Discovery of a novel non-steroidal GR antagonist with in vivo efficacy in the olanzapine-induced weight gain model in the rat.

We report the optimization of a series of non-steroidal GR antagonists that led to the identification of compound 7. This compound is efficacious when dosed orally in an olanzapine-induced weight gain model in rats.

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.

Selective glucocorticoid receptor (type II) antagonists prevent weight gain caused by olanzapine in rats.

The use of antipsychotic medication has consistently been associated with serious side effects including weight gain and metabolic abnormalities. Strategies for mitigating these side effects have been tested, yet effective interventions have not been identified. The current study tested whether two recently identified selective glucocorticoid receptor antagonists would prevent weight gain induced by the antipsychotic olanzapine. Female Sprague-Dawley rats fed a normal chow diet were randomized (n=10 per group) to receive one of the following for 18days: vehicle, olanzapine plus vehicle (2.4mg/kg), olanzapine plus CORT 112716 (20mg/kg), olanzapine plus CORT 112716 (60mg/kg), olanzapine plus CORT 113083 (20mg/kg), or olanzapine plus CORT 113083 (60mg/kg). Rats receiving olanzapine plus CORT 112716 (60mg/kg) or olanzapine plus CORT 113083 (60mg/kg) gained significantly less weight than rats receiving only olanzapine. Both glucocorticoid receptor antagonists significantly attenuated the weight gain induced by olanzapine in a dose dependent manner. Differences in weight gain were not attributable to decreased food intake.

Mifepristone reduces weight gain and improves metabolic abnormalities associated with risperidone treatment in normal men.

Antipsychotic medications are associated with significant weight gain, type 2 diabetes mellitus, dyslipidemia, and increased cardiovascular risk. The objective of this study was to determine whether mifepristone, a glucocorticoid receptor antagonist, could prevent risperidone-induced weight gain. Using a 2:2:1 randomization scheme, 76 lean, healthy men (BMI 18-23 kg/m(2)) age 18-40 years were randomized to risperidone (n = 30), risperidone plus mifepristone (n = 30) or mifepristone (n = 16) daily for 28 days in an institutional setting. Subjects were provided food ad libitum. Body weight was measured daily. Metabolic measures were taken at study onset, midpoint, and end. Analyses of covariance indicated that the group receiving risperidone plus placebo gained significantly more weight (P < 0.001) and exhibited a significantly greater increase in waist circumference (P < 0.05) than the group receiving risperidone plus mifepristone. Significant differences were also observed for metabolic measures including fasting insulin (P < 0.001) and triglyceride levels (P < 0.05). Mifepristone attenuated increases in weight and reduced the metabolic changes induced by risperidone use, replicating results from a prior study of olanzapine-induced weight gain. These findings suggest mechanistic involvement of the hypothalamic-pituitary-adrenal axis in the weight and cardiometabolic side effects of antipsychotic medications. Future research should continue to test the potential of glucocorticoid antagonists to alleviate the deleterious side effects associated with use of antipsychotic medications.

Mifepristone treatment of olanzapine-induced weight gain in healthy men.

INTRODUCTION: Antipsychotic medications are associated with significant weight gain, type 2 diabetes mellitus, dyslipidemia, and increased cardiovascular risk. Suggested mechanisms of weight gain from antipsychotic medication include antagonism of histamine and serotonin receptors, and effects on the hypothalamic-pituitary-adrenal axis. The objective of this study was to determine if mifepristone, a glucocorticoid receptor antagonist, could prevent olanzapine-induced weight gain. METHODS: This was a randomized, double-blind trial. Fifty-seven lean, healthy men (body mass index 18-25 kg/m(2)) aged 19-38 years were randomized to olanzapine (7.5 mg) (n=22), olanzapine (7.5 mg) plus mifepristone (600 mg) (n=24), or mifepristone (600 mg) (n=11) daily for 2 weeks in an institutional setting. Subjects were provided food ad libitum to accentuate weight gain. Body weight was measured daily. RESULTS: The mean change in baseline weight was +3.2+/-0.9 kg in subjects receiving olanzapine versus +2.0+/-1.2 kg in those receiving olanzapine plus mifepristone (P<0.0001). Subjects receiving mifepristone alone had a similar degree of weight gain compared to those receiving olanzapine plus mifepristone. The olanzapine group had significant increases in waist circumference when compared with the olanzapine plus mifepristone group (3.7+/-1.3 cm vs. 2.2+/-1.9 cm, respectively; P=0.006). Fasting insulin and triglycerides increased more in the olanzapine group, although differences were not statistically significant. CONCLUSION: Mifepristone was effective in attenuating the increase in weight associated with olanzapine treatment over a 2-week period. Longer-term studies are required to examine the durability and full magnitude of this response.

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.

Beyond the three-component model of organizational commitment.

This article offers a conceptual critique of the three-component model (TCM) of organizational commitment (Allen & Meyer, 1990) and proposes a reconceptualization based on standard attitude theory. The authors use the attitude-behavior model by Eagly and Chaiken (1993) to demonstrate that the TCM combines fundamentally different attitudinal phenomena. They argue that general organizational commitment can best be understood as an attitude regarding the organization, while normative and continuance commitment are attitudes regarding specific forms of behavior (i.e., staying or leaving). The conceptual analysis shows that the TCM fails to qualify as general model of organizational commitment but instead represents a specific model for predicting turnover. The authors suggest that the use of the TCM be restricted to this purpose and that Eagly and Chaiken's model be adopted as a generic commitment model template from which a range of models for predicting specific organizational behaviors can be extracted. Finally, they discuss the definition and measurement of the organizational commitment attitude. Covering the affective, cognitive, and behavioral facets of this attitude helps to enhance construct validity and to differentiate the construct from other constructs.