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Adv Ther (2009) 26(10):. DOI 10.1007/s12325-009-0070-1

ORIGINAL RESEARCH

Mifepristone Treatment of Olanzapine-Induced Weight Gain in Healthy Men Coleman Gross · Christine M. Blasey · Robert L. Roe · Kate Allen · Thaddeus S. Block · Joseph K. Belanoff

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Received: August 31, 2009 / Published online: / Printed: © Springer Healthcare 2009

ABSTRACT 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 hypothalamicpituitary-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. Fiftyseven 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 (P7% of their baseline body weight.5 Antipsychotic-induced weight gain has a quick onset, occurring in the first weeks of therapy, and continues unabated for many weeks. There are data to suggest that early weight gain, occurring within the first 1-3 weeks, is a predictor of sustained weight gain through 30 months of treatment.8 Although patients with psychiatric disorders may have lifestyle habits that predispose them to weight gain, a low body mass index (BMI) and young age seem to be risk factors for greater weight gain.6 Strategies for controlling weight gain associated with antipsychotic medication have included switching to an antipsychotic associated with less weight gain, lifestyle changes, and pharmacological therapies, all of which have had limited success.7 Most studies that have investigated pharmacological treatments have been in psychiatric patients. Histamine antagonists, selective serotonin reuptake inhibitors, metformin, rosiglitazone, sibutramine, phenylpropanolamine, amantadine, topiramate, modafinil, and alpha-lipoic acid have been

Adv Ther (2009) 26(10):.

studied in clinical trials and have shown modest to no effect on reducing weight or preventing weight gain in these studies.9-11 These pharmacological interventions have generally not been based on mechanistic considerations, which may partially underlie their lack of meaningful efficacy. It is not yet clear by what mechanism antipsychotic medications induce weight gain. Modulation of signaling pathways that regulate body weight via antagonism of histamine (H-1) and serotonin (5HT2c) receptors,12,13 and activation of the hypothalamic-pituitary-adrenal axis14 have been suggested to play an important role. Reports have documented increased caloric intake associated with these drugs as a contributor to weight gain,15-18 and recent data from animal studies suggest that reductions in energy expenditure (ie, thermogenesis, physical activity) may play a role.19 Reduction in insulin sensitivity may be an important component of the pathogenesis of antipsychotic medication-induced abnormalities in glucose homeostasis and the attendant dyslipidemia and increased cardiovascular risk.10 Patients treated with antipsychotics often have higher insulin levels and have been reported to have insulin resistance,20 but reports using euglycemic clamp methods in nonpsychiatric individuals receiving short courses of antipsychotics have not yielded consistent results. 21,22 The effects on insulin sensitivity may be different in psychiatric patients than in subjects free from mental disorder; van Nimwegen et al. 23 demonstrated that schizophrenic patients have hepatic insulin resistance under clamp-isotope methodology. Interestingly, Wu et al.24 have demonstrated that metformin, a drug that improves hepatic insulin sensitivity, prevented antipsychotic-induced weight gain in first episode schizophrenics treated with olanzapine.



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Cortisol is a mediator of insulin and adipose physiology and plays an important role in the etiology of obesity, insulin resistance, and cardiovascular risk.25,26 The enzyme 11β-hydroxysteroid dehydrogenase 1 is responsible for conversion of inactive 11-keto-glucocorticoids (GC) to GC receptor-activating 11-hydroxyglucocorticoids, is abundantly expressed in adipose and liver, and has been identified as an important etiological factor in obesity and associated metabolic derangements.27 Mifepristone, a potent type II GC antagonist, appeared to reverse the abnormal weight gain seen in young obese fa/fa Zucker rats, and improved elevated insulin levels.28 We have hypothesized that blocking the GC receptor would lead to improved insulin sensitivity and ameliorate the weight gain associated with olanzapine. In a previous study, we reported that mifepristone prevented weight gain in rats treated with olanzapine.29 In separate experiments with rats that had gained weight on olanzapine, mifepristone reversed weight gain to levels of control animals.29 The goal of this proof-of-concept study was to determine if mifepristone could prevent weight gain induced by olanzapine in normal-weight male volunteer subjects over a 2-week treatment period. Evaluation of metabolic changes associated with olanzapine compared with olanzapine plus mifepristone were exploratory in nature. To our knowledge, this is the first randomized controlled trial to investigate mifepristone in weight gain induced by an antipsychotic drug in people.

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of 18-25 kg/m2. After a complete description of the study to the subjects, informed consent was obtained. The study protocol was approved by the institutional review board and was conducted under a United States Food and Drug Administration Investigational New Drug Application with Indian regulatory approval. The trial was conducted in accordance with international (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) and regional guidelines and the Declaration of Helsinki (trial registration: www.clinicaltrials. gov/ct2/show/NCT00455442).

Unauthorized Use Prohibited Design

This study was a three-arm, double-blind, randomized clinical trial using a parallel-group design. After 1 week of inpatient observation, eligible subjects were randomized using a 2:2:1 randomization scheme to receive either olanzapine (7.5 mg) plus placebo (n=22), olanzapine (7.5 mg) plus mifepristone (600 mg) (n=24), or mifepristone (600 mg) plus placebo (n=11) daily for 2 weeks in an institutional setting. To maintain stable weights during the 1-week inpatient observation period, dietary intake was controlled based on individual nutritional assessments; during the dosing period (day 1 to day 14) food was provided ad libitum in a cafeteria-style setting. Olanzapine was started at 2.5 mg once daily and increased to 7.5 mg over the course of the initial 5 days of treatment. Subjects unable to tolerate 7.5 mg were allowed to continue on 5 mg daily. Due to the known risk of liver transaminase elevation associated with olanzapine,30,31 the protocol contained criteria requiring discontinuation of patients with abnormal liver biochemistries (transaminases >5 times the upper limit of normal, or >3 times the upper limit of normal with elevated bilirubin, or bilirubin >2 times


MATERIALS AND METHODS Participants

Lean, healthy Indian men were recruited to a single investigative site in Bangalore, India. The primary inclusion criteria included a BMI

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the upper limit of normal). Drug eruption or signs and symptoms of adrenal insufficiency were also protocol-specified reasons for withdrawal. Subjects were queried daily for signs and symptoms of adrenal insufficiency such as lightheadedness, fatigue, anorexia, abdominal pain, and myalgias. Physical examination including orthostatic vital signs were performed on a daily basis during the dosing period. The primary efficacy variable of the study was the mean change in absolute body weight from baseline to end of study. Body weight was measured daily during the dosing period. Waist circumference was measured at baseline and day 14. Change in BMI, waist circumference, and food intake were secondary study endpoints. Food was provided in premeasured units of predetermined energy and macronutrient content. Food intake was determined by assessing differences between the total provided and that left over each dining session. Changes in plasma lipids, fasting insulin, and fasting glucose were exploratory endpoints.

Adv Ther (2009) 26(10):.

both the intent-to-treat sample, defined as all subjects randomized who received at least one dose of study drug and one postbaseline weight assessment, and on the observed cases dataset. For intent-to-treat calculations, missing weight data were imputed by carrying the last observation forward (LOCF).


Statistical Analyses The three treatment groups were compared on mean change in weight using univariate analysis of covariance (ANCOVA). The treatment group was included as a between-subjects factor and baseline weight was entered as a covariate. Significance levels were derived from pairwise simple contrasts: the primary contrast of interest, specified a priori, was the comparison of the olanzapine plus placebo group with the olanzapine plus mifepristone group. For comparing groups on waist circumference and food consumption, an identical linear model was used. Exploratory analyses compared groups on fasting insulin and triglyceride levels using MannWhitney nonparametric t-tests normalized to a z distribution. The analyses were conducted on

RESULTS

Fifty-eight subjects were initially randomized. One subject discontinued after randomization and before receiving any medication. Subjects ranged in age from 19 to 38 years. At baseline, the mean BMI for the entire study group was 20.9±2.0 kg/m2 (range 17.9-24.2 kg/m2). There

were no statistically significant differences between groups at baseline in BMI, weight, or waist circumference (Table 1). Change in Weight Overall group differences in weight were statistically significant (intent to treat: omnibus F=10.7, df=3.57, ANCOVA P=0.0001). Mean increase in weight from baseline to day 14 was significantly greater in the olanzapine plus placebo group (3.2±0.9 kg) compared with the olanzapine plus mifepristone group (2.0±1.2 kg; P