Haloperidol and olanzapine mediate metabolic abnormalities through different molecular pathways

V Mondelli,S Kapur,S Natesan,M Modo,A Cattaneo,P Dazzan,C M Pariante,C Anacker,A C Vernon

doi:10.1038/tp.2012.138

V Mondelli, S Kapur + Show 7 more

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https://doi.org/10.1038/tp.2012.138

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Abstract

The pathogenesis of antipsychotic-induced disturbances of glucose homeostasis is still unclear. Increased visceral adiposity has been suggested to be a possible mediating mechanism. The aim of this study was to investigate, in an animal model, the differential effects of olanzapine and haloperidol on visceral fat deposition (using magnetic resonance imaging(MRI)) and on critical nodes of the insulin signaling pathway (liver-protein levels of IRS2 (insulin receptor substrate 2), GSK3α (glycogen synthase kinase-3α), GSK3β, GSK3α-Ser21, GSK3β-Ser9). To this end, we studied male Sprague–Dawley rats treated with vehicle (n=8), haloperidol (2 mg kg−1 per day, n=8), or olanzapine (10 mg kg−1per day, n=8), using osmotic minipumps, for 8 weeks. The haloperidol group showed a higher percentage of visceral fat than both the olanzapine group and the vehicle group, whereas there was no difference between the olanzapine and the vehicle group. In terms of insulin signaling pathway, the olanzapine group showed significantly reduced IRS2 levels, reduced phosphorylation of GSK3α and increased phosphorylation of GSK3β, whereas there was no difference between the haloperidol and the vehicle group. Our data suggest that different molecular pathways mediate the disturbances of glucose homeostasis induced by haloperidol and olanzapine with a direct effect of olanzapine on the insulin molecular pathway, possibly partly explaining the stronger propensity of olanzapine for adverse effects on glucose regulation when compared with haloperidol in clinical settings.

Highlights

The mortality rate of individuals with serious mental illnesses is two to three times higher than in the general population,[1] and up to 60% of the excess mortality rate in patients with schizophrenia is attributable to physical illnesses.[2]
The longitudinal change in body weight over time in the three separate groups has been previously reported, showing weight gain over the 8 weeks in all the three groups, with the antipsychotic-treated animals gaining less weight compared with the control group in the first 2 weeks.[21]
Our findings show different molecular mechanisms underlying the metabolic effects of olanzapine and haloperidol

Summary

Introduction

The mortality rate of individuals with serious mental illnesses is two to three times higher than in the general population,[1] and up to 60% of the excess mortality rate in patients with schizophrenia is attributable to physical illnesses.[2]. There is some evidence that olanzapine and clozapine are associated with an increased risk for diabetes compared with other antipsychotics.[5,6] Among the other antipsychotics, for example, haloperidol has been less consistently associated with weight gain and abnormal glucose regulation,[4] but again, whether olanzapine and haloperidol have different metabolic effects at a molecular level it is not well understood yet

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