Vasopressin 1B (V_1B) receptor has a pivotal role in the regulation of the hypothalamus-adrenal-pituitary axis, and V_1B receptor antagonists have shown efficacy in a number of preclinical models of depression. The efficacy and safety of, TS-121 (active ingredient: THY1773), a novel V_1B receptor antagonist, was investigated in patients with major depressive disorder (MDD) who had an inadequate response to current antidepressant therapy. In a randomized, double-blind, placebo-controlled phase 2 study, 51 MDD patients (43 of whom completed the study) were randomly assigned to either TS-121 10 mg, 50 mg or placebo for 6 weeks treatment period. The primary endpoint was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6. The study was conducted from Jul 2017 to Dec 2018.

The changes from baseline in MADRS score at week 6 (Least Square Mean [95% Confidence interval] were: TS-121 10 mg (-9.0 [-13.9, -4.1]), TS-121 50 mg (-9.0 [-13.4, -4.5]), and placebo (-6.4 [-10.7, -2.2]). TS-121 groups showed greater numerical reductions in MADRS score change from baseline compared to placebo, though these reductions did not achieve statistical significance. Similar trends of numerically greater improvements in TS-121 groups were observed across secondary endpoints. Higher baseline urinary and hair cortisol levels were associated with a greater separation between TS-121 groups and the placebo group in the primary endpoint. These findings, combined with favorable safety and tolerability, warrant further investigation of TS-121 in an adequately powered study in patients with MDD.

加压素1B（V _1B）受体在下丘脑-肾上腺-垂体轴的调节中起关键作用，V _1B受体拮抗剂已在许多抑郁症临床前模型中显示出功效。新型V _1B TS-121（有效成分：THY1773）的功效和安全性研究人员对目前对抗抑郁药治疗反应不足的重度抑郁症（MDD）患者进行了研究。在一项随机，双盲，安慰剂对照的2期研究中，将51名MDD患者（其中43位完成了研究）随机分配给TS-121 10 mg，50 mg或安慰剂，治疗期为6周。主要终点是第6周的蒙哥马利-奥斯伯格抑郁评定量表（MADRS）得分相对于基线的变化。该研究于2017年7月至2018年12月进行。

第6周（最小二乘均值[95％置信区间]）的MADRS评分相对于基线的变化为：TS-121 10 mg（-9.0 [-13.9，-4.1]），TS-121 50 mg（-9.0 [-13.4] ，-4.5]）和安慰剂（-6.4 [-10.7，-2.2]）。与安慰剂相比，TS-121组与基线相比MADRS得分变化的数值减少幅度更大，尽管这些减少并没有统计学意义。在次要终点观察到TS-121组的改善更大；基线尿液和头发皮质醇水平的升高与主要终点TS-121组和安慰剂组之间的更大隔离有关，这些发现以及良好的安全性和耐受性，有必要在对MDD患者进行充分研究的基础上进一步研究TS-121。