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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.

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Biomedical Research Center, Intramural Research Program, National Institute on Aging, National Institutes, Bethesda, MD, USA.
Biomedical Research Center, Intramural Research Program, National Institute on Aging, National Institutes, Bethesda, MD, USA.
Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
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.
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, MD, USA.
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.


(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.


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

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