Effects of Olanzapine and Ziprasidone on Glucose Tolerance in Healthy Volunteers

Sacher, Julia; Mossaheb, Nilufar; Spindelegger, Christoph; Klein, Nikolas; Geiss-Granadia, Thomas; Sauermann, Robert; Lackner, Edith; Joukhadar, Christian; Müller, Markus; Kasper, Siegfried

doi:10.1038/sj.npp.1301541

Cited by 87 publications

(58 citation statements)

References 69 publications

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“…Very recently, acute treatment with olanzapine was reported to produce insulin resistance in human subjects (14). The present study clearly indicates that a single injection of olanzapine, but not of aripiprazole, disrupts glucose tolerance.…”

supporting

confidence: 59%

Potentiation of the Antidepressant-Like Effect of Fluoxetine by Aripiprazole in the Mouse Tail Suspension Test

et al. 2008

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Abstract. We examined the effect of the novel atypical antipsychotic drug aripiprazole alone or in combination with the selective serotonin reuptake inhibitor fluoxetine in the mouse tail suspension test. We also investigated the effect of aripiprazole on glucose metabolism. Combined treatment with aripiprazole and a sub-effective dose of fluoxetine significantly decreased the duration of immobility in the tail suspension test. Aripiprazole by itself did not affect the duration of immobility. While olanzapine significantly increased blood glucose level in the glucose tolerance test, aripiprazole did not affect glucose metabolism. We suggest that aripiprazole augments the antidepressant-like effect of fluoxetine without affecting glucose metabolism.

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supporting

confidence: 59%

Potentiation of the Antidepressant-Like Effect of Fluoxetine by Aripiprazole in the Mouse Tail Suspension Test

et al. 2008

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“…In rodent models of antipsychotic-induced glucose dysregulation, increased HGP is arguably the most commonly observed perturbation; however, whether or not this is the case in humans is unclear. Of the currently published studies in normalweight healthy volunteers treated with short-term (1-10 days) Ola (Sacher et al 2008, Vidarsdottir et al 2010a,b, Albaugh et al 2011b, Teff et al 2013, two employed the HIEC and separately assessed peripheral and hepatic insulin sensitivity, and both suggested impairments in glucose uptake, but failed to note increases in glucose production (Vidarsdottir et al 2010a, Teff et al 2013. Although these findings require replication, they suggest that if peripheral insulin sensitivity is indeed most prominently impacted by APs in humans, use of Met for patients on antipsychotic medications who develop diabetes is open to question.…”

Section: Discussionmentioning

confidence: 99%

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

Remington

Teo

Wilson

et al. 2015

Journal of Endocrinology

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Antipsychotics (APs) are linked to diabetes, even without weight gain. Whether anti-diabetic drugs are efficacious in reversing the direct effects of APs on glucose pathways is largely undetermined. We tested two metformin (Met) doses to prevent impairments seen following a dose of olanzapine (Ola) (3 mg/kg); glucokinetics were measured using the hyperinsulinemic-euglycemic clamp (HIEC). Met (150 mg/kg; nZ13, or 400 mg/kg; nZ11) or vehicle (Veh) (nZ11) was administered through gavage preceding an overnight fast, followed by a second dose prior to the HIEC. Eleven additional animals were gavaged with Veh and received a Veh injection during the HIEC (Veh/Veh); all others received Ola. Basal glucose was similar across treatment groups. The Met 400 group had significantly greater glucose appearance (R a ) in the basal period (i.e., before Ola, or hyperinsulinemia) vs other groups. During hyperinsulinemia, glucose infusion rate (GINF) to maintain euglycemia (reflective of whole-body insulin sensitivity) was higher in Veh/Veh vs other groups. Met 150/Ola animals demonstrated increased GINF relative to Veh/Ola during early time points of the HIEC. Glucose utilization during hyperinsulinemia, relative to basal conditions, was significantly higher in Veh/Veh vs other groups. The change in hepatic glucose production (HGP) from basal to hyperinsulinemia demonstrated significantly greater decreases in Veh/Veh and Met 150/Ola groups vs Veh/Ola. Given the increase in basal R a with Met 400, we measured serum lactate (substrate for HGP), finding increased levels in Met 400 vs Veh and Met 150. In conclusion, Met attenuates hepatic insulin resistance observed with acute Ola administration, but fails to improve peripheral insulin resistance. Use of supra-therapeutic doses of Met may mask metabolic benefits by increasing lactate.

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“…The activity of 11-b-HSD has been reported to be increased in rats treated with the AAPD clozapine (Tulipano et al, 2007). In addition to weight gain, a decrease in insulin sensitivity has been reported during treatment with AAPDs (Sacher et al, 2008). Because excess glucocorticoids are implicated in both weight gain and decreased insulin sensitivity, GRAs are a logical target to try to mitigate these issues.…”

Section: Discussionmentioning

confidence: 99%

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

Sindelar¹,

Carson²,

Morin³

et al. 2013

J Pharmacol Exp Ther

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Weight gain and diabetes have been reported during treatment with atypical antipsychotic drugs (AAPDs). Patients treated with the glucocorticoid receptor antagonist (GRA) and the progesterone receptor antagonist (PRA) mifepristone [estra-4,9-dien-3-one, 11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-(11b,17b)-(9CI)] experienced significant reduction in the weight gain observed when patients were treated with olanzapine or risperidone. To understand the pharmacology responsible for this finding, we discovered LLY-2707, a novel and selective GRA, and evaluated its utility in preclinical models of AAPD-associated weight gain and diabetes. In vitro, LLY-2707 was a highly selective and potent GRA. GR occupancy in vivo was assessed using ex vivo binding where LLY-2707 inhibited [ Central activity of the GRAs was confirmed by their ability to suppress amphetamine-induced increases in locomotor activity. The increases in the body weight of female rats treated with olanzapine (2 mg/kg PO) over 14 days were reduced in a dosedependent manner by coadministration of LLY-2707. Similar decreases, although less robust, in body weight were seen with mifepristone and CORT-108297. In addition, sGRAs prevented the glucose excursion after intragastric olanzapine infusions consistent with a direct effect on the hyperglycemia observed during treatment with AAPDs. At doses effectively preventing weight gain, LLY-2707 did not substantially interfere with the dopamine D2 receptor occupancy by olanzapine. Therefore, GRA coadministration may provide a novel treatment modality to prevent the weight gain and diabetes observed during treatment with AAPDs.

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Effects of Olanzapine and Ziprasidone on Glucose Tolerance in Healthy Volunteers

Cited by 87 publications

References 69 publications

Potentiation of the Antidepressant-Like Effect of Fluoxetine by Aripiprazole in the Mouse Tail Suspension Test

Potentiation of the Antidepressant-Like Effect of Fluoxetine by Aripiprazole in the Mouse Tail Suspension Test

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

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

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