Mifepristone Reduces Weight Gain and Improves Metabolic Abnormalities Associated With Risperidone Treatment in Normal Men

Abstract

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...

Glucocorticoid antagonism limits adiposity rebound and glucose intolerance in young male rats following the cessation of daily exercise and caloric restriction

“…Previously, it had been shown that mifepristone treatment reduced adipose tissue mass gain and body weight gain in rodent models of diet-induced obesity (3,28,56). In addition, 2-4 wk of mifepristone treatment reduced risperidone-and olanzapine-induced weight gain in healthy men (23,24). This suggests that GCs play a significant role in contributing to fat deposition and weight gain in these studies.…”

Glucocorticoids and non-alcoholic fatty liver disease

“…Prolonged use is not recommended, however, after short-term administration beneficial effects have been seen. These include decreased triglycerides (91), changes in HDL metabolism (92), limitation of antipsychotic-induced weight gain (93,94) and reduced fasting glucose and enhanced insulin sensitivity (95,96). A detailed analysis of GR antagonism to modulate lipid homeostasis has not been undertaken, however, In patients with type 2 Diabetes Mellitus, GRantagonism combined with inhibition of cortisol synthesis had equally beneficial effects to lower glucose and improve insulin sensitivity in those patients with and without NAFLD (95).…”

LLY-2707, A Novel Nonsteroidal Glucocorticoid Antagonist That Reduces Atypical Antipsychotic–Associated Weight Gain in Rats

“…In a proof-of-concept clinical trial, mifepristone prevented the weight gain observed during treatment with olanzapine in healthy Indian men (Gross et al, 2009). In a similar trial, mifepristone also prevented the weight gain seen with risperidone (Gross et al, 2010). One of the challenges of finding novel clinical approaches has been identifying a suitable preclinical model to test a broad range of pharmacotherapies.…”

“…Statistically significant reductions in weight, body mass index (BMI), and waist circumference were observed over 14-day treatment in drug-naïve patients treated with mifepristone and olanzapine versus patients treated with olanzapine alone (Gross et al, 2009). When combined with risperidone for 28 days, patients treated with mifepristone experienced reduced weight gain compared with patients treated with risperidone alone (Gross et al, 2010). In addition, improvements were noted in the insulin tolerance test, plasma triglycerides, plasma insulin, and the homeostasis model assessment of insulin resistance (HOMA IR ).…”

“…In preclinical studies, estra-4,9-dien-3-one, 11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-(11b,17b)-(9CI), a GR antagonist (GRA) and progesterone receptor antagonist (PRA) medication (Ulmann et al, 1990), reduced the weight gain seen in young obese fa/fa Zucker rats (Langley and York, 1990) and decreased the elevated insulin levels and weight gain observed in olanzapine-treated rats (Beebe et al, 2006). Patients treated with mifepristone experienced a reduction in weight gain during treatment with AAPDs, which included risperidone (Gross et al, 2010) and olanzapine (Gross et al, 2009). Statistically significant reductions in weight, body mass index (BMI), and waist circumference were observed over 14-day treatment in drug-naïve patients treated with mifepristone and olanzapine versus patients treated with olanzapine alone (Gross et al, 2009).…”