From the Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston; Alkermes, Inc., Waltham, Mass.; the Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia; McLean Hospital, Belmont, Mass.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.
Am J Psychiatry. 2016 May 1;173(5):499-508. doi: 10.1176/appi.ajp.2015.15070921. Epub 2016 Feb 12.
Major depressive disorder has been associated with dysregulation of the endogenous opioid system. The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461, a combination of a μ- and κ-opioid partial agonist, buprenorphine, and a μ-opioid antagonist, samidorphan, would exhibit antidepressant activity in patients with major depression.
A multicenter, randomized, double-blind, placebo-controlled, two-stage sequential parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment. Participants were randomly assigned to receive adjunctive treatment with 2 mg/2 mg of buprenorphine/samidorphan (the 2/2 dosage group), 8 mg/8 mg of buprenorphine/samidorphan (the 8/8 dosage group), or placebo. Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Clinical Global Impressions severity scale (CGI-S).
Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures (HAM-D: -2.8, 95% CI=-5.1, -0.6; MADRS: -4.9, 95% CI=-8.2, -1.6; CGI-S: -0.5, 95% CI=-0.9, -0.1). There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance. Overall, the buprenorphine/samidorphan combinations were well tolerated, and there was no evidence of opioid withdrawal on treatment discontinuation.
The buprenorphine/samidorphan combination is a novel and promising candidate for treatment of major depressive disorder in patients who have an inadequate response to standard antidepressants.
重度抑郁症与内源性阿片系统失调有关。作者试图确定通过给予 ALKS 5461（μ-和 κ-阿片部分激动剂、丁丙诺啡和 μ-阿片拮抗剂萨米多福的组合）进行阿片调节是否会在对一种或两种抗抑郁治疗反应不足的重度抑郁症患者中表现出抗抑郁活性。
对一种或两种抗抑郁治疗反应不足的成人重度抑郁症患者进行了一项多中心、随机、双盲、安慰剂对照、两阶段序贯平行比较设计的研究。参与者被随机分配接受辅助治疗，给予 2 毫克/2 毫克丁丙诺啡/萨米多福（2/2 剂量组）、8 毫克/8 毫克丁丙诺啡/萨米多福（8/8 剂量组）或安慰剂。抗抑郁效果根据从基线到 4 周治疗结束时 17 项汉密尔顿抑郁评定量表（HAM-D）、蒙哥马利-阿斯伯格抑郁评定量表（MADRS）和临床总体印象严重程度量表（CGI-S）的变化来衡量。
与安慰剂组相比，2/2 剂量组在三个抑郁结局测量指标上均有显著更大的改善（HAM-D：-2.8，95%置信区间为-5.1，-0.6；MADRS：-4.9，95%置信区间为-8.2，-1.6；CGI-S：-0.5，95%置信区间为-0.9，-0.1）。8/8 剂量组也有改善的迹象，尽管没有达到统计学意义。总体而言，丁丙诺啡/萨米多福联合用药耐受性良好，停药时无阿片戒断迹象。
丁丙诺啡/萨米多福联合用药是一种治疗标准抗抑郁治疗反应不足的重度抑郁症患者的新型有前途的候选药物。
