Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity

https://doi.org/10.1016/j.jpsychires.2012.03.019Get rights and content

Abstract

Schizophrenia (SZ) is a debilitating neurodevelopmental disorder that strikes at a critical period of a young person’s life. Its pathophysiology could be the result of deregulation of synaptic plasticity, with downstream alterations of inflammatory immune processes regulate by cytokines, impaired antioxidant defense and increased lipid peroxidation. The aim of this study was to examine serum oxidative stress markers and inflammatory cytokines in early and late phases of chronic SZ. Twenty-two patients at early stage (within first 10 years of a psychotic episode), 39 at late stage (minimum 10 years after diagnosis of SZ) and their respective matched controls were included. Each subject had 5 ml blood samples collected by venipuncture to examined thiobarbituric acid-reactive substances (TBARS), total reactive antioxidant potential (TRAP), protein carbonyl content (PCC), Interleukins 6 and 10 (IL-6, IL-10) and tumor necrosis factor alpha (TNF-alpha). TBARS, IL-6 and PCC levels were significantly higher in patients with SZ at early and late stages than in controls. There were no differences for TRAP and TNF-alpha levels in patients with SZ at early and late stages than in controls. IL-10 levels were decreased in patients at late stage and a decrease trend in early stage was found. Results provided evidence consistent with comparable biological markers across chronic SZ. The concept of biochemical staging proposed by others for bipolar disorder is not seen in this cohort of patients with SZ, at least for cytokines and oxidative stress markers. Our findings reinforce the need of assessment of individuals in ultra high risk to develop psychosis and first-episode population.

Introduction

Schizophrenia (SZ) is a debilitating neurodevelopmental disorder that strikes at a critical period of a young person’s life (Kaur and Cadenhead, 2010). It has been accepted that SZ originates from abnormalities occurring during the early stages of neural development (Lieberman, 1999). The pathophysiology of SZ could be the result of deregulation of synaptic plasticity, with downstream alterations of neurotrophins, impaired antioxidant defense and increased lipid peroxidation (Gama et al., 2006, Gama et al., 2007, Gama et al., 2008a, Gama et al., 2008b).

Many lines of evidence support the hypothesis that inflammation-related pathways are involved on the pathophysiology of psychiatric disorders (Dean, 2011). Inflammatory immune processes have been strongly implicated in the pathophysiological mechanisms of SZ (Reddy and Yao, 1996, Sasayama et al., 2011, Kunz et al., 2011, Drexhage et al., 2011, Cazzullo et al., 2001, Miller et al., 2011, Francesconi et al., 2011). Cytokines regulate inflammation and coordinate both innate and adaptive arms of the immune system (Miller et al., 2011), being important mediators of the cross-talk between the central nervous system (CNS) and the immune system, which might have implications for clinical psychiatry (Kapczinski et al., 2010, Kapczinski et al., 2011). Recent data have emerged to suggest that changes in inflammation-related pathways are present in the CNS of subjects with psychiatric disorders (Kaur and Cadenhead, 2010). They can exert cellular effects that, if not adequately moderated or counteracted, ultimately lead to toxicities, physiological deregulation, and medical compromise (Kapczinski et al., 2010, Kapczinski et al., 2011).

Examples of cytokines include interleukins (IL) and tumor necrosis factors (TNF). IL-1, IL-6 and TNF-alpha are considered pro-inflammatory, in the sense that they augment the immune response to infection and inflammation by promoting leukocyte recruitment to inflammatory sites and/or by activating inflammatory cells (Potvin et al., 2008). IL-10 is an anti-inflammatory cytokine that contributes to dampen the immune and inflammatory response (Potvin et al., 2008).

Oxidative damage is a mechanism of cellular injury in a number of conditions, including cancer, inflammatory states, and neurodegeneration (Kapczinski et al., 2011). Increased neuronal oxidative stress levels produce deleterious effects on signal transduction, structural plasticity and cellular resilience, mostly by inducing lipid peroxidation in membranes and direct damage in protein and genes (Gama et al., 2007, Gama et al., 2008a, Gama et al., 2008b). Neurons and glia are particularly vulnerable to inflammatory processes and redox status, and are dependent on the maintenance of neurotrophic activity (Kapczinski et al., 2010, Kapczinski et al., 2011, Kunz et al., 2008, Kunz et al., 2011). Furthermore, oxidative stress has been identified as a possible element in the neuropathological processes of SZ (Riegel et al., 2010, Dietrich-Muszalska and Kontek, 2010, Kunz et al., 2008, Gama et al., 2006, Gama et al., 2008a, Gama et al., 2008b).

Thiobarbituric acid-reactive substances (TBARS) is one of the well-known secondary products of lipid peroxidation and was used as an indicator of oxidative damage for several diseases (Huang et al., 2010). TBARS has been studied in SZ, providing evidence of increased levels of lipid peroxidation (Gama et al., 2006, Gama et al., 2008a, Gama et al., 2008b). Major molecular mechanisms induced by oxidative stress are protein oxidation. Structural changes by oxidative stress in proteins are characterized by carbonyl formation, so the protein carbonyl content (PCC) indicates oxidative stress (Dietrich-Muszalska et al., 2009). Total reactive antioxidant potential (TRAP) is one of the methods most employed to estimate the antioxidant capacity of samples in vitro (Dresch et al., 2009).

A new approach to understanding severe mental disorders such as SZ is to adopt a clinical staging model (Wood et al., 2011). The clinical staging model is particularly useful as it differentiates early, milder clinical phenomena from those that accompany illness progression and chronicity (McGorry et al., 2010). A term called neuroprogression has been increasingly used to define the pathological reorganization of the CNS along the course of severe mental disorders (Berk et al., 2011). It could be a result of several insults, such as inflammation and oxidative stress (Berk et al., 2010).

Staging models for SZ (Agius et al., 2010, Wood et al., 2011) and bipolar disorder (BD) (Vieta et al., 2011, Kapczinski et al., 2009a, Kapczinski et al., 2009b, Berk et al., 2007) have been proposed in order to personalize and optimize treatments (Berk et al., 2009). The logic of staging is based on accessing people to give them different treatment approaches according to pathophysiological, symptomatic and structural changes (Francey et al., 2010).

The clinical staging model in SZ consists on prodrome, first episode and chronic phases (Agius et al., 2010). Unlike BD, SZ present a unique and severe clinical deterioration pattern at the very beginning of the disease (Kauer-Sant’Anna et al., 2008, Lieberman, 1999). Episode dependant deterioration pattern have been widely described in BD by serum biomarkers (Kauer-Sant’Anna et al., 2008, Berk et al., 2011), brain imaging (Strakowski et al., 2002, Velakoulis et al., 2006) and functioning (Reinares et al., 2010, Scott et al., 2006). The overt BD would be staged in four categories, according to functioning and cognition (Kapczinski et al., 2009b). However, in SZ, the overt syndrome would not indicate clinical staging possibilities (Agius et al., 2010) and, as far as we aware, there is no data on serum biomarkers staging in this population.

In order to characterize several biological markers in patients with overt SZ at early and late phases of chronicity, and to test for evidence of progression in oxidative stress and inflammatory impairment, the present study examined TBARS, TRAP, PCC, IL-6, IL-10 and TNF-alpha. The study included separate control groups for early and late stages.

Section snippets

Methods

This study protocol was approved by the Ethical Committee of the Hospital de Clínicas de Porto Alegre, RS, Brazil (HCPA). In accordance with the Declaration of Helsinki, all subjects were advised about the procedure and signed the informed consent prior to participation. Sixty-one patients with SZ and fifty-seven healthy controls matched for age, gender and education were recruited. The double case–control design included 22 patients with SZ at early stage of chronicity (within first 10 years

Results

The subjects’ characteristics are summarized in Table 1.

TBARS (p < 0.0001 for early and late-stage groups), IL-6 (p < 0.0001 for early, p = 0.003 for late stage) and PCC (p = 0.001 for early, p = 0.006 for late stage) levels were significantly higher in patients with SZ at early and late stages than in controls. There were no differences for TRAP (p = 0.083 for early, p = 0.731 for late stage) and TNF-alpha (p = 0.786 for early, p = 0.114 for late stage) levels in patients with SZ at early and late stages than

Discussion

In our knowledge, this is the first study to examine oxidative stress markers and inflammatory cytokines levels in a sample of two groups of chronic patients with SZ, differing in illness duration: 7.25 (5.34) years for early and 21.19 (9.20) years for late stage.

The results suggest that SZ is associated with a chronic immune activation and the concept of biochemical staging proposed by others for BD (Kapczinski et al., 2009a, Kauer-Sant’Anna et al., 2008, Berk et al., 2007) is not seen in this

Financial disclosures

Dr. Flavio Kapczinski has received research grants from INCT for Translational Medicine, FIPE/HCPA, CNPq, CAPES, SMRI, NARSAD, Lilly, AstraZeneca, and Janssen. Dr. Clarissa S. Gama has received grant/research support from CNPq, FIPEeHCPA, and FAPERGS, and has been a speaker/advisory for AstraZeneca, Lundbeck, Pfizer, Actelion. Dr. Marcia Kauer-Sant’Anna has received research grant/research support from CNPq, FIPE/HCPA, and has been a speaker/advisory for Ely Lilly. Other authors have declared

Role of funding sources

This study was supported by grants from CNPq (Universal 470326/2011-5 and PQ 302195/2011-4), FAPERGS (PqG 1009340-06/2010) and FAPERGS/CNPq (PRONEM 11/2057-2), Brazil. These agencies had no role in the study design, in the acquisition or interpretation of the data, or in writing the report.

Contributors

MP designed the study, wrote the protocol, was responsible for the analysis and interpretation of data, participated in data interpretation, drafting the article and final approval of this version. RM, GRF, MABP, CES, JCFM, ALT, MIRL, JCW and, PSBA participated in study design and final approval of this version. CSG, MKS and FK were responsible for study design and interpretation of data, drafting the article and final approval of this version.

Conflicts of interest

The authors have declared no conflict of interest in this matter.

Acknowledgments

We thank all authors of the included studies, particularly those who cooperated with us by sending necessary data for our study.

References (50)

  • C.S. Gama et al.

    Elevated serum thiobarbituric acid reactive substances in clinically symptomatic schizophrenic males

    Neuroscience Letters

    (2008)
  • S. Grignon et al.

    Assessment of malondialdehyde levels in schizophrenia: a meta-analysis and some methodological considerations

    Progress in Neuropsychopharmacology Biological Psychiatry

    (2007)
  • T.L. Huang et al.

    Serum thiobarbituric acid-reactive substances and free thiol levels in schizophrenia patients: effects of antipsychotic drugs

    Psychiatry Research

    (2010)
  • M.M. Khan et al.

    Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics

    Schizophrenia Research

    (2002)
  • F. Kapczinski et al.

    The potential use of biomarkers as an adjunctive tool for staging bipolardisorder

    Progress in Neuropsychopharmacology an Biological Psychiatry

    (2009)
  • F. Kapczinski et al.

    Peripheral biomarkers and illness activity in bipolar disorder

    Journal of Psychiatric Research

    (2011)
  • M. Kunz et al.

    Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia

    Progress in Neuropsychopharmacology and Biological Psychiatry

    (2008)
  • R.L. Levine et al.

    Determination of carbonyl content in oxidatively modified proteins

    Methods in Enzymology

    (1990)
  • B.J. Miller et al.

    Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects

    Biological Psychiatry

    (2011)
  • S. Potvin et al.

    Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review

    Biological Psychiatry

    (2008)
  • M. Reinares et al.

    The impact of staging bipolar disorder on treatment outcome of family psychoeducation

    Journal of Affective Disorders

    (2010)
  • R.E. Riegel et al.

    Intracerebroventricular ouabain administration induces oxidative stress in the rat brain

    International Journal of Developmental Neuroscience

    (2010)
  • D. Sasayama et al.

    Association of plasma IL-6 and soluble IL-6 receptor levels with the Asp358Ala polymorphism of the IL-6 receptor gene in schizophrenic patients

    Journal of Psychiatric Research

    (2011)
  • S.R. Sponheim et al.

    Cognitive deficits in recent-onset and chronic schizophrenia

    Journal of Psychiatric Research

    (2010)
  • D.D. Wayner et al.

    Quantitative measurement of the total, peroxyl radical-trapping antioxidant capability of human blood plasma by controlled peroxidation. The important contribution made by plasma proteins

    FEBS Letters

    (1985)
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      The overall finding is deregulation of pro-inflammatory and anti-inflammatory factors, but the most consistent finding is an increase of pro-inflammatory cytokines and other immune signaling factors (Table 1). Examples are interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), C reactive protein (CRP), and the interferon α/β (IFN-α/β) signaling pathway components in MDD [49, 51, 171, 172, 173, 174]; IL-6, IL-1β, TNF-α, soluble TNF receptors 1 and 2 (sTNFR1 and 2), and CRP in BD [69, 70, 71, 163, 170]; IL-1β, IL-6, IL-12, TNF-α, and transforming growth factor β (TGF-β) in SCZ [165, 170, 175, 176, 177, 178, 179]; and sTNFR2, IL-4, IL-5, and IL-13 in ASD [180, 181]. It is not clear however whether the immune system deregulation in patients shares the etiology with mental disorders [182, 183, 184], for example, via the kynurenine pathway [23, 163, 185, 186, 187, 188], or is a consequence of a chronic illness [189, 190].

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