BDNF and NGF Signalling in Early Phases of Psychosis: Relationship With Inflammation and Response to Antipsychotics After 1 Year

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Abstract

Previous studies have indicated systemic deregulation of the proinflammatory or anti-inflammatory balance in individuals with first-episode psychosis (FEP) that persists 12 months later. To identify potential risk/protective factors and associations with symptom severity, we assessed possible changes in plasma levels of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) and their receptors in peripheral blood mononuclear cells (PBMCs). Expression of the 2 forms of BDNF receptors (active TrkB-FL and inactiveTrkB-T1) in PBMCs of FEP patients changed over time, TrkB-FL expression increasing by 1 year after diagnosis, while TrkB-T1 expression decreased. The TrkB-FL/TrkB-T1 ratio (hereafter FL/T1 ratio) increased during follow-up in the nonaffective psychosis group only, suggesting different underlying pathophysiological mechanisms in subgroups of FEP patients. Further, the expression of the main NGF receptor, TrkA, generally increased in patients at follow-up. After adjusting for potential confounders, baseline levels of inducible isoforms of nitric oxide synthase, cyclooxygenase, and nuclear transcription factor were significantly associated with the FL/T1 ratio, suggesting that more inflammation is associated with higher values of this ratio. Interestingly, the FL/T1 ratio might have a role as a predictor of functioning, a regression model of functioning at 1 year suggesting that the effect of the FL/T1 ratio at baseline on functioning at 1 year depended on whether patients were treated with antipsychotics. These findings may have translational relevance; specifically, it might be useful to assess the expression of TrkB receptor isoforms before initiating antipsychotic treatment in FEPs.

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Most cited references 46

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The positive and negative syndrome scale (PANSS) for schizophrenia.

L Opler, Jennifer Kay, Paul Opler … (1986)

The variable results of positive-negative research with schizophrenics underscore the importance of well-characterized, standardized measurement techniques. We report on the development and initial standardization of the Positive and Negative Syndrome Scale (PANSS) for typological and dimensional assessment. Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology. It thus constitutes four scales measuring positive and negative syndromes, their differential, and general severity of illness. Study of 101 schizophrenics found the four scales to be normally distributed and supported their reliability and stability. Positive and negative scores were inversely correlated once their common association with general psychopathology was extracted, suggesting that they represent mutually exclusive constructs. Review of five studies involving the PANSS provided evidence of its criterion-related validity with antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both typological and dimensional assessment.

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Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects.

Brian Miller, Peter Buckley, Wesley Seabolt … (2011)

Schizophrenia is associated with immune system dysfunction, including aberrant cytokine levels. We performed a meta-analysis of these associations, considering effects of clinical status and antipsychotic treatment following an acute illness exacerbation. We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information and the reference lists of identified studies. Forty studies met the inclusion criteria. Effect sizes were similar for studies of acutely relapsed inpatients (AR) and first-episode psychosis (FEP). Interleukin (IL)-1β, IL-6, and transforming growth factor-β (TGF-β) appeared to be state markers, as they were increased in AR and FEP (p < .001 for each) and normalized with antipsychotic treatment (p < .001, p = .008, and p = .005, respectively). In contrast, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble IL-2 receptor (sIL-2R) appeared to be trait markers, as levels remained elevated in acute exacerbations and following antipsychotic treatment. There was no difference in IL-6 levels between stable medicated outpatients and control subjects (p = .69). In the cerebrospinal fluid, IL-1β was significantly decreased in schizophrenia versus controls (p = .01). Similar effect sizes in AR and FEP suggest that the association between cytokine abnormalities and acute exacerbations of schizophrenia is independent of antipsychotic medications. While some cytokines (IL-1β, IL-6, and TGF-β) may be state markers for acute exacerbations, others (IL-12, IFN-γ, TNF-α, and sIL-2R) may be trait markers. Although these results could provide the basis for future hypothesis testing, most studies did not control for potential confounding factors such as body mass index and smoking. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis.

Robert S. Green, John A. Shepherd, S Matheson … (2011)

Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Several studies report reduced peripheral (blood) levels of BDNF in schizophrenia, but findings are inconsistent. We undertook the first systematic review with meta-analysis of studies examining blood BDNF levels in schizophrenia compared with healthy controls, and examined potential effects of age, gender and medication. Included are individual studies of BDNF blood (serum or plasma) levels in schizophrenia (including schizoaffective disorder, or first episode psychosis), compared with age-matched healthy controls, obtained by electronic Medline and Embase searches, and hand searching. The decision to include or exclude studies, data extraction and quality assessment were completed by two independent reviewers. The initial search revealed 378 records, of which 342 were excluded on reading the Abstract, because they did not examine BDNF blood levels in schizophrenia compared with healthy controls. Of 36 papers screened in full, 17 were eligible for inclusion, but one was subsequently removed as an outlier. The remaining 16 studies provided moderate quality evidence of reduced blood BDNF levels in schizophrenia (Hedges g=-0.458, 95% confidence interval=-0.770 to -0.146, P<0.004, random effects model). Subgroup analyses reveal reduced BDNF in both drug-naïve and medicated patients, and in males and females with schizophrenia. Meta-regressions showed an association between reduced BDNF in schizophrenia and increasing age, but no effects of medication dosage. Overall, blood levels of BDNF are reduced in medicated and drug-naïve patients with schizophrenia; this evidence is of moderate quality, that is, precise but with considerable, unexplained heterogeneity across study results.

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Author and article information

Journal

Journal ID (nlm-ta): Schizophr Bull

Journal ID (iso-abbrev): Schizophr Bull

Journal ID (hwp): schbul

Journal ID (publisher-id): schbul

Title: Schizophrenia Bulletin

Publisher: Oxford University Press (US )

ISSN (Print): 0586-7614

ISSN (Electronic): 1745-1701

Publication date (Print): January 2016

Publication date (Electronic): 30 June 2015

Publication date PMC-release: 30 June 2015

Volume: 42

Issue: 1

Pages: 142-151

Affiliations

¹Araba University Hospital, Bioaraba Research Institute , Vitoria, Spain;

²Biomedical Research Networking Centre in Mental Health (CIBERSAM) , Madrid, Spain;

³National Distance Education University (UNED) , Vitoria, Spain;

⁴Department of Pharmacology, Faculty of Medicine, Universidad Complutense de Madrid, & Research Institute of Hospital 12 de Octubre (i+12) , Madrid, Spain;

⁵Department of Biostatistics, The University of Kansas Medical Center , Kansas City, KS;

⁶Research Institute of Hospital 12 de Octubre (i+12) , Madrid, Spain;

⁷Barcelona Clínic Schizophrenia Unit, Neuroscience Institute, Hospital Clínic de Barcelona , Spain;

⁸Department of Psychiatry and Clinical Psychobiology, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) , Barcelona, Spain;

⁹Department of Psychology, Psychobiology Area, Group of Research in Neuropsychopharmacology and Psychobiology (CTS-510), University of Cádiz , Spain;

¹⁰Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón School of Medicine, Universidad Complutense, IiSGM , Madrid, Spain;

¹¹Department of Psychiatry, Instituto de Investigación Sanitaria Aragón and University of Zaragoza , Spain;

¹²Department of Psychiatry, Faculty of Medicine, University of Oviedo. Instituto Universitario de Neurociencias del Principado de Asturias (INEUROPA) , Oviedo, Spain;

¹³University of the Basque Country (UPV-EHU) , Bilbao, Spain;

¹⁴CIBERNED Neuroscience , Zamudio, Vizcaya, Spain

¹⁵These authors have contributed equally to the article.

Author notes

*To whom correspondence should be addressed; Department of Psychiatry, Araba University Hospital, Olaguibel Street 29, 01004, Vitoria, Spain; tel: + 34 945007764, fax: + 34 945007764, e-mail: monica.martinezcengotitabengoa@ 123456osakidetza.net

†FLAMM-PEPs is a multicentre, collaborative, and translational group in CIBERSAM focusing on research into inflammatory pathways in psychosis, both as possible biomarkers and as possible new therapeutic targets, conducted as part of the PEPs study, a Spanish research project on first-episode psychosis.

Article

DOI: 10.1093/schbul/sbv078

PMC ID: 4681544

PubMed ID: 26130821

SO-VID: d6456d0d-9a53-4943-bb53-b0a55008ba4a

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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

BDNF and NGF Signalling in Early Phases of Psychosis: Relationship With Inflammation and Response to Antipsychotics After 1 Year

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Most cited references 46

The positive and negative syndrome scale (PANSS) for schizophrenia.

Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects.

Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis.

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