transforming-growth-factor-beta and Psychotic-Disorders

Immune parameters are elevated in psychosis, but it is unclear whether alterations are homogenous across patients or heterogeneity exists, consistent with the hypothesis that immune alterations are specific to a subgroup of patients. To address this, we examine whether antipsychotic-naïve first-episode psychosis patients exhibit greater variability in blood cytokines, C-reactive protein, and white cell counts compared with controls, and if group mean differences persist after adjusting for skewed data and potential confounds. Databases were searched for studies reporting levels of peripheral immune parameters. Means and variances were extracted and analyzed using multivariate meta-analysis of mean and variability of differences. Outcomes were (1) variability in patients relative to controls, indexed by variability ratio (VR) and coefficient of variation ratio (CVR); (2) mean differences indexed by Hedges g; (3) Modal distribution of raw immune parameter data using Hartigan's unimodality dip test. Thirty-five studies reporting on 1263 patients and 1470 controls were included. Variability of interleukin-6 (IL6) (VR = 0.19), tumor necrosis factor-α (TNFα) (VR = 0.36), interleukin-1β (VR = 0.35), interleukin-4 (VR = 0.55), and interleukin-8 (VR = 0.28) was reduced in patients. Results persisted for IL6 and IL8 after mean-scaling. Ninety-four percent and one hundred percent of raw data were unimodally distributed in psychosis and controls, respectively. Mean levels of IL6 (g = 0.62), TNFα (g = 0.56), interferon-γ (IFNγ) (g = 0.32), transforming growth factor-β (g = 0.53), and interleukin-17 (IL17) (g = 0.48) were elevated in psychosis. Sensitivity analyses indicated this is unlikely explained by confounders for IL6, IFNγ, and IL17. These findings show elevated cytokines in psychosis after accounting for confounds, and that the hypothesis of an immune subgroup is not supported by the variability or modal distribution.

Topics: C-Reactive Protein; Case-Control Studies; Cytokines; Humans; Interferon-gamma; Interleukin-17; Interleukin-1beta; Interleukin-4; Interleukin-6; Interleukin-8; Leukocyte Count; Lymphocyte Count; Models, Statistical; Prodromal Symptoms; Psychotic Disorders; Schizophrenia; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Although the loss of brain laterality is one of the most consistent modalities in schizophrenia (SCZ) and bipolar disorder (BD), its molecular basis remains elusive. Our limited previous studies indicated that epigenetic modifications are key to the asymmetric transcriptomes of brain hemispheres. We used whole-genome expression microarrays to profile postmortem brain samples from subjects with SCZ, psychotic BD [BD[+]] or non-psychotic BD [BD(-)], or matched controls (10/group) and performed whole-genome DNA methylation (DNAM) profiling of the same samples (3-4/group) to identify pathways associated with SCZ or BD[+] and genes/sites susceptible to epigenetic regulation. qRT-PCR and quantitative DNAM analysis were employed to validate findings in larger sample sets (35/group). Gene Set Enrichment Analysis (GSEA) demonstrated that BMP signaling and astrocyte and cerebral cortex development are significantly (FDR q < 0.25) coordinately upregulated in both SCZ and BD[+], and glutamate signaling and TGFβ signaling are significantly coordinately upregulated in SCZ. GSEA also indicated that collagens are downregulated in right versus left brain of controls, but not in SCZ or BD[+] patients. Ingenuity Pathway Analysis predicted that TGFB2 is an upstream regulator of these genes (p = .0012). While lateralized expression of TGFB2 in controls (p = .017) is associated with a corresponding change in DNAM (p ≤ .023), lateralized expression and DNAM of TGFB2 are absent in SCZ or BD. Loss of brain laterality in SCZ and BD corresponds to aberrant epigenetic regulation of TGFB2 and changes in TGFβ signaling, indicating potential avenues for disease prevention/treatment.

Topics: Adult; Autopsy; Bipolar Disorder; Brain; DNA Methylation; Epigenesis, Genetic; Epigenome; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Promoter Regions, Genetic; Psychotic Disorders; Schizophrenia; Signal Transduction; Transcriptome; Transforming Growth Factor beta; Whole Genome Sequencing

The aim of this study was to look into the balance of pro-inflammatory (TNF-α, IL-6) and anti-inflammatory (TGF-β) cytokines and their association with stress, alterations in HPA axis activity and the disease severity in acute psychosis. Socio-demographic and clinical details were collected from 41 in-patients with a diagnosis of Acute and Transient Psychotic Disorder. Holmes and Rahe Stress Scale for stress in the preceding year, and Brief Psychiatric Rating Scale at baseline and follow up (4-12 weeks) for psychopathology were applied. IL-6, TNF-α (pro-inflammatory), TGF-β (anti-inflammatory) and Cortisol (morning and afternoon values) were measured at baseline and follow up. A total of 30 out of 41 cases recruited had follow up data available. The levels of IL-6 (p<0.001), TNF-α (p<0.001) and TGF-β (p<0.001) at baseline were all found to be significantly elevated compared to 42 age and gender matched healthy controls. There was a significant increase in the levels of TNF-α (p=0.020) and morning levels of cortisol (p=0.009) and a significant decrease in the levels of TGF-β (p=0.004) and afternoon levels of cortisol (p=0.043) from baseline to follow up. This study showed that there was an increased level of both pro and anti-inflammatory cytokines at baseline and a prolonged pro - inflammatory compared to anti - inflammatory response which warrants larger prospective studies and comparative studies to patients with schizophrenia and bipolar disorders.

Topics: Acute Disease; Adolescent; Adult; Female; Follow-Up Studies; Humans; Hydrocortisone; Inpatients; Interleukin-6; Male; Middle Aged; Pilot Projects; Psychotic Disorders; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Young Adult