Neurodevelopmental pathogenesis of schizophrenia might be mediated by abnormalities in Insulin-like Growth Factor-1 (IGF-1). Developmental disturbances like obstetric complications, by themselves, as well as through the resultant hypercortisolemia due to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, can lead to deficient IGF-1 level. The relevance of IGF-1-Cortisol interactions in schizophrenia, especially in the context of antipsychotic treatment, is yet to be explored. In this study, thirty-three antipsychotic-naïve schizophrenia patients (13-men) were examined for serum IGF-1 and cortisol levels at baseline and after 3months of antipsychotic treatment. For baseline analyses, the patients were compared with 33 healthy controls matched for age, sex, socio-economic status, and physical activity. Symptoms were assessed using Scale for Assessment of Positive Symptoms (SAPS) and Scale for Assessment of Negative Symptoms (SANS). At baseline, schizophrenia patients had significantly lower levels of IGF-1 [t=4.6; p<0.0001] and higher levels of cortisol [t=3.9; p=0.0002] in comparison with healthy controls. Following treatment, IGF-1 level increased significantly [t=4.5; p<0.0001] whereas cortisol decreased significantly [t=2.5; p=0.02] in patients. There was a significant positive correlation between magnitude of increase in IGF-1 level and the magnitude of reduction in cortisol level [r=0.52; p=0.002]. Also, the greater the increase in IGF-1 the greater was the reduction in SAPS score [r=0.39; p=0.02]. Our study findings demonstrate that antipsychotic treatment can result in significant elevation of serum IGF-1 possibly mediated by reduction in cortisol levels. These observations suggest a possible link between HPA axis abnormalities and IGF-1 deficits in the neurodevelopmental pathogenesis of schizophrenia.
"Where studies were suspected to have duplicate or overlapping samples (Ritsner et al., 2004, 2007; Venkatasubramanian Figure 1 Flow diagram showing the flow of information through the different phases of this meta-analysis. et al., 2007, 2010), authors were contacted to clarify, resulting in the exclusion Venkatasubramanian et al. (2007) for all but one analysis (schizophrenia medication naïve subgroup analysis) owing to overlap with the later study by the same author (Venkatasubramanian et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Increased peripheral levels of morning cortisol have been reported in people with schizophrenia (SZ) and bipolar disorder (BD), but findings are inconsistent and few studies have conducted direct comparisons of these disorders. We undertook a meta-analysis of studies examining single measures of morning cortisol (before 10 a.m.) levels in SZ or BD, compared to controls, and to each other; we also sought to examine likely moderators of any observed effects by clinical and demographic variables. Included studies were obtained via systematic searches conducted using Medline, BIOSIS Previews and Embase databases, as well as hand searching. The decision to include or exclude studies, data extraction and quality assessment was completed in duplicate by LG, SM and AS. The initial search revealed 1459 records. Subsequently, 914 were excluded on reading the abstract because they did not meet one or more of the inclusion criteria; of the remaining 545 studies screened in full, included studies were 44 comparing SZ with controls, 19 comparing BD with controls, and 7 studies directly comparing schizophrenia with bipolar disorder. Meta-analysis of SZ (N=2613, g=0.387, p=0.001) and BD (N=704, g=0.269, p=0.004) revealed moderate quality evidence of increased morning cortisol levels in each group compared to controls, but no difference between the two disorders (N=392, g=0.038, p=0.738). Subgroup analyses revealed greater effect sizes for schizophrenia samples with an established diagnosis (as opposed to 'first-episode'), those that were free of medication, and those sampled in an inpatient setting (perhaps reflecting an acute illness phase). In BD, greater morning cortisol levels were found in outpatient and non-manic participants (as opposed to those in a manic state), relative to controls. Neither age nor sex affected cortisol levels in any group. However, earlier greater increases in SZ morning cortisol were evident in samples taken before 8 a.m. (relative to those taken after 8 a.m.). Multiple meta-regression showed that medication status was significantly associated with morning cortisol levels in SZ, when the effects of assay method, sampling time and illness stage were held constant. Heightened levels of morning cortisol in SZ and BD suggest long-term pathology of the hypothalamic-pituitary-adrenal (HPA) axis that may reflect a shared process of illness development in line with current stress-vulnerability models.
"At the circulatory level, IGF-I promotes cell differentiation and growth and may also function as an anti-apoptotic agent . Lower levels of IGF-1 have been found in serum of antipsychotic-naive  and antipsychotic-treated SZ patients , as well as in children with ASD [69-71]. A recent study reported a relationship between negative symptoms and IGF-1 plasma levels in first episode SZ . "
[Show abstract][Hide abstract] ABSTRACT: Background
Over the last decade, the transgenic N-methyl-D-aspartate receptor (NMDAR) NR1-knockdown mouse (NR1neo−/−) has been investigated as a glutamate hypofunction model for schizophrenia. Recent research has now revealed that the model also recapitulates cognitive and negative symptoms in the continuum of other psychiatric diseases, particularly autism spectrum disorders (ASD). As previous studies have mostly focussed on behavioural readouts, a molecular characterisation of this model will help to identify novel biomarkers or potential drug targets.
Here, we have used multiplex immunoassay analyses to investigate peripheral analyte alterations in serum of NR1neo−/− mice, as well as a combination of shotgun label-free liquid chromatography mass spectrometry, bioinformatic pathway analyses, and a shotgun-based 40-plex selected reaction monitoring (SRM) assay to investigate altered molecular pathways in the frontal cortex and hippocampus. All findings were cross compared to identify translatable findings between the brain and periphery.
Multiplex immunoassay profiling led to identification of 29 analytes that were significantly altered in sera of NR1neo−/− mice. The highest magnitude changes were found for neurotrophic factors (VEGFA, EGF, IGF-1), apolipoprotein A1, and fibrinogen. We also found decreased levels of several chemokines. Following this, LC-MSE profiling led to identification of 48 significantly changed proteins in the frontal cortex and 41 in the hippocampus. In particular, MARCS, the mitochondrial pyruvate kinase, and CamKII-alpha were affected. Based on the combination of protein set enrichment and bioinformatic pathway analysis, we designed orthogonal SRM-assays which validated the abnormalities of proteins involved in synaptic long-term potentiation, myelination, and the ERK-signalling pathway in both brain regions. In contrast, increased levels of proteins involved in neurotransmitter metabolism and release were found only in the frontal cortex and abnormalities of proteins involved in the purinergic system were found exclusively in the hippocampus.
Taken together, this multi-platform profiling study has identified peripheral changes which are potentially linked to central alterations in synaptic plasticity and neuronal function associated with NMDAR-NR1 hypofunction. Therefore, the reported proteomic changes may be useful as translational biomarkers in human and rodent model drug discovery efforts.
"The present study has several limitations. First, we were not able to measure laboratory factors closely associated with IGF-1, such as insulin, cortisol, growth hormone, inflammatory markers (Venkatasubramanian et al., 2010), and IGFBPs. An assessment of the relationships between these and the neurotrophic factors would provide a more comprehensive understanding of the pathophysiology of bipolar disorder. "
[Show abstract][Hide abstract] ABSTRACT: Neurotrophic factors exert substantial effects on the central nervous system. The present study investigates the roles of insulin-like growth factor-1 (IGF-1), β-nerve growth factor (β-NGF), and brain-derived neurotrophic factor (BDNF) in bipolar disorder.
Baseline levels of culture-stimulated IGF-1, β-NGF, and BDNF were compared in 116 patients with bipolar I disorder and 123 healthy controls. Neurotrophic factors were also compared in patients before and after 6 weeks of pharmacotherapy. A multivariate logistic regression analysis was used to investigate the influence of the neurotrophic factors analyzed in quartile form, in relation to confounding variables, such as age, sex, and body mass index.
IGF-1 was significantly higher in patients (mean=514.57, SD=259.78) than in healthy controls (mean=316.82, SD=270.00, p<0.0001) at baseline. Furthermore, higher levels of IGF-1 substantially increased the risk for bipolar I disorder. IGF-1 level was not significantly changed at 6-weeks (mean=506.41, SD=313.66). No changes in BDNF or β-NGF-1 levels were found following the 6-week treatment period. IGF-1 and β-NGF were negatively correlated in healthy controls, but not in patients. Severity of manic symptoms was not associated with any of the neurotrophic factors.
We did not measure cortisol, growth hormone, or IGF-1 receptors. This study is cross-sectional in design.
Elevated IGF-1 levels may be a trait marker for bipolar disorder. Further studies are needed to thoroughly investigate the role of IGF-1 in relation to other neuroendocrine factors and biological markers for bipolar disorder.
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