Alteration of Serum Levels of Cytokines in Schizophrenic Patients before and after Treatment with Risperidone
A growing body of evidence suggests the existence of abnormalities in the immune system of schizophrenic patients. The current study examined serum levels of interleukin (IL) -1β, IL-6, IL-2,interferon(IFN) -γ, and tumor necrosis factor(TNF)-α in schizophrenic patients before and after treatment with risperidone and correlated levels of these cytokines with symptomatology. The study group consisted of 24 schizophrenic patients as defined by Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria and 24 healthy controls. Serum cytokine levels were examined using enzyme-linked immunosorbent assay (ELISA). Schizophrenic symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS) questionnaire. The serum levels of TNF-α, IL-1β and IL-6 were significantly higher in participants before treatment compared with the healthy controls and after treatment (p<0.001). IFN-γ and IL-2 levels were significantly lower in participants after treatment compared with before treatment and the healthy controls (p<0.001). Except for IL-6 (p<0.05), there was no significant difference in the levels of TNF-α and IL-1β between the patients receiving treatment and the healthy subjects. Moreover, there was no significant difference in levels of IFN-γ and IL-2 between patients before treatment and the healthy subjects. There were no significant correlations between the concentration of cytokines studied and the PANSS. Positive intercorrelations between the production of IFN-γ and IL-2 were detected for sums of all groups(r=0.33, p=0.005). Clinical improvement of treated patients was associated with a reduction in the studied cytokines. It seems that changes in the cytokines level may play a significant role in the psychopathology of these patients.
2. Müller N, Weidinger E, Leitner B, Schwarz MJ. The role of inflammation in schizophrenia. Front Neurosci 2015;9:372.
3. Yarlagadda A, Hampe CS, Clayton AH. The Blood Brain Barrier and the Role of Ratiometric Molecular Analysis in Schizophrenia. Psychiatry (Edgmont) 2010;7(12):20-3.
4. Muller N, Ackenheil M. Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 1998;22(1):1-33.
5. Tourjman V, Kouassi E, Koue ME, Rocchetti M, Fortin-Fournier S, Fusar-Poli P, et al. Antipsychotics' effects on blood levels of cytokines in schizophrenia: a meta-analysis. Schizophr Res 2013;151(1-3):43-7.
6. Sugino H, Futamura T, Mitsumoto Y, et al. Atypical antipsychotics suppress production of proinflammatory cytokines and up-regulate interleukin-10 in lipopolysaccharide-treated mice. Prog Neuropsycho-pharmacol Biol Psychiatry 2009;33(2):303-7.
7. Maes M, Bosmans E, Calabrese J, Smith R, Meltzer HY. Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. J Psychiatr Res 1995;29(2):141-52.
8. Maes M, Bocchio Chiavetto L, Bignotti S, Battisa Tura G, Pioli R, Boin F, et al. Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics. Eur Neuropsychopharmacol 2000;10(2):119-24.
9. Chen ML, Tsai TC, Wang LK, Lin YY, Tsai YM, Lee MC, et al. Risperidone modulates the cytokine and chemokine release of dendritic cells and induces TNF-alpha-directed cell apoptosis in neutrophils. Int Immunopharmacol 2012;12(1):197-204.
10. Kato T, Monji A, Hashioka S, Kanba S. Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro. Schizophr Res 2007;92(1-3):108-15.
11. Boerrigter D, Weickert TW, Lenroot R, O'Donnell M, Galletly C, Liu D, et al. Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder. J Neuroinflammation 2017;14(1):188.
12. Noto C, Ota VK, Gouvea ES, Rizzo LB, Spindola LMN, Honda PHS, et al. Effects of Risperidone on Cytokine Profile in Drug-Naïve First-Episode Psychosis. Int J Neuropsychopharmacol 2014;18(4).
13. Song X FX, Li X, Zhang W, Gao J, Zhao J, Harrington A, Ziedonis, D LL. Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naive, first-episode schizophrenia. Psychopharmacology 2014;231(2):319–25.
14. Khandaker GM, Stochl J, Zammit S, Lewis G, Jones PB. Childhood Epstein-Barr Virus infection and subsequent risk of psychotic experiences in adolescence: A population-based prospective serological study. Schizophr Res 2014;158(1-3):19-24.
15. Krause D, K Wagner J, Wildenauer A, Matz J, Weidinger E, Riedel M, et al. Intracellular monocytic cytokine levels in schizophrenia show an alteration of IL-6. Eur Arch Psychiatry Clin Neurosci2012; 262(5):393-401.
16. Fonseka TM, Muller DJ, Kennedy SH. Inflammatory Cytokines and Antipsychotic-Induced Weight Gain: Review and Clinical Implications. Mol Neuropsychiatry 2016;2(1):1-14.
17. Erbagci AB, Herken H, Koyluoglu O, Yilmaz N, Tarakcioglu M. Serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha in schizophrenic patients, relation with symptomatology and responsiveness to risperidone treatment. Mediators Inflamm 2001;10(3):109-15.
18. Upthegrove R, Manzanares-Teson N, Barnes NM. Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophr Res 2014;155(1-3):101-8.
19. L Cazzullo C, Sacchetti E, Galluzzo A, Panariello A, Adorni A, Pegoraro M, et al. Cytokine profiles in schizophrenic patients treated with risperidone - A 3-month follow-up study. Prog Neuropsychopharmacol Biol Psychiatry2002; 26(1):33-9.
20. O'Shea JJ, Ma A, Lipsky P. Cytokines and autoimmunity. Nat Rev Immunol 2002;2(1):37-45.
21. Rosenzwajg M, Churlaud G, Hartemann A, Klatzmann D. Interleukin 2 in the pathogenesis and therapy of type 1 diabetes. Curr Diab Rep 2014;14(12):553.
22. Khandaker GM, Dantzer R, Jones PB. Immunopsychiatry: important facts. Psychological Medicine 2017; 47(13):2229-37.
23. Arolt V, Weitzsch C, Wilke I, Nolte A, Pinnow M, Rothermundt M, et al. Production of interferon-gamma in families with multiple occurrence of schizophrenia. Psychiatry Res 1997;66(2-3):145-52.
24. Drzyzga L, Obuchowicz E, Marcinowska A, Herman ZS. Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav Immun 2006;20(6):532-45.
25. Henderson DC. Schizophrenia and comorbid metabolic disorders. J Clin Psychiatry 2005;66(Suppl 6):11-20.
26. Kirkpatrick B, Miller BJ. Inflammation and schizophrenia. Schizophr Bull 2013;39(6):1174-9.
27. Srinivas L, Vellichirammal NN, Alex AM, Nair C, Nair IV, Banerjee M. Pro-inflammatory cytokines and their epistatic interactions in genetic susceptibility to schizophrenia. J Neuroinflammation 2016;13(1):105.
28. Igue R, Potvin S, Bah R, Stip E, Bouchard R-H, Lipp O, et al. Soluble interleukin-2 receptor levels correlated with positive symptoms during quetiapine treatment in schizophrenia-spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry2011;35(7):1695-8.
29. Coelho FM, Reis HJ, Nicolato R, Romano-Silva MA, Teixeira MM, Bauer ME, et al. Increased serum levels of inflammatory markers in chronic institutionalized patients with schizophrenia. Neuroimmunomodulation 2008;15(2):140-4.