About half of all patients with major depression have a raised cortisol output, which tends to return to normal on recovery. It is most consistently associated with an 'endogenous' pattern of illness (Chapter 4.5.i3). While cortisol is always regarded as a 'stress' hormone, and is secreted in response to various types of acute stress, the stresses that commonly result in long-term hypercortisolaemia are poorly understood. The idea that there is a relatively specific link between chronic high cortisol levels and mood disorder is notably persistent. In major depression there is peripheral hypertrophy of the adrenal glands, measurable in MRI body scans, and an enhanced response to corticotropin. The MRI change, like the hypercortisolaemia itself, reverses on recovery. (29)

Suppression of cortisol secretion occurs normally via glucocorticoid receptor-mediated inhibitory feedback to the hypothalamus; it is readily produced by dexamethasone, which is a potent exogenous glucocorticoid (the dexamethasone suppression test (DST)). Non-suppression of endogenous cortisol after dexamethasone occurs in Cushing's disease for example. It implies either reduced feedback and/or enhanced central drive to release cortisol. It was initially observed that the 1-mg DST showed high specificity (96 per cent) and sensitivity (67 per cent) as a putative diagnostic test for melancholia. (3,9 At the time this result attracted intense interest, but has since proved difficult to generalize. The high specificity established against normal controls was less against other patient groups. Thus, DST non-suppression has not been accepted as a diagnostic test. This failed effort to give medical respectability to psychiatric diagnosis came to devalue what remains an important observation. Non-suppression usually reflects hypercortisolaemia, which is itself a robust phenomenon of mood disorder that requires explanation like any other core biological symptom. Other symptoms that we identify as part of the depressive syndrome lend themselves less easily to investigation. The DST also has potential clinical uses beyond diagnosis. DST non-suppression predicts a low placebo response rate to drug treatment, (31) and hypercortisolaemia predicts a low rate of clinical response to psychological intervention. (32)

It remains unclear whether cortisol contributes to the clinical state of depression by a direct action on the brain. Exogenous cortisol administration is associated with affective symptoms, and chronic excessive cortisol secretion commonly appears to produce depressive symptoms in Cushing's disease. An HPA axis programmed to hypersecrete cortisol under stress could be a pathogenic mechanism explaining why depression or mania develops. This view has provoked efforts to treat mood disorder by inhibition of cortisol synthesis with metyrapone. Preliminary results suggest this may be effective.

However, when depressed patients are given large doses of cortisol they tend to show acute mood enhancement, (33> and oral dexamethasone has been reported to elevate mood in major depression, especially in hypersecretors.(34) This leads to the converse hypothesis that an HPA axis appropriately adapted to chronic stress early in development might be unable to mount a normal effective response to acute stress later in life. Cortisol may then be seen as a euphoriant (or antidepressant), and hypercortisolaemia as an antidepressant response of the stress-regulating mechanisms of the brain. Based on this view, all cortisol levels seen in depression may be set inappropriately low for the ongoing stress, however high or low they are compared with the normal range.

Whether one supposes cortisol levels to be set too high or too low in depression, it remains inconvenient that either a suppression or an augmentation of steroid effect seems, initially at least, to elevate mood. A way out of this complication may lie in cortisol's action on two receptors in the brain (the glucocorticoid and mineralocorticoid receptors) that may have opposite actions. However, we need better-controlled replicated data on the effects of steroid manipulations.

An increased cortisol production is associated with an increased release of hypothalamic b-endorphin (35) and probably a pulsatile increase in ACTH. The paraventricular nucleus of the hypothalamus represents the highest level of dedicated neurones in the HPA axis. The neurosecretory cells of the paraventricular nucleus release the peptides cRh and AVP into the portal hypophyseal blood. These hormones in turn stimulate the release of ACTH from the anterior pituitary. Major depression is characterized by a blunted ACTH response to CRH,(36) an elevated level of CRH in the cerebrospinal fluid, (37) and increased numbers of neurones expressing CRH mRNA in the paraventricular nucleus of the hypothalamus postmortem.(38) CRH is not confined to the paraventricular nucleus, but is expressed in a variety of other central nuclei whence it can produce anxiogenic behavioural effects. CRH receptors, which exist in two forms, are widely distributed in the hypothalamus and cortex. A related peptide, urocortin, has a similar pharmacology. Knocking out the CRH-1 receptor gene in mice impaired the HPA stress response and reduced anxiety-like behaviour. (39> Non-peptide CRH antagonists must be taken seriously as putative anxiolytics or antidepressants and are now in clinical trials. If effective, they will be among the first of a new generation of truly novel treatments based on peptide neurotransmission.

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