Ketamine metabolite pilot study in a suicidal depression trial
Open accessAbstract
Ketamine shows promise as a rapidly-acting treatment for depression and suicidal ideation, but side effects and abuse potential limit its use. Understanding its mechanism of action could help develop analogous but safer drugs. This post hoc study explored relationships of ketamine and metabolites, including hydroxynorketamine enantiomers, (2S,6S)- and (2R,6R)-HNK, to clinical response in a subgroup from a published trial in suicidal depression. Depressed adults with clinically significant suicidal ideation were randomized to double-blind infusion of sub-anesthetic ketamine or midazolam. Ketamine and metabolites were measured after infusion (N = 53). Plasma (2R,6R)-HNK was associated with change (higher levels correlated with less clinical improvement) from baseline to 24 h post-infusion of depression (HDRS-24: Spearman r = 0.37, p = 0.009) and suicidal thoughts (SSI: Spearman r = 0.29, p = 0.041). There were similar correlations with weekly follow-up clinical rating scores for both HNK enantiomers and dehydronorketamine (DHNK). Ketamine and norketamine were not associated with change in depression or suicidal ideation (unadjusted p > 0.28).
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An inverse relationship was observed between (2S,6S;2R,6R)-HNK concentration and antidepressant response at three and seven days after infusion, with lower levels associated with better response.
“However, an inverse relationship was observed between (2S,6S;2R,6R)-HNK concentration and antidepressant response at three and seven days post-infusion; lower rather than higher levels of (2S,6S;2R,6R)-HNK were associated with improved response [47].”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [47]
The Results (Associations with 24h Post-Infusion Ratings) report that higher (2R,6R)-HNK levels correlated with less improvement in depressive symptoms at 24 hours. The Results (Associations with Weeks 1–6 Follow-up Ratings) report similar associations for the separately measured HNK enantiomers at certain weekly follow-ups. They do not report an association for combined (2S,6S;2R,6R)-HNK at three and seven days post-infusion. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDespite repeated and robust demonstration of antidepressant effects across animal models with R,R-HNK, higher plasma levels appear to confer less improvement in clinical studies of depression and suicidal ideation.
“Despite repeated and robust demonstration of antidepressant effects across animal models with R,R-HNK, higher plasma levels appear to confer less improvement in clinical studies of depression and suicidal ideation [59,60].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [60]
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- Authors
- Grunebaum, M. F., Galfalvy, H. C., Choo, T.-H., Parris, M. S., Burke, A. K., Suckow, R. F., Cooper, T. B., & Mann, J. J.
- Affiliations
- Columbia University Irving Medical Center (US)
- Columbia University (US)
- New York State Psychiatric Institute (US)
- Nathan Kline Institute for Psychiatric Research (US)
- Corresponding author
- Grunebaum, Michael F.
- Venue
- Journal of Psychiatric Research
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 117
- Pages
- 129-134
- ISSN
- 0022-3956 (ISSN-L)
- PMC
- PMC6746183
- OpenAlex
- W2967193400
- Cited by
- 41
- References
- 42
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 10 · 2023: 7 · 2022: 6 · 2021: 7 · 2020: 6
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-12-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Psychiatric Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- 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, hydroxynorketamine, dehydronorketamine, ketamine metabolites, suicidal depression, suicidal ideation, depression, ketamine enantiomers, midazolam, rapid-acting antidepressants, plasma drug concentration, treatment response
- MeSH terms
- Adult, Antidepressive Agents, Major Depressive Disorder, Double-Blind Method, Humans, Infusions, Parenteral, Ketamine, Midazolam, Pilot Projects, Severity of Illness Index, Anti-Anxiety Agents, Outcome Assessment, Health Care, Suicidal Ideation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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