The hypothalamic-pituitary-adrenal (HPA) axis is the body’s main stress-response system, and cortisol is the major adrenal glucocorticoid hormone secreted in human beings. HPA axis activity and cortisol secretion is regulated by a negative feedback system involving glucocorticoid receptors. Dysregulation of the HPA axis and increased cortisol levels have been implicated in mood, psychotic, and other psychiatric disorders. Mifepristone, as a potent antagonist of glucocorticoid receptors, has been studied or is currently being investigated as a potential therapeutic agent for psychotic depression, posttraumatic stress disorder, and alcohol and cocaine dependence, as well as for mitigating the weight gain associated with the use of antipsychotic drugs and for improving cognitive dysfunction in schizophrenia and bipolar disorder. This article will review some of the work in these areas.
Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses grant funding from Corcept Therapeutics.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail:
Posted Online: June 07, 2013
The hypothalamic-pituitary-adrenal (HPA) axis is the body’s main stress-response system (Eddie Gabry, Chrousos, & Gold, 2003 ). Cortisol is the major adrenal glucocorticoid hormone secreted in human beings. Ordinarily, cortisol is secreted in a regular circadian (24-hour) pattern, with a morning peak and an evening nadir. Under conditions of stress, the HPA axis can be transiently activated to increase cortisol secretion from the adrenal glands. The activity of the HPA axis is regulated by a negative feedback system involving a balance between mineralocorticoid receptors (MCR) and glucocorticoid receptors (GCR). Cortisol binds with a high affinity to MCR and with a low affinity to GCR. Cortisol preferentially binds to high-affinity receptors before binding to low-affinity receptors. The binding of cortisol to MCR in the hippocampus exerts an inhibitory effect on the HPA axis via projections to the hypothalamus, and this negative feedback regulates the circadian cortisol pattern of morning peaks and evening nadirs. When cortisol levels are high, the binding of cortisol to GCR in the hippocampus, hypothalamus, and pituitary then begins to mediate a negative feedback on HPA activity.
The HPA axis has been extensively investigated in various psychiatric conditions, but there has been particular interest in HPA axis abnormalities in mood and psychotic disorders. Among depressed patients, greater degrees of increased HPA axis activity and elevated cortisol levels are found in older patients, hospitalized patients, melancholia, and psychotic depression (Stetler & Miller, 2011 ). In studies of patients with schizophrenia and other psychotic disorders (including psychotic depression), the following findings have been reported (Walker et al., 2013 ): (a) evidence of increased HPA activity and elevated cortisol levels; (b) antipsychotic drugs typically reduce cortisol levels; (c) drugs that increase dopamine or exacerbate/induce psychotic symptoms also increase HPA activity; (d) down-regulation of GCR is demonstrated (suggesting decreased negative feedback on the HPA axis); and (e) reduced size of the hippocampus is found.
Mifepristone (RU-486, Mifeprex®, Korlym™) is a synthetic steroid drug that is a derivative of the contraceptive norethindrone (Mahajan & London, 1997 ). Mifepristone is a potent progesterone receptor antagonist, which can cause termination of pregnancy. Amid considerable controversy (DiPierri, 1994 ; Hussar, 2001 ), it was approved by the U.S. Food and Drug Administration (FDA) as an abortifacient agent in 2000. At doses greater than 200 mg per day, mifepristone also is a potent GCR antagonist but has no effect on MCR. Cushing’s syndrome is an endocrine condition characterized by excessive and prolonged elevations of cortisol. Mifepristone is used to treat various clinical manifestations of increased cortisol in Cushing’s syndrome, and the drug has an FDA indication to treat hyperglycemia associated with this syndrome (Morgan & Laufgraben, 2013 ). Given that dysregulation of the HPA axis may play a central or significant role in some psychiatric disorders, mifepristone (and other drugs that inhibit cortisol synthesis or block the effects of cortisol) has been investigated as potential treatments in psychiatry.
Mifepristone for Psychotic Depression
In a previous article (Howland, 2006 ), I reviewed four preliminary studies using mifepristone for the treatment of psychotic depression. Because mifepristone showed apparent benefit and was generally well tolerated in these four small studies, three larger double-blind, placebo-controlled Phase III pivotal studies of mifepristone for psychotic depression were conducted.
In the first study (DeBattista et al., 2006 ), 221 medication-free patients received mifepristone 600 mg per day or placebo for 7 days, followed by 21 days of usual treatment alone (with antide-pressant and/or antipsychotic drugs). Although mifepristone-treated patients were significantly more likely to have a 30% decrease in scores on the Brief Psychiatric Rating Scale (BPRS) compared to placebo, there was no significant difference between groups on the primary outcome measure (a 50% improvement in the BPRS positive symptom scale) or on secondary measures of depression (Nihalani & Schwartz, 2007 ). In the second study (Blasey, DeBattista, Roe, Block, & Belanoff, 2009 ), 258 medication-free patients received mifepristone 600 mg per day or placebo for 7 days, followed by 49 days of antidepressant drug treatment alone. There were no significant differences between groups on the primary outcome measure (50% BPRS positive symptom scale improvement) or secondary measures. In the third study (Blasey, Block, Belanoff, & Roe, 2011 ), 433 patients treated with antidepressant agents were randomized to receive one of three mifepristone doses (300, 600, or 1,200 mg) or placebo for 7 days, followed by 49 days of continued antidepressant drug treatment alone. There were no significant differences between groups on the primary outcome measure (50% improvement on the BPRS positive symptom scale).
Although these studies demonstrated no significant benefit for mifepristone based on their main outcome measures (Nihalani & Schwartz, 2007 ), an analysis of mifepristone plasma concentrations from participants in all three studies demonstrated a statistically significant linear correlation between plasma concentration and psychotic symptom improvement (Blasey, McLain, & Belanoff, 2013 ). In two studies, the response rate of patients with mifepristone concentrations greater than 1,660 ng/mL was significantly greater than the response rate in placebo-treated patients. Based on this analysis, another psychotic depression study is being conducted in which participants are randomized to receive mifepristone 1,200 mg per day or placebo for 7 days, followed by 49 days of antidepressant drug treatment alone (see http://ClinicalTrials.gov, trial NCT00637494).
Mifepristone and Antipsychotic Drug-Associated Weight Gain
Increased cortisol is associated with the development of hypertension, insulin resistance, hyperglycemia, and obesity (seen, for example, in Cushing’s syndrome). Antipsychotic drugs also are associated with weight gain and other metabolic effects. Although the mechanism(s) mediating this drug effect has not been clearly elucidated, some work has suggested that the adrenal axis might play a role (Belanoff, Blasey, Clark, & Roe, 2010 ). Two randomized controlled studies (conducted in lean men who were psychiatrically and medically healthy) found that taking mifepristone 600 mg per day significantly attenuated the weight gain and some adverse metabolic effects associated with taking olanzapine (Zyprexa®) during a 14-day trial (Gross et al., 2009 ) and taking risperidone (Risperdal®) during a 28-day trial (Gross, Blasey, Roe, & Belanoff, 2010 ). Hence, the weight gain caused by taking olanzapine or risperidone alone was significantly lessened when either drug was taken together with mifepristone. Other investigational drugs that block GCR are being studied for their mitigating effects on antipsychotic drug-induced weight gain (Belanoff et al., 2010 ).
Mifepristone and Other Psychiatric Uses
The hippocampus has a central role in learning and memory, and it has high concentrations of MCR and GCR (which function as part of the negative feedback system for the HPA axis as noted above). Administration of glucocorticoid steroid drugs (e.g., prednisone) often results in cognitive impairment. Persistently elevated cortisol levels (i.e., in Cushing’s syndrome) are associated with cognitive impairment. Activation of GCR is associated with hippocampal damage. Imaging studies of patients with Cushing’s syndrome, severe depression, schizophrenia, and posttraumatic stress disorder (PTSD) have demonstrated hippocampal atrophy in subgroups of these patients. This finding has been attributed to persistently elevated cortisol. Although mifepristone affects cortisol levels in schizophrenia and bipolar disorder (Gallagher, Watson, Dye, Young, & Nicol Ferrier, 2008 ), the drug has been demonstrated to improve some measures of cognitive function only in bipolar depression (Watson et al., 2012 ) and not in schizophrenia (Gallagher, Watson, Smith, Ferrier, & Young, 2005 ). There is potential interest in the use of mifepristone for treating Alzheimer’s disease, but no definitive work has been conducted (Belanoff, Jurik, Schatzberg, DeBattista, & Schatzberg, 2002 ; Dhikav & Anand, 2007 ; Pomara, Doraiswamy, Tun, & Ferris, 2002 ). A small 8-participant, 1-week placebo-controlled pilot study found significant benefit for mifepristone 600 mg per day in combat-related PTSD (Golier, Caramanica, DeMaria, & Yehuda, 2012 ). Several studies of mifepristone and PTSD are currently listed on http://ClinicalTrials.gov (trials NCT01490697, NCT01739335, NCT00554177, NCT00046553, NCT00691067). “Stress” may play a role in addictions, and mifepristone has been shown to reduce cocaine and alcohol self-administration in animal studies (Uhart & Wand, 2009 ). Although no human studies have yet been published, two studies proposing to investigate the effect of mifepristone on cocaine and alcohol use are listed on http://ClinicalTrials.gov (trials NCT01134198 and NCT01548417).
Clinical Use of Mifepristone
The FDA-approved mifepristone dose range (for its labeled indications) is 300 to 1,200 mg per day. If ever approved for psychotic depression, high doses (to achieve higher serum concentrations) are likely to be necessary. It should be noted that the apparent antipsychotic effect of mife-pristone is greater than its antidepressant effect, and concurrent treatment with an antidepressant drug would be necessary. The duration of treatment with mifepristone for Cushing’s syndrome would be considered long term, whereas the investigational studies of psychotic depression used the drug for approximately 1 week. The reason for using mifepristone for close to 1 week in the psychotic depression studies was predicated on the fact that it has rapid biological effects on the HPA axis, that the apparent antipsychotic effects occurred rapidly, and that the biological and clinical effects persist for weeks after the drug is stopped. If mifepristone is further developed as a treatment for psychotropic drug–related weight gain, it would probably be used for an indefinite treatment duration.
Common adverse effects of mifepristone (based on studies in Cushing’s syndrome) include fatigue, nausea, vomiting, diarrhea, headache, edema, hypertension, and hypokalemia. Dysmenorrhea and abnormal vaginal bleeding can occur in women. Adrenal insufficiency and prolonged cardiac QT intervals are rare adverse effects. The clinical studies for psychotic depression and weight gain did not report significant or serious adverse effects for mifepristone. Mifepristone is metabolized by the cytochrome P-450 hepatic enzyme 3A4 (CYP3A4). Inhibitors of this enzyme will increase drug levels, whereas enzyme inducers will result in lower levels. Mifepristone also inhibits the hepatic enzymes CYP3A, CYP2C8/2C9, and CYP2B6, which will cause higher concentrations of drugs metabolized by these enzymes.
Mifepristone, an interesting drug with myriad real and potential clinical uses, is currently FDA approved for inducing abortion and for treating hyperglycemia in Cushing’s syndrome. The drug is being investigated for other medical uses (including certain cancers, endometriosis, uterine fibroids, and HIV infection). As described here, mifepristone also has several potential therapeutic uses in psychiatry. Depression is common in Cushing’s syndrome. Psychiatric nurses may see these patients, including some who might be taking mifepristone. For this reason—and given the potential future use of this drug for other clinical purposes—nurses should become familiar with mifepristone.
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