Benedetto Shannon R, Ionescu Adrian, Ge Tingting, Furey Maura, Lin Swan, Jha Manish K, Krystal Andrew, Shah Asim A, Walling David P, Shah Neel, Rizvi Sakina J, Kennedy Sidney, Laurenza Antonio, Murthy Venkatesha, Roberts Eiry, Singh Jaskaran B
Neurocrine Biosciences Inc., San Diego, CA.
Department of Psychiatry and Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas, TX.
J Clin Psychopharmacol. 2025;45(5):432-440. doi: 10.1097/JCP.0000000000002046. Epub 2025 Jul 28.
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.
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.
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.
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.
快感缺失是重度抑郁症（MDD）的核心症状，可能由外侧缰核异常活跃所致。靶向G蛋白偶联受体139（GPR139）可能通过调节外侧缰核活动来改善快感缺失。NBI-1065846是一种正在研究的GPR139激动剂，在啮齿动物模型中可改善快感缺失、焦虑和抑郁。
TERPSIS是一项2期概念验证临床研究。患有伴有快感缺失的重度抑郁发作的成年MDD患者按1:1随机分为NBI-1065846组或安慰剂组，治疗8周。主要终点是维度快感缺失评定量表（DARS）评分的变化。次要终点是基线17项汉密尔顿抑郁评定量表（HAM-D17）评分≥19（中度至重度）的参与者的蒙哥马利-Åsberg抑郁评定量表（MADRS）总分变化以及临床总体印象严重程度（CGI-S）评分变化。所有变化均为从基线到第57天。
共有93名参与者接受了研究治疗（NBI-1065846组，n = 46；安慰剂组，n = 47）。两组从基线到第57天的DARS评分均有显著改善（最小二乘均值变化：NBI-1065846组为13.5；安慰剂组为17.4），无统计学显著差异（NBI-1065846组与安慰剂组比较，P = 0.8663）。同样，MADRS评分（P = 0.7008）和CGI-S评分（P = 0.9051）在两组间也无显著差异。NBI-1065846组所有治疗中出现的不良事件严重程度均为轻度或中度。
TERPSIS研究未达到其主要或次要终点。NBI-1065846总体耐受性良好。解决快感缺失缺乏治疗选择的问题仍然是一项重要的未满足的临床需求。
