Efficacy and safety of TS-121, a novel vasopressin V1B receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study

Abstract Vasopressin 1B (V1B) receptor has a pivotal role in the regulation of the hypothalamus-adrenal-pituitary axis, and V1B 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 V1B 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-Asberg 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.