Pro-/anti-inflammatory dysregulation in patients with first episode of psychosis: toward an integrative inflammatory hypothesis of schizophrenia

Abstract

Background: Schizophrenia is a chronic syndrome of unknown etiology, predominantly defined by signs of psychosis. The onset of the disorder occurs typically in late adolescence or early adulthood. Efforts to study pathophysiological mechanisms in early stages of the disease are crucial in order to prompt intervention.

Methods: Case-control study of first-episode psychotic (FEP) patients and matched controls. We recruited 117 patients during the first year after their FEP according to the DSM-IV criteria and recruited 106 gender-, race-, and age-matched controls between September 2010 and June 2011.

Results: Biochemical studies carried out in peripheral mononuclear blood cells (PMBC) and plasma evidence a significant increase in intracellular components of a main proinflammatory pathway, along with a significant decrease in the anti-inflammatory ones. Multivariate logistic regression analyses identified the expression of inducible isoforms of nitric oxide synthase and cyclooxygenase in PMBC and homocysteine plasma levels as the most reliable potential risk factors and the inhibitor of the inflammatory transcription factor NFκB, IκBα, and the anti-inflammatory prostaglandin 15d-PGJ2 as potential protection factors.

Discussion: Taken as a whole, the results of this study indicate robust phenotypical differences at the cellular machinery level in PMBC of patients with FEP. Although more scientific evidence is needed, the determination of multiple components of pro- and anti-inflammatory cellular pathways including the activity of nuclear receptors has interesting potential as biological markers and potential risk/protective factors for FEP. Due to its soluble nature, a notable finding in this study is that the anti-inflammatory mediator 15d-PGJ2 might be used as plasmatic biomarker for first episodes of psychosis.

Keywords: biomarker; first-episode psychosis; inflammatory balance; schizophrenia.

Fig. 3.

Inflammatory dysregulation in peripheral mononuclear blood cells and plasma from patients with FEP. Increase in some intracellular components of the main proinflammatory pathway (in red, straight lines) has been also demonstrated: increase in NFκB transcriptional activity and increase in the expression of 2 of the main inflammatory and oxido/nitrosative inducible enzymes, iNOS and COX-2. On the other hand, a decrease in various components of the anti-inflammatory pathway (in green, dotted lines) has been also demonstrated: decrease in the production of 15d-PGJ₂, decrease in PPARγ transcriptional activity and decrease in the expression of the NFκB inhibitory subunit, IκBα. +: activation; −: inhibition.

Fig. 1.

Mean differences (SD) on biomarkers between FEP and controls (univariate analysis). (a) NFκB activity in PBMC nuclear extracts from FEP patients (n = 53) and controls (n = 35); (b) Western blot analysis of proinflammatory proteins iNOS (patients n = 91, controls, n = 88); (c) COX-2 in PBMC cytosolic extracts from FEP patients (n = 90) and controls (n = 88); and (d) plasma levels of nitrites (NO₂⁻; patients n = 50, controls, n = 61), (e) proinflammatory prostaglandin E₂ (patients n = 111, controls, n = 104), (f) thiobarbituric acid reactive substances (patients n = 105, controls, n = 104), and (g) homocysteine from FEP patients (n = 71) and controls (n = 41). AU, arbitrary units. Two-tailed nonparametric Mann-Whitney U test was used. ° represents an atypical value and * an extreme value.

Fig. 2.

Mean differences (SD) on (a) Western blot analysis of IκBα in PBMC cytosolic extracts (patients n = 91, controls, n = 88); (b) plasma levels of anti-inflammatory prostaglandin 15d-PGJ₂ (patients n = 108, controls, n = 104); (c) Western blot analysis of peroxisome proliferator activated receptor γ (PPARγ; patients n = 14, controls, n = 16); and (d) transcriptional activity of PPARγ (patients n = 78, controls, n = 87) in PBMC nuclear extracts. Two-tailed t test was assessed for PPARγ, and for the rest of variables, two-tailed nonparametric Mann-Whitney U test was used. ° represents an atypical value and * an extreme value.