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. 2023 Nov 23;26(12):108527.
doi: 10.1016/j.isci.2023.108527. eCollection 2023 Dec 15.

Cerebrospinal fluid exploratory proteomics and ketamine metabolite pharmacokinetics in human volunteers after ketamine infusion

Ruin Moaddel  1 , Cristan A Farmer  2 , Mani Yavi  2 , Bashkim Kadriu  2 , Min Zhu  1 , Jinshui Fan  1 , Qinghua Chen  1 , Elin Lehrmann  1 , Giovanna Fantoni  1 , Supriyo De  1 , Caio H Mazucanti  1 , Elia E Acevedo-Diaz  2 , Peixiong Yuan  2 , Todd D Gould  3   4 , Lawrence T Park  2 , Josephine M Egan  1 , Luigi Ferrucci  1 , Carlos A Zarate Jr  2
Affiliations

Cerebrospinal fluid exploratory proteomics and ketamine metabolite pharmacokinetics in human volunteers after ketamine infusion

Ruin Moaddel et al. iScience. .

Abstract

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.

Keywords: Health sciences; Medicine; Pharmacology; Psychiatry.

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Conflict of interest statement

Dr. Zarate is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation. Drs. Zarate and Moaddel are listed as coinventors on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. Drs. Zarate, Moaddel, and Gould are listed as co-inventors on a patent application for the crystal forms and methods of synthesis of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine and the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. Drs. Zarate and Moaddel 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. Dr. Gould has assigned his patent rights to the University of Maryland. All other authors have no conflict of interest to disclose, financial or otherwise. Clinical Trials Registration: NCT03065335.

Figures

None
Graphical abstract
Figure 1
Figure 1
CONSORT diagram.
Figure 2
Figure 2
Flow chart and circulating levels of ketamine and downstream metabolites in plasma and CSF of healthy volunteers after IV ketamine infusion (0.5 mg/kg) over 40 min (A) Study procedures for ketamine infusion and subsequent time points of blood and CSF draws. (B) Ketamine (K), norketamine (NK), (2S,6S;2R,6R)-hydroxynorketamine (HNK) levels in CSF and plasma post-ketamine infusion, where median and interquartile range (IQR) are provided .
Figure 3
Figure 3
Circulating levels of the enantiomers of ketamine metabolites, norketamine (NK), and hydroxynorketamine (HNK) in the plasma and CSF of healthy volunteers after IV ketamine infusion (0.5 mg/kg) over 40 min (A–C) (A) Area under the curve (AUC), (B) the percentage of the enantiomers over total, and (C) the resolution of (2R,6R)-HNK, (2S,6S)-HNK, (R)-NK, and (S)-NK in plasma and CSF at various timepoints through 1,680 min (28 h) post-ketamine infusion, where median and interquartile range (IQR) are provided.
Figure 4
Figure 4
The rapid antidepressant effects of ketamine in unmedicated individuals with treatment-resistant depression overlayed with CSF proteomic changes observed in healthy volunteers (n = 9) after IV ketamine infusion (0.5 mg/kg) over 40 min (Adapted from7).
Figure 5
Figure 5
Network representation of differentially expressed proteins in the CSF of healthy volunteers (n = 9) with a maximal increase 12 h after IV ketamine infusion (0.5 mg/kg) over 40 min STRING analysis for proteins with maximal increases 12 h post-infusion (108 proteins) using the full STRING network, active interaction sources (Textmining, experiments, databases, co-expression, neighborhood), highest confidence (0.900).
Figure 6
Figure 6
Network representation of differentially expressed proteins in the CSF of healthy volunteers (n = 9) with a maximal increase 24 h after IV ketamine infusion (0.5 mg/kg) over 40 min STRING analysis for proteins with maximal increases 24 h post-infusion (206 proteins) using the full STRING network, active interaction sources (Textmining, experiments, databases, co-expression, neighborhood), highest confidence (0.900).
Figure 7
Figure 7
Circulating levels of insulin in the CSF of healthy volunteers after IV ketamine infusion (0.5 mg/kg) over 40 min (A) CSF insulin levels (mU/L) at baseline, 12 h, and 24 h post-ketamine infusion. (B) Violin plot illustrating insulin levels between different timepoints.
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