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

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.

Alterations in Acylcarnitines, Amines, and Lipids Inform about Mechanism of Action of Citalopram/Escitalopram in Major Depression

“…Rotroff and colleagues have found a negative association between the levels of ornithine and citrulline with changes in the Montgomery-Åsberg depression rating scale after treatment with ketamine 20 . In line with our findings, several studies have reported lower levels of citrulline in MDD patients compared to healthy controls 51,52 , while another reported lower levels of arginine in MDD patients compared to healthy controls 53 . Hence, a full analysis of these pathways is warranted in which measurements of more metabolites are covered.…”

“…In our study, after 8 weeks of SSRI treatment, the short-chain acylcarnitinesspecifically propionyl carnitine (C3), butyryl/isobutyryl carnitine (C4) and isovaleryl/methylbutyryl carnitine (C5)were significantly increased while acetyl carnitine (C2) levels were decreased. Several studies have previously reported perturbations in C2 after antidepressant treatment in depressed patients 20,32,52 . In a rat model of depression, incomplete βoxidation of fatty acids has been associated with elevated medium-and long-chain acylcarnitines (Chen, Wei et al 2014).…”

“…Changes in the levels of amino acids and biogenic amines such as histidine, kynurenine, methionine sulfoxide, arginine, citrulline, ornithine and urea have been implicated in MDD [45][46][47][48][49][50][51][52][53] .…”

“…Using MetIDQ® software, we performed the technical validation of each analyzed kit plate, which is based on results obtained and defined acceptance criteria for blank, zero samples, calibration standards and curves, low/medium/high-level quality control (QC) samples, and measured signal intensity of internal standards over the plate. Several previous studies have used the same platform for MDD participants 20,52,64 . We analyzed de-identified samples following the manufacturer's protocol, with metabolomics labs blinded to clinical data.…”

“…Hence, altered plasma or serum acylcarnitine levels can be used as biomarkers that suggest abnormalities in beta-oxidation (e.g., inborn errors of metabolism) [39][40][41][42][43] . Elevated medium-and long-chain acylcarnitine concentrations in blood have been associated with incomplete β-oxidation of fatty acids in a rat model of depression 44 .Changes in the levels of amino acids and biogenic amines such as histidine, kynurenine, methionine sulfoxide, arginine, citrulline, ornithine and urea have been implicated in MDD [45][46][47][48][49][50][51][52][53] .Moreover, lipids are involved in crucial brain functions including cell membrane structure, membrane transmitters and regulation of synapses, as well as biological messenger functions, energy metabolism and neuroendocrine function 54 . Blood lipid profile changes have been implicated in the pathogenesis of depression, schizophrenia, and Alzheimer's disease [55][56][57][58][59] .…”