Neurotoxicity Research

, Volume 19, Issue 2, pp 308–318 | Cite as

Inflammatory Biomarkers and Depression

  • Norbert Müller
  • Aye-Mu Myint
  • Markus J. Schwarz


Antidepressants, predominantly serotonin- and/or noradrenaline reuptake inhibiting drugs have several shortcomings. The exact pathophysiological mechanisms leading to serotonergic-, noradrenergic- or dopaminergic dysfunction are still unclear. An inflammatory mechanism has been postulated and will be discussed here including possible therapeutic advantages of cyclooxygenase-2 (COX-2) inhibitors. Differences in the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and in the tryptophan–kynurenine metabolism resulting in an increased tryptophan and serotonin degradation and probably in an increased production of quinolinic acid might play a key role in major depression (MD). These differences are associated with an imbalance in the glutamatergic neurotransmission, which may contribute to an overweight of N-methyl-d-aspartate agonism in MD. The immunological imbalance results in an increased prostaglandin E2 production and probably also in an increased COX-2 expression. Although there is strong evidence for the view that the interactions of the immune system, IDO, the serotonergic system and the glutamatergic neurotransmission play a key role in MD, several gaps, e.g. the roles of genetics, disease course, sex, different psychopathological states, etc., have to be bridged by intense further research. There were already hints that anti-inflammatory therapy might have beneficial effects in MD. COX-2 inhibitors, however, have been tested in animal models and in preliminary clinical studies showing favourable effects compared to placebo in MD. The effects of COX-2 inhibition in the CNS as well as the different components of the inflammatory system, the kynurenine-metabolism and the glutamatergic neurotransmission, however, still need careful further scientific evaluation including clinical studies in bigger samples of patients.


Cyclooxygenase-2 Major depression Inflammation Psychoneuroimmunology Antidepressant 


  1. Akhondzadeh S, Jafari S, Raisi F et al (2009) A clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety 26:607–611PubMedGoogle Scholar
  2. Alberati GD, Ricciardi CP, Kohler C, Cesura AM (1996) Regulation of the kynurenine metabolic pathway by interferon-gamma in murine cloned macrophages and microglial cells. J Neurochem 66:996–1004Google Scholar
  3. Altamura CA, Mauri MC, Ferrara A, Moro AR, D’Andrea G, Zamberlan F (1993) Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry 150:1731–1733PubMedGoogle Scholar
  4. Bacher M, Meinhardt A, Lan HY, Dhabhar FS, Mu W, Metz CN, Chesney JA, Gemsa D, Donnelly T, Atkins RC, Bucala R (1998) MIF expression in the rat brain: implications for neuronal function. Mol Med 4:217–230PubMedGoogle Scholar
  5. Banks WA, Kastin AJ, Broadwell RD (1995) Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation 2:241–248PubMedGoogle Scholar
  6. Baron DA, Hardie T, Baron SH (1993) Possible association of interleukin-2 treatment with depression and suicide. J Am Osteopath Assoc 93:799–800PubMedGoogle Scholar
  7. Begemann M, Sargin D, Rossner MJ, Bartels C, Theis F, Wichert SP, Stender N, Fischer B, Sperling S, Stawicki S, Wiedl A, Falkai P, Nave KA, Ehrenreich H (2008) Episode-specific differential gene expression of peripheral blood mononuclear cells in rapid cycling supports novel treatment approaches. Mol Med 14:546–552PubMedGoogle Scholar
  8. Berk M, Wadee AA, Kuschke RH, O’Neill-Kerr A (1997) Acute phase proteins in major depression. J Psychosom Res 43:529–534PubMedGoogle Scholar
  9. Berkenbosch F, van Oers J, del Rey A, Tilders F, Besedovsky H (1987) Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science 238:524–526PubMedGoogle Scholar
  10. Besedovsky H, del Rey A, Sorkin E, Dinarello CA (1986) Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 233:652–654PubMedGoogle Scholar
  11. Bonaccorso S, Lin AH, Verkerk R, Van Hunsel F, Libbrecht I, Scharpe S, DeClerck L, Biondi M, Janca A, Maes M (1998) Immune markers in fibromyalgia: comparison with major depressed patients and normal volunteers. J Affect Disord 48:75–82PubMedGoogle Scholar
  12. Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M, Almerighi C, Verkerk R, Meltzer H, Maes M (2002) Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol 22:86–90PubMedGoogle Scholar
  13. Brambilla F, Maggioni M (1998) Blood levels of cytokines in elderly patients with major depressive disorder. Acta Psychiatr Scand 97:309–313PubMedGoogle Scholar
  14. Brambilla F, Monteleone P, Maj M (2004) Interleukin-1beta and tumor necrosis factor-alpha in children with major depressive disorder or dysthymia. J Affect Disord 78:273–277PubMedGoogle Scholar
  15. Braun D, Longman RS, Albert ML (2005) A two-step induction of indoleamine 2,3-dioxygenase (IDO) activity during dendritic-cell maturation. Blood 106:2375–2381PubMedGoogle Scholar
  16. Brunello N, Alboni S, Capone G, Benatti C, Blom JM, Tascedda F, Kriwin P, Mendlewicz J (2006) Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression. Int Clin Psychopharmacol 21:219–225PubMedGoogle Scholar
  17. Buchanan RW, Javitt DC, Marder SR, Schooler NR, Gold JM, McMahon RP, Heresco-Levy U, Carpenter WT (2007) The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry 164:1593–1602PubMedGoogle Scholar
  18. Burke HM, Davis MC, Otte C, Mohr DC (2005) Depression and cortisol responses to psychological stress: a meta-analysis. Psychoneuroendocrinology 30:846–856PubMedGoogle Scholar
  19. Calabrese JR, Skwerer RG, Barna B, Gulledge AD, Valenzuela R, Butkus A, Subichin S, Krupp NE (1986) Depression, immunocompetence, and prostaglandins of the E series. Psychiatry Res 17:41–47PubMedGoogle Scholar
  20. Campbell S, Macqueen G (2004) The role of the hippocampus in the pathophysiology of major depression. J Psychiatry Neurosci 29:417–426PubMedGoogle Scholar
  21. Cao C, Matsumura K, Ozaki M, Watanabe Y (1999) Lipopolysaccharide injected into the cerebral ventricle evokes fever through induction of cyclooxygenase-2 in brain endothelial cells. J Neurosci 19:716–725PubMedGoogle Scholar
  22. Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, Miller AH (2003) Interferon-alpha-induced changes in tryptophan metabolism. Relationship to depression and paroxetine treatment. Biol Psychiatry 54:906–914PubMedGoogle Scholar
  23. Casolini P, Catalani A, Zuena AR, Angelucci L (2002) Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat. J Neurosci Res 68:337–343PubMedGoogle Scholar
  24. Cizza G, Eskandari F, Coyle M, Krishnamurthy P, Wright EC, Mistry S, Csako G (2009) Plasma CRP levels in premenopausal women with major depression: a 12-month controlled study. Horm Metab Res 41:641–648Google Scholar
  25. Collantes-Esteves E, Fernandez-Perrez Ch (2003) Improved self-control of ostheoarthritis pain and self-reported health status in non-responders to celecoxib switched to rofecoxib: results of PAVIA, an open-label post-marketing survey in Spain. Curr Med Res Opin 19:402–410Google Scholar
  26. Coppen A, Swade C (1988) 5-HT and depression: the present position. In: Briley M, Fillion G (eds) New concepts in depression. MacMillan Press, London, pp 120–136Google Scholar
  27. Coric V, Milanovic S, Wasylink S, Patel P, Malison R, Krystal JH (2003) Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder. Psychopharmacology (Berl) 167:219–220Google Scholar
  28. Crane GE (1959) Cyloserine as an antidepressant agent. Am J Psychiatry 115:1025–1026PubMedGoogle Scholar
  29. Danner M, Kasl SV, Abramson JL, Vaccarino V (2003) Association between depression and elevated C-reactive protein. Psychosom Med 65:347–356PubMedGoogle Scholar
  30. Dantzer R (2001) Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 15:7–24PubMedGoogle Scholar
  31. Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer W, Versnel MA, Drexhage HA (2010) The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert Rev Neurother 10:59–76PubMedGoogle Scholar
  32. Duch DS, Woolf JH, Nichol CA, Davidson JR, Garbutt JC (1984) Urinary excretion of biopterin and neopterin in psychiatric disorders. Psychiatry Res 11:83–89PubMedGoogle Scholar
  33. Dunbar PR, Hill J, Neale TJ, Mellsop GW (1992) Neopterin measurement provides evidence of altered cell-mediated immunity in patients with depression, but not with schizophrenia. Psychol Med 22:1051–1057PubMedGoogle Scholar
  34. Ershler WB, Sun WH, Binkley N, Gravenstein S, Volk MJ, Kamoske G, Klopp RG, Roecker EB, Daynes RA, Weindruch R (1993) Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction. Lymphokine Cytokine Res 12:225–230PubMedGoogle Scholar
  35. Fertuzinhos SM, Oliveira JR, Nishimura AL, Pontual D, Carvalho DR, Sougey EB, Otto PA, Zatz M (2004) Analysis of IL-1alpha, IL-1beta, and IL-1RA [correction of IL-RA] polymorphisms in dysthymia. J Mol Neurosci 22:251–256PubMedGoogle Scholar
  36. Ford DE, Erlinger TP (2004) Depression and C-reactive protein in US adults: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 164:1010–1014PubMedGoogle Scholar
  37. Frizzo ME, Dall’Onder LP, Dalcin KB, Souza DO (2004) Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell Mol Neurobiol 24:123–128PubMedGoogle Scholar
  38. Frommberger UH, Bauer J, Haselbauer P, Fraulin A, Riemann D, Berger M (1997) Interleukin-6-(IL-6) plasma levels in depression and schizophrenia: comparison between the acute state and after remission. Eur Arch Psychiatry Clin Neurosci 247:228–233PubMedGoogle Scholar
  39. Gabay C, Kushner I (1999) Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340:448–454PubMedGoogle Scholar
  40. Gimeno D, Marmot MG, Singh-Manoux A (2008) Inflammatory markers and cognitive function in middle-aged adults: the Whitehall II study. Psychoneuroendocrinology 33:1322–1334PubMedGoogle Scholar
  41. Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kuhn M, Schuld A, Pollmacher T (1999) Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res 33:407–418PubMedGoogle Scholar
  42. Häfner S, Baghai TC, Eser D, Schule C, Rupprecht R, Bondy B, Bedarida G, von SC (2008) C-reactive protein is associated with polymorphisms of the angiotensin-converting enzyme gene in major depressed patients. J Psychiatr Res 42:163–165PubMedGoogle Scholar
  43. Hasler G, Drevets WC, Manji HK, Charney DS (2004) Discovering endophenotypes for major depression. Neuropsychopharmacology 29:1765–1781PubMedGoogle Scholar
  44. Herbert TB, Cohen S (1993) Depression and immunity: a meta-analytic review. Psychol Bull 113:472–486PubMedGoogle Scholar
  45. Hestad KA, Tonseth S, Stoen CD, Ueland T, Aukrust P (2003) Raised plasma levels of tumor necrosis factor alpha in patients with depression: normalization during electroconvulsive therapy. J ECT 19:183–188PubMedGoogle Scholar
  46. Himmerich H, Fulda S, Linseisen J, Seiler H, Wolfram G, Himmerich S, Gedrich K, Kloiber S, Lucae S, Ising M, Uhr M, Holsboer F, Pollmacher T (2008) Depression, comorbidities and the TNF-alpha system. Eur Psychiatry 23:421–429PubMedGoogle Scholar
  47. Hu F, Wang X, Pace TW, Wu H, Miller AH (2005) Inhibition of COX-2 by celecoxib enhances glucocorticoid receptor function. Mol Psychiatry 10:426–428PubMedGoogle Scholar
  48. Huber TJ, Dietrich DE, Emrich HM (1999) Possible use of amantadine in depression. Pharmacopsychiatry 32:47–55PubMedGoogle Scholar
  49. Irwin M (1999) Immune correlates of depression. Adv Exp Med Biol 461:1–24PubMedGoogle Scholar
  50. Jun TY, Pae CU, Hoon H, Chae JH, Bahk WM, Kim KS, Serretti A (2003) Possible association between -G308A tumour necrosis factor-alpha gene polymorphism and major depressive disorder in the Korean population. Psychiatr Genet 13:179–181PubMedGoogle Scholar
  51. Katila H, Appelberg B, Hurme M, Rimon R (1994) Plasma levels of interleukin-1 beta and interleukin-6 in schizophrenia, other psychoses, and affective disorders. Schizophr Res 12:29–34PubMedGoogle Scholar
  52. Kim JS, Schmid-Burgk W, Claus D, Kornhuber HH (1982) Increased serum glutamate in depressed patients. Arch Psychiatr Nervenkr 232:299–304PubMedGoogle Scholar
  53. Kling MA, Alesci S, Csako G, Costello R, Luckenbaugh DA, Bonne O, Duncko R, Drevets WC, Manji HK, Charney DS, Gold PW, Neumeister A (2007) Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A. Biol Psychiatry 62:309–313PubMedGoogle Scholar
  54. Kudoh A, Takahira Y, Katagai H, Takazawa T (2002) Small-dose ketamine improves the postoperative state of depressed patients. Anesth Analg 95:114–118 TablePubMedGoogle Scholar
  55. Kugaya A, Sanacora G (2005) Beyond monoamines: glutamatergic function in mood disorders. CNS Spectr 10:808–819PubMedGoogle Scholar
  56. Kwidzinski E, Bunse J, Aktas O, Richter D, Mutlu L, Zipp F, Nitsch R, Bechmann I (2005) Indolamine 2,3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation. FASEB J 19:1347–1349PubMedGoogle Scholar
  57. Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H (2000) Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 22:370–379PubMedGoogle Scholar
  58. Leonard BE, Myint A (2006) Inflammation and depression: is there a causal connection with dementia? Neurotox Res 10:149–160PubMedGoogle Scholar
  59. Lidberg L, Belfrage H, Bertilsson L, Evenden MM, Asberg M (2000) Suicide attempts and impulse control disorder are related to low cerebrospinal fluid 5-HIAA in mentally disordered violent offenders. Acta Psychiatr Scand 101:395–402PubMedGoogle Scholar
  60. Lin PY, Su KP (2007) A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry 68:1056–1061PubMedGoogle Scholar
  61. Linnoila M, Whorton AR, Rubinow DR, Cowdry RW, Ninan PT, Waters RN (1983) CSF prostaglandin levels in depressed and schizophrenic patients. Arch Gen Psychiatry 40:405–406PubMedGoogle Scholar
  62. Madrigal JL, Garcia-Bueno B, Moro MA, Lizasoain I, Lorenzo P, Leza JC (2003) Relationship between cyclooxygenase-2 and nitric oxide synthase-2 in rat cortex after stress. Eur J Neurosci 18:1701–1705PubMedGoogle Scholar
  63. Maes M, Scharpe S, Meltzer HY, Bosmans E, Suy E, Calabrese J, Cosyns P (1993) Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression. Psychiatry Res 49:11–27PubMedGoogle Scholar
  64. Maes M, Scharpe S, Meltzer HY, Okayli G, Bosmans E, D’Hondt P, Vanden Bossche BV, Cosyns P (1994) Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response. Psychiatry Res 54:143–160PubMedGoogle Scholar
  65. Maes M, Meltzer HY, Bosmans E, Bergmans R, Vandoolaeghe E, Ranjan R, Desnyder R (1995a) Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord 34:301–309PubMedGoogle Scholar
  66. Maes M, Meltzer HY, Buckley P, Bosmans E (1995b) Plasma-soluble interleukin-2 and transferrin receptor in schizophrenia and major depression. Eur Arch Psychiatry Clin Neurosci 244:325–329PubMedGoogle Scholar
  67. Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H (1997) Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 9:853–858PubMedGoogle Scholar
  68. Maes M, Verkerk R, Vandoolaeghe E, Lin A, Scharpe S (1998) Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment-resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivity. Acta Psychiatr Scand 97:302–308PubMedGoogle Scholar
  69. Maj J, Rogoz Z, Skuza G, Sowinska H (1992) Effects of MK-801 and antidepressant drugs in the forced swimming test in rats. Eur Neuropsychopharmacol 2:37–41PubMedGoogle Scholar
  70. Mann JJ, Malone KM (1997) Cerebrospinal fluid amines and higher-lethality suicide attempts in depressed inpatients. Biol Psychiatry 41:162–171PubMedGoogle Scholar
  71. Martin P, Carlsson ML, Hjorth S (1998) Systemic PCP treatment elevates brain extracellular 5-HT: a microdialysis study in awake rats. Neuroreport 9:2985–2988PubMedGoogle Scholar
  72. Matussek N (1966) Neurobiologie und depression. Med Monatsschr 3:109–112Google Scholar
  73. Matussek N (1988) Catecholamines and mood: neuroendocrine aspects. In: Ganten D, Pfaff D (eds) Current topics in neuroendocrinology. Springer, Heidelberg, pp 141–181Google Scholar
  74. Mauri MC, Ferrara A, Boscati L, Bravin S, Zamberlan F, Alecci M, Invernizzi G (1998) Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment. Neuropsychobiology 37:124–129PubMedGoogle Scholar
  75. Mellor AL, Munn DH (1999) Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today 20:469–473PubMedGoogle Scholar
  76. Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N (2006) Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol 21:227–231PubMedGoogle Scholar
  77. Mendlovic S, Mozes E, Eilat E, Doron A, Lereya J, Zakuth V, Spirer Z (1999) Immune activation in non-treated suicidal major depression. Immunol Lett 67:105–108PubMedGoogle Scholar
  78. Mikova O, Yakimova R, Bosmans E, Kenis G, Maes M (2001) Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis. Eur Neuropsychopharmacol 11:203–208PubMedGoogle Scholar
  79. Moghaddam B, Bolinao ML, Stein-Behrens B, Sapolsky R (1994) Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Res 655:251–254PubMedGoogle Scholar
  80. Müller N, Schwarz MJ (2002) Immunology in anxiety and depression. In: Kasper S, den Boer JA, Sitsen JMA (eds) Handbook of depression and anxiety. Marcel Dekker, New York, pp 267–288Google Scholar
  81. Müller N, Schwarz MJ (2007a) The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry 12:988–1000PubMedGoogle Scholar
  82. Müller N, Schwarz MJ (2007b) The immunological basis of glutamatergic disturbance in schizophrenia: towards an integrated view. J Neurotransmission Suppl 72:269–280Google Scholar
  83. Müller N, Hofschuster E, Ackenheil M, Mempel W, Eckstein R (1993) Investigations of the cellular immunity during depression and the free interval: evidence for an immune activation in affective psychosis. Prog Neuropsychopharmacol Biol Psychiatry 17:713–730PubMedGoogle Scholar
  84. Müller N, Riedel M, Scheppach C, Brandstätter B, Sokullu S, Krampe K, Ulmschneider M, Engel RR, Möller HJ, Schwarz MJ (2002) Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry 159:1029–1034PubMedGoogle Scholar
  85. Müller N, Schwarz MJ, Dehning S, Douhet A, Cerovecki A, Goldstein-Müller B, Spellmann I, Hetzel G, Maino K, Kleindienst N, Möller HJ, Arolt V, Riedel M (2006) 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 11:680–684PubMedGoogle Scholar
  86. Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL (1999) Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 189:1363–1372PubMedGoogle Scholar
  87. Myint AM, Steinbusch HW, Goeghegan L, Luchtman D, Kim YK, Leonard BE (2007) Effect of the COX-2 inhibitor celecoxib on behavioural and immune changes in an olfactory bulbectomised rat model of depression. Neuroimmunomodulation 14:65–71PubMedGoogle Scholar
  88. Nair A, Bonneau RH (2006) Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation. J Neuroimmunol 171:72–85PubMedGoogle Scholar
  89. Nassberger L, Traskman-Bendz L (1993) Increased soluble interleukin-2 receptor concentrations in suicide attempters. Acta Psychiatr Scand 88:48–52PubMedGoogle Scholar
  90. Nery FG, Monkul ES, Hatch JP, Fonseca M, Zunta-Soares GB, Frey BN, Bowden CL, Soares JC (2008) Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum Psychopharmacol 23:87–94PubMedGoogle Scholar
  91. Nguyen KT, Deak T, Owens SM, Kohno T, Fleshner M, Watkins LR, Maier SF (1998) Exposure to acute stress induces brain interleukin-1beta protein in the rat. J Neurosci 18:2239–2246PubMedGoogle Scholar
  92. Niino M, Ogata A, Kikuchi S, Tashiro K, Nishihira J (2000) Macrophage migration inhibitory factor in the cerebrospinal fluid of patients with conventional and optic-spinal forms of multiple sclerosis and neuro-Behcet’s disease. J Neurol Sci 179:127–131PubMedGoogle Scholar
  93. Nordstrom P, Samuelsson M, Asberg M, Traskman BL, Aberg WA, Nordin C, Bertilsson L (1994) CSF 5-HIAA predicts suicide risk after attempted suicide. Suicide Life Threat Behav 24:1–9PubMedGoogle Scholar
  94. Nowak G, Ordway GA, Paul IA (1995) Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res 675:157–164PubMedGoogle Scholar
  95. Nudmamud-Thanoi S, Reynolds GP (2004) The NR1 subunit of the glutamate/NMDA receptor in the superior temporal cortex in schizophrenia and affective disorders. Neurosci Lett 372:173–177PubMedGoogle Scholar
  96. Nunes SOV, Reiche EMV, Morimoto HK, Matsuo T, Itano EN, Xavier ECD, Yamashita CM, Vieira VR, Menoli AV, Silva SS, Costa FB, Reiche FV, Silva FLV, Kaminami MS (2002) Immune and hormonal activity in adults suffering from depression. Braz J Med Biol Res 35:581–587PubMedGoogle Scholar
  97. O’Brien SM, Scott LV, Dinan TG (2004) Cytokines: abnormalities in major depression and implications for pharmacological treatment. Hum Psychopharmacol 19:397–403PubMedGoogle Scholar
  98. Ohishi K, Ueno R, Nishino S, Sakai T, Hayaishi O (1988) Increased level of salivary prostaglandins in patients with major depression. Biol Psychiatry 23:326–334PubMedGoogle Scholar
  99. Olsson SK, Andersson AS, Linderholm KR, Holtze M, Nilsson-Todd LK, Schwieler L, Olsson E, Larsson K, Engberg G, Erhardt S (2009) Elevated levels of kynurenic acid change the dopaminergic response to amphetamine: implications for schizophrenia. Int J Neuropsychopharmacol 12:501–512PubMedGoogle Scholar
  100. Ossowska G, Klenk-Majewska B, Szymczyk G (1997) The effect of NMDA antagonists on footshock-induced fighting behavior in chronically stressed rats. J Physiol Pharmacol 48:127–135PubMedGoogle Scholar
  101. Ostroff R, Gonzales M, Sanacora G (2005) Antidepressant effect of ketamine during ECT. Am J Psychiatry 162:1385–1386PubMedGoogle Scholar
  102. Ovaskainen Y, Koponen H, Jokelainen J, Keinanen-Kiukaanniemi S, Kumpusalo E, Vanhala M (2009) Depressive symptomatology is associated with decreased interleukin-1 beta and increased interleukin-1 receptor antagonist levels in males. Psychiatry Res 167:73–79PubMedGoogle Scholar
  103. Padmos RC, Hillegers MH, Knijff EM, Vonk R, Bouvy A, Staal FJ, de RD, Kupka RW, Nolen WA, Drexhage HA (2008) A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. Arch Gen Psychiatry 65:395–407PubMedGoogle Scholar
  104. Penttinen J (1995) Hypothesis: low serum cholesterol, suicide, and interleukin-2. Am J Epidemiol 141:716–718PubMedGoogle Scholar
  105. Plata-Salaman CR (1991) Immunoregulators in the nervous system. Neurosci Biobehav Rev 15:185–215PubMedGoogle Scholar
  106. Pugh CR, Nguyen KT, Gonyea JL, Fleshner M, Wakins LR, Maier SF, Rudy JW (1999) Role of interleukin-1 beta in impairment of contextual fear conditioning caused by social isolation. Behav Brain Res 106:109–118PubMedGoogle Scholar
  107. Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, Pollmacher T (2001) Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 58:445–452PubMedGoogle Scholar
  108. Reichenberg A, Kraus T, Haack M, Schuld A, Pollmacher T, Yirmiya R (2002) Endotoxin-induced changes in food consumption in healthy volunteers are associated with TNF-alpha and IL-6 secretion. Psychoneuroendocrinology 27:945–956PubMedGoogle Scholar
  109. Robinson CM, Hale PT, Carlin JM (2005) The role of IFN-gamma and TNF-alpha-responsive regulatory elements in the synergistic induction of indoleamine dioxygenase. J Interferon Cytokine Res 25:20–30PubMedGoogle Scholar
  110. Rosa A, Peralta V, Papiol S, Cuesta MJ, Serrano F, Martinez-Larrea A, Fananas L (2004) Interleukin-1beta (IL-1beta) gene and increased risk for the depressive symptom-dimension in schizophrenia spectrum disorders. Am J Med Genet B Neuropsychiatr Genet 124:10–14Google Scholar
  111. Rothermundt M, Arolt V, Fenker J, Gutbrodt H, Peters M, Kirchner H (2001a) Different immune patterns in melancholic and non-melancholic major depression. Eur Arch Psychiatry Clin Neurosci 251:90–97PubMedGoogle Scholar
  112. Rothermundt M, Arolt V, Peters M, Gutbrodt H, Fenker J, Kersting A, Kirchner H (2001b) Inflammatory markers in major depression and melancholia. J Affect Disord 63:93–102PubMedGoogle Scholar
  113. Roy A, Pickar D, Paul S, Doran A, Chrousos GP, Gold PW (1987) CSF corticotropin-releasing hormone in depressed patients and normal control subjects. Am J Psychiatry 144:641–645PubMedGoogle Scholar
  114. Salzberg-Brenhouse HC, Chen EY, Emerich DF, Baldwin S, Hogeland K, Ranelli S, Lafreniere D, Perdomo B, Novak L, Kladis T, Fu K, Basile AS, Kordower JH, Bartus RT (2003) Inhibitors of cyclooxygenase-2, but not cyclooxygenase-1 provide structural and functional protection against quinolinic acid-induced neurodegeneration. J Pharmacol Exp Ther 306:218–228PubMedGoogle Scholar
  115. Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL, Krystal JH, Mason GF (2004a) Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61:705–713PubMedGoogle Scholar
  116. Sanacora G, Kendell SF, Fenton L, Coric V, Krystal JH (2004b) Riluzole augmentation for treatment-resistant depression. Am J Psychiatry 161:2132PubMedGoogle Scholar
  117. Sandrini M, Vitale G, Pini LA (2002) Effect of rofecoxib on nociception and the serotonin system in the rat brain. Inflamm Res 51:154–159PubMedGoogle Scholar
  118. Sapolsky RM (1985) A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults. J Neurosci 5:1228–1232PubMedGoogle Scholar
  119. Scarr E, Pavey G, Sundram S, MacKinnon A, Dean B (2003) Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. Bipolar Disord 5:257–264PubMedGoogle Scholar
  120. Schäfer M, Horn M, Schmidt F, Schmid-Wendtner MH, Volkenandt M, Ackenheil M, Müller N, Schwarz MJ (2004) Correlation between sICAM-1 and depressive symptoms during adjuvant treatment of melanoma with interferon-alpha. Brain Behav Immun 18:555–562Google Scholar
  121. Schiepers OJ, Wichers MC, Maes M (2005) Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 29:201–217PubMedGoogle Scholar
  122. Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H (1996a) Increased CD56+ natural killer cells and related cytokines in major depression. Clin Immunol Immunopathol 78:83–85PubMedGoogle Scholar
  123. Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H (1996b) Major depressive disorder is associated with elevated monocyte counts. Acta Psychiatr Scand 94:198–204PubMedGoogle Scholar
  124. Sluzewska A, Rybakowski J, Bosmans E, Sobieska M, Berghmans R, Maes M, Wiktorowicz K (1996) Indicators of immune activation in major depression. Psychiatry Res 64:161–167PubMedGoogle Scholar
  125. Smith RS (1991) The macrophage theory of depression. Med Hypotheses 35:298–306PubMedGoogle Scholar
  126. Song C, Leonard BE (2000) Fundamentals of psychoneuroimmunology. Wiley, ChichesterGoogle Scholar
  127. Song C, Lin A, Bonaccorso S, Heide C, Verkerk R, Kenis G, Bosmans E, Scharpe S, Whelan A, Cosyns P, De Jongh R, Maes M (1998) The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression. J Affect Disord 49:211–219PubMedGoogle Scholar
  128. Stein-Behrens BA, Lin WJ, Sapolsky RM (1994) Physiological elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus. J Neurochem 63:596–602PubMedGoogle Scholar
  129. Stryjer R, Strous RD, Shaked G, Bar F, Feldman B, Kotler M, Polak L, Rosenzcwaig S, Weizman A (2003) Amantadine as augmentation therapy in the management of treatment-resistant depression. Int Clin Psychopharmacol 18:93–96PubMedGoogle Scholar
  130. Sundar SK, Cierpial MA, Kilts C, Ritchie JC, Weiss JM (1990) Brain IL-1-induced immunosuppression occurs through activation of both pituitary-adrenal axis and sympathetic nervous system by corticotropin-releasing factor. J Neurosci 10:3701–3706PubMedGoogle Scholar
  131. Suzuki T, Ogata A, Tashiro K, Nagashima K, Tamura M, Yasui K, Nishihira J (2000) Japanese encephalitis virus up-regulates expression of macrophage migration inhibitory factor (MIF) mRNA in the mouse brain. Biochim Biophys Acta 1517:100–106PubMedGoogle Scholar
  132. Takahashi T, Kimoto T, Tanabe N, Hattori TA, Yasumatsu N, Kawato S (2002) Corticosterone acutely prolonged N-methyl-d-aspartate receptor-mediated Ca2+ elevation in cultured rat hippocampal neurons. J Neurochem 83:1441–1451PubMedGoogle Scholar
  133. Trullas R, Skolnick P (1990) Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 185:1–10PubMedGoogle Scholar
  134. Tuominen HJ, Tiihonen J, Wahlbeck K (2006) Glutamatergic drugs for schizophrenia. Cochrane Database Syst Rev 19:CD003730Google Scholar
  135. Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, Lalla D, Woolley M, Jahreis A, Zitnik R, Cella D, Krishnan R (2006) Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 367:29–35PubMedGoogle Scholar
  136. Vaccarino V, Brennan ML, Miller AH, Bremner JD, Ritchie JC, Lindau F, Veledar E, Su S, Murrah NV, Jones L, Jawed F, Dai J, Goldberg J, Hazen SL (2008) Association of major depressive disorder with serum myeloperoxidase and other markers of inflammation: a twin study. Biol Psychiatry 64:476–483PubMedGoogle Scholar
  137. Vadalouca A, Moka E, Chatzidimitriou A, Siafaka I, Sikioti P, Argyra E (2009) A randomized, double-blind, placebo-controlled study of preemptively administered intravenous parecoxib: effect on anxiety levels and procedural pain during epidural catheter placement for surgical operations or for chronic pain therapy. Pain Pract 9:181–194PubMedGoogle Scholar
  138. Weiss JM, Quan N, Sundar SK (1994) Immunological consequences of Interleukin-1 in the brain. Neuropsychopharmacol 10:833Google Scholar
  139. Weiss G, Murr C, Zoller H, Haun M, Widner B, Ludescher C, Fuchs D (1999) Modulation of neopterin formation and tryptophan degradation by Th1- and Th2-derived cytokines in human monocytic cells. Clin Exp Immunol 116:435–440PubMedGoogle Scholar
  140. Wirtz PH, Redwine LS, Linke S, Hong S, Rutledge T, Greenberg BH, Mills PJ (2010) Circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) independently predict depressive symptom severity after 12 months in heart failure patients. Brain Behav Immun 24:366–369PubMedGoogle Scholar
  141. Woolley CS, Gould E, McEwen BS (1990) Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 531:225–231PubMedGoogle Scholar
  142. Yan QS, Reith ME, Jobe PC, Dailey JW (1997) Dizocilpine (MK-801) increases not only dopamine but also serotonin and norepinephrine transmissions in the nucleus accumbens as measured by microdialysis in freely moving rats. Brain Res 765:149–158PubMedGoogle Scholar
  143. Yaron I, Shirazi I, Judovich R, Levartovsky D, Caspi D, Yaron M (1999) Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2, and hyaluronic acid production in human synovial cells and synovial tissue cultures. Arthritis Rheum 42:2561–2568PubMedGoogle Scholar
  144. Yilmaz A, Schulz D, Aksoy A, Canbeyli R (2002) Prolonged effect of an anesthetic dose of ketamine on behavioral despair. Pharmacol Biochem Behav 71:341–344PubMedGoogle Scholar
  145. Zarate CA Jr, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK (2004) An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry 161:171–174PubMedGoogle Scholar
  146. Zarate CA Jr, Quiroz JA, Singh JB, Denicoff KD, De Jesus G, Luckenbaugh DA, Charney DS, Manji HK (2005) An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry 57:430–432PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Norbert Müller
    • 1
  • Aye-Mu Myint
    • 1
  • Markus J. Schwarz
    • 1
  1. 1.Department of Psychiatry and PsychotherapyLudwig-Maximilians-Universität MünchenMünchenGermany

Personalised recommendations