Gene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving AKT1 that are corrected by antipsychotic medication

Abstract

Distinct gene expression profiles can be detected in peripheral blood mononuclear cells (PBMCs) in patients with schizophrenia; however, little is known about the effects of antipsychotic medication. This study compared gene expression profiles in PMBCs from treatment-naive patients with schizophrenia before and after antipsychotic drug treatment. PBMCs were obtained from 10 treatment-naive schizophrenia patients before and 6 wk after initiating antipsychotic drug treatment and compared to PMBCs collected from 11 healthy community volunteers. Genome-wide expression profiling was conducted using Illumina HumanHT-12 expression bead arrays and analysed using significance analysis of microarrays. This analysis identified 624 genes with altered expression (208 up-regulated, 416 down-regulated) prior to antipsychotic treatment (p < 0.05) including schizophrenia-associated genes AKT1, DISC1 and DGCR6. After 6-8 wk treatment of patients with risperidone or risperidone in combination with haloperidol, only 106 genes were altered, suggesting that the treatment corrected the expression of a large proportion of genes back to control levels. However, 67 genes continued to show the same directional change in expression after treatment. Ingenuity® pathway analysis and gene set enrichment analysis implicated dysregulation of biological functions and pathways related to inflammation and immunity in patients with schizophrenia. A number of the top canonical pathways dysregulated in treatment-naive patients signal through AKT1 that was up-regulated. After treatment, AKT1 returned to control levels and less dysregulation of these canonical pathways was observed. This study supports immune dysfunction and pathways involving AKT1 in the aetiopathophysiology of schizophrenia and their response to antipsychotic medication.

Increased white matter neuron density in a rat model of maternal immune activation — Implications for schizophrenia

“…Epidemiological evidence also suggests that infection during pregnancy increases the risk of offspring developing schizophrenia (Fillman et al, 2013;Gardiner et al, 2013;Kumarasinghe et al, 2013). Here we show that mimicking immune activation caused by a viral infection with a single injection of PolyI:C during late pregnancy in rats increased the density of IWMNs particularly those that contain SST, in the corpus callosum of adult offspring.…”

“…Several studies have shown people with schizophrenia have an underlying immune signature Kumarasinghe et al, 2013), with observations of increased expression of pro-inflammatory genes such as IL-6 in the prefrontal cortex (Fillman et al, 2013). In addition, higher cortical IL-6 expression (i.e.…”

“…Indeed, there is a growing body of evidence supporting changes in the expression of genes involved in the immune system and inflammation in the blood and brains of people with schizophrenia (Fillman et al, 2013;Gardiner et al, 2013;Kumarasinghe et al, 2013). In addition, epidemiological studies suggest prenatal exposure to infectious agents including viral pathogens (e.g.…”

Matrix Metalloproteinase-9 as a Novel Player in Synaptic Plasticity and Schizophrenia: Table 1.

“…A significantly higher frequency of positive MMP-9 activity in blood was found in schizophrenia patients compared with healthy controls. Another unbiased study demonstrated the possible involvement of MMP-9 in schizophrenia 55 and compared gene expression profiles in peripheral blood mononuclear cells between healthy individuals and treatment-naive schizophrenia patients before and 6 weeks after initiating pharmacological treatment. Notably, among the selected genes, MMP-9 mRNA was the most markedly upregulated in peripheral blood mononuclear cells in treatment-naive schizophrenia patients compared with controls, with a marked downregulation following treatment.…”

Alleviation of haloperidol induced oxidative stress in rats: Effects of sucrose vs grape seed extract

“…Previous research has also shown that coadministration of haloperidol and antioxidants such as vitamin E resulted in a beneficial effect in patients with tardive dyskinesia. 18 The aim of the present study was to investigate the effect of sucrose (as a source of energy) and grape seed extract (as a potent antioxidant) on the oxidative stress induced in rats by HP in both the liver and the brain. Oxidative stress was induced by injection of HP for 14 consecutive days which was concurrently administered with sucrose and GSE.…”