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

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

European Journal of Pharmacology 655 (2011) 117–120 Contents lists available at ScienceDirect European Journal of Pharmacology j o u r n a l h o m e...

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European Journal of Pharmacology 655 (2011) 117–120

Contents lists available at ScienceDirect

European Journal of Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r

Endocrine Pharmacology

Selective glucocorticoid receptor (type II) antagonists prevent weight gain caused by olanzapine in rats Joseph K. Belanoff a,b, Christine M. Blasey a,b,⁎, Robin D. Clark a, Robert L. Roe a a b

Corcept Therapeutics Incorporated, 149 Commonwealth Drive, Menlo Park, CA 94061, United States Stanford University, Department of Psychiatry, 401 Quarry Road, Palo Alto, CA 94304, United States

a r t i c l e

i n f o

Article history: Received 27 October 2010 Received in revised form 9 December 2010 Accepted 7 January 2011 Available online 24 January 2011 Keywords: Glucocorticoid HPA axis Mifepristone Olanzapine Olanzapine-induced weight gain Antipsychotic

a b s t r a c t 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 18 days: vehicle, olanzapine plus vehicle (2.4 mg/kg), olanzapine plus CORT 112716 (20 mg/kg), olanzapine plus CORT 112716 (60 mg/kg), olanzapine plus CORT 113083 (20 mg/kg), or olanzapine plus CORT 113083 (60 mg/kg). Rats receiving olanzapine plus CORT 112716 (60 mg/kg) or olanzapine plus CORT 113083 (60 mg/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. © 2011 Elsevier B.V. All rights reserved.

1. Introduction Use of atypical antipsychotic medication consistently leads to weight gain and adverse metabolic effects. While effectively reducing symptoms of severe psychiatric diseases, use of these medications increases patients' risk for a variety of medical problems including diabetes mellitus and metabolic syndrome. In addition to now widespread descriptions of these problems, the United States Food and Drug Administration (FDA) has issued a class warning for all second-generation antipsychotic medications (Rosack, 2003). Recent publications reporting the severity of adverse side effects in children have provided evidence about the scope of the problem (Correll et al., 2009; Varley and McClellan, 2009). Efforts have been made to discover effective treatments to ameliorate the side effects of antipsychotic medication. A variety of pharmacological and non-pharmacological interventions have been tested including exercise and lifestyle management, histamine antagonists, selective serotonin reuptake inhibitors, metformin, rosiglitazone, sibutramine, phenylpropanolamine, amantadine, topiramate, modafinil, and alpha-lipoic acid (Maayan et al., 2010; Wu et al., 2008; Faulkner et al., 2007; Narula et al., 2010). These intervention studies have not yielded positive results with the exception of a recent study of topiramate in India which showed a modest effect in ⁎ Corresponding author at: Corcept Therapeutics Incorporated, 149 Commonwealth Drive, Menlo Park, CA 94061, United States. Tel.: +1 650 688 8798; fax: +1 650 327 3218. E-mail address: [email protected] (C.M. Blasey). 0014-2999/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2011.01.019

treatment naive patients with schizophrenia (Narula et al., 2010). Two recent formal meta-analyses (Faulkner et al., 2007; Maayan et al., 2010) and one systematic literature review (Baptista et al., 2008) have synthesized the extant research on pharmacological interventions for antipsychotic induced weight gain. In a review of 18 trials, Faulkner et al. (2007) concluded that evidence for efficacy of pharmacological agents was insufficient to confirm utility. More recently, a review of 32 studies concluded that metformin showed the largest effect relative to placebo; however, the magnitude of the effect was modest and heterogeneous across studies (Maayan et al., 2010). In general, the pharmacological interventions tested thus far have not been based on mechanistic hypotheses (Gross et al., 2009; Maayan et al., 2010). Several recent publications have suggested that glucocorticoid receptor antagonists can block the weight gain caused by antipsychotic medication. 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). Two randomized clinical trials in humans demonstrated that mifepristone significantly attenuated the weight gain caused by antipsychotic medication. In a 14-day randomized clinical trial in healthy men (Gross et al., 2009), mifepristone reduced the weight gain caused by olanzapine. In a 28-day trial of weight gain

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induced by risperidone (Gross et al., 2010), mifepristone reduced the weight gain induced by risperidone use and reduced risperidone's effects on fasting insulin and triglycerides. A potent glucocorticoid receptor antagonist without mifepristone's progesterone receptor activity was recently shown to effectively mitigate olanzapineinduced weight gain in rats (Belanoff et al., 2010). The current study tested whether two recently identified compounds, both selective glucocorticoid receptor antagonists with no progesterone receptor activity, could prevent weight gain induced by the antipsychotic olanzapine. 2. Material and methods 2.1. Drug preparation Olanzapine is an antipsychotic medication manufactured by Eli Lilly. For this experiment, olanzapine was prepared daily at a nominal concentration of .6 mg/ml by mixing the test article with a vehicle solution (1.5% 1 N hydrochloric acid, 1% Cremephor™ EL, and 97.5% sterile water for injections, USP). This formulation was stored at room temperature. The test articles were 1) (R)-1-(4-fluorophenyl)4a-methoxymethyl-6-(6-morpholin-4-yl-pyridine-3-sulfonyl)4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and 2) (R)-4a-ethoxymethyl-1-(4-fluorophenyl)-6-(6-morpholin-4yl-pyridine-3-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene) and are henceforth described as CORT 113083 and CORT 112716 respectively. These test articles were manufactured by Corcept Therapeutics, Inc. The basic method for synthesizing compounds of this type has been described elsewhere (Clark et al., 2008). For this study, a single stock of each at 60 mg/ml was prepared in 100% dimethyl sulfoxide (DMSO), aliquoted for each daily need, stored in a dessicator frozen at −50 to −90 °C, and thawed in a dessicator before each preparation. These test articles were then added to a vehicle solution comprised of .1% Tween®80 and .5% hydroxypropyl methylcellulose in sterile water for injections, USP. 2.2. Animals Eight week old, young adult female, experimentally naïve Sprague–Dawley rats (Charles River Laboratories) (n = 60) were fed a Meal Lab Diet® (Certified Rodent Diet #5002, PMI Nutritional International, Inc.), which was provided ad libitum. Tap water was available ad libitum. Animals were individually housed in suspended stainless steel wire-mesh cages in an environmentally controlled room. Temperature and humidity were monitored and controlled, and fluorescent lighting was provided for 12 hours per day. Prior to the experiment there was a 22-day acclimation period to habituate the animals to the housing environment. Animals were observed daily with respect to general health and signs of disease. 2.3. Procedure Animals were randomly assigned (n = 10 per group) to receive 18 days of one of the following six treatments: vehicle plus vehicle, olanzapine (2.4 mg/kg/day) plus vehicle, olanzapine (2.4 mg/kg/day) plus CORT 112716 (20 mg/kg/day), olanzapine (2.4 mg/kg/day) plus CORT 112716 (60 mg/kg/day), olanzapine plus CORT 113083 (20 mg/ kg/day), or olanzapine plus CORT 113083 (60 mg/kg/day). All treatments were administered via oral gavage in divided doses, twice daily, for 18 consecutive days. The dosages for the new compounds were extrapolated from our previous animal studies on mifepristone (Beebe et al., 2006) and CORT 108297 (Belanoff et al., 2009). The dose for olanzapine was determined from previous publications that described animal models of olanzapine-induced weight gain (Arjona et al., 2004; Patil et al., 2006).

Measurement of the primary endpoint, body weight, was conducted on Days 1, 3, 5, 7, 9, 11, 13, 17 and on Day 19 prior to sacrifice and necropsy. Food consumption was measured daily. Clinical observations for morbidity, mortality, injury, general health, and the availability of food and water were conducted twice daily. The study, conducted at MPI Research (Mattawan, Michigan), was approved by their ethics committee in compliance with the USDA Animal Welfare Act 9 and the Guide for Care and Use of Laboratory Animals.

2.4. Statistical analyses Statistical analyses were performed using one way analysis of covariance (ANCOVA) using change from baseline weight as the dependent variable, treatment group as a fixed factor, and baseline weight as a covariate. The ANCOVA model was followed by linear contrasts comparing each group versus the vehicle reference group and each group versus the olanzapine reference group. The alpha for statistical significance was assumed at P b .05 two-tailed.

3. Results 3.1. Body weight Table 1 provides the mean changes from baseline to endpoint for each treatment group. Rats receiving olanzapine plus CORT 112716 (60 mg/kg/day) or olanzapine plus CORT 113083 (60 mg/kg dose) gained significantly less weight than rats receiving only olanzapine (olanzapine plus CORT 113083 versus olanzapine only: P = .006; olanzapine plus CORT 112716 versus olanzapine only: P = .004). Mean weight gain observed in the two groups receiving 60 mg/kg doses of the test compounds did not differ statistically from the mean weight gain observed in the group receiving only vehicle (CORT 113083 versus vehicle: P = .32; CORT 112716 versus vehicle: P = .40). Rats receiving the higher dose of CORT 112716 (60 mg/kg/day) gained significantly less weight than those receiving the lower dose (20 mg/kg/day; P b .05). Similarly, rats administered olanzapine plus 60 mg/kg/day of CORT 113083 gained significantly less weight than rats receiving olanzapine with only 20 mg/kg/day of CORT 113083 (P b .05).

Table 1 Mean changes from baseline in body weight by treatment (n = 10 per group). Treatment group

Mean change (S.E.M.)

Probabilitya (vehicle)

Probabilityb (olanzapine)

Vehicle Olanzapine only (2.4 mg/kg) Olanzapine + CORT 112716 (20 mg/kg) Olanzapine + CORT 112716 (60 mg/kg) Olanzapine + CORT 113083 (20 mg/kg) Olanzapine + CORT 113083 (60 mg/kg)

+ 16.0 (3.4) + 34.1 (3.8)

n/a b.00001

b.00001 n/a

+ 30.4 (2.1)

.003

.44

+ 20.7 (3.0)

.32

.006

+ 33.9 (2.1)

b.00001

.97

+ 20.0 (4.7)

.40

.004

a Significance levels derived from ANCOVA simple contrasts comparing the 6 groups on change from baseline in body weight (grams). Baseline entered as a covariate; reference group = vehicle. b Significance levels derived from ANCOVA simple contrasts comparing change from baseline in body weight (grams). Baseline entered as a covariate; reference group = olanzapine only.

J.K. Belanoff et al. / European Journal of Pharmacology 655 (2011) 117–120 Table 2 Mean daily food consumption in grams. Treatment group (n = 10 per group)

Mean

Standard deviation

P-valuea (versus olanzapine)

Vehicle Olanzapine only (2.4 mg/kg) Olanzapine + 112716 (20 mg/kg) Olanzapine + 112716 (60 mg/kg) Olanzapine + 113083 (20 mg/kg) Olanzapine + 113083 (60 mg/kg)

15.35 19.38 19.94 18.06 19.74 19.41

1.57 1.97 1.09 1.90 1.52 2.54

b.0001 n/a .99 .63 .99 .99

a

P values derived from Tukey's HSD tests.

3.2. Food consumption Average food intake for all treatment groups and significance tests from planned statistical comparisons are shown in Table 2. Mean daily food consumption was significantly greater in the group treated with only olanzapine (m = 19.4 g/day, sd = 2.0) compared to the group treated with only vehicle (m = 15.4 g/day, sd = 1.6; P b .0001). The four groups receiving CORT 112716 or CORT 113083 in conjunction with olanzapine did not differ in food consumption compared to the olanzapine group. 4. Discussion Over the past ten years, increasing numbers of studies describing the weight and metabolic side effects of atypical antipsychotic medication have been reported in the scientific literature (Faulkner et al., 2007; Baptista et al., 2008). These publications frequently suggest that future research is needed to develop targeted, mechanistically based strategies for managing these metabolic side effects (Baptista et al., 2008). Consistent with these needs, the current animal study tested whether two recently-identified selective glucocorticoid receptor antagonists, CORT 112716 and CORT 113083, could attenuate weight gain caused by olanzapine. Following administration for 18 days, olanzapine caused significant weight gain in rats. Rats that received olanzapine and concomitant treatment with either CORT 112716 or CORT 113083 gained significantly less weight than rats given olanzapine alone. At the higher dose level tested (60 mg/kg daily), both novel compounds resulted in weight gain that was comparable with the expected weight gain observed in the young adult rats receiving vehicle only (see Table 1). Although rats receiving olanzapine and a glucocorticoid receptor antagonist gained less weight than rats receiving olanzapine only, they ingested comparable amounts of food. The observation that weight gain prevention was not mediated by a decrease in food consumption suggests that these compounds may mechanistically operate on metabolic processes rather than by controlling appetite. The advantage of the newly identified compounds over the most frequently-tested glucocorticoid receptor antagonist (mifepristone) is their greater than 1000-fold selectivity for binding to the glucocorticoid receptor compared to the progesterone receptor. The progesterone antagonist activity of mifepristone causes endometrial thickening in premenopausal women and termination of early pregnancy. In addition to low affinity for the progesterone receptor, CORT 112716 and CORT 113083, have low affinity for the mineralcorticoid, estrogen, and androgen receptors (i.e., 1000-fold less binding affinity than at the glucocorticoid receptor). Like mifepristone, CORT 112716 and CORT 113083 are competitive glucocorticoid receptor antagonists. These crystalline compounds demonstrate binding affinity (Ki) for human GR of 0.3 nM (CORT 113083) and 0.7 nm (CORT 112716). CORT 112716 shows greater GR functional antagonism (7 nM) than CORT 113083 (44 nM) as measured in a reporter gene assay (Morgan et al., 2002).

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The mechanisms by which selective glucocorticoid antagonists prevent weight gain caused by antipsychotic medication have not been fully elucidated. However, several lines of previous research suggest that changes in insulin sensitivity may be involved. Increased glucocorticoid activity (cortisol in humans and corticosterone in rats) causes resistance to insulin (Andrews and Walker, 1999). It is common for patients with Cushing's syndrome to be insulin insensitive, hyperglycemic, and frankly diabetic (Chu et al., 2001). Glucocorticoid receptor antagonists cause increased sensitivity to insulin in both animal (Asagami et al., 2009) and human models (Gross et al., 2010). Perhaps this increased insulin sensitivity leads to more efficient metabolism and less weight gain in a system perturbed by antipsychotic medication. Whether these next generation compounds, including CORT 108297, CORT 112716, and CORT 113083 will be as effective as mifepristone in mitigating antipsychotic-induced weight gain in humans remains to be tested. 5. Conclusion These results combined with results from randomized clinical trials in humans (Gross et al., 2009, 2010) add to growing evidence that selective glucocorticoid antagonists have the potential to address the weight gain and metabolic side effects associated with the use of antipsychotic medication. Ultimately, this line of research may lead to the development of glucocorticoid receptor antagonists for the prevention and treatment of weight gain and its metabolic consequences for patients who need to use antipsychotic medication. Acknowledgements The authors thank Ruth Ann Gover for her editorial support in the submission of this manuscript. References Andrews, R.C., Walker, B.R., 1999. Glucocorticoids and insulin resistance: old hormones, new targets. Clin. Sci. 96, 513–523. Arjona, A.A., Zhang, S.X., Adamson, B., Wurtman, R.J., 2004. An animal model of antipsychotic-induced weight gain. Behav. Brain Res. 152, 121–127. Asagami, T., Belanoff, J.K., Clark, R.D., Tsao, P.S., 2009. Paper presented at the American Diabetes Association meeting in New Orleans, Louisiana, USA. Baptista, T., El Fakih, Y., Uzcategui, E., Sandia, I., Eduardo, Araujo, de Baptista, E., Beaulieu, S., 2008. Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs 22, 477–495. Beebe, K.L., Block, T., DeBattista, C., Blasey, C., Belanoff, J.K., 2006. The efficacy of mifepristone in the reduction and prevention of olanzapine-induced weight gain in rats. Behav. Brain Res. 171, 225–229. Belanoff, J.K., Blasey, C.M., Clark, R.D., Roe, R.L., 2010. Selective glucocorticoid receptor (type II)-antagonist prevents and reverses olanzapine-induced weight gain. Diab. Obes. Metab 12, 545–547. Chu, J.W., Matthias, D.F., Belanoff, J., Schatzberg, A., Hoffman, A.R., Feldman, D., 2001. Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone (RU 486). J. Clin. Endocrinol. Metab. 86, 3568–3573. Clark, R.D., Ray, N.C., Williams, K., Blaney, P., Ward, S., Crackett, P.H., Hurley, C., Dyke, H.J., Clark, D.E., Lockey, P., Devos, R., Wong, M., Porres, S.S., Bright, C.P., Jenkins, R.E., Belanoff, J., 2008. 1H-Pyrazole[3, 4-g]hexahydro-isoquinolines as selective glucocorticoid receptor antagonists with high functional activity. Bioorg. Med. Chem. Lett. 18, 1312–1317. Correll, C.U., Manu, P., Olshanskiy, V., Napolitano, B., Kane, J.M., Malhotra, A.K., 2009. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA 302, 1765–1773. Faulkner, G., Cohn, T., Remington, G., 2007. Interventions to reduce weight gain in schizophrenia. Cochrane Database Syst. Rev. 1, CD005148. Gross, C., Blasey, C.M., Roe, R.L., Allen, K., Block, T.S., Belanoff, J.K., 2009. Mifepristone treatment of olanzapine-induced weight gain in healthy men. Adv. Ther. 26, 959–969. Gross, C., Blasey, C.M., Roe, R.L., Belanoff, J.K., 2010. Mifepristone reduces weight gain and improves metabolic abnormalities associated with risperidone treatment in normal men. Obesity (Silver Spring) 18, 2295–2300. Maayan, L., Vakhrusheva, J., Correll, C.U., 2010. Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis. Neuropsychopharmacology 35, 1520–1530.

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