title: Metabolomic signatures of drug response phenotypes for ketamine and esketamine in subjects with refractory major depressive disorder: new mechanistic insights for rapid acting antidepressants.
abstract: Ketamine, at sub-anesthetic doses, is reported to rapidly decrease depression symptoms in patients with treatment-resistant major depressive disorder (MDD). Many patients do not respond to currently available antidepressants, (for example, serotonin reuptake inhibitors), making ketamine and its enantiomer, esketamine, potentially attractive options for treatment-resistant MDD. Although mechanisms by which ketamine/esketamine may produce antidepressant effects have been hypothesized on the basis of preclinical data, the neurobiological correlates of the rapid therapeutic response observed in patients receiving treatment have not been established. Here we use a pharmacometabolomics approach to map global metabolic effects of these compounds in treatment-refractory MDD patients upon 2 h from infusion with ketamine (n=33) or its S-enantiomer, esketamine (n=20). The effects of esketamine on metabolism were retested in the same subjects following a second exposure administered 4 days later. Two complementary metabolomics platforms were used to provide broad biochemical coverage. In addition, we investigated whether changes in particular metabolites correlated with treatment outcome. Both drugs altered metabolites related to tryptophan metabolism (for example, indole-3-acetate and methionine) and/or the urea cycle (for example, citrulline, arginine and ornithine) at 2 h post infusion (q<0.25). In addition, we observed changes in glutamate and circulating phospholipids that were significantly associated with decreases in depression severity. These data provide new insights into the mechanism underlying the rapid antidepressant effects of ketamine and esketamine, and constitute some of the first detailed metabolomics mapping for these promising therapies.
authors.affiliation: Department of Statistics, North Carolina State University, Raleigh, NC, USA.|Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Rotroff
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Corum
authors.affiliation: Department of Statistics, North Carolina State University, Raleigh, NC, USA.|Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Motsinger-Reif
authors.affiliation: UC Davis Genome Center, University of California Davis, Davis, CA, USA.|Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: O
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: Department of Neuroscience, Janssen Research and Development, Titusville, NJ, USA.
authors.forename: N
authors.initials: N
authors.lastname: Bottrel
authors.affiliation: Department of Neuroscience, Janssen Research and Development, Titusville, NJ, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Drevets
authors.affiliation: Department of Neuroscience, Janssen Research and Development, San Diego CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Singh
authors.affiliation: Department of Neuroscience, Janssen Research and Development, Titusville, NJ, USA.
authors.forename: G
authors.initials: G
authors.lastname: Salvadore
authors.affiliation: Department of Psychiatry, Duke University Medical Center, Durham NC, USA.|Duke Institute for Brain Sciences, Duke University, Durham, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kaddurah-Daouk
mesh_terms: D000328:Adult; D001120:Arginine / Q000378:metabolism; D002956:Citrulline / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007210:Indoleacetic Acids / Q000378:metabolism; D007262:Infusions, Intravenous; D007649:Ketamine / Q000627:therapeutic use*; D008297:Male; D055432:Metabolomics; D008715:Methionine / Q000378:metabolism; D008875:Middle Aged; D009952:Ornithine / Q000378:metabolism; D010641:Phenotype; D010743:Phospholipids / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism; D014508:Urea / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007210:Indoleacetic Acids; D010743:Phospholipids; D002956:Citrulline; D018698:Glutamic Acid; D007649:Ketamine; C030737:indoleacetic acid; D014364:Tryptophan; D014508:Urea; D001120:Arginine; D008715:Methionine; D009952:Ornithine