Glucocorticoids are important in the pathogenesis of depression, but this potentially serious psychological side effect is often overlooked in clinical practice. The unwanted behavioral effects of anabolic steroids are widely known, but those of glucocorticoid therapy, though recognized for over 45 years, receive less attention. Placebo-controlled studies have revealed that a third of patients taking glucocorticoids experience significant mood disturbance and sleep disruption. More importantly, up to 20% of patients on high-dose glucocorticoids report psychiatric disorders including depression, mania, psychosis, or a mixed affective state. A recent double-blind, placebo-controlled trial of corticosteroid administration in healthy individuals showed that 75% of subjects developed disturbances in mood and cognition, which reversed when steroids were stopped. Dysregulation of the HPA axis in depression is one of the oldest and most consistent findings in biological psychiatry. A large-scale meta-analysis of over 140 studies using the low-dose dexamethasone suppression test illustrated that persistent adrenocortical hyperactivity is a robust indicator of poor prognosis and a weaker predictor of suicide in depression. Overall, data from conditions of both exogenous and endogenous steroid excess provide support for a glucocorticoid theory of depression.

HPA axis hyperactivity is found in bipolar disorder related to depression and mixed states. Patients with bipolar disorder also have cognitive difficulties and endocrine disturbances may contribute to such dysfunction. Antiglucorticoid therapies are novel treatments of mood disorder. Preliminary data in psychotic depression suggest that mifepristone (RU-486), a glucocorticoid receptor antagonist (91), has antidepressant and salutary cognitive effects in a matter of days. The positive effects of mifepristone in severe bipolar depression in a parallel, double-blind, placebo-controlled experiment were recently reported with improvement in two-thirds of patients in the medium- and high-dose groups within 7 days.71 The other major treatment for psychotic major depression is a combination of antidepressants and antipsychotics, which improve symptoms in roughly 60% of cases.72 However, side effects from mifepristone are very low compared to these combinations of drugs.73 The glucocorticoid ORG 34517/34850 is also in Phase II clinical studies of BPAD.

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