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

Contents lists available at Journal of Psychiatric Research Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity Mariana Pedrini ,, Raffael Massuda Gabriel R. Fries ,, Matheus A. de Bittencourt Pasquali , Carlos Eduardo Schnorr José Claudio F. Moreira Antonio L. Teixeira Maria Ines R. Lobato Julio C. Walz Paulo Silva Belmonte-de-Abreu ,,Marcia Kauer-Sant'Anna ,, Flavio Kapczinski ,Clarissa S. Gama ,a Laboratory of Molecular Psychiatry, INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil b Programa de Pós-Graduação em Medicina: Psiquiatria, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil c Department of Biochemistry, Institute of Basic Health Sciences (ICBS), Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil d Laboratory of Immunopharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil Schizophrenia (SZ) is a debilitating neurodevelopmental disorder that strikes at a critical period of Received 7 November 2011 a young person's life. Its pathophysiology could be the result of deregulation of synaptic plasticity, with Received in revised form 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 Accepted 22 March 2012 markers and inflammatory cytokines in early and late phases of chronic SZ. Twenty-two patients at earlystage (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 Inflammatory cytokines 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 withSZ at early and late stages than in controls. IL-10 levels were decreased in patients at late stage anda decrease trend in early stage was found. Results provided evidence consistent with comparable bio-logical markers across chronic SZ. The concept of biochemical staging proposed by others for bipolardisorder 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 andfirst-episode population.
! 2012 Elsevier Ltd. All rights reserved.
defense and increased lipid peroxidation ).
Schizophrenia (SZ) is a debilitating neurodevelopmental Many lines of evidence support the hypothesis that disorder that strikes at a critical period of a young person's life inflammation-related pathways are involved on the pathophysi- ). It has been accepted that SZ origi- ology of psychiatric disorders (). Inflammatory immune nates from abnormalities occurring during the early stages of processes have been strongly implicated in the pathophysiological neural development The pathophysiology of SZ mechanisms of SZ could be the result of deregulation of synaptic plasticity, with downstream alterations of neurotrophins, impaired antioxidant ). Cytokines regulateinflammation and coordinate both innate and adaptive arms of the immune system (being important mediators of * Corresponding author. Hospital de Clínicas de Porto Alegre/CPE, Molecular the cross-talk between the central nervous system (CNS) and the Psychiatry Laboratory, Rua Ramiro Barcelos, 2350, Prédio Anexo, 90035-903 PortoAlegre, RS, Brazil. Tel.: immune system, which might have implications for clinical þ55 51 33598845; fax: þ55 51 33598846.
E-mail address: (C.S. Gama).
psychiatry ). Recent data have emerged 0022-3956/$ e see front matter ! 2012 Elsevier Ltd. All rights reserved.
doi: Please cite this article in press as: Pedrini M, et al., Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity, Journal of Psychiatric Research (2012), doi:10.1016/j.jpsychires.2012.03.019 M. Pedrini et al. / Journal of Psychiatric Research xxx (2012) 1e6 to suggest that changes in inflammation-related pathways are staged in four categories, according to functioning and cognition present in the CNS of subjects with psychiatric disorders ( ). However, in SZ, the overt syndrome They can exert cellular effects that, if not would not indicate clinical staging possibilities ( adequately moderated or counteracted, ultimately lead to toxicities, and, as far as we aware, there is no data on serum biomarkers physiological deregulation, and medical compromise staging in this population.
In order to characterize several biological markers in patients Examples of cytokines include interleukins (IL) and tumor with overt SZ at early and late phases of chronicity, and to test for necrosis factors (TNF). IL-1, IL-6 and TNF-alpha are considered pro- evidence of progression in oxidative stress and inflammatory inflammatory, in the sense that they augment the immune impairment, the present study examined TBARS, TRAP, PCC, IL-6, IL- response to infection and inflammation by promoting leukocyte 10 and TNF-alpha. The study included separate control groups for recruitment to inflammatory sites and/or by activating inflamma- early and late stages.
tory cells (IL-10 is an anti-inflammatory cyto- kine that contributes to dampen the immune and inflammatory Oxidative damage is a mechanism of cellular injury in a number of conditions, including cancer, inflammatory states, and neuro- This study protocol was approved by the Ethical Committee of degeneration Increased neuronal oxidative the Hospital de Clínicas de Porto Alegre, RS, Brazil (HCPA). In stress levels produce deleterious effects on signal transduction, accordance with the Declaration of Helsinki, all subjects were structural plasticity and cellular resilience, mostly by inducing lipid advised about the procedure and signed the informed consent peroxidation in membranes and direct damage in protein and prior to participation. Sixty-one patients with SZ and fifty-seven genes (Neurons and glia are particularly healthy controls matched for age, gender and education were vulnerable to inflammatory processes and redox status, and are recruited. The double caseecontrol design included 22 patients dependent on the maintenance of neurotrophic activity with SZ at early stage of chronicity (within first 10 years of Furthermore, oxidative a psychotic episode); 39 patients at late stage (minimum 10 years stress has been identified as a possible element in the neuropath- after diagnosis of SZ) and their respective matched controls (25 ological processes of SZ ( and 32 subjects). All patients had to fulfill the Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) for SZ and their Thiobarbituric acid-reactive substances (TBARS) is one of the psychopathological state were assessed by the 18-item Brief well-known secondary products of lipid peroxidation and was used Psychiatry Rating Scale (BPRS) (The as an indicator of oxidative damage for several diseases ( control group consisted of healthy volunteers who had no current TBARS has been studied in SZ, providing evidence of or previous history as well as no first-degree family history of increased levels of lipid peroxidation ).
a major psychiatric disorder, including dementia or mental retar- Major molecular mechanisms induced by oxidative stress are dation assessed by the non-patient version of the Structured protein oxidation. Structural changes by oxidative stress in proteins Clinical Interview for DSM-IV (SCID).
are characterized by carbonyl formation, so the protein carbonyl Patients were recruited from HCPA through the outpatients' content (PCC) indicates oxidative stress ( clinic. All subjects were required to be at least age 18 and no older ). Total reactive antioxidant potential (TRAP) is one of the than 60. None of them had any neurological disease, brain tumor, methods most employed to estimate the antioxidant capacity of thyroid disease, severe hepatic disease, severe cardiac disease or samples in vitro ().
any other psychiatric diagnosis. Included patients had body mass A new approach to understanding severe mental disorders such index at or below 27, they were non-smokers or smoked up to 10 as SZ is to adopt a clinical staging model ). The cigarettes per day.
clinical staging model is particularly useful as it differentiates Each subject had 5 ml blood samples collected by venipuncture early, milder clinical phenomena from those that accompany without anticoagulants, and serum was obtained by centrifugation illness progression and chronicity A term at 300 " g for 5 min and kept frozen at #70$ C for up to 6 months, called neuroprogression has been increasingly used to define the until the assay.
pathological reorganization of the CNS along the course of severe The levels of lipid peroxidation were measured using the TBARS mental disorders (). It could be a result of several method described by and data were expressed as insults, such as inflammation and oxidative stress nmol/mL. The oxidative damage to proteins was measured by the determination of carbonyl groups (protein carbonyl content) based Staging models for SZ and on the reaction with dinitrophenylhydrazine (DNPH), as previously bipolar disorder (BD) ( described (The non-enzymatic antioxidant ) have been proposed in order to personalize and cellular defenses were estimated by the total radical-trapping optimize treatments The logic of staging is based antioxidant parameter (TRAP), which determines the non- on accessing people to give them different treatment approaches enzymatic antioxidant potential, as previously described ( according to pathophysiological, symptomatic and structural ). Serum cytokines (IL-6, IL-10 and TNF-alpha) were measured according to the procedures supplied by the manufac- The clinical staging model in SZ consists on prodrome, first turer using highly sensitive sandwich-ELISA kits for TNF-alpha, IL-6 episode and chronic phases Unlike BD, SZ and IL-10 (Quantikine, R&D Systems, Minneapolis, Minn., USA). All present a unique and severe clinical deterioration pattern at the samples were assayed in duplicates.
very beginning of the disease ( Analysis was performed using SPSS Version 18.0. Demographic ). Episode dependant deterioration pattern have and clinical characteristics were analyzed using Chi-Square, been widely described in BD by serum biomarkers ManneWhitney or T-test. Descriptive analyses are presented as mean % SD or median (interquartile range) and p-values < 0.05 were considered significant. Appropriated tests for parametric or (). The overt BD would be nonparametric distribution are indicated in Please cite this article in press as: Pedrini M, et al., Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity, Journal of Psychiatric Research (2012), doi:10.1016/j.jpsychires.2012.03.019

M. Pedrini et al. / Journal of Psychiatric Research xxx (2012) 1e6 Table 1Characteristics of healthy controls and patients with schizophrenia (SZ).
Controls (n ¼ 25) Controls (n ¼ 32) Gender (Male/female) Years of illness (number of years after first episode) 9.03 (2.76e26.10) 3.62 (1.72e14.75) Antipsychotic daily dose, in mg of a Mean (SD).
b Median (interquartile range).
c Chi-square.
e ManneWhitney.
) is not seen in this cohort of patients withovert SZ, at least for cytokines and oxidative stress markers. For The subjects' characteristics are summarized in instance, IL-6 was increased in the early and late stages of SZ and IL- TBARS (p < 0.0001 for early and late-stage groups), IL-6 10 was decreased in late stages, with a decrease trend in early (p < 0.0001 for early, p ¼ 0.003 for late stage) and PCC (p ¼ 0.001 stages. However, TNF-alpha levels were similar in patients with SZ for early, p ¼ 0.006 for late stage) levels were significantly higher in at the early and late stages compared to controls. The results also patients with SZ at early and late stages than in controls. There were show an increased redox status, indicated by higher serum levels of no differences for TRAP (p ¼ 0.083 for early, p ¼ 0.731 for late stage) TBARS and PCC in the early and late stage of SZ, compared to and TNF-alpha (p ¼ 0.786 for early, p ¼ 0.114 for late stage) levels in controls. On the other hand, no differences found in TRAP levels at patients with SZ at early and late stages than in controls. IL-10 early and late stages compared to controls.
levels were decreased in patients at late stage (p ¼ 0.006) and Increased IL-6 levels are one of the most robust findings in the a decrease trend in early stage was found (p ¼ 0.053) ).
study of inflammatory markers in SZ, as evidenced by a meta- analysis of 19 studies and 1219 patients ). Consistent with our findings, a recent study with patients with recent-onset SZ found activation of pro- In our knowledge, this is the first study to examine oxidative inflammatory networks ().
stress markers and inflammatory cytokines levels in a sample of A recent study reports that patients with first episode of two groups of chronic patients with SZ, differing in illness duration: psychosis had increased levels of IL-6 gene expression when 7.25 (5.34) years for early and 21.19 (9.20) years for late stage.
compared with controls, suggesting a pro-inflammatory state to be The results suggest that SZ is associated with a chronic immune associated with decreased levels of BDNF and smaller hippocampus activation and the concept of biochemical staging proposed by volume (In accordance with our findings, an elegant meta-analysis has reported that blood IL-10 levels were Fig. 1. A) Box-plot of serum IL-6 levels in patients with SZ at early and late stages and their matched controls. Median levels are indicated by horizontal lines. ManneWhitney testwas performed to compare groups (control vs. SZ early, p < 0.0001; control vs. SZ late, p ¼ 0.003). B) Box-plot of serum IL-10 levels in patients with SZ at early and late stages and their matched controls. Median levels are indicated by horizontal lines. ManneWhitney test was performed to compare groups (control vs. SZ early, p ¼ 0.053; control vs. SZ late, p ¼ 0.006). C) Box-plot of serum TNF-alpha levels in patients with SZ at early and late stages and their matched controls. Median levels are indicated by horizontal lines. Man- neWhitney test was performed to compare groups (control vs. SZ early, p ¼ 0.786; control vs. SZ late, p ¼ 0.114).
Please cite this article in press as: Pedrini M, et al., Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity, Journal of Psychiatric Research (2012), doi:10.1016/j.jpsychires.2012.03.019

M. Pedrini et al. / Journal of Psychiatric Research xxx (2012) 1e6 Fig. 2. A) Error bar of serum TBARS levels in patients with SZ at early and late stages and their matched controls. Mean levels are indicated by squares. T-test was performed tocompare groups (control vs. SZ early, p < 0.0001; control vs. SZ late, p < 0.0001). B) Error bar of serum PCC levels in patients with SZ at early and late stages and their matchedcontrols. Mean levels are indicated by squares. T-test was performed to compare groups (control vs. SZ early, p ¼ 0.001; control vs. SZ late, p ¼ 0.001). C) Error bar of serum TRAP levels in patients with SZ at early and late stages and their matched controls. Mean levels are indicated by squares. T-test was performed to compare groups (control vs. SZ early,p ¼ 0.083; control vs. SZ late, p < 0.731).
significantly decreased and IL-6 levels were significantly increased Our report must be interpreted in light of its limitations. The in acutely relapsed patients compared to control subjects ( study design was cross-sectional; it did not allow us a direct exam- ). As reported by previous studies ination of the course of oxidative stress markers and inflammatory the fact that TNF-alpha levels were not cytokines in SZ. Nevertheless, the inclusion of two control groups different from those of the controls in our sample could be explained matched to early and late stage groups allowed differentiation of age, by the non-acute profile of the patients. In SZ, however, defining sex and diagnosis effects. The effect of medication on serum remission in a chronically ill and stable population may not allow for biomarkers could not be excluded, however it has been reported that a clear differentiation of state and trait effects ).
antipsychotics would decrease central and peripheral inflammation In line with our findings, a recent meta-analysis showed that as well as oxidative stress TBARS are significantly increased in SZ (). Previous The present study provided evidence consistent with compa- studies have found increased levels of serum TBARS predominantly rable biological markers across chronic SZ. It is conceivable that in never-medicated schizophrenia patients compared to controls increased cytokines levels and impaired anti-oxidative stress defense may synergistically function in favor of neuronal degen- oxidative stress has been suggested in the pathophysiology of SZ, eration in SZ. Overall, these clinical observations are consistent based on the increased peroxidation at the onset of psychosis in with differences reported in brain structure, metabolic and never-medicated patients (Gama et al., biochemical changes observed found elevated TBARS levels in chronically medicated SZ patients As corroborated by Sponheim et al., cognitive compared to controls, suggesting that the high level of TBARS is deficits could be comparable from early in the course of SZ to the a sign of peroxidative injury to membrane phospholipids chronic phase of the disorder, without progressing beyond what is expected with normal aging In our study, we presented elevated PCC levels in the early and In conclusion, our findings provide important information about late stage of chronic SZ, compared to controls. Corroborating our biological markers in early and late stages of chronic SZ, a data that findings, Dietrich-Muszalska et al. found, in platelet proteins from would be important to consider in interpreting findings of anom- patients with SZ, a statistically significant increase of the level of alous brain structure and function, reinforcing the need of assess- biomarkers of oxidative/nitrative stress such as carbonyl groups ment of individuals in ultra high risk to develop psychosis and first- (). Furthermore, we found total episode population. Prospective studies of cytokines and oxidative antioxidant defense, presented by TRAP levels, similar in both stages stress markers in SZ and in at-risk/first-episode populations, and controls. It seems that patients do not perform an antioxidant together with neuroimaging techniques, should stratify patients by action reactive to the illness injury. In line with our findings, earlier clinical status to better guide interventions.
results showed significantly increased TBARS levels in patients with SZ, whereas the activities of antioxidant defense enzymes were not Financial disclosures Our findings support the growing body of evidence corrobo- Dr. Flavio Kapczinski has received research grants from INCT rating the early central nervous system damage hypothesis in SZ, for Translational Medicine, FIPE/HCPA, CNPq, CAPES, SMRI, NAR- suggesting a different pattern of damage between SZ and BD, with SAD, Lilly, AstraZeneca, and Janssen. Dr. Clarissa S. Gama has an early degenerative component preceding the illness onset in SZ received grant/research support from CNPq, FIPEeHCPA, and (and an episode-dependent pattern of FAPERGS, and has been a speaker/advisory for AstraZeneca, deterioration in BD ). As reported by Kunz Lundbeck, Pfizer, Actelion. Dr. Marcia Kauer-Sant'Anna has et al., this observation brings us back to the classic differentiation received research grant/research support from CNPq, FIPE/HCPA, between SZ and BD, based on either an episodic or a chronic- and has been a speaker/advisory for Ely Lilly. Other authors have deteriorating course ). In the same venue, while declared no conflict of interest. These agencies had no role in the increased IL-6, TBARS and PCC seem to be a state effect in BD, it study design, in the acquisition or interpretation of the data, or in seems to be a trait effect in SZ ().
writing the report.
Please cite this article in press as: Pedrini M, et al., Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity, Journal of Psychiatric Research (2012), doi:10.1016/j.jpsychires.2012.03.019 M. Pedrini et al. / Journal of Psychiatric Research xxx (2012) 1e6 Role of funding sources of benefits, risks, neurobiology and ethics in the era of early intervention.
Schizophrenia Research 2010;119(1e3):1e10.
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06/2010) and FAPERGS/CNPq (PRONEM 11/2057-2), Brazil. These Progress in Neuro-Psychopharmacology and Biological Psychiatry 2006;30(3):512 agencies had no role in the study design, in the acquisition or Gama CS, Andreazza AC, Kunz M, Berk M, Belmonte-de-Abreu PS, Kapczinski F.
interpretation of the data, or in writing the report.
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Please cite this article in press as: Pedrini M, et al., Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity, Journal of Psychiatric Research (2012), doi:10.1016/j.jpsychires.2012.03.019

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