title: Preventing olanzapine-induced weight gain using betahistine: a study in a rat model with chronic olanzapine treatment.
abstract: Olanzapine is the one of first line antipsychotic drug for schizophrenia and other serious mental illness. However, it is associated with troublesome metabolic side-effects, particularly body weight gain and obesity. The antagonistic affinity to histamine H1 receptors (H1R) of antipsychotic drugs has been identified as one of the main contributors to weight gain/obesity side-effects. Our previous study showed that a short term (2 weeks) combination treatment of betahistine (an H1R agonist and H3R antagonist) and olanzapine (O+B) reduced (-45%) body weight gain induced by olanzapine in drug-naïve rats. A key issue is that clinical patients suffering with schizophrenia, bipolar disease and other mental disorders often face chronic, even life-time, antipsychotic treatment, in which they have often had previous antipsychotic exposure. Therefore, we investigated the effects of chronic O+B co-treatment in controlling body weight in female rats with chronic and repeated exposure of olanzapine. The results showed that co-administration of olanzapine (3 mg/kg, t.i.d.) and betahistine (9.6 mg/kg, t.i.d.) significantly reduced (-51.4%) weight gain induced by olanzapine. Co-treatment of O+B also led to a decrease in feeding efficiency, liver and fat mass. Consistently, the olanzapine-only treatment increased hypothalamic H1R protein levels, as well as hypothalamic pAMPKα, AMPKα and NPY protein levels, while reducing the hypothalamic POMC, and UCP1 and PGC-1α protein levels in brown adipose tissue (BAT). The olanzapine induced changes in hypothalamic H1R, pAMPKα, BAT UCP1 and PGC-1α could be reversed by co-treatment of O+B. These results supported further clinical trials to test the effectiveness of co-treatment of O+B for controlling weight gain/obesity side-effects in schizophrenia with chronic antipsychotic treatment.
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia; Centre for Translational Neuroscience, School of Medicine, and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Lian
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia; Schizophrenia Research Institute, Sydney, NSW, Australia.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
authors.forename: Nagesh
authors.initials: N
authors.lastname: Pai
authors.affiliation: Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia; Centre for Translational Neuroscience, School of Medicine, and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia; Schizophrenia Research Institute, Sydney, NSW, Australia.
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001569:Benzodiazepines / Q000009:adverse effects*; D001621:Betahistine / Q000494:pharmacology*; D004195:Disease Models, Animal; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D066292:Lipid Droplets / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D000077152:Olanzapine; D009929:Organ Size / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D001569:Benzodiazepines; D000077152:Olanzapine; D001621:Betahistine
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