Inflammatory Cytokine Alterations in Schizophrenia: A Systematic Quantitative Review

Department of Psychiatry, Faculty of Medicine, University of Montreal, Fernand-Seguin Research Center, Louis-H Lafontaine Hospital, Montreal, Quebec, Canada.
Biological psychiatry (Impact Factor: 10.26). 05/2008; 63(8):801-8. DOI: 10.1016/j.biopsych.2007.09.024
Source: PubMed


Cytokines play an important role in infection and inflammation and are crucial mediators of the cross-talk between the brain and the immune system. Schizophrenia would be associated with an imbalance in inflammatory cytokines, leading to a decrease in Th1 and an increase in Th2 cytokine secretion. However, data published so far have been inconsistent. The primary objective of the present meta-analysis was to verify whether the cytokine imbalance hypothesis of schizophrenia is substantiated by evidence.
Cross-sectional studies were included if they assessed in vivo plasma or serum cytokine concentrations and/or in vitro secretion of cytokines by peripheral blood leukocytes from schizophrenia patients and healthy volunteers.
Data from 62 studies involving a total sample size of 2298 schizophrenia patients and 1858 healthy volunteers remained for analysis. Ten cytokines were assessed, including the prototypic Th1 and Th2 cytokines gamma interferon (IFN-gamma) and interleukin 4 (IL-4) as well as IL-2, soluble IL-2 receptor (sIL-2R), IL-1beta, IL-1 receptor antagonist (IL-1RA), tumor necrosis factor-alpha (TNF-alpha), IL-6, soluble IL-6 receptor (sIL-6R), and IL-10. The results show that an increase occurs in in vivo IL-1RA, sIL-2R, and IL-6 and a decrease occurs in in vitro IL-2 in schizophrenia. No significant effect sizes were obtained for the other cytokines.
These findings provide the first evidence of establishment of an inflammatory syndrome in schizophrenia, which refutes the current hypothesis of a Th2 slant. Caveats are presented to data interpretation, including the role of stress and the effect of weight gain that develops in schizophrenia.

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    • "A further finding of our present study is the increased IL-2, IL-6, and IL-8 levels but decreased TNF-a levels in chronic schizophrenia patients. Many authors have observed the lack of consistent results regarding cytokines in schizophrenia (Potvin et al., 2008; Miller et al., 2011; Na et al., 2014). For example, although there is evidence of increased IL-2 (Potvin et al., 2008; Miller et al., 2011), IL-6 (Kubistova et al., 2012; Al-Asmari and Khan, 2014; Dunjic- Kostic et al., 2013; Kalmady et al., 2014; Sasayama et al., 2013; Song et al., 2014), and IL-8 (Maes et al., 2002; Brown et al., 2004; Zhang et al., 2004) levels in schizophrenia, some studies have not found a significant difference from healthy controls in IL-2 (Na et al., 2014), IL-6 (Baker et al., 1996), and IL-8 (O'Brien et al., 2008; Kubistova et al., 2012), or even a decrease in IL-2 (Miller et al., 2011; Na et al., 2014) and IL-6 levels compared to controls (Singh et al., 2009). "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) interacts with cytokines. Although both BDNF and cytokines occur at abnormal levels in schizophrenia patients, their interactions have not yet been examined. We therefore compared serum BDNF, TNF-α, interleukin (IL)-2, IL-6, and IL-8 levels in 92 chronically medicated schizophrenia patients and 60 healthy controls. We correlated these serum levels within these subject groups with each other and with clinical symptoms assessed according to the Positive and Negative Syndrome Scale (PANSS). Compared to the control group, the schizophrenia patients had significantly lower BDNF and TNF-α levels, and higher IL-2, IL-6, and IL-8 levels. The patients also showed a significant positive correlation between BDNF and both IL-2 and IL-8 levels, and low BDNF and TNF-α levels together were associated with poor performance on the PANSS cognitive factor. Thus, an interaction between cytokines and neurotrophic factors may be implicated in the pathophysiology of chronic schizophrenia. In particular, the cytokine TNF-α may interact with BNDF causing cognitive impairment.
    Brain Behavior and Immunity 09/2015; DOI:10.1016/j.bbi.2015.09.014 · 5.89 Impact Factor
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    • "Pathogenetic mechanisms that result from schizophrenia have been associated with abnormal activation of the immune system (Muller and Schwarz, 2007, 2010; Miller et al., 2011). Immune alterations can be found within the brain and cerebrospinal fluid, as well as in the blood serum and leukocytes of schizophrenia patients (Maino et al., 2007; Potvin et al., 2008; Chan et al., 2011; Drexhage et al., 2011a, 2011b; Miller et al., 2011; Schwarz et al., 2012). These findings suggest that systemic inflammatory alterations occur in schizophrenic patients. "
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    ABSTRACT: Objective: The main goal of the present study was to analyze levels of cytokines of the interleukin family (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8 and IL-10), interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP1), tumor necrosis factor-alpha (TNF-α), and vascular endothelial and endothelial growth factors (VEGF and EGF), in the blood samples of first-episode psychosis (FEP) patients before and seven months after the start of antipsychotic medication use. Method: 38 anti-psychotic medication-naïve FEP patients and 37 healthy controls (HC) were recruited. Biochip array technology was used to measure cytokines and growth factors. Results: The comparison of these markers in FEP patients and HC revealed significantly higher levels of EGF, IL-4 and IL-6 and significantly lower level of IL-1β in FEP patients before the antipsychotic treatment. Multiple regression analysis demonstrated significant correlations between FEP and EGF, IL-1β and smoking. Treatment with antipsychotic drugs resulted in a statistically significant amelioration of the symptoms of psychosis, but caused a significant increase in the body mass index (BMI) of patients. Levels of EGF, IL-2, VEGF, IL-6, IFN-γ, IL-4, IL-8 and IL-1α were significantly lower in treated FEP patients compared to premedication levels. Conclusions: According to the present study, EGF and IL-1β are markers of FEP. Antipsychotic drug treatment resulted in a significant clinical improvement of FEP patients and the suppression of positive symptoms was correlated with the decreased levels of EGF, IL-2 and IL-4. EGF was the strongest marker of FEP and treatment efficiency among the measured cytokines and growth factors.
    Schizophrenia Research 09/2015; DOI:10.1016/j.schres.2015.08.027 · 3.92 Impact Factor
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    • "There is now evidence that the activated immune-inflammatory pathways may play a key role in the pathophysiology of SCZ (Fineberg and Ellman, 2013; Song et al., 2009; Noto et al., 2013). Cytokine levels abnormalities were found in the peripheral blood and CSF of patients with SCZ (Potvin et al., 2008; Miller et al., 2011), and also in their relatives (Nunes et al., 2006). Additionally , Genome-Wide Association studies (GWAS) in SCZ have consistently identified the polymorphisms of major histocompatibility complex genes among the top hits for the comparison with control samples (Ripke et al., 2013). "
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    ABSTRACT: Previous studies of our group showed increased plasmatic Angiotensin-I Converting Enzyme (ACE) activity in schizophrenia (SCZ) patients compared to healthy controls, which was also associated to poor cognitive functioning. The ACE main product angiotensin II (Ang-II) has pro-inflammatory properties. Activated immune-inflammatory responses in SCZ and their association with disease progression and cognitive impairments are also well-described. Therefore, we examined here the association of plasma ACE activity and inflammatory mediators in 33 SCZ patients and 92 healthy controls. Non-parametric correlations were used to investigate the association of the enzyme activity and the peripheral levels of immune inflammatory markers as interleukins, tumor necrosis factor (TNF-α), and interferon (IFN-γ). Although no significant correlations could be observed for ACE activity and measured cytokines levels in healthy controls, a significant positive correlation for ACE enzymatic activity and IL-17a levels was observed in SCZ patients. Correcting for gender did not change these results. Moreover, a significant association for ACE activity and IFN-γ levels was also observed. To our knowledge, this is the first study to show a significant association between higher ACE activity and the levels of cytokines, namely IL-17a and IFN-γ, in patients with SCZ. Copyright © 2015. Published by Elsevier Ireland Ltd.
    08/2015; 229(3):PSYD1401230. DOI:10.1016/j.psychres.2015.08.018
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