title: Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression.
abstract: BACKGROUND
  Ketamine has rapid antidepressant effects lasting as long as 1 week in patients with major depressive disorder (MDD) and bipolar depression (BD). Ketamine is extensively metabolized. This study examined the relationship between ketamine metabolites and response, diagnosis, and psychotomimetic symptoms in MDD and BD patients.
  
  
  METHODS
  Following a 40-minute ketamine infusion (.5 mg/kg), plasma samples were collected at 40, 80, 110, and 230 minutes and day 1 postinfusion in 67 patients currently experiencing a major depressive episode (MDD, n = 45; BD, n = 22). Concentrations of ketamine, norketamine (NK), dehydronorketamine (DHNK), six hydroxynorketamine metabolites (HNK), and hydroxyketamine (HK) were measured. Plasma concentrations were analyzed by diagnostic group and correlated with patients' depressive, psychotic, and dissociative symptoms. The relationship between cytochrome P450 gene polymorphisms and metabolites, response, and diagnosis was also examined.
  
  
  RESULTS
  Ketamine, NK, DHNK, four of six HNKs, and HK were present during the first 230 minutes postinfusion. Patients with BD had higher plasma concentrations of DHNK, (2S,6S;2R,6R)-HNK, (2S,6R;2R,6S)-HNK, and (2S,5S;2R,5R)-HNK than patients with MDD, who, in turn, had higher concentrations of (2S,6S;2R,6R)-HK. Higher (2S,5S;2R,5R)-HNK concentrations were associated with nonresponse to ketamine in BD patients. Dehydronorketamine, HNK4c, and HNK4f levels were significantly negatively correlated with psychotic and dissociative symptoms at 40 minutes. No relationship was found between cytochrome P450 genes and any of the parameters examined.
  
  
  CONCLUSIONS
  A diagnostic difference was observed in the metabolism and disposition of ketamine. Concentrations of (2S,5S;2R,5R)-HNK were related to nonresponse to ketamine in BD. Some hydroxylated metabolites of ketamine correlated with psychotic and dissociative symptoms.
authors.affiliation: Experimental Therapeutics & Pathophysiology Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. zaratec@mail.nih.gov
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
authors.forename: Nancy
authors.initials: N
authors.lastname: Brutsche
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Laje
authors.forename: David A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.forename: Swarajya L Vattem
authors.initials: SL
authors.lastname: Venkata
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ramamoorthy
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000097:blood / Q000188:drug therapy*; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003865:Major Depressive Disorder / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007649:Ketamine / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic; D011569:Psychiatric Status Rating Scales
chemical_list: D000928:Antidepressive Agents; D007649:Ketamine; D003577:Cytochrome P-450 Enzyme System