Effects of Mu-Opiate Receptor Gene Polymorphism rs1799971 (A118G) on the Antidepressant and Dissociation Responses in Esketamine Nasal Spray Clinical Trials.

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-Asberg 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.