Persistent effects of mifepristone (RU-486) on cortisol levels in bipolar disorder and schizophrenia

Recent pre-clinical and clinical studies have examined the potential use of anti-glucocorticoid drug augmentation – including glucocorticoid receptor (GR) antagonists – as a method of improving treatment response in severe psychiatric illness. However, the direct and persistent effects such drugs exert on the hypothalamic–pituitary–adrenal (HPA) axis are unclear. We examined afternoon cortisol levels in 39 patients (19 with bipolar disorder, 20 with schizophrenia) at baseline, following treatment with mifepristone (600 mg/day for 7 days) or placebo and at +21 days. Following treatment with mifepristone (day +7) there was a significant increase in cortisol levels from baseline (mean change = 60,434 nmol/L × min, 95%CI = 44,755–76,112; t = 7.803, df = 38, p < 0.0001) which significantly decreased from this point by day +21 (mean change = −64,487 nmol/L × min, 95%CI = −49,974 to −79,001; t = 8.995, df = 38, p < 0.0001). Cortisol levels at day +21 were significantly lower than they were at baseline (mean change = −4054 nmol/L × min, 95%CI = −456 to −7652; t = 2.281, df = 38, p = 0.028). No significant changes occurred following placebo. These results provide preliminary evidence that subtle but significant reductions in HPA axis activity (measured by peripheral cortisol levels) are evident 14 days after cessation of treatment with the GR-antagonist mifepristone. This may in part underlie the putative therapeutic effects of such drugs.