Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, Canada.
Department of Psychiatry, University of British Columbia, Vancouver, Canada.
PLoS One. 2021 Jan 28;16(1):e0246211. doi: 10.1371/journal.pone.0246211. eCollection 2021.
The second generation antipsychotic drugs represent the most common form of pharmacotherapy for schizophrenia disorders. It is now well established that most of the second generation drugs cause metabolic side-effects. Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) are two commonly used antipsychotic drugs with moderate metabolic liability. However, there is a dearth of preclinical data that directly compares the metabolic effects of these two drugs, using sophisticated experimental procedures. The goal of the present study was to compare metabolic effects for each drug versus control animals.
Adult female rats were acutely treated with either risperidone (0.1, 0.5, 1, 2, 6 mg/kg), paliperidone (0.1, 0.5, 1, 2, 6 mg/kg) or vehicle and subjected to the glucose tolerance test; plasma was collected to measure insulin levels to measure insulin resistance with HOMA-IR. Separate groups of rats were treated with either risperidone (1, 6 mg/kg), paliperidone (1, 6 mg/kg) or vehicle, and subjected to the hyperinsulinemic euglycemic clamp.
Fasting glucose levels were increased by all but the lowest dose of risperidone, but only with the highest dose of paliperidone. HOMA-IR increased for both drugs with all but the lowest dose, while the three highest doses decreased glucose tolerance for both drugs. Risperidone and paliperidone both exhibited dose-dependent decreases in the glucose infusion rate in the clamp, reflecting pronounced insulin resistance.
In preclinical models, both risperidone and paliperidone exhibited notable metabolic side-effects that were dose-dependent. Differences between the two were modest, and most notable as effects on fasting glucose.
第二代抗精神病药物是治疗精神分裂症的最常见药物。现在已经确定，大多数第二代药物都会引起代谢副作用。利培酮及其活性代谢物帕利哌酮（9-羟基利培酮）是两种常用的抗精神病药物，代谢负担适中。然而，目前缺乏直接比较这两种药物代谢作用的临床前数据，也缺乏使用复杂的实验程序进行比较。本研究的目的是比较两种药物对每种药物的代谢作用与对照动物的代谢作用。
成年雌性大鼠急性给予利培酮（0.1、0.5、1、2、6 mg/kg）、帕利哌酮（0.1、0.5、1、2、6 mg/kg）或载体，并进行葡萄糖耐量试验；收集血浆以测量胰岛素水平，以 HOMA-IR 测量胰岛素抵抗。单独一组大鼠分别给予利培酮（1、6 mg/kg）、帕利哌酮（1、6 mg/kg）或载体，并进行高胰岛素正常血糖钳夹试验。
除最低剂量的利培酮外，所有剂量的利培酮均使空腹血糖水平升高，但只有最高剂量的帕利哌酮升高。两种药物的 HOMA-IR 均随除最低剂量外的所有剂量增加，而三种最高剂量均降低两种药物的葡萄糖耐量。利培酮和帕利哌酮均表现出剂量依赖性的葡萄糖输注率降低，反映出明显的胰岛素抵抗。
在临床前模型中，利培酮和帕利哌酮均表现出显著的剂量依赖性代谢副作用。两者之间的差异不大，最显著的是对空腹血糖的影响。
