BACKGROUND At ketamine and esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, non-competitive, NMDAR antagonists. However, at substantially higher doses, ketamine has shown mu-opioid receptor (MOR-gene symbol:OPRM1) agonist effects Preliminary clinical studies showed conflicting results on whether naltrexone, a MOR antagonist, blocks the antidepressant action of ketamine. We examined drug-induced or endogenous MOR involvement in the antidepressant and dissociative responses to esketamine by assessing the effects of a functional single nucleotide polymorphism rs1799971 (A118G) of OPRM1, which is known to alter MOR agonist-mediated responses. METHODS Participants with treatment-resistant depression from two phase 3, double-blind, controlled trials of esketamine or placebo nasal spray plus an oral antidepressant (AD) were genotyped for rs1799971. Participants received the experimental agents twice weekly for 4 weeks. Antidepressant responses were rated using the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score on days 2 and 28 post-dose initiation, and dissociative side effects were assessed using the Clinician-Administered Dissociative-States Scale at 40 minutes post-dose on days 1 and 25. RESULTS In the esketamine+AD arm no significant genotype effect of SNP rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or day 28. By contrast, in the AD+placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 toward an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses was detected. CONCLUSIONS Variation in rs1799971 (A118G) did not affect the antidepressant response to esketamine+AD. Antidepressant response to AD+placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect.

中文翻译：

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Mu-阿片受体基因多态性 rs1799971 (A118G) 对 Esketamine 喷鼻剂临床试验中抗抑郁药和解离反应的影响。

背景 在达到抗抑郁剂量的氯胺酮和艾氯胺酮剂量下，这些药剂是相对选择性的、非竞争性的 NMDAR 拮抗剂。然而，在高得多的剂量下，氯胺酮显示出μ-阿片受体（MOR 基因符号：OPRM1）激动剂作用 初步临床研究显示，关于纳曲酮（一种 MOR 拮抗剂）是否会阻断氯胺酮的抗抑郁作用，结果存在矛盾。我们通过评估 OPRM1 的功能性单核苷酸多态性 rs1799971 (A118G) 的影响，检查了药物诱导或内源性 MOR 参与抗抑郁药和对艾氯胺酮的解离反应，已知其会改变 MOR 激动剂介导的反应。方法 来自两个阶段 3、双盲、针对 rs1799971 对艾氯胺酮或安慰剂鼻喷雾剂加口服抗抑郁药 (AD) 的对照试验进行了基因分型。参与者每周接受两次实验药剂，持续 4 周。使用给药后第 2 天和第 28 天蒙哥马利-奥斯伯格抑郁评定量表 (MADRS) 评分的变化对抗抑郁反应进行评级，并在给药后 40 分钟使用临床医生管理的解离状态量表评估解离副作用第 1 天和第 25 天。 结果 在艾氯胺酮 + AD 组中，在第 2 天或第 28 天未检测到 SNP rs1799971 (A118G) 对 MADRS 评分降低的显着基因型影响。相比之下，在 AD +安慰剂组中，基因型对第 2 天 MADRS 评分降低的影响和第 28 天 G 等位基因携带者抑郁症状改善的非显着趋势。未检测到对解离反应的显着基因型影响。结论 rs1799971 (A118G) 的变异不影响对艾氯胺酮 + AD 的抗抑郁反应。G 等位基因携带者对 AD+安慰剂的抗抑郁反应增加，这与之前的报告一致，即内啡肽/脑啡肽的释放可能在介导安慰剂效应中发挥作用。