Relationship of Ketamines Plasma Metabolites with Response, Diagnosis, and Side Effects in Major Depression

Biological Psychiatry, 04/25/2012

A diagnostic difference was observed in the metabolism and disposition of ketamine. Concentrations of (2S,5S;2R,5R)–hydroxynorketamine metabolites were related to nonresponse to ketamine in bipolar depression. Some hydroxylated metabolites of ketamine correlated with psychotic and dissociative symptoms.


  • 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.


  • 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.

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