Joseph K. Belanoff

An open label trial of C-1073 (mifepristone) for psychotic major depression*

BACKGROUND The rationale for treating patients with psychotic major depression (PMD) with glucocorticosteroid receptor (GR) antagonists is explained. METHODS Thirty patients with PMD, with Hamilton Rating Scale for Depression (HAMD-21) scores of 18 or greater, were assigned in an open label trial to receive 50 mg, 600 mg, or 1200 mg of mifepristone for 7 days. RESULTS All the subjects completed the protocol; there were no dropouts. Side effects were mild and sporadic. Of 19 subjects in the combined 600- and 1200-mg group, 13 had a 30% or greater decline in their Brief Psychiatric Rating Scale (BPRS) scores, compared with 4 of 11 in the 50-mg group. In the 600- and 1200-mg group, 12 of 19 subjects showed a 50% decline in the BPRS positive symptom subscale, a more sensitive index for the symptoms seen in PMD, compared with 3 of 11 in the 50-mg group; 8 of 19 subjects in the 600- and 1200-mg group had a 50% decline in the HAMD-21, compared with 2 of 11 in the 50-mg group. CONCLUSIONS These results suggest that short term use of GR antagonists may be effective in the treatment of psychotic major depression and that further blinded studies are warranted.

Rapid reversal of psychotic depression using mifepristone

The rationale for treating psychotic major depression with glucocorticoid receptor (GR) antagonists is reviewed. Five patients with psychotic major depression were given 600 mg of mifepristone in a 4-day, double-blind, placebo-controlled crossover study. All the patients completed the protocol and adverse effects were not observed or reported. All of the five patients showed substantial improvements in their Hamilton Rating Scale for Depression scores while they were receiving mifepristone, and four of the five patients showed substantial improvement in their Brief Psychiatric Rating Scale scores. Little, if any, improvement was seen with placebo. These preliminary results suggest that short-term use of GR antagonists may be effective in the treatment of psychotic major depression and that additional study, perhaps using higher doses or more treatment days, seems warranted.

Corticosteroids and cognition.

The brain is a major target organ for corticosteroids. It has been observed that excessive circulatory levels of endogenous and exogenous corticosteroids are frequently associated with cognitive impairment in a wide variety of clinical disease states. Cognition and low levels of corticosteroids have been less well studied. In this paper we review the literature on glucocorticosteroid effects on cognition and delineate specific functions that appear to be causally affected. We draw a possible connection to specific areas of brain perturbation, including the hippocampus and frontal lobe regions. The possibility that cognitive dysfunction caused by glucocorticoids can be pharmacologically managed is introduced.

Mifepristone versus Placebo in the Treatment of Psychosis in Patients with Psychotic Major Depression

BACKGROUND Abnormalities in the hypothalamic pituitary adrenal axis have been implicated in the pathophysiology of psychotic major depression (PMD). Recent studies have suggested that the antiglucocorticoid, mifepristone might have a role in the treatment of PMD. The current study tested the efficacy of mifepristone treatment of the psychotic symptoms of PMD. METHODS 221 patients, aged 19 to 75 years, who met DSM-IV and SCID criteria for PMD and were not receiving antidepressants or antipsychotics, participated in a double blind, randomized, placebo controlled study. Patients were randomly assigned to either 7 days of mifepristone (n = 105) or placebo (n = 116) followed by 21 days of usual treatment. RESULTS Patients treated with mifepristone were significantly more likely to achieve response, defined as a 30% reduction in the Brief Psychiatric Rating Scale (BPRS). In addition, mifepristone treated patients were significantly more likely to achieve a 50% reduction in the BPRS Positive Symptom Scale (PSS). No significant differences were observed on measures of depression. CONCLUSION 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.

The use of mifepristone in the treatment of neuropsychiatric disorders.

Mifepristone is a potent glucocorticoid and progesterone 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 Alzheimers 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.

Gender Differences, But No Racial Group Differences, in Self-Reported Psychiatric Symptoms in Adolescents

OBJECTIVE To study gender differences in psychiatric symptoms and their relationship to minor delinquent behavior in high school seniors. METHOD This was a cross-sectional study of symptoms experienced during the past 2 weeks and the past year. Male (n = 249) and female (n = 248) high school seniors attending an inner-city and two suburban high schools rated themselves on a 46-item Hopkins Symptom Checklist and a 19-item Delinquency questionnaire. RESULTS Female adolescents, regardless of race, reported significantly higher levels of emotional distress, in particular depressed mood and anxiety, than did male adolescents. A separate factor analysis of male and female students generated anger-tension, school problems, and sadness-irritation, lethargy, respectively, as the first two factors. Trouble paying attention in school and marijuana, alcohol, and other drug use were associated with significantly higher levels of psychiatric symptoms. Black and white adolescents were similar in psychological adjustment. CONCLUSIONS This survey confirms sex differences in the level of psychiatric symptoms for 16- to 18-year-old adolescents, suggests gender-related qualitative differences in negative emotions, and emphasizes the importance of controlling for education when studying adolescents from different ethnic or racial backgrounds.

Slowing the progression of cognitive decline in Alzheimer's disease using mifepristone.

High circulating levels of glucocorticoid hormones adversely affect cognition. Previous studies exploring the hypothalamic-pituitary-adrenal (HPA) axis and basal cortisol levels in the elderly reported that subjects with mid-range cortisol levels outperformed subjects with high cortisol levels on assessments of memory and attention. This study examines the efficacy of mifepristone, a glucocorticoid-antagonist, in decelerating the rate of cortisol-related cognitive decline in subjects with mile-to-moderate Alzheimer’s disease (AD). Rate of cognitve decline is compared in AD subjects randomized to receive 200 mg of mifepristone daily for 6 mo or placebo. The Alzheimer’s Disease Assessment Scale (ADAS) and the Folstein Mini Mental Status Exam (MMSE) will be the primary measures used to assess change in cognitve function over the 6 mo period, supplemented by a neuropsychological battery testing memory and language and reasoning skills. During each visit, subjects will have samples collected for determination of plasma adrenocorticotropin (ACTH), serum cortisol and salivary cortisol levels to assess HPA axis activity. The placebo arm of this study also investigate whether subjects with high baseline cortisol levels experience greater declines in cognitive impairment over time relative to subjects with Ad who have low baseline cortisol levels. Additionally, this study test the hypothesis that AD subjects with elevated cortisol at baseline will perform more poorly on neuropsychological exams that do subjects with low cortisol.

1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as selective glucocorticoid receptor antagonists with high functional activity.

Addition of the 4-fluorophenylpyrazole group to the previously described 2-azadecalin glucocorticoid receptor (GR) antagonist 1 resulted in significantly enhanced functional activity. SAR of the bridgehead substituent indicated that whereas groups as small as methyl afforded high GR binding, GR functional activity was enhanced by larger groups such as benzyl, substituted ethers, and aminoalkyl derivatives. GR antagonists with binding and functional activity comparable to mifepristone were discovered (e.g., 52: GR binding K(i) 0.7 nM; GR reporter gene functional K(i) 0.6 nM) and found to be highly selective over other steroid receptors. Analogues 43 and 45 had >50% oral bioavailability in the dog.

Efficacy and safety of mifepristone for the treatment of psychotic depression.

Open-label studies and randomized clinical trials have suggested that mifepristone may be effective for the treatment of major depression with psychotic features (psychotic depression). A recent study reported a correlation between mifepristone plasma concentration and clinical response. The current study aimed to evaluate the safety and efficacy of mifepristone and, secondarily, to test whether response was significantly greater among patients with mifepristone plasma concentrations above an a priori hypothesized threshold. A total of 433 patients who met criteria for psychotic depression were randomly assigned to receive 7 days of either mifepristone (300, 600, or 1200 mg) or placebo. Response was defined as a 50% reduction in psychotic symptoms on both days 7 and 56. Cochran-Mantel-Haenszel tests compared (1) the proportion of responders among patients assigned mifepristone versus placebo and (2) the proportion of responders among the subset of patients with plasma concentrations greater than 1660 ng/mL versus placebo. Mifepristone was well tolerated at all 3 doses. The proportion of responders randomized to mifepristone did not statistically differ from placebo. Patients with trough mifepristone plasma concentrations greater than 1660 ng/mL were significantly more likely to have a rapid and sustained reduction in psychotic symptoms than those who received placebo. The study failed to demonstrate efficacy on its primary end point. However, the replication of a statistically significant linear association between mifepristone plasma concentration and clinical response indicates that mifepristone at sufficient plasma levels may potentially be effective in rapidly and durably reducing the psychotic symptoms of patients with psychotic depression.

A multisite trial of mifepristone for the treatment of psychotic depression: A site-by-treatment interaction

Major Depression with Psychotic Features (psychotic depression) is a common, debilitating psychiatric disease. We hypothesized that mifepristone, a cortisol receptor (GRII) antagonist, would significantly reduce psychotic symptoms in psychotic depression. Two hundred fifty-eight patients with psychotic depression enrolled at 29 sites were randomized to mifepristone or placebo for 7 days. The primary outcome was rapid and sustained response, defined as a 50% or greater decrease in Brief Psychiatric Rating Scale - Positive Symptom Subscale scores at the end of treatment (day7) and 49 days later (day 56). Cochran-Mantel-Haenszel compared proportions of responders to mifepristone versus placebo adjusting for site. Exploratory analyses compared response of patients with mifepristone plasma concentrations of > or =1800 ng/ml to placebo. The primary endpoint was not statistically significant. However, the Breslow-Day test indicated a statistically significant site-by-treatment interaction. Mifepristone produced significantly higher response among the twenty sites who participated from the trial onset (p<.05), whereas no difference was observed at the nine sites added late in the trial. Patients with mifepristone plasma levels > or =1800 ng/ml were significantly more likely to respond than placebo patients (Intent-to-Treat: OR=2.4, p=.03; Initial 20 sites: OR=4.1, p=.002). The results of this trial are instructive in two respects. First, while statistical adjustments for [corrected] site are common in multisite clinical trials, this study reminds trialists to formally evaluate the interaction of site by treatment.Second, the association between increased mifepristone plasma concentration levels and greater clinical response, detected despite the site-by-treatment interaction, suggests that higher plasma levels may be needed for maximizing the probability of a positive response.