When depression is comorbid with a variety of other disorders, such as multiple sclerosis, Alzheimer's disease, multi-infarct dementia, Hunting-ton's disease, and others, both CRF hypersecretion and HPA axis hyper-activity are common. In contrast, HPA axis dysfunction has rarely been reported in schizophrenia. Consistent with the role of CRF in both depression-like and anxiety-like behaviours in preclinical animal studies, increased CSF concentrations of CRF have been reported in post-traumatic stress disorder (PTSD) . A recent elegant study that used an in-dwelling cannula in the lumbar space, allowing repeated sampling of CSF several hours after the initial, and presumably stressful, lumbar puncture, demonstrated elevated CSF levels of CRF in combat veterans suffering from PTSD . In contrast, low serum cortisol and urinary free cortisol levels have been repeatedly, yet unexpectedly, detected in PTSD. One possible mechanism that has been proposed by Yehuda et al.  suggests heightened negative feedback within the HPA axis in patients with chronic PTSD. Finally, CRF neuronal degeneration is now well known to occur in the cerebral cortex of patients with Alzheimer's disease, with compensatory up-regulation of CRF receptor numbers, and this effect precedes the better-studied cholinergic neuronal involvement .
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