Research reportThe efficacy of mifepristone in the reduction and prevention of olanzapine-induced weight gain in rats
Introduction
Atypical antipsychotics have provided significant benefit to patients with schizophrenia [1], bipolar disorder [2] and other major psychiatric conditions. In current psychiatric practice, atypical antipsychotics are favored over conventional antipsychotics because of better tolerability and medication compliance [3]. However, significant side effects associated with atypical antipsychotics have emerged in recent years, namely the propensity to induce significant weight gain [4], contribution to metabolic syndrome [5] and an increased risk of diabetes mellitus and hyperglycemia. The FDA recently implemented a mandatory class warning for all atypical antipsychotics related to the risk of ‘Hyperglycemia and Diabetes Mellitus’. Weight gain is among the most common reasons that a patient might discontinue an effective antipsychotic [6]. Little is known about the etiology and the effective management of antipsychotic induced weight gain.
Clozapine was the first atypical antipsychotic shown to induce substantially more weight gain than conventional antipsychotics [7]. The weight gain exceeded 10% of initial body weight within 12 weeks in more than one third of patients [8], [9]. Subsequently, olanzapine was found to have a similar weight gain profile to clozapine. Olanzapine is widely prescribed for the treatment of many psychiatric conditions including schizophrenia, schizoaffective disorder, bipolar disorder and as antidepressant augmentation therapy for refractory major depressive disorder [10]. In a meta-analysis of antipsychotic trials involving over 30,000 patients, olanzapine and clozapine were the atypical agents associated with the greatest weight gain [4]. Some long-term studies indicate that the weight gain associated with olanzapine may not plateau for 30 weeks or longer [11].
The medical consequences of atypical antipsychotic induced weight gain are significant, including an increased risk of type II diabetes, hypertension, obstructive sleep apnea and other serious obesity-related medical problems [10]. In addition, antipsychotic induced obesity has been implicated in increasing triglyceride levels, decreased HDL cholesterol, and increasing LDL cholesterol [12]. These lipid abnormalities may contribute to a higher risk for coronary artery disease.
It is not clear by what mechanism antipsychotics induce weight gain. One possible mechanism is through antagonism of the H-1 receptor [5]. Olanzapine has a greater affinity for the H-1 receptor than other atypical agents, perhaps correlating to its greater risk of weight gain. Another proposed mechanism includes antagonism of the 5HT2c receptor subtypes [13]. Olanzapine and clozapine are both potent antagonists of the 5HT2c receptor, while aripiprazole and ziprasidone are both weak 5HT2c antagonists and have a more weight neutral profile. Other possible mechanisms for antipsychotic induced weight gain include endocrine factors such as greater insulin resistance, effects on glucocorticoids, and hyperprolactinemia [14]. Strategies for controlling antipsychotic induced weight gain have been of limited success, highlighting the need to further understand the physiology and treatment of antipsychotic induced weight gain [15], [16].
Multiple animal models of obesity have been designed to help further understand the physiological factors of obesity, including genetic models (fa/fa rats), induction of obesity through high fat diets, and through administration of atypical antipsychotics. Adrenal glucocorticoids appear to be important in the etiology of many types of obesity including dietary, hypothalamic and genetic forms of obesity [17]. Adrenalectomy prevents hyperphagia and reduces fat synthesis in animal models of obesity [18]. Preliminary work indicates that blocking the type II glucocorticoid receptor with mifepristone reverses genetic obesity in young fa/fa Zucker rats [19]. After 15 days of treatment with mifepristone, 5-week old obese Zucker rats resembled lean vehicle rats in terms of body composition. In addition, dietary obesity in Osborn–Mendel rats also appears to be reversed by mifepristone [20].
Mifepristone Mifeprex is both a potent type II glucocorticoid receptor antagonist and a progesterone receptor antagonist. Given the evidence from prior studies that mifepristone may reverse genetic and dietary obesity in rodent models, there may be a role for mifepristone in preventing or reversing antipsychotic induced weight gain as well. The objectives of these experiments were to test a reproducible model of atypical antipsychotic induced weight gain in rodents, and to demonstrate that mifepristone may mitigate and also prevent the weight gain associated with administration of olanzapine.
Section snippets
Animals
A total of 48 adult female Sprague–Dawley rats, age 8–11 weeks (CD®, Charles River Laboratories, Wilmington, MA, USA) were maintained under standard husbandry conditions following a 2–4 week acclimation period. Animals were exposed to a 12 h light/12 h dark cycle and food and water were provided ad libitum. The basal diet was standard rat chow (Lab Diet® Certified Rodent Diet #5002, PMI Nutrition International, Inc., St. Louis, MA, USA)
Experimental methods
Two separate experiments were conducted. In the first
Data analysis
Changes in body weight were compared across groups using repeated-measures analysis of variance models. These models included treatment group as a between-subjects factor and time as a within-subjects factor. When models were statistically significant (<0.05), one-way analyses of variance were conducted to compare groups. When no differences were observed between the three experimental groups (i.e., dose level was not a significant source of variance), they were combined for subsequent
Weight gain induction: baseline—day 35
At baseline, the mean body weight for all 48 animals was 249.5 g (m = 249.5 ± 13.3). Between baseline and day 35, repeated-measures ANOVA indicated a statistically significant within-subjects effect of time (F = 430.1, d.f. (source, error) = 15, 660; p < 0.0001); significant weight increases were observed in all four groups. Moreover, there was a statistically significant time by group interaction (F = 2.9, d.f. = 45, 660; p < 0.0001) indicating a differential rate of change across groups (see Fig. 1). The rats
Discussion
These data replicate an animal model of olanzapine-induced weight gain at therapeutically effective dose equivalents. In addition, the data suggest that mifepristone has significant effects on both mitigating and preventing olanzapine induced weight gain in this rat model.
Corticosteroids are implicated in multiple forms of obesity [21], and the use of mifepristone, a potent glucocorticoid (GRII) antagonist, has been shown to reduce obesity associated with genetics and high fat diet in animal
Acknowledgement
Drs. Beebe, Block, and Belanoff are employees of Corcept Therapeutics. Drs. DeBattista and Blasey are consultants. This study was conducted by Corcept Therapeutics.
References (27)
Pharmacogenetics of antipsychotic-induced weight gain
Pharmacol Res
(2004)- et al.
Obesity and endocrine disease
Endocrinol Metabol Clin North Am
(2003) - et al.
The metabolic syndrome and cardiovascular risk in Cushing's Syndrome
Endocrinol Metabol Clin North Am
(2005) - et al.
Impact of atypical antipsychotics on quality of life in patients with schizophrenia
CNS Drugs
(2004) Acute and maintenance treatment of bipolar mania: the role of atypical antipsychotics
Bipolar Disorders
(2003)- et al.
Time to study discontinuation, relapse, and compliance with atypical or conventional antipsychotics in schizophrenia and related disorders
Int Clin Psychopharmacol
(2002) - et al.
Antipsychotic-induced weight gain: a review of the literature
J Clin Psychiatry
(2001) Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives
Pharmacopsychiatry
(2002)Drug induced weight gain, an impediment to successful pharmacotherapy: focus on antipsychotics
Curr Drug Targets
(2004)Novel antipsychotics: comparison of weight gain liabilities
J Clin Psychiatry
(1999)
Clozapine-induced weight gain: prevalence and clinical relevance
Am J Psychiatry
Clozapine and weight gain
Am J Psychiatry
Metabolic syndrome: epidemiology and consequences
J Clin Psychiatry
Cited by (26)
Olanzapine-induced nonalcoholic fatty liver disease: The effects of differential food pattern and the involvement of PGRMC1 signaling
2023, Food and Chemical ToxicologyEffect of melatonin in reducing second-generation antipsychotic metabolic effects: A double blind controlled clinical trial
2018, Diabetes and Metabolic Syndrome: Clinical Research and ReviewsCitation Excerpt :On day 21, the rats had significant weight loss. The rats taking 200 mg/day had significantly less abdominal fat than the control group [53]. In another study in 2009, 57 men aged 19–38 years had weight gain and waist circumference significantly higher in the group receiving olanzapine and placebo than those taking the olanzapine and mifepristone [54].
Thoughts on interactions between PGRMC1 and diverse attested and potential hydrophobic ligands
2017, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :They found that antipsychotic drugs decreased levels of Insig-1 and PGRMC1, and increased expression of SREBP1 and SCAP which was associated with both lipogenesis and cholesterogenesis. Mifepristone (RU-486) is an antagonist of the classical P4 receptor (P4R), but not of PGRMC1 progestogen responsiveness [80], and has been used to treat antidepressant-induced weight gain in animals and humans [81–83]. Cotreatment with antidepressant drugs and RU-486 reversed the drug-dependent lipid metabolism, which Cai et al. argued involved PGRMC1 [79].
Discovery of a novel non-steroidal GR antagonist with in vivo efficacy in the olanzapine-induced weight gain model in the rat
2012, Bioorganic and Medicinal Chemistry LettersSelective glucocorticoid receptor (type II) antagonists prevent weight gain caused by olanzapine in rats
2011, European Journal of PharmacologyCitation Excerpt :Animal studies have shown that mifepristone, a glucocorticoid receptor (type II) and progesterone receptor antagonist, can both prevent and reverse weight gain caused by antipsychotic medication. In a 21-day study, rats treated with mifepristone plus olanzapine gained significantly less weight than animals treated with only olanzapine (Beebe et al., 2006). In a separate rat experiment, after significant weight gain had been induced by olanzapine, rats administered mifepristone concomitant with olanzapine lost a significant portion of their body weight and abdominal fat (Beebe et al., 2006).
Clock genes and body composition in patients with schizophrenia under treatment with antipsychotic drugs
2011, Schizophrenia ResearchCitation Excerpt :Generally, a reduction in glucocorticoid sensitivity is suggested to result in better metabolic parameters, with less abdominal fat (van Raalte et al., 2009). Recent studies in rat models have shown an effect of glucocorticoid antagonists on weight gain during treatment with olanzapine (Beebe et al., 2006; Belanoff et al., 2010), attenuating or even preventing olanzapine-induced weight gain in these animals. These results indicate that factors that decrease glucocorticoid sensitivity may also decrease metabolic derangements, which is the reason that agents that reduce local glucocorticoid concentrations are currently tested in the treatment of metabolic syndrome (van Raalte et al., 2009).