Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64.
Article CAS PubMed Google Scholar
Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74:250–56.
Article CAS PubMed Google Scholar
Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2020;25:1592–603.
Article CAS PubMed Google Scholar
Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharm Rev. 2018;70:621–60.
Article CAS PubMed PubMed Central Google Scholar
Kim J-W, Suzuki K, Kavalali ET, Monteggia LM. Bridging rapid and sustained antidepressant effects of ketamine. Trends Mol Med. 2023;29:364–75.
Article CAS PubMed PubMed Central Google Scholar
Brown KA, Gould TD. Targeting metaplasticity mechanisms to promote sustained antidepressant actions. Mol Psychiatry. 2024:29:1114–27.
Krystal JH, Kaye AP, Jefferson S, Girgenti MJ, Wilkinson ST, Sanacora G, et al. Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments. Proc Natl Acad Sci USA. 2023;120:e2305772120.
Article CAS PubMed PubMed Central Google Scholar
Abdallah CG, De Feyter HM, Averill LA, Jiang L, Averill CL, Chowdhury GM, et al. The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. Neuropsychopharmacology. 2018;43:2154–60.
Article CAS PubMed PubMed Central Google Scholar
Esterlis I, DellaGioia N, Pietrzak RH, Matuskey D, Nabulsi N, Abdallah CG, et al. Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C] ABP688 and PET imaging study in depression. Mol Psychiatry. 2018;23:824–32.
Article CAS PubMed Google Scholar
Chowdhury GM, Zhang J, Thomas M, Banasr M, Ma X, Pittman B, et al. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol Psychiatry. 2017;22:120–26.
Article CAS PubMed Google Scholar
Lorrain D, Baccei C, Bristow L, Anderson J, Varney M. Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience. 2003;117:697–706.
Article CAS PubMed Google Scholar
Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17:2921–27.
Article CAS PubMed PubMed Central Google Scholar
Zanos P, Gould T. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23:801–11.
Article CAS PubMed PubMed Central Google Scholar
Duman RS. Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections. Dialogues Clin Neurosci. 2014;16:11–27.
Article PubMed PubMed Central Google Scholar
Kavalali ET, Monteggia LM. Rapid homeostatic plasticity and neuropsychiatric therapeutics. Neuropsychopharmacology. 2023;48:54–60.
Chen M, Ma S, Liu H, Dong Y, Tang J, Ni Z, et al. Brain region–specific action of ketamine as a rapid antidepressant. Science. 2024;385:eado7010.
Article CAS PubMed PubMed Central Google Scholar
Ma S, Chen M, Jiang Y, Xiang X, Wang S, Wu Z, et al. Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb. Nature. 2023;622:802–09.
Article CAS PubMed PubMed Central Google Scholar
Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018;554:317–22.
Article CAS PubMed Google Scholar
Gould TD, Zarate CA Jr., Thompson SM. Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants. Annu Rev Pharm Toxicol. 2019;59:213–36.
Highland JN, Zanos P, Riggs LM, Georgiou P, Clark SM, Morris PJ, et al. Hydroxynorketamines: pharmacology and potential therapeutic applications. Pharm Rev. 2021;73:763–91.
Article CAS PubMed PubMed Central Google Scholar
Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6.
Article CAS PubMed PubMed Central Google Scholar
Raja SM, Guptill JT, Mack M, Peterson M, Byard S, Twieg R, et al. A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2 R, 6 R)‐Hydroxynorketamine in Healthy Volunteers. Clin Pharmacol Ther. 2024;116:1314–24.
Zanos P, Highland JN, Stewart BW, Georgiou P, Jenne CE, Lovett J, et al. (2R, 6R)-hydroxynorketamine exerts mGlu2 receptor-dependent antidepressant actions. Proc Natl Acad Sci USA. 2019;116:6441–50.
Dutheil F, Dauchy S, Diry M, Sazdovitch V, Cloarec O, Mellottée L, et al. Xenobiotic-metabolizing enzymes and transporters in the normal human brain: regional and cellular mapping as a basis for putative roles in cerebral function. Drug Metab Disposition. 2009;37:1528–38.
Brown KA, Zanos P, Powels CF, Fix CJ, Michaelides M, Pereira EF, et al. Ketamine preservative benzethonium chloride potentiates hippocampal synaptic transmission and binds neurotransmitter receptors and transporters. Neuropharmacology. 2023;225:109403.
Riggs LM, Aracava Y, Zanos P, Fischell J, Albuquerque EX, Pereira EFR, et al. (2R,6R)-hydroxynorketamine rapidly potentiates hippocampal glutamatergic transmission through a synapse-specific presynaptic mechanism. Neuropsychopharmacology. 2020;45:426–36.
Riggs LM, Thompson SM, Gould TD. (2R, 6R)-hydroxynorketamine rapidly potentiates optically-evoked Schaffer collateral synaptic activity. Neuropharmacology. 2022:109153.
Georgiou P, Zanos P, Mou T-CM, An X, Gerhard DM, Dryanovski DI, et al. Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor. Nat Neurosci. 2022;25:1191–200.
Article CAS PubMed PubMed Central Google Scholar
Brown KA, Carpenter JM, Preston CJ, Ludwig HD, Clay KB, Harn DA, et al. Lacto-N-fucopentaose-III ameliorates acute and persisting hippocampal synaptic plasticity and transmission deficits in a Gulf War Illness mouse model. Life Sci. 2021;279:119707.
Article CAS PubMed Google Scholar
Zanos P, Brown KA, Georgiou P, Yuan P, Zarate CA, Thompson SM, et al. NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine. J Neurosci. 2023;43:1038–50.
Article CAS PubMed PubMed Central Google Scholar
Thompson SM. Plasticity of synapses and reward circuit function in the genesis and treatment of depression. Neuropsychopharmacology. 2023;48:90–103.
Lumsden EW, Troppoli TA, Myers SJ, Zanos P, Aracava Y, Kehr J, et al. Antidepressant-relevant concentrations of the ketamine metabolite (2 R, 6 R)-hydroxynorketamine do not block NMDA receptor function. Proc Natl Acad Sci USA. 2019;116:5160–69.
Article CAS PubMed PubMed Central Google Scholar
Highland JN, Morris PJ, Konrath KM, Riggs LM, Hagen NR, Zanos P, et al. Hydroxynorketamine Pharmacokinetics and Antidepressant Behavioral Effects of (2, 6)-and (5 R)-Methyl-(2 R, 6 R)-hydroxynorketamines. ACS Chem Neurosci. 2022;13:510–23.
Article CAS PubMed Google Scholar
Zanos P, Highland JN, Liu X, Troppoli TA, Georgiou P, Lovett J, et al. (R)‐Ketamine exerts antidepressant actions partly via conversion to (2R, 6R)‐hydroxynorketamine, while causing adverse effects at sub‐anaesthetic doses. Br J Pharmacol. 2019;176:2573–92.
Highland JN, Morris PJ, Zanos P, Lovett J, Ghosh S, Wang AQ, et al. Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R, 6R)-hydroxynorketamine. J Psychopharmacol. 2019;33:12–24.
Article CAS PubMed Google Scholar
Riggs LM, Pereira EF, Thompson SM, Gould TD. cAMP-dependent protein kinase signaling is required for (2R, 6R)-hydroxynorketamine to potentiate hippocampal glutamatergic transmission. J Neurophysiol. 2024;131:64–74.
Comments (0)