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. 2012 Aug 15;72(4):331-8.
doi: 10.1016/j.biopsych.2012.03.004. Epub 2012 Apr 18.

Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression

Carlos A Zarate Jr  1 , Nancy Brutsche, Gonzalo Laje, David A Luckenbaugh, Swarajya L Vattem Venkata, Anuradha Ramamoorthy, Ruin Moaddel, Irving W Wainer
Affiliations

Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression

Carlos A Zarate Jr et al. Biol Psychiatry. .

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.

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Figures

Figure 1
Figure 1
The proposed metabolic pathways of ketamine. DHNK, dehydronorketamine; Ket, ketamine; HK, hydroxyketamine; HNK, hydroxynorketamine; NK, norketamine.
Figure 2
Figure 2
Plasma concentrations of ketamine and its metabolites over time in patients with treatment-resistant depression (bipolar depression [BD] patients [A] and major depressive disorder [MDD] patients [B]). See Table S1 in Supplement 1 for metabolite identification. DHNK, dehydronorketamine; Ket, ketamine; NK, norketamine.
Figure 3
Figure 3
Dehydronorketamine (DHNK) concentrations by response and diagnosis in patients with treatment-resistant depression. Dehydronorketamine plasma concentrations were significantly higher in patients with bipolar depression (BD) than in patients with major depressive disorder (MDD).
Figure 4
Figure 4
Hydroxynorketamine (HNK) 4a plasma concentrations by response and diagnosis in patients with treatment-resistant depression. Hydroxynorketamine 4a plasma concentrations were significantly higher in patients with bipolar depression (BD) than in patients with major depressive disorder (MDD).
Figure 5
Figure 5
Hydroxyketamine (HK) 5a plasma concentrations by response and diagnosis in patients with treatment-resistant depression. Hydroxyketamine 5a plasma concentrations were significantly higher in patients with major depressive disorder (MDD) than in patients with bipolar depression (BD).
Figure 6
Figure 6
Hydroxynorketamine (HNK) 4c plasma concentrations by response and diagnosis in patients with treatment-resistant depression. HNK 4c plasma concentrations were significantly higher in patients with bipolar depression (BD) than in patients with major depressive disorder (MDD). HNK 4c plasma concentrations were also significantly higher in BD patients who did not respond to ketamine than in those who did respond to ketamine.
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