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

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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.

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Funding

This research was supported by the Intramural research Program of the National Institutes of Health, National institute on Aging and National Institute on Mental Health and NCATS.

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Authors and Affiliations

  1. Biomedical Research Center, Intramural Research Program, National Institute on Aging, National Institutes, Bethesda, MD, USA

    Ruin Moaddel, Michelle Shardell, Mohammed Khadeer, Jacqueline Lovett & Luigi Ferrucci

  2. Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    Bashkim Kadriu, Peixiong Yuan & Carlos A. Zarate

  3. 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

    Sarangan Ravichandran

  4. Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, MD, USA

    Patrick J. Morris & Craig J. Thomas

  5. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

    Todd D. Gould

Authors
  1. Ruin Moaddel
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  2. Michelle Shardell
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  3. Mohammed Khadeer
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  4. Jacqueline Lovett
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  5. Bashkim Kadriu
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  6. Sarangan Ravichandran
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  7. Patrick J. Morris
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  8. Peixiong Yuan
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  9. Craig J. Thomas
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  10. Todd D. Gould
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  11. Luigi Ferrucci
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  12. Carlos A. Zarate
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Corresponding author

Correspondence to Ruin Moaddel.

Ethics declarations

The study was approved by the Combined Neuroscience Institutional Review Board (IRB) at the National Institutes of Health (NIH). All subjects provided written informed consent before entry into the study. Informed consents and ongoing study participation for patients with MDD were monitored by the Human Subjects Protection Office at NIH (NCT00088699).

Conflict of interest

C.A.Z. is listed as a co-inventor on a patent application for the use of ketamine in major depression. R.M. and C.A.Z. are listed as co-inventors on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro- and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. R.M., P.M., C.J.T., T.D.G., and C.A.Z are listed as co-inventors on a patent application for the use of (2R, 6R)-hydroxynorketamine and (2S, 6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. R.M., P.M., C.J.T., and C.A.Z have assigned their patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. T.D.G has assigned their patent rights to the University of Maryland Baltimore but will share a percentage of any royalties that may be received by the University of Maryland Baltimore.

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Moaddel, R., Shardell, M., Khadeer, M. et al. Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects. Psychopharmacology 235, 3017–3030 (2018). https://doi.org/10.1007/s00213-018-4992-7

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