1932

Abstract

Evidence from epidemiological, clinical, and biological research resulted in the immune hypothesis: the hypothesis that immune system dysfunction is involved in the pathophysiology of schizophrenia spectrum disorders (SSD). The promising implication of this hypothesis is the potential to use existing immunomodulatory treatment for innovative interventions for SSD. Here, we provide a selective historical review of important discoveries that have shaped our understanding of immune dysfunction in SSD. We first explain the basic principles of immune dysfunction, after which we travel more than a century back in time. Starting our journey with neurosyphilis-associated psychosis in the nineteenth century, we continue by evaluating the role of infections and autoimmunity in SSD and findings from assessment of immune function using new techniques, such as cytokine levels, microglia density, neuroimaging, and gene expression. Drawing from these findings, we discuss anti-inflammatory interventions for SSD, and we conclude with a look into the future.

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2024-07-12
2025-02-06
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Literature Cited

  1. Ai Y, Du Y, Chen L, Liu S-H, Liu Q, Cheng Y. 2023.. Brain inflammatory marker abnormalities in major psychiatric diseases: a systematic review of postmortem brain studies. . Mol. Neurobiol. 60:(4):211634
    [Crossref] [Google Scholar]
  2. Al Mousawi AH, Dunstan FD. 1998.. Changes in the risk of schizophrenia in Scotland: Is there an environmental factor?. Schizophr. Bull. 24:(4):52935
    [Crossref] [Google Scholar]
  3. Albrecht DS, Granziera C, Hooker JM, Loggia ML. 2016.. In vivo imaging of human neuroinflammation. . ACS Chem. Neurosci. 7:(4):47083
    [Crossref] [Google Scholar]
  4. Allswede DM, Yolken RH, Buka SL, Cannon TD. 2020.. Cytokine concentrations throughout pregnancy and risk for psychosis in adult offspring: a longitudinal case-control study. . Lancet Psychiatry 7:(3):25461
    [Crossref] [Google Scholar]
  5. Arango C, Díaz-Caneja CM, McGorry PD, Rapoport J, Sommer IE, et al. 2018.. Preventive strategies for mental health. . Lancet Psychiatry 5:(7):591604
    [Crossref] [Google Scholar]
  6. Avan A, Tavakoly Sany SB, Ghayour-Mobarhan M, Rahimi HR, Tajfard M, Ferns G. 2018.. Serum C-reactive protein in the prediction of cardiovascular diseases: overview of the latest clinical studies and public health practice. . J. Cell. Physiol. 233:(11):850825
    [Crossref] [Google Scholar]
  7. Bakhshi K, Chance SA. 2015.. The neuropathology of schizophrenia: a selective review of past studies and emerging themes in brain structure and cytoarchitecture. . Neuroscience 303::82102
    [Crossref] [Google Scholar]
  8. Benros ME, Mortensen PB. 2019.. Role of infection, autoimmunity, atopic disorders, and the immune system in schizophrenia: evidence from epidemiological and genetic studies. . In Neuroinflammation and Schizophrenia, ed. GM Khandaker, U Meyer, PB Jones , pp. 14159. Cham, Switz.:: Springer
    [Google Scholar]
  9. Benros ME, Mortensen PB, Eaton WW. 2012.. Autoimmune diseases and infections as risk factors for schizophrenia. . Ann. N.Y. Acad. Sci. 1262:(1):5666
    [Crossref] [Google Scholar]
  10. Birnbaum R, Weinberger DR. 2020.. A genetics perspective on the role of the (neuro)immune system in schizophrenia. . Schizophr. Res. 217::10513
    [Crossref] [Google Scholar]
  11. Blomström Å, Karlsson H, Svensson A, Frisell T, Lee BK, et al. 2014.. Hospital admission with infection during childhood and risk for psychotic illness—a population-based cohort study. . Schizophr. Bull. 40:(6):151825
    [Crossref] [Google Scholar]
  12. Boerrigter D, Weickert TW, Lenroot R, O'Donnell M, Galletly C, et al. 2017.. Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder. . J. Neuroinflammation 14:(1):188
    [Crossref] [Google Scholar]
  13. Borkent J, Ioannou M, Laman JD, Haarman BCM, Sommer IEC. 2022.. Role of the gut microbiome in three major psychiatric disorders. . Psychol. Med. 52:(7):122242
    [Crossref] [Google Scholar]
  14. Bower JE, Kuhlman KR. 2023.. Psychoneuroimmunology: an introduction to immune-to-brain communication and its implications for clinical psychology. . Annu. Rev. Clin. Psychol. 19::33159
    [Crossref] [Google Scholar]
  15. Breitmeyer R, Vogel S, Heider J, Hartmann S-M, Wüst R, et al. 2023.. Regulation of synaptic connectivity in schizophrenia spectrum by mutual neuron-microglia interaction. . Commun. Biol. 6:(1):472
    [Crossref] [Google Scholar]
  16. Brown AS, Derkits EJ. 2010.. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. . Am. J. Psychiatry 167:(3):26180
    [Crossref] [Google Scholar]
  17. Bruetsch WL, Bahr MA, Skobba JS, Dieter WJ. 1942.. The group of dementia praecox patients with an increase of the protein content of the cerebrospinal fluid. . J. Nerv. Ment. Dis. 95:(6):66979
    [Crossref] [Google Scholar]
  18. Bucci P, Mucci A, van Rossum IW, Aiello C, Arango C, et al. 2020.. Persistent negative symptoms in recent-onset psychosis: relationship to treatment response and psychosocial functioning. . Eur. Neuropsychopharmacol. 34::7686
    [Crossref] [Google Scholar]
  19. Çakici N, Sutterland AL, Penninx BWJH, Dalm VA, de Haan L, van Beveren NJM. 2020.. Altered peripheral blood compounds in drug-naïve first-episode patients with either schizophrenia or major depressive disorder: a meta-analysis. . Brain Behav. Immun. 88::54758
    [Crossref] [Google Scholar]
  20. Çakici N, Sutterland AL, Penninx BWJH, de Haan L, van Beveren NJM. 2021.. Changes in peripheral blood compounds following psychopharmacological treatment in drug-naïve first-episode patients with either schizophrenia or major depressive disorder: a meta-analysis. . Psychol. Med. 51:(4):53849
    [Crossref] [Google Scholar]
  21. Çakici N, van Beveren NJM, Judge-Hundal G, Koola MM, Sommer IEC. 2019.. An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis. . Psychol. Med. 49:(14):230719
    [Crossref] [Google Scholar]
  22. Carlsson A. 1978.. Antipsychotic drugs, neurotransmitters, and schizophrenia. . Am. J. Psychiatry 135:(2):16573
    [Crossref] [Google Scholar]
  23. Carreira Figueiredo I, Borgan F, Pasternak O, Turkheimer FE, Howes OD. 2022.. White-matter free-water diffusion MRI in schizophrenia: a systematic review and meta-analysis. . Neuropsychopharmacology 47::141320
    [Crossref] [Google Scholar]
  24. Cheslack-Postava K, Brown AS. 2022.. Prenatal infection and schizophrenia: a decade of further progress. . Schizophr. Res. 247::715
    [Crossref] [Google Scholar]
  25. Cheslack-Postava K, Brown AS, Chudal R, Suominen A, Huttunen J, et al. 2015.. Maternal exposure to sexually transmitted infections and schizophrenia among offspring. . Schizophr. Res. 166:(1–3):25560
    [Crossref] [Google Scholar]
  26. Colonna M, Butovsky O. 2017.. Microglia function in the central nervous system during health and neurodegeneration. . Annu. Rev. Immunol. 35::44168
    [Crossref] [Google Scholar]
  27. Corsi-Zuelli F, Deakin B. 2021.. Impaired regulatory T cell control of astroglial overdrive and microglial pruning in schizophrenia. . Neurosci. Biobehav. Rev. 125::63753
    [Crossref] [Google Scholar]
  28. Dalman C, Allebeck P, Gunnell D, Harrison G, Kristensson K, et al. 2008.. Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. . Am. J. Psychiatry 165:(1):5965
    [Crossref] [Google Scholar]
  29. Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, et al. 2019.. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. . Lancet Neurol. 18:(11):104557
    [Crossref] [Google Scholar]
  30. Das TK, Dey A, Sabesan P, Javadzadeh A, Théberge J, et al. 2018.. Putative astroglial dysfunction in schizophrenia: a meta-analysis of 1H-MRS studies of medial prefrontal myo-inositol. . Front. Psychiatry 9::00438
    [Crossref] [Google Scholar]
  31. de Haan L, Sutterland AL, Schotborgh JV, Schirmbeck F, de Haan L. 2021.. Association of Toxoplasma gondii seropositivity with cognitive function in healthy people. . JAMA Psychiatry 78:(10):110312
    [Crossref] [Google Scholar]
  32. de Witte LD, Hoffmann C, van Mierlo HC, Titulaer MJ, Kahn RS, Martinez-Martinez P. 2015.. Absence of N-methyl-d-aspartate receptor IgG autoantibodies in schizophrenia. . JAMA Psychiatry 72:(7):73133
    [Crossref] [Google Scholar]
  33. Deakin B, Suckling J, Barnes TRE, Byrne K, Chaudhry IB, et al. 2018.. The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial. . Lancet Psychiatry 5:(11):88594
    [Crossref] [Google Scholar]
  34. Del Giudice M, Gangestad SW. 2018.. Rethinking IL-6 and CRP: why they are more than inflammatory biomarkers, and why it matters. . Brain Behav. Immun. 70::6175
    [Crossref] [Google Scholar]
  35. Di Biase MA, Zalesky A, Cetin-Karayumak S, Rathi Y, Lv J, et al. 2021.. Large-scale evidence for an association between peripheral inflammation and white matter free water in schizophrenia and healthy individuals. . Schizophr. Bull. 47:(2):54251
    [Crossref] [Google Scholar]
  36. Diaz Heijtz R, Wang S, Anuar F, Qian Y, Björkholm B, et al. 2011.. Normal gut microbiota modulates brain development and behavior. . PNAS 108:(7):304752
    [Crossref] [Google Scholar]
  37. Do KQ. 2023.. Bridging the gaps towards precision psychiatry: mechanistic biomarkers for early detection and intervention. . Psychiatry Res. 321::115064
    [Crossref] [Google Scholar]
  38. Do KQ, Trabesinger AH, Kirsten-Krüger M, Lauer CJ, Dydak U, et al. 2000.. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. . Eur. J. Neurosci. 12:(10):372128
    [Crossref] [Google Scholar]
  39. Doorduin J, De Vries EFJ, Willemsen ATM, De Groot JC, Dierckx RA, Klein HC. 2009.. Neuroinflammation in schizophrenia-related psychosis: a PET study. . J. Nucl. Med. 50:(11):18017
    [Crossref] [Google Scholar]
  40. Dwir D, Khadimallah I, Xin L, Rahman M, Du F, et al. 2023.. Redox and immune signaling in schizophrenia: new therapeutic potential. . Int. J. Neuropsychopharmacol. 26:(5):30921
    [Crossref] [Google Scholar]
  41. Ermakov EA, Melamud MM, Buneva VN, Ivanova SA. 2022.. Immune system abnormalities in schizophrenia: an integrative view and translational perspectives. . Front. Psychiatry 13::880568
    [Crossref] [Google Scholar]
  42. Estes ML, McAllister AK. 2014.. Alterations in immune cells and mediators in the brain: It's not always neuroinflammation!. Brain Pathol. 24:(6):62330
    [Crossref] [Google Scholar]
  43. Feinberg I. 1983.. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence?. J. Psychiatr. Res. 17:(4):31934
    [Crossref] [Google Scholar]
  44. Firth J, Stubbs B, Teasdale SB, Ward PB, Veronese N, et al. 2018.. Diet as a hot topic in psychiatry: a population-scale study of nutritional intake and inflammatory potential in severe mental illness. . World Psychiatry 17:(3):36567
    [Crossref] [Google Scholar]
  45. Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. 2017.. Inflammaging and ‘garb-aging. .’ Trends Endocrinol. Metab. 28:(3):199212
    [Crossref] [Google Scholar]
  46. Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, et al. 2018.. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. . Science 362:(6420):eaat8127
    [Crossref] [Google Scholar]
  47. Gangadin SS, Mandl RCW, de Witte LD, van Haren NEM, Schutte MJL, et al. 2024.. Lower fractional anisotropy without evidence for neuro-inflammation in patients with early-phase schizophrenia spectrum disorders. . Schizophr. Res. 264::55766
    [Crossref] [Google Scholar]
  48. Gangadin SS, Nasib LG, Sommer IEC, Mandl RCW. 2019.. MRI investigation of immune dysregulation in schizophrenia. . Curr. Opin. Psychiatry 32:(3):16469
    [Crossref] [Google Scholar]
  49. Germann M, Brederoo SG, Sommer IEC. 2021.. Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders. . Curr. Opin. Psychiatry 34:(3):22227
    [Crossref] [Google Scholar]
  50. Guilarte TR, Rodichkin AN, McGlothan JL, Acanda De La Rocha AM, Azzam DJ. 2022.. Imaging neuroinflammation with TSPO: a new perspective on the cellular sources and subcellular localization. . Pharmacol. Ther. 234::108048
    [Crossref] [Google Scholar]
  51. Guo JY, Lesh TA, Niendam TA, Ragland JD, Tully LM, Carter CS. 2021.. Brain free water alterations in first-episode psychosis: a longitudinal analysis of diagnosis, course of illness, and medication effects. . Psychol. Med. 51:(6):100110
    [Crossref] [Google Scholar]
  52. Hagen JM, Sutterland AL, Edrisy S, Tan HL, de Haan L. 2020.. Accumulation rate of advanced glycation end products in recent onset psychosis: a longitudinal study. . Psychiatry Res. 291::113192
    [Crossref] [Google Scholar]
  53. Halstead S, Siskind D, Amft M, Wagner E, Yakimov V, et al. 2023.. Alteration patterns of peripheral concentrations of cytokines and associated inflammatory proteins in acute and chronic stages of schizophrenia: a systematic review and network meta-analysis. . Lancet Psychiatry 10:(4):26071
    [Crossref] [Google Scholar]
  54. Hansen N, Malchow B. 2023.. Monoclonal antibody therapy in autoantibody-associated psychotic disorders and schizophrenia: narrative review of past and current clinical trials. . Psychiatr. Danub. 35:(1):815
    [Crossref] [Google Scholar]
  55. He H, Yu Y, Liew Z, Gissler M, László KD, et al. 2022.. Association of maternal autoimmune diseases with risk of mental disorders in offspring in Denmark. . JAMA Netw. Open 5:(4):e227503
    [Crossref] [Google Scholar]
  56. Henkel ND, Wu X, O'Donovan SM, Devine EA, Jiron JM, et al. 2022.. Schizophrenia: a disorder of broken brain bioenergetics. . Mol. Psychiatry 27:(5):2393404
    [Crossref] [Google Scholar]
  57. Hogenaar JTT, van Bokhoven H. 2021.. Schizophrenia: complement cleaning or killing. . Genes 12:(2):259
    [Crossref] [Google Scholar]
  58. Howes OD, Kapur S. 2009.. The dopamine hypothesis of schizophrenia: version III—the final common pathway. . Schizophr. Bull. 35:(3):54962
    [Crossref] [Google Scholar]
  59. Howes OD, McCutcheon R. 2017.. Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization. . Transl. Psychiatry 7:(2):e1024
    [Crossref] [Google Scholar]
  60. Hutto B. 2001.. Syphilis in clinical psychiatry: a review. . Psychosomatics 42:(6):45360
    [Crossref] [Google Scholar]
  61. Insel TR. 2010.. Rethinking schizophrenia. . Nature 468:(7321):18793
    [Crossref] [Google Scholar]
  62. Ioannidis JPA. 2005.. Why most published research findings are false. . PLOS Med. 2:(8):e124
    [Crossref] [Google Scholar]
  63. Ioannou M, Foiselle M, Mallet J, Stam EL, Godin O, et al. 2021.. Towards precision medicine: what are the stratification hypotheses to identify homogeneous inflammatory subgroups. . Eur. Neuropsychopharmacol. 45::10821
    [Crossref] [Google Scholar]
  64. Jenkins AK, Lewis DA, Volk DW. 2023.. Altered expression of microglial markers of phagocytosis in schizophrenia. . Schizophr. Res. 251::2229
    [Crossref] [Google Scholar]
  65. Jeppesen R, Benros ME. 2019.. Autoimmune diseases and psychotic disorders. . Front. Psychiatry 10::00131
    [Crossref] [Google Scholar]
  66. Jeppesen R, Christensen RHB, Pedersen EMJ, Nordentoft M, Hjorthøj C, et al. 2020.. Efficacy and safety of anti-inflammatory agents in treatment of psychotic disorders—a comprehensive systematic review and meta-analysis. . Brain Behav. Immun. 90::36480
    [Crossref] [Google Scholar]
  67. Kadry H, Noorani B, Cucullo L. 2020.. A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity. . Fluids Barriers CNS 17:(1):69
    [Crossref] [Google Scholar]
  68. Karanikas E. 2023.. The immune-stress/endocrine-redox-metabolic nature of psychosis’ etiopathology; focus on the intersystemic pathways interactions. . Neurosci. Lett. 794::137011
    [Crossref] [Google Scholar]
  69. Kim M, Haney JR, Zhang P, Hernandez LM, Wang L, et al. 2021.. Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia. . Nat. Neurosci. 24::799809
    [Crossref] [Google Scholar]
  70. Klein SL, Flanagan KL. 2016.. Sex differences in immune responses. . Nat. Rev. Immunol. 16:(10):62638
    [Crossref] [Google Scholar]
  71. Knight JG. 1984.. Is schizophrenia an autoimmune disease? A review. . Methods Find. Exp. Clin. Pharmacol. 6:(7):395403
    [Google Scholar]
  72. Köhler O, Petersen L, Mors O, Mortensen PB, Yolken RH, et al. 2017.. Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study. . Acta Psychiatr. Scand. 135:(2):97105
    [Crossref] [Google Scholar]
  73. Kraepelin E. 1919.. Dementia Praecox and Paraphrenia. Edinburgh, UK:: Livingstone
    [Google Scholar]
  74. Lestra V, Romeo B, Martelli C, Benyamina A, Hamdani N. 2022.. Could CRP be a differential biomarker of illness stages in schizophrenia? A systematic review and meta-analysis. . Schizophr. Res. 246::17586
    [Crossref] [Google Scholar]
  75. Levi L, Bar Haim M, Burshtein S, Winter-Van Rossum I, Heres S, et al. 2020.. Duration of untreated psychosis and response to treatment: an analysis of response in the OPTiMiSE cohort. . Eur. Neuropsychopharmacol. 32::13135
    [Crossref] [Google Scholar]
  76. Lydholm CN, Köhler-Forsberg O, Nordentoft M, Yolken RH, Mortensen PB, et al. 2019.. Parental infections before, during, and after pregnancy as risk factors for mental disorders in childhood and adolescence: a nationwide Danish study. . Biol. Psychiatry 85:(4):31725
    [Crossref] [Google Scholar]
  77. Mandl RCW, Pasternak O, Cahn W, Kubicki M, Kahn RS, et al. 2015.. Comparing free water imaging and magnetization transfer measurements in schizophrenia. . Schizophr. Res. 161:(1):12632
    [Crossref] [Google Scholar]
  78. Marques TR, Ashok AH, Pillinger T, Veronese M, Turkheimer FE, et al. 2019.. Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies. . Psychol. Med. 49:(13):218696
    [Crossref] [Google Scholar]
  79. McKenna F, Gupta PK, Sui YV, Bertisch H, Gonen O, et al. 2023.. Microstructural and microvascular alterations in psychotic spectrum disorders: a three-compartment intravoxel incoherent imaging and free water model. . Schizophr. Bull. 49:(6):154253
    [Crossref] [Google Scholar]
  80. Meixensberger S, Kuzior H, Fiebich BL, Süß P, Runge K, et al. 2021.. Upregulation of sICAM-1 and sVCAM-1 levels in the cerebrospinal fluid of patients with schizophrenia spectrum disorders. . Diagnostics 11:(7):1134
    [Crossref] [Google Scholar]
  81. Metcalf SA, Jones PB, Nordstrom T, Timonen M, Mäki P, et al. 2017.. Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: a prospective birth cohort study. . Brain Behav. Immun. 59::25359
    [Crossref] [Google Scholar]
  82. Miller AH, Raison CL. 2023.. Burning down the house: reinventing drug discovery in psychiatry for the development of targeted therapies. . Mol. Psychiatry 28::6875
    [Crossref] [Google Scholar]
  83. Misiak B, Bartoli F, Carrà G, Stańczykiewicz B, Gładka A, et al. 2021.. Immune-inflammatory markers and psychosis risk: a systematic review and meta-analysis. . Psychoneuroendocrinology 127::105200
    [Crossref] [Google Scholar]
  84. Möller T, Bard F, Bhattacharya A, Biber K, Campbell B, et al. 2016.. Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor. . Glia 64:(10):178894
    [Crossref] [Google Scholar]
  85. Mongan D, Föcking M, Healy C, Susai SR, Heurich M, et al. 2021.. Development of proteomic prediction models for transition to psychotic disorder in the clinical high-risk state and psychotic experiences in adolescence. . JAMA Psychiatry 78:(1):7790
    [Crossref] [Google Scholar]
  86. Müller N, Riedel M, Scheppach C, Brandstätter B, Sokullu S, et al. 2002.. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. . Am. J. Psychiatry 159:(6):102934
    [Crossref] [Google Scholar]
  87. Murray N, Al Khalaf S, Bastiaanssen TFS, Kaulmann D, Lonergan E, et al. 2023.. Compositional and functional alterations in intestinal microbiota in patients with psychosis or schizophrenia: a systematic review and meta-analysis. . Schizophr. Bull. 49:(5):123955
    [Crossref] [Google Scholar]
  88. Najjar S, Steiner J, Najjar A, Bechter K. 2018.. A clinical approach to new-onset psychosis associated with immune dysregulation: the concept of autoimmune psychosis. . J. Neuroinflammation 15:(1):40
    [Crossref] [Google Scholar]
  89. Nasib LG, Gangadin SS, Rossum IW, Boudewijns ZSRM, de Witte LD, et al. 2021.. The effect of prednisolone on symptom severity in schizophrenia: a placebo-controlled, randomized controlled trial. . Schizophr. Res. 230::7986
    [Crossref] [Google Scholar]
  90. Nguyen TT, Eyler LT, Jeste DV. 2018.. Systemic biomarkers of accelerated aging in schizophrenia: a critical review and future directions. . Schizophr. Bull. 44:(2):398408
    [Crossref] [Google Scholar]
  91. Nielsen PR, Benros ME, Mortensen PB. 2014.. Hospital contacts with infection and risk of schizophrenia: a population-based cohort study with linkage of Danish national registers. . Schizophr. Bull. 40:(6):152632
    [Crossref] [Google Scholar]
  92. Noll R. 2007.. Kraepelin's ‘lost biological psychiatry’? Autointoxication, organotherapy and surgery for dementia praecox. . Hist. Psychiatry 18:(3):30120
    [Crossref] [Google Scholar]
  93. Notter T. 2021.. Astrocytes in schizophrenia. . Brain Neurosci. Adv. 5:. https://doi.org/10.1177/23982128211009148
    [Crossref] [Google Scholar]
  94. Orlovska-Waast S, Köhler-Forsberg O, Brix SW, Nordentoft M, Kondziella D, et al. 2019.. Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. . Mol. Psychiatry 24:(6):86987
    [Crossref] [Google Scholar]
  95. Palaniyappan L, Sabesan P, Li X, Luo Q. 2021.. Schizophrenia increases variability of the central antioxidant system: a meta-analysis of variance from MRS studies of glutathione. . Front. Psychiatry 12::796466
    [Crossref] [Google Scholar]
  96. Paolicelli RC, Sierra A, Stevens B, Tremblay M-E, Aguzzi A, et al. 2022.. Microglia states and nomenclature: a field at its crossroads. . Neuron 110:(21):345883
    [Crossref] [Google Scholar]
  97. Pasternak O, Kubicki M, Shenton ME. 2016.. In vivo imaging of neuroinflammation in schizophrenia. . Schizophr. Res. 173:(3):20012
    [Crossref] [Google Scholar]
  98. Pedersen MS, Benros ME, Agerbo E, Børglum AD, Mortensen PB. 2012.. Schizophrenia in patients with atopic disorders with particular emphasis on asthma: a Danish population-based study. . Schizophr. Res. 138:(1):5862
    [Crossref] [Google Scholar]
  99. Penninx BWJH, Lange SMM. 2018.. Metabolic syndrome in psychiatric patients: overview, mechanisms, and implications. . Dialogues Clin. Neurosci. 20::6373
    [Crossref] [Google Scholar]
  100. Pillinger T, Beck K, Gobjila C, Donocik JG, Jauhar S, Howes OD. 2017.. Impaired glucose homeostasis in first-episode schizophrenia. . JAMA Psychiatry 74:(3):26169
    [Crossref] [Google Scholar]
  101. Plavén-Sigray P, Matheson GJ, Collste K, Ashok AH, Coughlin JM, et al. 2018.. Positron emission tomography studies of the glial cell marker translocator protein in patients with psychosis: a meta-analysis using individual participant data. . Biol. Psychiatry 84:(6):43342
    [Crossref] [Google Scholar]
  102. Plavén-Sigray P, Matheson GJ, Coughlin JM, Hafizi S, Laurikainen H, et al. 2021.. Meta-analysis of the glial marker TSPO in psychosis revisited: reconciling inconclusive findings of patient–control differences. . Biol. Psychiatry 89:(3):e58
    [Crossref] [Google Scholar]
  103. Pollak TA, Lennox BR, Müller S, Benros ME, Prüss H, et al. 2020.. Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. . Lancet Psychiatry 7:(1):93108
    [Crossref] [Google Scholar]
  104. Pulendran B, Davis MM. 2020.. The science and medicine of human immunology. . Science 369:(6511):eaay4014
    [Crossref] [Google Scholar]
  105. Puvogel S, Palma V, Sommer IEC. 2022.. Brain vasculature disturbance in schizophrenia. . Curr. Opin. Psychiatry 35:(3):14656
    [Crossref] [Google Scholar]
  106. Radewicz K, Garey LJ, Gentleman SM, Reynolds R. 2000.. Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. . J. Neuropathol. Exp. Neurol. 59:(2):13750
    [Crossref] [Google Scholar]
  107. Rantakallio P, Jones P, Moring J, Von Wendt L. 1997.. Association between central nervous system infections during childhood and adult onset schizophrenia and other psychoses: a 28-year follow-up. . Int. J. Epidemiol. 26:(4):83743
    [Crossref] [Google Scholar]
  108. Reemst K, Noctor SC, Lucassen PJ, Hol EM. 2016.. The indispensable roles of microglia and astrocytes during brain development. . Front. Hum. Neurosci. 10::00566
    [Crossref] [Google Scholar]
  109. Rey R, Suaud-Chagny M-F, Bohec A-L, Dorey J-M, D'Amato T, et al. 2020.. Overexpression of complement component C4 in the dorsolateral prefrontal cortex, parietal cortex, superior temporal gyrus and associative striatum of patients with schizophrenia. . Brain Behav. Immun. 90::21625
    [Crossref] [Google Scholar]
  110. Rodrigues-Amorim D, Rivera-Baltanás T, Spuch C, Caruncho HJ, González-Fernandez Á, et al. 2018.. Cytokines dysregulation in schizophrenia: a systematic review of psychoneuroimmune relationship. . Schizophr. Res. 197::1933
    [Crossref] [Google Scholar]
  111. Rømer TB, Jeppesen R, Christensen RHB, Benros ME. 2023.. Biomarkers in the cerebrospinal fluid of patients with psychotic disorders compared to healthy controls: a systematic review and meta-analysis. . Mol. Psychiatry 28::227790
    [Crossref] [Google Scholar]
  112. Ruzzo EK, Geschwind DH. 2016.. Schizophrenia genetics complements its mechanistic understanding. . Nat. Neurosci. 19:(4):52325
    [Crossref] [Google Scholar]
  113. Schizophr. Work. Group Psychiatr. Genom. Consort. 2014.. Biological insights from 108 schizophrenia-associated genetic loci. . Nature 511:(7510):42127
    [Crossref] [Google Scholar]
  114. Schwalfenberg GK. 2021.. N-acetylcysteine: a review of clinical usefulness (an old drug with new tricks). . J. Nutr. Metab. 2021::9949453
    [Crossref] [Google Scholar]
  115. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, et al. 2016.. Schizophrenia risk from complex variation of complement component 4. . Nature 530:(7589):17783
    [Crossref] [Google Scholar]
  116. Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, et al. 2019.. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. . Nat. Neurosci. 22:(3):37485
    [Crossref] [Google Scholar]
  117. Selten J-P, Cantor-Graae E. 2005.. Social defeat: risk factor for schizophrenia?. Br. J. Psychiatry 187:(2):1012
    [Crossref] [Google Scholar]
  118. Severance EG, Alaedini A, Yang S, Halling M, Gressitt KL, et al. 2012.. Gastrointestinal inflammation and associated immune activation in schizophrenia. . Schizophr. Res. 138:(1):4853
    [Crossref] [Google Scholar]
  119. Sherwin E, Rea K, Dinan TG, Cryan JF. 2016.. A gut (microbiome) feeling about the brain. . Curr. Opin. Gastroenterol. 32:(2):96102
    [Crossref] [Google Scholar]
  120. Shivappa N, Steck SE, Hurley TG, Hussey JR, Hébert JR. 2014.. Designing and developing a literature-derived, population-based dietary inflammatory index. . Public Health Nutr. 17:(8):168996
    [Crossref] [Google Scholar]
  121. Sneeboer MAM, van der Doef T, Litjens M, Psy NBB, Melief J, et al. 2020.. Microglial activation in schizophrenia: Is translocator 18 kDa protein (TSPO) the right marker?. Schizophr. Res. 215::16772
    [Crossref] [Google Scholar]
  122. Snijders GJLJ, van Zuiden W, Sneeboer MAM, Berdenis van Berlekom A, Geest AT, et al. 2021.. A loss of mature microglial markers without immune activation in schizophrenia. . Glia 69:(5):125167
    [Crossref] [Google Scholar]
  123. Sommer IE, Bearden CE, van Dellen E, Breetvelt EJ, Duijff SN, et al. 2016.. Early interventions in risk groups for schizophrenia: What are we waiting for?. NPJ Schizophr. 2:(1):16003
    [Crossref] [Google Scholar]
  124. Sommer IEC, Gangadin SS, de Witte LD, Koops S, van Baal C, et al. 2021.. Simvastatin augmentation for patients with early-phase schizophrenia-spectrum disorders: a double-blind, randomized placebo-controlled trial. . Schizophr. Bull. 47:(4):110815
    [Crossref] [Google Scholar]
  125. Steinberg H, Kirkby K, Himmerich H. 2015.. The historical development of immunoendocrine concepts of psychiatric disorders and their therapy. . Int. J. Mol. Sci. 16:(12):2884169
    [Crossref] [Google Scholar]
  126. Sutterland AL, Mounir DA, Ribbens JJ, Kuiper B, van Gool T, de Haan L. 2020.. Toxoplasma gondii infection and clinical characteristics of patients with schizophrenia: a systematic review and meta-analysis. . Schizophr. Bull. Open 1:(1):sgaa042
    [Crossref] [Google Scholar]
  127. Thompson J, Stansfeld JL, Cooper RE, Morant N, Crellin NE, Moncrieff J. 2020.. Experiences of taking neuroleptic medication and impacts on symptoms, sense of self and agency: a systematic review and thematic synthesis of qualitative data. . Soc. Psychiatry Psychiatr. Epidemiol. 55:(2):15164
    [Crossref] [Google Scholar]
  128. Torrey EF. 2022.. Parasites, Pussycats and Psychosis: The Unknown Dangers of Human Toxoplasmosis. Cham, Switz:.: Springer
    [Google Scholar]
  129. Torrey EF, Bartko JJ, Lun Z-R, Yolken RH. 2007.. Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis. . Schizophr. Bull. 33:(3):72936
    [Crossref] [Google Scholar]
  130. Torrey EF, Yolken RH. 2003.. Toxoplasma gondii and schizophrenia. . Emerg. Infect. Dis. 9:(11):137580
    [Crossref] [Google Scholar]
  131. Trubetskoy V, Pardiñas AF, Qi T, Panagiotaropoulou G, Awasthi S, et al. 2022.. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. . Nature 604:(7906):5028
    [Crossref] [Google Scholar]
  132. Tsay CJ. 2013.. Julius Wagner-Jauregg and the legacy of malarial therapy for the treatment of general paresis of the insane. . Yale J. Biol. Med. 86:(2):24554
    [Google Scholar]
  133. van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, et al. 2008.. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. . Biol. Psychiatry 64:(9):82022
    [Crossref] [Google Scholar]
  134. van Daal MT, Folkerts G, Garssen J, Braber S. 2021.. Pharmacological modulation of immune responses by nutritional components. . Pharmacol. Rev. 73:(4):1369403
    [Crossref] [Google Scholar]
  135. van Kesteren CFMG, Gremmels H, de Witte LD, Hol EM, Van Gool AR, et al. 2017.. Immune involvement in the pathogenesis of schizophrenia: a meta-analysis on postmortem brain studies. . Transl. Psychiatry 7:(3):e1075
    [Crossref] [Google Scholar]
  136. van Mierlo HC, Schot A, Boks MPM, de Witte LD. 2020.. The association between schizophrenia and the immune system: review of the evidence from unbiased ‘omic-studies.’. Schizophr. Res. 217::11423
    [Crossref] [Google Scholar]
  137. van Zonneveld SM, Haarman BCM, van den Oever EJ, Nuninga JO, Sommer IEC. 2022.. Unhealthy diet in schizophrenia spectrum disorders. . Curr. Opin. Psychiatry 35:(3):17785
    [Crossref] [Google Scholar]
  138. Ventura J, Hellemann GS, Thames AD, Koellner V, Nuechterlein KH. 2009.. Symptoms as mediators of the relationship between neurocognition and functional outcome in schizophrenia: a meta-analysis. . Schizophr. Res. 113:(2–3):18999
    [Crossref] [Google Scholar]
  139. Vidal CN, Rapoport JL, Hayashi KM, Geaga JA, Sui Y, et al. 2006.. Dynamically spreading frontal and cingulate deficits mapped in adolescents with schizophrenia. . Arch. Gen. Psychiatry 63:(1):2534
    [Crossref] [Google Scholar]
  140. Weinberger DR. 1987.. Implications of normal brain development for the pathogenesis of schizophrenia. . Arch. Gen. Psychiatry 44:(7):66069
    [Crossref] [Google Scholar]
  141. Weiser M, Levi L, Burshtein S, Chiriță R, Cirjaliu D, et al. 2019.. The effect of minocycline on symptoms in schizophrenia: results from a randomized controlled trial. . Schizophr. Res. 206::32532
    [Crossref] [Google Scholar]
  142. Weiser M, Zamora D, Levi L, Nastas I, Gonen I, et al. 2021.. Adjunctive aspirin versus placebo in patients with schizophrenia: results of two randomized controlled trials. . Schizophr. Bull. 47:(4):107787
    [Crossref] [Google Scholar]
  143. Wilkinson NM, Chen H-C, Lechner MG, Su MA. 2022.. Sex differences in immunity. . Annu. Rev. Immunol. 40::7594
    [Crossref] [Google Scholar]
  144. Wium-Andersen MK, Ørsted DD, Nordestgaard BG. 2014.. Elevated C-reactive protein associated with late- and very-late-onset schizophrenia in the general population: a prospective study. . Schizophr. Bull. 40:(5):111727
    [Crossref] [Google Scholar]
  145. Woodburn SC, Bollinger JL, Wohleb ES. 2021.. The semantics of microglia activation: neuroinflammation, homeostasis, and stress. . J. Neuroinflammation 18::258
    [Crossref] [Google Scholar]
  146. Yolken RH, Torrey EF. 1995.. Viruses, schizophrenia, and bipolar disorder. . Clin. Microbiol. Rev. 8:(1):13145
    [Crossref] [Google Scholar]
  147. Zhang C, Fang X, Yao P, Mao Y, Cai J, et al. 2017.. Metabolic adverse effects of olanzapine on cognitive dysfunction: a possible relationship between BDNF and TNF-alpha. . Psychoneuroendocrinology 81::13843
    [Crossref] [Google Scholar]
  148. Zhang T, Zeng J, Ye J, Gao Y, Hu Y, et al. 2023.. Serum complement proteins rather than inflammatory factors is effective in predicting psychosis in individuals at clinical high risk. . Transl. Psychiatry 13:(1):9
    [Crossref] [Google Scholar]
  149. Zhu Y, Webster MJ, Walker AK, Massa P, Middleton FA, Weickert CS. 2023.. Increased prefrontal cortical cells positive for macrophage/microglial marker CD163 along blood vessels characterizes a neuropathology of neuroinflammatory schizophrenia. . Brain Behav. Immun. 111::4660
    [Crossref] [Google Scholar]
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