Neurobiological Principles: Psycho-Neuro-Immuno-Endocrinology

Living reference work entry


Mental disorders have a complex pathophysiology that remains only partially understood. In addition to changes in neurotransmitter systems and receptors – the effector systems that act on downstream signal transduction processes – there is increasing evidence that immunological mechanisms play an important role in the pathophysiology of mental disorders. In recent decades, psycho-neuro-immuno-endocrinology, which is concerned with the relationships between mental functions, psychiatric disorders, the immune system, and endocrine mechanisms, has become an important topic in psychiatry. Meanwhile, initial attempts have been made to make use of such psycho-neuro-immunological mechanisms as novel treatment strategies.



The author thanks the foundation ‘Immunität & Seele’ for its support


  1. Abbasi SH, Hosseini F, Modabbernia A, Ashrafi M, Akhondzadeh S. Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo-controlled study. J Affect Disord. 2012;141:308–14.PubMedCrossRefGoogle Scholar
  2. Ader R, Felten DL. Psychoneuroimmunology. San Diego/New York/Toronto: Academic Press; 1991.Google Scholar
  3. Ahuja N, Carroll BT. Possible anti-catatonic effects of minocycline in patients with schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2007;31:968–9.CrossRefGoogle Scholar
  4. Akhondzadeh S, Tabatabaee M, Amini H, Ahmadi Abhari SA, Abbasi SH, Behnam B. Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophr Res. 2007;90:179–85.PubMedCrossRefGoogle Scholar
  5. Akhondzadeh S, Jafari S, Raisi F, Ghoreishi A. A clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Paper presented at the WPA Section on Immunology and psychiatry – psychoneuroimmunology training workshop, Seeon, Munich, 11–13 July 2008.Google Scholar
  6. Alonso R, Chaudieu I, Diorio J, Krishnamurthy A, Quirion R, Boksa P. Interleukin-2 modulates evoked release of [3H]dopamine in rat cultured mesencephalic cells. J Neurochem. 1993;61:1284–90.PubMedCrossRefGoogle Scholar
  7. Amminger GP, Schafer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67:146–54.PubMedCrossRefGoogle Scholar
  8. Araujo DM, Lapchak PA, Chabot JG, Nair NP, Quirion R. Characterization and possible role of growth factor and lymphokine receptors in the regulation of cholinergic function in the mammalian brain. Prog Clin Biol Res. 1989;317:423–36.PubMedGoogle Scholar
  9. Arolt V, Rothermundt M, Wandinger KP, Kirchner H. Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment. Mol Psychiatry. 2000;5:150–8.PubMedCrossRefGoogle Scholar
  10. Avgustin B, Wraber B, Tavcar R. Increased Th1 and Th2 immune reactivity with relative Th2 dominance in patients with acute exacerbation of schizophrenia. Croat Med J. 2005;46:268–74.PubMedPubMedCentralGoogle Scholar
  11. Baker GA, Santalo R, Blumenstein J. Effect of psychotropic agents upon the blastogenic response of human t-lymphocytes. Biol Psychiatry. 1977;12:159–69.PubMedPubMedCentralGoogle Scholar
  12. Balschun D, Wetzel W, Del Rey A, Pitossi F, Schneider H, Zuschratter W, et al. Interleukin-6: a cytokine to forget. FASEB J. 2004;18:1788–90.PubMedCrossRefPubMedCentralGoogle Scholar
  13. Bechter K, Reiber H, Herzog S, Fuchs D, Tumani H, Maxeiner HG. Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunction. J Psychiatr Res. 2010;44:321–30.PubMedCrossRefPubMedCentralGoogle Scholar
  14. Benicky J, Sanchez-Lemus E, Honda M, Pang T, Orecna M, Wang J, et al. Angiotensin II AT1 receptor blockade ameliorates brain inflammation. Neuropsychopharmacology. 2011;36:857–70.PubMedCrossRefPubMedCentralGoogle Scholar
  15. Benros ME, Mortensen PB, Eaton WW. Autoimmune diseases and infections as risk factors for schizophrenia. Ann N Y Acad Sci. 2012;1262:56–66.PubMedCrossRefPubMedCentralGoogle Scholar
  16. Benveniste EN. Inflammatory cytokines within the central nervous system: sources, function, and mechanism of action. Am J Phys. 1992;263:C1–16.CrossRefGoogle Scholar
  17. Berrios GE, Quemada JI. Depressive illness in multiple sclerosis. Clinical and theoretical aspects of the association. Br J Psychiatry. 1990;156:10–6.PubMedCrossRefPubMedCentralGoogle Scholar
  18. Bertini R, Garattini S, Delgado R, Ghezzi P. Pharmacological activities of chlorpromazine involved in the inhibition of tumour necrosis factor production in vivo in mice. Immunology. 1993;79:217–9.PubMedPubMedCentralGoogle Scholar
  19. Besedovsky H, del Rey A, Sorkin E, Dinarello CA. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science. 1986;233:652–4.PubMedCrossRefGoogle Scholar
  20. Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P. Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett. 1995;202:17–20.PubMedCrossRefGoogle Scholar
  21. Bohar Z, Toldi J, Fulop F, Vecsei L. Changing the face of kynurenines and neurotoxicity: therapeutic considerations. Int J Mol Sci. 2015;16:9772–93.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Boros FA, Bohar Z, Vecsei L. Genetic alterations affecting the genes encoding the enzymes of the kynurenine pathway and their association with human diseases. Mutat Res. 2018;776:32–45.PubMedCrossRefGoogle Scholar
  23. Braida D, Sacerdote P, Panerai AE, Bianchi M, Aloisi AM, Iosue S, et al. Cognitive function in young and adult IL (interleukin)-6 deficient mice. Behav Brain Res. 2004;153:423–9.PubMedCrossRefGoogle Scholar
  24. Bresee C, Rapaport MH. Persistently increased serum soluble interleukin-2 receptors in continuously ill patients with schizophrenia. Int J Neuropsychopharmacol. 2009;12:861–5.PubMedCrossRefGoogle Scholar
  25. Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, et al. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry. 2004;161:889–95.PubMedCrossRefGoogle Scholar
  26. Bruce LC, Peebles AMS. Clinical and experimental observations in catatonia. J Ment Sci. 1903;49:614–28.CrossRefGoogle Scholar
  27. Brunello N, Alboni S, Capone G, Benatti C, Blom JM, Tascedda F, et al. Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression. Int Clin Psychopharmacol. 2006;21:219–25.PubMedCrossRefGoogle Scholar
  28. Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB, et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002;26:643–52.PubMedCrossRefGoogle Scholar
  29. Casolini P, Catalani A, Zuena AR, Angelucci L. Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat. J Neurosci Res. 2002;68:337–43.PubMedCrossRefGoogle Scholar
  30. Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, et al. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol. 2012;26:1185–93.PubMedCrossRefPubMedCentralGoogle Scholar
  31. Chittiprol S, Venkatasubramanian G, Neelakantachar N, Babu SV, Reddy NA, Shetty KT, et al. Oxidative stress and neopterin abnormalities in schizophrenia: a longitudinal study. J Psychiatr Res. 2010;44:310–3.PubMedCrossRefPubMedCentralGoogle Scholar
  32. Cumiskey D, Curran BP, Herron CE, O’Connor JJ. A role for inflammatory mediators in the IL-18 mediated attenuation of LTP in the rat dentate gyrus. Neuropharmacology. 2007;52:1616–23.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Dameshek W. White blood cells in dementia praecox and dementia paralytica. Arch Neurol Psychiatr. 1930;24:855.Google Scholar
  34. DeLisi LE, Goodman S, Neckers LM, Wyatt RJ. An analysis of lymphocyte subpopulations in schizophrenic patients. Biol Psychiatry. 1982;17:1003–9.PubMedPubMedCentralGoogle Scholar
  35. DeLisi LE, Weber RJ, Pert CB. Are there antibodies against brain in sera from schizophrenic patients? Review and prospectus. Biol Psychiatry. 1985;20:110–5.PubMedCrossRefPubMedCentralGoogle Scholar
  36. Denicoff KD, Rubinow DR, Papa MZ, Simpson C, Seipp CA, Lotze MT, et al. The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med. 1987;107:293–300.PubMedCrossRefPubMedCentralGoogle Scholar
  37. Denney DR, Stephenson LA, Penick EC, Weller RA. Lymphocyte subclasses and depression. J Abnorm Psychol. 1988;97:499–502.PubMedCrossRefPubMedCentralGoogle Scholar
  38. Duch DS, Woolf JH, Nichol CA, Davidson JR, Garbutt JC. Urinary excretion of biopterin and neopterin in psychiatric disorders. Psychiatry Res. 1984;11:83–9.PubMedCrossRefPubMedCentralGoogle Scholar
  39. Ellman LM, Deicken RF, Vinogradov S, Kremen WS, Poole JH, Kern DM, Tsai WY, Schaefer CA, Brown AS.Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8.Schizophr Res. 2010;121(1–3):46–54. Epub 2010 Jun 9PubMedPubMedCentralCrossRefGoogle Scholar
  40. Eikelenboom P, Rozemuller JM, Kraal G, Stam FC, McBride PA, Bruce ME, et al. Cerebral amyloid plaques in Alzheimer’s disease but not in scrapie-affected mice are closely associated with a local inflammatory process. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;60:329–36.PubMedCrossRefGoogle Scholar
  41. Frank MG, Baratta MV, Sprunger DB, Watkins LR, Maier SF. Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun. 2007;21:47–59.PubMedCrossRefGoogle Scholar
  42. Furukawa H, del Rey A, Monge-Arditi G, Besedovsky HO. Interleukin-1, but not stress, stimulates glucocorticoid output during early postnatal life in mice. Ann N Y Acad Sci. 1998;840:117–22.PubMedCrossRefGoogle Scholar
  43. Gimeno D, Marmot MG, Singh-Manoux A. Inflammatory markers and cognitive function in middle-aged adults: the Whitehall II study. Psychoneuroendocrinology. 2008;33:1322–34.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016;21:1696–709.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Gossec L, Steinberg G, Rouanet S, Combe B. Fatigue in rheumatoid arthritis: quantitative findings on the efficacy of tocilizumab and on factors associated with fatigue. The French multicentre prospective PEPS study. Clin Exp Rheumatol. 2015;33:664–70.PubMedGoogle Scholar
  46. Grosskopf A, Muller N, Malo A, Wank R. Potential role for the narcolepsy- and multiple sclerosis-associated HLA allele DQB1∗0602 in schizophrenia subtypes. Schizophr Res. 1998;30:187–9.PubMedCrossRefGoogle Scholar
  47. Gruber L, Bunse T, Weidinger E, Reichard H, Muller N. Adjunctive recombinant human interferon gamma-1b for treatment-resistant schizophrenia in 2 patients. J Clin Psychiatry. 2014;75:1266–7.PubMedCrossRefGoogle Scholar
  48. Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kuhn M, Schuld A, et al. Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res. 1999;33:407–18.PubMedCrossRefGoogle Scholar
  49. Hafner S, Baghai TC, Eser D, Schule C, Rupprecht R, Bondy B, et al. C-reactive protein is associated with polymorphisms of the angiotensin-converting enzyme gene in major depressed patients. J Psychiatr Res. 2008;42:163–5.PubMedCrossRefGoogle Scholar
  50. Hampel H, Schwarz MJ, Kötter HU, Schneider C, Müller N. Cell adhesion molecules in the central nervous system: significance and therapeutic perspectives in neuropsychiatric disorders. Drug News Perspect. 1996;9:69–81.Google Scholar
  51. Hampel H, Kotter HU, Padberg F, Korschenhausen DA, Moller HJ. Oligoclonal bands and blood--cerebrospinal-fluid barrier dysfunction in a subset of patients with Alzheimer disease: comparison with vascular dementia, major depression, and multiple sclerosis. Alzheimer Dis Assoc Disord. 1999;13:9–19.PubMedCrossRefPubMedCentralGoogle Scholar
  52. Hayley S, Wall P, Anisman H. Sensitization to the neuroendocrine, central monoamine and behavioural effects of murine tumor necrosis factor-alpha: peripheral and central mechanisms. Eur J Neurosci. 2002;15:1061–76.PubMedCrossRefPubMedCentralGoogle Scholar
  53. Henneberg A, Riedl B, Dumke HO, Kornhuber HH. T-lymphocyte subpopulations in schizophrenic patients. Eur Arch Psychiatry Neurol Sci. 1990;239:283–4.PubMedCrossRefGoogle Scholar
  54. Herbert TB, Cohen S. Depression and immunity: a meta-analytic review. Psychol Bull. 1993;113:472–86.PubMedCrossRefGoogle Scholar
  55. Heyser CJ, Masliah E, Samimi A, Campbell IL, Gold LH. Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain. Proc Natl Acad Sci U S A. 1997;94:1500–5.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Irwin M, Smith TL, Gillin JC. Low natural killer cytotoxicity in major depression. Life Sci. 1987;41:2127–33.PubMedCrossRefGoogle Scholar
  57. Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry. 2018;23:335–43.PubMedCrossRefGoogle Scholar
  58. Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci U S A. 2004;101:8180–5.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Knight JG. Dopamine-receptor-stimulating autoantibodies: a possible cause of schizophrenia. Lancet. 1982;2:1073–6.PubMedCrossRefGoogle Scholar
  60. Kohler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiat. 2014;71:1381–91.CrossRefGoogle Scholar
  61. Kohler O, Gasse C, Petersen L, Ingstrup KG, Nierenberg AA, Mors O, et al. The effect of concomitant treatment with SSRIs and statins: a population-based study. Am J Psychiatry. 2016;173:807–15.PubMedCrossRefGoogle Scholar
  62. Korte S, Arolt V, Peters M, Weitzsch C, Rothermundt M, Kirchner H. Increased serum neopterin levels in acutely ill and recovered schizophrenic patients. Schizophr Res. 1998;32:63–7.PubMedCrossRefGoogle Scholar
  63. Kurtz G, Muller N. The antiphospholipid syndrome and psychosis. Am J Psychiatry. 1994;151:1841–2.PubMedCrossRefGoogle Scholar
  64. Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2010;71:520–7.PubMedCrossRefGoogle Scholar
  65. Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology. 2000;22:370–9.PubMedCrossRefGoogle Scholar
  66. Lapchak PA. A role for interleukin-2 in the regulation of striatal dopaminergic function. Neuroreport. 1992;3:165–8.PubMedCrossRefGoogle Scholar
  67. Lehmann-Facius H. Serologisch-analytische Versuche mit Liquores und Seren von Schizophrenen. Allg Z Psychiatrie. 1939;110:232–43.Google Scholar
  68. Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010;71:138–49.PubMedCrossRefGoogle Scholar
  69. Levy EM, Borrelli DJ, Mirin SM, Salt P, Knapp PH, Peirce C, et al. Biological measures and cellular immunological function in depressed psychiatric inpatients. Psychiatry Res. 1991;36:157–67.PubMedCrossRefGoogle Scholar
  70. Lewandowski G, Hobbs MV, Bloom FE. Alteration of intracerebral cytokine production in mice infected with herpes simplex virus types 1 and 2. J Neuroimmunol. 1994;55:23–34.PubMedCrossRefGoogle Scholar
  71. Licinio J, Seibyl JP, Altemus M, Charney DS, Krystal JH. Elevated CSF levels of interleukin-2 in neuroleptic-free schizophrenic patients. Am J Psychiatry. 1993;150:1408–10.PubMedCrossRefGoogle Scholar
  72. Lieberman AP, Pitha PM, Shin HS, Shin ML. Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proc Natl Acad Sci U S A. 1989;86:6348–52.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuro-Psychopharmacol Biol Psychiatry. 1995;19:11–38.CrossRefGoogle Scholar
  74. Maes M, Bosmans E, Calabrese J, Smith R, Meltzer HY. Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. J Psychiatr Res. 1995a;29:141–52.PubMedCrossRefGoogle Scholar
  75. Maes M, Bosmans E, Meltzer HY. Immunoendocrine aspects of major depression. Relationships between plasma interleukin-6 and soluble interleukin-2 receptor, prolactin and cortisol. Eur Arch Psychiatry Clin Neurosci. 1995b;245:172–8.PubMedCrossRefGoogle Scholar
  76. Maes M, Bosmans E, Kenis G, De Jong R, Smith RS, Meltzer HY. In vivo immunomodulatory effects of clozapine in schizophrenia. Schizophr Res. 1997;26:221–5.PubMedCrossRefGoogle Scholar
  77. Maes M, Anderson G, Kubera M, Berk M. Targeting classical IL-6 signalling or IL-6 trans-signalling in depression? Expert Opin Ther Targets. 2014;18:495–512.PubMedCrossRefGoogle Scholar
  78. McAllister CG, Rapaport MH, Pickar D, Paul SM. Effects of short-term administration of antipsychotic drugs on lymphocyte subsets in schizophrenic patients. Arch Gen Psychiatry. 1989a;46:956–7.PubMedCrossRefGoogle Scholar
  79. McAllister CG, Rapaport MH, Pickar D, Podruchny TA, Christison G, Alphs LD, et al. Increased numbers of CD5+ B lymphocytes in schizophrenic patients. Arch Gen Psychiatry. 1989b;46:890–4.PubMedCrossRefGoogle Scholar
  80. McAllister CG, van Kammen DP, Rehn TJ, Miller AL, Gurklis J, Kelley ME, et al. Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. Am J Psychiatry. 1995;152:1291–7.PubMedCrossRefGoogle Scholar
  81. McGeer PL, Rogers J, McGeer EG. Inflammation, antiinflammatory agents, and Alzheimer’s disease: the last 22 years. J Alzheimers Dis. 2016;54:853–7.PubMedCrossRefGoogle Scholar
  82. Melnikova T, Savonenko A, Wang Q, Liang X, Hand T, Wu L, et al. Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer’s disease in a sex-dimorphic pattern. Neuroscience. 2006;141:1149–62.PubMedCrossRefGoogle Scholar
  83. Merrill JE. Tumor necrosis factor alpha, interleukin 1 and related cytokines in brain development: normal and pathological. Dev Neurosci. 1992;14:1–10.PubMedCrossRefGoogle Scholar
  84. Miller BJ, Buckley PF. The case for adjunctive monoclonal antibody immunotherapy in schizophrenia. Psychiatr Clin North Am. 2016;39:187–98.PubMedCrossRefGoogle Scholar
  85. Miller AH, Lackner C. Tricyclic antidepressants and immunity. In: Miller AH, editor. Depressive disorders and immunity. Washington: American Psychiatric Press; 1989.Google Scholar
  86. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70:663–71.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164:6166–73.PubMedCrossRefGoogle Scholar
  88. Mittleman BB, Castellanos FX, Jacobsen LK, Rapoport JL, Swedo SE, Shearer GM. Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. J Immunol. 1997;159:2994–9.PubMedGoogle Scholar
  89. Mizoguchi H, Takuma K, Fukakusa A, Ito Y, Nakatani A, Ibi D, et al. Improvement by minocycline of methamphetamine-induced impairment of recognition memory in mice. Psychopharmacology. 2008;196:233–41.PubMedCrossRefGoogle Scholar
  90. Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, et al. Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci Lett. 1994a;180:147–50.PubMedCrossRefGoogle Scholar
  91. Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T. Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett. 1994b;165:208–10.PubMedCrossRefGoogle Scholar
  92. Mogi M, Harada M, Kondo T, Narabayashi H, Riederer P, Nagatsu T. Transforming growth factor-beta 1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson’s disease. Neurosci Lett. 1995a;193:129–32.PubMedCrossRefGoogle Scholar
  93. Mogi M, Harada M, Kondo T, Riederer P, Nagatsu T. Brain beta 2-microglobulin levels are elevated in the striatum in Parkinson’s disease. J Neural Transm Park Dis Dement Sect. 1995b;9:87–92.PubMedCrossRefGoogle Scholar
  94. Molholm HB. Hyposensitivity to foreign protein in schizophrenic patients. Psychiatr Q. 1942;16:565–71.CrossRefGoogle Scholar
  95. Müller N. Psychoneuroimmunology: implications for the drug treatment of psychiatric disorders. CNS Drugs. 1995;4:125–40.CrossRefGoogle Scholar
  96. Muller N. COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Curr Opin Investig Drugs. 2010;11:31–42.PubMedPubMedCentralGoogle Scholar
  97. Müller N. Immunologische Behandlungsoptionen bei schizophrenen Störungen. Fortschr Neurol Psychiatr. 2013;82:210–9.Google Scholar
  98. Muller N. The role of intercellular adhesion molecule-1 in the pathogenesis of psychiatric disorders. Front Pharmacol. 2019;10:1251.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Muller N, Ackenheil M. The immune system and schizophrenia. In: Leonard BE, Miller K, editors. Stress, the immune system and psychiatry. New York/Chichester: Wiley; 1995a. p. 137–64.Google Scholar
  100. Muller N, Ackenheil M. Immunoglobulin and albumin content of cerebrospinal fluid in schizophrenic patients: relationship to negative symptomatology. Schizophr Res. 1995b;14:223–8.PubMedCrossRefPubMedCentralGoogle Scholar
  101. Muller N, Ackenheil M. Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog Neuro-Psychopharmacol Biol Psychiatry. 1998;22:1–33.CrossRefGoogle Scholar
  102. Müller N, Bechter K. The mild encephalitis concept for psychiatric disorders revisited in the light of current psychoneuroimmunological findings. Neurol Psychiatry Brain Res. 2013;19:87–101.CrossRefGoogle Scholar
  103. Muller N, Schwarz MJ. The immunological basis of glutamatergic disturbance in schizophrenia: towards an integrated view. J Neural Transm. 2007;(Suppl 72):269–80.Google Scholar
  104. Muller N, Schwarz MJ. Immune system and Schizophrenia. Curr Immunol Rev. 2010;6:213–20.PubMedPubMedCentralCrossRefGoogle Scholar
  105. Muller N, Ackenheil M, Hofschuster E, Mempel W, Eckstein R. Cellular immunity in schizophrenic patients before and during neuroleptic treatment. Psychiatry Res. 1991;37:147–60.PubMedCrossRefGoogle Scholar
  106. Muller N, Gizycki-Nienhaus B, Gunther W, Meurer M. Depression as a cerebral manifestation of scleroderma: immunological findings in serum and cerebrospinal fluid. Biol Psychiatry. 1992;31:1151–6.PubMedCrossRefGoogle Scholar
  107. Muller N, Empl M, Riedel M, Schwarz M, Ackenheil M. Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 1997;247:308–13.PubMedCrossRefGoogle Scholar
  108. Muller N, Riedel M, Hadjamu M, Schwarz MJ, Ackenheil M, Gruber R. Increase in expression of adhesion molecule receptors on T helper cells during antipsychotic treatment and relationship to blood-brain barrier permeability in schizophrenia. Am J Psychiatry. 1999;156:634–6.PubMedGoogle Scholar
  109. Muller N, Riedel M, Scheppach C, Brandstatter B, Sokullu S, Krampe K, et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry. 2002;159:1029–34.PubMedCrossRefGoogle Scholar
  110. Muller N, Riedel M, Schwarz MJ, Engel RR. Clinical effects of COX-2 inhibitors on cognition in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2005a;255:149–51.PubMedCrossRefGoogle Scholar
  111. Muller N, Schwarz MJ, Riedel M. COX-2 inhibition in schizophrenia: focus on clinical effects of celecoxib therapy and the role of TNF-alpha. In: Eaton WW, editor. Medical and psychiatric comorbidity over the course of life. Washington, DC: American Psychiatric Publishing; 2005b. p. 265–76.Google Scholar
  112. Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, 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.PubMedCrossRefGoogle Scholar
  113. Muller N, Krause D, Dehning S, Musil R, Schennach-Wolff R, Obermeier M, et al. Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment. Schizophr Res. 2010;121:118–24.PubMedCrossRefGoogle Scholar
  114. Muller N, Myint AM, Schwarz MJ. Immunological treatment options for schizophrenia. Curr Pharm Biotechnol. 2012a;13:1606–13.PubMedCrossRefGoogle Scholar
  115. Muller N, Myint AM, Schwarz MJ. Inflammation in schizophrenia. Adv Protein Chem Struct Biol. 2012b;88:49–68.PubMedCrossRefGoogle Scholar
  116. Murr C, Widner B, Wirleitner B, Fuchs D. Neopterin as a marker for immune system activation. Curr Drug Metab. 2002;3:175–87.PubMedCrossRefGoogle Scholar
  117. Myint AM, Steinbusch HW, Goeghegan L, Luchtman D, Kim YK, Leonard BE. Effect of the COX-2 inhibitor celecoxib on behavioural and immune changes in an olfactory bulbectomised rat model of depression. Neuroimmunomodulation. 2007;14:65–71.PubMedCrossRefGoogle Scholar
  118. Na KS, Lee KJ, Lee JS, Cho YS, Jung HY. Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis. Prog Neuro-Psychopharmacol Biol Psychiatry. 2014;48:79–85.CrossRefGoogle Scholar
  119. Nair A, Bonneau RH. Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation. J Neuroimmunol. 2006;171:72–85.PubMedCrossRefGoogle Scholar
  120. Nemni R, Iannaccone S, Quattrini A, Smirne S, Sessa M, Lodi M, et al. Effect of chronic treatment with recombinant interleukin-2 on the central nervous system of adult and old mice. Brain Res. 1992;591:248–52.PubMedCrossRefGoogle Scholar
  121. Nikkila HV, Muller K, Ahokas A, Rimon R, Andersson LC. Increased frequency of activated lymphocytes in the cerebrospinal fluid of patients with acute schizophrenia. Schizophr Res. 2001;49:99–105.PubMedCrossRefGoogle Scholar
  122. Nistico G, De Sarro G. Is interleukin 2 a neuromodulator in the brain? Trends Neurosci. 1991;14:146–50.PubMedCrossRefGoogle Scholar
  123. Nitta M, Kishimoto T, Muller N, Weiser M, Davidson M, Kane JM, et al. Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull. 2013;39:1230–41.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Norris JG, Benveniste EN. Interleukin-6 production by astrocytes: induction by the neurotransmitter norepinephrine. J Neuroimmunol. 1993;45:137–45.PubMedCrossRefGoogle Scholar
  125. Ogawa A, Yoshizaki A, Yanaba K, Ogawa F, Hara T, Muroi E, et al. The differential role of L-selectin and ICAM-1 in Th1-type and Th2-type contact hypersensitivity. J Invest Dermatol. 2010;130:1558–70.PubMedPubMedCentralCrossRefGoogle Scholar
  126. Pennisi E. Neuroimmunology. Tracing molecules that make the brain-body connection. Science. 1997;275:930–1.PubMedCrossRefGoogle Scholar
  127. Plangar I, Majlath Z, Vecsei L. Kynurenines in cognitive functions: their possible role in depression. Neuropsychopharmacol Hung. 2012;14:239–44.PubMedGoogle Scholar
  128. Plata-Salaman CR. Immunoregulators in the nervous system. Neurosci Biobehav Rev. 1991;15:185–215.PubMedCrossRefGoogle Scholar
  129. Pollmacher T, Hinze-Selch D, Mullington J, Holsboer F. Clozapine-induced increase in plasma levels of soluble interleukin-2 receptors. Arch Gen Psychiatry. 1995;52:877–8.PubMedCrossRefGoogle Scholar
  130. Pollmacher T, Schuld A, Kraus T, Haack M, Hinze-Selch D. On the clinical relevance of clozapine-triggered release of cytokines and soluble cytokine-receptors. Fortschr Neurol Psychiatr. 2001;69(Suppl 2):S65–74.PubMedCrossRefGoogle Scholar
  131. Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63:801–8.PubMedCrossRefGoogle Scholar
  132. Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52.PubMedCrossRefPubMedCentralGoogle Scholar
  133. Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiat. 2013;70:31–41.CrossRefGoogle Scholar
  134. Rapaport MH, Delrahim KK, Bresee CJ, Maddux RE, Ahmadpour O, Dolnak D. Celecoxib augmentation of continuously ill patients with schizophrenia. Biol Psychiatry. 2005;57:1594–6.PubMedCrossRefPubMedCentralGoogle Scholar
  135. Riedel M, Spellmann I, Schwarz MJ, Strassnig M, Sikorski C, Moller HJ, et al. Decreased T cellular immune response in schizophrenic patients. J Psychiatr Res. 2007;41:3–7.PubMedCrossRefPubMedCentralGoogle Scholar
  136. Ross BM, Seguin J, Sieswerda LE. Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid? Lipids Health Dis. 2007;6:21.PubMedPubMedCentralCrossRefGoogle Scholar
  137. Rothermundt M, Arolt V, Fenker J, Gutbrodt H, Peters M, Kirchner H. Different immune patterns in melancholic and non-melancholic major depression. Eur Arch Psychiatry Clin Neurosci. 2001;251:90–7.PubMedCrossRefGoogle Scholar
  138. Saavedra JM, Sanchez-Lemus E, Benicky J. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: therapeutic implications. Psychoneuroendocrinology. 2011;36:1–18.PubMedCrossRefGoogle Scholar
  139. Sandrini M, Vitale G, Pini LA. Effect of rofecoxib on nociception and the serotonin system in the rat brain. Inflamm Res. 2002;51:154–9.PubMedCrossRefGoogle Scholar
  140. Schennach H, Murr C, Gachter E, Mayersbach P, Schonitzer D, Fuchs D. Factors influencing serum neopterin concentrations in a population of blood donors. Clin Chem. 2002;48:643–5.PubMedCrossRefGoogle Scholar
  141. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.PubMedCentralCrossRefPubMedGoogle Scholar
  142. Schwarz MJ, Ackenheil M, Riedel M, Muller N. Blood-cerebrospinal fluid barrier impairment as indicator for an immune process in schizophrenia. Neurosci Lett. 1998;253:201–3.PubMedCrossRefGoogle Scholar
  143. Schwarz MJ, Riedel M, Ackenheil M, Muller N. Decreased levels of soluble intercellular adhesion molecule-1 (sICAM-1) in unmedicated and medicated schizophrenic patients. Biol Psychiatry. 2000;47:29–33.PubMedCrossRefGoogle Scholar
  144. Schwieler L, Erhardt S, Erhardt C, Engberg G. Prostaglandin-mediated control of rat brain kynurenic acid synthesis--opposite actions by COX-1 and COX-2 isoforms. J Neural Transm (Vienna). 2005;112:863–72.CrossRefGoogle Scholar
  145. Schwieler L, Larsson MK, Skogh E, Kegel ME, Orhan F, Abdelmoaty S, et al. Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia – significance for activation of the kynurenine pathway. J Psychiatry Neurosci. 2015;40:126–33.PubMedPubMedCentralGoogle Scholar
  146. Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H. Major depressive disorder is associated with elevated monocyte counts. Acta Psychiatr Scand. 1996;94:198–204.PubMedCrossRefGoogle Scholar
  147. Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. 2009;460:753–7.PubMedPubMedCentralCrossRefGoogle Scholar
  148. Sluzewska A, Rybakowski JK, Laciak M, Mackiewicz A, Sobieska M, Wiktorowicz K. Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine. Ann N Y Acad Sci. 1995;762:474–6.PubMedCrossRefGoogle Scholar
  149. Soliven B, Albert J. Tumor necrosis factor modulates the inactivation of catecholamine secretion in cultured sympathetic neurons. J Neurochem. 1992;58:1073–8.PubMedCrossRefGoogle Scholar
  150. Sommer IE, de Witte L, Begemann M, Kahn RS. Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry. 2012;73:414–9.PubMedCrossRefGoogle Scholar
  151. Sommer IE, van Westrhenen R, Begemann MJ, de Witte LD, Leucht S, Kahn RS. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2014;40:181–91.PubMedCrossRefGoogle Scholar
  152. Song C, Leonard BE. An acute phase protein response in the olfactory bulbectomised rat: effect of sertraline treatment. Med Sci Res. 1994;22:313–4.Google Scholar
  153. Sparkman NL, Johnson RW. Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. Neuroimmunomodulation. 2008;15:323–30.PubMedPubMedCentralCrossRefGoogle Scholar
  154. Spellberg B, Edwards JE Jr. Type 1/Type 2 immunity in infectious diseases. Clin Infect Dis. 2001;32:76–102.PubMedCrossRefPubMedCentralGoogle Scholar
  155. Sperner-Unterweger B, Gaggl S, Fleischhacker WW, Barnas C, Herold M, Geissler D. Effects of clozapine on hematopoiesis and the cytokine system. Biol Psychiatry. 1993;34:536–43.PubMedCrossRefPubMedCentralGoogle Scholar
  156. Sperner-Unterweger B, Miller C, Holzner B, Widner B, Fleischhacker WW, Fuchs D. Measurement of neopterin, kynurenine and tryptophan in sera of schizophrenic patients. In: Müller N, editor. Psychiatry, psychoimmunology, and viruses. Vienna/New York: Springer; 1999. p. 115–9.CrossRefGoogle Scholar
  157. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. Common variants conferring risk of schizophrenia. Nature. 2009;460:744–7.PubMedPubMedCentralCrossRefGoogle Scholar
  158. Stevens JR. Schizophrenia and multiple sclerosis. Schizophr Bull. 1988;14:231–41.PubMedCrossRefPubMedCentralGoogle Scholar
  159. Swerdlow NR, van Bergeijk DP, Bergsma F, Weber E, Talledo J. The effects of memantine on prepulse inhibition. Neuropsychopharmacology. 2009;34:1854–64.PubMedPubMedCentralCrossRefGoogle Scholar
  160. Syvalahti E, Eskola J, Ruuskanen O, Laine T. Nonsuppression of cortisol in depression and immune function. Prog Neuro-Psychopharmacol Biol Psychiatry. 1985;9:413–22.CrossRefGoogle Scholar
  161. Teunissen CE, van Boxtel MP, Bosma H, Bosmans E, Delanghe J, De Bruijn C, et al. Inflammation markers in relation to cognition in a healthy aging population. J Neuroimmunol. 2003;134:142–50.PubMedCrossRefPubMedCentralGoogle Scholar
  162. Traki L, Rostom S, Tahiri L, Bahiri R, Harzy T, Abouqal R, et al. Responsiveness of the EuroQol EQ-5D and Hospital Anxiety and Depression Scale (HADS) in rheumatoid arthritis patients receiving tocilizumab. Clin Rheumatol. 2014;33:1055–60.PubMedCrossRefPubMedCentralGoogle Scholar
  163. Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367:29–35.CrossRefGoogle Scholar
  164. Varga G, Nippe N, Balkow S, Peters T, Wild MK, Seeliger S, et al. LFA-1 contributes to signal I of T-cell activation and to the production of T(h)1 cytokines. J Invest Dermatol. 2010;130:1005–12.PubMedCrossRefPubMedCentralGoogle Scholar
  165. Vecsei L, Szalardy L, Fulop F, Toldi J. Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov. 2013;12:64–82.PubMedCrossRefGoogle Scholar
  166. Wagner-Jauregg J. Fieberbehandlung bei Psychosen. Wien Med Wochenschr. 1926;76:79–82.Google Scholar
  167. Wang AK, Miller BJ. Meta-analysis of cerebrospinal fluid cytokine and tryptophan catabolite alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder, and depression. Schizophr Bull. 2018;44:75–83.PubMedCrossRefGoogle Scholar
  168. Weitz-Schmidt G. Statins as anti-inflammatory agents. Trends Pharmacol Sci. 2002;23:482–6.PubMedCrossRefGoogle Scholar
  169. Wilke I, Arolt V, Rothermundt M, Weitzsch C, Hornberg M, Kirchner H. Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients. Eur Arch Psychiatry Clin Neurosci. 1996;246:279–84.PubMedCrossRefGoogle Scholar
  170. Yang C, Hashimoto K. Peripheral IL-6 signaling: a promising therapeutic target for depression? Expert Opin Investig Drugs. 2015;24:989–90.PubMedCrossRefGoogle Scholar
  171. Yang C, Shirayama Y, Zhang JC, Ren Q, Hashimoto K. Peripheral interleukin-6 promotes resilience versus susceptibility to inescapable electric stress. Acta Neuropsychiatr. 2015a;27:312–6.PubMedCrossRefGoogle Scholar
  172. Yang JJ, Wang N, Yang C, Shi JY, Yu HY, Hashimoto K. Serum interleukin-6 is a predictive biomarker for ketamine’s antidepressant effect in treatment-resistant patients with major depression. Biol Psychiatry. 2015b;77:e19–20.PubMedCrossRefPubMedCentralGoogle Scholar
  173. Zalcman S, Green-Johnson JM, Murray L, Nance DM, Dyck D, Anisman H, et al. Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6. Brain Res. 1994;643:40–9.PubMedCrossRefPubMedCentralGoogle Scholar
  174. Zarrabi MH, Zucker S, Miller F, Derman RM, Romano GS, Hartnett JA, et al. Immunologic and coagulation disorders in chlorpromazine-treated patients. Ann Intern Med. 1979;91:194–9.PubMedCrossRefPubMedCentralGoogle Scholar
  175. Zhou D, Kusnecov AW, Shurin MR, DePaoli M, Rabin BS. Exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic-pituitary-adrenal axis. Endocrinology. 1993;133:2523–30.PubMedCrossRefPubMedCentralGoogle Scholar
  176. Zhou AJ, Lee Y, Salvadore G, Hsu B, Fonseka TM, Kennedy SH, et al. Sirukumab: a potential treatment for mood disorders? Adv Ther. 2017;34:78–90.PubMedCrossRefGoogle Scholar
  177. Zhu J, Bengtsson BO, Mix E, Thorell LH, Olsson T, Link H. Effect of monoamine reuptake inhibiting antidepressants on major histocompatibility complex expression on macrophages in normal rats and rats with experimental allergic neuritis (EAN). Immunopharmacology. 1994;27:225–44.PubMedCrossRefGoogle Scholar

Authors and Affiliations

  1. 1.Department of Psychiatry and PsychotherapyLudwig-Maximilians-Universität Munich MunichGermany

Section editors and affiliations

  • Peter Riederer
    • 1
  1. 1.University Hospital, Center for Mental Health, Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy, University WuerzburgWuerzburgGermany

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