An Evaluation of the Effects of the Novel Antipsychotic Drug Lurasidone on Glucose Tolerance and Insulin Resistance: A Comparison with Olanzapine

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.

The Complex Relationship between Antipsychotic-Induced Weight Gain and Therapeutic Benefits: A Systematic Review and Implications for Treatment

“…Hypothetically, some of these pathways may be associated by proxy to weight gain, and explain why AIWG on its own in relation to clinically significant improvements psychopathology is not consistently replicated across studies. For example, antipsychotic-induced glucose dysregulation is well-established in rodent and human models to occur independently to AIWG through “direct” molecular pathways (Houseknecht et al, 2007 ; Sacher et al, 2008 ; Smith et al, 2008 ; Vidarsdottir et al, 2010 ; Albaugh et al, 2011 ; Roerig et al, 2011 ; Hahn et al, 2013 ; Wu et al, 2014 ). Moreover, schizophrenia is a heterogeneous disorder, and it may be that unknown, genetic predisposing factors determine which subset of patients may, for example, rely on pathways overlapping with AIWG (or other antipsychotic-induced metabolic effects) for treatment response.…”

Chronic olanzapine administration causes metabolic syndrome through inflammatory cytokines in rodent models of insulin resistance

“…Olanzapine was intraperitoneally injected with dose justification as described and discussed in Wu, et al . 50 . Briefly, the injection doses were 10 mg/kg, injection volume of 10 ml/kg, with 0.1 M hydrochloric acid as the control.…”

Animal models of metabolic syndrome: a review

“…Antipsychotic drugs are medications used to treat neuropsychiatric disorders, for examples, schizophrenia, depression, and bipolar disorder [ 95 ]. Antipsychotic drugs have been associated with a high incidence of MetS, evidenced by body weight gain, increased visceral fat, impaired glucose tolerance, and insulin resistance in animal studies [ 96 , 97 ]. However, the exact underlying mechanism involved in antipsychotic-induced MetS still remains an enigma.…”