Effects of depression on the cytokine profile in drug naïve first-episode psychosis Cristiano Noto a,b,1 , Vanessa Kiyomi Ota c,1 , Marcos Leite Santoro c , Bruno B. Ortiz a , Lucas B. Rizzo a , Cinthia Hiroko Higuchi a , Quirino Cordeiro a,b , Sintia Iole Belangero c , Rodrigo Affonseca Bressan a , Ary Gadelha a , Michael Maes d,e,f , Elisa Brietzke a, ⁎ a Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil b First Episode Psychosis Program, Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP), São Paulo, Brazil c Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), São Paulo, Brazil d Department of Psychiatry, Deakin University, Geelong, VIC, Australia e Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand f Health Sciences Graduate Program, Health Sciences Center, State University of Londrina (UEL), Brazil abstract article info Article history: Received 9 December 2014 Received in revised form 9 January 2015 Accepted 14 January 2015 Available online xxxx Keywords: Schizophrenia First-episode psychosis (FEP) Drug naïve Depression Cytokines Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n = 55) versus healthy controls (n = 57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune–inflammatory abnormalities described. © 2015 Elsevier B.V. All rights reserved. 1. Introduction Psychosis is a core symptom of schizophrenia, a severe neuro- developmental 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, stimu- lating cell-mediated response. M2 macrophages produce negative immu- noregulatory 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 neg- ative immunoregulatory effects and activated humoral immunity Schizophrenia Research xxx (2015) xxx–xxx ⁎ Corresponding author at: Rua Pedro de Toledo, 669, 3 o andar, CEP 04039-032, São Paulo, SP, Brazil. Tel.: +55 11 5576 4845. E-mail address: elisabrietzke@hotmail.com (E. Brietzke). 1 Both authors contributed equally to this work. SCHRES-06240; No of Pages 6 http://dx.doi.org/10.1016/j.schres.2015.01.026 0920-9964/© 2015 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Please cite this article as: Noto, C., et al., Effects of depression on the cytokine profile in drug naïve first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.01.026