The finding that people with a first episode of psychosis had smoked higher-potency cannabis, for longer and with greater frequency, than a healthy control group is consistent with the hypothesis that Delta 9-THC is the active ingredient increasing risk of psychosis. This has important public health implications, given the increased availability and use of high-potency cannabis.

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.

The integrity of brain white matter connections is central to a patient’s ability to respond to pharmacological interventions. This study tested this hypothesis using a specific measure of white matter integrity, and examining its relationship to treatment response using a prospective design in patients within their first episode of psychosis. Diffusion tensor imaging data were acquired in 63 patients with first episode psychosis and 52 healthy control subjects (baseline). Response was assessed after 12 weeks and patients were classified as responders or non-responders according to treatment outcome. At this second time-point, they also underwent a second diffusion tensor imaging scan. Tract-based spatial statistics were used to assess fractional anisotropy as a marker of white matter integrity. At baseline, non-responders showed lower fractional anisotropy than both responders and healthy control subjects (P < 0.05; family-wise error-corrected), mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. After 12 weeks, there was an increase in fractional anisotropy in both responders and non-responders, positively correlated with antipsychotic exposure. This represents one of the largest, controlled investigations of white matter integrity and response to antipsychotic treatment early in psychosis. These data, together with earlier findings on cortical grey matter, suggest that grey and white matter integrity at the start of treatment is an important moderator of response to antipsychotics. These findings can inform patient stratification to anticipate care needs, and raise the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response.