Abstract
Over the past two decades, there has been a notable rise in the use of antipsychotic drugs, as they are used to treat an increasing number of neuropsychiatric disorders. This rise has been led predominantly by greater use of the second generation antipsychotic (SGA) drugs, which have a low incidence of neurological side-effects. However, many SGAs cause metabolic dysregulation, including glucose intolerance and insulin resistance, thus increasing the risk of cardiometabolic disorders. The metabolic effects of the novel SGA lurasidone, which was approved by the Food and Drug Administration in 2010, remain largely unknown. As rodent models accurately predict the metabolic effects of SGAs in humans, the aim of the present study was to use sophisticated animal models of glucose tolerance and insulin resistance to measure the metabolic effects of lurasidone. In parallel, we compared the SGA olanzapine, which has established metabolic effects. Adult female rats were treated with vehicle, lurasidone (0.2, 0.8 or 2.0 mg/kg, s.c.) or olanzapine (10.0 mg/kg, s.c.) and subjected to the glucose tolerance test (GTT). Separate groups of rats were treated with vehicle, lurasidone (0.2, 0.8 or 2.0 mg/kg, s.c.) or olanzapine (1.5 and 15 mg/kg, s.c.) and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC). Compared to vehicle treated animals, lurasidone caused mild glucose intolerance in the GTT with a single dose, but there was no effect on insulin resistance in the GTT, measured by HOMA-IR. The HIEC also confirmed no effect of lurasidone on insulin resistance. In contrast, olanzapine demonstrated dose-dependent and potent glucose intolerance, and insulin resistance in both tests. Thus, in preclinical models, lurasidone demonstrates mild metabolic liability compared to existing SGAs such as olanzapine. However, confirmation of these effects in humans with equivalent tests should be confirmed.
Highlights
Second generation antipsychotic (SGA) drugs are widely used for the treatment and management of schizophrenia and other psychiatric disorders [1,2,3]
In a large head-to-head clinical trial of SGA drugs, the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study [a major, multi-center trial sponsored by NIMH] observed that 43% of patients treated with SGAs had metabolic syndrome
A similar effect was measured with insulin resistance calculated by the homeostatic model assessment of insulin resistance (HOMA-IR) equation, whereby there was a significant main effect of drug treatment [F(4,39) = 5.43, p,0.005] as the olanzapine treated group showed a significant increase in insulin resistance compared to all other groups (p,0.001) and no effect of lurasidone treatment (Table 1)
Summary
Second generation antipsychotic (SGA) drugs are widely used for the treatment and management of schizophrenia and other psychiatric disorders [1,2,3]. While SGAs have a lower likelihood of neurological side-effects than the first generation antipsychotic drugs, they are frequently associated with serious cardiometabolic side-effects [5,6,7,8] This has led to the development of newer SGA drugs with the goal of improving tolerability and reducing the risk of adverse events, such as weight gain, insulin resistance, glucose intolerance and dyslipidemia. These sequelae are established components of metabolic syndrome, which predisposes patients to secondary diseases, such as Type 2 Diabetes Mellitus (DM) and cardiovascular disease [9]. When controlling for BMI, CATIE men were 85%, and CATIE women 137% more likely to have metabolic syndrome than non-psychiatric counterparts [11]
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