Intracellular Signaling Pathways Involved in ( S )- and ( R )-Ketamine Antidepressant Actions
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Prefrontal synaptic plasticity (increased density and connectivity evident at 24 h post treatment and lasting for a week) plays a role.
“It also highlights the role of prefrontal synaptic plasticity-i.e., the increased density and connectivity evident at 24 h post treatment and lasting for a week [4,56].”
From The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects (2018) · cites this paper as [56]
The main text (page not provided) says ketamine-related signaling may produce synaptic plasticity changes that mediate prolonged antidepressant effects, and discusses signaling in the prefrontal cortex. It does not report increased synaptic density or connectivity at 24 hours, or establish that those changes last a week. (LLM, conf=0.86)
Experimental — accuracy not yet measuredmTOR activation is required for ketamine's behavioral antidepressant actions.
“Indeed, mTOR activation was shown to be required for ketamine’s behavioral antidepressant actions 182.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [182]
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Cites
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,501 · see citing works
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
Li, N., Lee, B., Liu, R.-J., Banasr, M., Dwyer, J. M., Iwata, M., Li, X.-Y., Aghajanian, G., & Duman, R. S. (2010) · Science · doi:10.1126/science.1190287 · Cited by 2,881 · cited 4× · see citing works
“Notably, only lower doses of ketamine enhance mTORC1 activity, whereas anesthetic doses of the drug do not influence mTOR signaling, in accordance with the antidepressant actions of the drug, which only occur at lower doses (7).”
BackgroundResultInfluentialNMDAR inhibition-independent antidepressant actions of ketamine metabolites
Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. I., Alkondon, M., Yuan, P., Pribut, H. J., Singh, N. S., et al. (2016) · Nature · doi:10.1038/nature17998 · Cited by 1,609 · cited 5× · see citing works
“Notably, the difference in antidepressant potency is not due to bioavailability differences since administration of equal doses of these enantiomers does not yield different drug concentrations in the brains of rodents (4, 5).”
BackgroundInfluentialSelf-citationLi, N., Liu, R.-J., Dwyer, J. M., Banasr, M., Lee, B., Son, H., Li, X.-Y., Aghajanian, G., & Duman, R. S. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.12.015 · Cited by 1,082 · cited 2× · see citing works
“Duman and colleagues showed that sub-anesthetic doses of ketamine induce rapid (within 30 min of administration), but transient (lasting up to 2 hours), phosphorylation/activation of mTORC1, leading to initiation of translation and protein synthesis (7, 8).”
BackgroundR-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects
Yang, C., Shirayama, Y., Zhang, J.-C., Ren, Q., Yao, W., Ma, M., Dong, C., & Hashimoto, K. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.136 · Cited by 605 · cited 6× · see citing works
“Published rodent data also indicate lower abuse potential of (R)-ketamine than (S)-ketamine (3), as predicted by the lesser NMDAR inhibition by (R)-ketamine.”
BackgroundInfluentialSignaling pathways underlying the rapid antidepressant actions of ketamine
Duman, R. S., Li, N., Liu, R.-J., Duric, V., & Aghajanian, G. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.08.044 · Cited by 537 · cited 2× · see citing works
“Although there is evidence of enhanced synaptic glutamatergic neurotransmission following administration of racemic ketamine (9) and (2R,6R)-HNK (4), the direct target responsible for these actions is not yet fully understood.”
BackgroundSingh, J. B., Fedgchin, M., Daly, E., Xi, L., Melman, C., De Bruecker, G., Tadic, A., Sienaert, P., Wiegand, F., Manji, H., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.10.018 · Cited by 466 · cited 1× · see citing works
“Similar to racemic ketamine, clinical studies in depressed patients have indicated that a 40-min, intravenous infusion of (S)-ketamine exerts rapid antidepressant actions (1).”
ResultR (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine
Zhang, J.-C., Li, S.-X., & Hashimoto, K. (2014) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.11.033 · Cited by 357 · see citing works
Acute suppression of spontaneous neurotransmission drives synaptic potentiation
Nosyreva, E., Szabla, K., Autry, A. E., Ryazanov, A. G., Monteggia, L. M., & Kavalali, E. T. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.4998-12.2013 · Cited by 283 · cited 2× · see citing works
“Alternatively, there is also evidence that BDNF translation/ release is upstream of ketamine-induced increases in excitatory neurotransmission since the latter was absent in mice where BDNF was removed from the forebrain (10).”
BackgroundAntidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine
Fukumoto, K., Toki, H., Iijima, M., Hashihayata, T., Yamaguchi, J.-I., Hashimoto, K., & Chaki, S. (2017) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.116.239228 · Cited by 252 · cited 2× · see citing works
“Notably, the difference in antidepressant potency is not due to bioavailability differences since administration of equal doses of these enantiomers does not yield different drug concentrations in the brains of rodents (4, 5).”
BackgroundYang, C., Ren, Q., Qu, Y., Zhang, J., Ma, M., Dong, C., & Hashimoto, K. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.05.016 · Cited by 252 · cited 3× · see citing works
“In addition, the authors show that inhibition of mTOR by intracerebroventricular preadministration of rapamycin or AZD8055 prevents the antidepressant actions of (S)-, but not (R)-ketamine in the chronic social defeat stress model in mice (6).”
BackgroundInfluential
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Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms
Zanos, P., Moaddel, R., Morris, P. J., Riggs, L. M., Highland, J. N., Georgiou, P., Pereira, E. F. R., Albuquerque, E. X., Thomas, C. J., Zarate, C. A., et al. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.015198 · Cited by 1,260 · see citing works
Self-citationMechanisms of ketamine action as an antidepressant
Zanos, P., & Gould, T. D. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.255 · Cited by 1,127 · see citing works
Self-citationThe effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects
Abdallah, C. G., De Feyter, H. M., Averill, L. A., Jiang, L., Averill, C. L., Chowdhury, G. M. I., Purohit, P., de Graaf, R. A., Esterlis, I., Juchem, C., et al. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0136-3 · Cited by 229 · see citing works
Convergent Mechanisms Underlying Rapid Antidepressant Action
Zanos, P., Thompson, S. M., Duman, R. S., Zarate, C. A., & Gould, T. D. (2018) · CNS Drugs · doi:10.1007/s40263-018-0492-x · Cited by 171 · see citing works
“These behavioral actions of (S)-ketamine in rodent tests require higher doses compared with the (R)-ketamine enantiomer [45, 64, 65], indicating that (R)-ketamine is a more potent antidepressant compared with the (S)-ketamine enantiomer [66], at least in rodents.”
BackgroundSelf-citationMechanisms of ketamine and its metabolites as antidepressants
Hess, E. M., Riggs, L. M., Michaelides, M., & Gould, T. D. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114892 · Cited by 169 · see citing works
Self-citationMolecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants
Gould, T. D., Zarate, C. A., & Thompson, S. M. (2019) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010617-052811 · Cited by 133 · see citing works
“It is critically important for future human clinical trials to assess the antidepressant efficacy of (R)ketamine and to compare the potency of (R)-ketamine to that of (S)-ketamine (83).”
BackgroundSelf-citationChou, D., Peng, H.-Y., Lin, T.-B., Lai, C.-Y., Hsieh, M.-C., Wen, Y.-C., Lee, A.-S., Wang, H.-H., Yang, P.-S., Chen, G.-D., et al. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.06.033 · Cited by 104 · see citing works
Roles of the medial and lateral orbitofrontal cortex in major depression and its treatment
Zhang, B., Rolls, E. T., Wang, X., Xie, C., Cheng, W., & Feng, J. (2024) · Molecular Psychiatry · doi:10.1038/s41380-023-02380-w · Cited by 104 · see citing works
“…of glutamate leads to elevated α -amino-3-hydroxy-5-methyl-4-iso- xazole propionic acid (AMPA) receptor activation, resulting in short-and long-term synaptic plasticity via activation of the brain-derived neurotrophic factor (BDNF) and via the mammalian target of rapamycin (mTOR) pathway [140].”
BackgroundAmidfar, M., Woelfer, M., Réus, G. Z., Quevedo, J., Walter, M., & Kim, Y.-K. (2019) · Progress in Neuro-psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.109668 · Cited by 86 · see citing works
Ketamine treatment for refractory anxiety: A systematic review
Tully, J. L., Dahlén, A. D., Haggarty, C. J., Schiöth, H. B., & Brooks, S. J. (2022) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.15374 · Cited by 87 · see citing works
Efficacy and safety of intranasal esketamine for the treatment of major depressive disorder
Kryst, J., Kawalec, P., & Pilc, A. (2019) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2019.1683161 · Cited by 78 · see citing works
“Differential effects of esketamine and arketamine might be mediated by different actions of ketamine’s enantiomers on intracellular signaling pathways as well as by the distinct metabolism profiles of each enantiomer [37].”
BackgroundEsketamine: new hope for the treatment of treatment-resistant depression? A narrative review
Salahudeen, M. S., Wright, C. M., & Peterson, G. M. (2020) · Therapeutic Advances in Drug Safety · doi:10.1177/2042098620937899 · Cited by 72 · see citing works
Humo, M., Ayazgök, B., Becker, L. J., Waltisperger, E., Rantamäki, T., & Yalçın, İ. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.109898 · Cited by 54 · see citing works
Wang, Y., Zhang, N., Liu, L., Jiang, H., Hu, D., Wang, Z., Chen, N., & Zhang, Y. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.01.024 · Cited by 46 · see citing works
Prophylactic efficacy of 5-HT4R agonists against stress
Chen, B. K., Mendez‐David, I., Luna, V. M., Faye, C., Gardier, A. M., David, D. J. P., & Denny, C. A. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0540-3 · Cited by 42 · see citing works
Badawy, A. A. ‐., Dawood, S., & Bano, S. (2023) · World Journal of Psychiatry · doi:10.5498/wjp.v13.i4.141 · Cited by 41 · see citing works
Ye, L., Ko, C., Huang, Y.-T., Zheng, C., Zheng, Y., & Chou, D. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107667 · Cited by 34 · see citing works
Ren, L. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2023.110910 · Cited by 23 · see citing works
“…by ( R )-ketamine last longer and are significantly more potent in rats than those of ( S )-ketamine, suggesting that the action of ketamine to exert its antidepressant-like effects is unlikely to solely result from NMDAR inhibition (Zhang et al., 2014; Yang et al., 2015; Zanos and Gould, 2018a).”
BackgroundPharmacological Treatments for Anhedonia
Klein, M. E., Grice, A. B., Sheth, S., Go, M., & Murrough, J. W. (2022) · Current topics in behavioral neurosciences · doi:10.1007/7854_2022_357 · Cited by 24 · see citing works
Jonkman, K., van der Schrier, R. M., van Velzen, M., Aarts, L. P. H. J., Olofsen, E., Sarton, E. Y., Niesters, M., & Dahan, A. (2018) · British Journal of Anaesthesia · doi:10.1016/j.bja.2018.01.022 · Cited by 21 · see citing works
Sayson, L. V., Botanas, C. J., Custodio, R. J. P., Abiero, A., Kim, M., Lee, H. J., Kim, H. J., Yoo, S. Y., Lee, K. W., Ryu, H. W., et al. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05219-x · Cited by 19 · see citing works
A review of ketamine’s role in ECT and non-ECT settings
Jankauskas, V., Necyk, C., Chue, J., & Chue, P. S. (2018) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s157233 · Cited by 17 · see citing works
“It has been reported that arketamine, compared to esketamine or racemic ketamine, may have a lower rate of adverse effects related to NMDA inhibition such as dissociation, dizziness, sensory, and perceptual deficits.(31) Additionally, rates of both cardiovascular and psychotomimetic effects appear to be lower if ketam…”
Ketamine: Leading us into the future for development of antidepressants
Carreno, F. R., Lodge, D. J., & Frazer, A. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112532 · Cited by 15 · see citing works
“More recent studies have replicated and expanded these studies and demonstrated antidepressant-like effects of arketamine [50, 51].”
ResultBokel, A., Rühlmann, A., Hutter, M. C., & Urlacher, V. B. (2020) · ACS Catalysis · doi:10.1021/acscatal.9b05384 · Cited by 15 · see citing works
Psychedelics, entactogens and psychoplastogens for depression and related disorders
Hoyer, D. (2025) · British Journal of Pharmacology · doi:10.1111/bph.70088 · Cited by 13 · see citing works
“…proposed that ketamine acts by N-methyl-D-aspartate (NMDA ) receptor modulation, GABA-ergic interneuron disinhibition, and that its hydroxynorketamine (HNK) metabolites are the active principle, that is, that ketamine is a prodrug (see, e.g., Zanos & Gould, 2018a, 2018b; Zanos et al., 2019, 2023).”
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Colloca, L., & D, M. F. M. (2024) · Nature Mental Health · doi:10.1038/s44220-024-00321-2 · Cited by 12 · see citing works
HCN channels: New targets for the design of an antidepressant with rapid effects
Luo, P., He, G., & Liu, D. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.11.081 · Cited by 11 · see citing works
Antidepressant Actions of Ketamine and Its Two Enantiomers
Chang, L., Wei, Y., & Hashimoto, K. (2020) · Springer eBooks · doi:10.1007/978-981-15-2902-3_7 · Cited by 4 · see citing works
Next generation antidepressants with novel mechanisms for treatment resistant depression
Chen, M., Tu, P., & Su, T. (2023) · Progress in brain research · doi:10.1016/bs.pbr.2023.02.005 · Cited by 3 · see citing works
Coutellier, L. D., Musazzi, L., & Pavlovic, Z. M. (2022) · Springer eBooks · doi:10.1007/978-3-030-87480-3_4 · Cited by 2 · see citing works
Bao, K. H. (2021) · Research Square · doi:10.21203/rs.3.rs-374465/v1 · Cited by 2 · see citing works
“This pathway seems to be essential for R-ketamine’s antidepressant effects, as opposed to S-ketamine which requires mTORC1 signaling [35, 36], as well as other traditional antidepressants [37].”
BackgroundKetamine 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
Ketamine in Psychiatric Disorders
Danyeli, L. V., Götting, F. N., Şen, Z. D., Li, M., & Walter, M. (2022) · Springer eBooks · doi:10.1007/978-3-030-62059-2_420 · Cited by 1 · see citing works
Ketamine in Psychiatric Disorders
Danyeli, L. V., Götting, F. N., Şen, Z. D., Li, M., & Walter, M. (2021) · Springer eBooks · doi:10.1007/978-3-319-56015-1_420-1
Filho, A. C., Lós, D. B., Soares, M. V.-R., Jucá, P. M., de Queiroz, T., da Silva, F. E. R., Saraiva, K., Silva, A. D. A., Azul, F. V. C. S., Leal, L. K. A. M., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1671211/v1
Filho, A. J. M. C., Lós, D. B., Soares, M. L., Jucá, P. M., de Queiroz, T., Rodrigues, F. E., Saraiva, K., Silva, A. K., Azul, F. V. C. S., Leal, L. K. A. M., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1671211/v2
Modeling treatment-resistant depression in the preclinical setting
Tye, S. J., Yates, C. G., & Postorivo, D. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-824067-0.00005-0
Overlap and Divergence in Ketamine and Lithium Response in Bipolar Disorder: A Scoping Review
Toulany, J., Cunningham, J. E. A., & Nunes, A. (2025) · Pharmaceuticals · doi:10.3390/ph18111662
Neuropathic pain and depression : molecular alterations in the anterior cingulate cortex
Humo, M. (2019) · theses.fr (ABES) · doi:10.70675/e72f9364z66cbz45c4z8b42zb7f3564cd3d0
- Authors
- Zanos, P., & Gould, T. D.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Gould, Todd D.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 83
- Issue
- 1
- Pages
- 2-4
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5735822
- OpenAlex
- W2768818139
- Cited by
- 42
- References
- 11
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 9 · 2021: 4 · 2020: 5 · 2019: 7 · 2018: 9
- FWCI
- 3.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH107615)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- ketamine, (R)-ketamine, esketamine, enantiomers, antidepressant effects, mTOR signaling, extracellular signal-regulated kinase, ERK signaling, intracellular signaling, social defeat stress, protein synthesis
- MeSH terms
- Antidepressive Agents, Ketamine, Stress, Psychological, Signal Transduction, Sirolimus
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