Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration

Abstract

Subanesthetic-dose racemic (R,S)-ketamine (ketamine) produces rapid, robust, and sustained antidepressant effects in major depressive disorder (MDD) and bipolar disorder (BD) and has also been shown to effectively treat neuropathic pain, complex regional pain syndrome, and post-traumatic stress disorder (PTSD). However, to date, its mechanism of action remains unclear. Preclinical studies found that (2 R,6 R;2 S,6 S)-hydroxynorketamine (HNK), a major circulating metabolite of ketamine, elicits antidepressant effects similar to those of ketamine. To help determine how (2 R,6 R)-HNK contributes to ketamine’s mechanism of action, an exploratory, targeted, metabolomic analysis was carried out on plasma and CSF of nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg). A parallel targeted metabolomic analysis in plasma, hippocampus, and hypothalamus was carried out in mice receiving either 10 mg/kg of ketamine, 10 mg/kg of (2 R,6 R)-HNK, or saline. Ketamine and (2 R,6 R)-HNK both affected multiple pathways associated with inflammatory conditions. In addition, several changes were unique to either the healthy human volunteers and/or the mouse arm of the study, indicating that different pathways may be differentially involved in ketamine’s effects in mice and humans. Mechanisms of action found to consistently underlie the effects of ketamine and/or (2 R,6 R)-HNK across both the human metabolome in plasma and CSF and the mouse arm of the study included LAT1, IDO1, NAD+, the nitric oxide (NO) signaling pathway, and sphingolipid rheostat.

Cerebrospinal fluid metabolomes of treatment-resistant depression subtypes and ketamine response: a pilot study

“…Comparison with a recent report describing principal metabolomic components in the plasma and the CSF in nine "normal" volunteers following a single IV ketamine infusion may provide additional context [ 32 ]. In that study, 87 CSF metabolites were clustered into four components, with only PC2 exhibiting consistent changes over 28 h. Serum and CSF loadings were in opposite directions for leucine, isoleucine, tryptophan, methionine, and tyrosine.…”

Cerebrospinal Fluid Metabolomics: Pilot Study of Using Metabolomics to Assess Diet and Metabolic Interventions in Alzheimer’s Disease and Mild Cognitive Impairment

“…In this study, circulating plasma levels of some metabolites did not always mirror CSF levels. For example, branched-chain amino acids increased in the plasma of healthy volunteers post-ketamine but decreased in the CSF, indicating the importance of assaying CSF for metabolic markers of interest in brain conditions [26].…”

Cross‐sectional analysis of healthy individuals across decades: Aging signatures across multiple physiological compartments

“…Metabolites were extracted in plasma (10 μL) following a previously described protocol (Moaddel et al, 2022). For urine samples (10 μL) were extracted following a similar protocol with slight changes (http://www.biocrates), including an extended calibration range to account for urine metabolite concentrations, an additional creatinine internal standard was added to account for higher creatinine concentrations with an additional drying step, and a solution of 350 mM urea, 15 mM NaHPO4, pH 6.0 was used as zero samples.…”

“…Consistent with this interpretation we observed an increase in Kyn and the immune checkpoint protein, indoleamine 2,3-dioxygenase (IDO) activity (Kyn/Trp ratio). IDO activity is upregulated by pro-inflammatory cytokines (Moaddel et al, 2022), is high in nonagenarians and has been found to be associated with higher mortality and frailty in older persons (Marttila et al, 2011).…”

“…Metabolites were extracted in plasma (10 μL) following a previously described protocol (Moaddel et al, 2022). For urine samples (10 μL)…”