Metabolic side-effects of the novel second-generation antipsychotic drugs asenapine and iloperidone: a comparison with olanzapine

Abstract

Background: The second generation antipsychotic (SGA) drugs are widely used in psychiatry due to their clinical efficacy and low incidence of neurological side-effects. However, many drugs in this class cause deleterious metabolic side-effects. Animal models accurately predict metabolic side-effects for SGAs with known clinical metabolic liability. We therefore used preclinical models to evaluate the metabolic side-effects of glucose intolerance and insulin resistance with the novel SGAs asenapine and iloperidone for the first time. Olanzapine was used as a comparator.

Methods: Adults female rats were treated with asenapine (0.01, 0.05, 0.1, 0.5, 1.0 mg/kg), iloperidone (0.03, 0.5, 1.0, 5.0, 10.0 mg/kg) or olanzapine (0.1, 0.5, 1.5, 5.0, 10.0 mg/kg) and subjected to the glucose tolerance test (GTT). Separate groups of rats were treated with asenapine (0.1 and 1.0 mg/kg), iloperidone (1.0 and 10 mg/kg) or olanzapine (1.5 and 15 mg/kg) and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC).

Results: Asenapine showed no metabolic effects at any dose in either test. Iloperidone caused large and significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with both doses in the HIEC. Olanzapine caused significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with the higher dose in the HIEC.

Conclusions: In preclinical models, asenapine shows negligible metabolic liability. By contrast, iloperidone exhibits substantial metabolic liability, comparable to olanzapine. These results emphasize the need for appropriate metabolic testing in patients treated with novel SGAs where current clinical data do not exist.

Figure 1. Experimental protocol.

Describing (A) the intraperitoneal glucose tolerance test and (B) the hyperinsulinemic-euglycemic clamp with acute antipsychotic drug treatment.

Figure 2. Acute effects of the antipsychotic drug asenapine on glucose levels in adult female rats.

(A) Animals (n = 8–10 per group) received a single injection of vehicle or asenapine (0.01, 0.05, 0.1, 0.5, 1 mg/kg, s.c). Glucose levels were recorded prior to drug treatment in overnight-fasted rats at Time 0, and then 30 minutes following drug administration (x-axis). Immediately following this glucose measurement, all rats were subjected to a glucose tolerance test by receiving an intraperitoneal challenge injection of 1 mg/ml/kg of glucose, and blood glucose levels were measured every 15 minutes for the next two hours. Total cumulative glucose levels for each treatment group are summed as the “area under the curve” during the glucose tolerance test by graph inset (top right). Values represent group means ± SEM. (B) A separate cohort of animals (n = 6–8 per group) were fasted overnight and subjected to the hyperinsulinemic-euglycemic clamp. After animals reached euglycemia (three consecutive blood glucose readings of 6.0±0.4 mmol/L), rats were treated with vehicle, low (0.1 mg/kg) or high dose (1.0 mg/kg) asenapine (arrow at t = 0 min). Glucose levels were recorded every 10 minutes and the glucose infusion rate was adjusted as needed. Glucose infusion rates for each treatment group are presented as change in glucose infusion rate from euglycemia. Values represent group means ± SEM.

Figure 3. Acute effects of the atypical antipsychotic drug iloperidone on glucose levels in adult female rats.

(A) Animals (n = 8–10 per group) received a single injection of vehicle or iloperidone (0.03, 0.5, 1.0, 5.0, 10.0 mg/kg, s.c). Glucose levels were recorded prior to drug treatment in overnight-fasted rats at Time 0, and then 30 minutes following drug administration (x-axis). Immediately following this glucose measurement, all rats were subjected to a glucose tolerance test by receiving an intraperitoneal challenge injection of 1 mg/ml/kg of glucose, and blood glucose levels were measured every 15 minutes for the next two hours. Total cumulative glucose levels for each treatment group are summed as the “area under the curve” during the glucose tolerance test by graph inset (top right). Values represent group means ± SEM. * indicates different from vehicle-treated animals, p<0.05; ** indicates different from vehicle and 0.03–1.0 mg/kg iloperidone-treated animals, p<0.01 (B). A separate cohort of animals (n = 6–8 per group) were fasted overnight and subjected to the hyperinsulinemic-euglycemic clamp. After animals reached euglycemia (three consecutive blood glucose readings of 6.0±0.4 mmol/L), rats were treated with vehicle, low (1.0 mg/kg) or high dose (10.0 mg/kg) iloperidone (arrow at t = 0 min). Glucose levels were recorded every 10 minutes and the glucose infusion rate was adjusted as needed. Glucose infusion rates for each treatment group are presented as change in glucose infusion rate from euglycemia Values represent group means ± SEM. * indicates different from vehicle-treated animals, p<0.05; ** indicates different from vehicle and 1.0 mg/kg iloperidone-treated animals, p<0.05.

Figure 4. Acute effects of the atypical antipsychotic drug olanzapine on glucose levels in adult female rats.

(A) Animals (n = 8–10 per group) received a single injection of vehicle or olanzapine (0.1, 0.5, 1.5, 5.0, 15.0 mg/kg, s.c). Glucose levels were recorded prior to drug treatment in overnight-fasted rats at Time 0, and then 30 minutes following drug administration (x-axis). Immediately following this glucose measurement, all rats were subjected to a glucose tolerance test by receiving an intraperitoneal challenge injection of 1 mg/ml/kg of glucose, and blood glucose levels were measured every 15 minutes for the next two hours. Total cumulative glucose levels for each treatment group are summed as the “area under the curve” during the glucose tolerance test by graph insets (top right). Values represent group means ± SEM. * indicates different from vehicle-treated animals, p<0.05; ** indicates different from vehicle-treated animals, p<0.01 (B). A separate cohort of animals (n = 6–8 per group) were fasted over-night and subjected to the hyperinsulinemic-euglycemic clamp. After animals reached euglycemia (three consecutive blood glucose readings of 6.0±0.4 mmol/L), rats were treated with vehicle, low (1.5 mg/kg) or high dose (15.0 mg/kg) olanzapine (arrow at t = 0 min). Glucose levels were recorded every 10 minutes and the glucose infusion rate was adjusted as needed. Glucose infusion rates for each treatment group are presented as change in glucose infusion rate from euglycemia. Values represent group means ± SEM. * indicates different from vehicle and low-dose olanzapine-treated animals, p<0.05.