A comparison of the metabolic side-effects of the second-generation antipsychotic drugs risperidone and paliperidone in animal models

Abstract

Background: The second generation antipsychotic drugs represent the most common form of pharmacotherapy for schizophrenia disorders. It is now well established that most of the second generation drugs cause metabolic side-effects. Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) are two commonly used antipsychotic drugs with moderate metabolic liability. However, there is a dearth of preclinical data that directly compares the metabolic effects of these two drugs, using sophisticated experimental procedures. The goal of the present study was to compare metabolic effects for each drug versus control animals.

Methods: Adult female rats were acutely treated with either risperidone (0.1, 0.5, 1, 2, 6 mg/kg), paliperidone (0.1, 0.5, 1, 2, 6 mg/kg) or vehicle and subjected to the glucose tolerance test; plasma was collected to measure insulin levels to measure insulin resistance with HOMA-IR. Separate groups of rats were treated with either risperidone (1, 6 mg/kg), paliperidone (1, 6 mg/kg) or vehicle, and subjected to the hyperinsulinemic euglycemic clamp.

Results: Fasting glucose levels were increased by all but the lowest dose of risperidone, but only with the highest dose of paliperidone. HOMA-IR increased for both drugs with all but the lowest dose, while the three highest doses decreased glucose tolerance for both drugs. Risperidone and paliperidone both exhibited dose-dependent decreases in the glucose infusion rate in the clamp, reflecting pronounced insulin resistance.

Conclusions: In preclinical models, both risperidone and paliperidone exhibited notable metabolic side-effects that were dose-dependent. Differences between the two were modest, and most notable as effects on fasting glucose.

Fig 1. Sequence of experimental procedures.

Figure graphically illustrates (A) intraperitoneal glucose tolerance test (IGTT) and (B) hyperinsulinemic-euglycemic clamp (HIEC) in which the two antipsychotic drugs risperidone and paliperidone are administered in vivo.

Fig 2. Effects of treatment with the antipsychotic drugs risperidone and paliperidone on fasting glucose levels and during the intraperitoneal glucose tolerance test.

Adult female rats (n = 8–9 per group) were administered an acute injection of drug vehicle, (A) risperidone (0.1, 0.5, 1, 0.5, 1, 2 or 6 mg/kg, s.c) or (B) paliperidone (0.1, 0.5, 1, 0.5, 1, 2 or 6 mg/kg, s.c). Plasma glucose levels were measured before antipsychotic administration in animals fasted overnight at baseline (= Time 0), and then thirty minutes after antipsychotic treatment. Upon completion of this measurement, animals were challenged with the intraperitoneal glucose tolerance test (1 mg/ml/kg of glucose). Plasma glucose levels were recorded every fifteen minutes for a 2 hour period. Cumulative amounts of plasma glucose (group means ± SEM) were added up and presented as the “area under the curve”, evident in the inset figure. Asterix (*) indicates statistically different from control rats, p < 0.05.

Fig 3. Insulin resistance following the acute administration of the antipsychotic drugs risperidone and paliperidone, measured with the hyperinsulinemic euglycemic clamp.

Fasted adult female rats (n = 5–6 per group) were assessed for insulin resistance by the hyperinsulinemic-euglycemic clamp. Animals were stabilized until euglycemia was obtained and then animals were administered vehicle or (A) a lower (1 mg/kg) or higher (6 mg/kg) dose of risperidone or (B) a lower (1 mg/kg) or higher (6 mg/kg) dose of paliperidone (at t = 0 min). Plasma glucose concentrations were measured every subsequent ten minutes, after which glucose infusion rates (GIRs) were modified if necessary. The GIRs are provided as the change in GIR from euglycemia (group means ± SEM). Asterix (*) represents significantly different compared to controls, p < 0.05; hashtag (#)represents significantly different versus the 1 mg/kg dose-treated animals, p < 0.05.