Hypothalamic–pituitary–adrenocortical system dysregulation and new treatment strategies in depression

Abstract

According to the corticoid receptor hypothesis of depression, hyperactivity of the hypothalamic–pituitary–adrenocortical (HPA) system is one of the major pathophysiological factors for the development of depression and opens a broad range of new antidepressant treatment options that are related to direct interventions in HPA system regulation in depressed patients. These new therapy strategies include inhibition of hypothalamic corticotropin-releasing hormone (CRH) release, antagonism at CRH1 receptors, antagonism at vasopressin V1b receptors, inhibition of cortisol synthesis, antiglucocorticoid treatment with dehydroepiandrosterone and treatment with glucocorticoid receptor antagonists. Although preclinical data support the view that CRH1 receptor antagonists are useful in the treatment of depression, currently no controlled studies are available that demonstrate clinical efficacy in depressed patients. The use of the antiglucocorticoid neuroactive steroid dehydroepiandrosterone, the cortisol synthesis inhibitor metyrapone and the glucocorticoid receptor antagonist mifepristone in depression has been demonstrated in some small, double-blind, placebo-controlled studies. However, three recently completed Phase III trials failed to significantly separate mifepristone from placebo in depression. Thus, it is unclear at present to what extent new, clinically effective antidepressant therapies can be developed based on the corticoid receptor hypothesis of depression.

Keywords::

• cortisol
• depression
• HPA system

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.