Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression
Open accessAbstract
A single, subanesthetic dose of (R,S)-ketamine (ketamine) exerts rapid and robust antidepressant effects. Several groups previously reported that (2S,6S;2R,6R)-hydroxynorketamine (HNK) had antidepressant effects in rodents, and that (2R,6R)-HNK increased cortical electroencephalographic gamma power. This exploratory study examined the relationship between ketamine metabolites, clinical response, psychotomimetic symptoms, and gamma power changes in 34 individuals (ages 18-65) with treatment-resistant depression (TRD) who received a single ketamine infusion (0.5 mg/kg) over 40 min. Plasma concentrations of ketamine, norketamine, and HNKs were measured at 40, 80, 120, and 230 min and at 1, 2, and 3 days post-infusion. Linear mixed models evaluated ketamine metabolites as mediators of antidepressant and psychotomimetic effects and their relationship to resting-state whole-brain magnetoencephalography (MEG) gamma power 6-9 h post-infusion. Three salient findings emerged. First, ketamine concentration positively predicted distal antidepressant response at Day 11 post-infusion, and an inverse relationship was observed between (2S,6S;2R,6R)-HNK concentration and antidepressant response at 3 and 7 days post-infusion. Norketamine concentration was not associated with antidepressant response. Second, ketamine, norketamine, and (2S,6S;2R,6R)-HNK concentrations at 40 min were positively associated with contemporaneous psychotomimetic symptoms; post-hoc analysis revealed that ketamine was the predominant contributor. Third, increased (2S,6S;2R,6R)-HNK maximum observed concentration (C max) was associated with increased MEG gamma power. While contrary to preclinical observations and our a priori hypotheses, these exploratory results replicate those of a recently published study documenting a relationship between higher (2S,6S;2R,6R)-HNK concentrations and weaker antidepressant response in humans and provide further rationale for studying gamma power changes as potential biomarkers of antidepressant response.
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In patients with TRD, higher R,R-HNK levels have been shown to correlate with increased encephalographic gamma power.
“Surprisingly, in patients with TRD, higher R,R-HNK levels have been shown to correlate with increased encephalographic gamma power—a putative measure of cortical disinhibition/excitation (i.e., decreased activity in GABAergic interneurons and increased activation of fast ionotropic glutamate receptors on pyramidal neurons) [59].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [59]
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.
“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 [59]
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Cited by
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“5 mg/kg) in patients with treatment-resistant MDD showed an inverse relationship between (2R,6R;2 S,6 S)-HNK concentration and antidepressant response [88], suggesting that (2R,6 R)-HNK might not contribute to the antidepressant action of (R,S)ketamine [89].”
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“17,18 Therefore, the metabolites of ketamine are assumed to mediate its long-term effects.”
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“…two studies have unexpectably identified a negative correlation between (2R,6R;2S,6S)-HNK plasma levels antidepressant responses in depressed subjects who received ketamine treatment (Farmer et al., 2020;Grunebaum et al., 2019), while one study identified no such relationship (Zarate et al., 2012).”
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“14 However, the same study found that (2 S ,6 S ;2 R ,6 R )-HNK was associated with increased gamma power, a biomarker of treatment response.”
BackgroundInfluentialSelf-citationAdvancing past ketamine: emerging glutamatergic compounds for the treatment of depression
Freudenberg, F., Reif-Leonhard, C., & Reif, A. (2024) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-024-01875-z · Cited by 12 · see citing works
“However, two independent clinical trials, one in patients with suicidal depression [58] and one in TRD patients [59], showed an inverse relationship of HNK levels post ketamine infusion with clinical outcome (i.e. lower HNK levels correlated with increased symptom improvement).”
Guhathakurta, D., Petrušková, A., Akdaş, E. Y., Perelló‐Amorós, B., Frischknecht, R., Anni, D., Weiss, E., Walter, M., & Fejtová, A. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02744-y · Cited by 10 · see citing works
Highland, J. N., Morris, P. J., Konrath, K. M., Riggs, L. M., Hagen, N. R., Zanos, P., Powels, C. F., Moaddel, R., Thomas, C. J., Wang, A. Q., et al. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00761 · Cited by 27 · see citing works
Self-citationHasan, M., Modeß, C., Roustom, T., Dokter, A., Grube, M., Link, A., Rey, H., Adler, S., Meissner, K., & Siegmund, W. (2021) · Anesthesiology · doi:10.1097/aln.0000000000003829 · Cited by 13 · see citing works
Enhancing Clinical Trials Through Synergistic Gamma Power Analysis
Honda, S., Matsumoto, M., Tajinda, K., & Mihara, T. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00537 · Cited by 11 · see citing works
“Thus, moderate NMDA receptor blockade biases the excitatory/ inhibitory balance toward increased excitability, which could yield beneficial effects on brain function, similar to the antidepressive effect of ketamine (47).”
BackgroundSajid, S., Galfalvy, H., Keilp, J., Burke, A., Mann, J., & Grunebaum, M. F. (2024) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyae017 · Cited by 10 · see citing works
“A previous post hoc analysis, however, found that ketamine and NK were uniquely related to dissociation (Farmer et al., 2020).”
MethodResultNguyen, T. M. L., Jollant, F., Tritschler, L., Colle, R., Corruble, E., & Gardier, A. M. (2023) · Pharmaceuticals · doi:10.3390/ph16040634 · Cited by 9 · see citing works
“Knowing that the dose of (R,S)-ketamine administered in patients with TRD is similar to that used in patients with suicidal ideation (0.5 mg/kg intravenously perfused over 40 min), it can be assumed that the treatment of suicidality with ketamine potentially goes through similar signaling pathways, i.e., the disinhibi…”
InfluentialJuneja, K., Afroze, S., Goti, Z., Sahu, S., Asawa, S., Bhuchakra, H. P., Natarajan, B., & Pandey, S. (2024) · Discover Mental Health · doi:10.1007/s44192-024-00077-2 · Cited by 7 · see citing works
Chang, L., & Hashimoto, K. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01766-6 · Cited by 7 · see citing works
“5 mg/kg) in treatment-resistant patients with depression was inversely related between (2S,6S; 2R,6R)-HNK concentration and antidepressant response at 3 and 7 days after a single infusion [14].”
BackgroundA synopsis of multitarget therapeutic effects of anesthetics on depression
Wu, G., & Xu, H. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.176032 · Cited by 6 · see citing works
Depression with comorbid borderline personality disorder - could ketamine be a treatment catalyst?
Więdłocha, M., Marcinowicz, P., Komarnicki, J., Tobiaszewska, M., Dębowska, W., Dębowska, M. D., & Szulc, A. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1398859 · Cited by 6 · see citing works
Burrows, M., Kotoula, V., Dipasquale, O., Stringaris, A. K., & Mehta, M. A. (2023) · Journal of Psychopharmacology · doi:10.1177/02698811231189432 · Cited by 6 · see citing works
“In humans, however, recent studies revealed that a higher concentration of (2R,6R)HNK post-infusion could be linked to a weaker and more shortlived improvement in depressive symptoms (Farmer et al., 2020).”
BackgroundReady for a “breakthrough” with ketamine? A look at recent pharmacological insights!
Himmelseher, S., & Kochs, E. F. (2021) · Current Opinion in Anaesthesiology · doi:10.1097/aco.0000000000001017 · Cited by 10 · see citing works
Al-Garni, A. M., Vázquez, G. H., Alotibi, T., Hernandorena, C. V., & Knyahnytska, Y. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.120475 · Cited by 5 · see citing works
Zhang, X., Huang, M., Wangyang, X., Leiming, D., Yu, Y., & Zeng, J. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.120133 · Cited by 4 · see citing works
La kétamine : un neuropsychotrope au mécanisme d’action innovant
Guilloux, J., Nguyen, T. M. L., & Gardier, A. M. (2023) · Biologie Aujourd hui · doi:10.1051/jbio/2023026 · Cited by 4 · see citing works
Courtes, A. C., Jones, G. H., Henter, I. D., Shahani, L., Fries, G. R., Juruena, M. F., Soares, J. C., Zarate, C. A., & Machado‐Vieira, R. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.120016 · Cited by 4 · see citing works
Self-citationde Miranda, A. S., Toscano, E. C. D. B., Venna, V. R., Graeff, F. G., & Teixeira, A. L. (2025) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2025.2460674 · Cited by 2 · see citing works
“Previous assumptions on the potential effects of (R,S)-ketamine metabolites must be taken cautiously, as they were associated with no or weak antidepressant responses in clinical trials in humans [71,72].”
Barrutieta-Arberas, I., Ortuzar, N., Vaquero-Rodríguez, A., Picó-Gallardo, M., Bengoetxea, H., Guevara, M., Gargiulo, P. A., & Lafuente, J. V. (2023) · Experimental Biology and Medicine · doi:10.1177/15353702231170007 · Cited by 5 · see citing works
Targeting Affective Mood Disorders With Ketamine to Prevent Chronic Postsurgical Pain
Willis, D. E., & Goldstein, P. A. (2022) · Frontiers in Pain Research · doi:10.3389/fpain.2022.872696 · Cited by 6 · see citing works
Irwin, M. N., & VandenBerg, A. (2021) · Mental Health Clinician · doi:10.9740/mhc.2021.05.200 · Cited by 6 · see citing works
Shinozuka, K., Rosso, M., Chaiken, A., Lissemore, J. I., Jones, R., Descalço, N., Subramani, V., Belgers, M., Cherian, K. N., Arns, M., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.20.713241 · Cited by 1 · see citing works
“For example, increases in gamma power and synchrony have been repeatedly associated with the antidepressant effects of ketamine (Farmer et al., 2020; Medeiros et al., 2023; Purohit et al., 2025).”
Prophylactic Ketamine: Current Knowledge and Future Directions
Cardona-Acosta, A. M., Parise, L. F., Bolaños‐Guzmán, C. A., & Parise, E. M. (2025) · Biological Psychiatry · doi:10.1016/j.biopsych.2025.03.015 · Cited by 2 · see citing works
Examining memory reconsolidation as a mechanism of nitrous oxide’s antidepressant action
Williams, E., Taujanskaitė, U., Kamboj, S. K., Murphy, S. E., & Harmer, C. J. (2025) · Neuropsychopharmacology · doi:10.1038/s41386-024-02049-0 · Cited by 3 · see citing works
“N 2 O and ketamine (indirectly via its metabolites) also interact with other non-NMDA receptors [32, 42], which may contribute to their antidepressant pro fi les [151, 152], but this remains contentious (see [153, 154]).”
Increasing the bioavailability of oral esketamine by a single dose of cobicistat: A case study
Vos, C. F., Hemminga, W. L., Aarnoutse, R. E., & Ruhé, H. G. (2024) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.2942 · Cited by 2 · see citing works
“26 This supports the potential for use of cobicistat as a booster drug for oral esketamine, which is particularly relevant since oral esketamine is considered more practical than intranasal or intravenous administration.”
BackgroundKetamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions
Nguyen, T. M. L., Guilloux, J., Defaix, C., Mendez-David, I., Etting, I., Alvarez, J.-C., McGowan, J. C., Highland, J. N., Zanos, P., Lovett, J., et al. (2024) · bioRxiv · doi:10.1101/2024.04.03.587904 · Cited by 2
“Achiral liquid chromatography–tandem mass spectrometry was used to determine the concentration of ketamine and its metabolites in plasma as previously described (Farmer et al., 2020) and in brain with slight modifications (Farmer et al., 2020).”
MethodSelf-citationJones, G. H., & Machado-Vieira, R. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02102-2 · Cited by 2 · see citing works
TREK-1 Channel Blockade Mediates the Antidepressant-like Effects of Hydroxynorketamine.
Song, Y.-C., Song, Y.-J., Du, W., Yu, X.-Y., Li, Y.-J., Chang, L., Huang, X.-Y., Ye, B., Li, T.-Y., Li, Y., et al. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110751 · Cited by 1 · see citing works
Recourt, K., van Gerven, J. V., Drenth, N., van der Grond, J., Nishigori, K., van der Wee, N. V. D., & Jacobs, G. E. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1531375 · Cited by 1 · see citing works
A computational model to characterize the time-course of response to rapid antidepressant therapies
Nunes, A., & Singh, S. (2024) · PLoS ONE · doi:10.1371/journal.pone.0297708 · Cited by 1 · see citing works
Wang, J.-L., Zhang, X.-C., Shi, H.-K., Guo, W.-T., Liu, S., & Dong, M. (2026) · Progress in Neuro-psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2026.111969
Jones, G. H., Gilbert, J. R., Johnston, J. N., Akula, N., Schulmann, A., Arakelian, M. H., Peng, S., Yuan, P., Winful, E. A., Yavi, M., et al. (2026) · Molecular Psychiatry · doi:10.1038/s41380-026-03777-z
“This study broadly identi fi ed clinically relevant biomarkers and novel therapeutic targets, underscoring the importance and bene fi t of multimodal approaches to reverse engineering the mechanism of action underlying RAADs [121].”
Self-citationGeneration of enantiospecific monoclonal antibodies against (2R,6R)-hydroxynorketamine.
Enriquez, U. M., Velázquez, N. M. G., Hossain, M. M., Kyzer, J. L., Guzei, I. A., & Wenthur, C. J. (2026) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2026.118573
Ketamine and Other Glutamate Receptor Antagonists As Fast-Actin
Chen, M., Su, T., & Tsai, S. (2022) · Neuromethods · doi:10.1007/978-1-0716-2083-0_19 · Cited by 1 · see citing works
Liyanage, W., Vyas, P., Kale, N. R., Labastida, J. A., Keuthan, C. J., Mehta, K., Berlinicke, C. A., Pokala, S., Kathuria, A., Zack, D. J., et al. (2026) · Nano Today · doi:10.1016/j.nantod.2026.103193
- Authors
- Farmer, C. A., Gilbert, J. R., Moaddel, R., George, J., Adeojo, L., Lovett, J., Nugent, A. C., Kadriu, B., Yuan, P., Gould, T. D., Park, L. T., & Zarate, C. A.
- Affiliations
- National Institutes of Health (US)
- University of Maryland, Baltimore (US)
- Corresponding author
- Zarate, Carlos A.
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2020-04-06
- Volume
- 45
- Issue
- 8
- Pages
- 1398-1404
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC7297997
- OpenAlex
- W3015053440
- Cited by
- 85
- References
- 0
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 15 · 2023: 15 · 2022: 15 · 2021: 14 · 2020: 7
- FWCI
- 7.64
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-05-06)
- Open access
- bronze
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (ZIAMH002857)
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (ZIAAG000297)
- U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (ZIAAG000297)
- 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, treatment-resistant depression, major depressive disorder, hydroxynorketamine, ketamine metabolites, norketamine, antidepressant response, gamma power, magnetoencephalography, plasma drug concentration
- MeSH terms
- Antidepressive Agents, Depression, Depressive Disorder, Major, Major Depressive Disorder, Humans, Ketamine, Cross-Over Studies
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