Effects of depression on the cytokine profile in drug naïve first-episode psychosis
Introduction
Psychosis is a core symptom of schizophrenia, a severe neurodevelopmental disorder, with large economical and social impact (Insel, 2010). Abnormal immune–inflammatory responses, including increased levels of pro-inflammatory cytokines are found in patients with schizophrenia (Potvin et al., 2008, Miller et al., 2011). In 1995, the immune–inflammatory theory of schizophrenia proposed that activated immune–inflammatory pathways, particularly activated macrophages and T-lymphocytes, may explain the higher offspring schizophrenia risk associated with gestational infections through the neurotoxic effects of pro-inflammatory cytokines and their detrimental consequences (Smith and Maes, 1995). More recently, several reviews addressed the role of activated immune–inflammatory pathways in the neurodevelopmental pathophysiology of schizophrenia (Anderson et al., 2013a, Meyer, 2013).
Cytokines are proteins involved in the activation, coordination and suppression of immune responses. Their neuromodulatory actions appear to be critical for the regulation of neuroplasticity, cell resilience and apoptosis (Boulanger and Shatz, 2004, Golan et al., 2004, Bauer et al., 2007). Macrophages are activated during innate immune response in two functional distinct states (M1 and M2), producing different cytokines. M1 macrophages produce pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-12 and tumor necrosis factor (TNF)α, stimulating cell-mediated response. M2 macrophages produce negative immunoregulatory cytokines, such as IL-10 and transforming growth factor (TGF)β (Seruga et al., 2008, Maes et al., 2012b). During the adaptive immune response, T lymphocytes differentiate into T helper (Th)1, Th17, T regulatory (Treg) and Th2 cells. Naïve cells are driven towards Th1 and Th2 phenotypes by M1 and M2 macrophages, respectively (Seruga et al., 2008, Maes et al., 2012b). A Th1-shift cytokine profile indicates immune activation, whereas a Th2-shift may indicate negative immunoregulatory effects and activated humoral immunity (Maes et al., 2012b). A recent meta-analysis showed that schizophrenia is accompanied by increased levels of pro-inflammatory cytokines indicating M1 activation and increased levels of Th1-like cytokines, indicating T cell activation (Miller et al., 2011). There are, however, few studies that have examined the associations between psychosis and levels of monocytic cytokines, Th1, Th2, Th17 and Treg cytokines simultaneously.
Meta-analyses (Potvin et al., 2008, Miller et al., 2011) demonstrated a notable heterogeneity of results in existing studies, possibly as a consequence of several confounding factors, such as use of medications and clinical features. The acute or (sub)chronic use of antipsychotic drugs, which have significant immune-regulatory effects (Maes et al., 2000, MacDowell et al., 2013, Tourjman et al., 2013), is one of those factors that may modify the levels of cytokines measured. Therefore, the analysis of the immune state in drug naïve patients is of paramount importance to examine the levels of monocytic, Th1, Th2, Th17 and Treg cytokines. Upthegrove et al. (2014) recently published a meta-analysis examining patients with drug naïve first episode psychosis (FEP). They found an elevation in pro-inflammatory cytokine (and receptor) levels in the serum of FEP patients with higher levels of IL-1β, soluble IL-2 receptor (sIL-2R), IL-6 and TNF-α, a profile suggesting M1 and Th1 activation.
The immune–inflammatory profile of patients with psychosis seems to be modulated by clinical characteristics. For example, a more disordered immune–inflammatory profile may be found in patients with a more severe course of the disorder (Noto et al., 2011, Asevedo et al., 2013, Noto et al., 2013). Another important clinical factor is the presence of depressive symptoms in patients with psychosis. The prevalence of depression in schizophrenia may be as high as 61% (Gozdzik-Zelazny et al., 2011) and in FEP the prevalence may be as high as 80% (Upthegrove et al., 2010, Sonmez et al., 2014). Despite being different disorders, schizophrenia and depression shared some clinical and biological characteristics. Both present cognitive and neurostructural changes suggestive of neuroprogressive processes. There is consistent evidence that depression is an immune–inflammatory disorder accompanied by increases in macrophage (M1), Th1, Th2 and Th17-like cytokines and lowered levels of Treg cytokines (Leonard and Maes, 2012, Noto et al., 2014a). Both schizophrenia and depression share significant overlaps in immune–inflammatory pathways, including increased levels of pro-inflammatory cytokines and Th1 cytokines (Maes et al., 1990, Leonard and Maes, 2012, Anderson et al., 2013a, Noto et al., 2014a). They also shared other biological pathways, such as activation of oxidative and nitrosative stress, decreased antioxidant levels, and activation of the tryptophan catabolite pathway through induction of indoleamine-2,3-dioxygenase (IDO). The association between both disorders is related with poor quality of life, impairments in social and vocational functioning, and higher rates of relapse. It may cause a worse outcome and increased suicide, even at early stages (Conley et al., 2007, Challis et al., 2013, Noto et al., 2013, Bjorkenstam et al., 2014, Schennach et al., 2015). At the FEP symptoms as loss of self-confidence, feelings of guilt and suicidal thoughts are one of the most prevalent (an der Heiden et al., 2005). Based on these findings it was hypothesized that schizophrenia is primed for an increased expression of depression via activated immune–inflammatory pathways (Anderson et al., 2013b).
The aims of the present study were to examine whether a) FEP is characterized by a specific cytokine profile indicating macrophage, Th1, Th2, Th17 or Treg activation (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17); and b) the presence of depressive symptoms in FEP individuals may be related to a specific cytokine profile.
Section snippets
Subjects
This study is part of a prospective cohort performed in Sao Paulo, Brazil, that combines the assessment of different characteristics of drug naïve FEP patients, such as gene expression, methylation, immune–inflammatory, and oxidative and nitrosative stress profiles. Further, patients were treated and followed, with analyses of the effects of antipsychotic treatment on these biomarkers (Noto et al., 2014b, Ota et al., 2014a, Ota et al., 2014b).
For the current study, fifty-five drug naïve FEP
Characteristics of the study sample
Table 1 shows the socio-demographic and clinical data of FEP patients and healthy controls. There were no significant differences in age and gender between the two study samples. There were significant differences in ethnicity, years of education and income between FEP patients and controls. Table 1 shows also the mean values of the rating scales in the FEP patients.
Cytokines profile in FEP vs healthy controls
Table 2 shows the results of GLM analyses with IL-6, IL-4, IL-10, TNFα and IL-17 as dependent variables and the diagnostic groups
Role of funding source
This study was funded through the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2010/08968-6, 2010/19176-3, 2011/50740-5 and 2013/10498-6), Brazil.
Contributors
C. Noto, V.K. Ota, A. Gadelha, M.L. Santoro, R.A. Bressan, S.I. Belangero and E. Brietzke designed the study and wrote the protocol. C. Noto, A. Gadelha, B.B. Ortiz, and Q. Cordeiro selected and interviewed the participants. C. Noto, M. Maes and E. Brietzke conducted the literature search, analyzed the data, and wrote the first draft of the manuscript. L.B. Rizzo and C.H. Higuchi performed the experiments. All of the authors revised the manuscript for important intellectual content.
Conflict of interest
Dr. Noto has received a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Dr. Gadelha was on the speakers' bureau and/or has acted as a consultant for Janssen-Cilag in the last 12 months and has also received research support from Brazilian government institutions (CNPq). Dr. Bressan has received research funding from FAPESP, CNPq, CAPES, Fundação Safra, Fundação ABADS, Janssen, Eli Lilly, Lundbeck, Novartis and Roche, has served as a speaker for Astra Zeneca,
Acknowledgments
The authors are thankful to Prof. Alexandre Basso and to Leandro Pires Araújo for their valuable help in measurements of cytokines.
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Both authors contributed equally to this work.