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Role of Immune-Inflammatory and Oxidative and Nitrosative Stress Pathways in the Etiology of Depression: Therapeutic Implications

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Abstract

Accumulating data have led to a re-conceptualization of depression that emphasizes the role of immune-inflammatory processes, coupled to oxidative and nitrosative stress (O&NS). These in turn drive the production of neuroregulatory tryptophan catabolites (TRYCATs), driving tryptophan away from serotonin, melatonin, and N-acetylserotonin production, and contributing to central dysregulation. This revised perspective better encompasses the diverse range of biological changes occurring in depression and in doing so provides novel and readily attainable treatment targets, as well as potential screening investigations prior to treatment initiation. We briefly review the role that immune-inflammatory, O&NS, and TRYCAT pathways play in the etiology, course, and treatment of depression. We then discuss the pharmacological treatment implications arising from this, including the potentiation of currently available antidepressants by the adjunctive use of immune- and O&NS-targeted therapies. The use of such a frame of reference and the treatment benefits attained are likely to have wider implications and utility for depression-associated conditions, including the neuroinflammatory and (neuro)degenerative disorders.

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References

  1. Maes M, Fišar Z, Medina M, et al. New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology. 2012;20(3):127–50.

    Google Scholar 

  2. Arroll B, Elley CR, Fishman T, et al. Antidepressants versus placebo for depression in primary care. Cochrane Database Syst Rev. 2009;(3):CD007954.

  3. Anderson G, Maes M. Oxidative/nitrosative stress and immune-inflammatory pathways in depression: treatment implications. Curr Pharmacol Design. 2013 (in press).

  4. Maes M, Bosmans E, Suy E, et al. Immune disturbances during major depression: upregulated expression of interleukin-2 receptors. Neuropsychobiology. 1990;24(3):115–20.

    PubMed  Google Scholar 

  5. Leonard B, Maes M. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev. 2012;36(2):764–85.

    CAS  PubMed  Google Scholar 

  6. Maes M, Galecki P, Chang YS, et al. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharm Biol Psychiatry. 2011;35(3):676–92.

    CAS  Google Scholar 

  7. Anderson G, Maes M, Berk M. Biological underpinnings of the commonalities in depression, somatization, and chronic fatigue syndrome. Med Hypotheses. 2012;78:752–6.

    PubMed  Google Scholar 

  8. Maes M, Kubera M, Obuchowiczwa E, et al. Depression’s multiple comorbidities explained by (neuro)inflammatory and oxidative and nitrosative stress pathways. Neuro Endocrinol Lett. 2011;32(1):7–24.

    CAS  PubMed  Google Scholar 

  9. Anderson G, Maes M. TRYCAT pathways link peripheral inflammation, nicotine, somatization and depression in the etiology and course of Parkinson’s disease. CNS Neurol Dis Drug Target. 2013 (in press).

  10. Anderson G, Maes M, Berk M. Schizophrenia is primed for an increased expression of depression through activation of immune-inflammatory, oxidative and nitrosative stress, and tryptophan catabolite pathways. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:101–14.

    CAS  PubMed  Google Scholar 

  11. Wachter H, Fuchs D, Hausen A, et al. Neopterin; biochemistry, methods, and clinical application. Berlin: Walter de Gruyter; 1992.

    Google Scholar 

  12. Song C, Halbreich U, Han C, et al. Imbalance between pro- and anti-inflammatory cytokines, and between Th1 and Th2 cytokines in depressed patients: the effect of electroacupuncture or fluoxetine treatment. Pharmacopsychiatry. 2009;42(5):182–8.

    CAS  PubMed  Google Scholar 

  13. Caruso C, Candore G, Cigna D, et al. Biological significance of soluble IL-2 receptor. Mediat Inflamm. 1993;2(1):3–21.

    CAS  Google Scholar 

  14. Maes M, Vandoolaeghe E, Ranjan R, et al. Increased serum soluble CD8 or suppressor/cytotoxic antigen concentrations in depression: suppressive effects of glucocorticoids. Biol Psychiatry. 1996;40(12):1273–81.

    CAS  PubMed  Google Scholar 

  15. Sluzewska A, Rybakowski J, Bosmans E, et al. Indicators of immune activation in major depression. Psychiatry Res. 1996;64(3):161–7.

    CAS  PubMed  Google Scholar 

  16. Lee KM, Kim YK. The role of IL-12 and TGF-beta1 in the pathophysiology of major depressive disorder. Int Pharmacol. 2006;6(8):1298–304.

    CAS  Google Scholar 

  17. Anderson G, Maes M, Berk M. Inflammation-related disorders in the tryptophan catabolite pathway in depression and somatization. Adv Protein Chem Struct Biol. 2012;88:27–48.

    CAS  PubMed  Google Scholar 

  18. Kim H, Chen L, Lim G, et al. Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. J Clin Invest. 2012;122(8):2940–54.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Liebau C, Baltzer AW, Schmidt S, et al. Interleukin-12 and interleukin-18 induce indoleamine 2,3-dioxygenase (IDO) activity in human osteosarcoma cell lines independently from interferon-gamma. Anticancer Res. 2002:22(2A):931–6.

    Google Scholar 

  20. Maes M, Scharpé S, Meltzer HY, et al. Increased neopterin and interferon-gamma secretion and lower availability of l-tryptophan in major depression: further evidence for an immune response. Psychiatry Res. 1994;54(2):143–60.

    CAS  PubMed  Google Scholar 

  21. Maes M, Leonard BE, Myint AM, et al. The new 5-HT hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):702–21.

    CAS  PubMed  Google Scholar 

  22. Maes M, Rief W. Diagnostic classifications in depression and somatization should include biomarkers, such as disorders in the tryptophan catabolite (TRYCAT) pathway. Psychiatr Res. 2012;196(23):243–9.

    CAS  Google Scholar 

  23. Saito K, Nowak TS Jr, Suyama K, et al. Kynurenine pathway enzymes in brain: responses to ischemic brain injury versus systemic immune activation. J Neurochem. 1993;61:2061–70.

    CAS  PubMed  Google Scholar 

  24. Maes M, Scharpé S, Meltzer HY, Bosmans E, Suy E, Calabrese J, Cosyns P. Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression. Psychiatry Res. 1993;49(1):11–27.

    Google Scholar 

  25. Nguyen NT, et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci USA. 2010;107:19961–6.

    CAS  PubMed  Google Scholar 

  26. Chen Y, Jiang T, Chen P, et al. Emerging tendency towards autoimmune process in major depressive patients: a novel insight from Th17 cells. Psychiatry Res. 2011;188(2):224–30.

    CAS  PubMed  Google Scholar 

  27. Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, et al. Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry. 2011;16(7):751–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Dean B, Tawadros N, Scarr E, et al. Regionally-specific changes in levels of tumour necrosis factor in the dorsolateral prefrontal cortex obtained postmortem from subjects with major depressive disorder. J Affect Disord. 2010;120(1–3):245–8.

    CAS  PubMed  Google Scholar 

  29. Yu YW, Chen TJ, Hong CJ, et al. Association study of the interleukin-1 beta (C-511 T) genetic polymorphism with major depressive disorder, associated symptomatology, and antidepressant response. Neuropsychopharmacology. 2003;28:1182–5.

    CAS  PubMed  Google Scholar 

  30. Bull SJ, Huezo-Diaz P, Binder EB, et al. Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. Mol Psychiatry. 2009;14:1095–104.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Jun TY, Pae CU, Hoon-Han, et al. Possible association between −G308A tumor necrosis factor-alpha gene polymorphism and major depressive disorder in the Korean population. Psychiatr Genet. 2003;13:179–81.

  32. Pae CU, Yu HS, Kim TS, et al. Monocyte chemoattractant protein-1 (MCP1) promoter −2518 polymorphism may confer a susceptibility to major depressive disorder in the Korean population. Psychiatry Res. 2004;127:279–81.

    CAS  PubMed  Google Scholar 

  33. Wong ML, Dong C, Maestre-Mesa J, et al. Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry. 2008;13:800–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Maes M. A review on the acute phase response in major depression. Rev Neurosci. 1993;4(4):407–16.

    CAS  PubMed  Google Scholar 

  35. Song C, Dinan T, Leonard BE. Changes in immunoglobulin, complement and acute phase protein levels in the depressed patients and normal controls. J Affect Disord. 1994;30(4):283–8.

    CAS  PubMed  Google Scholar 

  36. Berk M, Wadee AA, Kuschke RH, et al. Acute phase proteins in major depression. J Psychosom Res. 1997;43(5):529–34.

    CAS  PubMed  Google Scholar 

  37. Maes M, Bosmans E, Meltzer HY, Scharpé S, Suy E. Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression? Am J Psychiatry. 1993;150(8):1189–93.

    CAS  PubMed  Google Scholar 

  38. Soliman A, Udemgba C, Fan I, Xu X, Miler L, Rusjan P, Houle S, Wilson AA, Pruessner J, Ou XM, Meyer JH. Convergent effects of acute stress and glucocorticoid exposure upon MAO-A in humans. J Neurosci. 2012;32(48):17120–7.

    CAS  PubMed  Google Scholar 

  39. Zhu CB, Blakely RD, Hewlett WA. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology. 2006;31(10):2121–31.

    CAS  PubMed  Google Scholar 

  40. Song C, Wang H. Cytokines mediated inflammation and decreased neurogenesis in animal models of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):760–8.

    CAS  PubMed  Google Scholar 

  41. Phillips AC, Robertson T, Carroll D, et al. Do symptoms of depression predict telomere length? Evidence from the west of Scotland twenty-07 study. Psychosom Med. 2013;75(3):288–96.

    PubMed  Google Scholar 

  42. Sivonova M, Zitnanova I, Hlincikova L, et al. Oxidative stress in university students during examinations. Stress. 2004;7(3):183–8.

    CAS  PubMed  Google Scholar 

  43. Wadee AA, Kuschke RH, Kometz S, et al. Personality factors, stress and immunity. Stress Health. 2001;17(1):25–40.

    Google Scholar 

  44. Stefanescu C, Ciobica A. The relevance of oxidative stress status in first episode and recurrent depression. J Affect Disord. 2012;143(1–3):34–8.

    CAS  PubMed  Google Scholar 

  45. Maes M, Mihaylova I, Kubera M, et al. Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis/chronic fatigue syndrome. Neuro Endocrinol Lett. 2009;30(6):715–22.

    CAS  PubMed  Google Scholar 

  46. Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS ONE. 2012;7(7):e42357.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Wang JF, Shao L, Sun X, Young LT. Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia. Bipolar Disord. 2009;11(5):523–9.

    CAS  PubMed  Google Scholar 

  48. Zarkovic N. 4-Hydroxynonenal as a bioactive marker of pathophysiological processes. Mol Asp Med. 2003;24(4–5):281–91.

    CAS  Google Scholar 

  49. Maes M, Mihaylova I, Kubera M, Leunis JC, Geffard M. IgM-mediated autoimmune responses directed against multiple neoepitopes in depression: new pathways that underpin the inflammatory and neuroprogressive pathophysiology. J Affect Disord. 2011;135(1–3):414–8.

    CAS  PubMed  Google Scholar 

  50. Ohmori H, Kanayama N. Immunogenicity of an inflammation-associated product, tyrosine nitrated self-proteins. Autoimmun Rev. 2005;4(4):224–9.

    CAS  PubMed  Google Scholar 

  51. Owen AJ, Batterham MJ, Probst YC, et al. Low plasma vitamin E levels in major depression: diet or disease? Eur J Clin Nutr. 2005;59(2):304–6.

    CAS  PubMed  Google Scholar 

  52. Kodydková J, Vávrová L, Zeman M, et al. Antioxidative enzymes and increased oxidative stress in depressive women. Clin Biochem. 2009;42(13–14):1368–74.

    PubMed  Google Scholar 

  53. Maes M, Mihaylova I, Kubera M, et al. Lower plasma coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness. Neuro Endocrinol Lett. 2009;30(4):462–9.

    CAS  PubMed  Google Scholar 

  54. Maes M, Mihaylova I, Kubera M, et al. Lower whole blood glutathione peroxidase (GPX) activity in depression, but not in myalgic encephalomyelitis/chronic fatigue syndrome: lower GPX activity as another pathway explaining the increased incidence of coronary artery disease in depression. Neuro Endocrinol Lett. 2011;32(2):133–40.

    PubMed  Google Scholar 

  55. Khanzode SD, Dakhale GN, Khanzode SS, et al. Oxidative damage and major depression: the potential antioxidant action of selective serotonin re-uptake inhibitors. Redox Rep. 2003;8(6):365–70.

    CAS  PubMed  Google Scholar 

  56. Khaleghipour S, Masjedi M, Ahade H, et al. Morning and nocturnal serum melatonin rhythm levels in patients with major depressive disorder: an analytical cross-sectional study. Sao Paulo Med J. 2012;130(3):167–72.

    PubMed  Google Scholar 

  57. Pasco JA, Jacka FN, Williams LJ, et al. Dietary selenium and major depression: a nested case-control study. Complement Ther Med. 2012;20(3):119–23.

    PubMed  Google Scholar 

  58. Cumurcu BE, Ozyurt H, Etikan I, et al. Total antioxidant capacity and total oxidant status in patients with major depression: impact of antidepressant treatment. Psychiatry Clin Neurosci. 2009;63(5):639–45.

    CAS  PubMed  Google Scholar 

  59. Kim HJ, Barajas B, Wang M, et al. Nrf2 activation by sulforaphane restores the age-related decrease of T(H)1 immunity: role of dendritic cells. J Allergy Clin Immunol. 2008;121(5):1255–61.

    CAS  PubMed  Google Scholar 

  60. Maes M, Christophe A, Delanghe J, et al. Lowered omega3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Res. 1999;85(3):275–91.

    CAS  PubMed  Google Scholar 

  61. Jacka FN, Pasco JA, Henry MJ, et al. Dietary omega-3 fatty acids and depression in a community sample. Nutr Neurosci. 2004;7(2):101–6.

    CAS  PubMed  Google Scholar 

  62. Shao L, Martin MV, Watson SJ, et al. Mitochondrial involvement in psychiatric disorders. Ann Med. 2008;40(4):281–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Gardner A, Johansson A, Wibom R, et al. Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patients. J Affect Disord. 2003;76(1–3):55–68.

    CAS  PubMed  Google Scholar 

  64. Suomalainen A, Majander A, Haltia M, et al. Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia. J Clin Invest. 1992;90(1):61–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Nierenberg AA, Kansky C, Brennan BP, et al. Mitochondrial modulators for bipolar disorder: a pathophysiologically informed paradigm for new drug development. Aust N Z J Psychiatry. 2013;47(1):26–42.

    PubMed  Google Scholar 

  66. Berk M, Ng F, Dean O, et al. Glutathione: a novel treatment target in psychiatry. Trends Pharmacol Sci. 2008;29(7):346–51.

    CAS  PubMed  Google Scholar 

  67. Kishi T, Yoshimura R, Kitajima T, Okochi T, Okumura T, Tsunoka T, Yamanouchi Y, Kinoshita Y, Kawashima K, Fukuo Y, Naitoh H, Umene-Nakano W, Inada T, Nakamura J, Ozaki N, Iwata N. SIRT1 gene is associated with major depressive disorder in the Japanese population. J Affect Dis. 2010;126:167–73.

    CAS  PubMed  Google Scholar 

  68. Verdin E, Hirschey MD, Finley LWS, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci. 2010;35(12):669–75.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Fritz KS, Galligan JJ, Smathers RL, et al. 4-Hydroxynonenal inhibits SIRT3 via thiol-specific modification. Chem Res Toxicol. 2011;24(5):651–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Szewczyk B, Kubera M, Nowak G. The role of zinc in neurodegenerative and inflammatory pathways in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):693–701.

    CAS  PubMed  Google Scholar 

  71. Maes M, Mihaylova I, Kubera M, et al. Increased plasma peroxides and serum oxidized low density lipoprotein antibodies in major depression: markers that further explain the higher incidence of neurodegeneration and coronary artery disease. J Affect Disord. 2010;125(1–3):287–94.

    CAS  PubMed  Google Scholar 

  72. Maes M, Ringel K, Kubera M, et al. Increased autoimmune activity against 5-HT: a key component of depression that is associated with inflammation and activation of cell-mediated immunity, and with severity and staging of depression. J Affect Disord. 2012;136(3):386–92.

    CAS  PubMed  Google Scholar 

  73. Maes M, Kubera M, Leunis JC, et al. In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr Scand. 2013;127:344–54.

    CAS  PubMed  Google Scholar 

  74. Ghanizadeh A, Berk M. Molecular hydrogen: an overview of its neurobiological effects and therapeutic potential for bipolar disorder and schizophrenia. Med Gas Res. 2013;3(1):11.

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Anderson G, Beischlag TV, Vinciguerra M, Mazzoccoli G. The circadian clock circuitry and the AHR signaling pathway in physiology and pathology. Biochem Pharmacol. 2013;85:1405–16.

    CAS  PubMed  Google Scholar 

  76. Maes M. The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro Endocrinol Lett. 2008;29(3):287–91.

    CAS  PubMed  Google Scholar 

  77. Berk M. Neuroprogression: pathways to progressive brain changes in bipolar disorder. Int J Neuropsychopharmacol. 2009;12(4):441–5.

    CAS  PubMed  Google Scholar 

  78. Moylan S, Maes M, Wray NR, et al. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry. 2013;18(5):595–606.

    CAS  PubMed  Google Scholar 

  79. Maes M, Kubera M, Mihaylova I, et al. Increased autoimmune responses against auto-epitopes modified by oxidative and nitrosative damage in depression: implications for the pathways to chronic depression and neuroprogression. J Affect Disord. 2013;149:23–9.

    CAS  PubMed  Google Scholar 

  80. Dodd S, Berk M, Kelin K, et al. Treatment response for acute depression is not associated with number of previous episodes: lack of evidence for a clinical staging model for major depressive disorder. J Affect Disord. 2013;150:344–9.

    PubMed  Google Scholar 

  81. Maes M, Bosmans E, De Jongh R, et al. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine. 1997;9(11):853–8.

    CAS  PubMed  Google Scholar 

  82. Anttila S, Huuhka K, Huuhka M, et al. Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression. J Neural Transm. 2007;114(8):1065–8.

    CAS  PubMed  Google Scholar 

  83. Morris G, Anderson G, Berk M, et al. Coenzyme Q10 depletion in medical and neuropsychiatric disorders: potential repercussions and therapeutic implications. Mol Neurobiol. 2013 (in press).

  84. Maes M, Vandoolaeghe E, Neels H, et al. Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness. Biol Psychiatry. 1997;42(5):349–58.

    CAS  PubMed  Google Scholar 

  85. Yalcin A, Kilinc E, Kocturk S, et al. Effect of melatonin cotreatment against kainic acid on coenzyme Q10, lipid peroxidation and Trx mRNA in rat hippocampus. Int J Neurosci. 2004;114(9):1085–97.

    CAS  PubMed  Google Scholar 

  86. Liu YJ, Meng FT, Wang LL, Zhang LF, Cheng XP, Zhou JN. Apolipoprotein E influences melatonin biosynthesis by regulating NAT and MAOA expression in C6 cells. J Pineal Res. 2012;52(4):397–402.

    CAS  PubMed  Google Scholar 

  87. Pontes GN, Cardoso EC, Carneiro-Sampaio MM, et al. Pineal melatonin and the innate immune response: the TNF-alpha increase after cesarean section suppress nocturnal melatonin production. J Pineal Res. 2007;43:365–71.

    CAS  PubMed  Google Scholar 

  88. Wolkowitz OM, Mellon SH, Epel ES, et al. Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress: preliminary findings. PLoS ONE. 2011;6(3):e17837.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Martín M, Macías M, León J, et al. Melatonin increases the activity of the oxidative phosphorylation enzymes and the production of ATP in rat brain and liver mitochondria. Int J Biochem Cell Biol. 2002;34(4):348–57.

    PubMed  Google Scholar 

  90. Galecka E, Szemraj J, Florkowski A, et al. Single nucleotide polymorphisms and mRNA expression for melatonin MT(2) receptor in depression. Psychiatry Res. 2011;189(3):472–4.

    CAS  PubMed  Google Scholar 

  91. Maes M, Mihaylova I, Kubera M, et al. Activation of cell-mediated immunity in depression: association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2012;36(1):169–75.

    PubMed  Google Scholar 

  92. Maes M, Ombelet W, De Jongh R, Kenis G, Bosmans E. The inflammatory response following delivery is amplified in women who previously suffered from major depression, suggesting that major depression is accompanied by a sensitization of the inflammatory response system. J Affect Disord. 2001;63(1–3):85–92.

    CAS  PubMed  Google Scholar 

  93. Bate C, Kempster S, Last V, et al. Interferon-gamma increases neuronal death in response to amyloid-beta 1-42. J Neuroinflamm. 2006;3:7.

    Google Scholar 

  94. Portella MJ, de Diego-Adeliño J, Ballesteros J, et al. Can we really accelerate and enhance the selective serotonin reuptake inhibitor antidepressant effect? A randomized clinical trial and a meta-analysis of pindolol in nonresistant depression. J Clin Psychiatry. 2011;72(7):962–9.

    PubMed  Google Scholar 

  95. Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, Lalla D, Woolley M, Jahreis A, Zitnik R, Cella D, Krishnan R. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367:29–35.

    CAS  PubMed  Google Scholar 

  96. Lichtenstein GR, Bala M, Han C, DeWoody K, Schaible T. Infliximab improves quality of life in patients with Crohn’s disease. Inflamm Bowel Dis. 2002;8:237–43.

    PubMed  Google Scholar 

  97. Kasper S, Corruble E, Hale A, et al. Antidepressant efficacy of agomelatine versus SSRI/SNRI: results from a pooled analysis of head-to-head studies without a placebo control. Int Clin Psychopharmacol. 2013;28(1):12–9.

    PubMed  Google Scholar 

  98. Gałecki P, Szemraj J, Bienkiewicz M, et al. Oxidative stress parameters after combined fluoxetine and acetylsalicylic acid therapy in depressive patients. Hum Psychopharmacol. 2009;24:277–86.

    PubMed  Google Scholar 

  99. Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 2006;21(4):227–31.

    PubMed  Google Scholar 

  100. Samuni Y, Goldstein S, Dean OM, et al. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta. 2013;1830(8):4117–29.

    CAS  PubMed  Google Scholar 

  101. Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder: a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64(6):468–75.

    CAS  PubMed  Google Scholar 

  102. Arent CO, Réus GZ, Abelaira HM, et al. Synergist effects of n-acetylcysteine and deferoxamine treatment on behavioral and oxidative parameters induced by chronic mild stress in rats. Neurochem Int. 2012;61(7):1072–80.

    CAS  PubMed  Google Scholar 

  103. Lee YJ, Choi B, Lee EH, et al. Immobilization stress induces cell death through production of reactive oxygen species in the mouse cerebral cortex. Neurosci Lett. 2006;392(1–2):27–31.

    CAS  PubMed  Google Scholar 

  104. Posser T, Kaster MP, Baraúna SC, et al. Antidepressant-like effect of the organoselenium compound ebselen in mice: evidence for the involvement of the monoaminergic system. Eur J Pharmacol. 2009;602(1):85–91.

    CAS  PubMed  Google Scholar 

  105. McMartin SE, Jacka FN, Colman I. The association between fruit and vegetable consumption and mental health disorders: evidence from five waves of a national survey of Canadians. Prev Med. 2013;56(3–4):225–30.

    PubMed  Google Scholar 

  106. Payne ME, Steck SE, George RR, et al. Fruit, vegetable, and antioxidant intakes are lower in older adults with depression. J Acad Nutr Diet. 2012;112(12):2022–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Lakhwani L, Tongia SK, Pal VS, et al. Omega-3 fatty acids have antidepressant activity in forced swimming test in Wistar rats. Acta Pol Pharm. 2007;64(3):271–6.

    CAS  PubMed  Google Scholar 

  108. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007;68(7):1056–61.

    CAS  PubMed  Google Scholar 

  109. Siwek M, Dudek D, Paul IA, et al. Zinc supplementation augments efficacy of imipramine in treatment resistant patients: a double blind, placebo-controlled study. J Affect Disord. 2009;118(1–3):187–95.

    CAS  PubMed  Google Scholar 

  110. Pae CU, Marks DM, Han C, et al. Does minocycline have antidepressant effect? Biomed Pharmacother. 2008;62(5):308–11.

    CAS  PubMed  Google Scholar 

  111. Molina-Hernandez M, Tellez-Alcantara NP, Perez-Garcıa J, et al. Antidepressant-like actions of minocycline combined with several glutamate antagonists. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(2):380–6.

    CAS  PubMed  Google Scholar 

  112. Müller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006;11:680–4.

    PubMed  Google Scholar 

  113. Maes M. Targeting cyclooxygenase-2 in depression is not a viable therapeutic approach and may even aggravate the pathophysiology underpinning depression. Metab Brain Dis. 2012;27(4):405–13.

    CAS  PubMed  Google Scholar 

  114. Ji H, Wang H, Zhang F, Li X, Xiang L, Aiguo S. PPARγ agonist pioglitazone inhibits microglia inflammation by blocking p38 mitogen-activated protein kinase signaling pathways. Inflamm Res. 2010;59(11):921–9.

    CAS  PubMed  Google Scholar 

  115. Kashani L, Omidvar T, Farazmand B, et al. Does pioglitazone improve depression through insulin-sensitization? Results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression. Psychoneuroendocrinology. 2013;38(6):767–76.

    CAS  PubMed  Google Scholar 

  116. Bilici M, Efe H, Körogglu MA, et al. Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments. J Affect Disord. 2001;64(1):43–51.

    CAS  PubMed  Google Scholar 

  117. Anderson G, Rodriguez M. Multiple sclerosis, seizures and anti-epileptics: role of IL-18, IDO and melatonin. Eur J Neurol. 2011;18(5):680–5.

    CAS  PubMed  Google Scholar 

  118. Iwata M, Ota KT, Duman RS. The inflammasome: pathway linking psychological stress, depression, and systemic illnesses. Brain Behav Immun. 2013;31:105–14.

    CAS  PubMed  Google Scholar 

  119. Chakraborty S, Kaushik DK, Gupta M, Basu A. Inflammasome signaling at the heart of central nervous system pathology. J Neurosci Res. 2010;88(8):1615–31.

    CAS  PubMed  Google Scholar 

  120. Anderson G, Kubera M, Maes M. IL-6 and depression: role of IDO, MeCP2 1018 and local melatonin. Pharm Rep. 2013 (in press).

  121. Sharma R, Ottenhof T, Rzeczkowska PA, et al. Epigenetic targets for melatonin: induction of histone H3 hyperacetylation and gene expression in C17.2 neural stem cells. J Pineal Res. 2008;45(3):277–84.

    CAS  PubMed  Google Scholar 

  122. Dandrea M, Donadelli M, Costanzo C, et al. MeCP2/H3meK9 are involved in IL-6 gene silencing in pancreatic adenocarcinoma cell lines. Nucleic Acids Res. 2009;37(20):6681–90.

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Funakoshi H, Kanai M, Nakamura T. Modulation of tryptophan metabolism, promotion of neurogenesis and alteration of anxiety-related behavior in tryptophan 2,3-dioxygenase-deficient mice. Int J Tryptophan Res. 2011;4:7–18.

    CAS  PubMed Central  Google Scholar 

  124. Wischmeyer PE. Glutamine: role in gut protection in critical illness. Curr Opin Clin Nutr Metab Care. 2006;9(5):607–12.

    CAS  PubMed  Google Scholar 

  125. Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305–12.

    CAS  PubMed  Google Scholar 

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Acknowledgments

Authors’ contributions:

GA and MM participated in the design of this review, while all authors helped to draft the paper. All authors contributed equally to this paper. All authors read and approved the final version.

Conflict of interest

No specific funding was obtained for this specific review.

MBk has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon, Novartis, Mayne Pharma, and Servier, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay, and Wyeth, and served as a consultant to Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, and Servier. OMD has received grant support from the Brain and Behavior Foundation, Simons Autism Foundation, Cooperative Research Centre-Mental Health, Stanley Medical Research Institute, Lilly, and NHMRC, and received an ASBD/Servier grant.

The other authors, GA, MM, OD, and SM, declare that they have no competing interests.

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Authors and Affiliations

  1. CRC, Rm 30, 57 Laurel Street, Glasgow, G11 7QT, Scotland

    George Anderson

  2. IMPACT Strategic Research Centre and School of Medicine, Deakin University, Geelong, Australia

    Michael Berk, Olivia Dean, Steven Moylan & Michael Maes

  3. Department of Psychiatry, The University of Melbourne, Parkville, Australia

    Michael Berk & Olivia Dean

  4. Orygen Youth Health Research Centre, Parkville, Australia

    Michael Berk

  5. Florey Institute for Neuroscience and Mental Health, Parkville, Australia

    Michael Berk & Olivia Dean

  6. Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand

    Michael Maes

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  1. George Anderson
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  2. Michael Berk
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  3. Olivia Dean
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  4. Steven Moylan
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  5. Michael Maes
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Correspondence to Michael Maes.

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Anderson, G., Berk, M., Dean, O. et al. Role of Immune-Inflammatory and Oxidative and Nitrosative Stress Pathways in the Etiology of Depression: Therapeutic Implications. CNS Drugs 28, 1–10 (2014). https://doi.org/10.1007/s40263-013-0119-1

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