Cerebrospinal fluid exploratory proteomics and ketamine metabolite pharmacokinetics in human volunteers after ketamine infusion
Ruin Moaddel,
Cristan A. Farmer,
Mani Yavi,
Bashkim Kadriu,
Min Zhu,
Jinshui Fan,
Qinghua Chen,
Elin Lehrmann,
Giovanna Fantoni,
Supriyo De,
Caio H. Mazucanti,
Elia E. Acevedo-Diaz,
Peixiong Yuan,
Todd D. Gould,
Lawrence T. Park,
Josephine M. Egan,
Luigi Ferrucci,
Carlos A. Zarate, Jr.
Affiliations
Ruin Moaddel
Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA; Corresponding author
Cristan A. Farmer
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
Mani Yavi
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
Bashkim Kadriu
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
Min Zhu
Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
Jinshui Fan
Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
Qinghua Chen
Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
Elin Lehrmann
Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
Giovanna Fantoni
Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
Supriyo De
Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
Caio H. Mazucanti
Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
Elia E. Acevedo-Diaz
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
Peixiong Yuan
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
Todd D. Gould
Departments of Psychiatry, Pharmacology, and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Veterans Affairs Maryland Health Care System, Baltimore, MD 21201, USA
Lawrence T. Park
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
Josephine M. Egan
Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
Luigi Ferrucci
Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
Carlos A. Zarate, Jr.
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
Summary: Ketamine is a treatment for both refractory depression and chronic pain syndromes. In order to explore ketamine’s potential mechanism of action and whether ketamine or its metabolites cross the blood brain barrier, we examined the pharmacokinetics of ketamine and its metabolites—norketamine (NK), dehydronorketamine (DHNK), and hydroxynorketamines (HNKs)—in cerebrospinal fluid (CSF) and plasma, as well as in an exploratory proteomic analysis in the CSF of nine healthy volunteers who received ketamine intravenously (0.5 mg/kg IV). We found that ketamine, NK, and (2R,6R;2S,6S)-HNK readily crossed the blood brain barrier. Additionally, 354 proteins were altered in the CSF in at least two consecutive timepoints (p < 0.01). Proteins in the classes of tyrosine kinases, cellular adhesion molecules, and growth factors, including insulin, were most affected, suggesting an interplay of altered neurotransmission, neuroplasticity, neurogenesis, synaptogenesis, and neural network functions following ketamine administration.
