Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh 160014, India.
Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India.
Toxicol Appl Pharmacol. 2019 Sep 1;378:114643. doi: 10.1016/j.taap.2019.114643. Epub 2019 Jun 26.
Despite benefits, atypical antipsychotics produce troublesome metabolic adverse effects particularly hyperphagia, weight gain, dyslipidemia, hyperglycemia and insulin resistance which further develop metabolic and cardiac complications. The animal models studied for antipsychotic-induced weight gain only focused on metabolic alteration in antipsychotics treated animals but none has considered psychosis as a predisposing factor which mimics the clinical condition. The present study was aimed to rule out the impact of pharmacologically induced psychosis-like phenotype on metabolic alterations induced by antipsychotics. Female BALB/c mice (weighing 18-23 g) exhibiting schizophrenia-like behavior after 5 days of MK-801 treatment (0.1 mg/kg, i.p.) were administered olanzapine (3 and 6 mg/kg, per oral) and risperidone (2 and 4 mg/kg, per oral) for six weeks. Acute as well as chronic treatment with olanzapine and risperidone treatment significantly reduced locomotion, increased feed intake and body weight in a time-dependent manner, which confirms the face validity of the animal model. Olanzapine (6 mg/kg) treatment significantly altered glucose and lipid homeostasis which was further accompanied by elevated levels of proinflammatory cytokines, ghrelin and leptin. These metabolic and biochemical alterations have demonstrated construct validity. Further, no significant difference was observed in the metabolic parameters in control and schizophrenic mice treated with olanzapine which confers that antipsychotic-induced metabolic alterations are independent of psychosis. Our study concluded that six-week olanzapine (6 mg/kg) treatment in control mice induced most of the clinically relevant physiological, biochemical and metabolic alterations (clinically relevant), that is independent of pharmacologically-induced psychosis.
尽管有好处，但非典型抗精神病药会产生麻烦的代谢不良反应，特别是食欲亢进、体重增加、血脂异常、高血糖和胰岛素抵抗，这进一步导致代谢和心脏并发症。研究中用于研究抗精神病药引起的体重增加的动物模型仅关注抗精神病药治疗动物的代谢改变，但没有一个模型考虑到精神病作为一种易患因素，模拟临床情况。本研究旨在排除药理学诱导的类精神病表型对抗精神病药引起的代谢改变的影响。在 MK-801（0.1mg/kg，ip）处理 5 天后表现出类精神分裂症行为的雌性 BALB/c 小鼠（体重 18-23g），给予奥氮平（3 和 6mg/kg，口服）和利培酮（2 和 4mg/kg，口服）治疗 6 周。奥氮平和利培酮的急性和慢性治疗均显著减少了运动，以时间依赖性方式增加了摄食量和体重，这证实了动物模型的表面效度。奥氮平（6mg/kg）治疗显著改变了葡萄糖和脂质稳态，进一步伴有促炎细胞因子、ghrelin 和瘦素水平升高。这些代谢和生化改变表现出结构效度。此外，在接受奥氮平治疗的对照和精神分裂症小鼠中，代谢参数没有显著差异，这表明抗精神病药引起的代谢改变与精神病无关。我们的研究得出结论，6 周的奥氮平（6mg/kg）治疗在对照小鼠中引起了大多数临床相关的生理、生化和代谢改变（临床相关），这与药理学诱导的精神病无关。
