Cytokines dysregulation in schizophrenia: A systematic review of psychoneuroimmune relationship Daniela Rodrigues-Amorim a , Tania Rivera-Baltanás a , Carlos Spuch b , Hector J. Caruncho c , África González-Fernandez d , Jose M. Olivares a , Roberto C. Agís-Balboa a, ⁎ a Psychiatric Diseases Research Group, Galicia Sur Health Research Institute (IISGS), Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, CIBERSAM, Spain b Neurology Research Group, Galicia Sur Health Research Institute (IISGS), Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, CIBERSAM, Spain c Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada d Immunology, Biomedical Research Center (CINBIO) (Centro Singular de Investigación de Galicia), Galicia-Sur Health Research Institute (IISGS), University Campus, University of Vigo, Vigo, Spain abstract article info Article history: Received 31 July 2017 Received in revised form 15 November 2017 Accepted 18 November 2017 Available online xxxx Introduction: Schizophrenia is a multifactorial psychiatric disease with complex interactions among the brain and the immune system. A psycho-immune relationship underling schizophrenia is supported by several studies and integrates a specific area of knowledge - psychoneuroimmunology. Methods: A systematic review was performed by 2009 Preferred Reporting Items (PRISMA) recommendations. Based on the inclusion/exclusion criteria, publications with relevant information (evaluated by the Joanna Briggs Institute Critical Appraisals tools to quality assessment) were included. Results: In this review, we considered the inflammatory activity promoted by cytokine alterations in schizophre- nia aetiology, which reflects the systemic comprehension of this disease in opposition to the traditional approach focused solely on the brain. We focus on the analysis of several specific outcomes, such as proinflammatory cy- tokines, sample sort, laboratory techniques, diagnosis scales and results of each publication. Conclusion: This systematic review confirms the existence of cytokines abnormalities in schizophrenia disease. Immune imbalances such as increased levels of some cytokines (either at protein level or at mRNA expression), cytokine mRNAs, as well as cytokine gene polymorphisms have been reported with a large support in schizo- phrenia. These findings provide a strong evidence of a concomitant process of inflammatory activity in schizo- phrenia illness course. © 2017 Elsevier B.V. All rights reserved. Keywords: Schizophrenia Cytokines Cytokine polymorphisms Cytokine mRNAs Proinflammatory cytokines Psychoneuroimmunology 1. Introduction Schizophrenia is a severe psychotic disorder, which pathogenesis is still partially understood (van Kesteren et al., 2017). Given the multiple interaction between the brain and other organ systems that may have an incidence in the development of aberrant behavioural phenotypes, the aetiology of schizophrenia remains, in part, uncertain. One sug- gested mechanism that may putatively underlie schizophrenia develop- ment, implies disturbances of the immune system and their complex interactions with the nervous system, which may give a new insight on the pathogenesis and pathophysiology of this psychotic disorder (Khandaker et al., 2017; van Kesteren et al., 2017). This relationship was hypothesized over a century ago, and is reinforced by genetic and epidemiological studies linking infection and inflammation with brain disorders (Khandaker et al., 2015). Evidence demonstrates that the pathophysiology of schizophrenia could be associated with cytokine ab- normalities (Hope et al., 2013; Pandey et al., 2015; Potvin et al., 2008). Specifically, proinflammatory cytokines are involved in central nervous system (CNS) inflammation processes, disturbing the homeostasis and contributing to additional tissues injury (Müller et al., 2015). The in- crease of proinflammatory cytokines levels and their soluble receptors in human samples such as serum, plasma or cerebrospinal fluid (CSF) was reported in several studies (Debnath and Berk, 2014; Potvin et al., 2008; Wu et al., 2016). In the other hand, anti-inflammatory cytokines that down-regulate the inflammatory response are also altered in schizophrenia (Müller and Schwarz, 2010). Another important aspect pointing towards the involvement of immune system abnormalities in schizophrenia vulnerability is the presence of specific cytokine gene polymorphisms that may results in inflammatory events that putatively modulate the development of the schizophrenia syndrome by neurodevelopmental or neurodegenerative abnormalities (Fan et al., 2007). For example, the polymorphisms in the interleukin-1 (IL-1) or IL-6 genes have been associated to schizophrenia, with increasing blood levels of both cytokines (Debnath and Berk, 2014; Katila et al., 1999). In particular, evidence suggest an unequivocal role of the IL-6 Schizophrenia Research xxx (2017) xxx–xxx ⁎ Corresponding author at: Galicia Sur Health Research Institute, IISGS, Hospital Álvaro Cunqueiro, Bloque Técnico, Planta 2, Sala de Investigación, Estrada Clara Campoamor, 341, 36212 Vigo, Spain. E-mail address: roberto.carlos.agis.balboa@sergas.es (R.C. Agís-Balboa). SCHRES-07632; No of Pages 15 https://doi.org/10.1016/j.schres.2017.11.023 0920-9964/© 2017 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: Rodrigues-Amorim, D., et al., Cytokines dysregulation in schizophrenia: A systematic review of psychoneuroimmune relationship, Schizophr. Res. (2017), https://doi.org/10.1016/j.schres.2017.11.023