Prognostic value of chemokines in the first episode of paranoid schizophrenia before the start of antipsychotic therapy

Prognostic value of chemokines in the first episode of paranoid schizophrenia before the start of antipsychotic therapy

 

Authors

 

A.S. Prokhorov

Federal State Budgetary Educational Institution of Higher Education “Chita State Medical Academy” of the Ministry of Health of the Russian Federation, Chita, Russian Federation; State-Funded Healthcare Institution “Regional Clinical Psychiatric Hospital named after V.Kh. Kandinsky”, Chita, Russian Federation

S.E. Golygina

Federal State Budgetary Educational Institution of Higher Education “Chita State Medical Academy” of the Ministry of Health of the Russian Federation, Chita, Russian Federation

A.V. Sakharov

National Scientific Center for Narcology ‒ Branch of the Federal State Budgetary Institution “National Medical Research Center for Psychiatry and Narcology named after V.P. Serbsky" of the Ministry of Health of the Russian Federation, Moscow, Russian Federation

 

https://doi.org/10.26617/1810-3111-2024-4(125)-5-16

 

Journal: Siberian Herald of Psychiatry and Addiction Psychiatry. 2024; 4 (125):  5-16.

 

Abstract

Introduction. Chemokines are active participants in neuroinflammation, perform neuromodulatory functions, and their involvement in the mechanisms of schizophrenia development cannot be ruled out. At the same time, the construction of prognostic models based on neural networks using chemokine indices can be promising for early diagnosis of this disorder. Objective: to study the indices of some chemokines in the blood plasma of patients with the first episode of paranoid schizophrenia before the start of antipsychotic therapy, followed by determination of their prognostic value in the manifestation of this disorder through the construction of mathematical models. Materials and Methods. A total of 80 patients (49 men and 31 women) aged 18-35 years with a diagnosis of “Paranoid schizophrenia, observation period less than a year”(F20.09) were examined at the Kandinsky Regional Clinical Psychiatric Hospital. The content of 13 chemokines (MCP-1, MIP-1α, MIP-1 β, RANTES, Eotaxini-1, TARC, MIP-3α, GRO-α, ENA-78, IL-8, IP-10, MIG, I-TAC) in the blood serum of this group of patients before treatment was determined. Results. At the debut of schizophrenia, the content of IL-8 (CXCL8) in the blood of patients increased by 3.3 times, MCP-1 (CCL2) by 1.4 times, RANTES (CCL5) by 1.3 times, with a decrease in MIG (CXCL9) by 1.8 times, I-TAC (CXCL11) and TARC (CCL17) by 1.6 times, MIP-1β (CCL4) and ENA-78 (CXCL5) by 1.5 times. The analysis performed using a neural network established the prognostic value of the chemokines MIP-1 β, IL-8, RANTES, MCP-1, TARC in assessing the risk of developing psychosis in patients with schizophrenia. Conclusion. Significant shifts in the content of some chemokines in the blood serum of patients with the first episode of schizophrenia were established even before the start of antipsychotic therapy, which indicate the development of neuroimmunoinflammation with a predominance of innate immunity over adaptive immunity during the manifestation of schizophrenic psychosis. Special mathematical calculations confirmed the prognostic significance of a number of chemokines for diagnosing the risk of developing psychosis in schizophrenia.

 

Keywords: schizophrenia, first episode, chemokines, neuroimmunoinflammation, prognostic model, neural network.

 

Article (pdf)

 

Contacts

This email address is being protected from spambots. You need JavaScript enabled to view it.

 

Materials 

For citation: Prokhorov A.S., Golygina S.E., Sakharov A.V. Prognostic value of chemokines in the first episode of paranoid schizophrenia before the start of antipsychotic therapy. Siberian Herald of Psychiatry and Addiction Psychiatry.2024; 4 (125): 5-16. https://doi.org/10.26617/1810-3111-2024-4(125)-5-16

 

REFERENCES

  1. Klyushnik TP, Smulevich AB, Zozulya SA, Voronova EI. Neurobiology of schizophrenia and clinical-psychopathological correlates (towards the construction of a clinical-biological model). Psychiatry. 2021;19(1):6-15. doi: 10.30629/2618-6667-2021-19-1-6-15(in Russian).
  2. Ermakov EA, Melamud MM, Buneva VN, Ivanova SA. Immune system abnormalities in schizophrenia: An integrative view and translational perspectives. Front Psychiatry. 2022 Apr 25;13:880568. doi: 10.3389/fpsyt.2022.880568. PMID: 35546942; PMCID: PMC9082498.
  3. Ermakov EA, Melamud MM, Boiko AS, Kamaeva DA, Ivanova SA, Nevinsky GA, Buneva VN. Association of peripheral inflammatory biomarkers and growth factors levels with sex, therapy and other clinical factors in schizophrenia and patient stratification based on these data. Brain Sci. 2023 May 22;13(5):836. doi: 10.3390/brainsci13050836. PMID: 37239308; PMCID: PMC10216189.
  4. Mednova IA, Boiko AS, Kornetova EG, Semke AV, Bokhan NA, Ivanova SA. Cytokines as potential biomarkers of clinical characteristics of schizophrenia. Life (Basel). 2022 Nov 25;12(12):1972. doi: 10.3390/life12121972. PMID: 36556337; PMCID: PMC9784438.
  5. Ermakov EA, Mednova IA, Boiko AS, Buneva VN, Ivanova SA. Chemokine dysregulation and neuroinflammation in schizophrenia: A systematic review. Int J Mol Sci. 2023 Jan 22;24(3):2215. doi: 10.3390/ijms24032215. PMID: 36768537; PMCID: PMC9917146.
  6. Prokhorov AS, Golygina SE, Sakharov AV. Chemokines in the central nervous system, possible pathogenetic role in schizophrenia (literature review). Mental Health. 2022;17(11):100-110 (in Russian).
  7. Jaerve A, Müller HW. Chemokines in CNS injury and repair. Cell Tissue Res. 2012 Jul;349(1):229-48. doi: 10.1007/s00441-012-1427-3. Epub 2012 May 22. PMID: 22700007.
  8. Van Steenwinckel J, Reaux-Le Goazigo A, Pommier B, Mauborgne A, Dansereau MA, Kitabgi P, Sarret P, Pohl M, Mélik Parsadaniantz S. CCL2 released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain after peripheral nerve injury. J Neurosci. 2011 Apr 13;31(15):5865-75. doi: 10.1523/JNEUROSCI.5986-10.2011. PMID: 21490228; PMCID: PMC6622829.
  9. Rostène W, Guyon A, Kular L, Godefroy D, Barbieri F, Bajetto A, Banisadr G, Callewaere C, Conductier G, Rovère C, Mélik-Parsadaniantz S, Florio T. Chemokines and chemokine receptors: new actors in neuroendocrine regulations. Front Neuroendocrinol. 2011 Jan;32(1):10-24. doi: 10.1016/j.yfrne.2010.07.001. Epub 2010 Jul 17. PMID: 20624414.
  10. Kozyrev EA, Ermakov EA, Boiko AS, Mednova IA, Kornetova EG, Bokhan NA, Ivanova SA. Building predictive models for schizophrenia diagnosis with peripheral inflammatory biomarkers. Biomedicines. 2023 Jul 14;11(7):1990. doi: 10.3390/biomedicines11071990. PMID: 37509629; PMCID: PMC10377576.
  11. Sakharov AV, Mynduskin IV, Golygina SE. Prognostic value of some neuromarkers in the first episode of paranoid schizophrenia before therapy. Russian Psychiatric Journal. 2023;2:38-45 (in Russian).
  12. Frydecka D, Krzystek-Korpacka M, Lubeiro A, Stramecki F, Stańczykiewicz B, Beszłej JA, Piotrowski P, Kotowicz K, Szewczuk-Bogusławska M, Pawlak-Adamska E, Misiak B. Profiling inflammatory signatures of schizophrenia: A cross-sectional and meta-analysis study. Brain Behav Immun. 2018 Jul;71:28-36. doi: 10.1016/j.bbi.2018.05.002. Epub 2018 May 3. PMID: 29730395.
  13. Dimitrijevic OB, Stamatovic SM, Keep RF, Andjelkovic AV. Effects of the chemokine CCL2 on blood-brain barrier permeability during ischemia-reperfusion injury. J Cereb Blood Flow Metab. 2006 Jun;26(6):797-810. doi: 10.1038/sj.jcbfm.9600229. PMID: 16192992.
  14. Klaus F, Mitchell K, Liou SC, Eyler LT, Nguyen TT. Chemokine MCP1 is associated with cognitive flexibility in schizophrenia: A preliminary analysis. J Psychiatr Res. 2021 Jun;138:139-145. doi: 10.1016/j.jpsychires.2021.04.007. Epub 2021 Apr 3. PMID: 33852994; PMCID: PMC8192469.
  15. Réaux-Le Goazigo A, Van Steenwinckel J, Rostène W, Mélik Parsadaniantz S. Current status of chemokines in the adult CNS. Prog Neurobiol. 2013 May;104:67-92. doi: 10.1016/j.pneurobio.2013.02.001. Epub 2013 Feb 27. PMID: 23454481.
  16. Estevao C, Bowers CE, Luo D, Sarker M, Hoeh AE, Frudd K, Turowski P, Greenwood J. CCL4 induces inflammatory signalling and barrier disruption in the neurovascular endothelium. Brain Behav Immun Health. 2021 Oct 22;18:100370. doi: 10.1016/j.bbih.2021.100370. PMID: 34755124; PMCID: PMC8560974.
  17. Guan E, Wang J, Norcross MA. Identification of human macrophage inflammatory proteins 1alpha and 1beta as a native secreted heterodimer. J Biol Chem. 2001 Apr 13;276(15):12404-9. doi: 10.1074/jbc.M006327200. Epub 2001 Jan 16. PMID: 11278300.
  18. Séguin R, Biernacki K, Prat A, Wosik K, Kim HJ, Blain M, McCrea E, Bar-Or A, Antel JP. Differential effects of Th1 and Th2 lymphocyte supernatants on human microglia. Glia. 2003 Apr 1;42(1):36-45. doi: 10.1002/glia.10201. PMID: 12594735.
  19. Zhang Z, Li Y, Jiang S, Shi FD, Shi K, Jin WN. Targeting CCL5 signaling attenuates neuroinflammation after seizure. CNS Neurosci Ther. 2023 Jan;29(1):317-330. doi: 10.1111/cns.14006. Epub 2022 Nov 28. PMID: 36440924; PMCID: PMC9804050.
  20. Di Prisco S, Summa M, Chellakudam V, Rossi PI, Pittaluga A. RANTES-mediated control of excitatory amino acid release in mouse spinal cord. J Neurochem. 2012 May;121(3):428-37. doi: 10.1111/j.1471-4159.2012.07720.x. Epub 2012 Mar 21. PMID: 22385043.
  21. Baruch K, Ron-Harel N, Gal H, Deczkowska A, Shifrut E, Ndifon W, Mirlas-Neisberg N, Cardon M, Vaknin I, Cahalon L, Berkutzki T, Mattson MP, Gomez-Pinilla F, Friedman N, Schwartz M. CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2264-9. doi: 10.1073/pnas.1211270110. Epub 2013 Jan 18. PMID: 23335631; PMCID: PMC3568380.
  22. Khavinson VK, Kuznik BI, Ryzhak GA, Lin’kova NS, Kozina LS, Sall TS. “Protein of old age” CCL11, “protein of youth” GDF11 and their role in age-related pathology. Advances in Gerontology. 2016;29(5):722-731 (in Russian).
  23. Teixeira AL, Reis HJ, Nicolato R, Brito-Melo G, Correa H, Teixeira MM, Romano-Silva MA. Increased serum levels of CCL11/eotaxin in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Apr 1;32(3):710-4. doi: 10.1016/j.pnpbp.2007.11.019. Epub 2007 Nov 23. PMID: 18096286.
  24. Al-Hakeim HK, Almulla AF, Maes M. The neuroimmune and neurotoxic fingerprint of major neurocognitive psychosis or deficit schizophrenia: a supervised machine learning study. Neurotox Res. 2020 Mar;37(3):753-771. doi: 10.1007/s12640-019-00112-z. Epub 2020 Jan 8. PMID: 31916129.
  25. Ivanovska M, Abdi Z, Murdjeva M, Macedo D, Maes A, Maes M. CCL-11 or Eotaxin-1: An immune marker for ageing and accelerated ageing in neuro-psychiatric disorders. Pharmaceuticals (Basel). 2020 Sep 2;13(9):230. doi: 10.3390/ph13090230. PMID: 32887304; PMCID: PMC7558796.
  26. Malmqvist A, Schwieler L, Orhan F, Fatouros-Bergman H, Bauer M, Flyckt L, Cervenka S, Engberg G, Piehl F; Karolinska Schizophrenia Project (KaSP) consortium; Erhardt S. Increased peripheral levels of TARC/CCL17 in first episode psychosis patients. Schizophr Res. 2019 Aug;210:221-227. doi: 10.1016/j.schres.2018.12.033. Epub 2019 Jan 3. PMID: 30612841.
  27. Deng S, Jin P, Sherchan P, Liu S, Cui Y, Huang L, Zhang JH, Gong Y, Tang J. Recombinant CCL17-dependent CCR4 activation alleviates neuroinflammation and neuronal apoptosis through the PI3K/AKT/Foxo1 signaling pathway after ICH in mice. J Neuroinflammation. 2021 Mar 1;18(1):62. doi: 10.1186/s12974-021-02112-3. PMID: 33648537; PMCID: PMC7923481.
  28. Zhang A, Liu Y, Xu H, Zhang Z, Wang X, Yuan L, Lenahan C, Zhang C, Jiang J, Fang C, Fang Y, Zhang J, Chen S. CCL17 exerts neuroprotection through activation of CCR4/mTORC2 axis in microglia after subarachnoid haemorrhage in rats. Stroke Vasc Neurol. 2022 Jul 26;8(1):4–16. doi: 10.1136/svn-2022-001659. Epub ahead of print. PMID: 35882433; PMCID: PMC9985806.
  29. Hong S, Lee EE, Martin AS, Soontornniyomkij B, Soontornniyomkij V, Achim CL, Reuter C, Irwin MR, Eyler LT, Jeste DV. Abnormalities in chemokine levels in schizophrenia and their clinical correlates. Schizophr Res. 2017 Mar;181:63-69. doi: 10.1016/j.schres.2016.09.019. Epub 2016 Sep 17. PMID: 27650194; PMCID: PMC5357211.
  30. Rothhammer V, Quintana FJ. Control of autoimmune CNS inflammation by astrocytes. Semin Immunopathol. 2015 Nov;37(6):625-38. doi: 10.1007/s00281-015-0515-3. Epub 2015 Jul 30. PMID: 26223505; PMCID: PMC4618768.
  31. Akkouh IA, Ueland T, Hansson L, Inderhaug E, Hughes T, Steen NE, Aukrust P, Andreassen OA, Szabo A, Djurovic S. Decreased IL-1β-induced CCL20 response in human iPSC-astrocytes in schizophrenia: Potential attenuating effects on recruitment of regulatory T cells. Brain Behav Immun. 2020 Jul;87:634-644. doi: 10.1016/j.bbi.2020.02.008. Epub 2020 Feb 25. PMID: 32109548.
  32. Klaus F, Guetter K, Schlegel R, Spiller TR, Seifritz E, Cathomas F, Kaiser S. Common and disorder-specific upregulation of the inflammatory markers TRAIL and CCL20 in depression and schizophrenia. Sci Rep. 2021 Sep 28;11(1):19204. doi: 10.1038/s41598-021-98769-0. PMID: 34584171; PMCID: PMC8479067.
  33. Duan F, Zhao S, Xia C, Ren Z, Yuan N, Xie L, Wang L, Xiong Y, Yu P, Chen Y, Tian J, Dai J, Lu J, Xia Y, Liu X, Chen C, Liu C. Changes of immune-related factors in the blood of schizophrenia and bipolar disorder patients receiving monotherapy. Transl Psychiatry. 2022 May 26;12(1):212. doi: 10.1038/s41398-022-01968-0. PMID: 35618730; PMCID: PMC9135722.
  34. Wu F, Zhao Y, Jiao T, Shi D, Zhu X, Zhang M, Shi M, Zhou H. CXCR2 is essential for cerebral endothelial activation and leukocyte recruitment during neuroinflammation. J Neuroinflammation. 2015 May 21;12:98. doi: 10.1186/s12974-015-0316-6. PMID: 25990934; PMCID: PMC4438521.
  35. Perez-Nievas BG, Johnson L, Beltran-Lobo P, Hughes MM, Gammallieri L, Tarsitano F, Myszczynska MA, Vazquez-Villasenor I, Jimenez-Sanchez M, Troakes C, Wharton SB, Ferraiuolo L, Noble W. Astrocytic C-X-C motif chemokine ligand-1 mediates β-amyloid-induced synaptotoxicity. J Neuroinflammation. 2021 Dec 28;18(1):306. doi: 10.1186/s12974-021-02371-0. PMID: 34963475; PMCID: PMC8715604.
  36. Mäntylä T, Mantere O, Raij TT, Kieseppä T, Laitinen H, Leiviskä J, Torniainen M, Tuominen L, Vaarala O, Suvisaari J. Altered activation of innate immunity associates with white matter volume and diffusion in first-episode psychosis. PLoS One. 2015 May 13;10(5):e0125112. doi: 10.1371/journal.pone.0125112. PMID: 25970596; PMCID: PMC4430522.
  37. Dimitrov DH, Lee S, Yantis J, Valdez C, Paredes RM, Braida N, Velligan D, Walss-Bass C. Differential correlations between inflammatory cytokines and psychopathology in veterans with schizophrenia: potential role for IL-17 pathway. Schizophr Res. 2013 Dec;151(1-3):29-35. doi: 10.1016/j.schres.2013.10.019. Epub 2013 Nov 5. PMID: 24210870.
  38. Li Z, Wang Z, Zhang C, Chen J, Su Y, Huang J, Yi Z, Yuan C, Hong W, Wang Y, Wu Z, Hu Y, Cao L, Peng D, Guan Y, Zou Y, Yu S, Cui D, Fang Y. Reduced ENA78 levels as novel biomarker for major depressive disorder and venlafaxine efficiency: Result from a prospective longitudinal study. Psychoneuroendocrinology. 2017 Jul;81:113-121. doi: 10.1016/j.psyneuen.2017.03.015. Epub 2017 Mar 18. PMID: 28441588.
  39. Xu L, Qi X, Zhu C, Wan L. Activation of IL-8 and its participation in cancer in schizophrenia patients: new evidence for the autoimmune hypothesis of schizophrenia. Neuropsychiatr Dis Treat. 2018 Dec 13;14:3393-3403. doi: 10.2147/NDT.S188210. PMID: 30587991; PMCID: PMC6298395.
  40. Robinson KF, Narasipura SD, Wallace J, Ritz EM, Al-Harthi L. Negative regulation of IL-8 in human astrocytes depends on β-catenin while positive regulation is mediated by TCFs/LEF/ATF2 interaction. Cytokine. 2020 Dec;136:155252. doi: 10.1016/j.cyto.2020.155252. Epub 2020 Aug 17. PMID: 32818703; PMCID: PMC7554258.
  41. GovorinNV, OzorninaNV, OzorninAS. Changes in the level of some serum cytokines in patients with the first psychotic episode of schizophrenia during psychopharmacotherapy. Social and Clinical Psychiatry. 2011;21(1):20-24 (in Russian).
  42. Çakici N, Sutterland AL, Penninx BWJH, Dalm VA, de Haan L, van Beveren NJM. Altered peripheral blood compounds in drug-naïve first-episode patients with either schizophrenia or major depressive disorder: a meta-analysis. Brain Behav Immun. 2020 Aug;88:547-558. doi: 10.1016/j.bbi.2020.04.039. Epub 2020 Apr 21. PMID: 32330592.
  43. Koper OM, Kamińska J, Sawicki K, Kemona H. CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration. Adv Clin Exp Med. 2018 Jun;27(6):849-856. doi: 10.17219/acem/68846. PMID: 29893515.