A Randomized Trial to Examine the Effect of Mifepristone on Neuropsychological Performance and Mood in Patients with Bipolar Depression

Abstract

Deficits in neuropsychological performance are found in patients with bipolar disorder and represent a potential treatment target for novel therapeutic strategies. We have previously demonstrated a beneficial effect on spatial working memory (SWM) of treatment for 1 week with the progesterone and glucocorticoid receptor antagonist mifepristone, evident 2 weeks after the cessation of treatment. We examined the longer-term efficacy of 600 mg/day of mifepristone as an adjunctive treatment, for 1 week, in a placebo-controlled, randomized, double-blind trial in 60 patients with bipolar depression, with SWM as the primary outcome measure. A comparator group of healthy control subjects was also recruited. At baseline, neuropsychological performance of patients was impaired, but hypothalamic-pituitary-adrenal axis function did not differ from that of control subjects. Mifepristone treatment was associated with a time-limited increase in cortisol awakening response and with a sustained improvement in SWM performance, which was evident 7 weeks after the cessation of treatment. The magnitude of this neuropsychological response was predicted by the magnitude of the cortisol response to mifepristone. The response occurred in the absence of a significant improvement in depressed mood. These data accord with the findings of animal studies and demonstrate that brief treatment with mifepristone is associated with a sustained improvement in SWM, an effect that might be mediated by a persistent enhancement in hippocampal mineralocorticoid receptor function.