Overall, when examining all trials together over all affective episodes, the mean change (weighted mean difference;
baseline to endpoint) in Hamilton Depression Rating Scale (HDRS) scores indicated a significant difference in favour of treatment. A number of small-scale clinical trials have examined the role of cortisol biosynthesis inhibitors such as ketoconazole, aminoglutethimide and metyrapone in the Inhibitors,research,lifescience,medical treatment of depression [Murphy, 1997; Murphy et al. 1998; O’Dwyer et al. 1995; Thakore and Dinan, 1995; Wolkowitz et al. 1993] and these are discussed in the section on ‘Metyrapone and treatment-resistant depression’ below. Another strategy which has been used to target the HPA axis for the treatment of depression is the use of GR antagonists [e.g. RU486 (mifepristone), Org34517]. The mechanism of action of these drugs has not been fully elucidated, but Inhibitors,research,lifescience,medical it
is speculated that they may act by enhancing MR function or by a rebound increase in GR function [Thomson and Craighead, 2008] suggesting the possibility that short-term treatment may exert persistent effects. Inhibitors,research,lifescience,medical Studies with RU486 suggest that it can reduce the psychiatric symptoms associated with Cushing’s disease [van der Lely et al. 1991]. There have also been a number of studies conducted using mifepristone in (non-Cushing’s) patients with pMDD. Positive findings in the initial open studies [Belanoff et al. 2001, 2002; Simpson et al. 2005] and randomized controlled trials [DeBattista et al. 2006; Flores et al. 2006] have been followed by a selleck larger negative trial [Blasey et al. 2011], which
used reduction in psychotic symptoms as the outcome measure. The authors argue that higher Inhibitors,research,lifescience,medical mifepristone doses may have led to a more robust response. An organon compound which acts as an antagonist at GRs has also been reported to have Inhibitors,research,lifescience,medical antidepressant properties in a poster and abstract but not in a full paper [Hoyberg et al. 2002]. CRH receptor antagonists have been developed and tested extensively in preclinical models below to investigate their anxiolytic and antidepressant properties [Jones et al. 1998; van Gaalen et al. 2002; Zorrilla et al. 2002]. Most of the clinical trials done in this area are small scale and a definite role for these drugs can only be established after large-scale trials. A CRH receptor antagonist, R121919, was able to significantly reduce depression and anxiety scores in a cohort of 20 patients in an open-label clinical trial [Zobel et al. 2000]. Further studies showed that R121919 was effective in improving sleep and showed a good tolerability profile in patients with depression [Held et al. 2004; Kunzel et al. 2003, 2005; Zobel et al. 2000]. The increased liver enzymes seen in some patients after treatment [Zobel et al. 2000] has led to the discontinuation of development of this product.