Publication Date
9-1-2025
Journal
Journal of Clinical Psychopharmacology
DOI
10.1097/JCP.0000000000002046
PMID
40719142
PMCID
PMC12379779
PubMedCentral® Posted Date
7-28-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Background: Anhedonia is a core symptom of major depressive disorder (MDD) that may result from aberrant lateral habenula hyperactivity. Targeting G-protein coupled receptor 139 (GPR139) may improve anhedonia by modulating lateral habenula activity. NBI-1065846 is an investigational GPR139 agonist that improved anhedonia, anxiety, and depression in rodent models.
Methods: TERPSIS was a phase 2, proof-of-concept clinical study. Adults with MDD experiencing a major depressive episode with anhedonia were randomized 1:1 to NBI-1065846 or placebo for 8 weeks. The primary endpoint was the change in the Dimensional Anhedonia Rating Scale (DARS) score. Secondary endpoints were change in total Montgomery Åsberg Depression Rating Scale (MADRS) score in participants with a baseline 17-item Hamilton Depression Rating Scale (HAM-D17) score of ≥19 (moderate to severe) and change in Clinical Global Impression of Severity (CGI-S) score. All changes were from baseline to Day 57.
Results: In total, 93 participants received study treatment (NBI-1065846, n = 46; placebo, n = 47). Both groups showed notable improvements in DARS scores from baseline to day 57 (least-squares mean change: NBI-1065846, 13.5; placebo, 17.4), with no statistically significant difference (NBI-1065846 vs. placebo, P = 0.8663). Similarly, MADRS ( P = 0.7008) and CGI-S ( P = 0.9051) scores showed no significant difference between groups. All treatment-emergent adverse events in the NBI-1065846 group were mild or moderate in severity.
Conclusions: The TERPSIS study did not meet its primary or secondary endpoints. NBI-1065846 was generally well tolerated. Addressing the lack of treatment options for anhedonia remains an important unmet clinical need.
Keywords
Humans, Depressive Disorder, Major, Male, Female, Adult, Anhedonia, Middle Aged, Double-Blind Method, Proof of Concept Study, Psychiatric Status Rating Scales, Young Adult, Acetamides, Triazines, anhedonia, major depressive disorder, dimensional anhedonia rating scale, GPR139 agonist, NBI-1065846
Published Open-Access
yes
Recommended Citation
Benedetto, Shannon R; Ionescu, Adrian; Ge, Tingting; et al., "A Phase 2 Randomized Trial of NBI-1065846 (TAK-041) in Patients With Anhedonia Associated With Major Depressive Disorder: Results of the TERPSIS Study" (2025). Faculty, Staff and Students Publications. 6074.
https://digitalcommons.library.tmc.edu/baylor_docs/6074
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