Review
`
`TRENDS in Endocrinology and Metabolism Vol.17 No.3 April 2006
`
`The use of mifepristone in the
`treatment of neuropsychiatric
`disorders
`
`Charles DeBattista and Joseph Belanoff
`
`Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305, USA
`
`Mifepristone is a potent glucocorticoid and progester-
`one receptor antagonist. The pathophysiology of a
`number of neuropsychiatric disorders implicates
`abnormalities in glucocorticoid function. These include
`mood disorders such as psychotic major depression and
`bipolar depression. In addition, cognitive disorders such
`as Alzheimer’s disease might also be partially mediated
`by abnormalities in the hypothalamic–pituitary–adrenal
`axis. Preliminary studies suggest that mifepristone
`might have a role in the treatment of a number of
`neuropsychiatric disorders.
`
`Introduction
`Mifepristone is a derivative of the progestin northindone,
`which has a high affinity for the progesterone and
`glucocorticoid II (GRII) receptors [1]. In addition, mife-
`pristone is a low affinity binder of the androgen receptor. It
`has little or no effect on estrogen, monoamine, histamine,
`muscarinic or mineralocorticoid receptors [2]. Its anti-
`progesterone effects became evident at Roussel Uclaf,
`where it was synthesized in the early 1980s, and its
`applications in the medical termination of pregnancy have
`been responsible for most of the controversy surrounding
`the drug. The application of the antiprogesterone effects of
`the drug have led to investigation of mifepristone in the
`treatment of endometriosis [3], as a contraceptive [4] and
`in the treatment of progesterone-sensitive tumors such as
`meningioma, utererine myomas [5] and breast, prostate
`and ovarian cancer [6].
`By contrast,
`investigations into the application of
`mifepristone as an antiglucocorticoid agent have lagged
`behind the more extensive work that has been completed
`on antiprogesterone effects [7]. Mifepristone has been
`used successfully in the treatment of Cushing’s syndrome
`secondary to ectopic adrenocorticotropic hormone (ACTH)
`hypersecretion or adrenal tumors.
`Mifepristone appears to have a specific effect on
`glucocorticoid receptors. Two types of glucocorticoid
`receptors have been identified: GRI and GRII. GRI also a
`the mineralocorticoid receptor is a high-affinity receptor
`for cortisol [8]. GRI has approximately ten times the
`affinity for circulating cortisol than does GRII. Thus, the
`GRII receptor will only be occupied when GRI is
`
`Corresponding author: DeBattista, C. (debattista@stanford.edu).
`
`saturated. Whereas GRI appears to mediate more rapid
`adaptations of the hypothalamic–pituitary–adrenal (HPA)
`axis, GRII appears to be more involved in the long-term
`effects on the stress response.
`Mifepristone eliminates the negative feedback control
`of cortisol on ACTH [9]. Thus, mifepristone results in an
`increase in both cortisol and ACTH. The antiglucocorticoid
`effects of mifepristone are dose dependent and can be
`reversed by glucocorticoids. For example, 1 mg of dexa-
`methasone antagonizes 400 mg of mifepristone [7]. Unlike
`other antiglucocorticoids, mifepristone appears to spare
`pituitary and adrenocortical reserves with short-term use
`[10]. In addition, mifepristone might have mild glucocor-
`ticoid agonist activity [11]. The selective antagonist and
`mild agonist properties of mifepristone in the absence of
`endogenous or exogenous corticosteroid might explain
`why even chronic use of the drug has rarely been
`associated with hypoadrenalism. [12,13]. However, the
`rate of hypoadrenalism in patients on mifepristone is
`difficult to assess because mifepristone will raise cortisol
`and ACTH levels and confound the laboratory assessment
`of hypoadrenalism. Thus, the diagnosis of adrenal
`insufficiency in mifepristone treated patients must be
`made by the evaluation of clinical signs and symptoms
`rather than by measuring cortisol levels.
`
`Rationale for use of a glucocorticoid receptor antagonist
`in psychiatry
`A number of neuropsychiatric disorders have been
`characterized by abnormalities in the HPA axis, including
`major depression and its subtypes, anxiety disorders such
`as post-traumatic stress disorder and panic disorder, and
`cognitive disorders such as Alzheimer’s disease and
`minimal cognitive impairment of aging [14].
`The HPA abnormalities in major depression have been
`studied more extensively than have any other psychiatric
`disorders. Major depression is associated with elevated
`levels of urinary free cortisol and, in plasma, 24-hour 17-
`hydroxycorticoid, basal cortisol and corticotropin-releas-
`ing factor (CRF), and nonsuppression in the dexametha-
`sone suppression test (DST)
`[15]. Psychotic major
`depression has been particularly associated with HPA
`abnormalities [16].
`Cortisol hypersecretion and resistance to dexametha-
`sone suppression might be an artifact of chronic stress
`states, including depression. Alternatively, abnormalities
`
`www.sciencedirect.com 1043-2760/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2006.02.006
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`
`in the HPA axis might directly contribute to symptoms of
`neuropsychiatric disorders.
`At least two lines of evidence suggest that HPA
`overactivity might lead directly to the symptoms of some
`disorders. One piece of evidence is that exogenous
`glucocorticoids are frequently associated with psychiatric
`symptoms. Glucocorticoids, such as cortisol and predni-
`sone, particularly when given at high doses for extended
`periods of time, might produce symptoms that include
`depression, hypomania, insomnia, cognitive deficits and
`psychosis [17]. Another source of evidence that HPA
`abnormalities are involved directly in the pathophysiology
`of some neuropsychiatric disorders comes from patients
`with Cushing’s syndrome. This condition is frequently
`associated with mood and cognitive symptoms, and in
`some cases with suicidality and psychosis [18]. There
`appears to be a direct correlation between the severity of
`symptoms and circulating cortisol
`levels [19]. As the
`cortisol levels normalize with treatment, neuropsychiatric
`symptoms tend to resolve [20]. Thus, both exogenous and
`endogenous hypercortisolemia might produce, and not
`just be a consequence of, neuropsychiatric symptoms.
`DST nonsuppression has been associated with specific
`symptoms,
`including cognitive deficits, mood lability,
`anxiety and decreased libido. In one study, Reus [21]
`found that nonsuppressors in the DST tended to be more
`anxious and have more suicidal thoughts as well as
`insomnia, regardless of their primary diagnosis.
`If hypercortisolemia is involved directly in the patho-
`physiology of neuropsychiatric disorders, then antigluco-
`corticoid agents would be expected to have a role in the
`treatment of these disorders. Several types of anticortisol
`agent have been investigated in psychiatric disorders.
`These include cortisol synthesis inhibitors such as
`ketoconazole, CRF antagonists and glucocorticoid receptor
`antagonists such as mifepristone.
`A number of small, open-label and double-blind studies
`have examined the use of cortisol synthesis inhibitors in
`the treatment of depression. For example, in a double-
`blind study of 20 depressed patients, ketoconazole was
`associated with significant antidepressant effects only in
`those patients who were hypercortisolemic at baseline
`[22]. A number of open-label studies also support an
`antidepressant effect of ketoconazole, metyrapone and
`aminoglutethimide in unipolar and bipolar depression
`[23]. In addition, there is a suggestion that ketoconazole
`might relieve depressive but not psychotic symptoms in
`patients with schizophrenia and schizoaffective disorder
`[24]. The available literature on cortisol synthesis
`inhibitors in the treatment of depression includes fewer
`than 120 patients [25]. Although the majority of studies
`have suggested that cortisol synthesis inhibitors have
`antidepressant benefits, limited conclusions can be drawn,
`given the small sample sizes and primarily open-label
`design of these studies. In addition, cortisol synthesis
`inhibitors such as ketoconazole might also have signifi-
`cant side effects at doses that suppress cortisol synthesis
`(usually greater than 400 mg/day). These include
`decreased androgen and aldosterone synthesis, elevations
`in pregnenolone, nausea, vomiting and, more rarely,
`hypoadrenalism and hepatotoxicity [26].
`
`www.sciencedirect.com
`
`A second anticortisol strategy involves the use of CRF
`antagonists. Central administration of CRF in laboratory
`animals produces symptoms akin to depression, including
`sleep disruption, a reduction in exploratory behaviors,
`increased nervousness, decreased appetite, psychomotor
`slowing and decreased libido [27,28]. A number of studies
`suggest that CRF is hypersecreted in depression [29,30].
`In animal models of depression, CRF antagonists appear
`to have antidepressant and anxiolytic properties [31].
`However, only one human open-label Phase II study has
`been completed to date. In a 30-day study, 20 patients
`received two different dosing regimens of the CRF
`antagonist R121919 [32]. The patients experienced sig-
`nificant improvements in depression and anxiety at the
`day 30 endpoint. In addition, affective symptoms wor-
`sened when the drug was withdrawn.
`
`Mifepristone in the treatment of neuropsychiatric
`disorders
`Mifepristone might have advantages over other cortisol-
`specific strategies in the treatment of psychiatric dis-
`orders. It appears to be well tolerated and has not been
`associated with adrenal insufficiency or hepatotoxicity. It
`has been extensively studied since the early 1980s and
`much is known about the safety profile of mifepristone.
`Evidence that mifepristone might have psychotropic
`effects emerged in a study by Van der Lely et al. [33]. Two
`patients with advanced Cushing’s syndrome who
`developed severe depression, suicidality and psychoses
`had substantial resolution of these symptoms within
`48 hours after the administration of mifepristone.
`Mifepristone has been investigated primarily in the
`treatment of depressive disorders (Table 1). Murphy et al.
`[34] completed an open-label study of mifepristone
`200 mg/day in four nonpsychotic patients with chronic
`depression. Patients were treated for up to eight weeks,
`and three of the four were said to have improved.
`However, only one patient completed the full eight
`weeks, and this patient did not achieve substantial
`benefit. The other patients discontinued between two
`and six weeks as a result of side effects, which might not
`have been related to mifepristone, including diarrhea and
`worsened hip pain. Because psychotic depression might be
`characterized by more consistent HPA dysregulation than
`is the case for other types of depression, Belanoff et al. [35]
`examined the psychotropic effects of mifepristone in a
`group of five patients with psychotic depression. In a
`double-blind, crossover design, patients were treated for
`four days with mifepristone 600 mg/day or placebo and
`then crossed over to the alternate treatment. All five
`patients showed a substantial improvement in depression,
`and four of five also experienced an improvement in
`psychotic symptoms. An open-label study examined the
`dose-related effects of mifepristone in psychotic
`depression [36]. Thirty patients were randomized to
`seven days of open-label treatment with 50 mg/day,
`600 mg/day or 1200 mg/day mifepristone. The low dose,
`50 mg/day, is thought to have significant antiprogesterone
`effects but no substantial effects on cortisol. Of the 19
`patients treated in the 600–1200 mg group, 13 had at least
`a 30% decrease in psychotic symptoms, as measured by
`
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`119
`
`Table 1. Mifepristone in the treatment of neuropsychiatric disorders
`Psychiatric disorder
`Study design
`n
`Dose
`Duration
`Depression
`Open label
`4
`200 mg/day
`8 weeks
`Psychotic depression
`Double blind
`5
`600 mg/day
`4 days
`crossover
`Open label
`
`Psychotic depression
`
`30
`
`50 mg/day
`600 mg/day
`1200 mg/day
`
`7 days
`
`Outcome
`3 out of 4 improved
`5out of 5 improvement in depression
`4out of 5 improvement in psychosis
`13 out of 19 in 600–1200 mg/day group
`improved
`4 out of 11 in 50 mg/day group
`improved
`No significant difference between
`treatment groups
`
`Improvement in psychosis in
`mifepristone groupOimprovement in
`placebo group at day 7, sustained to
`day 28
`Improvement in psychosis and
`depression at week 4
`
`Improvement in mood and cognition in
`mifepristone groupOplacebo group
`MifepristoneOplacebo in Alzheimer’s
`disease assessment scale cognitive
`subtest
`Mifepristone Z placebo
`
`Refs
`[34]
`[35]
`
`[36]
`
`[38]
`
`[39]
`
`[37]
`
`[41]
`
`[42]
`
`[44]
`
`Psychotic depression
`
`Psychotic depression
`
`Double blind
`parallel group
`
`Double blind
`parallel group
`
`208
`
`600 mg/day
`
`221
`
`600 mg/day
`
`Psychotic depression
`
`Open label
`
`Psychotic depression
`Bipolar depression
`
`Alzheimer’s disease
`
`Double blind
`Double blind
`crossover
`Double blind
`
`20
`
`30
`20
`
`9
`
`600 mg/day
`
`600 mg/day
`600 mg/day
`
`200 mg/day
`
`7 days dosing C usual
`treatment with 28-day
`follow-up
`7 days dosing
`mifepristone versus
`placebo with up to 56-
`day follow-up
`6 days of dosing with 8
`week follow-up
`8 days
`7 days dosing with 6-
`week follow-up
`6 weeks
`
`Schizophrenia
`
`Double blind
`crossover
`
`20
`
`600 mg/day
`
`7 days
`
`the Brief Psychiatric Rating Scale (BPRS) versus 4 out of
`11 patients in the 50 mg/day group. Similarly, 8 out of 19
`patients in the high-dose group had a more than 50%
`improvement in depression, versus only 2 out of 11
`patients in the low-dose group. Patients in the high-dose
`group also experienced the expected rise in cortisol and
`ACTH levels, whereas the 50 mg/day group did not. More
`recently, another open-label study found that mifepris-
`tone-treated patients with psychotic depression showed
`significant benefits in both depression and psychosis after
`six days of treatment [37].
`Two larger double-blind placebo-controlled trials have
`now been completed on mifepristone in the treatment of
`psychotic depression. In the first study of 208 psychotic-
`ally depressed patients, the effect of adding seven days of
`mifepristone or placebo to usual treatment was examined
`in patients hospitalized for the purposes of the study [38].
`Patients admitted to the study were taking an average of
`four psychotropic drugs. Both treatment groups improved
`significantly from baseline but did not differ from each
`other on the primary endpoint (a 30% reduction in the
`BPRS at seven and 28 days). However,
`in post hoc
`analyses, patients who received mifepristone were more
`likely to achieve a complete response (i.e. becoming
`largely asymptomatic on the Hamilton depression scale
`[HamD] and the BPRS [HamD!7, BPRS!25]). In
`addition, mifepristone-treated patients were less likely
`to require antipsychotic drugs and were more likely to be
`discharged earlier from the hospital. The use of treat-
`ments known to be effective (concurrent antidepressant
`or antipsychotic use and hospitalization) might have
`reduced the ability to demonstrate a difference between
`groups on the primary endpoint. In the second study, the
`use of antidepressant or antipsychotic medication was
`not allowed for at least seven days prior to randomization
`or for the duration of the seven days of study drug
`administration in 221 psychotically depressed patients
`
`www.sciencedirect.com
`
`[39]. Study participants received either placebo or
`mifepristone 600 mg/day for seven days and were then
`followed for up to 56 days. Mifepristone-treated patients
`were significantly more likely to show an improvement in
`psychotic symptoms by day 7, persisting up to 28 days on
`the BPRS (pZ0.041) and the positive symptom subscale
`of the BPRS (pZ0.006). Significant antipsychotic benefits
`appeared to persist up to day 56, seven weeks after the
`study drug was discontinued. Antidepressant effects were
`not seen at days 7 or 28. However, a trend to
`improvement on the HamD was seen at day 56 (pZ
`0.056). In both studies, seven days of mifepristone
`treatment appeared to be well tolerated, with only rash
`appearing statistically more commonly in mifepristone-
`treated patient (4%) than in placebo-treated patients.
`Except for the expected and temporary rise in ACTH and
`cortisol in mifepristone-treated patients, there were no
`clinically significant differences between groups on
`laboratory studies,
`including blood chemistry, blood
`counts and electocardiograms. Most recently, Flores et
`al. [40] evaluated 30 psychotically depressed patients
`randomized to mifepristone 600 mg/day or placebo for
`eight days. Mifepristone patients were significantly more
`likely to experience a 50% reduction in psychotic
`symptoms, as measured by the BPRS, than were
`placebo-treated patients. Depression also appeared to
`improve more in the mifepristone-treated patients but
`this effect did not reach statistical significance.
`Mifepristone has also been examined in the treatment
`of bipolar depression. Young et al. [41] investigated the
`benefits of mifepristone 600 mg/day for seven days versus
`placebo in 20 patients with bipolar depression. Mifepris-
`tone-treated patients experienced significantly greater
`improvements in cognition (working spatial memory)
`and mood, as measured by the HamD and Montgomery–
`Asberg depression scale. In addition, the drug appeared to
`be well tolerated.
`
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`Another possible application of mifepristone is in the
`treatment of cognitive disorders, including Alzheimer’s
`disease. Pomara et al. [42] completed a small double-blind
`study of mifepristone in patients with mild to moderate
`Alzheimer’s disease. Nine patients were treated with
`either mifepristone 200 mg/day or placebo for six weeks.
`Mifepristone-treated patients performed better on the
`Alzheimer’s disease assessment scale cognitive subtest
`total score by six weeks, with a 2.67-point improvement on
`active drug versus a 1.67-point worsening in placebo-
`treated patients. This difference did not achieve statistical
`significance perhaps because of the small sample size.
`Although mifepristone appeared to be generally well
`tolerated, two mifepristone-treated patients developed a
`rash and one developed a clinically nonsignificant
`hypokalemia. A more adequately powered double-blind
`study is currently underway to evaluate the efficacy of
`mifepristone in the adjunctive treatment of Alzheimer’s
`disease [43].
`Given the preliminary data suggesting that mifepris-
`tone might improve cognition in patients with Alzheimer’s
`disease and bipolar depression, Gallagher et al. [44]
`examined the effects of mifepristone on cognition and
`psychosis in schizophrenia. They treated 20 schizophrenic
`patients with mifepristone 600 mg/day or placebo and
`then crossed patients over to the alternative treatment.
`There were no significant differences between groups on
`measures of cognition or psychosis.
`
`Conclusions
`Mifepristone is a drug with a unique pharmacological
`profile that appears to have potential in the treatment of a
`number of neuropsychiatric disorders (Table 1). Thus far,
`the most convincing evidence is that mifepristone appears
`to produce a rapid reduction in psychotic symptoms in
`patients with psychotic depression. There is also the
`suggestion that mifepristone might have some utility in
`the treatment of other mood disorders and Alzheimer’s
`disease. In addition, many other neuropsychiatric dis-
`orders characterized by abnormalities in the HPA axis
`might also be treated by a potent glucocorticoid receptor
`antagonist. These include post-traumatic stress disorder,
`panic disorder, other psychotic disorders, such as schi-
`zoaffective disorder, and the minimal cognitive impair-
`ment of aging. The favorable side-effect profile of
`mifepristone relative to cortisol synthesis inhibitors
`might also provide a low cost-to-benefit ratio if the drug
`is proven to be effective in the treatment of any of these
`disorders. Controlled studies, now underway, will help to
`establish the potential role of mifepristone in the
`treatment of many neuropsychiatric disorders character-
`ized by abnormalities in the HPA axis.
`
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