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Psychopharmacology (Berl). 2018 Oct;235(10):3017-3030. doi: 10.1007/s00213-018-4992-7. Epub 2018 Aug 16.

Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects.

Author information

1
Biomedical Research Center, Intramural Research Program, National Institute on Aging, National Institutes, Bethesda, MD, USA. moaddelru@mail.nih.gov.
2
Biomedical Research Center, Intramural Research Program, National Institute on Aging, National Institutes, Bethesda, MD, USA.
3
Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
4
Advanced Biomedical and Computational Sciences, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Leidos Biomedical Research Inc, Fredrick, MD, 21702, USA.
5
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, MD, USA.
6
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

Abstract

(R,S)-Ketamine produces rapid, robust, and sustained antidepressant effects in major depressive disorder. Specifically, its pharmacological efficacy in treatment refractory depression is considered a major breakthrough in the field. However, the mechanism of action of ketamine's rapid effect remains to be determined. In order to identify pathways that are responsible for ketamine's effect, a targeted metabolomic approach was carried out using a double-blind, placebo-controlled crossover design, with infusion order randomized with medication-free patients with treatment-resistant major depressive disorder (29 subjects) and healthy controls (25 subjects). The metabolomic profile of these subjects was characterized at multiple time points, and a comprehensive analysis was investigated between the following: MDD and healthy controls, treatment and placebo in both groups and the corresponding response to ketamine treatment. Ketamine treatment resulted in a general increase in circulating sphingomyelins, levels which were not correlated with response. Ketamine response resulted in more pronounced effects in the kynurenine pathway and the arginine pathway at 4 h post-infusion, where a larger decrease in circulating kynurenine levels and a larger increase in the bioavailability of arginine were observed in responders to ketamine treatment, suggesting possible mechanisms for response to ketamine treatment.

KEYWORDS:

(R,S)-ketamine; Global Arginine Bioavailability Ratio; Kynurenine metabolites; Metabolomics; Sphingomyelins

PMID:
30116859
PMCID:
PMC6193489
DOI:
10.1007/s00213-018-4992-7
[Indexed for MEDLINE]
Free PMC Article

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