Several studies in major medical journals have been undertaken to determine how practical it would be, and how effective, to use mifepristone (an "antiglucocorticoid") as a treatment for psychotic major depression.

For instance, according to the 2006 study "Mifepristone versus Placebo in the Treatment of Psychosis in Patients with Psychotic Major Depression" by DeBattista et al:

A seven day course of mifepristone followed by usual treatment appears to be effective and well tolerated in the treatment of psychosis in PMD. This study suggests that the antiglucocorticoid, mifepristone, might represent an alternative to traditional treatments of psychosis in psychotic depression.


Mifepristone is also known as RU-486 and it is used to procure abortion while the fetus (or embryo) is still very small.

If it reduced psychotic effects, would using mifepristone help people suffering from depression?

  • @fredsbend, it's political in the US because a woman who could be pregnant may only use mifepristone if it's OK to have an abortion. And it's only OK to have an abortion because of today's Supreme Court precedent. And today's Supreme Court precedent has been regarded by some folks as "up in the air" if Brett Kavanaugh, accused of misconduct by Dr. Christine Blasey Ford, were to become a Supreme Court justice. Sep 28, 2018 at 17:16
  • I'm sorry, but the on label and off label use of any drug has nothing to do with politics, nor who wrote any articles regarding the science therein. The fact that Kavanagh may not support abortion rights and that Ford wrote an article regarding an off label use of an abortion pill is a coincidence.
    – user11643
    Sep 28, 2018 at 17:18
  • 1
    @Elliot Are you suggesting some conspiracy? Only a coincidence make sense. There is no clear path suggesting anything regarding Ford's article on this pill or Kavanagh's support or non support of abortion rights. I agree with the previous assessment. Putting Ford's name in the title and politics in the tags is plain clickbait. This is not a politics question, and the author of the article is irrelevant to testing the claim.
    – user11643
    Sep 28, 2018 at 17:24
  • 2
    I can't speak to what politics SE would allow, but as for this site and this question I think the question is fine, but you've managed to ask it disingenuously. I'm going to down vote and move on. Let me know when you've changed the title and removed the tag and I'll turn it into an up vote.
    – user11643
    Sep 28, 2018 at 17:30
  • 5
    I edited the question to remove any references to Ford, as it had nothing to do with the actual question of whether the medicine could help depression, and was clearly causing things to get off-topic.
    – Giter
    Sep 28, 2018 at 18:05

3 Answers 3


Does mifepristone (RU-486) help cure depression?

The usage of the word "help" facilitates an answer:
In the sense that it might be a valuable tool to treat some types of depression,
and that it is a valuable tool in studying depression already.

Clinical trials are still not enough in numbers and rigor, but they are starting to come in.

This is currently a very hot field, as evidenced by the publication dates. In animals:

Dalm S, Karssen AM, Meijer OC, Belanoff JK, de Kloet ER: "Resetting the Stress System with a Mifepristone Challenge", Cell Mol Neurobiol. 2018 Sep 1. doi: 10.1007/s10571-018-0614-5.

Psychotic depression is characterized by elevated circulating cortisol, and high daily doses of the glucocorticoid/progesterone antagonist mifepristone for 1 week are required for significant improvement. Using a rodent model, we find that such high doses of mifepristone are needed because the antagonist is rapidly degraded and poorly penetrates the blood-brain barrier, but seems to facilitate the entry of cortisol. We also report that in male C57BL/6J mice, after a 7-day treatment with a high dose of mifepristone, basal blood corticosterone levels were similar to that of vehicle controls. This is surprising because after the first mifepristone challenge, corticosterone remained elevated for about 16 h, and then decreased towards vehicle control levels at 24 h. At that time, stress-induced corticosterone levels of the 1xMIF were sevenfold higher than the 7xMIF group, the latter response being twofold lower than controls. The 1xMIF mice showed behavioral hyperactivity during exploration of the circular hole board, while the 7xMIF mice rather engaged in serial search patterns. To explain this rapid reset of corticosterone secretion upon recurrent mifepristone administration, we suggest the following: (i) A rebound glucocorticoid feedback after cessation of mifepristone treatment. (ii) Glucocorticoid agonism in transrepression and recruitment of cell-specific coregulator cocktails. (iii) A more prominent role of brain MR function in control of stress circuit activity. An overview table of neuroendocrine MIF effects is provided. The data are of interest for understanding the mechanistic underpinning of stress system reset as treatment strategy for stress-related diseases.

Roat-Shumway S, Wroolie TE, Watson K, Schatzberg AF, Rasgon NL: "Cognitive effects of mifepristone in overweight, euthymic adults with depressive disorders", J Affect Disord. 2018 Oct 15;239:242-246. doi: 10.1016/j.jad.2018.07.014.

Background: Previous studies have shown that individuals with mood disorders have a higher prevalence of both hypercortisolemia and insulin resistance. Insulin resistance is posited to contribute to the cognitive deficits observed in individuals who have depression. However, the mechanistic relationship between cortisol and insulin within the central nervous system remains to be further elucidated. This study aimed to evaluate the effects of the antiglucocorticoid agent, mifepristone, on metabolic function and cognitive performance in individuals receiving treatment for depressive disorders who were euthymic at baseline.
Methods: Participants were administered a 600 mg/day dose of mifepristone for 28 days. Oral glucose tolerance tests (OGTTs) and cognitive assessments measuring verbal memory and executive functioning were administered at baseline and after 28 days of treatment.
Results: Improvements in attention and verbal learning were associated with reduction of fasting plasma glucose (FPG) in response to mifepristone treatment.
Limitations: Limitations include the open-label design of this study and a small sample size.
The findings from this study suggest that improvement in fasting plasma glucose levels, upon administration of mifepristone, is associated with the improvement in early input of verbal information. Further studies are warranted in order to better evaluate the use of mifepristone or other antiglucocorticoid agents in treatment of mood disorders characterized by metabolic dysfunction.

Lamontagne SJ, Melendez SI, Olmstead MC: "Investigating dopamine and glucocorticoid systems as underlying mechanisms of anhedonia", Psychopharmacology (Berl). 2018 Aug 22. doi: 10.1007/s00213-018-5007-4.

Rationale: Anhedonia, a deficit in reward processing, is an endophenotype of several neuropsychiatric conditions. Despite its prevalence and debilitating effects, treatments for anhedonia are lacking, primarily because its underlying mechanisms are poorly understood. Dopamine (DA) has been implicated in anhedonia through its role in reward-related learning; glucocorticoid systems may also be involved in that anhedonia is often preceded by chronic stress.
Objective: This study investigated DA and glucocorticoid systems in anhedonia using a rat version of the probabilistic reward task (PRT).
Methods: Adult male Wistar rats were trained on the PRT and then tested following: (1) activation or inhibition of DA activity induced by amphetamine (AMPH) or pramipexole (PRAMI) injections, (2) chronic mild stress (CMS), or (3) glucocorticoid system activation (dexamethasone (DEX)) or inhibition (mifepristone (MIFE)).
Results: AMPH increased and PRAMI decreased response bias, pointing to enhanced and diminished reward responsiveness with DA agonism and antagonism, respectively. CMS reduced response bias but only in a subpopulation of rats. DEX also decreased response bias, suggesting that glucocorticoid processes contribute to anhedonia, although glucocorticoid inhibition (MIFE) had no effect. None of the manipulations altered the ability to detect and respond to reward-paired stimuli.
Conclusions: These results confirm a role of DA in anhedonia and elucidate the contribution of the glucocorticoid system to this effect. In addition, chronic stress may interfere with normal DA functioning, leading to impaired reward-related learning in some animals. These findings may direct future treatment of anhedonia by targeting DA and glucocorticoid systems, as well as a possible interaction between the two.

Zhang YP, Wang HY, Zhang C, Liu BP, Peng ZL, Li YY, Liu FM, Song C: "Mifepristone attenuates depression-like changes induced by chronic central administration of interleukin-1β in rats", Behav Brain Res. 2018 Jul 16;347:436-445. doi: 10.1016/j.bbr.2018.03.033.

Increased proinflammatory cytokines, such as interleukin (IL)-1β, may play an important role in the etiology of depression because they cause the hypothalamic-pituitary-adrenal axis to release glucocorticoids (GC) and induce dysfunction of serotonin and norepinephrine neurotransmission. Sustained increase in GC may activate microglia to induce neuroinflammation, and suppress astrocytes to produce neurotrophins, which lead to neuronal apoptosis. Here, we tested the hypothesis that glucocorticoid receptor (GR) antagonist mifepristone (RU486) may attenuate IL-1β-induced depression-like behavior by regulating the neuroinflammation and neurotrophin functions of microglia and astrocytes. Rats received intracerebroventricular injections of IL-1β (10 ng) and/or subcutaneous injections of RU486 for 14 days. Then animal depression-like behaviors, serum corticosterone concentration, the levels of pro-inflammatory cytokines (TNF-α, IL-6), mRNA and protein expressions of CD11b, GFAP and neurotrophins (pro-BDNF, BDNF, GDNF and their receptors TrkB, p75, GFRα-1 and GFRα-2) in the amygdala were studied. Compared to controls, significantly decreased rearing score and increased defecation in the open field test, decreases in ratio of open/closed time in the elevated plus maze and in sucrose preference, while increased level of corticosterone in the serum were found in the rats administrated with IL-1β. IL-1β administration also reduced the expressions of GFAP, BDNF, GDNF and its receptor GFR-α1, but increased the expressions of CD11b, pro-BDNF, p75 and pro-inflammatory cytokines (TNF-α, IL-6) concentrations. RU486 treatment markedly attenuated these changes induced by IL-1β, except for the expressions of GFR-α1. In conclusion, RU486 may improve depression-like changes by suppressing microglia and inflammation and promoting astrocytes to restore neurotrophin function.

But in humans as well:

Block TS, Kushner H, Kalin N, Nelson C, Belanoff J, Schatzberg A: "Combined Analysis of Mifepristone for Psychotic Depression: Plasma Levels Associated With Clinical Response", Biol Psychiatry. 2018 Jul 1;84(1):46-54. doi: 10.1016/j.biopsych.2018.01.008.

Background: Patients with psychotic depression exhibit elevated cortisol levels. Competitively antagonizing cortisol at the glucocorticoid receptor with mifepristone demonstrated therapeutic benefit in early studies of patients with psychotic depression. We present a combined analysis of all controlled phase 2 and 3 studies to report antipsychotic differences between treatment with mifepristone or placebo and to evaluate the relative contributions to response of attaining an a priori-defined, high mifepristone plasma level and markers of glucocorticoid receptor antagonism (increases in adrenocorticotropin hormone and cortisol) with treatment.
Methods: Data from five similarly designed double-blind phase 2 or 3 studies evaluating the efficacy and safety of 7-day treatment with mifepristone for the psychotic symptoms of psychotic depression were pooled for analysis (mifepristone n = 833; placebo n = 627). Clinical assessments were performed at baseline and on days 7, 14, 28, 42, and 56. Mifepristone, adrenocorticotropin hormone, and cortisol samples were collected at baseline and day 7.
Results: Combined results demonstrated meaningful efficacy (p < .004) for mifepristone in reducing psychotic symptoms with wide safety margins. Patients in the a priori-defined, high mifepristone plasma level group (≥1637 ng/mL) demonstrated a more significant treatment effect over placebo (p = .0004). A number needed to treat of 7 and 48 was observed in the high and low mifepristone plasma level groups, respectively. Adverse events were similar in mifepristone- and placebo-treated patients.
Conclusions: A high mifepristone plasma level carried the strongest association with response, followed by changes in adrenocorticotropin hormone and cortisol. Therapeutic plasma levels of mifepristone were most likely to be achieved with the 1200 mg/day dose.

  • 1
    And nine or more articles by Dr. Christine Blasey (Ford). scholar.google.com/… Sep 28, 2018 at 22:01
  • @elliotsvensson Thx. Reading the comments and edits below the Q: I do not know that person. Can you explain (short) why she causes this controversy here? (I wanted to exclude results by her, because of that) Sep 28, 2018 at 22:05
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    This summer, Dr. Christine Blasey Ford accused a Republican's nominee to the US Supreme Court, Brett Kavanaugh, of sexual misconduct at a time many years ago. If the nomination proceeds, the US Supreme Court's presumed political balance will turn 5-4 against free abortion, resulting (people say) in new abortion restrictions. If those restrictions come about, the application of mifepristone for mental health benefits may be limited to people who are not and could not be pregnant in some US states. Sep 28, 2018 at 22:07
  • @elliotsvensson Oooh. Many thx. Embarrassingly, it never rang a bell. Need to read more news on SC topics then… Sep 28, 2018 at 22:11
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    @elliotsvensson it's already approved for hypercortisolism, which is what it's treating in psychotic depression. There are many pregnancy category X drugs, and nobody has tried to regulate them in this way. It seems like you're trying to stir up a controversy, but there isn't one.
    – De Novo
    Sep 28, 2018 at 22:31

It's important to realize, here, that the study you linked does not claim mifepristone is effective for the treatment of depression. It provides some evidence for the treatment of psychosis in psychotic depression, which is a very particular type of depression that involves, among other things, a high level of cortisol.

Mifepristone is a glucocorticoid receptor antagonist, approved for use in Cushing syndrome and, in combination with misoprostol, for early medical abortion. Just like every other pregnancy category X drug, the prescribers information includes a boxed warning that pregnancy must be excluded before initiating treatment.

In Cushing syndrome, a condition involving excess cortisol, a short course of mifepristone seems to be effective in response to crises, in particular for cortisol-induced psychosis.

As far as psychotic depression is concerned, since the pathophysiology involves high levels of cortisol, there have been a number of studies looking at glucocorticoid antagonists for the treatment of psychosis in psychotic depression. Many are included in this 2016 Cochrane meta analysis, which concluded that more study should be done. For mifepristone in particular, there was an improvement in psychotic symptoms but not depressive symptoms. A more recent (2018) pooled analysis of studies that used a short (7 day) course shows dose related improvement in psychotic symptoms with a better safety margin. This strategy (short course, higher peak plasma level, better safety margin) is consistent with the physiology and pathophysiology of glucocorticoids.

These trials aren't perfect, and results are not mind blowing, but it seems to be a useful additional therapeutic strategy for a very particular problem. The fact that this particular glucocorticoid antagonist is also used as part of a drug combination for medical (i.e., not surgical) abortion isn't really relevant here. Many drugs (in particular, many psychiatric or neurological drugs) are contraindicated in pregnancy.


Besides any salutary mental health effects, mifepristone may also cause abortion. According to the 2008 report by the APA Task Force on Mental Health and Abortion:

"The best scientific evidence published indicates that among adult women who have an unplanned pregnancy, the relative risk of mental health problems is no greater if they have a single elective first-trimester abortion or deliver that pregnancy," said Brenda Major, PhD, chair of the task force. "The evidence regarding the relative mental health risks associated with multiple abortions is more uncertain."


To me it seems dangerous to apply medication to cure depression that can also cause depression under certain conditions.


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