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Cognition and psychopathology in first-episode psychosis: are they related to inflammation?

Published online by Cambridge University Press:  08 April 2016

B. Cabrera
Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, Spain Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain
M. Bioque
Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, Spain Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain
R. Penadés
Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, Spain Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain
A. González-Pinto
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain Hospital Universitario de Álava (sede Santiago), BIOARABA, Universidad del País Vasco, Vitoria, Spain
M. Parellada
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain Child and Adolescent Psychiatry Department, IIS Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain
J. Bobes
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain Psychiatry Department, University of Oviedo, Spain
A. Lobo
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain Universidad de Zaragoza, Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain
B. García-Bueno
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain Department of Pharmacology, School of Medicine, Complutense University, Instituto de Investigación Hospital 12 de Octubre (I+12), Madrid, Spain
J. C. Leza
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain Department of Pharmacology, School of Medicine, Complutense University, Instituto de Investigación Hospital 12 de Octubre (I+12), Madrid, Spain
M. Bernardo*
Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, Spain Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain
*Address for correspondence: Dr M. Bernardo, Barcelona Clínic Schizophrenia Unit, Neuroscience Institute, Hospital Clínic de Barcelona, Spain. (Email:



Cognitive deficits are present from the onset of psychosis and are considered a core feature of the disorder. Increasing evidence suggests that cognitive function is associated with inflammatory processes. This study evaluated the association between cognition and inflammatory biomarkers in first-episode psychosis (FEP), in order to identify cognitive phenotypes from inflammatory expression profiles.


A case-control study of 92 FEP patients and 80 matched controls was used. Neurocognitive assessment, including verbal ability, sustained attention, verbal memory, working memory and executive function, was performed. The expression of pro- and anti-inflammatory mediators of the main intracellular inflammatory pathway was measured in peripheral blood mononuclear cells and plasma.


FEP patients performed worse in all cognitive domains compared to controls and had higher expression of pro-inflammatory mediators and lower expression of anti-inflammatory mediators. In the FEP group, cognition and psychopathology were associated with inflammation. Hierarchical regression analysis showed that association between the anti-inflammatory prostaglandin 15d-PGJ2 and sustained attention on one hand, and COX-2 expression and executive function on the other, were statistically significant.


Our study provides evidence for an association between anti-inflammatory biomarkers and cognition in FEP. The identification of a subgroup of patients based on these measures could be useful to guide treatment programmes by providing tools to select a personalized treatment approach, but longitudinal studies are needed before. In the future, establishment of biomarkers linked to cognition would be useful to monitor the course of cognitive impairment, but substantially more data will be required. Determination of IκBα, the inhibitory protein of the pro-inflammatory transcription factor NFκB, could be useful in early phases to assess clinical severity.

Original Articles
Copyright © Cambridge University Press 2016 

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APA (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV). American Psychiatric Association: Arlington, VA.Google ScholarPubMed
Becker, HE, Nieman, DH, Wiltink, S, Dingemans, PM, van de Fliert, JR, Velthorst, E, de Haan, L, van Amelsvoort, TA, Linszen, DH (2010). Neurocognitive functioning before and after the first psychotic episode: does psychosis result in cognitive deterioration? Psychological Medicine 40, 15991606.CrossRefGoogle Scholar
Benedet, MJ (1998 a). Test de Aprendizaje Verbal España-Complutense (TAVEC). Tea Ediciones: Madrid.Google Scholar
Benedet, MJ (1998 b). Test de Aprendizaje Verbal España-Complutense infantil (TAVECi). Tea Ediciones: Madrid.Google Scholar
Bernardo, M, Bioque, M (2014). What have we learned from research into first-episode psychosis? Revista de Psiquiatría y Salud Mental 7, 6163.CrossRefGoogle Scholar
Bernardo, M, Bioque, M, Parellada, M, Saiz Ruiz, J, Cuesta, MJ, Llerena, A, Sanjuan, J, Castro-Fornieles, J, Arango, C, Cabrera, B, PEPs Group (2013). Assessing clinical and functional outcomes in a gene-environment interaction study in first episode of psychosis (PEPs). Revista de Psiquiatría y Salud Mental 6, 416.CrossRefGoogle Scholar
Bilder, RM, Goldman, RS, Robinson, D, Reiter, G, Bell, L, Bates, JA, Pappadopulos, E, Willson, DF, Alvir, JM, Woerner, MG, Geisler, S, Kane, JM, Lieberman, JA (2000). Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. American Journal of Psychiatry 157, 549559.CrossRefGoogle ScholarPubMed
Carter, CS, Barch, DM, Buchanan, RW, Bullmore, E, Krystal, JH, Cohen, J, Geyer, M, Green, M, Nuechterlein, KH, Robbins, T, Silverstein, S, Smith, EE, Strauss, M, Wykes, T, Heinssen, R (2008). Identifying cognitive mechanisms targeted for treatment development in schizophrenia: an overview of the first meeting of the cognitive neuroscience treatment research to improve cognition in schizophrenia initiative. Biological Psychiatry 64, 410.CrossRefGoogle ScholarPubMed
Chang, WC, Hui, CL, Tang, JY, Wong, GH, Chan, SK, Lee, EH, Chen, EY (2013). Impacts of duration of untreated psychosis on cognition and negative symptoms in first-episode schizophrenia: a 3-year prospective follow-up study. Psychological Medicine 43, 18831893.CrossRefGoogle ScholarPubMed
Conners, CK (2004). Continuous Performance Test II. Multi-Health Systems: North Tonawanda, NY.Google Scholar
Cornblatt, BA, Erlenmeyer-Kimling, L (1985). Global attentional deviance as a marker of risk for schizophrenia: specificity and predictive validity. Journal of Abnormal Psychology 94, 470486.CrossRefGoogle ScholarPubMed
Cuesta, MJ, Sanchez-Torres, AM, Cabrera, B, Bioque, M, Merchan-Naranjo, J, Corripio, I, Gonzalez-Pinto, A, Lobo, A, Bombin, I, de la Serna, E, Sanjuan, J, Parellada, M, Saiz-Ruiz, J, Bernardo, M, PEPs Group (2015). Premorbid adjustment and clinical correlates of cognitive impairment in first-episode psychosis. The PEPsCog study. Schizophrenia Research 164, 6573.CrossRefGoogle ScholarPubMed
Davidson, M, Reichenberg, A, Rabinowitz, J, Weiser, M, Kaplan, Z, Mark, M (1999). Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. American Journal of Psychiatry 156, 13281335.Google ScholarPubMed
DeRosse, P, Kaplan, A, Burdick, KE, Lencz, T, Malhotra, AK (2010). Cannabis use disorders in schizophrenia: effects on cognition and symptoms. Schizophrenia Research 120, 95100.CrossRefGoogle Scholar
Dickerson, F, Stallings, C, Origoni, A, Boronow, J, Yolken, R (2007). C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophrenia Research 93, 261265.CrossRefGoogle Scholar
Endicott, J, Spitzer, RL, Fleiss, JL, Cohen, J (1976). The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Archives of General Psychiatry 33, 766771.CrossRefGoogle ScholarPubMed
Erlenmeyer-Kimling, L, Rock, D, Roberts, SA, Janal, M, Kestenbaum, C, Cornblatt, B, Adamo, UH, Gottesman II (2000). Attention, memory, and motor skills as childhood predictors of schizophrenia-related psychoses: the New York high-risk project. American Journal of Psychiatry 157, 14161422.CrossRefGoogle ScholarPubMed
Farreras, P, Rozman, C (2012). Esquizofrenia y tratornos relacionados. In Medicina Interna, pp. 14651467. Elsevier: Madrid.Google Scholar
Felger, JC, Lotrich, FE (2013). Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 246, 199229.CrossRefGoogle ScholarPubMed
First, M, Gibbon, M, Spitzer, R, Williams, J (1997). Structured Clinical Interview for DSM-IV Axis II Personality Disorders. American Psychiatric Publishing: Washington, DC.Google Scholar
First, M, Spitzer, R, Gibbon, M, Williams, J (1994). Structured Clinical Interview for DSM-IV Axis I Disorders. American Psychiatric Press: Washington, D.C.Google Scholar
Garcia-Bueno, B, Bioque, M, Mac-Dowell, KS, Barcones, MF, Martinez-Cengotitabengoa, M, Pina-Camacho, L, Rodriguez-Jimenez, R, Saiz, PA, Castro, C, Lafuente, A, Santabarbara, J, Gonzalez-Pinto, A, Parellada, M, Rubio, G, Garcia-Portilla, MP, Mico, JA, Bernardo, M, Leza, JC (2013). Pro/anti-inflammatory dysregulation in patients with first episode of psychosis: toward an integrative inflammatory hypothesis of schizophrenia. Schizophrenia Bulletin 40, 376387.CrossRefGoogle ScholarPubMed
Garcia-Bueno, B, Bioque, M, MacDowell, KS, Santabarbara, J, Martinez-Cengotitabengoa, M, Moreno, C, Saiz, PA, Berrocoso, E, Gasso, P, Fe Barcones, M, Gonzalez-Pinto, A, Parellada, M, Bobes, J, Mico, JA, Bernardo, M, Leza, JC (2014). Pro-/antiinflammatory dysregulation in early psychosis: results from a 1-year follow-up study. International Journal of Neuropsychopharmacology. Published online: 31 October 2014. doi:10.1093/ijnp/pyu037.Google Scholar
Garcia-Bueno, B, Caso, JR, Perez-Nievas, BG, Lorenzo, P, Leza, JC (2007). Effects of peroxisome proliferator-activated receptor gamma agonists on brain glucose and glutamate transporters after stress in rats. Neuropsychopharmacology 32, 12511260.CrossRefGoogle ScholarPubMed
Gardner, DM, Murphy, AL, O'Donnell, H, Centorrino, F, Baldessarini, RJ (2010). International consensus study of antipsychotic dosing. American Journal of Psychiatry 167, 686693.CrossRefGoogle ScholarPubMed
Gimeno, D, Kivimaki, M, Brunner, EJ, Elovainio, M, De Vogli, R, Steptoe, A, Kumari, M, Lowe, GD, Rumley, A, Marmot, MG, Ferrie, JE (2009). Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychological Medicine 39, 413423.CrossRefGoogle ScholarPubMed
Green, MF (1996). What are the functional consequences of neurocognitive deficits in schizophrenia? American Journal of Psychiatry 153, 321330.Google Scholar
Green, MF, Kern, RS, Heaton, RK (2004 a). Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophrenia Research 72, 4151.CrossRefGoogle ScholarPubMed
Green, MF, Nuechterlein, KH, Gold, JM, Barch, DM, Cohen, J, Essock, S, Fenton, WS, Frese, F, Goldberg, TE, Heaton, RK, Keefe, RS, Kern, RS, Kraemer, H, Stover, E, Weinberger, DR, Zalcman, S, Marder, SR (2004 b). Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biological Psychiatry 56, 301307.CrossRefGoogle Scholar
Harvey, PD (2009). When does cognitive decline occur in the period prior to the first episode of schizophrenia? Psychiatry (Edgmont) 6, 1214.Google ScholarPubMed
Heaton, R (1993). Wisconsin Card Sorting Test Manual. Psychological Assessment Resources: Odessa, Florida.Google Scholar
Heinrichs, RW, Zakzanis, KK (1998). Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12, 426445.CrossRefGoogle Scholar
Hollingshead, AB, Redlich, FC (1958). Social class and mental illness: a community study. 1958. American Journal of Public Health 97, 17561757.Google ScholarPubMed
Kapur, S, Phillips, AG, Insel, TR (2012). Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Molecular Psychiatry 17, 11741179.CrossRefGoogle Scholar
Kaufman, J, Birmaher, B, Brent, D, Rao, U, Flynn, C, Moreci, P, Williamson, D, Ryan, N (1997). Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. Journal of the American Academy of Child and Adolescent Psychiatry 36, 980988.CrossRefGoogle ScholarPubMed
Kay, SR, Fiszbein, A, Opler, LA (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261276.CrossRefGoogle Scholar
Keefe, RS, Fenton, WS (2007). How should DSM-V criteria for schizophrenia include cognitive impairment? Schizophrenia Bulletin 33, 912920.CrossRefGoogle ScholarPubMed
Kirkpatrick, B (2009). Schizophrenia as a systemic disease. Schizophrenia Bulletin 35, 381382.CrossRefGoogle ScholarPubMed
Kokkevi, A, Hartgers, C (1995). EuroASI: European adaptation of a multidimensional assessment instrument for drug and alcohol dependence. European Addiction Research 1, 208210.CrossRefGoogle Scholar
Lewandowski, KE, Sperry, SH, Cohen, BM, Ongur, D (2014). Cognitive variability in psychotic disorders: a cross-diagnostic cluster analysis. Psychological Medicine 44, 32393248.CrossRefGoogle ScholarPubMed
Leza, JC, Garcia-Bueno, B, Bioque, M, Arango, C, Parellada, M, Do, K, O'Donnell, P, Bernardo, M (2015). Inflammation in schizophrenia: a question of balance. Neuroscience and Biobehavioral Reviews 55, 612626.CrossRefGoogle Scholar
Liu, SK, Chiu, CH, Chang, CJ, Hwang, TJ, Hwu, HG, Chen, WJ (2002). Deficits in sustained attention in schizophrenia and affective disorders: stable versus state-dependent markers. American Journal of Psychiatry 159, 975982.CrossRefGoogle ScholarPubMed
MacDowell, KS, Garcia-Bueno, B, Madrigal, JL, Parellada, M, Arango, C, Mico, JA, Leza, JC (2013). Risperidone normalizes increased inflammatory parameters and restores anti-inflammatory pathways in a model of neuroinflammation. International Journal of Neuropsychopharmacology 16, 121135.CrossRefGoogle Scholar
Martinez-Cengotitabengoa, M, Mac-Dowell, KS, Leza, JC, Mico, JA, Fernandez, M, Echevarria, E, Sanjuan, J, Elorza, J, Gonzalez-Pinto, A (2012). Cognitive impairment is related to oxidative stress and chemokine levels in first psychotic episodes. Schizophrenia Research 137, 6672.CrossRefGoogle ScholarPubMed
Martinez-Cengotitabengoa, M, Mico, JA, Arango, C, Castro-Fornieles, J, Graell, M, Paya, B, Leza, JC, Zorrilla, I, Parellada, M, Lopez, MP, Baeza, I, Moreno, C, Rapado-Castro, M, Gonzalez-Pinto, A (2014). Basal low antioxidant capacity correlates with cognitive deficits in early onset psychosis. A 2-year follow-up study. Schizophrenia Research 156, 2329.CrossRefGoogle ScholarPubMed
Martinez-Gras, I, Perez-Nievas, BG, Garcia-Bueno, B, Madrigal, JL, Andres-Esteban, E, Rodriguez-Jimenez, R, Hoenicka, J, Palomo, T, Rubio, G, Leza, JC (2011). The anti-inflammatory prostaglandin 15d-PGJ2 and its nuclear receptor PPARgamma are decreased in schizophrenia. Schizophrenia Research 128, 1522.CrossRefGoogle Scholar
Meyer, U, Schwarz, MJ, Muller, N (2011). Inflammatory processes in schizophrenia: a promising neuroimmunological target for the treatment of negative/cognitive symptoms and beyond. Pharmacology and Therapeutics 132, 96110.CrossRefGoogle ScholarPubMed
Miller, BJ, Buckley, P, Seabolt, W, Mellor, A, Kirkpatrick, B (2011). Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biological Psychiatry 70, 663671.CrossRefGoogle ScholarPubMed
Mohamed, S, Paulsen, JS, O'Leary, D, Arndt, S, Andreasen, N (1999). Generalized cognitive deficits in schizophrenia: a study of first-episode patients. Archives of General Psychiatry 56, 749754.CrossRefGoogle ScholarPubMed
Montgomery, SA, Asberg, M (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry 134, 382389.CrossRefGoogle ScholarPubMed
Moss, TG, Sacco, KA, Allen, TM, Weinberger, AH, Vessicchio, JC, George, TP (2009). Prefrontal cognitive dysfunction is associated with tobacco dependence treatment failure in smokers with schizophrenia. Drug and Alcohol Dependence 104, 9499.CrossRefGoogle ScholarPubMed
Muller, N, Riedel, M, Schwarz, MJ, Engel, RR (2005). Clinical effects of COX-2 inhibitors on cognition in schizophrenia. European Archives of Psychiatry and Clinical Neuroscience 255, 149151.CrossRefGoogle ScholarPubMed
Nuechterlein, KH, Barch, DM, Gold, JM, Goldberg, TE, Green, MF, Heaton, RK (2004). Identification of separable cognitive factors in schizophrenia. Schizophrenia Research 72, 2939.CrossRefGoogle Scholar
Penades, R, Garcia-Rizo, C, Bioque, M, Gonzalez-Rodriguez, A, Cabrera, B, Mezquida, G, Bernardo, M (2015). The search for new biomarkers for cognition in schizophrenia. Schizophrenia Research: Cognition 2, 172178.CrossRefGoogle Scholar
Peralta, V, Cuesta, MJ (1994). Psychometric properties of the positive and negative syndrome scale (PANSS) in schizophrenia. Psychiatry Research 53, 3140.CrossRefGoogle Scholar
Ribeiro-Santos, A, Lucio Teixeira, A, Salgado, JV (2014). Evidence for an immune role on cognition in schizophrenia: a systematic review. Current Neuropharmacology 12, 273280.CrossRefGoogle ScholarPubMed
Shaffer, D, Gould, MS, Brasic, J, Ambrosini, P, Fisher, P, Bird, H, Aluwahlia, S (1983). A children's global assessment scale (CGAS). Archives of General Psychiatry 40, 12281231.CrossRefGoogle Scholar
Singh, RB, Gupta, S, Dherange, P, De Meester, F, Wilczynska, A, Alam, SE, Pella, D, Wilson, DW (2012). Metabolic syndrome: a brain disease. Canadian Journal of Physiology and Pharmacology 90, 11711183.CrossRefGoogle ScholarPubMed
Strimbu, K, Tavel, JA (2010). What are biomarkers? Current Opinion in HIV and AIDS 5, 463466.CrossRefGoogle ScholarPubMed
Stubbs, B, Gardner-Sood, P, Smith, S, Ismail, K, Greenwood, K, Farmer, R, Gaughran, F (2015). Sedentary behaviour is associated with elevated C-reactive protein levels in people with psychosis. Schizophrenia Research 168, 461464.CrossRefGoogle ScholarPubMed
Van Os, J, Kapur, S (2009). Schizophrenia. Lancet 374, 635645.CrossRefGoogle ScholarPubMed
Wechsler, D (1997). Wechsler Adult Intelligence Scale – III (WAIS-III) . Psychological Corporation: San Antonio, TX.Google Scholar
Wechsler, D (2003). Wechsler Intelligence Scale for Children – IV (WISC-IV) . The Psychological Corporation: San Antonio, TX.Google Scholar
Young, RC, Biggs, JT, Ziegler, VE, Meyer, DA (1978). A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry 133, 429435.CrossRefGoogle ScholarPubMed
Zajkowska, Z, Mondelli, V (2014). First-episode psychosis: an inflammatory state? Neuroimmunomodulation 21, 102108.CrossRefGoogle Scholar
Zhang, XY, Chen da, C, Xiu, MH, Tang, W, Zhang, F, Liu, L, Chen, Y, Liu, J, Yao, JK, Kosten, TA, Kosten, TR (2013). Plasma total antioxidant status and cognitive impairments in schizophrenia. Schizophrenia Research 139, 6672.CrossRefGoogle Scholar
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