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Differences in the regulation of inflammatory pathways in adolescent- and adult-onset first-episode psychosis

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Abstract

A precise description of the inflammatory response in first-episode psychosis (FEP) by age of onset does not exist. We explored baseline and 6-month follow-up differences in the pro/anti-inflammatory balance in plasma and peripheral blood mononuclear cells in adolescent-onset FEP (≤ 18 y.o., N = 27) and adult-onset FEP (≥ 25 y.o., N = 43) using non-parametric 1-category ANCOVA, with age group as an independent variable and values of pro- and anti-inflammatory markers at baseline and at follow-up as dependent variables. We used a non-parametric repeated-measures mixed-effects model to explore the baseline/6-month change in pro- and anti-inflammatory markers within adolescent- and adult-onset groups, exploring differential trajectories of change by means of the interaction of time by age-of-onset group. Levels of the nuclear transcription factor (NFκB), a master regulator of the inflammatory and oxido/nitrosative status of cells, were higher in adolescent-onset FEP both at baseline and after 6 months. During follow-up, we found further increases in levels of soluble inflammatory markers (PGE2 and NO2−) only in adolescent-onset FEP. In contrast, in adult-onset FEP, the expression of inducible NO synthase (iNOS), which is also pro-inflammatory, tended to decrease, with no further increase in other pro-inflammatory markers. Significant differences in the direction of change by age-of-onset cohort exist only for NFκB (F = 4.165, df = 2, 70.95, p = 0.019). Our results support the existence of changes in the pro/anti-inflammatory balance in FEP depending on the neurodevelopmental stage at illness onset. These results also suggest that inflammation may be a potential therapeutic target in adolescent-onset FEP.

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Acknowledgements

Supported by CIBERSAM Intramural Projects 2010 (P02): Flamm-PEPs, Inflammatory alterations in schizophrenia: search of biological markers in first-psychotic episodes; the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (PI08/0208, PI 11/00325, PI12/01303, PI14/02069, PI17/02227); co-financed by ERDF Funds from the European Commission, “A way of making Europe”, CIBERSAM; Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds and European Union Seventh Framework Program under grant agreements FP7-HEALTH-2009-2.2.1-2-241909 (Project EU-GEI), FP7-HEALTH-2009-2.2.1-3-242114 (Project OPTiMISE), FP7-HEALTH-2013-2.2.1-2-603196 (Project PSYSCAN) and FP7- HEALTH-2013-2.2.1-2-602478 (Project METSY); the Government of Catalonia, Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2014SGR441); Fundación Alicia Koplowitz, Fundación Familia Alonso, and Fundación Mutua Madrileña. This work was developed (in part) at the Centro Esther Koplowitz (Barcelona).

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Authors and Affiliations

  1. Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense (UCM), IiSGM, Madrid, Spain

    C. Moreno & M. Parellada

  2. Department of Pharmacology and Toxicology, Faculty of Medicine, UCM, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), IUINQ, Madrid, Spain

    K. S. MacDowell, B. García-Bueno & J. C. Leza

  3. Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, Barcelona, Spain

    B. Cabrera & M. Bernardo

  4. Hospital Universitario, Alava, EHU/UPV, BIOARABA, Vitoria, Spain

    A. González-Pinto

  5. Department of Psychiatry, Faculty of Medicine, University of Oviedo, Oviedo, Spain

    P. Saiz

  6. Department of Psychiatry, Instituto de Investigación Sanitaria Aragón, University of Zaragoza, Zaragoza, Spain

    A. Lobo

  7. Department of Psychiatry, Instituto de Investigación Hospital, 12 de Octubre (i+12), Madrid, Spain

    R. Rodriguez-Jimenez

  8. CogPsy-Group, Universidad Complutense de Madrid (UCM), Madrid, Spain

    R. Rodriguez-Jimenez

  9. Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, University of Cádiz, Cádiz, Spain

    E. Berrocoso

  10. Institut D’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain

    M. Bernardo

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From the FLAMM-PEPs study, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)

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Conflict of interest

C Moreno reports grants from European Union Funds, Instituto de Salud Carlos III Spanish Ministry of Economy and Competitiveness, and consultancy for Janssen, Servier, Nuvelution, Otsuka and Lundbeck unrelated to the submitted work; M Parellada reports grants from Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, during the conduct of the study; grants from CIBERSAM, grants from Fundación Alicia Koplowitz, Horizon 2020 and consultancy for Servier, unrelated to the submitted work; A Gonzalez-Pinto has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Janssen-Cilag, Lundbeck, Merck, Otsuka, Pfizer, Sanofi-Aventis, Servier, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), the Basque Governement, the Stanley Medical Research Institute, and Wyeth.; P Saiz has been a consultant to or has received honoraria or grants from Adamed, AstraZeneca, Brainpharma, Bristol-Myers Squibb, CIBERSAM, Esteve, European Comission, Ferrer inCode, GlaxoSmithKline, Instituto de Salud Carlos III, Janssen-Cilag, Lilly, Lundbeck, Otsuka, Pfizer, Plan Nacional Sobre Drogas, Rovi and Servier.; A Lobo reports personal fees from Lundbeck, personal fees from Lilly, unrelated to the submitted work; R Rodriguez-Jimenez has been a consultant for, spoken at activities of, or received  grants from: Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/ BMD-2422 AGES), Janssen Cilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste; M Bernardo has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Almirall, AMGEN, Boehringer, Eli Lilly, Ferrer, Forum Pharmaceuticals, Gedeon, Hersill, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Roche, Servier and has obtained research funding from the Spanish Ministry of Health, the Spanish Ministry of Science and Education, the Spanish Ministry of Economy and Competiveness, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), by the Government of Catalonia, Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and the 7th Framework Program of the European Union. The remaining authors have nothing to disclose apart from grants from National or Regional public scientific agencies.

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FLAMM-PEPs is a multicentre, collaborative and translational research group within CIBERSAM whose aim is to study inflammatory pathways in psychosis, both as possible biomarkers and as possible new therapeutic targets. FLAMM-PEPs is now part of the PEPs study, a Spanish project for research into first-episode psychosis.

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Moreno, C., Parellada, M., MacDowell, K.S. et al. Differences in the regulation of inflammatory pathways in adolescent- and adult-onset first-episode psychosis. Eur Child Adolesc Psychiatry 28, 1395–1405 (2019). https://doi.org/10.1007/s00787-019-01295-8

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