Abstract
BackgroundThe 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.MethodsAdults 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).ResultsAsenapine 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.ConclusionsIn 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.
Highlights
The second generation antipsychotic (SGA) drugs represent the preferred choice of pharmacological treatment for schizophrenia
Intraperitoneal Glucose Tolerance Test (IGTT) Analysis of the IGTT with asenapine revealed no significant effect of drug treatment on fasting glucose levels or glucose intolerance following glucose challenge (Figure 2A)
Asenapine significantly affected insulin resistance [F(5,43) = 2.59, p,0.05], measured by homeostatic model assessment of insulin resistance (HOMA-IR), as insulin resistance was significantly reduced with the lowest asenapine dose (0.01 mg/kg) and a strong trend with the two doses (0.05 and 0.1 mg/kg) (Table 1)
Summary
The second generation antipsychotic (SGA) drugs represent the preferred choice of pharmacological treatment for schizophrenia. Despite the lower incidence of extrapyramidal side-effects with SGAs compared to their predecessors, over the last decade it has become clear that the majority of SGAs are associated with substantial unwanted side-effects These side-effects are predominantly metabolic disturbances which include the components of metabolic syndrome [2,3,4,5]: weight-gain, adiposity, hyperlipidemia, glucose intolerance and insulin resistance. Numerous studies have confirmed a continuum of metabolic liability, with the drugs clozapine and olanzapine causing greatest weight-gain, through intermediate effects with drugs including risperidone and quetiapine, to least weight-gain with ziprasidone and aripiprazole.
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