R E V I E W
`
`Mifepristone (RU-486) treatment for
`depression and psychosis: a review of the
`therapeutic implications
`
`Peter Gallagher
`Allan H Young
`
`Stanley Research Centre, School of
`Neurology, Neurobiology and
`Psychiatry; University of Newcastle
`upon Tyne, UK
`
`Correspondence: Peter Gallagher
`School of Neurology, Neurobiology and
`Psychiatry, University of Newcastle upon
`Tyne, Leazes Wing (Psychiatry), Royal
`Victoria Infirmary, Queen Victoria Road,
`Newcastle upon Tyne, NE1 4LP, UK
`Tel + 44 191 282 4065
`Fax + 44 191 222 6162
`Email peter.gallagher@ncl.ac.uk
`
`Abstract: The mechanisms underlying the pathophysiology of severe psychiatric illnesses
`are complex, involving multiple neuronal and neurochemical pathways. A growing body of
`evidence indicates that alterations in hypothalamic–pituitary–adrenal (HPA) axis function
`may be a trait marker in both mood disorders and psychosis, and may exert significant causal
`and exacerbating effects on symptoms and neurocognition. At present, however, no available
`treatments preferentially target HPA axis abnormalities, although many drugs do increase
`feedback-regulation of the HPA axis at the level of the glucocorticoid receptor (GR). This
`action may in part underpin their therapeutic efficacy. Therapeutic interventions directly
`targeted at GR function may therefore have clinical benefit. The present review examines the
`current literature for the clinical utility of GR antagonists (specifically mifepristone) in mood
`disorders and psychosis. At present, most studies are at the “proof-of-concept” stage, although
`the results of preliminary, randomized, controlled trials are encouraging. The optimum strategy
`for the clinical application of GR antagonists is yet to be established, their potential role as
`first-line or adjunctive treatments being unclear. The therapeutic utility of such drugs will
`become known within the next few years following the results of larger clinical trials currently
`underway.
`Keywords: mifepristone, RU486, glucocorticoid receptor, cortisol, mood disorders, psychosis,
`treatment
`
`Introduction
`Overview
`Dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis has long been
`implicated in the pathogenesis and etiology of severe psychiatric illness. Studies
`have found evidence of reduced glucocorticoid receptor (GR) mRNA expression in
`post-mortem brain tissue samples from patients with mood disorders and psychosis
`(Knable et al 2001; Webster et al 2002; Lopez et al 2003). Many antidepressant
`drugs increase GR binding and/or number in brain tissue, suggesting that GR
`regulation may be one aspect of the therapeutic mechanism of action of antidepressants
`(and mood stabilizers), and the ability of a drug to regulate GR number may be a
`good predictor of therapeutic efficacy in patients with hypercortisolemia (McQuade
`and Young 2000). No drugs primarily or preferentially target the GR for use in
`psychiatry, although several are at present being examined for this purpose. The
`present review examines the current literature and proof-of-concept evidence for
`the clinical utility of GR antagonists (specifically mifepristone) in mood disorders
`and psychosis.
`
`Neuropsychiatric Disease and Treatment 2006:2(1) 33–42
`© 2006 Dove Medical Press Limited. All rights reserved
`
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`Gallagher and Young
`
`Search strategy
`In order to include other antiglucocorticoid agents that
`specifically target the GR, the terms (“mifepristone” or “RU
`486” or “RU 38486” or “ORG 34850”’ or “ORG 34116” or
`“ORG 34517”) were used in the initial search and combined
`with the terms (“mood disorders” or “psychosis” or
`“depression” or “bipolar disorder” or “schizophrenia”). The
`following databases were searched electronically: EMBASE
`(1980 to present), Medline (1966 to present), CINAHL
`(1982 to present), PsycINFO (1887 to present), and ISI Web
`of Science (1981 to present). Citation lists of relevant studies
`and reviews were checked for other relevant trials.
`
`Background
`The hypothalamic–pituitary–adrenal
`(HPA) axis
`One of the major hormonal systems activated during stress
`is the HPA axis. Neurones in the paraventricular nucleus
`(PVN) of the hypothalamus secrete corticotrophin-releasing
`hormone (CRH) which is transported via the hypothalamo-
`pituitary portal circulation to the anterior pituitary where
`adrenocorticotropic hormone (ACTH) is secreted through
`stimulation of pituitary corticotrophs. ACTH then enters the
`peripheral circulation and stimulates the adrenal cortex to
`secrete glucocorticoids: corticosterone in rats, and cortisol
`in humans.
`Cortisol is essential for life. It is involved in the
`maintenance of glucose production from protein, facilitates
`fat metabolism, supports responsiveness of the vascular tree,
`modulates central nervous system function, and profoundly
`affects the immune system (Berne and Levy 1998).
`Importantly, it is a major regulator of the physiological stress
`response, through a negative feedback mechanism via
`corticosteroid receptors. Two distinct corticosteroid receptor
`subtypes have been identified: the mineralocorticoid
`receptor (MR; Type I) and the glucocorticoid receptor (GR;
`Type II). Both receptor types have been implicated in
`mediating glucocorticoid feedback (Reul and de Kloet
`1985), but there are several differences in the distribution,
`occupancy, and binding properties of the two receptors that
`affect their physiological role.
`The MR is highly expressed in the limbic system whereas
`the GR is ubiquitous, being present in both subcortical and
`cortical structures, with a preferential distribution in the
`prefrontal cortex (Patel et al 2000). Glucocorticoids bind to
`the MR with 6–10 times higher affinity than to GR (de Kloet
`et al 1999). Consequently, at basal levels near complete
`
`occupation (~90%) of MRs occurs. GRs, however, are little
`occupied at this point (~10%), and only during times of
`high cortisol secretion, such as the circadian peak or during
`stress, do MRs become saturated and GR occupancy
`increases (to ~67%–74%) (Reul and de Kloet 1985). GR
`function is therefore critical in the regulation of the HPA
`axis at times of glucocorticoid excess and it is now
`recognized that disruption of this self-regulating system may
`be a major factor in the pathophysiology of mood disorders
`and psychosis.
`
`The HPA axis in mood disorders and
`psychosis
`The first observations of an elevation in basal cortisol levels
`in patients with depression were made almost half a century
`ago by Board and colleagues, and these observations have
`been repeatedly replicated (Board et al 1956; Gibbons 1964).
`It should be noted that the extent of HPA axis dysfunction
`differs by severity and subtype of depression. For example,
`a recent study found no evidence of hypercortisolism in
`women with major depression from a community-based
`setting (Strickland et al 2002), while pronounced HPA axis
`dysfunction has been described in depressed subjects with
`psychotic features (Posener et al 2000). The presence of
`psychosis may be related to hypercortisolism independently
`of mood symptoms (Christie et al 1986). Hypercortisolism
`has also been recognized in symptomatic schizophrenic
`patients (Ritsner et al 2004; Ryan et al 2004).
`Improvements in the methodology utilized has overcome
`some of the complexities surrounding the profiling of HPA
`axis dysfunction, revealing alterations in the diurnal pattern
`of cortisol secretion in depression (Deuschle et al 1997;
`Posener et al 2000), while employing less precise techniques
`such as total 24-hour cortisol output can fail to detect
`dysfunction (Brouwer et al 2005). Similarly, the measure-
`ment of the molar ratio of cortisol to other adrenal steroids
`can reveal differences – in the absence of hypercortisolism
`per se – in moderately depressed, non-psychotic outpatients
`(Young et al 2002). The most sensitive tests of HPA axis
`function, however, are “activating” tests, whereby
`neuroendocrine responses are measured following pharma-
`cological challenge. These are preferred not only because of
`their increased sensitivity, but because they elucidate
`functional changes in the HPA axis at the receptor level.
`The GR agonist dexamethasone has been used widely
`to examine HPA axis negative feedback integrity (Rush et
`al 1996). An abnormal (nonsuppressed) cortisol response
`
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`to dexamethasone administration has been described in
`schizophrenia (Castro et al 1983; Muck-Seler et al 1999)
`(but also see Ismail et al 1998) and mood disorders (Rush
`et al 1996), and may be exacerbated by psychotic features
`(Duval et al 2000). The combined dexamethasone–
`corticotrophin-releasing hormone (dex–CRH) test is also
`abnormal in bipolar patients during relapse and recovery
`(Schmider et al 1995; Rybakowski and Twardowska 1999;
`Watson et al 2004). Furthermore, GR abnormalities have
`been observed in post-mortem studies which show evidence
`of reduced GR mRNA expression in post-mortem brain
`tissue samples from patients with bipolar disorder and
`schizophrenia (Knable et al 2001; Webster et al 2002; Lopez
`et al 2003).
`
`Consequences of HPA axis
`dysregulation and implications for
`treatment
`Pronounced neurocognitive dysfunction is frequently
`described in mood disorder (Porter et al 2003; Thompson
`et al 2005); this may be worse in patients with psychotic
`features (Fleming et al 2004). In schizophrenia, the
`symptomatic clinical profile of the illness is complex and
`diverse, but neurocognitive impairment is consistently
`reported and some authors have argued that such
`impairments may be the cardinal feature of the illness
`(Elvevag and Goldberg 2000).
`Elevated levels of corticosteroids are known to impair
`learning and memory. This has been demonstrated by acute
`(Lupien and McEwen 1997; Modell et al 1997) and
`subchronic (Young et al 1999) administration of exogenous
`corticosteroids in healthy volunteers and in conditions
`associated with a chronic elevation of endogenous cortisol
`levels, for example Cushing’s disease (Starkman et al 2001;
`Forget et al 2002), which is also associated with a high
`incidence of depression that notably resolves with correction
`of the hypercortisolemia (Dorn et al 1997). Patients receiving
`systemic corticosteroid therapy also often exhibit cognitive
`impairment and, in some instances, symptoms of
`(hypo)mania, depression, and psychosis (Brown and
`Chandler 2001). HPA axis dysregulation therefore has been
`suggested to be one of the principal causes of both low mood
`and neurocognitive impairment, possibly through inter-
`actions with other neurotransmitter system (McAllister-
`Williams et al 1998; Porter et al 2004).
`The known consequences of hypercortisolemia on
`neurocognitive function and mood, and the central role of
`
`Mifepristone for depression and psychosis
`
`corticosteroid receptors in HPA axis regulation, therefore
`indicate a possible use for antiglucocorticoid drugs and make
`the GR specifically a potentially viable target for therapeutic
`intervention.
`
`Mifepristone (RU-486)
`Discovery and development
`Mifepristone (or RU-486) is a synthetic steroid with both
`antiprogesterone and antiglucocorticoid properties. The
`compound is a 19-nor steroid with substitutions at positions
`C11 and C17 (17 beta-hydroxy-11 beta-[4-dimethylamino
`phenyl] 17 alpha-[1-propynyl]estra-4,9-dien-3-one) which
`antagonizes cortisol action competitively at the receptor level
`(Nieman et al 1985). It was discovered in the early 1980s
`by the French pharmaceutical company Roussel–Uclaf
`(Herrmann et al 1982; Jung-Testas and Baulieu 1983). At
`present it is licenced in the UK for the medical termination
`of pregnancy (trade name: Mifegyne®; marketing
`authorization holder: Exelgyn Laboratories, Paris, France).
`Mifepristone was the first antiprogestin to be developed and
`it has been evaluated extensively for its use as an
`abortifacient. The original target for the research group,
`however, was the discovery and development of compounds
`with antiglucocorticoid properties (Hazra and Pore 2001),
`and it is these properties that are of greatest interest for their
`application in the treatment of severe mood disorders and
`psychosis.
`
`Pharmacokinetics and
`pharmacodynamic activity
`The pharmacokinetics of mifepristone are dose-dependent
`in humans (Ashok et al 2002). Due to saturation of the
`serum-binding capacity, high-dose mifepristone results in
`nonlinear kinetics, whereas lower doses show a linear pattern
`(Leminen et al 2003). For example, following administration
`of doses of 50–800 mg, after the absorption and distribution
`phase of approximately 4–6 hours, the serum concentration
`of mifepristone remains in the micromolar range for the
`next 24–48 hours. Within the dose range of 2–25 mg, serum
`concentrations of mifepristone, as well as the areas under
`the concentration–time curves (AUC), increase according
`to dose (Sitruk-Ware and Spitz 2003).
`Following a single oral dose of 600 mg mifepristone,
`the binding equivalent is present in measurable
`concentrations 7 days after administration, only decreasing
`below assay detection limits > 7–14 days (Foldesi et al 1996).
`In this study, the concentration of the mifepristone binding
`
`Neuropsychiatric Disease and Treatment 2006:2(1)
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`Gallagher and Young
`
`equivalent reached a peak within approximately 2 hours
`(doses 200–600 mg), indicating rapid absorption. Peak levels
`were significantly greater following the 600 mg dose
`(Cmax = 12.3 µmol/L vs 200 mg: 6.30 µmol/L), while the
`bioavailability as assessed by the AUC was significantly
`greater following 600 mg dose than both 200 and 400 mg.
`These were not, however, directly proportional to the dose
`increase (Foldesi et al 1996).
`In contrast to mifepristone plasma concentrations,
`plasma concentrations of its metabolites do increase in a
`dose-dependent manner when larger doses are administered,
`so that serum metabolite concentrations are close to, or even
`in excess of, those of the parent compound (Lahteenmaki
`et al 1987). These metabolites have some antiprogestin
`and antiglucocorticoid properties, and therefore may
`mediate some of the actions of mifepristone (Spitz and
`Bardin 1993).
`
`Side effects of chronic mifepristone
`administration
`Laue and colleagues reported that in healthy male normal
`volunteers who received mifepristone (10 mg/kg/day), 8 of
`11 subjects developed generalized exanthem after 9 days.
`One subject developed symptoms and signs consistent with
`the diagnosis of adrenal insufficiency (Laue et al 1990).
`For immune function, it was reported that total white blood
`cell counts, absolute lymphocyte, neutrophil, and eosinophil
`counts, erythrocyte sedimentation rate, and quantitative
`immunoglobulins did not change. Similarly, T-, B-, and
`natural killer cell subsets did not change during treatment.
`Furthermore, functional evaluation of lymphocyte
`cytotoxicity and proliferation revealed no changes.
`A study using lower doses (200 mg/day for 2 to > 31
`months) in 14 patients with unresectable meningiomas
`reported milder side effects. Most commonly, fatigue was
`noted in 11 of the 14 patients (Grunberg et al 1991).
`However, in a study of mifepristone (200 mg/day for up to
`8 weeks) in chronic depression, 1 of 4 patients discontinued
`treatment prematurely because of the appearance of a rash
`(Murphy et al 1993). In patients with psychotic depression
`receiving mifepristone (50–1200 mg/day for 7 days), 2 of
`10 patients in the 600-mg group and 1 of 9 in the 1200-mg
`group reported uterine cramping, while 1 of 11 patients in
`the 50-mg group and 1 of 9 patients in the 1200-mg group
`(but none in the 600-mg group) reported a rash. In both
`cases, this had abated 1–2 months after study completion
`(Belanoff et al 2002).
`
`Antiglucocorticoid effects of
`mifepristone
`A large amount of human clinical data on the anti-
`glucocorticoid actions of mifepristone have come from
`studies in Cushing’s disease (Sartor and Cutler 1996).
`Nieman and colleagues administered mifepristone orally at
`increasing doses of 5, 10, 15, and 20 mg/kg/day for a
`9-week period to a patient with Cushing’s syndrome due to
`ectopic ACTH secretion. Following treatment, the somatic
`features associated with Cushing’s syndrome ameliorated
`and blood pressure normalized. Importantly, suicidal
`ideation and depression also resolved, and all biochemical
`glucocorticoid-sensitive parameters normalized (Nieman et
`al 1985).
`Mifepristone has also been shown to rapidly reverse
`acute psychosis in Cushing’s syndrome (van der Lely et al
`1991). More recently, high-dose (up to 25 mg/kg/day), long-
`term mifepristone administration was shown to normalize
`all biochemical glucocorticoid-sensitive measurements, as
`well as significantly reverse psychotic depression in a patient
`with Cushing’s syndrome caused by an ACTH-secreting
`pituitary macroadenoma (Chu et al 2001). Although the
`adrenal axis also normalized, the 18-month-long
`mifepristone treatment course led to the development of
`severe hypokalemia (attributed to excessive cortisol
`activation of MRs), which responded to spironolactone
`administration.
`
`Use of mifepristone in mood
`disorders and psychosis (Table 1)
`Early work highlighted the potential for antiglucocorticoid
`strategies in depression. Initially the focus of studies utilizing
`mifepristone was on the effect on endocrine parameters
`(Kling et al 1989; Krishnan et al 1992). In the first open
`trial of mifepristone treatment of major depression, Murphy
`and colleagues administered mifepristone (200 mg each
`morning) for as long as it was tolerated, for up to 8 weeks
`to 4 patients with “drug-resistant” depression. Data were
`presented as a case-series and showed improvements of
`between 16% and 66% on the Hamilton Depression Rating
`Scale (HDRS) (Murphy et al 1993). The trial terminated,
`however, due to problems obtaining the trial medication (the
`supplier cancelled the contract).
`Recent studies have renewed interest in the potential
`therapeutic efficacy of GR antagonists in the treatment of
`mood disorders and psychosis.
`
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`Mifepristone for depression and psychosis
`
`Table 1 Studies of glucocorticoid receptor antagonists in mood disorders and psychosis (see text for further details)
`Effects on
`neurocognitive
`function
`
`Study
`
`Drug
`
`Dose
`
`Study
`design
`
`Patient Concomitant
`N group
`medications
`
`Effects on
`symptoms
`
`(Kling et al
`1989)
`
`Mifepristone 10 mg/kg
`single dose
`
`(Krishnan et al Mifepristone 400 mg
`1992)
`single dose
`
`aExperimental
`
`8 MDD
`
`Drug-free (2 weeks)
`
`n/a
`
`aExperimental
`
`7 MDD
`
`Drug-free (1 week)
`
`n/a
`
`n/a
`
`n/a
`
`(Murphy et al
`1993)
`
`Mifepristone 200 mg/day, Open-label
`up to
`8 weeks
`
`4 MDD
`
`(Høyberg et al ORG34517
`2002)
`
`Double-blind, 142 MDD
`randomized,
`paroxetine
`controlled
`
`150–
`300 mg/day,
`450–
`600 mg/day,
`up to 4
`weeks
`
`Drug-free;
`benzodiazepines and
`acetaminophen
`permitted
`
`Drug-free;
`benzodiazepines
`permitted
`
`HDRS scores decreased n/a
`between 16% and 66%
`for all patients.
`
`n/a
`
`All groups improved.
`Larger improvement
`from baseline in low-
`dose ORG group at day
`10. Patients reaching full
`remission significantly
`higher in low- than both
`the high-dose and
`paroxetine-treated
`groups (39.1% vs 20.5%
`and 31.0% respectively).
`
`(Belanoff et al Mifepristone 600 mg/day, Double-blind,
`2001)
`4 days
`placebo
`controlled,
`crossover
`
`5 Psychotic Antipsychotic free (3 HDRS scores declined
`MDD
`days); benzodiazepines during mifepristone
`and acetaminophen
`treatment in all patients.
`permitted
`BPRS scores declined in
`4 of 5 patients.
`
`n/a
`
`(Belanoff et al Mifepristone 50, 600,
`1200 mg/day,
`2002)
`7 days
`
`Open-label
`
`30 Psychotic Stable for 1 week
`MDD
`prior
`
`HDRS response by dose n/a
`in 2/11 (18.2%) 5/10,
`(50%), 3/9 (33%) patients
`respectively. BPRS
`response in 4/11 (36.4%),
`7/10 (70%), 6/9 (66.7%)
`respectively.
`
`(Simpson et al Mifepristone 200 mg tid, Open-label
`2005)
`6 days
`
`CGI and HDRS improved n/a
`20 Psychotic Drug-free (1 week)
`MDD
`except for lorazepam after week 1, and
`between week 1 to 4.
`BPRS improved after
`week 4
`
`(Young et al
`2004)
`
`Mifepristone 600 mg/day, Double-blind,
`7 days
`placebo
`controlled
`RCT
`
`Stable for 6 weeks
`20 Bipolar
`prior
`disorder
`(depressed)
`
`HDRS (5.1 points),
`MADRS (6 points),
`BPRS (4 points)
`improved from baseline
`at day 14 with active
`drug.
`
`(Gallagher et al Mifepristone 600 mg/day, Double-blind,
`2005)
`7 days
`placebo
`controlled
`RCT
`
`Stable for 6 weeks
`prior
`
`20 Schizo-
`phrenia
`(chronic,
`sympto-
`matic)
`
`No effect on BPRS or
`Calgary. Improvements in
`HDRS and MADRS in
`both arms of the study
`(nonspecific effect).
`
`SWM improved
`19.8% over
`placebo at day 21.
`Spatial recognition,
`verbal fluency
`improved from
`baseline following
`active drug.
`
`No effect
`
`a These studies examined HPA axis responses only.
`Abbreviations: BPRS, Brief Psychiatric Rating Scale; Calgary, Calgary Depression Scale; CGI, Clinical Global Impression; HDRS, Hamilton Depression Rating Scale;
`HPA, hypothalamic–pituitary–adrenal; MADRS, Montgomery-Åsberg Depression Rating Scale; MDD, Major Depressive Disorder; n/a, not assessed; RCT, randomized
`clinical trial; SWM, Spatial Working Memory (CANTAB); tid, three times daily.
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`Psychotic depression
`In a double-blind, placebo-controlled crossover case-series
`in 5 patients with psychotic depression, Belanoff and
`colleagues found a rapid improvement in depression ratings
`and psychotic symptoms following 4 days’ treatment with
`mifepristone (Belanoff et al 2001). Subsequently they have
`replicated these findings in an open-label study in 30
`psychotic depressed patients (Belanoff et al 2002). Patients
`received mifepristone, either 50 mg/day (n = 11), 600 mg/day
`(n = 10), or 1200 mg/day (n = 9) for 7 days. Criteria for
`response were defined as a 50% reduction on the Hamilton
`Rating Scale for Depression-21 (HAMD-21), a 30%
`reduction on the Brief Psychiatric Rating Scale (BPRS), and
`a 50% reduction on the BPRS positive symptom subscale.
`Using these criteria, respectively, it was found that 18.2%,
`36.4%, and 27.3% of patients responded to 50 mg/day; 50%,
`70%, and 60% responded to 600 mg/day, and 33%, 66.7%,
`and 66.7% responded to 1200 mg/day. The results of this
`study also suggested that high-dose treatment (≥ 600 mg)
`for short periods (≤ 7 days) was the optimal method of
`administration.
`A second trial has been carried out recently with a longer
`follow-up period (Simpson et al 2005). Twenty MDD
`patients (with psychotic features) were treated with
`mifepristone 200 mg 3 times daily, open-label for 6 days.
`All patients had been psychotropic medication-free (except
`lorazepam for sleep) for at least 1 week prior to baseline
`ratings. Significant improvements in HDRS and Clinical
`Global Impression (CGI) scores were observed in the group
`(from baseline) after 1 week and between weeks 1 and 4.
`This effect remained stable to follow-up at 8 weeks. BPRS
`scores also improved after week 4. A number of patients
`did not complete the trial, however, because of good clinical
`response (discharged and lost to follow-up) or nonresponse
`(alternative clinical intervention required).
`Preliminary communications have also been made on
`the results of larger trials (n > 200) of mifepristone in
`psychotic depression (Belanoff and DeBattista 2004;
`DeBattista and Belanoff 2004). These studies suggest that
`the effect on psychotic symptoms, particularly, may be rapid
`and persistent. The publication of these results is awaited
`and will provide clearer data on the efficacy of GR
`antagonists in this condition.
`
`Bipolar disorder
`We have recently completed the first proof-of-concept study
`on the use of GR antagonists in the treatment of bipolar
`
`depression, in a double-blind, placebo-controlled crossover
`design (Young et al 2004). We hypothesized that
`mifepristone (administered adjunctively to existing
`medication) would improve neurocognitive function and
`attenuate depressive symptoms in this disorder. Twenty
`patients, ages 18 to 65, with a diagnosis of bipolar depression
`(confirmed using the Structured Clinical Interview for DSM-
`IV; SCID [First et al 1995]) and residual depressive
`symptoms were recruited. Patients’ medication had been
`unchanged for 6 weeks prior to participation and remained
`so throughout the study period.
`On the basis of previous research, it was predicted that
`the principal cognitive domains that would be most sensitive
`to changes in HPA axis function were working memory and
`verbal declarative memory. Neurocognitive tests were
`therefore administered to explore these domains. Following
`treatment with mifepristone, selective improvement in
`neurocognitive functioning was observed. Spatial working
`memory performance was significantly improved compared
`with placebo (19.8% improvement over placebo). Measures
`of verbal fluency and spatial recognition memory also
`significantly improved from baseline levels after
`mifepristone. No significant change occurred after placebo.
`Beneficial effects on mood were found; HDRS scores
`were significantly reduced compared with baseline (mean
`reduction of 5.1 points) as were Montgomery–Åsberg
`Depression Rating Scale scores (mean reduction of 6.05
`points). No significant change occurred after placebo.
`Furthermore, baseline cortisol output correlated positively
`with the percentage improvement in spatial working memory
`error rate following mifepristone administration.
`
`Schizophrenia
`Utilizing the same experimental design as described above
`(Young et al 2004), we have recently completed the first
`trial to examine the efficacy of adjunctive mifepristone
`administration in schizophrenia (Gallagher et al 2005). In
`contrast to the findings on bipolar disorder, mifepristone
`had no significant effect on symptoms or neurocognitive
`functioning despite a pronounced effect on the HPA axis.
`There are several possible explanations for this discrepancy.
`As described above, mifepristone has been shown to have
`some positive effects on depressive symptoms in bipolar
`disorder as well as on psychosis in psychotic major
`depression. Also, the effects of mifepristone were more
`pronounced on neurocognitive function in bipolar patients.
`This may suggest that affective symptoms or affective
`
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`psychosis may be modulated primarily by the HPA axis and
`that neurocognitive dysfunction in mood disorders is steroid-
`dependent and a consequence of HPA axis dysregulation,
`whereas in schizophrenia these may be attributable to
`different underlying neurobiological abnormalities.
`Alternatively, it may be that the schizophrenic patients
`recruited in this study did not have an abnormal HPA axis
`at baseline. There is some evidence that the chronicity of
`psychotic illness directly affects the neurobiology of the
`HPA axis. Pariante and colleagues (2004) found that first-
`episode psychosis was associated with a larger pituitary
`volume, which was suggested to be a consequence of
`activation of the HPA axis. In “established” schizophrenia
`(such as in the population in our study), smaller pituitary
`volume was observed (Pariante et al 2004b). Therefore, the
`schizophrenic patients may not respond to a GR antagonist
`in the same manner as patients with affective illnesses.
`
`Other GR antagonists
`ORG 34517 was designed as a specific antiglucocorticoid
`to selectively target the GR. A preliminary report comparing
`low- and high-dose ORG 34517 administration and
`paroxetine found that all treatment groups showed
`improvements in HDRS scores over the 4-week treatment
`period (Høyberg et al 2002). Low-dose ORG 34517
`appeared to increase the speed of response, however, HDRS
`scores being significantly lower (from baseline) than both
`other treatment arms by day 10 of the trial. This effect was
`greater in subjects with a higher degree of HPA axis
`dysfunction. The proportion of subjects in full remission
`by the end of the trial was also significantly greater than the
`proportion of both the high-dose and paroxetine-treated
`groups (39.1% vs 20.5% and 31.0% respectively).
`
`Mechanisms of action
`Corticosteroid receptor imbalance
`The mechanism through which mifepristone may be exerting
`effects on symptoms and neurocognitive function is unclear.
`It has been suggested that by blocking the GR a “resetting”
`of the HPA axis may occur (Belanoff et al 2002).
`Interestingly, animal work has shown that in comparison
`with other selective GR antagonists, mifepristone was the
`only compound to increase GR binding in the frontal cortex,
`although an increase in MR binding was also observed
`(Bachmann et al 2003). In the neocortex, however,
`mifepristone selectively decreased MR binding.
`
`Mifepristone for depression and psychosis
`
`GR integrity has consistently been shown to be lowered
`in patients with severe psychiatric disorders both
`functionally, using the DST (Rush et al 1996), and
`structurally, with reduced GR mRNA expression in post-
`mortem brain tissue samples (Webster et al 2002). There is
`some evidence, however, that MR function may be normal
`or even enhanced in mood disorders (Young et al 2003).
`Although speculative, some of the therapeutic actions of
`mifepristone may operate through the ability of the drug to
`modulate corticosteroid receptor balance (ie, exposing brain
`MR to the elevated cortisol levels caused by GR blockade).
`This may be particularly so for neurocognitive functioning,
`which depends on the relative ratio of corticosteroid receptor
`occupancy (Lupien and McEwen 1997).
`
`Transport of cortisol into the brain
`Recent work has shown that many antidepressant drugs have
`actions on blood-brain barrier steroid transporters (such as
`multidrug resistance p-glycoprotein). Plasma cortisol cannot
`freely enter the brain by passive diffusion because its access
`is limited by such membrane steroid transporters which
`actively expel cortisol from the brain. It has been suggested
`that some antidepressants may inhibit membrane steroid
`transporters at the blood–brain barrier and in neurones, so
`that more cortisol is able to enter the brain (Pariante 2004;
`Pariante et al 2004a), thereby restoring glucocorticoid-
`mediated negative feedback of the HPA axis (Pariante et al
`2004a). Hypercortisolemia is therefore argued to be a
`possible compensatory adaptive response to a central
`hypocortisolemic state (Pariante 2003). Considering
`mifepristone: the antagonist action of mifepristone on GR
`causes a robust (2- to 3-fold) elevation in cortisol levels and
`this may facilitate HPA axis negative feedback. Certainly,
`this may be the case when mifepristone is administered
`adjunctively with other antidepressant medications (see
`above). This mechanism may underlie some of the clinical
`benefits of the drug.
`
`Speed of response
`One notable characteristic of antiglucocorticoid strategies
`in studies to date is that they appear to initiate a rapid, short-
`term clinical response. The study of the ORG 34517 by
`Høyberg and colleagues in medication-free patients with
`major depression showed that differences between treatment
`arms emerged after day 7 of the trial, with significant benefits
`being observed at day 10–14. This was especially
`pronounced in patients with clearly defined HPA axis
`
`Neuropsychiatric Disease and Treatment 2006:2(1)
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`39
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`Gallagher and Young
`
`abnormalities. After this time, response rates were
`approximately equivalent (Høyberg et al 2002). Rapid
`responses have also been observed following mifepristone
`administration in psychotic depression (Belanoff et al 2001;
`Belanoff et al 2002; Simpson et al 2005).
`Alternative antiglucocorticoid strategies such as cortisol
`synthesis inhibition similarly alter the course of clinical
`response. Jahn and colleagues administered metyrapone or
`placebo to 63 (psychotropic) medication-free patients with
`major depression. A higher proportion of patients receiving
`metyrapone showed a positive treatment response, but
`importantly the response began within a week of initiation
`of treatment, suggesting an earlier onset of action (Jahn et
`al 2004).
`The ability of such drugs to rapidly improve treatment
`response suggests that they may be used either to increase
`efficacy of treatment regimens in medicated patients or
`initiate a response that can be maintained with conventional
`treatments. The optimum strategy for the clinical application
`of GR antagonists has yet to be established, with their
`potential role as either first-line or adjunctive treatments
`being unclear.
`
`Effects on neurocognitive function
`Although few studies to date have examined the neuro-
`cognitive effects, mifepristone may be efficacious in this
`respect in mood disorder.
`In a recent study in rats, mifepristone was the only GR
`antagonist examined to increase both MR and GR binding
`in the frontal cortex (Bachmann et al 2003). This may
`underpin the selective pattern of improvement in neuro-
`cognitive function seen in our study (Young et al 2004),
`which was restricted to tests that have been s