon MS, Burger B, Weidinger E, Wijkhuijs A, Arolt V, Birkenhager TK, Musil R, Müller N, Drexhage HA. Low-grade inflammation as a predictor ofantidepressant and anti-inflammatorytherapy response in MDD patients: a systematicreviewoftheliterature in combinationwithananalysisof experimental data collected in the EU-MOODINFLAME consortium. Frontiers in psychiatry. 2019 Jul 9;10:458.
6. Petralia MC, Mazzon E, Fagone P, Basile MS, Lenzo V, Quattropani MC, Bendtzen K, Nicoletti F. PathogeniccontributionoftheMacrophagemigrationinhibitory factor familytomajordepressivedisorder and emergingtailoredtherapeuticapproaches. Journalofaffectivedisorders. 2020 Feb 15;263:15-24.
7. Kamran M, Bibi F, ur. Rehman A, Morris DW. Majordepressivedisorder: existinghypothesesaboutpathophysiologicalmechanisms and new geneticfindings. Genes. 2022 Apr 6;13(4):646.
8. Tran AA, De Smet M, Grant GD, Khoo TK, Pountney DL. Investigatingtheconvergentmechanismsbetweenmajordepressivedisorder and Parkinson’sdisease. ComplexPsychiatry. 2021 Feb 16;6(3-4):47-61.
9. Ignácio ZM, da Silva RS, Plissari ME, Quevedo J, Réus GZ. Physicalexercise and neuroinflammation in majordepressivedisorder. Molecular neurobiology. 2019 Dec;56(12):8323-35.
10. Öztürk M, YalınSapmaz Ş, Kandemir H, Taneli F, Aydemir Ö. The role ofthekynureninepathway and quinolinicacid in adolescentmajordepressivedisorder. International journalofclinicalpractice. 2021 Apr;75(4):e13739.
11. Ploski JE, Vaidya VA. Theneurocircuitryof PTSD and majordepression: insightsintooverlapping and distinctcircuitdysfunction-a tribute to Ron Duman. Biologicalpsychiatry. 2021 Apr 24;90(2):109.
12. Maffioletti E, Minelli A, Tardito D, Gennarelli M. Blues in thebrain and beyond: molecular basesofmajordepressivedisorder and relativepharmacological and non-pharmacologicaltreatments. Genes. 2020 Sep 18;11(9):1089.
13. Duan J, Xie P. Thepotentialformetabolomics in thestudy and treatmentofmajordepressivedisorder and relatedconditions. ExpertReviewofProteomics. 2020 Apr 2;17(4):309-22.
14. Wang L, Wang R, Liu L, Qiao D, Baldwin DS, Hou R. EffectsofSSRIsonperipheralinflammatorymarkers in patientswithmajordepressivedisorder: a systematicreview and meta-analysis. Brain, behavior, and immunity. 2019 Jul 1;79:24-38.
15. Ning L, Yang Z, Chen J, Hu Z, Jiang W, Guo L, Xu Y, Li H, Xu F, Deng D. A novel 4 immune-related genes as diagnosticmarkers and correlatedwithimmuneinfiltrates in majordepressivedisorder. BMC immunology. 2022 Feb 13;23(1):6.
16. Yao Q, Li Y. Increasedserumlevelsofcomplement C1q in majordepressivedisorder. JournalofPsychosomaticResearch. 2020 Jun 1;133:110105.
17. Repple J, König A, de Lange SC, Opel N, Redlich R, Meinert S, Grotegerd D, Mauritz M, Hahn T, Borgers T, Leehr EJ. Associationbetweengeneticriskfortype 2 diabetes and structuralbrainconnectivity in majordepressivedisorder. BiologicalPsychiatry: CognitiveNeuroscience and Neuroimaging. 2022 Mar 1;7(3):333-40.
18. Ortega MA, Fraile-Martínez Ó, García-Montero C, Alvarez-Mon MA, Lahera G, Monserrat J, Llavero-Valero M, Gutiérrez-Rojas L, Molina R, Rodríguez-Jimenez R, Quintero J. Biological role ofnutrients, food and dietarypatterns in theprevention and clinicalmanagementofmajordepressivedisorder. Nutrients. 2022 Jul 28;14(15):3099.
19. Fries GR, Saldana VA, Finnstein J, Rein T. Molecular pathwaysofmajordepressivedisorder converge onthesynapse. Molecular Psychiatry. 2023 Jan;28(1):284-97.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Vishakha Ganvir, Prashant Modi, Nimarpreet Kaur, Jagtej Singh, Bhavani Pentela, Frederick Sidney Correa (Author)

This work is licensed under a Creative Commons Attribution 4.0 International License.
The article is distributed under the Creative Commons Attribution 4.0 License. Unless otherwise stated, associated published material is distributed under the same licence.