Effect of antipsychotic treatment on Insulin-like Growth Factor-1 and cortisol in schizophrenia: A longitudinal study
ABSTRACT 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.
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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.Psychoneuroendocrinology 07/2014; 49C:187-206. DOI:10.1016/j.psyneuen.2014.07.013 · 5.59 Impact Factor
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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.Journal of Affective Disorders 08/2013; 151(2). DOI:10.1016/j.jad.2013.07.041 · 3.71 Impact Factor
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ABSTRACT: Serine/threonine protein kinase v-akt murine thymoma viral oncogene homolog (Akt) is one of the survival kinases with multiple biological functions in the brain and throughout the body. Schizophrenia is one of the most devastating psychiatric disorders. Accumulating evidence has indicated the involvement of the Akt signaling pathway in the pathogenesis of this disorder. Genetic linkage and association studies have identified Akt-1 as a candidate susceptibility gene related for schizophrenia. The level of Akt-1 protein and its kinase activity decreased significantly both in white blood cells from schizophrenic patients and in postmortem brain tissue of schizophrenic patients. Consistent with these findings, alterations in the upstream and downstream pathways of Akt have also been found in many psychiatric disorders. Furthermore, both typical and atypical antipsychotic drugs modify the Akt signaling pathway in a variety of conditions relative to schizophrenia. In addition as a survival kinase, Akt participates in neurodevelopment, synaptic plasticity, protein synthesis and neurotransmission in the central nervous system. It is thought that reduced activity of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway could at least partially explain the cognitive impairment, synaptic morphologic abnormality, neuronal atrophy and dysfunction of neurotransmitter signaling in schizophrenia. In addition, reduced levels of Akt may increase the effects of risk factors on neurodevelopment, attenuate the effects of growth factors on neurodevelopment and reduce the response of patients to antipsychotic agents. More recently, the role of Akt signaling in the functions of schizophrenia susceptibility genes such as disrupted-in-schizophrenia 1 (DISC-1), neuregulin-1 (NRG-1) and dysbindin-1 has been reported. Thus, Akt deficiency may create a context permissive for the expression of risk-gene effects in neuronal morphology and function. This paper reviews the role of Akt in the pathophysiology of schizophrenia and as a potential therapeutic strategy targeting Akt.Brain research 07/2012; 1470:145-58. DOI:10.1016/j.brainres.2012.06.032 · 2.83 Impact Factor