Skip to main content
SpringerLink
Log in

The Future of Psychoneuroimmunology: Promises and Challenges

  • Chapter
  • First Online:
Advances in Psychiatry

Abstract

This chapter aims to provide an overview of the burgeoning field of psychoneuroimmunology as it relates to psychiatric and neuropsychiatric disorders. It is a relatively young field, having come of age only recently, but the progress that has been made just in the past three decades has exceeded all expectations. It is fair to say that the field has opened up new horizons in our understanding of the complex interrelationships between the immune and nervous systems or as is otherwise referred to as the brain-immune interaction. Hitherto unknown biochemical pathways have been identified, and their complex interactions with neurotransmitters and immune mediators present opportunities for innovative research and identification of new targets for drug development. Biomarkers are being established that hold great promise for more precise diagnostic classification of psychiatric disorders but also understanding of the high comorbidity between specific psychiatric disease entities and a host of medical and neurological diseases. At the same time, immune biomarkers, neurotrophins, and antibodies enable prediction of response and understanding of treatment resistance. Imaging techniques of increasing sophistication hold great promise for visualization of aberrant connectivity and dysfunctional brain circuitry. The goal of practicing personalized psychiatry is now closer to becoming reality than ever before in the history of our specialty. The coauthors of this chapter have each contributed subsections commensurate with their individual expertise.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 229.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Pariante CM. Psychoneuroimmunology or immunopsychiatry? Lancet Psychiatry. 2015;2(3):197–9.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Halaris A. Inflammation, heart disease and depression. Curr Psychiatry Rep. 2013;15:400. https://doi.org/10.1007/s11920-013-0400-5.

    Article  PubMed  Google Scholar 

  3. Halaris A. Neurological disorders, depression and inflammation: is there a common link? Future Neurol. 2015;10(4):327–43.

    Article  CAS  Google Scholar 

  4. Halaris A. Inflammation-associated co-morbidity between depression and cardiovascular disease. Curr Top Behav Neurosci. 2017;31:45–70. https://doi.org/10.1007/7854_2016_28.

    Article  PubMed  CAS  Google Scholar 

  5. Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A. 2007;104(4):1319–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R, Caspi A. Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry. 2008;65(4):409–15.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Baumeister D, Akhtar R, Ciufolini S, Pariante CM, Mondelli V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatry. 2016;21(5):642–9.

    Article  PubMed  CAS  Google Scholar 

  8. Plant DT, Pawlby S, Sharp D, Zunszain PA, Pariante CM. Prenatal maternal depression is associated with offspring inflammation at 25 years: a prospective longitudinal cohort study. Transl Psychiatry. 2016;6(11):e936.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Pawlby S, Hay D, Sharp D, Waters CS, Pariante CM. Antenatal depression and offspring psychopathology: the influence of childhood maltreatment. Br J Psychiatry. 2011;199(2):106–12.

    Article  Google Scholar 

  10. Plant DT, Barker ED, Waters CS, Pawlby S, Pariante CM. Intergenerational transmission of maltreatment and psychopathology: the role of antenatal depression. Psychol Med. 2013;43(3):519–28.

    Article  PubMed  CAS  Google Scholar 

  11. Plant DT, Pariante CM, Sharp D, Pawlby S. Maternal depression during pregnancy and offspring depression in adulthood: role of child maltreatment. Br J Psychiatry. 2015;207(3):213–20.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Du Preez A, Leveson J, Zunszain PA, Pariante CM. Inflammatory insults and mental health consequences: does timing matter when it comes to depression? Psychol Med. 2016;46(10):2041–57.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446–57.

    Article  PubMed  CAS  Google Scholar 

  14. Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009;71:171–86.

    Article  PubMed  CAS  Google Scholar 

  15. Valkanova V, Ebmeier KP, Allan CL. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord. 2013;150(3):736–44.

    Article  PubMed  CAS  Google Scholar 

  16. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Schiepers OJ, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:201–17.

    Article  PubMed  CAS  Google Scholar 

  18. Cattaneo A, Gennarelli M, Uher R, Breen G, Farmer A, Aitchison KJ, Craig IW, Anacker C, Zunsztain PA, McGuffin P, Pariante CM. Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology. 2013;38(3):377–85.

    Article  PubMed  CAS  Google Scholar 

  19. Carvalho LA, Garner BA, Dew T, Fazakerley H, Pariante CM. Antidepressants, but not antipsychotics, modulate GR function in human whole blood: an insight into molecular mechanisms. Eur Neuropsychopharmacol. 2010;20(6):379–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Carvalho LA, Juruena MF, Papadopoulos AS, Poon L, Kerwin R, Cleare AJ, Pariante CM. Clomipramine in vitro reduces glucocorticoid receptor function in healthy subjects but not in patients with major depression. Neuropsychopharmacology. 2008;33(13):3182–9.

    Article  PubMed  CAS  Google Scholar 

  21. Carvalho LA, Torre JP, Papadopoulos AS, Poon L, Juruena MF, Markopoulou K, Cleare AJ, Pariante CM. Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. J Affect Disord. 2013;148(1):136–40.

    Article  PubMed  CAS  Google Scholar 

  22. Nikkheslat N, Zunszain PA, Horowitz MA, Barbosa IG, Parker JA, Myint AM, Schwarz MJ, Tylee AT, Carvalho LA, Pariante CM. Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression. Brain Behav Immun. 2015;48:8–18.

    Article  PubMed  CAS  Google Scholar 

  23. Cattaneo A, Ferrari C, Uher R, Bocchio-Chiavetto L, Riva MA, Pariante CM, MRC ImmunoPsychiatry Consortium. Absolute measurements of macrophage migration inhibitory factor and interleukin-1-β mRNA levels accurately predict treatment response in depressed patients. Int J Neuropsychopharmacol. 2016;19(10):pyw045.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Hepgul N, Cattaneo A, Zunszain PA, Pariante CM. Depression pathogenesis and treatment: what can we learn from blood mRNA expression? BMC Med. 2013;11:28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Hepgul N, Cattaneo A, Agarwal K, Baraldi S, Borsini A, Bufalino C, Forton DM, Mondelli V, Nikkheslat N, Lopizzo N, Riva MA, Russell A, Hotopf M, Pariante CM. Transcriptomics in interferon-α-treated patients identifies inflammation, neuroplasticity- and oxidative stress-related signatures as predictors and correlates of depression. Neuropsychopharmacology. 2016;41(10):2502–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Leonard BE. Brain cytokines and the psychopathology of depression. In: Leonard BE, editor. Antidepressants. Basel: Birkhauser Verlag; 2001. p. 109–20.

    Chapter  Google Scholar 

  27. Mendelson SD. The current status of the platelet 5-HT (2A) receptor in depression. J Affect Disord. 2000;57:13–24.

    Article  PubMed  CAS  Google Scholar 

  28. Hrdina PD, Bakish D, Chudzik J, Ravindran A, Lapierre YD. Serotonergic markers in platelets of patients with major depression: upregulation of 5-HT2 receptors. J Psychiatry Neurosci. 1995;20:11–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  29. Neuger J, El Khoury A, Kjellman BF, Wahlund B, Aberg-Wistedt A, Stain-Malgren R. Platelet serotonin functions in untreated major depression. Psychiatry Res. 1999;85:189–98.

    Article  PubMed  CAS  Google Scholar 

  30. Shimbo D, Child J, Davidson K, Geer E, Osende JI, Reddy S, et al. Exaggerated serotonin-mediated platelet reactivity as a possible link in depression and acute coronary syndromes. Am J Cardiol. 2002;89:331–3.

    Article  PubMed  CAS  Google Scholar 

  31. Whyte EM, Pollock BG, Wagner WR, Mulsant BH, Ferrell RE, Mazumdar S, et al. Influence of serotonin-transporter-linked promoter region polymorphism on platelet activation in geriatric depression. Am J Psychiatry. 2001;158:2074–6.

    Article  PubMed  CAS  Google Scholar 

  32. Palazzolo DL, Quadri SK. Interleukin-1 inhibits serotonin release from the hypothalamus in vitro. Life Sci. 1992;51:1797–802.

    Article  PubMed  CAS  Google Scholar 

  33. Zhu CB, Blakely RD, Hewlett WA. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology. 2005;31:2121–31.

    Google Scholar 

  34. Kop WJ, Gottdiener JS, Tangen CM, Fried LP, McBurnie MA, Walston J. Inflammation and coagulation factors on persons >65 years of age with symptoms of depression but without evidence of myocardial ischemia. Am J Cardiol. 2002;89:419–24.

    Article  PubMed  CAS  Google Scholar 

  35. Maes M, der Planken V, Van Gastel A, Desnyder R. Blood coagulation and platelet aggression in major depression. J Affect Disord. 1996;40:35–40.

    Article  PubMed  CAS  Google Scholar 

  36. Musselman DL, Miller AH, Porter MR, Manatunga A, Gao F, Penna S. Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings. Am J Psychiatry. 2001;158:1252–7.

    Article  PubMed  CAS  Google Scholar 

  37. Christmas DM, Potokar JP, Davies SJC. A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase. Neuropsychiatr Dis Treat. 2011;7:431–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol. 2002;5:375–88.

    Article  PubMed  CAS  Google Scholar 

  39. Myint AM, Kim YK, Verkerk R, Scharpé S, Steinbusch HWM, Leonard BE. Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord. 2007;89(1):143–51.

    Article  CAS  Google Scholar 

  40. Myint AM, Kim YK. Cytokine-serotonin interaction through IDO; a neurodegeneration hypothesis of depression. Med Hypotheses. 2003;61(5–6):519–25.

    Article  PubMed  CAS  Google Scholar 

  41. Miller CL, Llenos IC, Dulay JR, Weis S. Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. Brain Res. 2006;1073–1074:25–37.

    Article  PubMed  CAS  Google Scholar 

  42. Myint AM, Kim YK, Verkerk R, Park SH, Scharpe S, Steinbusch HW, et al. Tryptophan breakdown pathway in bipolar mania. J Affect Disord. 2007;102(1–3):65–72.

    Article  PubMed  CAS  Google Scholar 

  43. Lapin IP, Oxenkrug GF. Identification of central serotonergic processes as possible determinators of the thymoleptic affect. Lancet. 1969;1:32–9.

    Google Scholar 

  44. Lapin IP. Kynurenines as probable participants in depression. Pharmacopsychiatr Neuropsychopharmakol. 1973;6:273–9.

    Article  CAS  Google Scholar 

  45. Gal EM, Sherman AD. L-kynurenine: its synthesis and possible regulatory function in brain. Neurochem Res. 1980;5:223–39.

    Article  PubMed  CAS  Google Scholar 

  46. Perkins MN, Stone TW. An iontophoretic investigation of the action of convulsant kynurenines and their interaction with endogenous excitant quinolinic acid. Brain Res. 1982;247:184–7.

    Article  PubMed  CAS  Google Scholar 

  47. Steiner J, Bielau H, Brisch R, et al. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res. 2008;42:151–7.

    Article  PubMed  Google Scholar 

  48. Han Q, Tao DA, Li J. Structure, expression and function of kynurenine aminotransferase in human and rodent brain. Cell Mol Life Sci. 2010;67:353–68.

    Article  PubMed  CAS  Google Scholar 

  49. Oxenkrug GF. Insulin resistance and dysregulation of the tryptophan-kynurenine-NAD pathway. Mol Neurobiol. 2013;48:294–301.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Sas K, Robotka H, Toldie J, Vecsei L. Mitochondria metabolic disturbance, oxidative stress and the kynurenine system with a focus on neurodegenerative disorders. J Neurol Sci. 2009;257:221–39.

    Article  CAS  Google Scholar 

  51. Barnes J, Mondelli V, Pariante CM. Genetic contributions of inflammation to depression. Neuropsychopharmacology. 2017;42(1):81–98.

    Article  PubMed  CAS  Google Scholar 

  52. Bull SJ, Huezo-Diaz P, Binder EB, Cubells JF, Ranjith G, Maddock C, Miyazaki C, Alexander N, Hotopf M, Cleare AJ, Norris S, Cassidy E, Aitchison KJ, Miller AH, Pariante CM. 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(12):1095–104.

    Article  PubMed  CAS  Google Scholar 

  53. Su KP, Huang SY, Peng CY, Lai HC, Huang CL, Chen YC, Aitchison KJ, Pariante CM. Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels. Biol Psychiatry. 2010;67(6):550–7.

    Article  PubMed  CAS  Google Scholar 

  54. Geerlings MT, Schoevers RA, Beckman AT, et al. Depression and risk of cognitive decline and Alzheimer’s disease. Br J Psychiatry. 2000;176:568–75.

    Article  PubMed  CAS  Google Scholar 

  55. Visser PJ, Verhey FR, Ponds RW, et al. Distinction between preclinical Alzheimer’s disease and depression. Am J Geriatr Soc. 2000;48:479–84.

    Article  CAS  Google Scholar 

  56. Modrego PJ, Fernandez J. Depression in patients with mild cognitive impairment increases the risk of developing dementia of the Alzheimer type. Arch Neurol. 2004;61:1290–3.

    Article  PubMed  Google Scholar 

  57. Steffens DC, Plassman BL, Helms MJ, et al. A twin study of late onset depression and apolipoprotein E4 as risk factors for Alzheimer’s disease. Biol Psychiatry. 1997;41:851–6.

    Article  PubMed  CAS  Google Scholar 

  58. Kang J, Lemaire HG, Unterbeck A, et al. The precursor of Alzheimer’s disease, amyloid A4 protein, resembles a cell surface receptor. Nature. 1987;325(6106):733–6.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  60. Maes M, Galecki P, Chang YS, Berk M. A review on the oxidative and nitrosative stress pathways in major depression and their possible contribution to the neurodegenerative process in that illness. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:676–92.

    Article  PubMed  CAS  Google Scholar 

  61. Finch CE, Morgan TE. Systematic inflammation, infection, ApoE alleles and Alzheimer’s disease a position paper. Curr Alzheimer Res. 2007;4:185–9.

    Article  PubMed  CAS  Google Scholar 

  62. Bloom GS. Amyloid beta and tau: the trigger and bullet in Alzheimer’s disease. JAMA Neurol. 2014;71:505–8.

    Article  PubMed  Google Scholar 

  63. Margarinos AM, McEwen BS, Flugge G, Fuchs E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci. 1996;16:3534–40.

    Article  Google Scholar 

  64. Sapolsky RM, Uno H, Rebert CS, Finch CE. Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J Neurosci. 1990;10:2897–902.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. McEwen BS. Possible mechanisms for atrophied human hippocampus. Mol Psychiatry. 1997;2:255–62.

    Article  PubMed  CAS  Google Scholar 

  66. Ragnarsson O, Berglund P, Eder DN, Johannsson G. Long-term cognitive impairments and attentional deficits in patients with Cushing’s disease and cortisol producing adrenal adenoma in remission. J Clin Endocrinol Metab. 2012;97:1640–8.

    Article  CAS  Google Scholar 

  67. Sapolsky RM. Stress, glucocorticoids and damage to the nervous system: the current state of confusion. Stress. 1996;1:1–19.

    Article  PubMed  CAS  Google Scholar 

  68. Gilbertson HW, Sherton ME, Ciszewski A, et al. Smaller hippocampal volume predicts pathological vulnerability to psychological trauma. Nat Neurosci. 2002;5:1242–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Attwood CS, Obrenovich ME, Liu T, et al. Amyloid beta; a chameleon walking in two worlds: a review of the trophic and toxic properties of beta amyloid. Brain Res Rev. 2003;43:1–16.

    Article  CAS  Google Scholar 

  70. Delpech J-C, Madoc C, Nadjar A, et al. Microglia in neuronal plasticity: influence of stress. Neuropharmacology. 2015;96:19–28. https://doi.org/10.1016/j.neuropharm.2014.12.034.

    Article  PubMed  CAS  Google Scholar 

  71. Rapp MA, Dahlman K, Sano M, et al. Neuropsychological differences between late-onset and recurrent geriatric major depression. Am J Psychiatry. 2005;162:691–8.

    Article  PubMed  Google Scholar 

  72. Rapp MA, Schneider-Beeri M, Grossman HT, et al. Increased hippocampal plaques and tangles in patients with Alzheimer’s disease with a life-long history of major depression. Arch Gen Psychiatry. 2006;63:161–7.

    Article  PubMed  Google Scholar 

  73. Borsini A, Zunszain PA, Thuret S, Pariante CM. The role of inflammatory cytokines as key modulators of neurogenesis. Trends Neurosci. 2015;38:145–57.

    Article  PubMed  CAS  Google Scholar 

  74. Gillespie MT, Horwood NJ. IL-18: perspectives on the newest interleukin. Cytokine Growth Factor Rev. 1998;9:109–16.

    Article  PubMed  CAS  Google Scholar 

  75. Ojala J, Alafuzoff I, Herukka SK, et al. Expression of IL-18 is increased in the brains of Alzheimer’s disease patients. Neurobiol Aging. 2009;30:198–209.

    Article  PubMed  CAS  Google Scholar 

  76. Jurcoicova J. Glucose transport in brain: effect of inflammation for neurologic disease. Neurol Endocrin Regul. 2014;48:35–48.

    Article  CAS  Google Scholar 

  77. Yu JT, Tau L, Song JH, et al. Il-18 promotes polymorphisms and risk of late Alzheimer’s disease. Brain Res. 2009;1253:169–75.

    Article  PubMed  CAS  Google Scholar 

  78. Castren E, Rautamaki T. The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol. 2010;70:289–97.

    Article  PubMed  CAS  Google Scholar 

  79. Chou YH, Ling JF, Hsieh WC, et al. Neither cortisol nor BDNF is associated with serotonin transport in bipolar disorder. Eur J Neuropharmacol. 2015;26(2):280–7. https://doi.org/10.1016/j.euroneuro2015.12.011.

  80. Kapczinski F, Frey BN, Kauer-Sant’Anna M, Grassi-Oliveia B. Brain-derived neurotrophic factors and neuroplasticity in bipolar disorder. Exp Rev Neurother. 2008;8(7):1101–13. https://doi.org/10.1586/14737175.8.7.1101.

    Article  CAS  Google Scholar 

  81. Leonard BE, Myint A-M. Inflammation and depression: is there a causal connection with dementia? Neurotox Res. 2006;10:149–60.

    Article  PubMed  CAS  Google Scholar 

  82. Khansari PS, Sperlagh B. Inflammation in neurological and psychiatric diseases. Inflammopharmacology. 2012;20:103–7.

    Article  PubMed  CAS  Google Scholar 

  83. Lyman M, Lloyd DG, Ji X, Vizcaychipi MP, Ma D. Neuroinflammation: the role and consequences. Neurosci Res. 2014;79:1–12.

    Article  PubMed  CAS  Google Scholar 

  84. McEwen BS. Stress, adaptation, and disease allostasis and allostatic load. Ann N Y Acad Sci. 1998;840(1):33–4.

    Article  PubMed  CAS  Google Scholar 

  85. 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.

    PubMed  CAS  Google Scholar 

  86. Singhal G, Jaehne EJ, Corrigan F, Toben C, Baune BT. Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front Neurosci. 2014;8:1–13.

    Article  Google Scholar 

  87. Kipp M, Norkute A, Johann S, et al. Brain-region-specific astroglial responses in vitro after LPS exposure. J Mol Neurosci. 2008;35:235–43.

    Article  PubMed  CAS  Google Scholar 

  88. Insel TR. Rethinking schizophrenia. Nature. 2010;468:187–93.

    Article  PubMed  CAS  Google Scholar 

  89. Bechter K. Diagnosis of infectious or inflammatory psychosyndromes. Open Neurol J. 2012;6(Suppl 1-M6):113–8.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Bachmann S, Degen C, Geider FJ, Schröder J. Neurological soft signs in the clinical course of schizophrenia: results of a meta-analysis. Front Psychiatry. 2014;5:185.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Bechter K. Updating the mild encephalitis hypothesis of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;42:71–91.

    Article  CAS  Google Scholar 

  92. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Herken J, Pruess H. Red flags: clinical signs for identifying autoimmune encephalitis in psychiatric patients. Front Psychiatry. 2017;8:25.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Lang K, Prüß H. Anti-NMDA-Rezeptor-Enzephalitis eine wichtige Differenzialdiagnose. InFo Neurol Psychiatr. 2016;18:7–8.

    Article  Google Scholar 

  95. Lennox BR, Coles AJ, Vincent A. Antibody-mediated encephalitis: a treatable cause of schizophrenia. Br J Psychiatry. 2012;200(2):92–4.

    Article  PubMed  Google Scholar 

  96. Steiner J, Walter M, Glanz W, Sarnyai Z, Bernstein HG, Vielhaber S, et al. Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry. 2013;70(3):271–8.

    Article  PubMed  Google Scholar 

  97. Ehrenreich H, Castillo-Gomez E, Oliveira B, Ott C, Steiner J, Weissenborn K. Circulating NMDAR1 autoantibodies of different immunoglobulin classes modulate evolution of lesion size in acute ischemic stroke. Neurol Psychiatry Brain Res. 2016;22:9–10.

    Article  Google Scholar 

  98. Hammer C, Stepniak B, Schneider A, Papiol S, Tantra M, Begemann M, et al. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity. Mol Psychiatry. 2013;19:1143–9.

    Article  PubMed  CAS  Google Scholar 

  99. Hammer C, Zerche M, Schneider A, Begemann M, Nave KA, Ehrenreich H. Apolipoprotein E4 carrier status plus circulating anti-NMDAR1 autoantibodies: association with schizoaffective disorder. Mol Psychiatry. 2014;19:1045–56.

    Google Scholar 

  100. Najjar S, Pearlman D, Devinsky O, Najjar A, Nadkarni S, Butler T, et al. Neuropsychiatric autoimmune encephalitis without VGKC-complex, NMDAR, and GAD autoantibodies: case report and literature review. Cogn Behav Neurol. 2013;26(1):36–49.

    Article  PubMed  Google Scholar 

  101. Kreye J, Wenke NK, Chayka M, Leubner J, Murugan M, Maier N, et al. Human cerebrospinal fluid monoclonal N-methyl-aspartate-receptor autoantibodies are sufficient for encephalitis pathogenesis. Brain. 2016;139:2641–52.

    Article  PubMed  Google Scholar 

  102. Schwarz E, van Beveren NJM, Ramsey J, Leweke FM, Rothermundt M, Bogerts B, et al. Identification of subgroups of schizophrenia patients with changes in either immune or growth factor and hormonal pathway. Schizophr Bull. 2014;40(4):787–95.

    Article  PubMed  CAS  Google Scholar 

  103. Myint AM, Kim YK. Network beyond IDO in psychiatric disorders: revisiting neurodegeneration hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:304–13.

    Article  PubMed  CAS  Google Scholar 

  104. Leboyer M, Tamouza R, Charron D, Faucard R, Perron H. Human endogenous retrovirus type W (HERV-W) in schizophrenia: a new avenue of research at the gene-environment interface. World J Biol Psychiatry. 2013;14(2):80–90.

    Article  PubMed  Google Scholar 

  105. Müller N, Riedel M, Blendinger C, Oberle K, Jacobs E, Abele-Horn M. Mycoplasma pneumoniae infection and Tourette’s syndrome. Psychiatry Res. 2004;129:119–25.

    Article  PubMed  CAS  Google Scholar 

  106. Bay-Richter C, Linderholm KR, Lim CK, Samuelsson M, Träskman-Bendz L, Guillemin GJ, et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. Brain Behav Immun. 2015;43:110–7.

    Article  PubMed  CAS  Google Scholar 

  107. Fernandez BS, Steiner J, Molendijk ML, Dodd S, Nardin P, Goncalves C-A, et al. C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3(12):1147–56.

    Article  Google Scholar 

  108. Czepielewski LS, Wang L, Gama CS, Barch DM. The relationship of intellectual functioning and cognitive performance to brain structure in schizophrenia. Schizophr Bull. 2016;43(2):355–64. https://doi.org/10.1093/schbull/sbw090.

    Article  PubMed Central  Google Scholar 

  109. Houenou J, d’Albis MA, Daban C, Hamdani N, Delavest M, Lepine JP, et al. Cytomegalovirus seropositivity and serointensity are associated with hippocampal volume and verbal memory in schizophrenia and bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:142–8.

    Article  PubMed  CAS  Google Scholar 

  110. Debnath M, Berk M. Functional implications of the IL-23/IL-17 immune axis in schizophrenia. Mol Neurobiol. 2016. https://doi.org/10.1007/s12035-016-0309-1.

  111. Anderson G, Berk M, Dodd SK, Bechter AC, Altamura B, Dell'Osso S, Kanba A, Monji SH, Fatemi P, Buckley M, Debnath UN, Das U, Meyer N, Müller B, Kanchanatawan B, Maes M. Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;42(C):1–4.

    Article  CAS  Google Scholar 

  112. Doorduin J, deVries EF, Willemsen AT, deGroot JC, Dierckx RA, Klein HC. Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med. 2009;50:1801–7.

    Article  PubMed  Google Scholar 

  113. Sekar A, Bialas A, de Rivera H, Davis A, Hammond T, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component. Nature. 2016;530:177–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Davis J, Moylan S, Harvey BH, Maes M, Berk M. Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry. 2014;48(6):512–29.

    Article  PubMed  Google Scholar 

  115. Cannon TD, Chung Y, He G, Sun D, Jacobson A, van Erp TGM, et al. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol Psychiatry. 2015;77:147–57.

    Article  PubMed  Google Scholar 

  116. Cannon TD. Microglial activation and the onset of psychosis. Am J Psychiatry. 2016;173:3–4.

    Article  PubMed  Google Scholar 

  117. Benros ME, Mortensen PB, Eaton WW. Autoimmune diseases and infections as risk factors for schizophrenia. Ann N Y Acad Sci. 2012;1262:65–6.

    Article  Google Scholar 

  118. Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J, Mortensen PB. Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiatry. 2013;70(8):812–20.

    Article  PubMed  Google Scholar 

  119. Bechter K. Mild encephalitis underlying psychiatric disorder – a reconsideration and hypothesis exemplified on Borna disease. Neurol Psyciatry Brain Res. 2001;9:55–70.

    Google Scholar 

  120. Bakken TE, Miller JA, Ding S-L, Sunkin SM, Smith KA, Ng L, et al. A comprehensive transcriptional map of primate brain development. Nature. 2016;535:367–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Bechter K, Herzog S, Behr W, Schüttler R. Investigations of cerebrospinal fluid in Borna disease virus seropositive psychiatric patients. Eur Psychiatry. 1995;10:250–8.

    Article  PubMed  CAS  Google Scholar 

  122. Bechter K, et al. 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(5):321–30.

    Article  PubMed  CAS  Google Scholar 

  123. Endres D, Perlov E, Baumgartner A, Hottenrott T, Dersch R, Stich O, et al. Immunological findings in psychotic syndromes: a tertiary care hospital’s CSF sample of 180 patients. Front Hum Neurosci. 2015;9:476.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Endres D, Perlov E, Dersch R, Baumgartner A, Hottenrott T, Berger B, et al. Evidence of cerebrospinal fluid abnormalities in patients with depressive syndromes. J Affect Disord. 2016;198:178–84.

    Article  PubMed  Google Scholar 

  125. Endres D, Dersch R, Hottenrott T, Perlov E, Maier S, van Calker D, Hochstuhl B, Venhoff N, Stich O, Tebartz van Elst L. Alterations in cerebrospinal fluid in patients with bipolar syndromes. Front Psychiatry. 2016;7:194.

    PubMed  PubMed Central  Google Scholar 

  126. Vasic N, Connemann BJ, Wolf RC, Tumani H, Brettschneider J. Cerebrospinal fluid biomarker candidates of schizophrenia: where do we stand? Eur Arch Psychiatry Clin Neurosci. 2012;262(5):375–91.

    Article  PubMed  Google Scholar 

  127. Bechter K. CSF diagnostics in psychiatry-present status-future developments. Neurol Psychiatry Brain Res. 2016;22:69–74.

    Article  Google Scholar 

  128. Johansson V, Nybom R, Wetterberg L, Hultman CM, Cannon TD, Johansson GM, Ekman CJ, Landen M. Microscopic particles in two fractions of fresh cerebrospinal fluid in twins with schizophrenia or bipolar disorder and in healthy controls. PLoS One. 2012;7(9):e45994.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Schneider EM, Bechter K, Strunz M, Mostafa H, Zink F, Fuchs D, Loewe R. Characterization of microparticles derived from cultured macrophages and cerebrospinal fluid of patients with schizophrenic and affective disorders. Neurol Psychiatry Brain Res. 2016;22:19.

    Article  Google Scholar 

  130. Borroto-Escuela DO, Agnati LF, Bechter K, Jansson A, Tarakanov AO, Fuxe K. The role of transmitter diffusion and flow versus extracellular vesicles in volume transmission in the brain neural–glial networks. Philos Trans R Soc B. 2015;370:20140183.

    Article  CAS  Google Scholar 

  131. Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, et al. Aging-induce type I interferon response at the choroid plexus negatively affects brain function. Science. 2014;346(6205):89–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, Overall CC, et al. Unexpected role of interferon-g in regulating neuronal connectivity and social behavior. Nature. 2016;535:425–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Bogerts B, Winopal D, Schwarz S, Schlaaff K, Dobrowolny H, Mawrin C, Frodl T, Steiner J. Evidence of neuroinflammation in subgroups of schizophrenia and mood disorder patients: a semiquantitative postmortem study of CD3 and CD20 immunoreactive lymphocytes in several brain regions. Neurol Psychiatry Brain Res. 2017;23:2–9.

    Article  Google Scholar 

  134. Berk M, Conus P, Kapczinski F, Andreazza AC, Yucel M, Wood SJ, et al. From neuroprogression to neuroprotection: implications for clinical care. Med J Aust. 2010;193(4 Suppl):S36–40.

    PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  136. Di Nicola M, Cattaneo A, Hepgul N, Di Forti M, Aitchison KJ, Janiri L, Murray RM, Dazzan P, Pariante CM, Mondelli V. Serum and gene expression profile of cytokines in first-episode psychosis. Brain Behav Immun. 2013;31:90–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Handley R, Mondelli V, Zelaya F, Marques T, Taylor H, Reinders AA, Chaddock C, McQueen G, Hubbard K, Papadopoulos A, Williams S, McGuire P, Pariante C, Dazzan P. Effects of antipsychotics on cortisol, interleukin-6 and hippocampal perfusion in healthy volunteers. Schizophr Res. 2016;174(1–3):99–105.

    Article  PubMed  Google Scholar 

  138. Hepgul N, Pariante CM, Dipasquale S, DiForti M, Taylor H, Marques TR, Morgan C, Dazzan P, Murray RM, Mondelli V. Childhood maltreatment is associated with increased body mass index and increased C-reactive protein levels in first-episode psychosis patients. Psychol Med. 2012;42(9):1893–901.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Mondelli V, Cattaneo A, Murri MB, Di Forti M, Handley R, Hepgul N, Miorelli A, Navari S, Papadopoulos AS, Aitchison KJ, Morgan C, Murray RM, Dazzan P, Pariante CM. Stress and inflammation reduce brain-derived neurotrophic factor expression in first-episode psychosis: a pathway to smaller hippocampal volume. J Clin Psychiatry. 2011;72(12):1677–84.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Mondelli V, Ciufolini S, Belvederi Murri M, Bonaccorso S, Di Forti M, Giordano A, Marques TR, Zunszain PA, Morgan C, Murray RM, Pariante CM, Dazzan P. Cortisol and inflammatory biomarkers predict poor treatment response in first episode psychosis. Schizophr Bull. 2015;41(5):1162–70.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Russell A, Ciufolini S, Gardner-Sood P, Bonaccorso S, Gaughran F, Dazzan P, Pariante CM, Mondelli V. Inflammation and metabolic changes in first episode psychosis: preliminary results from a longitudinal study. Brain Behav Immun. 2015;49:25–9.

    Article  PubMed  CAS  Google Scholar 

  142. Bale TL, Baram TZ, Brown AS, Goldstein JM, Insel TR, McCarthy MM, Nemeroff CB, Reyes TM, Simerly RB, Susser ES, Nestler EJ. Early life programming and neurodevelopmental disorders. Biol Psychiatry. 2010;68(4):314–9.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Cattaneo AF, Macchi G, Plazzotta B, Veronica L, Bocchio-Chiavetto MA, Riva C, Pariante M. Inflammation and neuronal plasticity: a link between childhood trauma and depression pathogenesis. Front Cell Neurosci. 2015;9:40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. McDade TW. Early environments and the ecology of inflammation. Proc Natl Acad Sci. 2012;109(2):17281–8.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Bilbo SD. Early-life programming of later-life brain and behavior: a critical role for the immune system. Front Behav Neurosci. 2009;3:14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Moylan S, Maes M, Wray NR, Berk M. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry. 2012;18(5):595–606.

    Article  PubMed  Google Scholar 

  147. Netea MG, Latz E, Mills KHG, O’Neill LAJ. Innate immune memory: a paradigm shift in understanding host defense. Nat Immunol. 2015;16(7):675–9.

    Article  PubMed  CAS  Google Scholar 

  148. Bakunina N, Pariante CM, Zunszain PA. Immune mechanisms linked to depression via oxidative stress and neuroprogression. Immunology. 2015;144:365–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  149. Felger JC, Li Z, Haroon E, Woolwine BJ, Jung MY, Hu X, et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. 2016;21(10):1358–65.

    Article  PubMed  CAS  Google Scholar 

  150. Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety. 2013;30(4):297–306.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Cowen PJ. Not fade away: the HPA axis and depression. Psychol Med. 2010;40:1–4.

    Article  PubMed  CAS  Google Scholar 

  152. Stetler C, Miller GE. Depression and HPA activation: a quantitative summary of 4 decades of research. Psychosom Med. 2011;73:114–26.

    Article  PubMed  Google Scholar 

  153. McEwen BS. Protective and damaging effects of stress mediators: central role of the brain. Dial Clin Neurosci. 2006;8:367–81.

    Google Scholar 

  154. Duman RS. Depression: a case of a neuronal life and death? Biol Psychiatry. 2004;56:140–5.

    Article  PubMed  Google Scholar 

  155. Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10:1110–5.

    Article  PubMed  CAS  Google Scholar 

  156. Davis KL, Davis BM, Greenwald BS, et al. Cortisol and Alzheimer’s disease: Basal studies. Am J Psychiatry. 1986;143:300–5.

    Article  PubMed  CAS  Google Scholar 

  157. Hartmann A, Veldhuis JD, Deuschle M, et al. Twenty-four hour cortisol release profiles in patients with Alzheimer’s disease and Parkinson’s disease compared to normal controls in ultradian secretory pulsatility and diurnal variation. Neurobiol Aging. 1997;18:285–9.

    Article  PubMed  CAS  Google Scholar 

  158. Peskind ER, Wilkinson CW, Petrie EC, et al. Increased CSF cortisol is a function of ApoE genotype. Neurology. 2001;56:1094–8.

    Article  PubMed  CAS  Google Scholar 

  159. Munkholm K, Brauner JV, Kessing LV, Vinberg M. Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J Psychiatr Res. 2013;47(9):1119–33.

    Article  PubMed  Google Scholar 

  160. Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012;37(1):137–62.

    Article  PubMed  CAS  Google Scholar 

  161. Halaris A, Meresh E, Sharma A, Alvi N, Sinacore J. Inflammation control augments antidepressant response in bipolar depression. Brain Behav Immun. 2013;32:e26.

    Article  Google Scholar 

  162. 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 Psychiatry. 2013;70(1):31–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011;35(3):804–17.

    Article  PubMed  CAS  Google Scholar 

  164. Miller AH, Haroon E, Felger JC. Therapeutic implications of brain-immune interactions: treatment in translation. Neuropsychopharmacology. 2017;42(1):334–59.

    Article  PubMed  CAS  Google Scholar 

  165. Braitenberg V, Schüz A. Cortex: statistics and geometry of neuronal connectivity. Berlin Heidelberg: Springer Science & Business Media; 2013.

    Google Scholar 

  166. Danbolt NC. Glutamate uptake. Prog Neurobiol. 2001;65(1):1–105.

    Article  PubMed  CAS  Google Scholar 

  167. Haroon E, Miller AH, Sanacora G. Inflammation, glutamate, and glia: a trio of trouble in mood disorders. Neuropsychopharmacology. 2017;42(1):193–215.

    Article  PubMed  CAS  Google Scholar 

  168. Sanacora G, Banasr M. From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders. Biol Psychiatry. 2013;73(12):1172–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, et al. Interferon-alpha-induced changes in tryptophan metabolism. Relationship to depression and paroxetine treatment. Biol Psychiatry. 2003;54(9):906–14.

    Article  PubMed  CAS  Google Scholar 

  170. Raison CL, Borisov AS, Woolwine BJ, Massung B, Vogt G, Miller AH. Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol Psychiatry. 2010;15(5):535–47.

    Article  PubMed  CAS  Google Scholar 

  171. Haroon E, Woolwine BJ, Chen X, Pace TW, Parekh S, Spivey JR, et al. IFN-alpha-induced cortical and subcortical glutamate changes assessed by magnetic resonance spectroscopy. Neuropsychopharmacology. 2014;39(7):1777–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Haroon E, Felger JC, Woolwine BJ, Chen X, Parekh S, Spivey JR, et al. Age-related increases in basal ganglia glutamate are associated with TNF, reduced motivation and decreased psychomotor speed during IFN-alpha treatment: preliminary findings. Brain Behav Immun. 2015;46:17–22.

    Article  PubMed  CAS  Google Scholar 

  173. Godbout JP, Johnson RW. Age and neuroinflammation: a lifetime of psychoneuroimmune consequences. Immunol Allergy Clin N Am. 2009;29(2):321–37.

    Article  Google Scholar 

  174. Niraula A, Sheridan JF, Godbout JP. Microglia priming with aging and stress. Neuropsychopharmacology. 2017;42(1):318–33.

    Article  PubMed  Google Scholar 

  175. Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun. 2014;42:50–9.

    Article  PubMed  CAS  Google Scholar 

  176. Haroon E, Fleischer CC, Felger JC, Chen X, Woolwine BJ, Patel T, et al. Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Mol Psychiatry. 2016;21(10):1351–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation. 2003;107(3):363–9.

    Article  PubMed  Google Scholar 

  178. Ridker PM. From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection. Circ Res. 2016;118(1):145–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007;21(2):153–60.

    Article  PubMed  CAS  Google Scholar 

  180. Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B, et al. NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology. 2013;38(9):1609–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  182. Iwata M, Ota KT, Li XY, Sakaue F, Li N, Dutheil S, et al. Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor. Biol Psychiatry. 2016;80(1):12–22.

    Article  PubMed  CAS  Google Scholar 

  183. Banasr M, Duman RS. Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry. 2008;64(10):863–70.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Bernard R, Kerman IA, Thompson RC, Jones EG, Bunney WE, Barchas JD, et al. Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol Psychiatry. 2011;16(6):634–46.

    Article  PubMed  CAS  Google Scholar 

  185. Mechawar N, Savitz J. Neuropathology of mood disorders: do we see the stigmata of inflammation? Transl Psychiatry. 2016;6(11):e946.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Ongur D, Bechtholt AJ, Carlezon WA Jr, Cohen BM. Glial abnormalities in mood disorders. Harv Rev Psychiatry. 2014;22(6):334–7.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Rajkowska G, Stockmeier CA. Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets. 2013;14(11):1225–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Miller BJ, Goldsmith DR. Towards an immunophenotype of schizophrenia: progress, potential mechanisms, and future directions. Neuropsychopharmacology. 2017;42(1):299–317.

    Article  PubMed  CAS  Google Scholar 

  189. 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(7):680–4.

    Article  PubMed  CAS  Google Scholar 

  190. 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.

    Article  CAS  Google Scholar 

  191. Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB, et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172(10):950–66.

    Article  PubMed  Google Scholar 

  192. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856–64.

    Article  PubMed  CAS  Google Scholar 

  193. Hashimoto K. Inflammatory biomarkers as differential predictors of antidepressant response. Int J Mol Sci. 2015;16(4):7796–801.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Machado-Vieira R, Gold PW, Luckenbaugh DA, Ballard ED, Richards EM, Henter ID, et al. The role of adipokines in the rapid antidepressant effects of ketamine. Mol Psychiatry. 2017;22(1):127–33. https://doi.org/10.1038/mp.2016.36.

    Article  PubMed  CAS  Google Scholar 

  195. Walker AJ, Foley BM, Sutor SL, McGillivray JA, Frye MA, Tye SJ. Peripheral proinflammatory markers associated with ketamine response in a preclinical model of antidepressant-resistance. Behav Brain Res. 2015;293:198–202.

    Article  PubMed  CAS  Google Scholar 

  196. Walker AJ, Kim Y, Price JB, Kale RP, McGillivray JA, Berk M, et al. Stress, inflammation, and cellular vulnerability during early stages of affective disorders: biomarker strategies and opportunities for prevention and intervention. Front Psychiatry. 2014;5:34.

    Article  PubMed  PubMed Central  Google Scholar 

  197. Mathew S, Fava M, Guerguieva R, Sanacora G, editors. A randomized placebo-controlled adjunctive trial of riluzole in treatment-resistant major depressive disorder – NCT01204918 – efficacy and tolerability of riluzole in treatment resistant depression. ASCP Annual Meeting (NCDEU). Miami, FL, USA; 2015.

    Google Scholar 

  198. Niciu MJ, Luckenbaugh DA, Ionescu DF, Richards EM, Vande Voort JL, Ballard ED, et al. Riluzole likely lacks antidepressant efficacy in ketamine non-responders. J Psychiatr Res. 2014;58:197–9.

    Article  PubMed  PubMed Central  Google Scholar 

  199. Pittenger C, Coric V, Banasr M, Bloch M, Krystal JH, Sanacora G. Riluzole in the treatment of mood and anxiety disorders. CNS Drugs. 2008;22(9):761–86.

    Article  PubMed  CAS  Google Scholar 

  200. Salardini E, Zeinoddini A, Mohammadinejad P, Khodaie-Ardakani MR, Zahraei N, Zeinoddini A, et al. Riluzole combination therapy for moderate-to-severe major depressive disorder: a randomized, double-blind, placebo-controlled trial. J Psychiatr Res. 2016;75:24–30.

    Article  PubMed  Google Scholar 

  201. Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7(5):426–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Beurel E, Grieco SF, Amadei C, Downey K, Jope RS. Ketamine-induced inhibition of glycogen synthase kinase-3 contributes to the augmentation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor signaling. Bipolar Disord. 2016;18(6):473–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Gigante AD, Bond DJ, Lafer B, Lam RW, Young LT, Yatham LN. Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis. Bipolar Disord. 2012;14(5):478–87.

    Article  PubMed  CAS  Google Scholar 

  204. Yuksel C, Ongur D. Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry. 2010;68(9):785–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Jope RS. Glycogen synthase kinase-3 in the etiology and treatment of mood disorders. Front Mol Neurosci. 2011;4:16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  206. Krystal JH, Sanacora G, Blumberg H, Anand A, Charney DS, Marek G, et al. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry. 2002;7(Suppl 1):S71–80.

    Article  PubMed  CAS  Google Scholar 

  207. Machado-Vieira R, Manji HK, Zarate CA Jr. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord. 2009;11(Suppl 2):92–109.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Frye MA, Watzl J, Banakar S, O’Neill J, Mintz J, Davanzo P, et al. Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression. Neuropsychopharmacology. 2007;32(12):2490–9.

    Article  PubMed  CAS  Google Scholar 

  209. Alboni S, Gibellini L, Montanari C, Benatti C, Benatti S, Tascedda F, Brunello N, Cossarizza A, Pariante CM. N-acetyl-cysteine prevents toxic oxidative effects induced by IFN-α in human neurons. Int J Neuropsychopharmacol. 2013;16(8):1849–65.

    Article  PubMed  CAS  Google Scholar 

  210. Horowitz MA, Wertz J, Zhu D, Cattaneo A, Musaelyan K, Nikkheslat N, Thuret S, Pariante CM, Zunszain PA. Antidepressant compounds can be both pro- and anti-inflammatory in human hippocampal cells. Int J Neuropsychopharmacol. 2014;18(3):pyu076.

    Article  PubMed  CAS  Google Scholar 

  211. Zunszain PA, Anacker C, Cattaneo A, Choudhury S, Musaelyan K, Myint AM, Thuret S, Price J, Pariante CM. Interleukin-1β: a new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacology. 2012 Mar;37(4):939–49.

    Article  PubMed  CAS  Google Scholar 

  212. Haroon E, Miller AH. Inflammation effects on brain glutamate in depression: mechanistic considerations and treatment implications. Curr Top Behav Neurosci. 2017;31:173–98. https://doi.org/10.1007/7854_2016_40.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Neuroscience, Loyola University Chicago, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL, USA

    Angelos Halaris

  2. Department of Psychiatry and Psychotherapy, Ulm University, Günzburg, Germany

    Karl Bechter

  3. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    Ebrahim Haroon

  4. Pharmacology Department, National University of Ireland, Galway, Ireland

    Brain E. Leonard

  5. Emory Behavioral Immunology Program, Department of Psychiatry and Behavioral Sciences, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    Andrew Miller

  6. Stress, Psychiatry and Immunology Laboratory (SPI-Lab), Department of Psychological Medicine, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, England

    Carmine Pariante & Patricia Zunszain

Authors
  1. Angelos Halaris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karl Bechter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ebrahim Haroon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brain E. Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carmine Pariante
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Patricia Zunszain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Angelos Halaris .

Editor information

Editors and Affiliations

  1. The Medical Centre, Nuneaton, United Kingdom

    Afzal Javed

  2. Division of Neuroscience Medicine, Aristotle University, Division of Neuroscience Medicine, Thessaloniki, Greece

    Kostas N. Fountoulakis

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Halaris, A. et al. (2019). The Future of Psychoneuroimmunology: Promises and Challenges. In: Javed, A., Fountoulakis, K. (eds) Advances in Psychiatry. Springer, Cham. https://doi.org/10.1007/978-3-319-70554-5_15

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-70554-5_15

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-70553-8

  • Online ISBN: 978-3-319-70554-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation