Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions. Although this finding has been met with enthusiasm, ketamine’s widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine’s antidepressant actions but lack its undesirable effects. Here we review hypotheses for the mechanism of action of ketamine as an antidepressant, including synaptic or GluN2B-selective extra-synaptic N-methyl-D-aspartate receptor (NMDAR) inhibition, inhibition of NMDARs localized on GABAergic interneurons, inhibition of NMDAR-dependent burst firing of lateral habenula neurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor activation. We also discuss links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine’s (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine’s action are not mutually exclusive and may act in a complementary manner to exert acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine’s antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression.
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289: 3095–3105.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163: 1905–1917.
Insel TR, Wang PS . The STAR*D trial: revealing the need for better treatments. Psychiatr Serv 2009; 60: 1466–1467.
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47: 351–354.
Zarate CA Jr., 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: 856–864.
Price RB, Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK, Iqbal SZ et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress Anxiety 2014; 31: 335–343.
DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry 2010; 71: 1605–1611.
Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry 2014; 76: 970–976.
Maeng S, Zarate CA Jr., Du J, Schloesser RJ, McCammon J, Chen G et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 2008; 63: 349–352.
Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011; 475: 91–95.
Li N, Liu R-J, Dwyer JM, Banasr M, Lee B, Son H et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011; 69: 754–761.
Poleszak E, Wlaz P, Szewczyk B, Wlaz A, Kasperek R, Wrobel A et al. A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice. J Neural Transm 2011; 118: 1535–1546.
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: 481–486.
Zanos P, Piantadosi SC, Wu HQ, Pribut HJ, Dell MJ, Can A et al. The prodrug 4-chlorokynurenine causes ketamine-like antidepressant effects, but not side effects, by NMDA/glycineB-site inhibition. J Pharmacol Exp Ther 2015; 355: 76–85.
Zanos P, Gould TD . Convergent mechanisms underlying rapid antidepressant action. CNS Drugs 2018; In Press. doi: https://doi.org/10.1007/s40263-018-0492-x.
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199–214.
Marland S, Ellerton J, Andolfatto G, Strapazzon G, Thomassen O, Brandner B et al. Ketamine: use in anesthesia. CNS Neurosci Ther 2013; 19: 381–389.
Singh JB, Fedgchin M, Daly E, Xi L, Melman C, De Bruecker G et al. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol Psychiatry 2016; 80: 424–431.
Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013; 170: 1134–1142.
Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010; 67: 793–802.
Zarate CA Jr., Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A et al. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry 2012; 71: 939–946.
Jick H, Kaye JA, Jick SS . Antidepressants and the risk of suicidal behaviors. JAMA 2004; 292: 338–343.
Price RB, Nock MK, Charney DS, Mathew SJ . Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry 2009; 66: 522–526.
Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM, Luckenbaugh DA et al. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J Psychiatr Res 2014; 58: 161–166.
Ballard ED, Wills K, Lally N, Richards EM, Luckenbaugh DA, Walls T et al. Anhedonia as a clinical correlate of suicidal thoughts in clinical ketamine trials. J Affect Disord 2017; 218: 195–200.
Lally N, Nugent AC, Luckenbaugh DA, Niciu MJ, Roiser JP, Zarate CA Jr . Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J Psychopharmacol 2015; 29: 596–607.
Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA . Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry 2014; 4: e469.
Vyklicky V, Korinek M, Smejkalova T, Balik A, Krausova B, Kaniakova M et al. Structure, function, and pharmacology of NMDA receptor channels. Physiol Res 2014; 63 (Suppl 1): S191–S203.
Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 2010; 62: 405–496.
Trullas R, Skolnick P . Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 1990; 185: 1–10.
Paul IA, Nowak G, Layer RT, Popik P, Skolnick P . Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments. J Pharmacol Exp Ther 1994; 269: 95–102.
Nowak G, Li Y, Paul IA . Adaptation of cortical but not hippocampal NMDA receptors after chronic citalopram treatment. Eur J Pharmacol 1996; 295: 75–85.
Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R . Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry 1996; 29: 23–26.
Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D . Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 1997; 154: 805–811.
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: 2921–2927.
Homayoun H, Moghaddam B . NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 2007; 27: 11496–11500.
Farber NB, Newcomer JW, Olney JW . The glutamate synapse in neuropsychiatric disorders. Focus on schizophrenia and Alzheimer’s disease. Prog Brain Res 1998; 116: 421–437.
Neske GT, Patrick SL, Connors BW . Contributions of diverse excitatory and inhibitory neurons to recurrent network activity in cerebral cortex. J Neurosci 2015; 35: 1089–1105.
Seamans J . Losing inhibition with ketamine. Nat Chem Biol 2008; 4: 91–93.
Kotermanski SE, Johnson JW . Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer’s drug memantine. J Neurosci 2009; 29: 2774–2779.
Khlestova E, Johnson JW, Krystal JH, Lisman J . The Role of GluN2C-Containing NMDA Receptors in Ketamine’s Psychotogenic Action and in Schizophrenia Models. J Neurosci 2016; 36: 11151–11157.
Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH . Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 1994; 12: 529–540.
Perszyk RE, DiRaddo JO, Strong KL, Low CM, Ogden KK, Khatri A et al. GluN2D-Containing N-methyl-d-Aspartate Receptors Mediate Synaptic Transmission in Hippocampal Interneurons and Regulate Interneuron Activity. Mol Pharmacol 2016; 90: 689–702.
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: 120–126.
Towers SK, Gloveli T, Traub RD, Driver JE, Engel D, Fradley R et al. Alpha 5 subunit-containing GABAA receptors affect the dynamic range of mouse hippocampal kainate-induced gamma frequency oscillations in vitro. J Physiol 2004; 559 (Pt 3): 721–728.
Fischell J, Van Dyke AM, Kvarta MD, LeGates TA, Thompson SM . Rapid antidepressant action and restoration of excitatory synaptic strength after chronic stress by negative modulators of alpha5-containing GABAA receptors. Neuropsychopharmacology 2015; 40: 2499–2509.
Zanos P, Nelson ME, Highland JN, Krimmel SR, Georgiou P, Gould TD et al. A negative allosteric modulator for alpha5 subunit-containing GABA Receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in mice. eneuro 2017; 4 doi: 10.1523/ENEURO.0285-16.2017).
Carreno FR, Collins GT, Frazer A, Lodge DJ . Selective pharmacological augmentation of hippocampal activity produces a sustained antidepressant-like response without abuse-related or psychotomimetic effects. Int J Neuropsychopharmacol 2017; 20: 504–509.
Pinault D . N-methyl d-aspartate receptor antagonists ketamine and MK-801 induce wake-related aberrant gamma oscillations in the rat neocortex. Biol Psychiatry 2008; 63: 730–735.
Hong LE, Summerfelt A, Buchanan RW, O'Donnell P, Thaker GK, Weiler MA et al. Gamma and delta neural oscillations and association with clinical symptoms under subanesthetic ketamine. Neuropsychopharmacology 2010; 35: 632–640.
Ehrlichman RS, Gandal MJ, Maxwell CR, Lazarewicz MT, Finkel LH, Contreras D et al. N-methyl-d-aspartic acid receptor antagonist-induced frequency oscillations in mice recreate pattern of electrophysiological deficits in schizophrenia. Neuroscience 2009; 158: 705–712.
Caixeta FV, Cornelio AM, Scheffer-Teixeira R, Ribeiro S, Tort AB . Ketamine alters oscillatory coupling in the hippocampus. Sci Rep 2013; 3: 2348.
Ren Z, Pribiag H, Jefferson SJ, Shorey M, Fuchs T, Stellwagen D et al. Bidirectional homeostatic regulation of a depression-related brain state by gamma-aminobutyric acidergic deficits and ketamine treatment. Biol Psychiatry 2016; 80: 457–468.
Fuchs T, Jefferson SJ, Hooper A, Yee P-HP, Maguire J, Luscher B . Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state. Mol Psychiatry 2017; 22: 920–930.
Frankowska M, Filip M, Przegalinski E . Effects of GABAB receptor ligands in animal tests of depression and anxiety. Pharmacol Rep 2007; 59: 645–655.
Slattery DA, Neumann ID, Cryan JF . Transient inactivation of the infralimbic cortex induces antidepressant-like effects in the rat. J Psychopharmacol 2011; 25: 1295–1303.
Pozzi L, Pollak Dorocic I, Wang X, Carlen M, Meletis K . Mice lacking NMDA receptors in parvalbumin neurons display normal depression-related behavior and response to antidepressant action of NMDAR antagonists. PLoS ONE 2014; 9: e83879.
Fatt P, Katz B . Spontaneous subthreshold activity at motor nerve endings. J Physiol 1952; 117: 109–128.
Heuser JE, Reese TS, Dennis MJ, Jan Y, Jan L, Evans L . Synaptic vesicle exocytosis captured by quick freezing and correlated with quantal transmitter release. J Cell Biol 1979; 81: 275–300.
Sutton MA, Wall NR, Aakalu GN, Schuman EM . Regulation of dendritic protein synthesis by miniature synaptic events. Science 2004; 304: 1979–1983.
Sutton MA, Ito HT, Cressy P, Kempf C, Woo JC, Schuman EM . Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis. Cell 2006; 125: 785–799.
Sutton MA, Taylor AM, Ito HT, Pham A, Schuman EM . Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis. Neuron 2007; 55: 648–661.
Nosyreva E, Szabla K, Autry AE, Ryazanov AG, Monteggia LM, Kavalali ET . Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J Neurosci 2013; 33: 6990–7002.
Gideons ES, Kavalali ET, Monteggia LM . Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc Natl Acad Sci USA 2014; 111: 8649–8654.
Zarate CA Jr., Singh JB, Quiroz JA, De Jesus G, Denicoff KK, Luckenbaugh DA et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry 2006; 163: 153–155.
Lenze EJ, Skidmore ER, Begley AE, Newcomer JW, Butters MA, Whyte EM . Memantine for late-life depression and apathy after a disabling medical event: a 12-week, double-blind placebo-controlled pilot study. Int J Geriatr Psychiatry 2012; 27: 974–980.
Ferguson JM, Shingleton RN . An open-label, flexible-dose study of memantine in major depressive disorder. Clin Neuropharmacol 2007; 30: 136–144.
Hardingham GE, Bading H . Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 2010; 11: 682–696.
Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996; 16: 675–686.
Guo H, Lai L, Butchbach ME, Stockinger MP, Shan X, Bishop GA et al. Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. Hum Mol Genet 2003; 12: 2519–2532.
Miller OH, Yang L, Wang CC, Hargroder EA, Zhang Y, Delpire E et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. Elife 2014; 3: e03581.
Wang CC, Held RG, Chang SC, Yang L, Delpire E, Ghosh A et al. A critical role for GluN2B-containing NMDA receptors in cortical development and function. Neuron 2011; 72: 789–805.
Wang CC, Held RG, Hall BJ . SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks. PLoS ONE 2013; 8: e83941.
Gray JA, Shi Y, Usui H, During MJ, Sakimura K, Nicoll RA . Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo. Neuron 2011; 71: 1085–1101.
Kiselycznyk C, Jury NJ, Halladay LR, Nakazawa K, Mishina M, Sprengel R et al. NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism. Behav Brain Res 2015; 287: 89–95.
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329: 959–964.
Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011; 69: 754–761.
Jimenez-Sanchez L, Campa L, Auberson YP, Adell A . The role of GluN2A and GluN2B subunits on the effects of NMDA receptor antagonists in modeling schizophrenia and treating refractory depression. Neuropsychopharmacology 2014; 39: 2673–2680.
Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW . An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 2008; 28: 631–637.
Hashimoto K . Comments on "An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606 in patients with treatment-refractory major depressive disorder". J Clin Psychopharmacol 2009; 29: 411–412, author reply 412.
Hashimoto K, London ED . Further characterization of [3H]ifenprodil binding to sigma receptors in rat brain. Eur J Pharmacol 1993; 236: 159–163.
Hashimoto K, Ishiwata K . Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals. Curr Pharm Des 2006; 12: 3857–3876.
Stahl SM . The sigma enigma: can sigma receptors provide a novel target for disorders of mood and cognition? J Clin Psychiatry 2008; 69: 1673–1674.
Hashimoto K . Sigma-1 receptors and selective serotonin reuptake inhibitors: clinical implications of their relationship. Cent Nerv Syst Agents Med Chem 2009; 9: 197–204.
Ibrahim L, Diaz Granados N, Jolkovsky L, Brutsche N, Luckenbaugh DA, Herring WJ et al. A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. J Clin Psychopharmacol 2012; 32: 551–557.
Sanacora G . What are we learning from early-phase clinical trials with glutamate targeting medications for the treatment of major depressive disorder. JAMA Psychiatry 2016; 73: 651–652.
Sutherland RJ . The dorsal diencephalic conduction system: a review of the anatomy and functions of the habenular complex. Neurosci Biobehav Rev 1982; 6: 1–13.
Boulos LJ, Darcq E, Kieffer BL . Translating the Habenula-From Rodents to Humans. Biol Psychiatry 81: 296–305.
Hikosaka O . The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci 2010; 11: 503–513.
Wang D, Li Y, Feng Q, Guo Q, Zhou J, Luo M . Learning shapes the aversion and reward responses of lateral habenula neurons. Elife 6.
Ji H, Shepard PD . Lateral Habenula Stimulation Inhibits Rat Midbrain Dopamine Neurons through a GABAA Receptor-Mediated Mechanism. The Journal of Neuroscience 2007; 27: 6923–6930.
Brown PL, Palacorolla H, Brady D, Riegger K, Elmer GI, Shepard PD . Habenula-Induced Inhibition of Midbrain Dopamine Neurons Is Diminished by Lesions of the Rostromedial Tegmental Nucleus. J Neurosci 2017; 37: 217–225.
Jhou TC, Geisler S, Marinelli M, Degarmo BA, Zahm DS . The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta. J Comp Neurol 2009/02/24 edn, 5132009: 566–596.
Yang Y, Wang H, Hu J, Hu H . Lateral habenula in the pathophysiology of depression. Curr Opin Neurobiol 2017; 48: 90–96.
Cui Y, Yang Y, Ni Z, Dong Y, Cai G, Foncelle A et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature 2018; 554: 323–327.
Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 2011; 470: 535–539.
Lawson RP, Nord CL, Seymour B, Thomas DL, Dayan P, Pilling S et al. Disrupted habenula function in major depression. Mol Psychiatry 2017; 22: 202–208.
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: 317–322.
Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB . Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry 2015; 172: 950–966.
Zarate CA Jr., Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I et al. A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biol Psychiatry 2013; 74: 257–264.
Sanacora G, Smith MA, Pathak S, Su HL, Boeijinga PH, McCarthy DJ et al. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol Psychiatry 2014; 19: 978–985.
Sanacora G, Johnson MR, Khan A, Atkinson SD, Riesenberg RR, Schronen JP et al. Adjunctive lanicemine (AZD6765) in patients with major depressive disorder and history of inadequate response to antidepressants: a randomized, placebo-controlled study. Neuropsychopharmacology 2017; 42: 844–853.
Yang B, Ren Q, Ma M, Chen QX, Hashimoto K . Antidepressant effects of (+)-MK-801 and (-)-MK-801 in the social defeat stress model. Int J Neuropsychopharmacol 2016; 19: 1–5.
Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC et al. A randomized add-on trial of high-dose D-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol 2013; 16: 501–506.
Moskal JR, Burgdorf JS, Stanton PK, Kroes RA, Disterhoft JF, Burch RM et al. The development of rapastinel (Formerly GLYX-13); a rapid acting and long lasting antidepressant. Curr Neuropharmacol 2017; 15: 47–56.
Yang B, Zhang JC, Han M, Yao W, Yang C, Ren Q et al. Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression. Psychopharmacology (Berl) 2016; 233: 3647–3657.
Burgdorf J, Zhang X-l, Weiss C, Gross A, Boikess SR, Kroes RA et al. The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus. Neuroscience 2015; 308: 202–211.
Liu RJ, Duman C, Kato T, Hare B, Lopresto D, Bang E et al. GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. Neuropsychopharmacology 2017; 42: 1231–1242.
Burgdorf J, Zhang XL, Nicholson KL, Balster RL, Leander JD, Stanton PK et al. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology 2013; 38: 729–742.
Rajagopal L, Burgdorf JS, Moskal JR, Meltzer HY . GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice. Behav Brain Res 2016; 299: 105–110.
Morris PJ, Moaddel R, Zanos P, Moore CE, Gould T, Zarate CA et al. Synthesis and N-methyl-d-aspartate (NMDA) receptor activity of ketamine metabolites. Org Lett 2017; 19: 4572–4575.
Moaddel R, Abdrakhmanova G, Kozak J, Jozwiak K, Toll L, Jimenez L et al. Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in alpha7 nicotinic acetylcholine receptors. Eur J Pharmacol 2013; 698: 228–234.
Kohrs R, Durieux ME . Ketamine: teaching an old drug new tricks. Anesth Analg 1998; 87: 1186–1193.
Ebert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM . Norketamine the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol 1997; 333: 99–104.
Domino EF . Taming the ketamine tiger. 1965. Anesthesiology 2010; 113: 678–684.
Zhang JC, Li SX, Hashimoto K . R(-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacol Biochem Behav 2014; 116: 137–141.
Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M et al. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry 2015; 5: e632.
Fukumoto K, Toki H, Iijima M, Hashihayata T, Yamaguchi J-i, Hashimoto K et al. Antidepressant potential of (R)-ketamine in rodent models: comparison with (S)-ketamine. J Pharmacol Exp Ther 2017; 361: 9–16.
Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. AMA Psychiatry 2017.
Zarate CA Jr., Brutsche N, Laje G, Luckenbaugh DA, Venkata SL, Ramamoorthy A et al. Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression. Biol Psychiatry 2012; 72: 331–338.
Zanos P, Moaddel R, Morris PJ, Wainer IW, Albuquerque EX, Thompson SM et al. Reply to: Antidepressant actions of ketamine versus hydroxynorketamine. Biol Psychiatry 2017; 81: e69–e71.
Leung LY, Baillie TA . Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine. J Med Chem 1986; 29: 2396–2399.
Singh NS, Zarate CA Jr., Moaddel R, Bernier M, Wainer IW . What is hydroxynorketamine and what can it bring to neurotherapeutics? Expert Rev Neurother 2014; 14: 1239–1242.
Carrier N, Kabbaj M . Sex differences in the antidepressant-like effects of ketamine. Neuropharmacology 2013; 70: 27–34.
Sarkar A, Kabbaj M . Sex differences in effects of ketamine on behavior, spine density, and synaptic proteins in socially isolated rats. Biol Psychiatry 2016; 80: 448–456.
Pham TH, Defaix C, Xu X, Deng S-X, Fabresse N, Alvarez J-C et al. Common neurotransmission recruited in (R,S)-ketamine and (2R,6R)-hydroxynorketamine–induced sustained antidepressant-like effects. Biological psychiatry 2017 In press.
Fukumoto K, Toki H, Iijima M, Hashihayata T, Yamaguchi J-i, Hashimoto K et al. Antidepressant potential of (R)-ketamine in rodent models: comparison with (S)-ketamine. J Pharmacol Exp Ther 2017.
Yang C, Qu Y, Abe M, Nozawa D, Chaki S, Hashimoto K . R)-Ketamine shows greater potency and longer lasting antidepressant effects than its metabolite (2R,6R)-hydroxynorketamine. Biol Psychiatry 2017; 82: e43–e44.
Suzuki K, Nosyreva E, Hunt KW, Kavalali ET, Monteggia LM . Effects of a ketamine metabolite on synaptic NMDAR function. Nature 2017; 546: E1–E3.
Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI et al. Reply to: Effects of a ketamine metabolite on synaptic NMDAR function. Nature 2017; 546: E4–E5.
Derkach VA, Oh MC, Guire ES, Soderling TR . Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat Rev Neurosci 2007; 8: 101–113.
Henley JM, Wilkinson KA . Synaptic AMPA receptor composition in development, plasticity and disease. Nat Rev Neurosci 2016; 17: 337–350.
Citri A, Malenka RC . Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology 2008; 33: 18–41.
Duman RS, Aghajanian GK, Sanacora G, Krystal JH . Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 2016; 22: 238–249.
Kocsis B . Differential role of NR2A and NR2B subunits in NMDA receptor antagonist-induced aberrant cortical gamma oscillations. Biol Psychiatry 2012; 71: 987–995.
Whittington MA, Traub RD, Kopell N, Ermentrout B, Buhl EH . Inhibition-based rhythms: experimental and mathematical observations on network dynamics. Int J Psychophysiol 2000; 38: 315–336.
Cunningham MO, Davies CH, Buhl EH, Kopell N, Whittington MA . Gamma oscillations induced by kainate receptor activation in the entorhinal cortex in vitro. J Neurosci 2003; 23: 9761–9769.
Muthukumaraswamy SD, Shaw AD, Jackson LE, Hall J, Moran R, Saxena N . Evidence that subanesthetic doses of ketamine cause sustained disruptions of NMDA and AMPA-mediated frontoparietal connectivity in humans. J Neurosci 2015; 35: 11694–11706.
Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ . Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry 2014; 29: 419–423.
Koike H, Chaki S . Requirement of AMPA receptor stimulation for the sustained antidepressant activity of ketamine and LY341495 during the forced swim test in rats. Behav Brain Res 2014; 271: 111–115.
Koike H, Iijima M, Chaki S . Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 2011; 224: 107–111.
Fukumoto K, Iijima M, Chaki S . Serotonin-1A receptor stimulation mediates effects of a metabotropic glutamate 2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and an N-methyl-D-aspartate receptor antagonist, ketamine, in the novelty-suppressed feeding test. Psychopharmacology (Berl) 2014; 231: 2291–2298.
Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B et al. NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology 2013; 38: 1609–1616.
Wolak M, Siwek A, Szewczyk B, Poleszak E, Pilc A, Popik P et al. Involvement of NMDA and AMPA receptors in the antidepressant-like activity of antidepressant drugs in the forced swim test. Pharmacol Rep 2013; 65: 991–997.
Bjorkholm C, Jardemark K, Schilstrom B, Svensson TH . Ketamine-like effects of a combination of olanzapine and fluoxetine on AMPA and NMDA receptor-mediated transmission in the medial prefrontal cortex of the rat. Eur Neuropsychopharmacol 2015; 25: 1842–1847.
El Iskandrani KS, Oosterhof CA, El Mansari M, Blier P . Impact of subanesthetic doses of ketamine on AMPA-mediated responses in rats: an in vivo electrophysiological study on monoaminergic and glutamatergic neurons. J Psychopharmacol 2015; 29: 792–801.
Zhang K, Xu T, Yuan Z, Wei Z, Yamaki VN, Huang M et al. Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine. Sci Signal 2016; 9: ra123.
Nosyreva E, Autry AE, Kavalali ET, Monteggia LM . Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade. Front Mol Neurosci 2014; 7: 94.
Autry AE, Monteggia LM . Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 2012; 64: 238–258.
Castren E, Kojima M . Brain-derived neurotrophic factor in mood disorders and antidepressant treatments. Neurobiol Dis 2017; 97, (Pt B) 119–126.
Castrén E, Võikar V, Rantamäki T . Role of neurotrophic factors in depression. Curr Opin Pharmacol 2007; 7: 18–21.
Lindholm JSO, Castrén E . Mice with altered BDNF signaling as models for mood disorders and antidepressant effects. Front Behav Neurosci 2014; 8: 143.
Hoshaw BA, Malberg JE, Lucki I . Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects. Brain Res 2005; 1037: 204–208.
Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS . Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 2002; 22: 3251–3261.
Schmidt HD, Duman RS . Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology 2010; 35: 2378–2391.
Taliaz D, Loya A, Gersner R, Haramati S, Chen A, Zangen A . Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor. J Neurosci 2011; 31: 4475–4483.
Rantamaki T, Hendolin P, Kankaanpaa A, Mijatovic J, Piepponen P, Domenici E et al. Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain. Neuropsychopharmacology 2007; 32: 2152–2162.
Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 2003; 23: 349–357.
Bjorkholm C, Monteggia LM . BDNF - a key transducer of antidepressant effects. Neuropharmacology 2016; 102: 72–79.
Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM, Andreazza AC et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 140–144.
Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS . BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol 2014; 18: 1.
Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 2006; 314: 140–143.
Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK . Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 2012; 71: 996–1005.
Laje G, Lally N, Mathews D, Brutsche N, Chemerinski A, Akula N et al. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol Psychiatry 2012; 72: e27–e28.
Taha E, Gildish I, Gal-Ben-Ari S, Rosenblum K . The role of eEF2 pathway in learning and synaptic plasticity. Neurobiol Learn Mem 2013; 105: 100–106.
Chotiner JK, Khorasani H, Nairn AC, O'Dell TJ, Watson JB . Adenylyl cyclase-dependent form of chemical long-term potentiation triggers translational regulation at the elongation step. Neuroscience 2003; 116: 743–752.
Park S, Park JM, Kim S, Kim JA, Shepherd JD, Smith-Hicks CL et al. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 2008; 59: 70–83.
Taha E, Gildish I, Gal-Ben-Ari S, Rosenblum K . The role of eEF2 pathway in learning and synaptic plasticity. Neurobiol Learn Mem 2013; 105: 100–106.
Browne GJ, Proud CG . A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. Mol Cell Biol 2004; 24: 2986–2997.
Redpath NT, Foulstone EJ, Proud CG . Regulation of translation elongation factor-2 by insulin via a rapamycin-sensitive signalling pathway. EMBO J 1996; 15: 2291–2297.
Reichardt LF . Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 2006; 361: 1545–1564.
Yoshii A, Constantine-Paton M . Post-synaptic BDNF-TrkB signaling in synapse maturation, plasticity and disease. Dev Neurobiol 2010; 70: 304–322.
Duman RS, Li N, Liu RJ, Duric V, Aghajanian G . Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 2012; 62: 35–41.
Hay N, Sonenberg N . Upstream and downstream of mTOR. Genes Dev 2004; 18: 1926–1945.
Hoeffer CA, Klann E . mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 2010; 33: 67–75.
Park SW, Lee JG, Seo MK, Lee CH, Cho HY, Lee BJ et al. Differential effects of antidepressant drugs on mTOR signalling in rat hippocampal neurons. Int J Neuropsychopharmacol 2014; 17: 1831–1846.
Paul RK, Singh NS, Khadeer M, Moaddel R, Sanghvi M, Green CE et al. (R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin (mTOR) function. Anesthesiology 2014; 121: 149–159.
Yang C, Hu YM, Zhou ZQ, Zhang GF, Yang JJ . Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test. Ups J Med Sci 2013; 118: 3–8.
Zhang K, Yamaki VN, Wei Z, Zheng Y, Cai X . Differential regulation of GluA1 expression by ketamine and memantine. Behav Brain Res 2017; 316: 152–159.
Popp S, Behl B, Joshi JJ, Lanz TA, Spedding M, Schenker E et al. In search of the mechanisms of ketamine’s antidepressant effects: how robust is the evidence behind the mTor activation hypothesis. F1000Research 2016; 5: 634.
Murrough JW . Ketamine for depression: an update. Biol Psychiatry 2016; 80: 416–418.
Zanos P, Gould TD . Intracellular Signaling Pathways Involved in (S)- and (R)-Ketamine Antidepressant Actions. Biol Psychiatry 2018; 83: 2–4.
Holubova K, Kleteckova L, Skurlova M, Ricny J, Stuchlik A, Vales K . Rapamycin blocks the antidepressant effect of ketamine in task-dependent manner. Psychopharmacology (Berl) 2016; 233: 2077–2097.
Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 2006; 126: 955–968.
Jin T, George Fantus I, Sun J . Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of beta-catenin. Cell Signal 2008; 20: 1697–1704.
Beurel E, Song L, Jope RS . Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry 2011; 16: 1068–1070.
Liu R-J, Fuchikami M, Dwyer JM, Lepack AE, Duman RS, Aghajanian GK . GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology 2013; 38: 2268–2277.
Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA . Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995; 378: 785–789.
Zhou W, Dong L, Wang N, Shi JY, Yang JJ, Zuo ZY et al. Akt mediates GSK-3beta phosphorylation in the rat prefrontal cortex during the process of ketamine exerting rapid antidepressant actions. Neuroimmunomodulation 2014; 21: 183–188.
Thompson SM, Kallarackal AJ, Kvarta MD, Van Dyke AM, LeGates TA, Cai X . An excitatory synapse hypothesis of depression. Trends Neurosci 2015; 38: 279–294.
Witkin JM, Monn JA, Schoepp DD, Li X, Overshiner C, Mitchell SN et al. The rapidly acting antidepressant ketamine and the mGlu2/3 receptor antagonist LY341495 rapidly engage dopaminergic mood circuits. J Pharmacol Exp Ther 2016; 358: 71–82.
Li Y, Zhu ZR, Ou BC, Wang YQ, Tan ZB, Deng CM et al. Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim test. Behav Brain Res 2015; 279: 100–105.
Gigliucci V, O'Dowd G, Casey S, Egan D, Gibney S, Harkin A . Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism. Psychopharmacology (Berl) 2013; 228: 157–166.
Can A, Zanos P, Moaddel R, Kang HJ, Dossou KS, Wainer IW et al. Effects of ketamine and ketamine metabolites on evoked striatal dopamine release, dopamine receptors, and monoamine transporters. J Pharmacol Exp Ther 2016; 359: 159–170.
Sleigh J, Harvey M, Voss L, Denny B . Ketamine–more mechanisms of action than just NMDA blockade. Trends Anaesth Crit Care 2014; 4: 76–81.
Loix S, De Kock M, Henin P . The anti-inflammatory effects of ketamine: state of the art. Acta Anaesthesiol Belg 2011; 62: 47–58.
Bowdle TA, Radant AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP . Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations. Anesthesiology 1998; 88: 82–88.
Pomarol-Clotet E, Honey GD, Murray GK, Corlett PR, Absalom AR, Lee M et al. Psychological effects of ketamine in healthy volunteers. Phenomenological study. Br J Psychiatry 2006; 189: 173–179.
Coull JT, Morgan H, Cambridge VC, Moore JW, Giorlando F, Adapa R et al. Ketamine perturbs perception of the flow of time in healthy volunteers. Psychopharmacology (Berl) 2011; 218: 543–556.
Kalsi SS, Wood DM, Dargan PI . The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use. Emerg Health Threats J 2011; 4: 7107.
Wolff K, Winstock AR . Ketamine: from medicine to misuse. CNS Drugs 2006; 20: 199–218.
This is supported by an NIH grant MH107615 and a Harrington Discovery Institute Scholar-Innovator grant to TDG. We thank Dr. Paul Shepard for reviewing the LHb text section and Ms. Jaclyn Highland for proof-reading the manuscript.
PZ and TDG are listed as co-authors in a patent applications related to the pharmacology and use of (2S,6S)- and (2R,6R)-HNK in the treatment of depression, anxiety, anhedonia, suicidal ideation and post-traumatic stress disorders.
About this article
Cite this article
Zanos, P., Gould, T. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 23, 801–811 (2018). https://doi.org/10.1038/mp.2017.255
Journal of Biomedical Science (2021)
HDAC6 is critical for ketamine-induced impairment of dendritic and spine growth in GABAergic projection neurons
Acta Pharmacologica Sinica (2021)
Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine
Molecular Psychiatry (2021)
The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons
Molecular Psychiatry (2021)