Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2020 Dec 3;23(9):549-558.
doi: 10.1093/ijnp/pyaa030.

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

Ziad Saad  1 , Derrek Hibar  2 , Maggie Fedgchin  3 , Vanina Popova  4 , Maura L Furey  1 , Jaskaran B Singh  1 , Hartmuth Kolb  1 , Wayne C Drevets  1 , Guang Chen  1
Affiliations
Clinical Trial

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

Ziad Saad et al. Int J Neuropsychopharmacol. .

Abstract

Background: At ketamine and esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, noncompetitive, N-methyl-D-aspartate receptor 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 2 phase III, double-blind, controlled trials of esketamine (or placebo) nasal spray plus an oral antidepressant 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 + antidepressant arm, no significant genotype effect of single nucleotide polymorphism rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or 28. By contrast, in the antidepressant + placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 towards an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses were detected.

Conclusions: Variation in rs1799971 (A118G) did not affect the antidepressant response to esketamine + antidepressant. Antidepressant response to antidepressant + placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect.

Trial registration: NCT02417064 and NCT02418585; www.clinicaltrials.gov.

Keywords: depression; esketamine; ketamine; mu-opioid receptor; polymorphism.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Effects of OPRM1 single nucleotide polymorphism (SNP) rs1799971 (A118G) alleles on improvements in depression severity, assessed as reductions from baseline in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score on day 2. Black dot, mean; boxed annotation: mean (SD); error bars, 95% mean confidence interval.
Figure 2.
Figure 2.
Effects of OPRM1 single nucleotide polymorphism (SNP) rs1799971 (A118G) alleles on improvements in depression severity, assessed as reductions from baseline in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score on day 28. Black dot, mean; boxed annotation, mean (SD); error bars, 95% mean confidence interval.
See this image and copyright information in PMC

References

    1. Aalto S, Ihalainen J, Hirvonen J, Kajander J, Scheinin H, Tanila H, Någren K, Vilkman H, Gustafsson LL, Syvälahti E, Hietala J (2005) Cortical glutamate-dopamine interaction and ketamine-induced psychotic symptoms in man. Psychopharmacology (Berl) 182:375–383. - PubMed
    1. Aslaksen PM, Forsberg JT, Gjerstad J (2018) The opioid receptor mu 1 (OPRM1) rs1799971 and catechol-O-methyltransferase (COMT) rs4680 as genetic markers for placebo analgesia. Pain 159:2585–2592. - PubMed
    1. Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, Gong J, Schluger J, Strong JA, Leal SM, Tischfield JA, Kreek MJ, Yu L (1998) Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 95:9608–9613. - PMC - PubMed
    1. Browne CA, Erickson RL, Blendy JA, Lucki I (2017) Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism. Neuropharmacology 117:401–407. - PMC - PubMed
    1. Browne CA, Lucki I (2019) Targeting opioid dysregulation in depression for the development of novel therapeutics. Pharmacol Ther 201:51–76. - PMC - PubMed

Publication types

Associated data