Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China.
Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, China.
Psychopharmacology (Berl). 2020 Aug;237(8):2257-2277. doi: 10.1007/s00213-020-05524-w. Epub 2020 Jun 25.
Second-generation antipsychotics are the first-line medications prescribed for schizophrenic patients; however, some of them, such as olanzapine and risperidone, may induce metabolic dysfunctions during short-term treatment. Metformin is an effective adjuvant that attenuates antipsychotic-induced metabolic dysfunctions (AIMD) in clinical practice. Whether metformin can reverse AIMD and whether metformin affects the therapeutic effects of antipsychotics in animal models of schizophrenia are questions that still need to be investigated.
In this study, an animal model of schizophrenia was established by consecutive injections of MK801 during the neurodevelopmental period. In adulthood, different dosages of olanzapine or risperidone treatment were administered to the schizophrenia model animals for 14 days. Both therapeutic effects and metabolic adverse effects were measured by behavioral tests, histopathological tests, and biochemical tests. The coadministration of different doses of metformin with olanzapine or risperidone was used to evaluate the effects of metformin on both AIMD and the therapeutic effect of those antipsychotics.
The MK801-treated rats showed schizophrenia-like behavior and variations in the shape and volume of the hippocampus. Both olanzapine and risperidone reversed the MK801-induced behavioral abnormalities as the dosage increased; however, they degenerated the hepatocytes in the liver and influenced the blood lipid levels and blood glucose levels. The coadministration of metformin did not affect the therapeutic effects of olanzapine or risperidone on behavioral abnormalities but attenuated the metabolic dysfunctions induced by those antipsychotics.
Metformin attenuated the olanzapine- and risperidone-induced metabolic dysfunctions in MK801-induced schizophrenia-like rats without reducing the therapeutic effects of the antipsychotics.
第二代抗精神病药是精神分裂症患者的一线用药；然而，其中一些药物，如奥氮平和利培酮，在短期治疗中可能会引起代谢功能障碍。二甲双胍是一种有效的辅助药物，可减轻临床实践中抗精神病药引起的代谢功能障碍（AIMD）。二甲双胍是否能逆转 AIMD 以及二甲双胍是否会影响精神分裂症动物模型中抗精神病药的治疗效果，这些问题仍需要研究。
本研究通过在神经发育期间连续注射 MK801 建立精神分裂症动物模型。在成年期，用不同剂量的奥氮平或利培酮治疗精神分裂症模型动物 14 天。通过行为测试、组织病理学测试和生化测试来测量治疗效果和代谢不良反应。用不同剂量的二甲双胍与奥氮平或利培酮联合给药，来评估二甲双胍对 AIMD 及这些抗精神病药治疗效果的影响。
MK801 处理的大鼠表现出类精神分裂症的行为和海马体形状和体积的变化。奥氮平和利培酮都随着剂量的增加逆转了 MK801 引起的行为异常，但它们使肝细胞变性，并影响血脂水平和血糖水平。二甲双胍的联合使用不影响奥氮平和利培酮对行为异常的治疗效果，但减轻了这些抗精神病药引起的代谢功能障碍。
二甲双胍减轻了 MK801 诱导的类精神分裂症大鼠中奥氮平和利培酮引起的代谢功能障碍，而不降低抗精神病药的治疗效果。
