Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2 R ,6 R )-hydroxynorketamine
Open accessAbstract
Significance: A metabolite of ketamine, (2 R ,6 R )-hydroxynorketamine [(2 R ,6 R )-HNK], produces rapid and sustained antidepressant effects in animal models but without the side effects of ketamine. Notably, (2 R ,6 R )-HNK does not block the NMDA receptor, the primary target of ketamine. Here, we demonstrate that the antidepressant effects of (2 R ,6 R )-HNK require activity dependent release of BDNF that is mediated by stimulation of voltage-dependent Ca 2+ channels. Importantly, increased BDNF release leads to activation of downstream TrkB and mechanistic target of rapamycin complex 1 signaling that increases synaptic function of pyramidal neurons in the medial prefrontal cortex. Stimulation of BDNF release and increased synaptic function block or reverse the detrimental effects of stress and depression and thereby underlie the antidepressant actions of (2 R ,6 R )-HNK.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Hydroxynorketamine (HNK) rapidly induces synaptogenesis and antidepressant-like effects without psychotomimetic effects in animal models.
“hydroxynorketamine (HNK - a metabolite of ketamine which rapidly induces synaptogenesis and antidepressant-like effects without psychotomimetic effects in animal models) 44”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [44]
The Introduction and Discussion describe (2R,6R)-HNK as a ketamine metabolite with rapid antidepressant effects in rodent models and without ketamine’s side-effect profile. But the paper does not establish rapid synaptogenesis: the Results report increased synaptic function without an increase in spine density, and the Discussion says a synaptogenic response may be absent or below detection. The claim therefore overstates the synaptogenesis finding. (LLM, conf=0.90)
Experimental — accuracy not yet measured(2R,6R)-HNK at 30 mg/kg intraperitoneally produced antidepressant-like effects in mice in the forced swim test and female urine sniffing test 24 hours after treatment.
“(2R,6R)-HNK (30 mg/kg i.p.) produced antidepressant-like effects in mice tested in the forced swim test and female urine sniffing test 24 hours post-treatment”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Fukumoto et al., 2019
The effects of (2R,6R)-HNK in the forced swim test and novelty suppressed feeding test were blocked in mice carrying the BDNF Val66Met allele, including heterozygous Val/Met and homozygous Met/Met mice.
“The effects of (2R,6R)-HNK in the forced swim test and novelty suppressed feeding were blocked in mice containing the BDNF Val66Met allele (heterozygous Val/Met and homozygous Met/Met mice) (Fukumoto et al., 2019).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Fukumoto et al., 2019
The literature on the antidepressant effects of 2R,6R-HNK is controversial, with several contradictory reports.
“However, the literature on the antidepressant effects of 2R,6R-HNK is controversial, with several contradictory reports.41,48–52”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [49]
mTORC1 signaling is necessary and may be sufficient to produce rapid synaptic and antidepressant behavioral responses.
“These studies indicate that mTORC1 signaling is necessary and may be sufficient to produce rapid synaptic and antidepressant behavioral responses.”
From Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation (2019) · cites this paper as [10]
Infusion of rapamycin alone into the mPFC has no effect on these behaviors.
“Previous studies demonstrate that infusion of rapamycin alone into the mPFC has no effect on these behaviors (7, 8, 10, 12).”
From Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation (2019) · cites this paper as [10]
Ketamine's actions occur via a burst of glutamate and require AMPA receptor activation.
“While the effects of NV-5138 and ketamine converge on mTORC1 signaling, the actions of ketamine occur via a burst of glutamate and require AMPA receptor activation, based on evidence that pretreatment with an AMPA receptor antagonist (NBQX) blocks the antidepressant actions of ketamine as well as other rapid-acting agents (7, 10, 12, 39, 40).”
From Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation (2019) · cites this paper as [10]
Pretreatment with an AMPA receptor antagonist (NBQX) blocks the antidepressant actions of ketamine and other rapid-acting agents.
“While the effects of NV-5138 and ketamine converge on mTORC1 signaling, the actions of ketamine occur via a burst of glutamate and require AMPA receptor activation, based on evidence that pretreatment with an AMPA receptor antagonist (NBQX) blocks the antidepressant actions of ketamine as well as other rapid-acting agents (7, 10, 12, 39, 40).”
From Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation (2019) · cites this paper as [10]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
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
Kessler, R. C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K. R., Rush, A. J., Walters, E. E., & Wang, P. S. (2003) · JAMA · doi:10.1001/jama.289.23.3095 · Cited by 7,988 · see citing works
Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., Niederehe, G., Thase, M. E., Lavori, P. W., Lebowitz, B. D., et al. (2006) · American Journal of Psychiatry · doi:10.1176/ajp.2006.163.11.1905 · Cited by 5,643 · cited 1× · see citing works
“Currently available antidepressants take weeks to months to produce a therapeutic response, and more than 30% of patients fail to respond to these agents and are considered treatment resistant (3).”
Backgroundda Luz, A. C. D. D. S., Dias, G. P., Bevilaqua, M. C. D. N., Cocks, G. D., Gardino, P. F., Thuret, S., & Nardi, A. E. (2013) · Neuropsychobiology · doi:10.1159/000353269 · Cited by 4,012 · see citing works
Antidepressant effects of ketamine in depressed patients
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00230-9 · Cited by 3,856 · see citing works
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.8.856 · Cited by 3,766 · 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 · see citing works
Self-citationNMDA receptor blockade at rest triggers rapid behavioural antidepressant responses
Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P.-F., Kavalali, E. T., & Monteggia, L. M. (2011) · Nature · doi:10.1038/nature10130 · Cited by 1,926 · see citing works
Moghaddam, B., Adams, B., Verma, A., & Daly, D. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-08-02921.1997 · Cited by 1,793 · see citing works
Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants
Duman, R. S., Aghajanian, G. K., Sanacora, G., & Krystal, J. H. (2016) · Nature Medicine · doi:10.1038/nm.4050 · Cited by 1,750 · see citing works
Self-citationBrain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression
Shirayama, Y., Chen, A. C.-H., Nakagawa, S., Russell, D. S., & Duman, R. S. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-08-03251.2002 · Cited by 1,654 · see citing works
Self-citationSynaptic Dysfunction in Depression: Potential Therapeutic Targets
Duman, R. S., & Aghajanian, G. K. (2012) · Science · doi:10.1126/science.1222939 · Cited by 1,651 · see citing works
Self-citationNMDAR 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 · see citing works
Neurocircuitry of Mood Disorders
Price, J. L., & Drevets, W. C. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.104 · Cited by 1,606 · see citing works
Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior
Chen, Z.-Y., Jing, D., Bath, K. G., Ieraci, A., Khan, T., Siao, C.-J., Herrera, D. G., Toth, M., Yang, C., McEwen, B. S., et al. (2006) · Science · doi:10.1126/science.1129663 · Cited by 1,340 · see citing works
Maeng, S., Zarate, C. A., Du, J., Schloesser, R. J., McCammon, J., Chen, G., & Manji, H. K. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.05.028 · Cited by 1,103 · see citing works
Li, 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 · see citing works
Self-citationRecurrence after recovery from major depressive disorder during 15 years of observational follow-up
Mueller, T. I., Leon, A. C., Keller, M. B., Solomon, D. A., Endicott, J., Coryell, W., Warshaw, M., & Maser, J. D. (1999) · American Journal of Psychiatry · doi:10.1176/ajp.156.7.1000 · Cited by 897 · see citing works
A simple role for BDNF in learning and memory?
Cunha, C. (2010) · Frontiers in Molecular Neuroscience · doi:10.3389/neuro.02.001.2010 · Cited by 778 · see citing works
Structural and Molecular Remodeling of Dendritic Spine Substructures during Long-Term Potentiation
Bosch, M., Castro, J., Saneyoshi, T., Matsuno, H., Sur, M., & Hayashi, Y. (2014) · Neuron · doi:10.1016/j.neuron.2014.03.021 · Cited by 637 · see citing works
Rodriguez, A., Ehlenberger, D. B., Dickstein, D. L., Hof, P. R., & Wearne, S. L. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001997 · Cited by 571 · see citing works
Aghajanian, G. K., & Marek, G. J. (1997) · Neuropharmacology · doi:10.1016/s0028-3908(97)00051-8 · Cited by 516 · see citing works
Stress-induced prefrontal reorganization and executive dysfunction in rodents
Holmes, A., & Wellman, C. L. (2009) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2008.11.005 · Cited by 469 · see citing works
Ketamine for Depression: Where Do We Go from Here?
aan het Rot, M., Zarate, C. A., Charney, D. S., & Mathew, S. J. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.05.003 · Cited by 418 · see citing works
Regulation of hippocampal synaptic plasticity by BDNF
Leal, G., Afonso, P. M., Salazar, I. L., & Duarte, C. B. (2015) · Brain Research · doi:10.1016/j.brainres.2014.10.019 · Cited by 410 · see citing works
Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond
Krystal, J. H., Sanacora, G., & Duman, R. S. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.03.026 · Cited by 406 · see citing works
Self-citationLiu, R.-J., Lee, F. S., Li, X.-Y., Bambico, F., Duman, R. S., & Aghajanian, G. K. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.09.030 · Cited by 403 · see citing works
Self-citationCazorla, M., Prémont, J., Mann, A., Girard, N., Kellendonk, C., & Rognan, D. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43992 · Cited by 392 · see citing works
BDNF release is required for the behavioral actions of ketamine
Lepack, A. E., Fuchikami, M., Dwyer, J. M., Banasr, M., & Duman, R. S. (2015) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyu033 · Cited by 368 · see citing works
Self-citationMiller, O. H., Yang, L., Wang, C.-C., Hargroder, E. A., Zhang, Y., Delpire, E., & Hall, B. J. (2014) · eLife · doi:10.7554/elife.03581 · Cited by 358 · see citing works
Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects
Hoshaw, B. A., Malberg, J. E., & Lucki, I. (2005) · Brain Research · doi:10.1016/j.brainres.2005.01.007 · Cited by 348 · see citing works
Burgdorf, J., Zhang, X.-L., Nicholson, K. L., Balster, R. L., David Leander, J., Stanton, P. K., Gross, A. L., Kroes, R. A., & Moskal, J. R. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2012.246 · Cited by 284 · see citing works
Fuchikami, M., Thomas, A., Liu, R., Wohleb, E. S., Land, B. B., DiLeone, R. J., Aghajanian, G. K., & Duman, R. S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1414728112 · Cited by 265 · see citing works
Self-citationVoleti, B., Navarria, A., Liu, R.-J., Banasr, M., Li, N., Terwilliger, R., Sanacora, G., Eid, T., Aghajanian, G., & Duman, R. S. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.04.025 · Cited by 264 · see citing works
Self-citationLiu, R.-J., Fuchikami, M., Dwyer, J. M., Lepack, A. E., Duman, R. S., & Aghajanian, G. K. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.128 · Cited by 256 · see citing works
Self-citationRho GTPase complementation underlies BDNF-dependent homo- and heterosynaptic plasticity
Hedrick, N. G., Harward, S. C., Hall, C. E., Murakoshi, H., McNamara, J. O., & Yasuda, R. (2016) · Nature · doi:10.1038/nature19784 · Cited by 240 · see citing works
Jourdi, H., Hsu, Y.-T., Zhou, M., Qin, Q., Bi, X., & Baudry, M. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.6078-08.2009 · Cited by 226 · see citing works
BDNF at the synapse: why location matters
Song, M., Martinowich, K., & Lee, F. S. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.144 · Cited by 198 · see citing works
Effects of a ketamine metabolite on synaptic NMDAR function
Suzuki, K., Nosyreva, E., Hunt, K. W., Kavalali, E. T., & Monteggia, L. M. (2017) · Nature · doi:10.1038/nature22084 · Cited by 180 · see citing works
Lepack, A. E., Bang, E., Lee, B., Dwyer, J. M., & Duman, R. S. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.09.011 · Cited by 174 · see citing works
Self-citationLai, K., Wong, A. S. L., Cheung, M. C., Xu, P., Liang, Z., Lok, K.-C., Xie, H., Palko, M. E., Yung, W., Tessarollo, L., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.3237 · Cited by 172 · see citing works
Ketamine as a Novel Antidepressant: From Synapse to Behavior
Murrough, J. W. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2011.244 · Cited by 172 · see citing works
Yang, C., Qu, Y., Abe, M., Nozawa, D., Chaki, S., & Hashimoto, K. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.12.020 · Cited by 162 · see citing works
Ketamine Produces Lasting Disruptions in Encoding of Sensory Stimuli
Maxwell, C. R., Ehrlichman, R. S., Liang, Y., Trief, D., Kanes, S., Karp, J. D., & Siegel, S. J. (2005) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.091199 · Cited by 160 · see citing works
Molecular and Cellular Mechanisms of Rapid-Acting Antidepressants Ketamine and Scopolamine
Wohleb, E. S., Gerhard, D. M., Thomas, A., & Duman, R. S. (2016) · Current Neuropharmacology · doi:10.2174/1570159x14666160309114549 · Cited by 151 · see citing works
Self-citationPham, T. H., Defaix, C., Xu, X., Deng, S.-X., Fabresse, N., Alvarez, J.-C., Landry, D. W., Brachman, R. A., Denny, C. A., & Gardier, A. M. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.020 · Cited by 131 · see citing works
Lambe, E. K., & Aghajanian, G. K. (2003) · Neuron · doi:10.1016/s0896-6273(03)00598-1 · Cited by 127 · see citing works
Ionescu, D. F., Swee, M. B., Pavone, K. J., Taylor, N., Akeju, O., Baer, L., Nyer, M., Cassano, P., Mischoulon, D., Alpert, J. E., et al. (2016) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.15m10056 · Cited by 126 · see citing works
VGF function in depression and antidepressant efficacy
Jiang, C. S., Lin, W.-J., Sadahiro, M., Labonté, B., Ménard, C., Pfau, M. L., Tamminga, C. A., Turecki, G., Nestler, E. J., Russo, S. J., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.233 · Cited by 123 · see citing works
Navarria, A., Wohleb, E. S., Voleti, B., Ota, K. T., Dutheil, S., Lepack, A. E., Dwyer, J. M., Fuchikami, M., Becker, A., Drago, F., et al. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.06.012 · Cited by 118 · see citing works
Self-citationGhosal, S., Bang, E., Yue, W., Hare, B. D., Lepack, A. E., Girgenti, M. J., & Duman, R. S. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.06.017 · Cited by 111 · see citing works
Self-citationShirayama, Y., & Hashimoto, K. (2017) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyx108 · Cited by 111 · see citing works
Liu, R.-J., Duman, C., Kato, T., Hare, B., Lopresto, D., Bang, E., Burgdorf, J., Moskal, J., Taylor, J., Aghajanian, G., et al. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.202 · Cited by 105 · see citing works
Self-citationKoike, H., Fukumoto, K., Iijima, M., & Chaki, S. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.10.023 · Cited by 94 · see citing works
Self-citationAntidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation
Harraz, M. M., Tyagi, R., Cortés, P., & Snyder, S. H. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.211 · Cited by 94 · see citing works
BDNF Release and Signaling Are Required for the Antidepressant Actions of GLYX-13
Kato, T., Fogaça, M. V., Deyama, S., Li, X.-Y., Fukumoto, K., & Duman, R. S. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.220 · Cited by 88 · see citing works
Self-citationZhang, J.-C., Yao, W., Ren, Q., Yang, C., Dong, C., Ma, M., Wu, J., & Hashimoto, K. (2016) · Scientific Reports · doi:10.1038/srep36705 · Cited by 64 · see citing works
Naumenko, V. S., Kondaurova, E. M., Базовкина, Д. В., Tsybko, A. S., Tikhonova, M. A., Kulikov, A. V., & Popova, N. K. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.04.031 · Cited by 59 · see citing works
What Are the Causes for Discrepancies of Antidepressant Actions of (2R,6R)-Hydroxynorketamine?
Hashimoto, K., & Shirayama, Y. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.12.007 · Cited by 31 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action
Castrén, E., & Monteggia, L. M. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.05.008 · Cited by 540 · see citing works
Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions
Fogaça, M. V., & Duman, R. S. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00087 · Cited by 396 · see citing works
Self-citationHashimoto, K. (2019) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12902 · Cited by 335 · see citing works
Duman, R. S., Deyama, S., & Fogaça, M. V. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.14630 · Cited by 321 · see citing works
Self-citationYan, Z., & Rein, B. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01092-3 · Cited by 300 · see citing works
Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor
Wei, Y., Chang, L., & Hashimoto, K. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01121-1 · Cited by 248 · see citing works
Matveychuk, D., Thomas, R. K., Swainson, J., Khullar, A., MacKay, M.-A., Baker, G. B., & Dursun, S. M. (2020) · Therapeutic Advances in Psychopharmacology · doi:10.1177/2045125320916657 · Cited by 209 · see citing works
Yang, C., Yang, J., Luo, A., & Hashimoto, K. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0624-1 · Cited by 190 · see citing works
Alnefeesi, Y., Chen-Li, D., Krane, E., Jawad, M. Y., Rodrigues, N. B., Ceban, F., Di Vincenzo, J. D., Meshkat, S., Ho, R. C. M., Gill, H., et al. (2022) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2022.04.037 · Cited by 186 · see citing works
Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine
Deyama, S., & Duman, R. S. (2020) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.172837 · Cited by 186 · see citing works
Self-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
Lumsden, E. W., Troppoli, T. A., Myers, S. J., Zanos, P., Aracava, Y., Kehr, J., Lovett, J., Kim, S., Wang, F.-H., Schmidt, S., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1816071116 · Cited by 158 · see citing works
Zanos, P., Highland, J. N., Stewart, B. W., Georgiou, P., Jenne, C. E., Lovett, J., Morris, P. J., Thomas, C. J., Moaddel, R., Zarate, C. A., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1819540116 · Cited by 152 · see citing works
Antidepressant actions of ketamine engage cell-specific translation via eIF4E
Aguilar-Valles, A., De Gregorio, D., Matta-Camacho, E., Eslamizade, M. J., Khlaifia, A., Skaleka, A., Lopez-Canul, M., Torres-Berrio, A., Bermudez, S., Rurak, G. M., et al. (2021) · Nature · doi:10.1038/s41586-020-03047-0 · Cited by 144 · see citing works
Transient stimulation with psychoplastogens is sufficient to initiate neuronal growth
Ly, C., Greb, A. C., Vargas, M. V., Duim, W. C., Grodzki, A. C. G., Lein, P. J., & Olson, D. E. (2021) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.0c00065 · Cited by 123 · see citing works
Fogaça, M. V., Wu, M., Li, C., Li, X.-Y., Picciotto, M. R., & Duman, R. S. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-00916-y · Cited by 129 · see citing works
Self-citationThe molecular pathophysiology of depression and the new therapeutics
Tian, H., Hu, Z., Xu, J., & Wang, C. (2022) · MedComm · doi:10.1002/mco2.156 · Cited by 122 · see citing works
Zanos, P., Brown, K. A., Georgiou, P., Yuan, P., Zarate, C. A., Thompson, S. M., & Gould, T. D. (2023) · The Journal of Neuroscience · doi:10.1523/jneurosci.1316-22.2022 · Cited by 115 · see citing works
A Synaptic Locus for TrkB Signaling Underlying Ketamine Rapid Antidepressant Action
Lin, P.-Y., Ma, Z. Z., Mahgoub, M., Kavalali, E. T., & Monteggia, L. M. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109513 · Cited by 99 · see citing works
Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications
Highland, J. N., Zanos, P., Riggs, L. M., Georgiou, P., Clark, S. M., Morris, P. J., Moaddel, R., Thomas, C. J., Zarate, C. A., Pereira, E. F. R., et al. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000149 · Cited by 92 · see citing works
Ago, Y., Tanabe, W., Higuchi, M., Tsukada, S., Tanaka, T., Yamaguchi, T., Igarashi, H., Yokoyama, R., Seiriki, K., Kasai, A., et al. (2019) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyz041 · Cited by 92 · see citing works
Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation
Kato, T., Pothula, S., Liu, R.-J., Duman, C. H., Terwilliger, R., Vlasuk, G. P., Saiah, E., Hahm, S., & Duman, R. S. (2019) · Journal of Clinical Investigation · doi:10.1172/jci126859 · Cited by 88 · see citing works
Self-citationKetamine and the Future of Rapid-Acting Antidepressants
Riggs, L. M., & Gould, T. D. (2021) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-072120-014126 · Cited by 87 · see citing works
Imaging the effect of ketamine on synaptic density (SV2A) in the living brain
Holmes, S. E., Finnema, S. J., Naganawa, M., DellaGioia, N., Holden, D., Fowles, K., Davis, M., Ropchan, J., Emory, P., Ye, Y., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01465-2 · Cited by 78 · see citing works
“In a parallel [(11)C]UCB-J PET study in rhesus macaques, we examined the effects of both ketamine and hydroxynorketamine (HNK—a metabolite of ketamine which rapidly induces synaptogenesis and antidepressant-like effects without psychotomimetic effects in animal models) [44], on synaptic density at 24 h, 1 week and 4–6…”
BackgroundSelf-citationZanos, P., Highland, J. N., Liu, X., Troppoli, T. A., Georgiou, P., Lovett, J., Morris, P. J., Stewart, B. W., Thomas, C. J., Thompson, S. M., et al. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14683 · Cited by 82 · see citing works
Kang, M. J. Y., Hawken, E., & Vazquez, G. H. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.860882 · Cited by 77 · see citing works
Riggs, L. M., Aracava, Y., Zanos, P., Fischell, J., Albuquerque, E. X., Pereira, E. F. R., Thompson, S. M., & Gould, T. D. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-019-0443-3 · Cited by 66 · see citing works
Neurobiology of the rapid-acting antidepressant effects of ketamine: impact and opportunities
Shinohara, R., Aghajanian, G. K., & Abdallah, C. G. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.12.006 · Cited by 54 · see citing works
Targeting metaplasticity mechanisms to promote sustained antidepressant actions
Brown, K. A., & Gould, T. D. (2024) · Molecular Psychiatry · doi:10.1038/s41380-023-02397-1 · Cited by 49 · see citing works
Höflich, A., Kraus, C., Pfeiffer, R. M., Seiger, R., Rujescu, D., Zarate, C. A., Kasper, S., Winkler, D., & Lanzenberger, R. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01318-6 · Cited by 34 · see citing works
Chou, D. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108068 · Cited by 29 · see citing works
Anderzhanova, E., Hafner, K., Genewsky, A. J., Soliman, A., Pöhlmann, M. L., Schmidt, M. V., Blum, R., Wotjak, C. T., & Gassen, N. C. (2020) · Neurobiology of Stress · doi:10.1016/j.ynstr.2020.100239 · Cited by 29 · see citing works
Pharmacological evaluation of clinically relevant concentrations of (2R,6R)-hydroxynorketamine
Shaffer, C. L., Dutra, J. K., Tseng, W. C., Weber, M. L., Bogart, L. J., Hales, K., Pang, J., Volfson, D., am Ende, C. W., Green, M. E., et al. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.04.019 · Cited by 28 · see citing works
Ketamine Metabolite (2<i>R</i>,6<i>R</i>)-Hydroxynorketamine Interacts with μ and κ Opioid Receptors
Joseph, T. T., Bu, W., Lin, W., Zoubak, L., Yeliseev, A., Liu, R., Eckenhoff, R. G., & Brannigan, G. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00741 · Cited by 28 · see citing works
Self-citationNV-5138 as a fast-acting antidepressant via direct activation of mTORC1 signaling
Hasegawa, Y., Zhu, X., & Kamiya, A. (2019) · Journal of Clinical Investigation · doi:10.1172/jci129702 · Cited by 20 · see citing works
- Authors
- Fukumoto, K., Fogaça, M. V., Liu, R.-J., Duman, C., Kato, T., Li, X.-Y., & Duman, R. S.
- Affiliations
- Taisho Pharmaceutical (Japan) (JP)
- Department of Psychiatry, Yale School of Medicine, New Haven, CT 06520;
- Yale University (US)
- Sumitomo Dainippon Pharma (Japan) (JP)
- Corresponding author
- Duman, Ronald S.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-12-17
- Volume
- 116
- Issue
- 1
- Pages
- 297-302
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6320534
- OpenAlex
- W2903713826
- Cited by
- 188
- References
- 59
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 22 · 2023: 22 · 2022: 32 · 2021: 37 · 2020: 24 · 2019: 24
- FWCI
- 13.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Mental Health (MH093897, MH105910)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- (2R,6R)-hydroxynorketamine, ketamine metabolites, antidepressant effects, brain-derived neurotrophic factor, voltage-gated calcium channels, TrkB signaling, mTORC1 signaling, medial prefrontal cortex, pyramidal neurons, synaptic function, stress and depression, depression
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Antidepressive Agents, Cells, Cultured, Depression, Disease Models, Animal, Dose-Response Relationship, Drug, Ketamine, Synaptic Transmission, Neurons, Signal Transduction, Brain-Derived Neurotrophic Factor
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 ›
Are you an author, or do you see a problem with this page? Request a review
