Makino S, Gold PW, Schulkin J. in some patients with depression, including those refractory to other agents; however, there is a need for more controlled studies. Several lines of data suggest that the mechanism of action of these agents may not be solely a function of inhibition of adrenal cortisol production. Conclusions The authors propose that CSIs may be efficacious in part by reducing glucocorticoid enhancement of CRH action in neurons of the central nucleus of the amygdala and other structures outside the endocrine hypothalamus. Possible effects of systemically administered CSIs on glucocorticoid receptor regulation, neuroactive steroids, and classical monoamine systems are also discussed. We conclude that available clinical data suggest a potential role for CSIs in the management of depressive disorders, especially major depression with psychotic features. strong class=”kwd-title” Keywords: antiglucocorticoids, depression, mifepristone, ketoconazole, CRH, cortisol, glucocorticoid inhibition INTRODUCTION Major depressive disorder (MDD) is a common,usually recurrent, and debilitating condition that affects about 121 million people worldwide and is the leading cause of disability worldwide.[1] Episodes of MDD are characterized by a period of at least 2 weeks during which there is either depressed mood or the loss of interest or pleasure in almost all activities.[2] Significant distress or impaired functioning must be present to qualify for a diagnosis of MDD. There is evidence that MDD with psychotic features (i.e., psychotic depression) is a relatively distinct subtype of MDD that is more severe and is characterized by a greater degree of anxiety and psychomotor agitation than is usually seen in depression without psychotic features. Psychotic depression affects roughly 20% of hospitalized patients with major depression.[3] Significant differences between MDD and psychotic depression have been noted in presenting features, neurocognitive features, biological features, familial transmission, course and outcome, and response to treatment.[4,5] Given the Rabbit Polyclonal to RNF149 variability in treatment response for psychotic depression and the knowledge that treatment strategies for depression in general may take weeks or months to take effect, researchers have turned their focus to antiglucocorticoids as a possible treatment approach. Hypercortisolism is one of the most consistent and reproducible biological abnormalities seen in patients with major depression[6,7]; thus, the overlap between symptoms associated with depressive episodes and those occurring during acute stress has led to a closer examination of the association between this depression and elevated levels of glucocorticoids, which are among the most consistent and important effectors of stress responses.[8-12] There are reports that patients with psychotic depression have specific abnormalities in the hypothalamicCpituitaryCadrenal (HPA) axis activity, tend to have the highest rates of nonsuppression on the dexamethasone suppression test among clinically defined subtypes, and have markedly elevated postdexamethasone cortisol levels.[13,14] This study will focus on reviewing the literature pertaining to the hypercortisolism associated with depression (MDD) and psychotic depression, the efficacy of antiglucocorticoid drugs to treat it, and suggest that extrahypothalamic corticotropin-releasing hormone (CRH) may be implicated in this type of treatment. HYPERCORTISOLISM IN DEPRESSION For many years, researchers have noted Lapatinib (free base) that about 40C60% of all severely depressed people have raised levels of cortisol.[12] As depressive symptoms are a frequent concomitant of the hypercortisolism seen in patients with Cushings syndrome[7,15-17] and in patients undergoing sustained treatment with corticosteroid anti-inflammatory agents,[18] a hypothesis that interfering with cortisol secretion and/or actions may be beneficial to patients with major depression was developed.[19,20] This hypothesis is Lapatinib (free base) based on the proposition Lapatinib (free base) that depressive symptomatology is at least in part a consequence of excess cortisol.[21,22] However, it is now known that there are distinct differences in the pathophysiology of hypercortisolism Lapatinib (free base) between major depression and Cushings disease, the most common form of endogenous Cushings syndrome and perhaps the most extensively studied in terms of pathophysiology. Thus, researchers[23-25] have advanced evidence suggesting that the hypercortisolism of major depression is associated with a defect at or above the level of Lapatinib (free base) the hypothalamus resulting in the hypersecretion of CRH. Studies have shown that the initial recovery of the HPA.