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Postmortem evidence of brain inflammatory markers in bipolar disorder: a systematic review

Molecular Psychiatry volume 25, pages 94–113 (2020)Cite this article

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Abstract

Bipolar disorder (BD) is a chronic affective disorder with extreme mood swings that include mania or hypomania and depression. Though the exact mechanism of BD is unknown, neuroinflammation is one of the numerous investigated etiopathophysiological causes of BD. This article presents a systematic review of the data regarding brain inflammation evaluating microglia, astrocytes, cytokines, chemokines, adhesion molecules, and other inflammatory markers in postmortem BD brain samples. This systematic review was performed according to PRISMA recommendations, and relevant studies were identified by searching the PubMed/MEDLINE, PsycINFO, EMBASE, LILACS, IBECS, and Web of Science databases for peer-reviewed journal articles published by March 2019. Quality of included studies appraised using the QUADAS-2 tool. Among the 1814 articles included in the primary screening, 51 articles measured inflammatory markers in postmortem BD brain samples. A number of studies have shown evidence of inflammation in BD postmortem brain samples. However, an absolute statement cannot be concluded whether neuroinflammation is present in BD due to the large number of studies did not evaluate the presence of infiltrating peripheral immune cells in the central nervous system (CNS) parenchyma, cytokines levels, and microglia activation in the same postmortem brain sample. For example, out of 15 studies that evaluated microglia cells markers, 8 studies found no effect of BD on these cells. Similarly, 17 out of 51 studies evaluating astrocytes markers, 9 studies did not find any effect of BD on astrocyte cells, whereas 8 studies found a decrease and 2 studies presented both increase and decrease in different brain regions. In addition, multiple factors account for the variability across the studies, including postmortem interval, brain area studied, age at diagnosis, undergoing treatment, and others. Future analyses should rectify these potential sources of heterogeneity and reach a consensus regarding the inflammatory markers in postmortem BD brain samples.

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References

  1. Barnett R. Bipolar disorder. Lancet. 2018;392:1510.

    PubMed  Google Scholar 

  2. Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68:241–51.

    PubMed  PubMed Central  Google Scholar 

  3. Bauer M, Andreassen OA, Geddes JR, Vedel Kessing L, Lewitzka U, Schulze TG, et al. Areas of uncertainties and unmet needs in bipolar disorders: clinical and research perspectives. Lancet Psychiatry. 2018;5:930–9.

    PubMed  Google Scholar 

  4. Cao B, Bauer IE, Sharma AN, Mwangi B, Frazier T, Lavagnino L, et al. Reduced hippocampus volume and memory performance in bipolar disorder patients carrying the BDNF val66met met allele. J Affect Disord. 2016;198:198–205.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Abe C, Ekman CJ, Sellgren C, Petrovic P, Ingvar M, Landen M. Manic episodes are related to changes in frontal cortex: a longitudinal neuroimaging study of bipolar disorder 1. Brain. 2015;138:3440–8.

    PubMed  Google Scholar 

  6. Naaldijk YM, Bittencourt MC, Sack U, Ulrich H. Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis. Biol Chem. 2016;397:283–96.

    CAS  PubMed  Google Scholar 

  7. Sigitova E, Fisar Z, Hroudova J, Cikankova T, Raboch J. Biological hypotheses and biomarkers of bipolar disorder. Psychiatry Clin Neurosci. 2017;71:77–103.

    PubMed  Google Scholar 

  8. Reus GZ, Fries GR, Stertz L, Badawy M, Passos IC, Barichello T, et al. The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience. 2015;300:141–54.

    CAS  PubMed  Google Scholar 

  9. Barley K, Dracheva S, Byne W. Subcortical oligodendrocyte- and astrocyte-associated gene expression in subjects with schizophrenia, major depression and bipolar disorder. Schizophr Res. 2009;112:54–64.

    PubMed  Google Scholar 

  10. Rao JS, Keleshian VL, Klein S, Rapoport SI. Epigenetic modifications in frontal cortex from Alzheimer’s disease and bipolar disorder patients. Transl Psychiatry. 2012;2:e132.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Rao JS, Harry GJ, Rapoport SI, Kim HW. Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol Psychiatry. 2010;15:384–92.

    CAS  PubMed  Google Scholar 

  12. Estes ML, McAllister AK. Alterations in immune cells and mediators in the brain: it’s not always neuroinflammation! Brain Pathol. 2014;24:623–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. DiSabato DJ, Quan N, Godbout JP. Neuroinflammation: the devil is in the details. J Neurochem. 2016;139:136–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Muldoon LL, Alvarez JI, Begley DJ, Boado RJ, Del Zoppo GJ, Doolittle ND, et al. Immunologic privilege in the central nervous system and the blood–brain barrier. J Cereb Blood Flow Metab. 2013;33:13–21.

    CAS  PubMed  Google Scholar 

  15. Stephenson J, Nutma E, van der Valk P, Amor S. Inflammation in CNS neurodegenerative diseases. Immunology. 2018;154:204–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 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.

    CAS  PubMed  Google Scholar 

  17. van Neerven S, Nemes A, Imholz P, Regen T, Denecke B, Johann S, et al. Inflammatory cytokine release of astrocytes in vitro is reduced by all-trans retinoic acid. J Neuroimmunol. 2010;229:169–79.

    PubMed  Google Scholar 

  18. Hercher C, Chopra V, Beasley CL. Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder. J Psychiatry Neurosci. 2014;39:376–85.

    PubMed  PubMed Central  Google Scholar 

  19. Gos T, Schroeter ML, Lessel W, Bernstein HG, Dobrowolny H, Schiltz K, et al. S100B-immunopositive astrocytes and oligodendrocytes in the hippocampus are differentially afflicted in unipolar and bipolar depression: a postmortem study. J Psychiatr Res. 2013;47:1694–9.

    PubMed  Google Scholar 

  20. Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, et al. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry. 2000;5:142–9.

    CAS  PubMed  Google Scholar 

  21. Sayana P, Colpo GD, Simoes LR, Giridharan VV, Teixeira AL, Quevedo J, et al. A systematic review of evidence for the role of inflammatory biomarkers in bipolar patients. J Psychiatr Res. 2017;92:160–82.

    PubMed  Google Scholar 

  22. 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;47:1119–33.

    PubMed  Google Scholar 

  23. Wesseling H, Gottschalk MG, Bahn S. Targeted multiplexed selected reaction monitoring analysis evaluates protein expression changes of molecular risk factors for major psychiatric disorders. Int J Neuropsychopharmacol. 2014;18:1.

    Google Scholar 

  24. Mauney SPC, Goldstein JM, Petryshen T, Seidman LJ, Shenton ME, McCarley R, et al. Gene expression profiling of oligodendrocytes in dorsolateral prefrontal cortex deep white matter in bipolar disorder and schizophrenia. Schizophr Bull. 2013;39:S212.

    Google Scholar 

  25. Schmitt A, Bernstein HG, Steiner J, Schmitz C, Bogerts B, Rossner M, et al. Histological and gene expression studies of the hippocampus in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2013;263:S40.

    Google Scholar 

  26. Haarman BC, Riemersma-Van der Lek RF, de Groot JC, Ruhe HG, Klein HC, Zandstra TE, et al. Neuroinflammation in bipolar disorder—A [(11)C]-(R)-PK11195 positron emission tomography study. Brain Behav Immun. 2014;40:219–25.

    CAS  PubMed  Google Scholar 

  27. Hibar DP, Westlye LT, Doan NT, Jahanshad N, Cheung JW, Ching CRK, et al. Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Mol Psychiatry. 2018;23:932–42.

    CAS  PubMed  Google Scholar 

  28. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62:1006–12.

    PubMed  Google Scholar 

  29. Whiting P, Harbord R, Kleijnen J. No role for quality scores in systematic reviews of diagnostic accuracy studies. BMC Med Res Methodol. 2005;5:19.

    PubMed  PubMed Central  Google Scholar 

  30. Liedtke W, Edelmann W, Bieri PL, Chiu FC, Cowan NJ, Kucherlapati R, et al. GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination. Neuron. 1996;17:607–15.

    CAS  PubMed  Google Scholar 

  31. Meyer-Franke A, Shen S, Barres BA. Astrocytes induce oligodendrocyte processes to align with and adhere to axons. Mol Cell Neurosci. 1999;14:385–97.

    CAS  PubMed  Google Scholar 

  32. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Patanow CM, Day JR, Billingsley ML. Alterations in hippocampal expression of SNAP-25, GAP-43, stannin and glial fibrillary acidic protein following mechanical and trimethyltin-induced injury in the rat. Neuroscience. 1997;76:187–202.

    CAS  PubMed  Google Scholar 

  34. Montgomery DL. Astrocytes: form, functions, and roles in disease. Vet Pathol. 1994;31:145–67.

    CAS  PubMed  Google Scholar 

  35. Coyle JT, Schwarcz R. Mind glue: implications of glial cell biology for psychiatry. Arch Gen Psychiatry. 2000;57:90–3.

    CAS  PubMed  Google Scholar 

  36. Rajkowska G, Miguel-Hidalgo JJ, Makkos Z, Meltzer H, Overholser J, Stockmeier C. Layer-specific reductions in GFAP-reactive astroglia in the dorsolateral prefrontal cortex in schizophrenia. Schizophr Res. 2002;57:127–38.

    PubMed  Google Scholar 

  37. Moises HW, Zoega T, Gottesman II. The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. BMC Psychiatry. 2002;2:8.

    PubMed  PubMed Central  Google Scholar 

  38. Fatemi SH, Emamian ES, Sidwell RW, Kist DA, Stary JM, Earle JA, et al. Human influenza viral infection in utero alters glial fibrillary acidic protein immunoreactivity in the developing brains of neonatal mice. Mol Psychiatry. 2002;7:633–40.

    CAS  PubMed  Google Scholar 

  39. Laping NJ, Nichols NR, Day JR, Johnson SA, Finch CE. Transcriptional control of glial fibrillary acidic protein and glutamine synthetase in vivo shows opposite responses to corticosterone in the hippocampus. Endocrinology. 1994;135:1928–33.

    CAS  PubMed  Google Scholar 

  40. Norton WT, Aquino DA, Hozumi I, Chiu FC, Brosnan CF. Quantitative aspects of reactive gliosis: a review. Neurochem Res. 1992;17:877–85.

    CAS  PubMed  Google Scholar 

  41. Comte I, Al-Shammari A, Szele FG. The human subventricular zone in neuropsychiatric disease. J Neurochem. 2013;125:31

    Google Scholar 

  42. Damadzic R, Bigelow LB, Krimer LS, Goldenson DA, Saunders RC, Kleinman JE, et al. A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia, bipolar disorder and major depression: absence of significant astrocytosis. Brain Res Bull. 2001;55:611–8.

    CAS  PubMed  Google Scholar 

  43. Pantazopoulos H, Woo TU, Lim MP, Lange N, Berretta S. Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry. 2010;67:155–66.

    PubMed  PubMed Central  Google Scholar 

  44. Dean B, Gray L, Scarr E. Regionally specific changes in levels of cortical S100beta in bipolar 1 disorder but not schizophrenia. Aust N Z J Psychiatry. 2006;40:217–24.

    PubMed  Google Scholar 

  45. Webster MJ, Knable MB, Johnston-Wilson N, Nagata K, Inagaki M, Yolken RH. Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression. Brain Behav Immun. 2001;15:388–400.

    CAS  PubMed  Google Scholar 

  46. Muller MB, Lucassen PJ, Yassouridis A, Hoogendijk WJ, Holsboer F, Swaab DF. Neither major depression nor glucocorticoid treatment affects the cellular integrity of the human hippocampus. Eur J Neurosci. 2001;14:1603–12.

    CAS  PubMed  Google Scholar 

  47. Fatemi SH, Laurence JA, Araghi-Niknam M, Stary JM, Schulz SC, Lee S, et al. Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression, but not schizophrenia. Schizophr Res. 2004;69:317–23.

    PubMed  Google Scholar 

  48. Toro CT, Hallak JE, Dunham JS, Deakin JF. Glial fibrillary acidic protein and glutamine synthetase in subregions of prefrontal cortex in schizophrenia and mood disorder. Neurosci Lett. 2006;404:276–81.

    CAS  PubMed  Google Scholar 

  49. Webster MJ, O’Grady J, Kleinman JE, Weickert CS. Glial fibrillary acidic protein mRNA levels in the cingulate cortex of individuals with depression, bipolar disorder and schizophrenia. Neuroscience. 2005;133:453–61.

    CAS  PubMed  Google Scholar 

  50. Feresten AH, Barakauskas V, Ypsilanti A, Barr AM, Beasley CL. Increased expression of glial fibrillary acidic protein in prefrontal cortex in psychotic illness. Schizophr Res. 2013;150:252–7.

    PubMed  Google Scholar 

  51. Dean B, Gibbons AS, Tawadros N, Brooks L, Everall IP, Scarr E. Different changes in cortical tumor necrosis factor-alpha-related pathways in schizophrenia and mood disorders. Mol Psychiatry. 2013;18:767–73.

    CAS  PubMed  Google Scholar 

  52. Rao JS. Overlapping molecular neuropathology in post-mortem frontal cortex from bipolar disorder and schizophrenic patients. Neuropsychopharmacology. 2010;35:S47.

    Google Scholar 

  53. Ferensztajn-Rochowiak E, Tarnowski M, Samochowiec J, Michalak M, Ratajczak MZ, Rybakowski JK. Increased mRNA expression of peripheral glial cell markers in bipolar disorder: The effect of long-term lithium treatment. Eur Neuropsychopharmacol. 2016;26:1516–21.

    CAS  PubMed  Google Scholar 

  54. Tardy M, Fages C, Le Prince G, Rolland B, Nunez J. Regulation of the glial fibrillary acidic protein (GFAP) and of its encoding mRNA in the developing brain and in cultured astrocytes. Adv Exp Med Biol. 1990;265:41–52.

    CAS  PubMed  Google Scholar 

  55. Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, et al. S100B’s double life: intracellular regulator and extracellular signal. Biochim Biophys Acta. 2009;1793:1008–22.

    CAS  Google Scholar 

  56. Steiner J, Bernstein HG, Bielau H, Berndt A, Brisch R, Mawrin C, et al. Evidence for a wide extra-astrocytic distribution of S100B in human brain. BMC Neurosci. 2007;8:2.

    PubMed  PubMed Central  Google Scholar 

  57. Rothermundt M, Arolt V, Wiesmann M, Missler U, Peters M, Rudolf S, et al. S-100B is increased in melancholic but not in non-melancholic major depression. J Affect Disord. 2001;66:89–93.

    CAS  PubMed  Google Scholar 

  58. Schroeter ML, Abdul-Khaliq H, Sacher J, Steiner J, Blasig IE, Mueller K. Mood disorders are glial disorders: evidence from in vivo studies. Cardiovasc Psychiatry Neurol. 2010;2010:780645.

    PubMed  PubMed Central  Google Scholar 

  59. Hamidi M, Drevets WC, Price JL. Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biol Psychiatry. 2004;55:563–9.

    PubMed  Google Scholar 

  60. Grandi N, Tramontano E. Human endogenous retroviruses are ancient acquired elements still shaping innate immune responses. Front Immunol. 2018;9:2039.

    PubMed  PubMed Central  Google Scholar 

  61. Lower R, Lower J, Kurth R. The viruses in all of us: characteristics and biological significance of human endogenous retrovirus sequences. Proc Natl Acad Sci USA. 1996;93:5177–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Taruscio D, Mantovani A. Human endogenous retroviral sequences: possible roles in reproductive physiopathology. Biol Reprod. 1998;59:713–24.

    CAS  PubMed  Google Scholar 

  63. Obermayer-Straub P, Manns MP. Hepatitis C and D, retroviruses and autoimmune manifestations. J Autoimmun. 2001;16:275–85.

    CAS  PubMed  Google Scholar 

  64. Weis S, Llenos IC, Sabunciyan S, Dulay JR, Isler L, Yolken R, et al. Reduced expression of human endogenous retrovirus (HERV)-W GAG protein in the cingulate gyrus and hippocampus in schizophrenia, bipolar disorder, and depression. J Neural Transm. 2007;114:645–55.

    CAS  PubMed  Google Scholar 

  65. Thion MS, Low D, Silvin A, Chen J, Grisel P, Schulte-Schrepping J, et al. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell. 2018;172:500–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Rajkowska G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry. 2000;48:766–77.

    CAS  PubMed  Google Scholar 

  67. Schroeter MI, Steiner J, Mueller K. Glial pathology is modified by age in mood disorders—a systematic meta-analysis of serum 100B invivio studies. J Affect Disord. 2011;134:32–8.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  69. Ransohoff RM. A polarizing question: do M1 and M2 microglia exist? Nat Neurosci. 2016;19:987–91.

    CAS  PubMed  Google Scholar 

  70. Brisch R, Steiner J, Mawrin C, Krzyzanowska M, Jankowski Z, Gos T. Microglia in the dorsal raphe nucleus plays a potential role in both suicide facilitation and prevention in affective disorders. Eur Arch Psychiatry Clin Neurosci. 2017;267:403–15.

    PubMed  PubMed Central  Google Scholar 

  71. Seredenina T, Sorce S, Herrmann FR, Ma Mulone XJ, Plastre O, Aguzzi A, et al. Decreased NOX2 expression in the brain of patients with bipolar disorder: association with valproic acid prescription and substance abuse. Transl Psychiatry. 2017;7:e1206.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Busse M, Busse S, Myint AM, Gos T, Dobrowolny H, Muller UJ, et al. Decreased quinolinic acid in the hippocampus of depressive patients: evidence for local anti-inflammatory and neuroprotective responses? Eur Arch Psychiatry Clin Neurosci. 2015;265:321–9.

    PubMed  Google Scholar 

  73. Weis S, Haybaeck J, Dulay JR, Llenos IC. Expression of cellular prion protein (PrP(c)) in schizophrenia, bipolar disorder, and depression. J Neural Transm. 2008;115:761–71.

    CAS  PubMed  Google Scholar 

  74. Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, 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.

    PubMed  Google Scholar 

  75. Schmitt AB, Brook GA, Buss A, Nacimiento W, Noth J, Kreutzberg GW. Dynamics of microglial activation in the spinal cord after cerebral infarction are revealed by expression of MHC class II antigen. Neuropathol Appl Neurobiol. 1998;24:167–76.

    CAS  PubMed  Google Scholar 

  76. Kano S, Nwulia E, Niwa M, Chen Y, Sawa A, Cascella N. Altered MHC class I expression in dorsolateral prefrontal cortex of nonsmoker patients with schizophrenia. Neurosci Res. 2011;71:289–93.

    CAS  PubMed  Google Scholar 

  77. Chen YKS, Nwulia E, Niwa M, Webster M, Torrey F, Yolken R, et al. Altered MHC class I expression in dorsolateral prefrontal cortex of nonsmoker patients with schizophrenia. Biol Psychiatry. 2011;69:225S.

    Google Scholar 

  78. Sawa AKS, Nwulia E, Niwa M, Cascella NG. Expression of immune molecules (MHC class I and complement C3) in postmortem brains of patients with schizophrenia. Schizophr Bull. 2011;37:195.

    Google Scholar 

  79. Nakatani N, Hattori E, Ohnishi T, Dean B, Iwayama Y, Matsumoto I, et al. Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation. Hum Mol Genet. 2006;15:1949–62.

    CAS  PubMed  Google Scholar 

  80. Rajkowska G, Halaris A, Selemon LD. Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol Psychiatry. 2001;49:741–52.

    CAS  PubMed  Google Scholar 

  81. Kretzschmar HA, Prusiner SB, Stowring LE, DeArmond SJ. Scrapie prion proteins are synthesized in neurons. Am J Pathol. 1986;122:1–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Brown DR, Besinger A, Herms JW, Kretzschmar HA. Microglial expression of the prion protein. Neuroreport. 1998;9:1425–9.

    CAS  PubMed  Google Scholar 

  83. Foster R, Kandanearatchi A, Beasley C, Williams B, Khan N, Fagerhol MK, et al. Calprotectin in microglia from frontal cortex is up-regulated in schizophrenia: evidence for an inflammatory process? Eur J Neurosci. 2006;24:3561–66.

    PubMed  Google Scholar 

  84. Kaminsky Z, Tochigi M, Jia P, Pal M, Mill J, Kwan A, et al. A multi-tissueanalysis identifies HLA complex group 9 gene methylation differences in bipolar disorder. Mol Psychiatry. 2012;17:728–40.

    CAS  PubMed  Google Scholar 

  85. Dinarello CA. Proinflammatory cytokines. Chest. 2000;118:503–8.

    CAS  PubMed  Google Scholar 

  86. Ortiz-Dominguez A, Hernandez ME, Berlanga C, Gutierrez-Mora D, Moreno J, Heinze G, et al. Immune variations in bipolar disorder: phasic differences. Bipolar Disord. 2007;9:596–602.

    CAS  PubMed  Google Scholar 

  87. Quinones MP, Perez-Algorta G, Jimenez F, Clark K, Bowden CL, Ahuja SS. Upregulation of type i immune responses in the brain of individuals with bipolar disorder: Uncoupling of central and peripheral responses. Biol Psychiatry. 2009;65:64S

    Google Scholar 

  88. Pandey GN. Inflammatory and innate immune markers of neuroprogression in depressed and teenage suicide brain. Mod Trends Pharmacopsychiatry. 2017;31:79–95.

    PubMed  Google Scholar 

  89. Naude PJ, den Boer JA, Luiten PG, Eisel UL. Tumor necrosis factor receptor cross-talk. FEBS J. 2011;278:888–98.

    CAS  PubMed  Google Scholar 

  90. Clark IA, Vissel B. A neurologist’s guide to TNF biology and to the principles behind the therapeutic removal of excess TNF in disease. Neural Plast. 2015;2015:358263.

    PubMed  PubMed Central  Google Scholar 

  91. Hoseth EZ, Ueland T, Dieset I, Birnbaum R, Shin JH, Kleinman JE, et al. A study of TNF pathway activation in schizophrenia and bipolar disorder in plasma and brain tissue. Schizophr Bull. 2017;43:881–90.

    PubMed  PubMed Central  Google Scholar 

  92. Kim HK, Andreazza AC, Elmi N, Chen W, Young LT. Nod-like receptor pyrin containing 3 (NLRP3) in the post-mortem frontal cortex from patients with bipolar disorder: a potential mediator between mitochondria and immune-activation. J Psychiatr Res. 2016;72:43–50.

    PubMed  Google Scholar 

  93. Brietzke E, Kauer-Sant’Anna M, Teixeira AL, Kapczinski F. Abnormalities in serum chemokine levels in euthymic patients with bipolar disorder. Brain Behav Immun. 2009;23:1079–82.

    CAS  PubMed  Google Scholar 

  94. Bellani M, Bergami A, Tomelleri L, Perlini C, Cerruti S, Ferro A, et al. Altered mRNA levels of chemokines and cytokines in schizophrenia and bipolar disorder. Schizophr Res. 2010;117:251–2.

    Google Scholar 

  95. Isgren A, Sellgren C, Ekman CJ, Holmen-Larsson J, Blennow K, Zetterberg H, et al. Markers of neuroinflammation and neuronal injury in bipolar disorder: Relation to prospective clinical outcomes. Brain Behav Immun. 2017;65:195–201.

    PubMed  Google Scholar 

  96. Jakobsson J, Bjerke M, Sahebi S, Isgren A, Ekman CJ, Sellgren C, et al. Monocyte and microglial activation in patients with mood-stabilized bipolar disorder. J Psychiatry Neurosci. 2015;40:250–8.

    PubMed  PubMed Central  Google Scholar 

  97. Barbosa IG, Rocha NP, Bauer ME, de Miranda AS, Huguet RB, Reis HJ, et al. Chemokines in bipolar disorder: trait or state? Eur Arch Psychiatry Clin Neurosci. 2013;263:159–65.

    PubMed  Google Scholar 

  98. Quinones MP, Jimenez F, Perez-Algorta G, Clark K, Ahuja SS, Bowden CL. Central and peripheral immune activation in bipolar illness: Possible role of the chemokine CXCL5 in disease pathogenesis. Biol Psychiatry. 2009;65:169S.

    Google Scholar 

  99. Webster MJ, Vawter MP, Freed WJ. Immunohistochemical localization of the cell adhesion molecules Thy-1 and L1 in the human prefrontal cortex patients with schizophrenia, bipolar disorder, and depression. Mol Psychiatry. 1999;4:46–52.

    CAS  PubMed  Google Scholar 

  100. van de Stolpe A, van der Saag PT. Intercellular adhesion molecule-1. J Mol Med. 1996;74:13–33.

    PubMed  Google Scholar 

  101. Thomas AJ, Davis S, Ferrier IN, Kalaria RN, O’Brien JT. Elevation of cell adhesion molecule immunoreactivity in the anterior cingulate cortex in bipolar disorder. Biol Psychiatry. 2004;55:652–5.

    CAS  PubMed  Google Scholar 

  102. Rybakowski JK, Twardowska K. The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness. J Psychiatr Res. 1999;33:363–70.

    CAS  PubMed  Google Scholar 

  103. Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflamm. 2011;8:94.

    CAS  Google Scholar 

  104. 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.

    PubMed  Google Scholar 

  105. Schain M, Kreisl WC. Neuroinflammation in neurodegenerative disorders—a review. Curr Neurol Neurosci Rep. 2017;17:25.

    PubMed  Google Scholar 

  106. Palumbo S. Pathogenesis and progression of multiple sclerosis: the role of arachidonic acid-mediated neuroinflammation. In: Zagon IS, McLaughlin PJ, (eds). Multiple sclerosis: perspectives in treatment and pathogenesis. Brisbane (AU): Codon Publications Copyright: The Authors; 2017.

    Google Scholar 

  107. Hu J, Xu J, Pang L, Zhao H, Li F, Deng Y, et al. Systematically characterizing dysfunctional long intergenic non-coding RNAs in multiple brain regions of major psychosis. Oncotarget. 2016;7:71087–98.

    PubMed  PubMed Central  Google Scholar 

  108. Pacifico R, Davis RL. Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder. Mol Psychiatry. 2017;22:441–9.

    CAS  PubMed  Google Scholar 

  109. Abdolmaleky HM, Gower AC, Wong CK, Cox JW, Zhang X, Thiagalingam A, et al. Aberrant transcriptomes and DNA methylomes define pathways that drive pathogenesis and loss of brain laterality/asymmetry in schizophrenia and bipolar disorder. Am J Med Genet B Neuropsychiatr Genet. 2019;180:138–49.

    CAS  PubMed  Google Scholar 

  110. Bezchlibnyk YB, Wang JF, McQueen GM, Young LT. Gene expression differences in bipolar disorder revealed by cDNA array analysis of post-mortem frontal cortex. J Neurochem. 2001;79:826–34.

    CAS  PubMed  Google Scholar 

  111. Rowland T, Perry BI, Upthegrove R, Barnes N, Chatterjee J, Gallacher D, et al. Neurotrophins, cytokines, oxidative stress mediators and mood state in bipolar disorder: systematic review and meta-analyses. Br J Psychiatry: J Ment Sci. 2018;213:514–25.

    Google Scholar 

  112. Siwek M, Sowa-Kucma M, Styczen K, Misztak P, Nowak RJ, Szewczyk B, et al. Associations of serum cytokine receptor levels with melancholia, staging of illness, depressive and manic phases, and severity of depression in bipolar disorder. Mol Neurobiol. 2017;54:5883–93.

    CAS  PubMed  Google Scholar 

  113. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Setiawan E, Attwells S, Wilson AA, Mizrahi R, Rusjan PM, Miler L, et al. Association of translocator protein total distribution volume with duration of untreated major depressive disorder: a cross-sectional study. Lancet Psychiatry. 2018;5:339–47.

    PubMed  Google Scholar 

  115. van der Doef TF, Doorduin J, van Berckel BNM, Cervenka S. Assessing brain immune activation in psychiatric disorders: clinical and preclinical PET imaging studies of the 18-kDa translocator protein. Clin Transl Imaging. 2015;3:449–60.

    PubMed  PubMed Central  Google Scholar 

  116. Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012;32:1–5.

    CAS  PubMed  Google Scholar 

  117. Borst K, Schwabenland M, Prinz M. Microglia metabolism in health and disease. Neurochem Int. (In Press, 2018). https://doi.org/10.1016/j.neuint.2018.11.006

    PubMed  Google Scholar 

  118. Banks WA, Kastin AJ, Broadwell RD. Passage of cytokines across the blood–brain barrier. Neuroimmunomodulation. 1995;2:241–8.

    CAS  PubMed  Google Scholar 

  119. Yarlagadda A, Alfson E, Clayton AH. The blood brain barrier and the role of cytokines in neuropsychiatry. Psychiatry. 2009;6:18–22.

    PubMed  PubMed Central  Google Scholar 

  120. Banks WA, Farr SA, Morley JE. Entry of blood-borne cytokines into the central nervous system: effects on cognitive processes. Neuroimmunomodulation. 2002;10:319–27.

    CAS  PubMed  Google Scholar 

  121. Altshuler LL, Abulseoud OA, Foland-Ross L, Bartzokis G, Chang S, Mintz J, et al. Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder. Bipolar Disord. 2010;12:541–9. https://doi.org/10.1111/j.1399-5618.2010.00838.x

    Article  PubMed  Google Scholar 

  122. Brauch RA, Adnan El-Masri M, Parker JC Jr., El-Mallakh RS. Glial cell number and neuron/glial cell ratios in postmortem brains of bipolar individuals. J Affective Disord. 2006;91:87–90. https://doi.org/10.1016/j.jad.2005.08.015

    Article  Google Scholar 

  123. Cotter D, Mackay D, Landau S, Kerwin R, Everall I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry. 2001;58:545–53.

    CAS  PubMed  Google Scholar 

  124. Cotter D, Mackay D, Frangou S, Hudson L, Landau S. Cell density and cortical thickness in Heschl’s gyrus in schizophrenia, major depression and bipolar disorder. Br J Psychiatry: J Ment Sci. 2004;185:258–9. https://doi.org/10.1192/bjp.185.3.258

    Article  Google Scholar 

  125. Cotter D, Hudson L, Landau S. Evidence for orbitofrontal pathology in bipolar disorder and major depression, but not in schizophrenia. Bipolar Disord. 2005;7:358–69. https://doi.org/10.1111/j.1399-5618.2005.00230.x

    Article  PubMed  Google Scholar 

  126. Gilmore JH, Bouldin TW. Analysis of ependymal abnormalities in subjects with schizophrenia, bipolar disorder, and depression. Schizophr Res. 2002;57:267–71.

    PubMed  Google Scholar 

  127. Schmitt A, Steyskal C, Strocka S, Frank F, Wetzestein K, Bernstein HG, et al. Histological studies of oligodendrocytes in psychiatric diseases. Eur Arch Psychiatry Clin Neurosci. 2011;261:S45.

    Google Scholar 

  128. de Baumont A, Maschietto M, Lima L, Carraro DM, Olivieri EH, Fiorini A, et al. Innate immune response is differentially dysregulated between bipolar disease and schizophrenia. Schizophr Res. 2015;161:215–21.

    PubMed  Google Scholar 

  129. Fillman SG, Sinclair D, Fung SJ, Webster MJ, Weickert CS. Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder. Transl Psychiatry. 2014;4:e365.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The Translational Psychiatry Program (USA) is funded by the Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth). The Laboratory of Neurosciences (Brazil) is one of the centers of the National Institute for Molecular Medicine (INCT-MM) and one of the members of the Centre of Excellence in Applied Neurosciences of Santa Catarina (NENASC). Its research is supported by grants from the National Council for Scientific and Technological Development (CNPq) (JQ and TB), the Foundation for Research and Innovation of the State of Santa Catarina (FAPESC) (JQ and TB), and the InstitutoCérebro e Mente (JQ) and UNESC (JQ and TB).

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Authors and Affiliations

  1. Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    Vijayasree V. Giridharan, Pavani Sayana, Omar F. Pinjari, Naveed Ahmad, João Quevedo & Tatiana Barichello

  2. Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil

    Maria Ines da Rosa & Tatiana Barichello

  3. Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    João Quevedo

  4. Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    João Quevedo & Tatiana Barichello

  5. Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil

    João Quevedo

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  1. Vijayasree V. Giridharan
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Correspondence to Tatiana Barichello.

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Conflict of interest

JQ: Clinical Research Support: Allergan (Clinical Trial), Janssen Pharmaceuticals, Inc. (Clinical Trial). Advisory Boards, Speaker Bureaus, Expert Witness, or Consultant. Assurex Health, Inc. (Speaker Bureau), Daiichi Sankyo (Speaker Bureau), Janssen Pharmaceuticals, Inc. (Speaker Bureau). Patent, Equity, or Royalty: Instituto de Neurociencias. Dr. Joao Quevedo (Stockholder), Other Artmed Editora (Copyright), Artmed Panamericana (Copyright), Elsevier (Copyright). The other authors declare that they have no conflict of interest.

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Giridharan, V.V., Sayana, P., Pinjari, O.F. et al. Postmortem evidence of brain inflammatory markers in bipolar disorder: a systematic review. Mol Psychiatry 25, 94–113 (2020). https://doi.org/10.1038/s41380-019-0448-7

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