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First-episode psychosis (FEP) patients show hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, but the mechanisms leading to this are still unclear. The aim of this study was to investigate the role of stress and antipsychotic treatment on diurnal cortisol levels, and on cortisol awakening response, in FEP. Recent stressful events, perceived stress and childhood trauma were collected in 50 FEP patients and 36 healthy controls using structured instruments. Salivary cortisol was obtained at awakening, at 15, 30, and 60 min after awakening, and at 12 and 8 pm. Patients experienced more recent stressful events, perceived stress and childhood trauma than controls (p < 0.001). Patients had a trend for higher diurnal cortisol levels (p=0.055), with those with less than two weeks of antipsychotics showing significantly higher cortisol levels than both patients with more than two weeks of antipsychotics (p=0.005) and controls (p=0.002). Moreover, patients showed a blunted cortisol awakening response compared with controls, irrespectively of antipsychotic treatment (p=0.049). These abnormalities in patients were not driven by the excess of stressors: diurnal cortisol levels were negatively correlated with the number of recent stressful events (r=−0.36, p=0.014), and cortisol awakening response was positively correlated with a history of sexual childhood abuse (r=0.33, p=0.033). No significant correlations were found between perceived stress or severity of symptoms and cortisol levels, either diurnal or in the awakening response. Our study shows that antipsychotics normalize diurnal cortisol hypersecretion but not the blunted cortisol awakening response in FEP; factors other than the excess of psychosocial stress explain HPA axis abnormalities in FEP.

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Background Reduced brain-derived neurotrophic factor (BDNF) levels have been reported in the serum and plasma of patients with psychosis. The aim of this study was to investigate potential causes and consequences of reduced BDNF expression in these patients, by examining the association between BDNF levels and measures of stress, inflammation and hippocampal volume in first-episode psychosis. Methods BDNF, interleukin (IL)-6, and tumour-necrosis-factor (TNF) alpha mRNA levels were measured in leukocytes of 49 first-episode psychosis patients (DSM-IV criteria) and 30 healthy controls, recruited between January 2006 and December 2008. In the same subjects, we measured salivary cortisol levels, and collected information about psychosocial stressors (number of childhood trauma, number of recent stressors, and perceived stress). Finally, hippocampal volume was measured, using brain MRI, in a subsample of 19 patients. Results Patients had reduced BDNF (effect size d=1.3, p<0.001) and increased IL-6 (effect size d=1.1, p<0.001) and TNF-alpha (effect size d=1.7, p<0.001) gene expression levels, when compared with controls, as well as higher levels of psychosocial stressors. A linear regression analysis in patients showed that a history of childhood trauma and high levels of recent stressors predicted lower BDNF expression through an inflammation-mediated pathway (adjusted R square=0.23, p=0.009). In turn, lower BDNF expression, increased IL-6 expression, and increased cortisol levels, all significantly and independently predicted a smaller left hippocampal volume (adjusted R square=0.71, p<0.001). Conclusions Biological changes activated by stress represent a significant factor influencing brain structure and function in first-episode psychosis, through an effect on BDNF.

Background Evidence from animal and human studies suggests that early-life stress such as physical maltreatment has long-lasting effects on the hypothalamic-pituitary-adrenal (HPA) axis and is associated with blunted HPA axis reactivity in adulthood. Few studies have investigated whether blunted HPA axis reactivity observed in children exposed to early-life stress signals social, emotional, and behavioral problems. Methods Participants were 190 12-year-old children (50.5% males) recruited from the Environmental Risk Longitudinal Twin Study, a nationally representative 1994 to 1995 cohort of families with twins. Cortisol responses to psychosocial stress were measured in maltreated/ bullied (n = 64) and comparison children (n = 126). We ascertained maltreatment and bullying victimization using mothers’ reports and assessed children’s social, emotional, and behavioral problems at ages 5 and 12 using mothers’ and teachers’ reports. Results Piecewise multilevel growth curve analyses indicated that maltreated/bullied and comparison children showed distinct cortisol responses to stress. Specifically, maltreated/bullied children had lower cortisol responses than comparison children who exhibited a significant increase. Lower cortisol responses were, in turn, associated with more social and behavioral problems among maltreated/bullied children. Conclusions These findings provide support for the influence of childhood harm on blunted HPAaxis reactivity and its potential impacton children’s functioning. Our findings emphasize the need to integrate stress biomarkers in guiding prevention efforts for young victims.

The weight of current evidence supports the presence of the following factors related to hypothalamic-pituitary-adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS): mild hypocortisolism; attenuated diurnal variation of cortisol; enhanced negative feedback to the HPA axis; and blunted HPA axis responsiveness. Furthermore, HPA axis changes seem clinically relevant, as they are associated with worse symptoms and/or disability and with poorer outcomes to standard treatments for CFS. Regarding etiology, women with CFS are more likely to have reduced cortisol levels. Studies published in the past 8 years provide further support for a multifactorial model in which several factors interact to moderate HPA axis changes. In particular, low activity levels, depression and early-life stress appear to reduce cortisol levels, whereas the use of psychotropic medication can increase cortisol. Addressing these factors-for example, with cognitive behavioral therapy-can increase cortisol levels and is probably the first-line approach for correcting HPA axis dysfunction at present, as steroid replacement is not recommended. Given what is now a fairly consistent pattern of findings for the type of HPA axis changes found in CFS, we recommend that future work focuses on improving our understanding of the cause and relevance of these observed changes.

This naturalistic test of the HPA axis response to stress showed impaired HPA axis function in CFS.

We suggest that the additional effects of prednisolone on the MR explain the different responses to these glucocorticoids in the same depressed patients.