Immunoinflammatory Profile in Patients with Episodic and Continuous Paranoid Schizophrenia

Abstract

Introduction. Associations of disturbances in innate and adaptive immunity during the clinical course of schizophrenia have been found in a number of studies. Yet, the relationship of immune parameters and systemic inflammation in relation to the clinical course of the disease and its prognosis, remains poorly understood, which highlights an interesting topic for further research. The goal of this study was to research the immuno-inflammatory changes in patients with clinical continuous and episodic paranoid schizophrenia, to assess the pathogenetic significance of these changes.

Methods. Thirty-six patients with paranoid schizophrenia, of which 20 had episodic symptoms and 16 had continuous symptoms, consented to participate in the study, together with 30 healthy volunteers. In the study we assessed the parameters of innate immune response (serum levels of key pro-inflammatory and anti-inflammatory cytokines, C-reactive protein) and the adaptive immune response, including humoral-mediated immunity (serum immunoglobulins IgA, IgM, IgG, circulating immune complexes), as well as the cell link of adaptive immunity (key lymphocyte subpopulations). Positive and negative symptoms were assessed with the positive and negative symptoms scale; frontal dysfunction was assessed by Frontal Assessment Battery (FAB).

Results. Both patient groups had higher than normal levels of C-reactive protein and IL-8. There was a significant elevation of circulating immune complexes among patients with continuous symptoms of schizophrenia, compared to patients with episodic symptoms and healthy controls. Levels of CD45+CD3+ lymphocytes (T-cells) differed between clinical groups, with higher values identified among patients with episodic symptoms and lower values among those with continuous symptoms. In addition, patients with episodic symptoms had significantly increased levels of CD45+CD3+CD4+CD25+CD127- regulatory T-cells. Finally, the level of CD45+CD3-CD19+ B-cells was significantly higher among patients with continuous symptoms vs. patients with episodic symptoms and the control groups. Markers of activation of humoral immunity were associated with the severity of frontal disorders in these patients.

Discussion. Comprehensive data on the serum level of cytokines and the parameters of adaptive immunity among individuals with continuous schizophrenia, by comparison with patients with episodic schizophrenia, are practically absent in the literature. We have shown that among those with continuous schizophrenia, there are signs of systemic inflammation and chronic activation of the adaptive humoral immune response, while among patients with episodic symptoms of the disease, there are signs of systemic inflammation and certain activation of cell-mediated immunity, without significant changes in the humoral link of adaptive immunity.

Conclusion. More studies are needed, but the data obtained in this study are important for subsequent clinical studies of new treatment methods, based on various immunophenotypes of schizophrenia.

Keywords

adaptive immunity / cytokines / inflammation / innate immunity / schizophrenia

References

[1] Lyubov EB, Yastrebov VS, Schevchenko LS, et al. Economic burden of schizophrenia in Russia. Article in Russian. Socialnaya i klinicheskaya psikhiatriya = Social and Clinical Psychiatry. 2012;22(3):36-42.

[2] Bechter K. Updating the mild encephalitis hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:71-91. doi:10.1016/j.pnpbp.2012.06.019

[3] Müller N, Weidinger E, Leitner B, et al. The role of inflammation in schizophrenia. Front Neurosci. 2015;9:372. doi:10.3389/fnins.2015.00372

[4] Kinney DK, Hintz K, Shearer EM, et al. A unifying hypothesis of schizophrenia: abnormal immune system development may help explain roles of prenatal hazards, post-pubertal onset, stress, genes, climate, infections, and brain dysfunction. Med Hypotheses. 2010;74(3):555-563. doi:10.1016/j.mehy.2009.09.040

[5] 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(12):1696-1709. doi:10.1038/mp.2016.3

[6] Miller BJ, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663-671. doi:10.1016/j.biopsych.2011.04.013

[7] Potvin S, Stip E, Sepehry AA, et al. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63(8):801-808. doi:10.1016/j.biopsych.2007.09.024

[8] Boerrigter D, Weickert TW, Lenroot R, et al. Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder. J Neuroinflammation. 2017;14:188. doi:10.1186/s12974-017-0962-y

[9] Ushakov VL, Malashenkova IK, Kostyuk GP, et al. The relationship between inflammation, cognitive impairment, and neuroimaging data in schizophrenia. Article in Russian. Zh Nevrol Psikhiatr Im S S Korsakova. 2020. In press.

[10] Zozulya SA, Oleichik IV, Androsova LV, et al. Monitoring trend of endogenous psychoses by immunological parameters. Article in Russian. Psikhicheskoe zdorovie. 2017;15(1):11-18.

[11] Torrey EF, Yolken RH. Toxoplasma gondii and schizophrenia. Emerg Infect Dis. 2003;9(11):1375-1380.

[12] Leweke FM, Gerth CW, Koethe D, et al. Antibodies to infectious agents in individuals with recent onset schizophrenia. Eur Arch Psychiat Clin Neurosci. 2004;254(1):4-8. doi:10.1007/s00406-004-0481-6

[13] Eaton W, Byrne M, Ewald H, et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiat. 2006;163(3):521-528. doi:10.1176/appi.ajp.163.3.521

[14] Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiat. 1998;173:11-53. doi:10.1192/bjp.173.1.11

[15] Klyushnik TP, Androsova LV, Zozulya SA, et al. Comparative analysis of inflammatory markers in endogenous and non-psychotic mental disorders. Article in Russian. Sibirskii vestnik psikhiatrii i narkologii=Siberian Herald of Psychiatry and Addiction Psychiatry. 2018;(2):64-69. doi:10.26617/1810-3111-2018-2(99)-64-69

[16] Drexhage RC, Padmos RC, de Wit H, et al. Patients with schizophrenia show raised serum levels of the pro-inflammatory chemokine CCL2: Association with the metabolic syndrome in patients? Schizophr Res. 2008;102(1):352-355. doi:10.1016/j.schres.2008.03.018

[17] Noto C, Maes M, Ota VK, et al. High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance. World J Biol Psychiatry. 2015;16(6):422-429. doi:10.3109/15622975.2015.1062552

[18] Fernandes BS, Steiner J, Bernstein HG, et al. C-reactive protein is increased in schizophrenia but is not altered by antipsychotics:meta-analysis and implications. Mol Psychiatry. 2016;21(4):554-564. doi:10.1038/mp.2015.87

[19] Johnsen E, Fathian F, Kroken RA, et al. The serum level of C-reactive protein (CRP) is associated with cognitive performance in acute phase psychosis. BMC Psychiatry. 2016;16:60. doi:10.1186/s12888-016-0769-x

[20] Fillman SG, Weickert TW, Lenroot RK, et al. Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca’s area volume. Mol Psychiatry. 2016;21(8):1090-1098. doi:10.1038/mp.2015.90

[21] Siegel BI, Sengupta EJ, Edelson JR, et al. Elevated viral restriction factor levels in cortical blood vessels in schizophrenia. Biol Psychiatry. 2014;76(2):160-167. doi:10.1016/j.biopsych.2013.09.019

[22] Volk DW, Chitrapu A, Edelson JR, et al. Molecular mechanisms and timing of cortical immune activation in schizophrenia. Am J Psychiatry. 2015;172(11):1112-1121. doi:10.1176/appi.ajp.2015.15010019

[23] Craddock RM, Lockstone HE, Rider DA, et al. Altered T-cell function in schizophrenia: a cellular model to investigate molecular disease mechanisms. PLoS One. 2007;2(8):692. doi:10.1371/journal.pone.0000692

[24] Debnath M. Adaptive immunity in schizophrenia: functional implications of T cells in the etiology, course and treatment. J Neuroimmune Pharmacol. 2015;10(4):610-629. doi:10.1007/s11481-015-9626-9

[25] Fond G, Lançon C, Korchia T, et al. The role of inflammation in the treatment of schizophrenia. Front Psychiatry. 2020;11:160. doi:10.3389/fpsyt.2020.00160

[26] Miller BJ, Gassama B, Sebastian D, et al. Meta-analysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2013;73(10):993-999. doi:10.1016/j.biopsych.2012.09.007

[27] Ozdin S, Boke O. Neutrophil/lymphocyte, platelet/lymphocyte and monocyte/lymphocyte ratios in different stages of schizophrenia. Psychiatry Res. 2019;271:131-135. doi:10.1016/j.psychres.2018.11.043

[28] Mørch RH, Dieset I, Færden A, et al. Inflammatory markers are altered in severe mental disorders independent of comorbid cardiometabolic disease risk factors. Psychol Med. 2019;49(10):1749-1757. doi:10.1017/S0033291718004142

[29] Steiner J, Jacobs R, Panteli B, et al. Acute schizophrenia is accompanied by reduced T cell and increased B cell immunity. Eur Arch Psychiatry Clin Neurosci. 2010;260(7):509-518. doi:10.1007/s00406-010-0098-x

[30] Miller BJ, Goldsmith DR. Towards an immunophenotype of schizophrenia: progress, potential mechanisms, and future directions. Neuropsychopharmacology. 2017;42(1):299-317. doi:10.1038/npp.2016.211

[31] Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a frontal assessment battery at bedside. Neurology. 2000;55(11):1621-1626. doi:10.1212/wnl.55.11.1621

[32] Govorin NV, Ozornina NV, Ozornin AS. Changes in the cytokines levels in the course of psychopharmacotherapy of patients with the first psychotic episode in schizophrenia. Article in Russian. Sotsialnaya i klinicheskaya psikhiatriya. 2011;21(1):20-24.

[33] Kowalski J, Blada P, Kucia K, et al. Neuroleptics normalizeincreased release of interleukin- 1 beta and tumor necrosis factor-alpha frommonocytes in schizophrenia. Schizophr Res. 2001;50(3):169-175. doi:10.1016/S0920-9964(00)00156-0

[34] Ryazantseva NV, Melnikov AP, Agarkov AP, et al. Imbalance of immunoregulatory Th1 / Th2 cytokines in patients with paranoid schizophrenia. Article in Russian. Fundamentalnie issledovaniya. 2007;(8):62-63.

[35] Malashenkova IK, Krynskiy SA, Ogurtsov DP, et al. A role of the immune system in the pathogenesis of schizophrenia. Article in Russian. Zh Nevrol Psikhiatr Im S S Korsakova. 2018;118(12):72-80. doi:10.17116/jnevro201811812172

Funding

NRC “Kurchatov Institute”(1361)

RFFR(17-29-02518)

RIGHTS & PERMISSIONS

Malashenkova I.K., Krynskiy S.A., Ogurtsov D.P., Hailov N.A., Zakharova N.V., Bravve L.V., Kaydan M.A., Chekulaeva E.I., Andreyuk D.S., Ushakov V.L., Didkovsky N.A., Kostyuk G.P.