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.

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.

Twenty-four patients with rheumatoid arthritis were tested in a randomized, double-blind. Latin-square comparison of 250, 750 and 1500 mg of naproxen daily. Each received each dose for 2 wk and baseline disease activity was established during withdrawal of medication before and after the study. Nine standard measures of efficacy were tested at each evaluation. No order effect or change in baseline was found. Total and unbound naproxen concentrations were measured by high-pressure liquid chromatography and equilibrium dialysis, respectively. A linear dose-response relationship (P less than 0.05) was demonstrated between naproxen and joint count, patient's pain assessment, activities of daily living index, physician's global assessment, and grip strength. The relationship to patients' global assessment was of uncertain significance (P less than 0.07). A positive dose to serum level correlation (1, 2, and 12 hr after dose) was apparent (r greater than 0.78). When patients were defined as responders or nonresponders by a summed efficacy score, there was a serum concentration-response relationship; the percentage of responding patients increased with each serum level quartile: 25%, 31%, 59%, and 75%. Patients with a trough total serum naproxen concentration under 18 micrograms/ml did not respond, while 76% of patients with trough total serum concentrations above 50 micrograms/ml responded. No serum naproxen toxicity level relationship was established.

IntroductIonThe potential for serious medical problems resulting from the use of second-generation antipsychotic medications has received extensive attention in the scientific literature. The propensity to induce significant weight gain, increase the risk of metabolic problems, and increase the risk of diabetes mellitus and hyperglycemia was first described in the early 1990s, shortly after the medications were approved by the US Food and Drug Administration. The earliest research reports noted significant weight gain, and several case reports were published describing both diabetes and diabetic complications in patients taking second-generation antipsychotic medications (1). In the subsequent decade, consistent evidence of significant weight gain and metabolic problems continued to emerge (2-5). Although the magnitude and nature of the association between medication usage, weight gain, and metabolic consequences was not yet understood (6), the extant evidence was sufficient to receive US Food and Drug Administration attention in 2003, when a mandatory class warning was implemented and applied to all second-generation antipsychotic medications, for risk of "Hyperglycemia and Diabetes Mellitus" (7).Concern has continued to mount over the weight gain and cardiometabolic risk incurred by patients taking second-generation antipsychotic medications (8)(9)(10)(11). Clinical studies and meta-analyses have demonstrated large effect sizes for weight gain and significant metabolic perturbations for most antipsychotic medications (10,12,13). Current concern regarding the safety profile of second-generation antipsychotics is underscored by a recent study that reported that children taking antipsychotic medication gained substantial weight in a very short time period and experienced negative metabolic and cardiovascular effects (12,14).Despite the important safety problems, second-generation antipsychotic medications clearly provide substantial clinical benefit. Efficacy studies have shown robust symptom reductions in patients with debilitating, prevalent psychiatric conditions, including schizophrenia and bipolar disorder (15-17). Although efficacy comparisons with first generation antipsychotics have yielded inconsistent results (16), secondgeneration medications are considered to have a "broader spectrum" of efficacy because of their ability to reduce both positive and negative symptoms of schizophrenia (15,18 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. Metaboli...

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