Novel Co-Treatment Strategies to Attenuate Acute Olanzapine-Induced Metabolic Dysfunction

Olanzapine is a second-generation antipsychotic (SGA) that is commonly prescribed for the treatment of schizophrenia and several on- and off-label conditions. While effective in reducing psychoses, acute olanzapine treatment causes rapid hyperglycemia, insulin resistance, and dyslipidemia and these perturbations are linked to an increased risk of developing cardiometabolic disease. The aim of this thesis was to investigate novel pharmacological approaches with GLP1 and/or amylin analogs to offset the acute negative metabolic side effects of olanzapine. In study 1, it was found that co-treatment with glucagon-like peptide-1 (GLP1) receptor agonists protect against olanzapine-induced hyperglycemia and lipidemia while these outcomes are worsened by GLP1 receptor antagonism. Study 2 investigated compounds which synergistically enhance endogenous GLP1 as a strategy to reduce the metabolic side effects of olanzapine. In this study it was found that raising endogenous GLP1 concentrations to pharmacological levels can attenuate olanzapine-induced perturbations in glucose and lipid metabolism under glucose stimulated conditions. Study 3 explored the efficacy of amylin analogs such as pramlintide, to combat the metabolic side effects of olanzapine and found that pramlintide tended to reduce olanzapine-induced hyperglycemia and enhanced the protective effects of low dose liraglutide, a GLP1 receptor agonist, against olanzapine-induced metabolic dysfunction. Together, the studies in this thesis highlight new benefits of common pharmacological treatments which leverage GLP1 and/or amylin signalling to exert protection against acute olanzapine-induced metabolic dysfunction and could be important in designing novel treatment strategies to alleviate side effects of antipsychotics. This research was supported by a Project Grant (PJT 159538) from the Canadian Institutes of Health Research to DCW. KDM was supported by a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council (NSERC) of Canada.