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

(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...

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Bibliographic Details
Published in:Psychopharmacology 2018-10, Vol.235 (10), p.3017-3030
Main Authors: Moaddel, Ruin, Shardell, Michelle, Khadeer, Mohammed, Lovett, Jacqueline, Kadriu, Bashkim, Ravichandran, Sarangan, Morris, Patrick J., Yuan, Peixiong, Thomas, Craig J., Gould, Todd D., Ferrucci, Luigi, Zarate, Carlos A.
Format: Article
Language:English
Subjects:
Adult
Amino Acids, Essential - metabolism
Antidepressants
Antidepressive Agents - pharmacology
Arginine
Bioavailability
Biogenic Amines - metabolism
Biomedical and Life Sciences
Biomedical research
Biomedicine
Care and treatment
Carnitine - analogs & derivatives
Carnitine - metabolism
Cross-Over Studies
Depressive Disorder, Major - drug therapy
Depressive Disorder, Major - metabolism
Depressive Disorder, Treatment-Resistant - drug therapy
Depressive Disorder, Treatment-Resistant - metabolism
Double-Blind Method
Female
Glycerophospholipids - metabolism
Health aspects
Humans
Ketamine
Ketamine - pharmacology
Ketamine - therapeutic use
Lipids
Major depressive disorder
Male
Medical research
Mental depression
Mental health
Metabolism
Metabolites
Metabolomics
Middle Aged
Neurosciences
Original Investigation
Patients
Pharmacology/Toxicology
Psychiatry
Psychopharmacology
Psychosis
Sphingolipids - metabolism
Young Adult
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Summary:(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.
ISSN:0033-3158
1432-2072
DOI:10.1007/s00213-018-4992-7