Double-blind, placebo-controlled trial of mifepristone on cognition and depression in alcohol dependence

Abstract

Background Alcohol dependence is a significant issue contributing to disease burden. Changes in cortisol concentrations during alcohol withdrawal are associated with cognitive deficits and symptoms of depression. Current treatments are only successful for a small proportion of people and do not target cognitive deficits and symptoms of depression experienced by those who are alcohol dependent. The aim of this research is to determine the potential efficacy of mifepristone, a type II glucocorticoid receptor antagonist, to prevent symptoms of depression and cognitive deficits following alcohol detoxification. Methods This was a phase 2 therapeutic use trial. It was a double-blind randomised controlled clinical trial of mifepristone versus inactive placebo treatment. The trial aimed to recruit 120 participants who met the inclusion criteria: (1) male, (2) aged 18–60 years inclusive, and (3) alcohol dependent for 5 or more years. Participants were randomised to 600 mg a day mifepristone (200 mg morning, afternoon, and evening) for 7 days and 400 mg for the subsequent 7 days (200 mg morning and evening) or the equivalent number of placebo tablets for 14 days. Primary outcome measures were cognitive function (measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB)) and symptoms of depression (measured using the Beck Depression Inventory (BDI)) at 4 weeks post-randomisation. Results Difficulties recruiting participants due to significant changes in the provision of inpatient care for alcohol dependence resulted in only 27 participants recruited to the trial, with data available for 21 participants. Fourteen participants were randomised to receive mifepristone and 13 to receive placebo. Conclusion Larger trials would be needed to draw conclusions about the efficacy of mifepristone. Trial registration ISRCTN registry ISRCTN54001953. Registered on 29 September 2011.

Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy

“…Side effects even after long-term daily use of high doses of Mfp, due to its binding to progesterone and glucocorticoid receptors, are only very mild (reversible asthenia and rashes). 26 Human equivalent doses (HEDs) exceeding those of 50 mg/kg in rodents have been safely applied for 14 consecutive days in males, 36 and HEDs exceeding 20 mg/kg in rats have been safely applied to males and non-pregnant women daily for several months. 37 , 38 …”

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder

“…Reduced ethanol-seeking in rodents [177,178] Mixed results in primates; reduced chronic voluntary alcohol use but did not prevent relapse [179,180] Reduced alcohol craving and consumption [178,181,182] Reduce drinking…”

“…In a human laboratory study with 56 alcohol-dependent participants, mifepristone (taken for one week) was effective in reducing alcohol craving and consumption relative to placebo, improved liver-function markers, and was overall well tolerated [ 178 ]. A two-week Phase 4 RCT examining the effects of mifepristone on cognition in AUD was recently conducted, but recruitment challenges rendered the results inconclusive [ 181 , 182 ]. Of note, in this trial, participants who received mifepristone had higher Beck Depression Inventory scores compared to placebo at 4 weeks post-randomization despite similar scores at baseline between the two groups, indicating a greater severity of depression symptoms caused by the medication.…”

Novel Pharmacological Approaches to the Treatment of Depression

“…Mifepristone, a GR antagonist, decreased psychotic symptoms and cortisol levels specifically in PMD patients [259]. Mifepristone could also treat alcohol dependence-induced depression and cognitive deficits with no major side effects [260].…”