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

Makoto Kamiya; Helene D Sabia; Julie Marella; Maurizio Fava; Charles B Nemeroff; Hideo Umeuchi; Michihiko Iijima; Shigeyuki Chaki; Izumi Nishino

doi:10.1016/j.jpsychires.2020.05.017

Efficacy and safety of TS-121, a novel vasopressin V_1B receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study

J Psychiatr Res. 2020 Sep:128:43-51. doi: 10.1016/j.jpsychires.2020.05.017. Epub 2020 May 31.

Authors

Makoto Kamiya¹, Helene D Sabia², Julie Marella², Maurizio Fava³, Charles B Nemeroff⁴, Hideo Umeuchi⁵, Michihiko Iijima⁶, Shigeyuki Chaki⁶, Izumi Nishino⁵

Affiliations

¹ Taisho Pharmaceutical R&D Inc., 350 Mount Kemble Avenue, Morristown, NJ, 07960, USA. Electronic address: ma-kamiya@taisho.co.jp.
² Taisho Pharmaceutical R&D Inc., 350 Mount Kemble Avenue, Morristown, NJ, 07960, USA.
³ Massachusetts General Hospital, 55 Fruit Street, Bulfinch 351, Boston, MA, 02114, USA.
⁴ University of Texas Dell Medical School in Austin, 1601 Trinity Street, Stop Z0600, Office HDB 4.112, Austin, TX, 78712, USA.
⁵ Taisho Pharmaceutical Co., Ltd., Development Headquarters, 3-24-1 Takada, Toshima-ku, Tokyo, 170-8633, Japan.
⁶ Taisho Pharmaceutical Co., Ltd., Research Headquarters, 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama, 331-9530, Japan.

PMID: 32521250
DOI: 10.1016/j.jpsychires.2020.05.017

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03093025.

Keywords: Antidepressant; MDD adjunctive treatment; Major depressive disorder; THY1773; TS-121; V(1B) receptor antagonist.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Antidepressive Agents / therapeutic use
Depressive Disorder, Major* / drug therapy
Double-Blind Method
Humans
Treatment Outcome
Vasopressins / therapeutic use

Substances

Antidepressive Agents
Vasopressins

Associated data

ClinicalTrials.gov/NCT03093025