Neuroscience and Biobehavioral Reviews 55 (2015) 612–626 Contents lists available at ScienceDirect Neuroscience and Biobehavioral Reviews journal h om epa ge: www.elsevier.com/locate/neubiorev Review Inflammation in schizophrenia: A question of balance Juan C. Leza a,b,d,∗ , Borja García-Bueno a,b,d , Miquel Bioque a,e , Celso Arango a,c,f , Mara Parellada a,c,f , Kim Do g , Patricio O’Donnell h , Miguel Bernardo a,e a Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Complutense University, Madrid, Spain b Department of Pharmacology, Faculty of Medicine, Complutense University, Madrid, Spain c Department of Psychiatry, Faculty of Medicine, Complutense University, Madrid, Spain d Instituto de Investigación Sanitaria (IIS) Hospital 12 de Octubre (i+12), Madrid, Spain e Barcelona Clínic Schizophrenia Unit, Hospital Clínic Barcelona, University of Barcelona, IDIBAPS, Barcelona, Spain f Child and Adolescent Psychiatry Department, IIS Hospital Gregorio Mara˜ nón (IISGM), Madrid, Spain g Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland h Pfizer Neuroscience Research Unit, Cambridge, MA, USA a r t i c l e i n f o Article history: Received 17 December 2014 Received in revised form 22 April 2015 Accepted 18 May 2015 Available online 16 June 2015 Keywords: Schizophrenia Psychosis Inflammation Oxidative stress Immune system Antiinflammatory drugs a b s t r a c t In the past decade, there has been renewed interest in immune/inflammatory changes and their asso- ciated oxidative/nitrosative consequences as key pathophysiological mechanisms in schizophrenia and related disorders. Both brain cell components (microglia, astrocytes, and neurons) and peripheral immune cells have been implicated in inflammation and the resulting oxidative/nitrosative stress (O&NS) in schizophrenia. Furthermore, down-regulation of endogenous antioxidant and anti-inflammatory mech- anisms has been identified in biological samples from patients, although the degree and progression of the inflammatory process and the nature of its self-regulatory mechanisms vary from early onset to full- blown disease. This review focuses on the interactions between inflammation and O&NS, their damaging consequences for brain cells in schizophrenia, the possible origins of inflammation and increased O&NS in the disorder, and current pharmacological strategies to deal with these processes (mainly treatments with anti-inflammatory or antioxidant drugs as add-ons to antipsychotics). © 2015 Elsevier Ltd. All rights reserved. Contents 1. General aspects of inflammation and oxidative/nitrosative (O&NS) stress of special interest for schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 2. Evidence about oxidative stress and inflammation in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614 3. Mechanisms whereby O&NS and inflammation lead to brain cell damage and/or neurodegeneration in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . 615 4. Is peripheral inflammation and ox/nox stress related to brain function in schizophrenia? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617 5. Possible origin of increased O&NS and inflammation in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618 6. Oxidative stress and inflammation as possible trait/state biomarkers of schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618 7. The question of non-selectivity of the findings: the broad shadow of stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619 8. Antioxidant and anti-inflammatory agents in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619 9. Anti-inflammatory effect of antipsychotic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620 10. Clinical and research implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622 ∗ Corresponding author at: Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain. Tel.: +34 91 394 1478. E-mail address: jcleza@med.ucm.es (J.C. Leza). http://dx.doi.org/10.1016/j.neubiorev.2015.05.014 0149-7634/© 2015 Elsevier Ltd. All rights reserved.