Abstract
Rationale
Although the immune system is thought to contribute to the etiology of schizophrenia, the mechanism has not been elucidated. Clarifying the relationship between them is important in terms of diagnosis, treatment, and prevention approaches.
Objective
In this study, it is aimed to determine whether there is any difference in serum levels of neutrophil gelatinase-associated lipocalin (NGAL) and tumor necrosis factor-alpha (TNF-α) in the group of patients with schizophrenia and healthy volunteers, whether these values are changed by medical treatment, whether there is any relation between these values and the severity of the symptoms of patients with schizophrenia, and whether NGAL can be used as a biomarker in the diagnosis and the follow-up of the schizophrenia.
Methods
A total of 64 patients who were hospitalized in the Psychiatry Clinic of Ankara City Hospital and diagnosed with schizophrenia and 55 healthy volunteers were included in the study. A sociodemographic information form was given to all participants and TNF-α and NGAL values were measured. Positive and Negative Symptoms Rating Scale (PANSS) were applied to the schizophrenia group on admission and follow-up. TNF-α and NGAL levels were re-measured in the 4th week after the start of antipsychotic treatment.
Results
As a result of the present study, it was found that NGAL levels decreased significantly after antipsychotic treatment of schizophrenia patients hospitalized with exacerbation. There was no significant correlation between NGAL and TNF-α levels among schizophrenia and the control group.
Conclusion
In psychiatric diseases, especially schizophrenia, there may be differences in immune and inflammatory markers compared to the healthy population. After treatment, the NGAL levels of the patients at follow-up were reduced compared to the levels at admission. It can be thought that NGAL may be related to psychopathology in schizophrenia and antipsychotic treatment. This is the first follow-up study for NGAL levels in schizophrenia.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
Data available on request from the authors.
References
Addington D, Addington J, Maticka-Tyndale E (1994) Specificity of the Calgary Depression Scale for schizophrenics. Schizophr Res 11(3):239–244. https://doi.org/10.1016/0920-9964(94)90017-5
Aydemir O, EsenDanacı A, Deveci A, İcelli İ (2000) Calgary Şizofrenide Depresyon Ölçeği’nin Türkçe versiyonunun duyarlılığı ve özgüllüğü. Nöropsikiyatri Arşivi 37(3):210–213
Azorin JM (1997) A differential role for interleukin-6 and tumor necrosis factor-alpha in schizophrenia? Schizophr Res 26:227–233. https://doi.org/10.1016/S0920-9964(97)00059-5
Benevides L, Gonc RB, Coletta RD, Silve KG, Casati MZ (2011) Impact of smoking on inflammation. overview of molecular mechanisms. Inflamm Res 60(5):409–424. https://doi.org/10.1007/s00011-011-0308-7
Borovcanin M et al (2012) Elevated serum level of type-2 cytokine and low IL-17 in first episode psychosis and schizophrenia in relapse. J Psychiatr Res 46:1421–1426. https://doi.org/10.1016/j.jpsychires.2012.08.016
Borovcanin M et al (2013) Antipsychotics can modulate the cytokine profile in schizophrenia: Attenuation of the type-2 inflammatory response. Schizophr Res 147:103–109. https://doi.org/10.1016/j.schres.2013.03.027
Brien SMO, Scully P, Dinan TG (2008) Increased tumor necrosis factor-alpha concentrations with interleukin-4 concentrations in exacerbations of schizophrenia. Psychiatry Res 160:256–262. https://doi.org/10.1016/j.psychres.2007.11.014
Capuzzi AE, Bartoli F, Clerici M, Carr G (2017) Acute variations of cytokine levels after antipsychotic treatment in drug-naïve subjects with a first-episode psychosis: a meta-analysis. Neurosci Biobehav Rev. https://doi.org/10.1016/j.neubiorev.2017.03.003
Casey DE et al (2004) Antipsychotic-induced weight gain and metabolic abnormalities: implications for increased mortality in patients with schizophrenia. J Clin Psychiatry 65(Suppl 7):4–18
Choi J, Lee H, Suk K (2011) Journal of the neurological sciences increased plasma levels of lipocalin 2 in mild cognitive impairment. J Neurol Sci 305:28–33. https://doi.org/10.1016/j.jns.2011.03.023
Clarke MC, Tanskanen A, Huttunen M, Whittaker JC, Cannon M (2009) Evidence for an interaction between familial liability and prenatal exposure to infection in the causation of schizophrenia. Am J Psychiatry 166(9):1025–1030. https://doi.org/10.1176/appi.ajp.2009.08010031
Coelho FM, Reis HJ, Nicolato R, Romano-Silva MA, Teixeira MM, Bauer ME, Teixeira AL (2008) Increased serum levels of inflammatory markers in chronic institutionalized patients with schizophrenia. NeuroImmunoModulation 15(2):140–144. https://doi.org/10.1159/000148197
Connor MO et al (2009) To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers. Brain Behav Immun 23:887–897. https://doi.org/10.1016/j.bbi.2009.04.005
De Witte L et al (2014) Cytokine alterations in first-episode schizophrenia patients before and after antipsychotic treatment. Schizophr Res 154:23–29. https://doi.org/10.1016/j.schres.2014.02.005
Demirjian L, Abboud RT, Li H, Duronio V (2006) Acute effect of cigarette smoke on TNF-α release by macrophages mediated through the erk1/2 pathway. Biochim Biophys Acta-Molecular Basis Dis 1762:592–597. https://doi.org/10.1016/j.bbadis.2006.04.004
Di M et al (2012) Serum and gene expression profile of cytokines in first-episode psychosis. Brain Behav Immun 31:90–95. https://doi.org/10.1016/j.bbi.2012.06.010
Di Grande A, Giuffrida C, Carpinteri G, Narbone G, Pirrone G, Di Mauro A, Calandra S, Noto P, Le Moli C, Alongi B, Nigro F (2009) Neutrophil gelatinase-associated lipocalin : a novel biomarker for the early diagnosis of acute kidney injury in the Emergency Department. Eur Rev Med Pharmacol Sci 13(3):197–200
Erbagci AB, Herken H, Koyluoglu O, Yilmaz N, Tarakcioglu M (2001) Serum IL-1β, sIL-2R, IL-6, IL-8 and TNF-α in schizophrenic patients, relation with symptomatology and responsiveness to risperidone treatment. Mediat Inflamm 10(3):109–115. https://doi.org/10.1080/09629350123895
Eyre H, Baune BT (2012) Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology 37:1397–1416. https://doi.org/10.1016/j.psyneuen.2012.03.019
Fan X, Goff DC, Henderson DC (2007) Inflammation and schizophrenia. Expert rev Neurother 7(7):789–796. https://doi.org/10.1586/14737175.7.7.789
Flo TH et al (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432:917–921
Francesconi LP et al (2011) Increased annexin-V and decreased TNF-alpha serum levels in chronic-medicated patients with schizophrenia. Neurosci Lett 502:143–146. https://doi.org/10.1016/j.neulet.2011.06.042
Freudenreich O et al (2010) Analysis of peripheral immune activation in schizophrenia using quantitative reverse-transcription polymerase chain reaction (RT-PCR). Psychiatry Res 176:99–102. https://doi.org/10.1016/j.psychres.2008.11.007
Ganguli R, Gubbi A (1997) Clinical and immunological characteristics of a subgroup of patients suffering from schizophrenia. Immunol Alterations Psychiatr Dis Adv Biol Psychiatry 18:35–43
Gouweleeuw L et al (2015) The role of neutrophil gelatinase-associated lipocalin ( NGAL ) as biological constituent linking depression and cardiovascular disease. Brain Behav Immun. https://doi.org/10.1016/j.bbi.2014.12.026
Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kühn M, Schuld A, Pollmächer T (1999) Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res 33:5407–5418. https://doi.org/10.1016/S0022-3956(99)00021-7
Hai-Min X, Wei J, Hemmings GP (1994) Changes of plasma concentrations of interleukin-1α and interleukin-6 with neuroleptic treatment for schizophrenia. Br J Psychiatry 164(2):251–253. https://doi.org/10.1192/bjp.164.2.251
Insel TR (2010) Rethinking schizophrenia. Nature. https://doi.org/10.1038/nature09552
Ip JPK et al (2011) Lipocalin 2 in the central nervous system host response to systemic lipopolysaccharide administration. J Neuroinflammation 8(1):1–16
Jang Y, Lee JH, Wang Y, Sweeney G (2012) Emerging clinical and experimental evidence for the role of lipocalin-2 in metabolic syndrome. Clin Exp Pharmacol Physiol 39(2):194–199. https://doi.org/10.1111/j.1440-1681.2011.05557
Jang E et al (2013) Secreted protein lipocalin-2 promotes microglial M1 polarization. FASEB J 27:1176–1190. https://doi.org/10.1096/fj.12-222257
Kato TA, Monji A et al (2011) Anti-inflammatory properties of antipsychotics via microglia modulations: are antipsychotics a ‘fire extinguisher’in the brain of schizophrenia? Mini Rev Med Chem 11(7):565–574. https://doi.org/10.2174/138955711795906941
Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276. https://doi.org/10.1093/schbul/13.2.261
Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB (2015) Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry 2(3):258–270. https://doi.org/10.1016/S2215-0366(14)00122-9
Kirkpatrick B, Miller BJ (2013) Inflammation and schizophrenia. Schizophr Bull 39(6):1174–1179. https://doi.org/10.1093/schbul/sbt141
Kjeldsen BL, Bainton F, Sengelsv H, Borregaard N (1994) Identification of neutrophil gelatinase-associated lipocalin as a novel matrix protein of specific granules in human neutrophils. Blood 83(3):799–807. https://doi.org/10.1182/blood.V83.3.799.799
Klemettila JP, Kampman O, Seppala N, Viikki M, Hamalainen M, Moilanen E et al (2014) Cytokine and adipokine alterations in patients with schizophrenia treated with clozapine. Psychiatry Res 218:277–283. https://doi.org/10.1016/j.psychres.2014.04.049
Kostakoglu AE, Batur S, Tiryaki A, Gogus A (1999) Reliability and validity of the Turkish version of the Positive and Negative Syndrome Scale (PANSS). Turkish Journal of Psychology 14(44):23–32
Kubistova A, Horacek J, Novak T (2012) Increased interleukin-6 and tumor necrosis factor-alpha in first-episode schizophrenia patients versus healthy controls. Psychiatr Danub 24(suppl 1):153–156
Kunz M et al (2011) Serum levels of IL-6, IL-10, and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance. Rev Bras Psiquiatr 33:268–274. https://doi.org/10.1590/S1516-44462011000300010
Lv MH et al (2015) Decreased serum TNF-alpha levels in chronic schizophrenia patients on long-term antipsychotics: correlation with psychopathology and cognition. Psychopharmacology 232(1):165–172. https://doi.org/10.1007/s00213-014-3650-y
Maes M, BocchioChiavetto L, Bignotti S, Battisa Tura G, Pioli R, Boin F et al (2000) Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics. Eur Neuropsychopharmaco 10(2):119–124. https://doi.org/10.1016/S0924-977X(99)00062-0
Magnusson NE et al (2012) Plasma neutrophil gelatinase-associated lipocalin (NGAL) is associated with kidney function in uraemic patients before and after kidney transplantation. BMC Nephrol 13(1):1–8. https://doi.org/10.1186/1471-2369-13-8
McAllister CG, Kammen DPV, Rehn TI, Miller AL, Gurklis J, Kelley ME et al (1995) Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. Am J Psychiatry 152(9):1291–1297
Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick (2011) Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 70(7):663–671. https://doi.org/10.1016/j.biopsych.2011.04.013
Miller BJ, Graham KL, Bodenheimer CM, Culpepper NH, Waller JL (2013) Prevalence study of urinary tract infections in acute relapse of schizophrenia. J Clin Psychiatry 74:271–277. https://doi.org/10.4088/JCP.12m08050
Monji A, Kato T, Kanba S (2009) Cytokines and schizophrenia: microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci 63(3):257–265. https://doi.org/10.1111/j.1440-1819.2009.01945.x
Muller N, Schwarz J (2010) The role of immune system in schizophrenia. Curr Immunol Rev. https://doi.org/10.2174/157339510791823673
Naudé PJ, Nyakas C, Eiden EL, Ait-Ali D, Van Der Heide R, Engelborghs S et al (2012) Lipocalin 2: a novel component of proinflammatory signaling in Alzheimer’s disease. FASEB J 26(7):2811–2823. https://doi.org/10.1096/fj.11-202457
Naudé PJW et al (2013) Neutrophil gelatinase-associated lipocalin: a novel inflammatory marker associated with late-life depression. J Psychosom Res 75:444–450. https://doi.org/10.1016/j.jpsychores.2013.08.023
Naudé PJW et al (2014) Neutrophil gelatinase-associated lipocalin and depression in patients with chronic heart failure. Brain Behav Immun 38:59–65. https://doi.org/10.1016/j.bbi.2013.12.023
O’Connell KE, Thakore J, Dev KK (2014) Pro-inflammatory cytokine levels are raised in female schizophrenia patients treated with clozapine. Schizophr Res 156:1–8. https://doi.org/10.1016/j.schres.2014.03.020
Pedrini M, Massuda R, Fries GR, de BittencourtPasquali MA, Schnorr CE, Moreira JCF et al (2012) Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity. J Psychiatr Res 46:819–824. https://doi.org/10.1016/j.jpsychires.2012.03.019
Perry SW, Dewhurst S, Bellizzi MJ, Gelbard HA (2002) Tumor necrosis factor-alpha in the normal and diseased brain: Conflicting effects via intraneuronal receptor crosstalk? J Neurovirol 8(6):611–624. https://doi.org/10.1080/13550280290101021
Pinyopornpanish K, Chattipakorn N, Chattipakorn SC (2019) Lipocalin-2: its perspectives in brain pathology and possible roles in cognition. J Neuroendocrinol 31(10):e12779. https://doi.org/10.1111/jne.12779
Roerig JL, Steffen KJ, Mitchell JE (2011) Atypical antipsychotic-induced weight gain. CNS Drugs 25(12):1035–1059. https://doi.org/10.2165/11596300-000000000-00000
Sadock BJ, Sadock VA, R P (2015) Kaplan and Sadock’s Synopsis of Psychiatry Behavioural Sciences/Clinical Psychiatry 11th edn. Wolters Kluwer, pp 303–307
Schmitt A, Bertsch T, Tost H, Bergmann A, Henning U, Klimke A, Falkai P (2005) Increased serum interleukin-1β and interleukin-6 in elderly, chronic schizophrenic patients on stable antipsychotic medication. Neuropsychiatr Dis Treat 1:171. https://doi.org/10.2147/nedt.1.2.171.61048
Song X, Fan X, Li X, Zhang W (2014) Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia. Psychopharmacology 231(2):319–325. https://doi.org/10.1007/s00213-013-3382-4
Spitzer RL, First MB, Gibbon M, Williams JB (1990) Structured clinical interview for DSM-III-R. Press, Am. Psychiatr
Strieter RM, Kunkel SL, Bone RC (1993) Role of tumor necrosis factor-alpha in disease states and inflammation. Crit Care Med 21(10 Suppl):S447–S463. https://doi.org/10.1097/00003246-199310001-00006
Theodoropoulou S et al (2001) Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res 47(1):13–25. https://doi.org/10.1016/S0920-9964(00)00007-4
Tourjman V et al (2013) Antipsychotics’ effects on blood levels of cytokines in schizophrenia: a meta-analysis. Schizophr Res 151:43–47. https://doi.org/10.1016/j.schres.2013.10.011
Upthegrove R, Manzanares-teson N, Barnes NM (2014) Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophr Res 155:101–108. https://doi.org/10.1016/j.schres.2014.03.005
Wang Y et al (2007) Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans. Clin Chem 53(1):34–41. https://doi.org/10.1373/clinchem.2006.075614
Wei L, Du Y, Wu W, Fu X, Xia Q (2018) Journal of affective disorders elevation of plasma neutrophil gelatinase-associated lipocalin (NGAL) levels in schizophrenia patients. J Affect Disord 226:307–312. https://doi.org/10.1016/j.jad.2017.10.002
Yndestad A et al (2009) Increased systemic and myocardial expression of neutrophil gelatinase-associated lipocalin in clinical and experimental heart failure. Eur Heart J 30(10):1229–1236. https://doi.org/10.1093/eurheartj/ehp088
Zadina J, Harlan R, Weber J, Banks W, Kastin AJ (1997) Tumor necrosis factor-α: a neuromodulator in the CNS. Neurosci Biobehav Rev 21(5):603–613. https://doi.org/10.1016/S0149-7634(96)00047-4
Zhang J et al (2008) The role of Lipocalin 2 in the regulation of inflammation in adipocytes and macrophages. Mol Endocrinol 22(6):1416–1426. https://doi.org/10.1210/me.2007-0420
Zhao P, Elks CM, Stephens JM (2014) The induction of lipocalin-2 protein expression in vivo and in vitro. J Biol Chem 289:5960–5969. https://doi.org/10.1074/jbc.M113.532234
Funding
This study was funded by the Turkish Republic SBU Scientific Research Projects Coordinatorship. (Project no: 2020/013).
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Gül Çakıl, A., Kaya, H., Sakallı Nural, A. et al. Neutrophil gelatinase-associated lipocalin (NGAL) and tumor necrosis factor-α (TNF-α) levels in patients with schizophrenia. Psychopharmacology 240, 1091–1101 (2023). https://doi.org/10.1007/s00213-023-06346-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-023-06346-2