Elsevier

Biological Psychiatry

Volume 72, Issue 4, 15 August 2012, Pages 331-338
Biological Psychiatry

Archival Report
Relationship of Ketamine's Plasma Metabolites with Response, Diagnosis, and Side Effects in Major Depression

https://doi.org/10.1016/j.biopsych.2012.03.004Get rights and content

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.

Section snippets

Participants

Sixty-seven patients with TRD (MDD = 45; BD = 22) currently experiencing a major depressive episode without psychotic features were enrolled in this study; diagnosis was confirmed by the Structured Clinical Interview for Axis I DSM-IV Disorders–Patient Version (27). The efficacy and side effects of ketamine in a subset of these patients were previously published (9, 10, 28, 29). All subjects were studied as inpatients at the National Institute of Mental Health Clinical Research Center, Mood

Subject Characteristics

The subject population in this study included 67 subjects (33 female subjects, 34 male subjects; age range: 21 to 65 years [mean 46.1 ± 12.5 years]; Table 1).

Differences were observed between diagnostic groups in both the proportion of female subjects and the response rate at 230 minutes.

Patients with BD

Concentrations of ketamine and its major metabolites were analyzed in the plasma samples obtained from BD patients using the liquid chromatography-tandem mass spectrometry assay; a representative chromatogram

Discussion

To our knowledge, this study is the first to examine the relationship between plasma concentrations of downstream ketamine metabolites and antidepressant efficacy, diagnosis, and psychotic and dissociative symptoms in patients with TRD.

One of the most interesting findings was that levels of several ketamine metabolites—specifically, DHNK, HNK4a, and HNK4c—were consistently higher in patients with BD than in patients with MDD. Only plasma ketamine levels at the 40-minute time point and HK5a

References (42)

  • L.E. Phelps et al.

    Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist

    Biol Psychiatry

    (2009)
  • R. Moaddel et al.

    A parallel chiral-achiral liquid chromatographic method for the determination of the stereoisomers of ketamine and ketamine metabolites in the plasma and urine of patients with complex regional pain syndrome

    Talanta

    (2010)
  • T.R. Insel et al.

    Cure therapeutics and strategic prevention: Raising the bar for mental health research

    Mol Psychiatry

    (2006)
  • R. Machado-Vieira et al.

    Rapid onset of antidepressant action: A new paradigm in the research and treatment of major depressive disorder

    J Clin Psychiatry

    (2008)
  • C.A. Zarate et al.

    A double-blind, placebo-controlled study of memantine in the treatment of major depression

    Am J Psychiatry

    (2006)
  • C.A. Zarate et al.

    A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression

    Arch Gen Psychiatry

    (2006)
  • N. Diazgranados et al.

    A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression

    Arch Gen Psychiatry

    (2010)
  • C.A. Zarate et al.

    Replication of ketamine's antidepressant efficacy in bipolar depression: A randomized controlled add-on trial

    Biol Psychiatry

    (2012)
  • N. Li et al.

    mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists

    Science

    (2010)
  • A.E. Autry et al.

    NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

    Nature

    (2011)
  • G. Salvadore et al.

    Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine

    Neuropsychopharmacology

    (2010)
  • Cited by (224)

    View all citing articles on Scopus
    View full text