title: Olanzapine depot exposure in male rats: Dose-dependent lipogenic effects without concomitant weight gain.
abstract: Treatment with second-generation antipsychotic agents such as olanzapine frequently results in metabolic adverse effects, e.g. hyperphagia, weight gain and dyslipidaemia in patients of both genders. The molecular mechanisms underlying metabolic adverse effects are still largely unknown, and studies in rodents represent an important approach in their exploration. However, the validity of the rodent model is hampered by the fact that antipsychotics induce weight gain in female, but not male, rats. When administered orally, the short half-life of olanzapine in rats prevents stable plasma concentrations of the drug. We recently showed that a single intramuscular injection of long-acting olanzapine formulation yields clinically relevant plasma concentrations accompanied by several dysmetabolic features in the female rat. In the current study, we show that depot injections of 100-250 mg/kg olanzapine yielded clinically relevant plasma olanzapine concentrations also in male rats. In spite of transient hyperphagia, however, olanzapine resulted in weight loss rather than weight gain. The resultant negative feed efficiency was accompanied by a slight elevation of thermogenesis markers in brown adipose tissue for the highest olanzapine dose, but the olanzapine-related reduction in weight gain remains to be explained. In spite of the absence of weight gain, an olanzapine dose of 200mg/kg or above induced significantly elevated plasma cholesterol levels and pronounced activation of lipogenic gene expression in the liver. These results confirm that olanzapine stimulates lipogenic effects, independent of weight gain, and raise the possibility that endocrine factors may influence gender specificity of metabolic effects of antipsychotics in the rat.
authors.affiliation: Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Bergen, Norway; The Norwegian Centre for Mental Disorders Research (NORMENT) and the K.G. Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Norway. Electronic address: johan.ferno@k2.uib.no.
authors.forename: J
authors.initials: J
authors.lastname: Fernø
authors.affiliation: Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Bergen, Norway; The Norwegian Centre for Mental Disorders Research (NORMENT) and the K.G. Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Norway.
authors.forename: K M
authors.initials: KM
authors.lastname: Ersland
authors.affiliation: Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Bergen, Norway; The Norwegian Centre for Mental Disorders Research (NORMENT) and the K.G. Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Norway.
authors.forename: I H
authors.initials: IH
authors.lastname: Duus
authors.affiliation: Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Bergen, Norway; The Norwegian Centre for Mental Disorders Research (NORMENT) and the K.G. Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Norway.
authors.forename: I
authors.initials: I
authors.lastname: González-García
authors.affiliation: Section of Clinical Pharmacology, Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway.
authors.forename: K O
authors.initials: KO
authors.lastname: Fossan
authors.affiliation: The Lipid Research Group, Section for Medical Biochemistry, Department of Clinical Science, University of Bergen, 5021 Norway; Department of Heart Disease, University of Bergen, 5021 Norway.
authors.forename: R K
authors.initials: RK
authors.lastname: Berge
authors.affiliation: Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Bergen, Norway; The Norwegian Centre for Mental Disorders Research (NORMENT) and the K.G. Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Norway.
authors.forename: V M
authors.initials: VM
authors.lastname: Steen
authors.affiliation: Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Bergen, Norway; The Norwegian Centre for Mental Disorders Research (NORMENT) and the K.G. Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Skrede
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D001569:Benzodiazepines / Q000494:pharmacology*; D001786:Blood Glucose; D001835:Body Weight / Q000187:drug effects*; D003692:Delayed-Action Preparations / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005215:Fasting; D005260:Female; D008055:Lipids / Q000097:blood; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley; D022722:Thermogenesis / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000932:Antiemetics; D001786:Blood Glucose; D003692:Delayed-Action Preparations; D008055:Lipids; D014157:Transcription Factors; D001569:Benzodiazepines; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077152:Olanzapine
keywords: Lipogenic; Male rat; Metabolism; Olanzapine depot formulation; Weight gain