Faculty of Medicine, Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.
Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
Neuropharmacology. 2020 Sep 15;175:107717. doi: 10.1016/j.neuropharm.2019.107717. Epub 2019 Jul 23.
The second generation antipsychotic drug clozapine is a psychotherapeutic agent with superior efficacy for treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of neurological side-effects, but a high propensity to induce weight gain and metabolic dysregulation. The primary metabolite of clozapine is norclozapine (N-Desmethylclozapine), which has psychoactive properties itself, but its effects on metabolic function remains unknown. The goal of the present study was to determine whether directly administered norclozapine could cause metabolic dysregulation, similar to clozapine.
Adult female rats were treated with a range of doses of clozapine and norclozapine (0.5, 2, 8 & 20 mg/kg, i.p.) and then subjected to the intraperitoneal glucose tolerance test (IGTT), where glucose levels were recorded for 2 h following a glucose challenge. In parallel, rats were tested with two doses of clozapine and norclozapine (2 & 20 mg/kg, i.p.) in the hyperinsulinemic-euglycemic clamp (HIEC), to measure whole body insulin resistance.
In the IGTT, clozapine demonstrated dose-dependent effects on fasting glucose levels and total glucose area-under-the-curve following the glucose challenge, with the two highest doses strongly increasing glucose levels. Only the highest dose of norclozapine increased fasting glucose levels, and caused a non-significant increase in glucose levels following the challenge. By contrast, both doses of clozapine and norclozapine caused a potent and long-lasting decrease in the glucose infusion rate in the HIEC, indicating that both compounds cause whole body insulin resistance.
While not as potent as its parent compound, norclozapine clearly exerts acute metabolic effects, particularly on insulin resistance. This article is part of the issue entitled 'Special Issue on Antipsychotics'.
第二代抗精神病药物氯氮平是一种治疗难治性精神分裂症的疗效较好的心理治疗药物。氯氮平与较低的神经副作用发生率相关，但易引起体重增加和代谢失调。氯氮平的主要代谢产物是去甲氯氮平（N-去甲基氯氮平），它本身具有精神活性，但它对代谢功能的影响尚不清楚。本研究的目的是确定直接给予去甲氯氮平是否会引起类似于氯氮平的代谢失调。
成年雌性大鼠接受了一系列氯氮平和去甲氯氮平剂量（0.5、2、8 和 20mg/kg，ip）的治疗，然后进行腹腔内葡萄糖耐量试验（IGTT），在葡萄糖挑战后 2 小时记录葡萄糖水平。同时，大鼠接受了氯氮平和去甲氯氮平（2 和 20mg/kg，ip）的两个剂量的高胰岛素-正常血糖钳夹（HIEC）测试，以测量全身胰岛素抵抗。
在 IGTT 中，氯氮平对空腹血糖水平和葡萄糖挑战后的总葡萄糖 AUC 呈剂量依赖性影响，其中两个最高剂量显著增加了葡萄糖水平。只有去甲氯氮平的最高剂量增加了空腹血糖水平，并且在挑战后引起葡萄糖水平的非显著增加。相比之下，氯氮平和去甲氯氮平的两个剂量都导致 HIEC 中葡萄糖输注率的强烈和持久下降，表明这两种化合物都导致全身胰岛素抵抗。
虽然不如其母体化合物有效，但去甲氯氮平显然会产生急性代谢作用，特别是对胰岛素抵抗。本文是题为“抗精神病药物特刊”的一部分。
