The Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Norway.
Dr. Einar Martens' Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
Int J Neuropsychopharmacol. 2019 May 1;22(5):358-369. doi: 10.1093/ijnp/pyz012.
Antipsychotic drugs can negatively affect the metabolic status of patients, with olanzapine as one of the most potent drugs. While patients are often medicated for long time periods, experiments in rats typically run for 1 to 12 weeks, showing olanzapine-related weight gain and increased plasma lipid levels, with transcriptional upregulation of lipogenic genes in liver and adipose tissue. It remains unknown whether metabolic status will deteriorate with time.
To examine long-term metabolic effects, we administered intramuscular long-acting injections of olanzapine (100 mg/kg BW) or control substance to female rats for up to 13 months.
Exposure to olanzapine long-acting injections led to rapid weight gain, which was sustained throughout the experiment. At 1, 6, and 13 months, plasma lipid levels were measured in separate cohorts of rats, displaying no increase. Hepatic transcription of lipid-related genes was transiently upregulated at 1 month. Glucose and insulin tolerance tests indicated insulin resistance in olanzapine-treated rats after 12 months.
Our data show that the continuous increase in body weight in response to long-term olanzapine exposure was accompanied by surprisingly few concomitant changes in plasma lipids and lipogenic gene expression, suggesting that adaptive mechanisms are involved to reduce long-term metabolic adverse effects of this antipsychotic agent in rats.
抗精神病药物会对患者的代谢状况产生负面影响，而奥氮平是其中作用最强的药物之一。由于患者通常需要长期服药，因此大鼠实验通常持续 1 至 12 周，结果显示奥氮平会导致体重增加和血浆脂质水平升高，肝脏和脂肪组织中与脂质生成相关的基因转录上调。目前尚不清楚代谢状况是否会随时间恶化。
为了研究长期的代谢影响，我们给雌性大鼠肌肉内注射长效奥氮平（100mg/kgBW）或对照物质，最长可达 13 个月。
奥氮平长效注射暴露导致体重迅速增加，整个实验过程中持续增加。在 1、6 和 13 个月时，分别在不同批次的大鼠中测量血浆脂质水平，未发现增加。肝脏脂质相关基因的转录在 1 个月时短暂上调。葡萄糖和胰岛素耐量试验表明，奥氮平治疗的大鼠在 12 个月后出现胰岛素抵抗。
我们的数据表明，长期奥氮平暴露导致的体重持续增加，同时血浆脂质和脂肪生成基因表达几乎没有伴随其他变化，这表明机体存在适应性机制，可减少这种抗精神病药物在大鼠中的长期代谢不良反应。
