Efficacy and Safety of Mifepristone for the Treatment of Psychotic Depression

Abstract

Open-label studies and randomized clinical trials have suggested that mifepristone may be effective for the treatment of major depression with psychotic features (psychotic depression). A recent study reported a correlation between mifepristone plasma concentration and clinical response. The current study aimed to evaluate the safety and efficacy of mifepristone and, secondarily, to test whether response was significantly greater among patients with mifepristone plasma concentrations above an a priori hypothesized threshold. A total of 433 patients who met criteria for psychotic depression were randomly assigned to receive 7 days of either mifepristone (300, 600, or 1200 mg) or placebo. Response was defined as a 50% reduction in psychotic symptoms on both days 7 and 56. Cochran-Mantel-Haenszel tests compared (1) the proportion of responders among patients assigned mifepristone versus placebo and (2) the proportion of responders among the subset of patients with plasma concentrations greater than 1660 ng/mL versus placebo. Mifepristone was well tolerated at all 3 doses. The proportion of responders randomized to mifepristone did not statistically differ from placebo. Patients with trough mifepristone plasma concentrations greater than 1660 ng/mL were significantly more likely to have a rapid and sustained reduction in psychotic symptoms than those who received placebo. The study failed to demonstrate efficacy on its primary end point. However, the replication of a statistically significant linear association between mifepristone plasma concentration and clinical response indicates that mifepristone at sufficient plasma levels may potentially be effective in rapidly and durably reducing the psychotic symptoms of patients with psychotic depression.

Unraveling the Time Domains of Corticosteroid Hormone Influences on Brain Activity: Rapid, Slow, and Chronic Modes

“…Similar normalizing effects of mifepristone treatment were observed with regard to neurogenesis in the dentate gyrus (Oomen et al, 2007). These cellular actions of the antiglucocorticoid possibly contribute to its beneficial effect in severe cases of psychotic depression, provided sufficiently high concentrations in plasma are achieved (DeBattista et al, 2006;Gallagher et al, 2008;Blasey et al, 2011). Whether mifepristone exerts its effects only via blockade of GRs is hard to judge, given the many adaptive actions that may occur, both peripherally and in the brain (Kling et al, 2009).…”

Metyrapone in treatment-resistant depression

“…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[Belanoff et al , 2002Simpson et al 2005] and randomized controlled trials [DeBattista et al 2006; Flores et al 2006] have been followed by a larger negative trial [Blasey et al 2011], which used reduction in psychotic symptoms as the outcome measure. The authors argue that higher mifepristone doses may have led to a more robust response.…”

Role of corticosteroids in the antidepressant response

“…133 A further trial has shown the importance of plasma levels of mifepristone, with a benefit seen in patients whose levels were above a cut-off point. 134 The group is conducting a further clinical trial of mifepristone in psychotic major depression using the higher (1,200 mg) dose. 135 Our group 136 reported selective improvements in spatial working memory performance, verbal fluency, and spatial recognition memory following treatment with mifepristone 600 mg/day in a 3-week, double-blind, crossover design in bipolar depression.…”