Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression
Open accessAbstract
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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Ketamine, norketamine, DHNK, and (2R,6R)-HNK plasma levels remained above 4 ng/mL one day after ketamine 0.5 mg/kg IV over 40 minutes in patients.
“Plasma levels of ketamine, norketamine, DHNK, and (2R,6R)-HNK were still detectable (>4 ng/mL) one-day post-ketamine infusion (0.5 mg/kg i.v. over 40 minutes) in patients”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Zarate et al., 2012
The Results (Plasma Concentrations of Ketamine and Metabolites; page unavailable) report day-1 concentrations of at least 4 ng/mL for ketamine, NK, DHNK, and HNK4a in patients with bipolar depression. The corresponding MDD passage instead prints day-1 concentrations as <4 ng/mL. The paper reports HNK4a as the (2S,6S;2R,6R) pair, so it does not establish that the specific (2R,6R) enantiomer alone exceeded 4 ng/mL. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNorketamine, DHNK, and (2R,6R;2S,6S)-HNK appear in human plasma as early as 40 minutes after an antidepressant ketamine dose, with (2R,6R;2S,6S)-HNK and (2S,6R;2R,6S)-HNK being the most abundant HNKs.
“Norketamine, DHNK, and (2R,6R;2S,6S)-HNK in particular are detected in human plasma as early as 40 minutes following an antidepressant dose of ketamine (0.5 mg/kg i.v. over 40 minutes) with the most abundant HNKs being (2R,6R;2S,6S)-HNK and (2S,6R;2R,6S)-HNK”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Zarate et al., 2012
There may be sufficient total exposure of (2S,6S;2R,6R)-HNK to exert biologically meaningful effects, but other ketamine metabolites may be additive in humans to exert full antidepressant actions.
“These data indicate that there may be sufficient total exposure of (2S,6S;2R,6R)-HNK to exert biologically meaningful effects, but also suggest the possibility that other ketamine metabolites may be additive in humans to exert the full antidepressant actions of ketamine.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [120]
Following ketamine administration, (2S,6S;2R,6R)-HNK is the major HNK metabolite found in plasma and brain of mice, as well as plasma of humans.
“Following ketamine administration, (2S,6S;2R,6R)-HNK is the major HNK metabolite found in the plasma and brain of mice 13, as well as the plasma of humans 120.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [120]
Maximal concentrations of (2S,6S;2R,6R)-HNK in plasma of patients receiving ketamine are lower than ketamine levels (0.16 vs 0.78 μM), but total exposure of HNK is higher than parent drug (5.72 vs 4.36 μM).
“While maximal concentrations of (2S,6S;2R,6R)-HNK in the plasma of patients receiving ketamine are lower than ketamine levels (0.16 vs 0.78 μM, respectively), total exposure of (2S,6S;2R,6R)-HNK is higher than that of the parent drug (5.72 vs 4.36 μM) 120.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [120]
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- Authors
- Zarate, C. A., Brutsche, N., Laje, G., Luckenbaugh, D. A., Venkata, S. L. V., Ramamoorthy, A., Moaddel, R., & Wainer, I. W.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Zarate, Carlos A.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 72
- Issue
- 4
- Pages
- 331-338
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3442255
- OpenAlex
- W2052665050
- Cited by
- 282
- References
- 42
- Citations by year
- 2026: 6 · 2025: 18 · 2024: 24 · 2023: 15 · 2022: 24 · 2021: 23 · 2020: 34 · 2019: 20 · 2018: 24 · 2017: 19 · 2016: 20 · 2015: 22 · 2014: 20 · 2013: 9 · 2012: 3
- FWCI
- 12.70
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (MH085098-01)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- ketamine, major depressive disorder, bipolar depression, ketamine metabolites, norketamine, dehydronorketamine, hydroxynorketamine, antidepressant response, dissociative symptoms, plasma drug concentration, rapid-acting antidepressants
- MeSH terms
- Adult, Aged, Antidepressive Agents, Bipolar Disorder, Chromatography, Liquid, Cytochrome P-450 Enzyme System, Major Depressive Disorder, Depressive Disorder, Major, Dose-Response Relationship, Drug, Female, Humans, Ketamine, Male, Middle Aged, Pharmacogenetics, Polymorphism, Genetic, Psychiatric Status Rating Scales, Mass Spectrometry
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