Skip to main content

Advertisement

SpringerLink
Log in

Inflammatory Pathways in Psychiatric Disorders: the Case of Schizophrenia and Depression

  • Psychosis (A Ahmed, Section Editor)
  • Published:
Current Behavioral Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

A better understanding of the key molecules/pathways underlying the pathophysiology of depression and schizophrenia may contribute to novel therapeutic strategies. In this review, we have discussed the recent developments on the role of inflammatory pathways in the pathogenesis of depression and schizophrenia.

Recent Findings

Inflammation is an innate immune response that can be triggered by various factors, including pathogens, stress, and injury. Under normal conditions, the inflammatory responses quiet after pathogen clearance and tissue repair. However, abnormal long-term or chronic inflammation can lead to damaging effects. Accumulating evidence suggest that dysregulated inflammation is linked to the pathogenesis of neuropsychiatric disorders. In this review, we have discussed the roles of complement system, infiltration of peripheral immune cells into the central nervous system (CNS), the gut-brain axis, and the kynurenine pathway in depression and schizophrenia.

Summary

There is a large body of compelling evidence on the role of inflammatory pathways in depression and schizophrenia. Although most of these findings show their roles in the pathophysiology of the above disorders, additional studies are warranted to investigate the therapeutic potential of various immune signaling targets discussed in this article.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data Availability

Not applicable.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Rathinam VAK, Chan FK. Inflammasome, inflammation, and tissue homeostasis. Trends Mol Med. 2018;24(3):304–18. https://doi.org/10.1016/j.molmed.2018.01.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140(6):871–82. https://doi.org/10.1016/j.cell.2010.02.029.

    Article  CAS  PubMed  Google Scholar 

  3. • Yuan N, Chen Y, Xia Y, Dai J, Liu C. Inflammation-related biomarkers in major psychiatric disorders: a cross-disorder assessment of reproducibility and specificity in 43 meta-analyses. Transl Psychiatry. 2019;9(1):233. https://doi.org/10.1038/s41398-019-0570-yThis study systematically reviewed meta-analyses of inflammation-related factor changes in eight major psychiatric disorders and calculated the effect size and statistical power for every inflammation-related factor in each disorder.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bauer ME, Teixeira AL. Inflammation in psychiatric disorders: what comes first? Ann N Y Acad Sci. 2019;1437(1):57–67. https://doi.org/10.1111/nyas.13712.

    Article  CAS  PubMed  Google Scholar 

  5. Orlovska-Waast S, Kohler-Forsberg O, Brix SW, Nordentoft M, Kondziella D, Krogh J, et al. Correction: cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Mol Psychiatry. 2019;24(6):929–34. https://doi.org/10.1038/s41380-019-0381-9.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Boerrigter D, Weickert TW, Lenroot R, O'Donnell M, Galletly C, Liu D, et al. Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder. J Neuroinflammation. 2017;14(1):188. https://doi.org/10.1186/s12974-017-0962-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013;246:199–229. https://doi.org/10.1016/j.neuroscience.2013.04.060.

    Article  CAS  PubMed  Google Scholar 

  8. Cheng Y, Jope RS, Beurel E. A pre-conditioning stress accelerates increases in mouse plasma inflammatory cytokines induced by stress. BMC Neurosci. 2015;16:31. https://doi.org/10.1186/s12868-015-0169-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang P, Gao Z, Zhang H, Fang Z, Wu C, Xu H, et al. Changes in proinflammatory cytokines and white matter in chronically stressed rats. Neuropsychiatr Dis Treat. 2015;11:597–607. https://doi.org/10.2147/NDT.S78131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bennabi D, Charpeaud T, Yrondi A, Genty JB, Destouches S, Lancrenon S, et al. Clinical guidelines for the management of treatment-resistant depression: French recommendations from experts, the French Association for Biological Psychiatry and Neuropsychopharmacology and the fondation FondaMental. BMC Psychiatry. 2019;19(1):262. https://doi.org/10.1186/s12888-019-2237-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369–88. https://doi.org/10.2147/PPA.S29716.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Souery D, Amsterdam J, de Montigny C, Lecrubier Y, Montgomery S, Lipp O, et al. Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol. 1999;9(1–2):83–91. https://doi.org/10.1016/s0924-977x(98)00004-2.

    Article  CAS  PubMed  Google Scholar 

  13. Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology. 2000;22(4):370–9. https://doi.org/10.1016/S0893-133X(99)00134-7.

    Article  CAS  PubMed  Google Scholar 

  14. Bai S, Guo W, Feng Y, Deng H, Li G, Nie H, et al. Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020;91(1):21–32. https://doi.org/10.1136/jnnp-2019-320912.

    Article  PubMed  Google Scholar 

  15. Koola MM, Raines JK, Hamilton RG, McMahon RP. Can anti-inflammatory medications improve symptoms and reduce mortality in schizophrenia? Curr Psychiatr Ther. 2016;15(5):52–7.

    Google Scholar 

  16. Andrade C. Anti-inflammatory strategies in the treatment of schizophrenia. Expert Rev Clin Pharmacol. 2016;9(2):161–3. https://doi.org/10.1586/17512433.2016.1095086.

    Article  CAS  PubMed  Google Scholar 

  17. Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement system. Part I—molecular mechanisms of activation and regulation. Front Immunol. 2015;6:262. https://doi.org/10.3389/fimmu.2015.00262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Merle NS, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT. Complement system part II: role in immunity. Front Immunol. 2015;6:257. https://doi.org/10.3389/fimmu.2015.00257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Veerhuis R, Nielsen HM, Tenner AJ. Complement in the brain. Mol Immunol. 2011;48(14):1592–603. https://doi.org/10.1016/j.molimm.2011.04.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gasque P, Fontaine M, Morgan BP. Complement expression in human brain. Biosynthesis of terminal pathway components and regulators in human glial cells and cell lines. J Immunol. 1995;154(9):4726–33.

    CAS  PubMed  Google Scholar 

  21. Veerhuis R, Janssen I, De Groot CJ, Van Muiswinkel FL, Hack CE, Eikelenboom P. Cytokines associated with amyloid plaques in Alzheimer's disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor. Exp Neurol. 1999;160(1):289–99. https://doi.org/10.1006/exnr.1999.7199.

    Article  CAS  PubMed  Google Scholar 

  22. Woodruff TM, Ager RR, Tenner AJ, Noakes PG, Taylor SM. The role of the complement system and the activation fragment C5a in the central nervous system. NeuroMolecular Med. 2010;12(2):179–92. https://doi.org/10.1007/s12017-009-8085-y.

    Article  CAS  PubMed  Google Scholar 

  23. Perez-Alcazar M, Daborg J, Stokowska A, Wasling P, Bjorefeldt A, Kalm M, et al. Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3. Exp Neurol. 2014;253:154–64. https://doi.org/10.1016/j.expneurol.2013.12.013.

    Article  PubMed  Google Scholar 

  24. Shi Q, Colodner KJ, Matousek SB, Merry K, Hong S, Kenison JE, et al. Complement C3-deficient mice fail to display age-related hippocampal decline. J Neurosci. 2015;35(38):13029–42. https://doi.org/10.1523/JNEUROSCI.1698-15.2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Crider A, Feng T, Pandya CD, Davis T, Nair A, Ahmed AO, et al. Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior. Brain Behav Immun. 2018;70:246–56. https://doi.org/10.1016/j.bbi.2018.03.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kronfol Z, House JD. Lymphocyte mitogenesis, immunoglobulin and complement levels in depressed patients and normal controls. Acta Psychiatr Scand. 1989;80(2):142–7. https://doi.org/10.1111/j.1600-0447.1989.tb01316.x.

    Article  CAS  PubMed  Google Scholar 

  27. Song C, Dinan T, Leonard BE. Changes in immunoglobulin, complement and acute phase protein levels in the depressed patients and normal controls. J Affect Disord. 1994;30(4):283–8. https://doi.org/10.1016/0165-0327(94)90135-x.

    Article  CAS  PubMed  Google Scholar 

  28. Berk M, Wadee AA, Kuschke RH, O'Neill-Kerr A. Acute phase proteins in major depression. J Psychosom Res. 1997;43(5):529–34. https://doi.org/10.1016/s0022-3999(97)00139-6.

    Article  CAS  PubMed  Google Scholar 

  29. Boyle SH, Jackson WG, Suarez EC. Hostility, anger, and depression predict increases in C3 over a 10-year period. Brain Behav Immun. 2007;21(6):816–23. https://doi.org/10.1016/j.bbi.2007.01.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ishii T, Hattori K, Miyakawa T, Watanabe K, Hidese S, Sasayama D, et al. Increased cerebrospinal fluid complement C5 levels in major depressive disorder and schizophrenia. Biochem Biophys Res Commun. 2018;497(2):683–8. https://doi.org/10.1016/j.bbrc.2018.02.131.

    Article  CAS  PubMed  Google Scholar 

  31. Wang Q, Yu C, Shi S, Su X, Zhang J, Ding Y, et al. An analysis of plasma reveals proteins in the acute phase response pathway to be candidate diagnostic biomarkers for depression. Psychiatry Res. 2019;272:404–10. https://doi.org/10.1016/j.psychres.2018.11.069.

    Article  CAS  PubMed  Google Scholar 

  32. Woo JJ, Pouget JG, Zai CC, Kennedy JL. The complement system in schizophrenia: where are we now and what's next? Mol Psychiatry. 2020;25(1):114–30. https://doi.org/10.1038/s41380-019-0479-0.

    Article  CAS  PubMed  Google Scholar 

  33. Mayilyan KR, Weinberger DR, Sim RB. The complement system in schizophrenia. Drug News Perspect. 2008;21(4):200–10. https://doi.org/10.1358/dnp.2008.21.4.1213349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530(7589):177–83. https://doi.org/10.1038/nature16549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Prasad KM, Chowdari KV, D'Aiuto LA, Iyengar S, Stanley JA, Nimgaonkar VL. Neuropil contraction in relation to complement C4 gene copy numbers in independent cohorts of adolescent-onset and young adult-onset schizophrenia patients-a pilot study. Transl Psychiatry. 2018;8(1):134. https://doi.org/10.1038/s41398-018-0181-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Havik B, Le Hellard S, Rietschel M, Lybaek H, Djurovic S, Mattheisen M, et al. The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia. Biol Psychiatry. 2011;70(1):35–42. https://doi.org/10.1016/j.biopsych.2011.01.030.

    Article  CAS  PubMed  Google Scholar 

  37. Escudero-Esparza A, Kalchishkova N, Kurbasic E, Jiang WG, Blom AM. The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I-mediated degradation of C4b and C3b and inhibits the membrane attack complex assembly. FASEB J. 2013;27(12):5083–93. https://doi.org/10.1096/fj.13-230706.

    Article  CAS  PubMed  Google Scholar 

  38. Schizophrenia Psychiatric Genome-Wide Association Study C. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43(10):969–76. https://doi.org/10.1038/ng.940.

    Article  CAS  Google Scholar 

  39. Boyajyan A, Khoyetsyan A, Chavushyan A. Alternative complement pathway in schizophrenia. Neurochem Res. 2010;35(6):894–8. https://doi.org/10.1007/s11064-010-0126-2.

    Article  CAS  PubMed  Google Scholar 

  40. • Focking M, Sabherwal S, Cates HM, Scaife C, Dicker P, Hryniewiecka M, et al. Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-018-0306-zThis study is unique in that it focused on the entire plasma complement pathway proteins at age 12 and associated those proteins with psychotic experiences at age 18.

  41. Blaylock RL. Immunology primer for neurosurgeons and neurologists part 2: innate brain immunity. Surg Neurol Int. 2013;4:118. https://doi.org/10.4103/2152-7806.118349.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kealy J, Greene C, Campbell M. Blood-brain barrier regulation in psychiatric disorders. Neurosci Lett. 2018;133664:133664. https://doi.org/10.1016/j.neulet.2018.06.033.

    Article  CAS  Google Scholar 

  43. 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(5):321–30. https://doi.org/10.1016/j.jpsychires.2009.08.008.

    Article  CAS  PubMed  Google Scholar 

  44. Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, et al. Social stress induces neurovascular pathology promoting depression. Nat Neurosci. 2017;20(12):1752–60. https://doi.org/10.1038/s41593-017-0010-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Menard C, Hodes GE, Russo SJ. Pathogenesis of depression: insights from human and rodent studies. Neuroscience. 2016;321:138–62. https://doi.org/10.1016/j.neuroscience.2015.05.053.

    Article  CAS  PubMed  Google Scholar 

  46. Ataka K, Asakawa A, Nagaishi K, Kaimoto K, Sawada A, Hayakawa Y, et al. Bone marrow-derived microglia infiltrate into the paraventricular nucleus of chronic psychological stress-loaded mice. PLoS One. 2013;8(11):e81744. https://doi.org/10.1371/journal.pone.0081744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Brevet M, Kojima H, Asakawa A, Atsuchi K, Ushikai M, Ataka K, et al. Chronic foot-shock stress potentiates the influx of bone marrow-derived microglia into hippocampus. J Neurosci Res. 2010;88(9):1890–7. https://doi.org/10.1002/jnr.22362.

    Article  CAS  PubMed  Google Scholar 

  48. Weber MD, Godbout JP, Sheridan JF. Repeated social defeat, neuroinflammation, and behavior: monocytes carry the signal. Neuropsychopharmacology. 2017;42(1):46–61. https://doi.org/10.1038/npp.2016.102.

    Article  PubMed  Google Scholar 

  49. Wohleb ES, Powell ND, Godbout JP, Sheridan JF. Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J Neurosci. 2013;33(34):13820–33. https://doi.org/10.1523/JNEUROSCI.1671-13.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. McKim DB, Weber MD, Niraula A, Sawicki CM, Liu X, Jarrett BL, et al. Microglial recruitment of IL-1beta-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry. 2018;23(6):1421–31. https://doi.org/10.1038/mp.2017.64.

    Article  CAS  PubMed  Google Scholar 

  51. Zang X, Zheng X, Hou Y, Hu M, Wang H, Bao X, et al. Regulation of proinflammatory monocyte activation by the kynurenine-AhR axis underlies immunometabolic control of depressive behavior in mice. FASEB J. 2018;32(4):1944–56. https://doi.org/10.1096/fj.201700853R.

    Article  CAS  PubMed  Google Scholar 

  52. Aguilar-Valles A, Kim J, Jung S, Woodside B, Luheshi GN. Role of brain transmigrating neutrophils in depression-like behavior during systemic infection. Mol Psychiatry. 2014;19(5):599–606. https://doi.org/10.1038/mp.2013.137.

    Article  CAS  PubMed  Google Scholar 

  53. Beurel E, Lowell JA. Th17 cells in depression. Brain Behav Immun. 2018;69:28–34. https://doi.org/10.1016/j.bbi.2017.08.001.

    Article  CAS  PubMed  Google Scholar 

  54. • Najjar S, Pahlajani S, De Sanctis V, Stern JNH, Najjar A, Chong D. Neurovascular unit dysfunction and blood-brain barrier hyperpermeability contribute to schizophrenia neurobiology: a theoretical integration of clinical and experimental evidence. Front Psychiatry. 2017;8:83. https://doi.org/10.3389/fpsyt.2017.00083This review presented a theoretical integration of human and animal data linking oxidative stress and neuroinflammation to neurovascular endotheliopathy and BBB breakdown in schizophrenia.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Cai HQ, Catts VS, Webster MJ, Galletly C, Liu D, O'Donnell M, et al. Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0235-x.

  56. Fernandez-Egea E, Vertes PE, Flint SM, Turner L, Mustafa S, Hatton A, et al. Peripheral immune cell populations associated with cognitive deficits and negative symptoms of treatment-resistant schizophrenia. PLoS One. 2016;11(5):e0155631. https://doi.org/10.1371/journal.pone.0155631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Steiner J, Frodl T, Schiltz K, Dobrowolny H, Jacobs R, Fernandes BS, et al. Innate immune cells and C-reactive protein in acute first-episode psychosis and schizophrenia: relationship to psychopathology and treatment. Schizophr Bull. 2019. https://doi.org/10.1093/schbul/sbz068.

  58. Singh V, Roth S, Llovera G, Sadler R, Garzetti D, Stecher B, et al. Microbiota dysbiosis controls the neuroinflammatory response after stroke. J Neurosci. 2016;36(28):7428–40. https://doi.org/10.1523/JNEUROSCI.1114-16.2016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Treangen TJ, Wagner J, Burns MP, Villapol S. Traumatic brain injury in mice induces acute bacterial dysbiosis within the fecal microbiome. Front Immunol. 2018;9:2757. https://doi.org/10.3389/fimmu.2018.02757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yang D, Zhao D, Ali Shah SZ, Wu W, Lai M, Zhang X, et al. The role of the gut microbiota in the pathogenesis of Parkinson's disease. Front Neurol. 2019;10:1155. https://doi.org/10.3389/fneur.2019.01155.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Frohlich EE, Farzi A, Mayerhofer R, Reichmann F, Jacan A, Wagner B, et al. Cognitive impairment by antibiotic-induced gut dysbiosis: analysis of gut microbiota-brain communication. Brain Behav Immun. 2016;56:140–55. https://doi.org/10.1016/j.bbi.2016.02.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ahern PP, Maloy KJ. Understanding immune-microbiota interactions in the intestine. Immunology. 2020;159(1):4–14. https://doi.org/10.1111/imm.13150.

    Article  CAS  PubMed  Google Scholar 

  63. Hao WZ, Li XJ, Zhang PW, Chen JX. A review of antibiotics, depression, and the gut microbiome. Psychiatry Res. 2020;284:112691. https://doi.org/10.1016/j.psychres.2019.112691.

    Article  CAS  PubMed  Google Scholar 

  64. Caspani G, Kennedy S, Foster JA, Swann J. Gut microbial metabolites in depression: understanding the biochemical mechanisms. Microb Cell. 2019;6(10):454–81. https://doi.org/10.15698/mic2019.10.693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Naseribafrouei A, Hestad K, Avershina E, Sekelja M, Linlokken A, Wilson R, et al. Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil. 2014;26(8):1155–62. https://doi.org/10.1111/nmo.12378.

    Article  CAS  PubMed  Google Scholar 

  66. Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Mol Psychiatry. 2016;21(6):786–96. https://doi.org/10.1038/mp.2016.44.

    Article  CAS  PubMed  Google Scholar 

  67. Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett. 2008;29(1):117–24.

    PubMed  Google Scholar 

  68. Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun. 2011;25(3):397–407. https://doi.org/10.1016/j.bbi.2010.10.023.

    Article  CAS  PubMed  Google Scholar 

  69. Jang HM, Lee HJ, Jang SE, Han MJ, Kim DH. Evidence for interplay among antibacterial-induced gut microbiota disturbance, neuro-inflammation, and anxiety in mice. Mucosal Immunol. 2018;11(5):1386–97. https://doi.org/10.1038/s41385-018-0042-3.

    Article  CAS  PubMed  Google Scholar 

  70. van de Wouw M, Boehme M, Dinan TG, Cryan JF. Monocyte mobilisation, microbiota & mental illness. Brain Behav Immun. 2019;81:74–91. https://doi.org/10.1016/j.bbi.2019.07.019.

    Article  CAS  PubMed  Google Scholar 

  71. Golofast B, Vales K. The connection between microbiome and schizophrenia. Neurosci Biobehav Rev. 2020;108:712–31. https://doi.org/10.1016/j.neubiorev.2019.12.011.

    Article  PubMed  Google Scholar 

  72. Xu R, Wu B, Liang J, He F, Gu W, Li K, et al. Altered gut microbiota and mucosal immunity in patients with schizophrenia. Brain Behav Immun. 2019;85:120–7. https://doi.org/10.1016/j.bbi.2019.06.039.

    Article  CAS  PubMed  Google Scholar 

  73. • Zheng P, Zeng B, Liu M, Chen J, Pan J, Han Y, et al. The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice. Sci Adv. 2019;5(2):eaau8317. https://doi.org/10.1126/sciadv.aau8317This study showed that gut microbiome can modulate brain function and behaviors through the microbiota-gut-brain axis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Severance EG, Gressitt KL, Stallings CR, Origoni AE, Khushalani S, Leweke FM, et al. Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophr Res. 2013;148(1–3):130–7. https://doi.org/10.1016/j.schres.2013.05.018.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Maes M, Kanchanatawan B, Sirivichayakul S, Carvalho AF. In schizophrenia, increased plasma IgM/IgA responses to gut commensal bacteria are associated with negative symptoms, neurocognitive impairments, and the deficit phenotype. Neurotox Res. 2019;35(3):684–98. https://doi.org/10.1007/s12640-018-9987-y.

    Article  CAS  PubMed  Google Scholar 

  76. Treiner E, Duban L, Moura IC, Hansen T, Gilfillan S, Lantz O. Mucosal-associated invariant T (MAIT) cells: an evolutionarily conserved T cell subset. Microbes Infect. 2005;7(3):552–9. https://doi.org/10.1016/j.micinf.2004.12.013.

    Article  CAS  PubMed  Google Scholar 

  77. Varun CN, Venkataswamy MM, Ravikumar R, Nagaraju R, Debnath M, Varambally S, et al. Th17 and MAIT cell mediated inflammation in antipsychotic free schizophrenia patients. Schizophr Res. 2019;212:47–53. https://doi.org/10.1016/j.schres.2019.08.013.

    Article  PubMed  Google Scholar 

  78. Gonzalez A, Varo N, Alegre E, Diaz A, Melero I. Immunosuppression routed via the kynurenine pathway: a biochemical and pathophysiologic approach. Adv Clin Chem. 2008;45:155–97. https://doi.org/10.1016/s0065-2423(07)00007-8.

    Article  CAS  PubMed  Google Scholar 

  79. • Savitz J. The kynurenine pathway: a finger in every pie. Mol Psychiatry. 2020;25(1):131–47. https://doi.org/10.1038/s41380-019-0414-4This review provides a broad overview of the mechanistic pathways of kynurenines interaction and novel therapeutic approaches targeting the KP are discussed.

    Article  PubMed  Google Scholar 

  80. Strasser B, Becker K, Fuchs D, Gostner JM. Kynurenine pathway metabolism and immune activation: Peripheral measurements in psychiatric and co-morbid conditions. Neuropharmacology. 2017;112(Pt B):286–96. https://doi.org/10.1016/j.neuropharm.2016.02.030.

    Article  CAS  PubMed  Google Scholar 

  81. Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health. Science. 2017;357(6349):eaaf9794. https://doi.org/10.1126/science.aaf9794.

    Article  CAS  PubMed  Google Scholar 

  82. Liu H, Ding L, Zhang H, Mellor D, Wu H, Zhao D, et al. The metabolic factor kynurenic acid of kynurenine pathway predicts major depressive disorder. Front Psychiatry. 2018;9:552. https://doi.org/10.3389/fpsyt.2018.00552.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Dantzer R. Role of the Kynurenine metabolism pathway in inflammation-induced depression: preclinical approaches. Curr Top Behav Neurosci. 2017;31:117–38. https://doi.org/10.1007/7854_2016_6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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. https://doi.org/10.1016/j.bbi.2014.07.012.

    Article  CAS  PubMed  Google Scholar 

  85. Haroon E, Welle JR, Woolwine BJ, Goldsmith DR, Baer W, Patel T, et al. Associations among peripheral and central kynurenine pathway metabolites and inflammation in depression. Neuropsychopharmacology. 2020;45(6):998–1007. https://doi.org/10.1038/s41386-020-0607-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry. 2010;15(4):393–403. https://doi.org/10.1038/mp.2009.116.

    Article  CAS  PubMed  Google Scholar 

  87. Savitz J, Dantzer R, Meier TB, Wurfel BE, Victor TA, McIntosh SA, et al. Activation of the kynurenine pathway is associated with striatal volume in major depressive disorder. Psychoneuroendocrinology. 2015;62:54–8. https://doi.org/10.1016/j.psyneuen.2015.07.609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cho HJ, Savitz J, Dantzer R, Teague TK, Drevets WC, Irwin MR. Sleep disturbance and kynurenine metabolism in depression. J Psychosom Res. 2017;99:1–7. https://doi.org/10.1016/j.jpsychores.2017.05.016.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Fuertig R, Azzinnari D, Bergamini G, Cathomas F, Sigrist H, Seifritz E, et al. Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: both effects are reversed by inhibition of indoleamine 2,3-dioxygenase. Brain Behav Immun. 2016;54:59–72. https://doi.org/10.1016/j.bbi.2015.12.020.

    Article  CAS  PubMed  Google Scholar 

  90. Laumet G, Zhou W, Dantzer R, Edralin JD, Huo X, Budac DP, et al. Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain. Brain Behav Immun. 2017;66:94–102. https://doi.org/10.1016/j.bbi.2017.07.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang B, Lian YJ, Su WJ, Peng W, Dong X, Liu LL, et al. HMGB1 mediates depressive behavior induced by chronic stress through activating the kynurenine pathway. Brain Behav Immun. 2018;72:51–60. https://doi.org/10.1016/j.bbi.2017.11.017.

    Article  CAS  PubMed  Google Scholar 

  92. Sathyasaikumar KV, Stachowski EK, Wonodi I, Roberts RC, Rassoulpour A, McMahon RP, et al. Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia. Schizophr Bull. 2011;37(6):1147–56. https://doi.org/10.1093/schbul/sbq112.

    Article  PubMed  Google Scholar 

  93. Linderholm KR, Skogh E, Olsson SK, Dahl ML, Holtze M, Engberg G, et al. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr Bull. 2012;38(3):426–32. https://doi.org/10.1093/schbul/sbq086.

    Article  PubMed  Google Scholar 

  94. Erhardt S, Schwieler L, Imbeault S, Engberg G. The kynurenine pathway in schizophrenia and bipolar disorder. Neuropharmacology. 2017;112(Pt B):297–306. https://doi.org/10.1016/j.neuropharm.2016.05.020.

    Article  CAS  PubMed  Google Scholar 

  95. Fujigaki H, Mouri A, Yamamoto Y, Nabeshima T, Saito K. Linking phencyclidine intoxication to the tryptophan-kynurenine pathway: therapeutic implications for schizophrenia. Neurochem Int. 2019;125:1–6. https://doi.org/10.1016/j.neuint.2019.02.001.

    Article  CAS  PubMed  Google Scholar 

  96. Reus GZ, Becker IRT, Scaini G, Petronilho F, Oses JP, Kaddurah-Daouk R, et al. The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2018;81:55–63. https://doi.org/10.1016/j.pnpbp.2017.10.009.

    Article  CAS  Google Scholar 

  97. Joaquim HPG, Costa AC, Gattaz WF, Talib LL. Kynurenine is correlated with IL-1beta in plasma of schizophrenia patients. J Neural Transm (Vienna). 2018;125(5):869–73. https://doi.org/10.1007/s00702-018-1838-8.

    Article  CAS  Google Scholar 

  98. Goeden N, Notarangelo FM, Pocivavsek A, Beggiato S, Bonnin A, Schwarcz R. Prenatal dynamics of kynurenine pathway metabolism in mice: focus on kynurenic acid. Dev Neurosci. 2017;39(6):519–28. https://doi.org/10.1159/000481168.

    Article  CAS  PubMed  Google Scholar 

  99. Kindler J, Lim CK, Weickert CS, Boerrigter D, Galletly C, Liu D, et al. Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0401-9.

  100. Zhu F, Guo R, Wang W, Ju Y, Wang Q, Ma Q, et al. Transplantation of microbiota from drug-free patients with schizophrenia causes schizophrenia-like abnormal behaviors and dysregulated kynurenine metabolism in mice. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0475-4.

Download references

Copyright

The figure in the manuscript is original and created entirely by AT.

Code Availability

Not applicable.

Funding

This work was supported by US National Institute of Health/ National Institute of Mental Health (NIMH) grants (MH120876 and MH121959) and the Merit Review Award (BX004758) from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development to AP. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA, 30912, USA

    Tami Feng, Ashutosh Tripathi & Anilkumar Pillai

  2. Research and Development, Charlie Norwood VA Medical Center, Augusta, GA, USA

    Anilkumar Pillai

Authors
  1. Tami Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ashutosh Tripathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anilkumar Pillai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anilkumar Pillai.

Ethics declarations

Conflicts of Interest

Dr. Pillai reports grants from NIH (MH120876 and MH121959) and grant from Veteran Affairs (BX004758) during the conduct of the study. Dr. Tripathi and Dr. Feng have nothing to disclose.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Psychosis

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feng, T., Tripathi, A. & Pillai, A. Inflammatory Pathways in Psychiatric Disorders: the Case of Schizophrenia and Depression. Curr Behav Neurosci Rep 7, 128–138 (2020). https://doi.org/10.1007/s40473-020-00207-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40473-020-00207-4

Keywords

Search

Navigation