Mifepristone (RU-486) treatment for depression and psychosis: a review of the therapeutic implications

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 measurement 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 pharmacological 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 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}).

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 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 (C_max = 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}).

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 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.

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 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 shown to be sensitive to frontal lobe dysfunction. Oitzl and colleagues have shown that mifepristone (RU-38486) injected locally into the dorsal hippocampus dose-dependently improved the performance of male Wistar rats in the water maze 24 hours after treatment (^{Oitzl et al 1998a}). Importantly, opposing effects on spatial memory have been shown to occur after either phasic or continuous blockade of brain GR by intracerebroventricular administration of mifepristone. Phasic blockade was found to dose-dependently impair spatial memory (Morris water maze), examined after a daily pretraining administration, whereas continuous GR blockade resulted in a long-lasting facilitation of spatial performance (^{Oitzl et al 1998b}). In humans, aspects of spatial memory are affected in various degrees in patients with hippocampal lesions (^{Kessels et al 2001}), some tasks such as (spatial) working memory being more dependent on the integrity of the frontal lobes (^{Owen et al 1995; Owen et al 1996; Kessels et al 2000; Kessels et al 2001}). Consequently, the effects of mifepristone on corticosteroid receptor expression may explain the observed pattern of neurocognitive improvement observed in studies to date.