title: A pilot study of plasma metabolomic patterns from patients treated with ketamine for bipolar depression: evidence for a response-related difference in mitochondrial networks.
abstract: OBJECTIVE
  (R,S)-ketamine produces rapid and significant antidepressant effects in approximately 65% of patients suffering from treatment-resistant bipolar depression (BD). The genetic, pharmacological and biochemical differences between ketamine responders and non-responders have not been identified. The purpose of this study was to employ a metabolomics approach, a global, non-targeted determination of endogenous metabolic patterns, to identify potential markers of ketamine response and non-response.
  
  
  METHODS
  Plasma samples from 22 BD patients were analyzed to produce metabolomic patterns. The patients had received ketamine in a placebo-controlled crossover study and the samples were obtained 230 min post-administration at which time the patients were categorized as responders or non-responders. Matching plasma samples from the placebo arm of the study were also analysed. During the study, the patients were maintained on either lithium or valproate.
  
  
  RESULTS
  The metabolomic patterns were significantly different between the patients maintained on lithium and those maintained on valproate, irrespective of response to ketamine. In the patients maintained on lithium, 18 biomarkers were identified. In responders, lysophosphatidylethanolamines (4) and lysophosphatidylcholines (9) were increased relative to non-responders.
  
  
  CONCLUSIONS
  The results indicate that the differences between patients who respond to ketamine and those who do not are due to alterations in the mitochondrial β-oxidation of fatty acids. These differences were not produced by ketamine administration. The data indicate that pretreatment metabolomics screening may be a guide to the prediction of response and a potential approach to the individualization of ketamine therapy.
authors.affiliation: Center for Metabolomics and Bioanalysis (CEMBIO), Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Villaseñor
authors.forename: A
authors.initials: A
authors.lastname: Ramamoorthy
authors.forename: M
authors.initials: M
authors.lastname: Silva dos Santos
authors.forename: M P
authors.initials: MP
authors.lastname: Lorenzo
authors.forename: G
authors.initials: G
authors.lastname: Laje
authors.forename: C
authors.initials: C
authors.lastname: Zarate
authors.forename: C
authors.initials: C
authors.lastname: Barbas
authors.forename: I W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000097:blood; D001714:Bipolar Disorder / Q000097:blood*; D018592:Cross-Over Studies; D061218:Depressive Disorder, Treatment-Resistant / Q000097:blood* / Q000188:drug therapy; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007649:Ketamine / Q000494:pharmacology / Q000627:therapeutic use*; D008094:Lithium / Q000627:therapeutic use; D008244:Lysophosphatidylcholines / Q000097:blood*; D008246:Lysophospholipids / Q000097:blood*; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D008875:Middle Aged; D010865:Pilot Projects; D014635:Valproic Acid / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D054316:Biomarkers, Pharmacological; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; C008301:lysophosphatidylethanolamine; D014635:Valproic Acid; D007649:Ketamine; D008094:Lithium
keywords: fatty acid metabolism; lithium; mitochondrial function; pharmacometabolomics; valproate