Mathew Sanjay J, Cutler Andrew J, Visitacion Nicole C, Gold Michael, Yuan Jason, Aurora Bill
From the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX.
Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY.
J Clin Psychopharmacol. 2025;45(3):267-276. doi: 10.1097/JCP.0000000000001967. Epub 2025 Apr 9.
PURPOSE/BACKGROUND: This phase 2a randomized, double-blind, placebo-controlled, 8-week trial assessed the efficacy and safety of navacaprant, a highly selective kappa opioid receptor antagonist, in adults with major depressive disorder (MDD).
METHODS/PROCEDURES: Participants with 17-Item Hamilton Depression Rating Scale (HAMD-17) scores of 14 to 30 were randomized 1:1 to once-daily navacaprant 80 mg or placebo (n = 102 each). The primary endpoint was HAMD-17 change from baseline (CFB) to week 8. Secondary endpoints included CFB in Snaith-Hamilton Pleasure Scale (SHAPS). No adjustment for multiple comparisons was made.
FINDINGS/RESULTS: At week 8, HAMD-17 CFB was not statistically significantly improved with navacaprant vs placebo (least squares mean difference -1.7 [standard error, 1.08], P = 0.121; mixed-models repeated-measures) in the efficacy population. In a prespecified sensitivity analysis using last-observation-carried-forward, navacaprant statistically significantly improved HAMD-17 CFB (-2.9 [0.88], P = 0.002; -2.2 [0.98], P = 0.024) and SHAPS CFB (-2.8 [0.96], P = 0.004; -3.4 [1.10], P = 0.002) vs placebo at weeks 4 and 8. In the prespecified subgroup with moderate-to-severe MDD (baseline HAMD-17 score ≥22; n = 100), navacaprant statistically significantly improved HAMD-17 CFB at both timepoints (-3.0 [1.20], P = 0.015; -2.8 [1.33], P = 0.037) and SHAPS CFB at week 8 (-4.8 [1.35], P = 0.001) vs placebo. Most frequently reported adverse events (AEs) included headache (4.9% both) and nausea (4.9% navacaprant, 1.0% placebo); no serious AEs were reported with navacaprant.
IMPLICATIONS/CONCLUSIONS: Although the primary endpoint was not met in the efficacy population, which included participants with mild depression, statistically significant improvements with navacaprant on depressive symptoms including anhedonia in the moderate-to-severe MDD subgroup, along with a favorable safety profile, support further study of navacaprant for the treatment of MDD.
目的/背景：这项2a期随机、双盲、安慰剂对照、为期8周的试验评估了高选择性κ阿片受体拮抗剂纳伐普兰特在重度抑郁症（MDD）成年患者中的疗效和安全性。
方法/步骤：汉密尔顿抑郁量表（HAMD-17）评分为14至30分的参与者按1:1随机分配，每日一次服用80mg纳伐普兰特或安慰剂（每组n = 102）。主要终点是从基线（CFB）到第8周的HAMD-17变化。次要终点包括斯奈斯-汉密尔顿愉悦量表（SHAPS）的CFB。未进行多重比较调整。
在第8周时，在疗效人群中，与安慰剂相比，纳伐普兰特组的HAMD-17 CFB没有统计学上的显著改善（最小二乘均值差异为-1.7[标准误差，1.08]，P = 0.121；混合模型重复测量）。在使用末次观察结转的预先指定的敏感性分析中，在第4周和第8周时，与安慰剂相比，纳伐普兰特在统计学上显著改善了HAMD-17 CFB（-2.9[0.88]，P = 0.002；-2.2[0.98]，P = 0.024）和SHAPS CFB（-2.8[0.96]，P = 0.004；-3.4[1.10]，P = 0.002）。在预先指定的中度至重度MDD亚组（基线HAMD-17评分≥22；n = 100）中，与安慰剂相比，纳伐普兰特在两个时间点均显著改善了HAMD-17 CFB（-3.0[1.20]，P = 0.015；-2.8[1.33]，P = 0.037），并在第8周时显著改善了SHAPS CFB（-4.8[1.35]，P = 0.001）。最常报告的不良事件（AE）包括头痛（两组均为4.9%）和恶心（纳伐普兰特组为4.9%，安慰剂组为1.0%）；未报告纳伐普兰特的严重不良事件。
意义/结论：尽管在包括轻度抑郁症患者的疗效人群中未达到主要终点，但纳伐普兰特在中度至重度MDD亚组中对包括快感缺失在内的抑郁症状有统计学上的显著改善，且安全性良好，这支持进一步研究纳伐普兰特用于治疗MDD。
