Objective:

Altered glutamatergic neurotransmission is implicated in the pathogenesis of major depressive disorder. AXS-05 (dextromethorphan-bupropion) is an oral NMDA receptor antagonist and sigma-1 receptor agonist, which utilizes inhibition of CYP2D6 to increase its bioavailability. This phase 2 trial assessed the efficacy and safety of dextromethorphan-bupropion in the treatment of major depressive disorder.

Methods:

This randomized, double-blind, multicenter, parallel-group trial evaluated dextromethorphan-bupropion versus the active comparator sustained-release bupropion in patients 18–65 years old with a diagnosis of major depressive disorder of moderate or greater severity. Patients were randomly assigned to receive either dextromethorphan-bupropion (45 mg/105 mg tablet) or bupropion (105 mg tablet), once daily for the first 3 days and twice daily thereafter, for a total of 6 weeks. The primary endpoint was overall treatment effect on Montgomery-Åsberg Depression Rating Scale (MADRS) score (average of the change from baseline for weeks 1–6), assessed in all randomized patients whose diagnosis and severity were confirmed by an independent assessor and who received at least one dose of study medication and had at least one postbaseline assessment.

Results:

Of 97 patients randomized, 17 did not have a confirmed diagnosis and severity based on the independent assessment, resulting in 80 patients in the efficacy population (dextromethorphan-bupropion, N=43; bupropion, N=37). The mean change from baseline in MADRS score over weeks 1–6 (overall treatment effect) was significantly greater with dextromethorphan-bupropion than with bupropion (−13.7 points vs. −8.8 points; least-squares mean difference=−4.9; 95% CI=−3.1, −6.8). MADRS score change with dextromethorphan-bupropion was significantly greater than with bupropion at week 2 and every time point thereafter (week 6: −17.3 vs. −12.1 points; least-squares mean difference=−5.2, 95% CI=−1.1, −9.3). Remission rates were significantly greater with dextromethorphan-bupropion at week 2 and every time point thereafter (week 6: 46.5% vs. 16.2%; least-squares mean difference=30.3%, 95% CI=11.2, 49.4). Response rates (≥50% decrease in MADRS score from baseline) at week 6 were 60.5% with dextromethorphan-bupropion and 40.5% with bupropion (least-squares mean difference=19.9%, 95% CI=−1.6, 41). Most secondary outcomes favored dextromethorphan-bupropion. The most common adverse events with dextromethorphan-bupropion were dizziness, nausea, dry mouth, decreased appetite, and anxiety. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or sexual dysfunction.

Conclusions:

In patients with major depression, dextromethorphan-bupropion (AXS-05) significantly improved depressive symptoms compared with bupropion and was generally well tolerated.

中文翻译：

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AXS-05（右美沙芬-安非他酮）在重度抑郁症中的作用：一项随机双盲对照试验

客观的：

改变的谷氨酸能神经传递与重度抑郁症的发病机制有关。AXS-05（右美沙芬-安非他酮）是一种口服 NMDA 受体拮抗剂和 sigma-1 受体激动剂，它利用 CYP2D6 的抑制作用来增加其生物利用度。该 2 期试验评估了右美沙芬-安非他酮治疗重度抑郁症的疗效和安全性。

方法：

这项随机、双盲、多中心、平行组试验在 18-65 岁诊断为中度或更严重的重度抑郁症的患者中评估了右美沙芬-安非他酮与活性比较剂缓释安非他酮的疗效。患者被随机分配接受右美沙芬-安非他酮（45 mg/105 mg 片剂）或安非他酮（105 mg 片剂），前 3 天每天一次，之后每天两次，共 6 周。主要终点是对 Montgomery-Åsberg 抑郁评定量表 (MADRS) 评分（第 1-6 周从基线变化的平均值）的总体治疗效果，在所有随机患者中进行评估，这些患者的诊断和严重程度已由独立评估员确认并接受了至少一剂研究药物并进行了至少一项基线后评估。

结果：

在随机分组的 97 名患者中，有 17 名没有根据独立评估得到确诊和严重程度，导致疗效人群中有 80 名患者（右美沙芬-安非他酮，N=43；安非他酮，N=37）。与安非他酮相比，右美沙芬-安非他酮在第 1-6 周内 MDRS 评分相对于基线的平均变化（整体治疗效果）显着大于安非他酮（-13.7 分对 -8.8 分；最小二乘均值差 = -4.9；95% CI =−3.1，−6.8）。在第 2 周和之后的每个时间点，右美沙芬-安非他酮的 MADRS 评分变化显着大于安非他酮（第 6 周：-17.3 对 -12.1 分；最小二乘均值差=-5.2，95% CI=-1.1，- 9.3)。在第 2 周和之后的每个时间点，右美沙芬-安非他酮的缓解率显着更高（第 6 周：46.5% 对 16.2%；最小二乘均值差=30.3%, 95% CI=11.2, 49.4)。第 6 周时，右美沙芬-安非他酮的缓解率（MADRS 评分比基线降低 50% 以上）为 60.5%，安非他酮为 40.5%（最小二乘均数差 = 19.9%，95% CI = -1.6, 41）。大多数次要结果有利于右美沙芬-安非他酮。右美沙芬-安非他酮最常见的不良事件是头晕、恶心、口干、食欲下降和焦虑。右美沙芬-安非他酮与拟精神病作用、体重增加或性功能障碍无关。右美沙芬-安非他酮最常见的不良事件是头晕、恶心、口干、食欲下降和焦虑。右美沙芬-安非他酮与拟精神病作用、体重增加或性功能障碍无关。右美沙芬-安非他酮最常见的不良事件是头晕、恶心、口干、食欲下降和焦虑。右美沙芬-安非他酮与拟精神病作用、体重增加或性功能障碍无关。

结论：

在重度抑郁症患者中，与安非他酮相比，右美沙芬-安非他酮 (AXS-05) 显着改善了抑郁症状，并且通常耐受性良好。