Article

Inflammatory gene expression in monocytes of patients with schizophrenia: Overlap and difference with bipolar disorder. A study in naturalistically treated patients

Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
The International Journal of Neuropsychopharmacology (Impact Factor: 5.26). 11/2010; 13(10):1369-81. DOI: 10.1017/S1461145710000799
Source: PubMed

ABSTRACT Accumulating evidence indicates an activated inflammatory response system as a vulnerability factor for schizophrenia (SZ) and bipolar disorder (BD). We aimed to detect a specific inflammatory monocyte gene expression signature in SZ and compare such signature with our recently described inflammatory monocyte gene signature in BD. A quantitative-polymerase chain reaction (Q-PCR) case-control gene expression study was performed on monocytes of 27 SZ patients and compared to outcomes collected in 56 BD patients (all patients naturalistically treated). For Q-PCR we used nine 'SZ specific genes' (found in whole genome analysis), the 19 BD signature genes (previously found by us) and six recently described autoimmune diabetes inflammatory monocyte genes. Monocytes of SZ patients had (similar to those of BD patients) a high inflammatory set point composed of three subsets of strongly correlating genes characterized by different sets of transcription/MAPK regulating factors. Subset 1A, characterized by ATF3 and DUSP2, and subset 1B, characterized by EGR3 and MXD1, were shared between BD and SZ patients (up-regulated in 67% and 51%, and 34% and 41%, respectively). Subset 2, characterized by PTPN7 and NAB2 was up-regulated in the monocytes of 62% BD, but down-regulated in the monocytes of 48% of SZ patients. Our approach shows that monocytes of SZ and BD patients overlap, but also differ in inflammatory gene expression. Our approach opens new avenues for nosological classifications of psychoses based on the inflammatory state of patients, enabling selection of those patients who might benefit from an anti-inflammatory treatment.

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    • "Others have noted the small difference in the molecular profiles of BD and SZ and the concordant expression level of genes in both diseases in relation to control (Zhao et al., 2014). A comparison of inflammatory monocyte gene expression profiles revealed three subsets of strongly correlating genes characterized by different sets of transcription/MAPK regulating factors, with only one subset showing a different profile: up-regulated in the monocytes of BD but down-regulated in SZ (Drexhage et al., 2010). "
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    ABSTRACT: Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric conditions with a neurodevelopmental component. Genetic findings indicate the existence of an overlap in genetic susceptibility across the disorders. Also, image studies provide evidence for a shared neurobiological basis, contributing to a dimensional diagnostic approach. This study aimed to identify the molecular mechanisms that differentiate SZ and BD patients from health controls but also that distinguish both from health individuals. Comparison of gene expression profiling in post-mortem brains of both disorders and health controls (30 cases), followed by a further comparison between 29 BD and 29 SZ revealed 28 differentially expressed genes. These genes were used in co-expression analysesthat revealed the pairs CCR1/SERPINA1, CCR5/HCST, C1QA/CD68, CCR5/S100A11 and SERPINA1/TLR1 as presenting the most significant difference in co-expression between SZ and BD. Next, a protein-protein interaction (PPI) network using the 28 differentially expressed genes as seeds revealed CASP4, TYROBP, CCR1, SERPINA1, CCR5 and C1QA as having a central role in the diseases manifestation. Both co-expression and network topological analyses pointed to genes related to microglia functions. Based on this data, we suggest that differences between SZ and BP are due to genes involved with response to stimulus, defense response, immune system process and response to stress biological processes, all having a role in the communication of environmental factors to the cells and associated to microglia. Copyright © 2014 Elsevier B.V. All rights reserved.
    Schizophrenia Research 12/2014; 161(2-3). DOI:10.1016/j.schres.2014.10.055 · 4.43 Impact Factor
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    • "Table 1). As there is evidence from previous studies (Drexhage et al., 2010; Carvalho et al., 2014) that the included genes form two interrelated clusters, we additionally calculated two separate supplemental gene scores comprising distinct sets of genes: subcluster 1, consisting primarily of pro-inflammatory mediators (ATF3, BCL2A1, CCL20, CXCL2, DUSP2, EREG, IL-1B, IL-6, PDE4B, PTGS2, PTX3, TNF, TNFAIP3) and subcluster 2, consisting of chemotaxis, adhesion, and motility gens (CCL2, CCL7, CDC42, DHRS3, EMP1, MAPK6, NAB2, PTPN7, STX1A). "
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    ABSTRACT: Increased inflammatory activation might only be present in a subgroup of depressed individuals in which immune processes are especially relevant to disease development. We aimed to analyze demographic, depression, and trauma characteristics of major depressive disorder (MDD) patients with regard to inflammatory monocyte gene expression. Fifty-six naturalistically treated MDD patients (32 ±12 years) and 57 healthy controls (HC; 31 ±11 years) were analyzed by the Inventory of Depressive Symptomatology (IDS) and by the Childhood Trauma Questionnaire (CTQ). We determined the expression of 38 inflammatory and immune activation genes including the glucocorticoid receptor (GR)α and GRβ genes in purified CD14(+) monocytes using quantitative-polymerase chain reaction (RT-qPCR). Monocyte gene expression was age-dependent, particularly in MDD patients. Increased monocyte gene expression and decreased GRα/β ratio were only present in MDD patients aged ⩾28 years. Post hoc analyses of monocyte immune activation in patients <28 years showed two subgroups: a subgroup with a severe course of depression (recurrent type, onset <15 years) - additionally characterized by panic/arousal symptoms and childhood trauma - that had a monocyte gene expression similar to HC, and a second subgroup with a milder course of the disorder (73% first episode depression, onset ⩾15 years) - additionally characterized by the absence of panic symptoms - that exhibited a strongly reduced inflammatory monocyte activation compared to HC. In conclusion, monocyte immune activation was not uniformly raised in MDD patients but was increased only in patients of 28 years and older.
    Brain Behavior and Immunity 08/2014; 44. DOI:10.1016/j.bbi.2014.08.004 · 6.13 Impact Factor
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    • "Several studies have suggested a role of the mononuclear phagocyte system in the pathophysiology of psychiatric disorders (Drexhage et al., 2010; Drexhage et al., 2011). For example , changes in inflammatory gene expression patterns were observed in monocytes of 60% of recent onset patients with schizophrenia (Drexhage et al., 2010). Blood cells from schizophrenia patients show abnormalities not only in numbers, but also in function, such as altered responses to mitogenic stimulation (Craddock et al., 2007) and in association with smoking (Herberth et al., 2010). "
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    ABSTRACT: Schizophrenia is a heterogeneous psychiatric disorder with a broad spectrum of clinical and biological manifestations. Due to the lack of objective tests, the accurate diagnosis and selection of effective treatments for schizophrenia remains challenging. Numerous technologies have been employed in search of schizophrenia biomarkers. These studies have suggested that neuroinflammatory processes may play a role in schizophrenia pathogenesis, at least in a subgroup of patients. The evidence indicates alterations in both pro- and anti-inflammatory molecules in the central nervous system, which have also been found in peripheral tissues and may correlate with schizophrenia symptoms. In line with these findings, certain immunomodulatory interventions have shown beneficial effects on psychotic symptoms in schizophrenia patients, in particular those with distinct immune signatures. In this review, we evaluate these findings and their potential for more targeted drug interventions and the development of companion diagnostics. Although currently no validated markers exist for schizophrenia patient stratification or the prediction of treatment efficacy, we propose that utilisation of inflammatory markers for diagnostic and theranostic purposes may lead to novel therapeutic approaches and deliver more effective care for schizophrenia patients.
    Schizophrenia Research 08/2014; DOI:10.1016/j.schres.2014.07.025 · 4.43 Impact Factor
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