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Vasopressin V1B Receptor Antagonists as Potential Antidepressants
International Journal of Neuropsychopharmacology ( IF 4.5 ) Pub Date : 2021-03-16 , DOI: 10.1093/ijnp/pyab013
Shigeyuki Chaki 1
Affiliation  

Accumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-vasopressin (AVP) is one of the primary factors in HPA axis regulation under stress situations, and AVP and its receptor subtype (V1B receptor) play a pivotal role in HPA axis abnormalities observed in depression. Based on this hypothesis, several non-peptide V1B receptor antagonists have been synthesized, and the efficacies of some V1B receptor antagonists have been investigated in both animals and humans. V1B receptor antagonists exert antidepressant-like effects in several animal models at doses that attenuate the hyperactivity of the HPA axis, and some of their detailed mechanisms have been delineated. These results obtained in animal models were, at least partly, reproduced in clinical trials. At least 2 V1B receptor antagonists (TS-121 and ABT-436) showed tendencies to reduce the depression scores of patients with major depressive disorder at doses that attenuate HPA axis hyperactivity or block the pituitary V1B receptor. Importantly, TS-121 showed a clearer efficacy for patients with higher basal cortisol levels than for those with lower basal cortisol levels, which was consistent with the hypothesis that V1B receptor antagonists may be more effective for patients with HPA axis hyperactivity. Therefore, V1B receptor antagonists are promising approaches for the treatment of depression involving HPA axis impairment such as depression.

中文翻译:

加压素 V1B 受体拮抗剂作为潜在的抗抑郁药

越来越多的证据表明,某些抑郁症患者群体的下丘脑-垂体-肾上腺 (HPA) 轴功能受损。精氨酸加压素(AVP)是应激情况下HPA轴调节的主要因素之一,AVP及其受体亚型(V1B受体)在抑郁症中观察到的HPA轴异常中起关键作用。基于这一假设,已经合成了几种非肽 V1B 受体拮抗剂,并且已经在动物和人类中研究了一些 V1B 受体拮抗剂的功效。V1B 受体拮抗剂在几种动物模型中以减弱 HPA 轴过度活跃的剂量发挥抗抑郁样作用,并且已经描述了它们的一些详细机制。在动物模型中获得的这些结果至少部分地在临床试验中重现。至少 2 种 V1B 受体拮抗剂(TS-121 和 ABT-436)在减弱 HPA 轴过度活跃或阻断垂体 V1B 受体的剂量下显示出降低重度抑郁症患者抑郁评分的趋势。重要的是,与基础皮质醇水平较低的患者相比,TS-121 对基础皮质醇水平较高的患者显示出更明显的疗效,这与 V1B 受体拮抗剂可能对 HPA 轴多动症患者更有效的假设一致。因此,V1B 受体拮抗剂是治疗涉及 HPA 轴损伤(如抑郁症)的抑郁症的有希望的方法。
更新日期:2021-03-16
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