Indian Journal of Psychological Medicine

REVIEW ARTICLE
Year
: 2016  |  Volume : 38  |  Issue : 2  |  Page : 97--100

Cytokines in schizophrenia: Hope or hype?


Maju Mathew Koola 
 Department of Psychiatry and Behavioral Sciences, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

Correspondence Address:
Maju Mathew Koola
Clinical Research Program, Sheppard Pratt Health System, 6501 N Charles Street, Baltimore, Maryland 21204
USA

Abstract

Although there is a cumulative evidence for the inflammation pathophysiology in schizophrenia, it has not been conclusively proven yet. One reason for this is the lack of studies that have controlled for major confounding factors such as obesity, smoking, antipsychotic use, and stress. The studies in which the major confounding factors were controlled were done in subjects in acute relapse and in treatment-resistant schizophrenia. To date, no studies have been done in stable outpatients with schizophrenia controlling for major confounding factors. Data on cerebrospinal fluid cytokines in large sample independent of confounding factors are also lacking. The efficacy signal from anti-inflammatory medications in schizophrenia has been modest. In this study, the inconsistent and nonvalidated cytokine findings independent of the confounding factors are discussed.



How to cite this article:
Koola MM. Cytokines in schizophrenia: Hope or hype?.Indian J Psychol Med 2016;38:97-100


How to cite this URL:
Koola MM. Cytokines in schizophrenia: Hope or hype?. Indian J Psychol Med [serial online] 2016 [cited 2019 Oct 13 ];38:97-100
Available from: http://www.ijpm.info/text.asp?2016/38/2/97/178766


Full Text

 INTRODUCTION



Although there is a cumulative evidence for the inflammation pathophysiology in schizophrenia, it has not been conclusively proven yet. One reason for this is the lack of studies that have controlled for major confounding factors such as obesity, smoking, antipsychotic use, and stress. [1],[2] Of the 83 schizophrenia studies included in the meta-analyses, [1],[2] only three studies controlled for smoking [3],[4],[5] and only two studies controlled for both body mass index (BMI) and smoking. [6],[7] The purpose of this review study is to highlight the inconsistent and nonvalidated cytokine findings independent of the confounding factors mentioned above.

 Are cytokine abnormalities independent of potential confounding factors?



Multiple factors modify cytokine concentrations including age, gender, infection, cancer, trauma, rheumatologic diseases, metabolic syndrome, obesity, and smoking. In women, use of oral contraceptives, menopausal status, and hormone replacement therapy can affect cytokine concentration. [8] Studies have consistently demonstrated that African-Americans and Hispanics have higher levels of inflammatory markers than the whites. [9],[10] Socioeconomic status (SES) is associated with inflammatory state. People from lower SES have higher levels of inflammatory biomarkers. [11],[12],[13] Most of the people with schizophrenia have low SES. Exercise can impact inflammatory cytokines. [14] Diet [15],[16] including caffeine intake [17],[18] can affect cytokine concentrations. Insomnia, common in people with schizophrenia, is associated with abnormal cytokine concentrations. [19] Medications commonly prescribed for people with schizophrenia including but not limited to selective serotonin reuptake inhibitors, [8],[20] aspirin, [21] statins, [22] and antihypertensives [23] influence cytokines.

 CYTOKINES INDEPENDENT OF SMOKING



Serum interleukin (IL)-6, IL-1 receptor antagonist (RA), IL-8, and IL-10 in participants with schizophrenia (n = 31) were significantly different compared to controls (n = 7) even after controlling for smoking. This study was done in participants with treatment-resistant schizophrenia. [4],[5] IL-12 level did not differ between smokers (n = 32) and nonsmokers (n = 24) in 56 drug-naïve participants with first episode psychosis in acute relapse. [3]

 CYTOKINES INDEPENDENT OF BODY MASS INDEX AND SMOKING



In 361 in patients with psychiatric diagnoses (schizophrenia n = 59, schizoaffective disorder n = 29), there were no significant differences in IL-1RA, soluble IL-2 receptor (sIL-2R), soluble tumor necrosis factor-receptor (sTNF-R), p75, and IL-6 compared to 64 controls after controlling for age, gender, BMI, smoking, ongoing or recent infectious diseases, or prior medications. [6] This study was done in patients who were in acute relapse.

 Cytokines in Schizophrenia In Antipsychotic-NaΟVe Subjects



IL-2 and interferon-gamma (IFN-γ) were not significantly different in 10 antipsychotic-naïve participants with schizophrenia compared to 15 controls. [24] In 12 participants with schizophrenia who were antipsychotic-naïve, sIL-2R was significantly elevated compared to 14 controls. [25] TNF-α and serum neopterin were not significantly different in 23 antipsychotic-naïve participants with schizophrenia compared to 16 controls. [26] In 14 antipsychotic-naïve participants with schizophrenia, IL-1RA was significantly higher and Clara cell protein 16 was significantly lower compared to 30 controls. [27] In 26 participants with schizophrenia who were antipsychotic-naïve, IL-2sRα, IL-6, and IL-1RA concentrations were higher compared to 27 controls. [28] In 25 antipsychotic-free male participants with schizophrenia who were in acute relapse, IL-2 and homovanillic acid were significantly higher compared to 25 controls. [29] IL-2 was significantly lower and IL-1β and TNF-α were significantly higher in 53 antipsychotic-naïve participants with schizophrenia compared to 62 controls. [30] In 88 participants with schizophrenia who were antipsychotic-naοve or antipsychotic-free for 4 months, IFN-γ and transforming growth factor beta 1 were significantly higher and IL-4 was significantly lower compared to 88 controls. [31] In another study with 56 participants who were antipsychotic-naïve, IL-12 concentrations were higher compared to 28 controls. [3] In 71 participants with schizophrenia who were antipsychotic-naïve or antipsychotic-free for 4 months, IFN-γ, TNF-α, and IL-6 were significantly higher, IL-2 and IL-4 significantly lower compared to 174 controls. [32] Finally, blood mononuclear cells mRNA expressions of IL-1β and TNF-α were significantly higher in 83 antipsychotic-naïve participants with first episode schizophrenia compared to 65 controls. [33]

 Cytokines In Antipsychotic-NaΟVe Schizophrenia Independent of Body Mass Index and Smoking



In 34 drug-free participants with schizophrenia with acute exacerbation, IL-1β, sIL-2R, IL-6, IL-8, and TNF-α concentrations adjusted for age, gender, BMI, and smoking were not different compared to 23 controls. [34] In 50 participants (schizophrenia n = 35), with a recent diagnosis of nonaffective psychosis who were antipsychotic-naïve, IL-6 concentration was significantly higher compared to 50 controls. This finding is also independent of BMI and smoking. This study was done in participants who were in acute relapse. [7] In deficit schizophrenia (n = 20), IL-6 and C-reactive protein concentrations were significantly higher compared to nondeficit schizophrenia (n = 42) in newly diagnosed participants with nonaffective psychosis who were antipsychotic-naïve. [35] Cytokines in 180 antipsychotic-naïve first episode schizophrenia participants were compared to 350 controls matched for potential confounding factors including age, sex, smoking, and BMI. Of nine cytokines (IL-1α, IL-1RA, IL-5, IL-10, IL-12p40, IL-15, IL-18, IFN-γ, and TNF-α), the concentrations of IL-1RA, IL-10, and IL-15 were increased significantly in participants with schizophrenia. The changes in IL-10 levels on antipsychotic treatment were significantly correlated with the improvements in symptoms. This suggests that both pro- and anti-inflammatory cytokines may be altered in people with first episode psychosis. [36]

 Modest Anti-Inflammatory Treatment Response



A review of 26 double-blind randomized controlled trials (RCTs) in schizophrenia looked at the anti-inflammatory effects of the following medications: Aspirin, celecoxib, davunetide, and fatty acids such as eicosapentaenoic acids and docosahexaenoic acids, estrogens, minocycline, and N-acetylcysteine (NAC). Of these, aspirin, estrogens, and NAC had a modest effect size of 0.3, 0.5, and 0.45, respectively. Celecoxib, minocycline, davunetide, and fatty acids showed no significant effect. [37] In a meta-analysis of eight RCTs (n = 774), adjunctive nonsteroidal anti-inflammatory drugs for schizophrenia had only a minimal benefit in positive symptoms in participants on antipsychotics. [38] In an RCT published recently, the effect of minocycline (n = 29) on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant compared to 23 participants on placebo. [39] There are two ongoing studies with tocilizumab in schizophrenia (NCT01696929, NCT02034474).

Taken together, the evidence for the inflammation hypothesis is not compelling despite all the studies that have controlled for the confounding factors coupled with the modest anti-inflammatory treatment response. To date, no studies have been done in stable outpatients with schizophrenia controlling for major confounding factors. Furthermore, studies are also limited by small sample sizes and other methodological issues [40],[41] to draw any firm conclusions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in schizophrenia: A systematic quantitative review. Biol Psychiatry 2008;63: 801-8.
2Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects. Biol Psychiatry 2011;70:663-71.
3Crespo-Facorro B, Carrasco-Marín E, Pérez-Iglesias R, Pelayo-Terán JM, Fernandez-Prieto L, Leyva-Cobián F, et al. Interleukin-12 plasma levels in drug-naïve patients with a first episode of psychosis: Effects of antipsychotic drugs. Psychiatry Res 2008;158:206-16.
4Maes 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;10:119-24.
5Maes M, Bocchio Chiavetto L, Bignotti S, Battisa Tura GJ, Pioli R, Boin F, et al. Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophr Res 2002;54:281-91.
6Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kühn M, Schuld A, et al. Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: Effects of confounding factors and diagnosis. J Psychiatr Res 1999;33:407-18.
7Fernandez-Egea E, Bernardo M, Donner T, Conget I, Parellada E, Justicia A, et al. Metabolic profile of antipsychotic-naive individuals with non-affective psychosis. Br J Psychiatry 2009;194:434-8.
8O′Connor MF, Bower JE, Cho HJ, Creswell JD, Dimitrov S, Hamby ME, et al. To assess, to control, to exclude: Effects of biobehavioral factors on circulating inflammatory markers. Brain Behav Immun 2009;23:887-97.
9Kelley-Hedgepeth A, Lloyd-Jones DM, Colvin A, Matthews KA, Johnston J, Sowers MR, et al. Ethnic differences in C-reactive protein concentrations. Clin Chem 2008;54:1027-37.
10Matthews KA, Sowers MF, Derby CA, Stein E, Miracle-McMahill H, Crawford SL, et al. Ethnic differences in cardiovascular risk factor burden among middle-aged women: Study of Women′s Health Across the Nation (SWAN). Am Heart J 2005;149:1066-73.
11Steptoe A, O′Donnell K, Badrick E, Kumari M, Marmot M. Neuroendocrine and inflammatory factors associated with positive affect in healthy men and women: The Whitehall II study. Am J Epidemiol 2008;167:96-102.
12Koster A, Bosma H, Penninx BW, Newman AB, Harris TB, van Eijk JT, et al. Association of inflammatory markers with socioeconomic status. J Gerontol A Biol Sci Med Sci 2006;61:284-90.
13Gimeno D, Ferrie JE, Elovainio M, Pulkki-Raback L, Keltikangas-Jarvinen L, Eklund C, et al. When do social inequalities in C-reactive protein start? A life course perspective from conception to adulthood in the Cardiovascular Risk in Young Finns Study. Int J Epidemiol 2008;37:290-8.
14Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol 2005;98:1154-62.
15Jiang R, Jacobs DR Jr, Mayer-Davis E, Szklo M, Herrington D, Jenny NS, et al. Nut and seed consumption and inflammatory markers in the multi-ethnic study of atherosclerosis. Am J Epidemiol 2006;163:222-31.
16Lopez-Garcia E, Schulze MB, Fung TT, Meigs JB, Rifai N, Manson JE, et al. Major dietary patterns are related to plasma concentrations of markers of inflammation and endothelial dysfunction. Am J Clin Nutr 2004;80:1029-35.
17Panagiotakos DB, Pitsavos C, Zampelas A, Zeimbekis A, Chrysohoou C, Papademetriou L, et al. The association between coffee consumption and plasma total homocysteine levels: The "ATTICA" study. Heart Vessels 2004;19:280-6.
18Zampelas A, Panagiotakos DB, Pitsavos C, Chrysohoou C, Stefanadis C. Associations between coffee consumption and inflammatory markers in healthy persons: The ATTICA study. Am J Clin Nutr 2004;80:862-7.
19Vgontzas AN, Zoumakis E, Bixler EO, Lin HM, Follett H, Kales A, et al. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab 2004;89:2119-26.
20Maes 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;29:141-52.
21Solheim S, Arnesen H, Eikvar L, Hurlen M, Seljeflot I. Influence of aspirin on inflammatory markers in patients after acute myocardial infarction. Am J Cardiol 2003;92: 843-5.
22Ridker PM, Rifai N, Lowenthal SP. Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation 2001;103:1191-3.
23Palmas W, Ma S, Psaty B, Goff DC Jr, Darwin C, Barr RG. Antihypertensive medications and C-reactive protein in the multi-ethnic study of atherosclerosis. Am J Hypertens 2007;20:233-41.
24Gattaz WF, Dalgalarrondo P, Schröder HC. Abnormalities in serum concentrations of interleukin-2, interferon-alpha and interferon-gamma in schizophrenia not detected. Schizophr Res 1992;6:237-41.
25Rapaport MH, Lohr JB. Serum-soluble interleukin-2 receptors in neuroleptic-naive schizophrenic subjects and in medicated schizophrenic subjects with and without tardive dyskinesia. Acta Psychiatr Scand 1994;90:311-5.
26Schattner A, Cori Y, Hahn T, Sirota P. No evidence for autoimmunity in schizophrenia. J Autoimmun 1996;9:661-6.
27Maes M, Bosmans E, Ranjan R, Vandoolaeghe E, Meltzer HY, De Ley M, et al. Lower plasma CC16, a natural anti-inflammatory protein, and increased plasma interleukin-1 receptor antagonist in schizophrenia: Effects of antipsychotic drugs. Schizophr Res 1996;21:39-50.
28Akiyama K. Serum levels of soluble IL-2 receptor alpha, IL-6 and IL-1 receptor antagonist in schizophrenia before and during neuroleptic administration. Schizophr Res 1999;37:97-106.
29Kim YK, Kim L, Lee MS. Relationships between interleukins, neurotransmitters and psychopathology in drug-free male schizophrenics. Schizophr Res 2000;44:165-75.
30Theodoropoulou S, Spanakos G, Baxevanis CN, Economou M, Gritzapis AD, Papamichail MP, et al. Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res 2001;47:13-25.
31Kim YK, Myint AM, Lee BH, Han CS, Lee HJ, Kim DJ, et al. Th1, Th2 and Th3 cytokine alteration in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:1129-34.
32Kim YK, Myint AM, Verkerk R, Scharpe S, Steinbusch H, Leonard B. Cytokine changes and tryptophan metabolites in medication-naïve and medication-free schizophrenic patients. Neuropsychobiology 2009;59:123-9.
33Song XQ, Lv LX, Li WQ, Hao YH, Zhao JP. The interaction of nuclear factor-kappa B and cytokines is associated with schizophrenia. Biol Psychiatry 2009;65:481-8.
34Erbagci AB, Herken H, Köylüoglu O, Yilmaz N, Tarakçioglu 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;10:109-15.
35Garcia-Rizo C, Fernandez-Egea E, Oliveira C, Justicia A, Bernardo M, Kirkpatrick B. Inflammatory markers in antipsychotic-naïve patients with nonaffective psychosis and deficit vs. nondeficit features. Psychiatry Res 2012;198: 212-5.
36de Witte L, Tomasik J, Schwarz E, Guest PC, Rahmoune H, Kahn RS, et al. Cytokine alterations in first-episode schizophrenia patients before and after antipsychotic treatment. Schizophr Res 2014;154:23-9.
37Sommer IE, van Westrhenen R, Begemann MJ, de Witte LD, Leucht S, Kahn RS. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: An update. Schizophr Bull 2014;40:181-91.
38Nitta M, Kishimoto T, Müller N, Weiser M, Davidson M, Kane JM, et al. Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: A meta-analytic investigation of randomized controlled trials. Schizophr Bull 2013;39:1230-41.
39Kelly DL, Sullivan KM, McEvoy JP, McMahon RP, Wehring HJ, Gold JM, et al. Adjunctive minocycline in clozapine-treated schizophrenia patients with persistent symptoms. J Clin Psychopharmacol 2015;35:374-81.
40Koola MM, Duncan EJ. Cytokines in schizophrenia: Methodological issues. Schizophr Res 2015;166:360-1.
41Koola MM. Methodological issues in cytokine measurement in schizophrenia. Indian J Psychol Med 2016;38:6-9.