Metyrapone in treatment-resistant depression

Abstract

Depression affects a significant proportion of the population, with 1-year and lifetime prevalence of 3-5% and 10-30% respectively. Full remission is achieved in only a third of patients following treatment with first-line antidepressant. There is a need for novel treatments for treatment-resistant depression (TRD). Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been described in patients with depression. There is persistent rise in the levels of cortisol (end product of the HPA axis) and impairment of the negative feedback inhibition mechanism of the HPA axis. Dysregulation of the HPA axis has been found to be linked to nonresponse to antidepressants and relapse following successful treatment. The efficacy of pharmacological agents that intervene with the mechanisms involved in dysregulation of cortisol synthesis and release are being explored in depression, particularly in TRD. Studies have been carried out with these drugs as augmenting agents for antidepressants or as monotherapy. The strongest evidence has come from studies using metyrapone, a cortisol synthesis inhibitor, and this has been described in detail in this review. The most robust evidence for its antidepressant efficacy in depression comes from a double-blind, randomized, placebo-controlled study of augmentation of serotonergic antidepressants with metyrapone. A 3-week augmentation of serotonergic antidepressants with 1 g metyrapone daily was shown to be superior to placebo in reducing the MontgomeryAsberg Depression Rating Scale by 50%, 5 weeks following initiation of treatment. The mechanism of the antidepressant action of metyrapone is not clear but the evidence for various potential mechanisms is discussed. Keywords 436597T PP242045125312436597PD Sigalas, H GargTherapeutic Advances in Psychopharmacology 2012Therapeutic Advances in Psychopharmacology 2 (4) 140 http://tpp.sagepub.com the evidence of antiglucocorticoids in depressive illness (for instance (Gallagher et al., 2008)). To the authors knowledge this is the first review that focuses on the use of metyrapone in depressive illness. Background The hypothalamic-pituitary-adrenal axisThe HPA axis is a neuroendocrine system which incorporates the hypothalamus, the pituitary and the adrenal cortex. In addition to its role in the regulation of hormone secretion it is involved in responding to challenges to homeostasis, the regulation of the immune system, energy release and storage, sleep and sexual behaviour and emotions.It is under tight feedback control and is modulated by afferent connection from multiple brain areas, including the amygdala and hippocampus.In the hypothalamus, arginine vasopressin and corticotrophin-releasing hormone (CRH) are synthesized by parvocellular neurones of the paraventricular nuclei which project widely to the limbic system, brain stem and spinal cord and to the median eminence. Secretion into the hypothalamo-pituitary portal system of these two peptides regulates the secretion from the anterior lobe of the pituitary gland into...

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