1,367
Views
36
CrossRef citations to date
0
Altmetric
Review

An update on NMDA antagonists in depression

, &
Pages 1055-1067 | Received 19 Mar 2019, Accepted 10 Jul 2019, Published online: 22 Jul 2019

References

  • Reiner A, Levitz J. Glutamatergic signaling in the central nervous system: ionotropic and metabotropic receptors in concert. Neuron. 2018;98(6):1080–1098.
  • CT L, KC Y, Lin WC. Glutamatergic dysfunction and glutamatergic compounds for major psychiatric disorders: evidence from clinical neuroimaging studies. Front Psychiatry. 2018;9:767.
  • Ohgi Y, Futamura T, Hashimoto K. Glutamate signaling in synaptogenesis and NMDA receptors as potential therapeutic targets for psychiatric disorders. Curr Mol Med. 2015;15(3):206–221.
  • Javitt DC, Schoepp D, Kalivas PW, et al. Translating glutamate: from pathophysiology to treatment. Sci Transl Med. 2011;3(102):102mr102.
  • Ulbrich MH, Isacoff EY. Rules of engagement for NMDA receptor subunits. Proc Natl Acad Sci U S A. 2008;105(37):14163–14168.
  • Peyrovian B, Rosenblat JD, Pan Z, et al. The glycine site of NMDA receptors: A target for cognitive enhancement in psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2019;92:387–404.
  • Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990;185(1):1–10.
  • Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959–964.
  • Maeng S, Zarate CA Jr., Du J, 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(4):349–352.
  • Moryl E, Danysz W, Quack G. Potential antidepressive properties of amantadine, memantine and bifemelane. Toxicol Pharmacol. 1993;72(6):394–397.
  • Poleszak E, Szewczyk B, Kedzierska E, et al. Antidepressant- and anxiolytic-like activity of magnesium in mice. Pharmacol Biochem Behav. 2004;78(1):7–12.
  • Skolnick P, Kos T, Czekaj J, et al. Effect of NMDAR antagonists in the tetrabenazine test for antidepressants: comparison with the tail suspension test. Acta Neuropsychiatr. 2015;27(4):228–234.
  • Gordillo-Salas M, Pilar-Cuellar F, Auberson YP, et al. Signaling pathways responsible for the rapid antidepressant-like effects of a GluN2A-preferring NMDA receptor antagonist. Transl Psychiatry. 2018;8(1):84.
  • Jimenez-Sanchez L, Campa L, Auberson YP, et al. The role of GluN2A and GluN2B subunits on the effects of NMDA receptor antagonists in modeling schizophrenia and treating refractory depression. Neuropsychopharmacology. 2014;39(11):2673–2680.
  • Pochwat B, Rafalo-Ulinska A, Domin H, et al. Involvement of extracellular signal-regulated kinase (ERK) in the short and long-lasting antidepressant-like activity of NMDA receptor antagonists (zinc and Ro 25–6981) in the forced swim test in rats. Neuropharmacology. 2017;125:333–342.
  • Refsgaard LK, Pickering DS, Andreasen JT. Investigation of antidepressant-like and anxiolytic-like actions and cognitive and motor side effects of four N-methyl-D-aspartate receptor antagonists in mice. Behav Pharmacol. 2017;28(1):37–47.
  • Zanos P, Piantadosi SC, Wu HQ, 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(1):76–85.
  • Zhu WL, Wang SJ, Liu MM, et al. Glycine site N-methyl-D-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats. J Psychiatry Neurosci. 2013;38(5):306–316.
  • Manosso LM, Moretti M, Ribeiro CM, et al. Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation. Prog Neuropsychopharmacol Biol Psychiatry. 2015;59:59–67.
  • Satala G, Duszynska B, Stachowicz K, et al. Concentration-dependent dual mode of Zn action at serotonin 5-HT1A receptors: in vitro and in vivo studies. Mol Neurobiol. 2016;53(10):6869–6881.
  • Szewczyk B, Pochwat B, Rafalo A, et al. Activation of mTOR dependent signaling pathway is a necessary mechanism of antidepressant-like activity of zinc. Neuropharmacology. 2015;99:517–526.
  • Szewczyk B, Poleszak E, Sowa-Kucma M, et al. The involvement of NMDA and AMPA receptors in the mechanism of antidepressant-like action of zinc in the forced swim test. Amino Acids. 2010;39(1):205–217.
  • Popik P, Holuj M, Kos T, et al. Comparison of the psychopharmacological effects of tiletamine and ketamine in rodents. Neurotox Res. 2017;32(4):544–554.
  • Popik P, Kos T, Sowa-Kucma M, et al. Lack of persistent effects of ketamine in rodent models of depression. Psychopharmacology (Berl). 2008;198(3):421–430.
  • Autry AE, Adachi M, Nosyreva E, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475(7354):91–95.
  • Gideons ES, Kavalali ET, Monteggia LM. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc Natl Acad Sci U S A. 2014;111(23):8649–8654.
  • Pochwat B, Szewczyk B, Sowa-Kucma M, et al. Antidepressant-like activity of magnesium in the chronic mild stress model in rats: alterations in the NMDA receptor subunits. Int J Neuropsychopharmacol. 2014;17(3):393–405.
  • Quan MN, Zhang N, Wang YY, et al. Possible antidepressant effects and mechanisms of memantine in behaviors and synaptic plasticity of a depression rat model. Neuroscience. 2011;182:88–97.
  • Reus GZ, Abelaira HM, Stringari RB, et al. Memantine treatment reverses anhedonia, normalizes corticosterone levels and increases BDNF levels in the prefrontal cortex induced by chronic mild stress in rats. Metab Brain Dis. 2012;27(2):175–182.
  • Sowa-Kucma M, Legutko B, Szewczyk B, et al. Antidepressant-like activity of zinc: further behavioral and molecular evidence. J Neural Transm (Vienna). 2008;115(12):1621–1628.
  • Christiansen SH, Olesen MV, Wortwein G, et al. Fluoxetine reverts chronic restraint stress-induced depression-like behaviour and increases neuropeptide Y and galanin expression in mice. Behav Brain Res. 2011;216(2):585–591.
  • Grippo AJ, Beltz TG, Weiss RM, et al. The effects of chronic fluoxetine treatment on chronic mild stress-induced cardiovascular changes and anhedonia. Biol Psychiatry. 2006;59(4):309–316.
  • Nowak G, Szewczyk B, Wieronska JM, et al. Antidepressant-like effects of acute and chronic treatment with zinc in forced swim test and olfactory bulbectomy model in rats. Brain Res Bull. 2003;61(2):159–164.
  • Fukumoto K, Toki H, Iijima M, et al. Antidepressant potential of (R)-ketamine in rodent models: comparison with (S)-ketamine. J Pharmacol Exp Ther. 2017;361(1):9–16.
  • Li N, Liu RJ, Dwyer JM, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69(8):754–761.
  • Neis VB, Bettio LEB, Moretti M, et al. Acute agmatine administration, similar to ketamine, reverses depressive-like behavior induced by chronic unpredictable stress in mice. Pharmacol Biochem Behav. 2016;150–151:108–114.
  • Tan S, Wang Y, Chen K, et al. Ketamine alleviates depressive-like behaviors via down-regulating inflammatory cytokines induced by chronic restraint stress in mice. Biol Pharm Bull. 2017;40(8):1260–1267.
  • Zhang WJ, Wang HH, Lv YD, et al. Downregulation of Egr-1 expression level via GluN2B underlies the antidepressant effects of ketamine in a chronic unpredictable stress animal model of depression. Neuroscience. 2018;372:38–45.
  • Brachman RA, McGowan JC, Perusini JN, et al. Ketamine as a prophylactic against stress-induced depressive-like behavior. Biol Psychiatry. 2016;79(9):776–786.
  • Talbot JN, Geffert LM, Jorvig JE, et al. Rapid and sustained antidepressant properties of an NMDA antagonist/monoamine reuptake inhibitor identified via transporter-based virtual screening. Pharmacol Biochem Behav. 2016;150-151:22–30.
  • Pochwat B, Szewczyk B, Kotarska K, et al. Hyperforin potentiates antidepressant-like activity of lanicemine in mice. Front Mol Neurosci. 2018;11:456.
  • Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481–486.
  • Yang B, Ren Q, Ma M, et al. Antidepressant Effects of (+)-MK-801 and (-)-MK-801 in the social defeat stress model. Int J Neuropsychopharmacol. 2016;19:12.
  • Yang BK, Qin J, Nie Y, et al. Sustained antidepressant action of the N-methyl-D-aspartate receptor antagonist MK-801 in a chronic unpredictable mild stress model. Exp Ther Med. 2018;16(6):5376–5383.
  • Widman AJ, McMahon LL. Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. Proc Natl Acad Sci U S A. 2018;115(13):E3007–E3016.
  • Chowdhury GM, Zhang J, Thomas M, et al. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol Psychiatry. 2017;22(1):120–126.
  • Pham TH, Defaix C, Xu X, et al. Common neurotransmission recruited in (R,S)-ketamine and (2R,6R)-hydroxynorketamine-induced sustained antidepressant-like effects. Biol Psychiatry. 2018;84(1):e3–e6.
  • Zanos P, Thompson SM, Duman RS, et al. Convergent mechanisms underlying rapid antidepressant action. CNS Drugs. 2018;32(3):197–227.
  • Lepack AE, Fuchikami M, Dwyer JM, et al. BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol. 2014;18:1.
  • Lepack AE, Bang E, Lee B, et al. Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures. Neuropharmacology. 2016;111:242–252.
  • Workman ER, Niere F, Raab-Graham KF. mTORC1-dependent protein synthesis underlying rapid antidepressant effect requires GABABR signaling. Neuropharmacology. 2013;73:192–203.
  • Abdallah CA, Gueorguieva LA, Goktas R, et al. an immunosupressant and mTORCI inhibitor, triples the antidepressant response rate of ketamine at 2 weks following treatment: A double-blind, placebo-controlled, cross-over, randomized clinical trail. BioRxiv, The Preprint Server for Biology, Cold Spring Harbor laboratory. 2018.
  • Sutton MA, Ito HT, Cressy P, et al. Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis. Cell. 2006;125(4):785–799.
  • Duman RS. Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide. F1000Res. 2018;7.
  • Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23(4):801–811.
  • Tornese P, Sala N, Bonini D, et al. Chronic mild stress induces anhedonic behavior and changes in glutamate release, BDNF trafficking and dendrite morphology only in stress vulnerable rats. The rapid restorative action of ketamine. Neurobiol Stress. 2019 Apr 2;10:100160. doi: 10.1016/j.ynstr.2019.100160. eCollection 2019 Feb.
  • Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev. 2012;64(2):238–258.
  • Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59(12):1116–1127.
  • Groves JO. Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry. 2007;12(12):1079–1088.
  • Brown PL, Palacorolla H, Brady D, et al. Habenula-induced inhibition of midbrain dopamine neurons is diminished by lesions of the rostromedial tegmental nucleus. J Neurosci. 2017;37(1):217–225.
  • Li B, Piriz J, Mirrione M, et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature. 2011;470(7335):535–539.
  • Yang Y, Cui Y, Sang K, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018;554(7692):317–322.
  • Tian Z, Dong C, Zhang K, et al. Lack of antidepressant effects of low-voltage-sensitive T-type calcium channel blocker ethosuximide in a chronic social defeat stress model: comparison with (R)-ketamine. Int J Neuropsychopharmacol. 2018;21(11):1031–1036.
  • Yang C, Shirayama Y, Zhang JC, et al. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry. 2015;5(9):e632.
  • Yang C, Ren Q, Qu Y, et al. Mechanistic target of rapamycin-independent antidepressant effects of (R)-ketamine in a social defeat stress model. Biol Psychiatry. 2018;83(1):18–28.
  • Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018;70(3):621–660.
  • Yoshii A, Constantine-Paton M. Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol. 2010;70(5):304–322.
  • Ide S, Ikekubo Y, Mishina M, et al. Role of NMDA receptor GluN2D subunit in the antidepressant effects of enantiomers of ketamine. J Pharmacol Sci. 2017;135(3):138–140.
  • Qu Y, Yang C, Ren Q, et al. Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model. Sci Rep. 2017;7(1):15725.
  • Salat K, Siwek A, Starowicz G, et al. Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: role of activity at NMDA receptor. Neuropharmacology. 2015;99:301–307.
  • Yang C, Kobayashi S, Nakao K, et al. AMPA receptor activation-independent antidepressant actions of ketamine metabolite (S)-norketamine. Biol Psychiatry. 2018;84(8):591–600.
  • Zanos P, Highland JN, Stewart BW, et al. (2R,6R)-hydroxynorketamine exerts mGlu2 receptor-dependent antidepressant actions. Proc Natl Acad Sci U S A. 2019;116(13):6441–6450.
  • Shirayama Y, Hashimoto K. Lack of antidepressant effects of (2R,6R)-hydroxynorketamine in a rat learned helplessness model: comparison with (R)-ketamine. Int J Neuropsychopharmacol. 2018;21(1):84–88.
  • Yang C, Qu Y, Abe M, et al. (R)-ketamine shows greater potency and longer lasting antidepressant effects than its metabolite (2R,6R)-hydroxynorketamine. Biol Psychiatry. 2017;82(5):e43–e44.
  • Zhang K, Hashimoto K. An update on ketamine and its two enantiomers as rapid-acting antidepressants. Expert Rev Neurother. 2019;19(1):83–92.
  • Hashimoto K, Shirayama Y. What are the causes for discrepancies of antidepressant actions of (2R,6R)-hydroxynorketamine? Biol Psychiatry. 2018;84(1):e7–e8.
  • Lumsden EW, Troppoli TA, Myers SJ, et al. Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function. Proc Natl Acad Sci U S A. 2019;116(11):5160–5169.
  • Fukumoto K, Fogaca MV, Liu RJ, et al. Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine. Proc Natl Acad Sci U S A. 2019;116(1):297–302.
  • Liu RJ, Lee FS, Li XY, et al. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry. 2012;71(11):996–1005.
  • Wray NH, Schappi JM, Singh H, et al. NMDAR-independent, cAMP-dependent antidepressant actions of ketamine. Mol Psychiatry. 2018.
  • Chou D, Peng HY, Lin TB, et al. (2R,6R)-hydroxynorketamine rescues chronic stress-induced depression-like behavior through its actions in the midbrain periaqueductal gray. Neuropharmacology. 2018;139:1–12.
  • Yao N, Skiteva O, Zhang X, et al. Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit. Mol Psychiatry. 2018;23(10):2066–2077.
  • Caddy C, Amit BH, McCloud TL, et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev. 2015;(9):CD011612. DOI: 10.1002/14651858.CD011612.pub2
  • Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351–354.
  • DiazGranados N, Ibrahim LA, Brutsche NE, 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(12):1605–1611.
  • Zarate CA Jr., Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856–864.
  • Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67(8):793–802.
  • Zarate CA Jr., Brutsche NE, Ibrahim L, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71(11):939–946.
  • Price RB, Nock MK, Charney DS, et al. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66(5):522–526.
  • Feder A, Parides MK, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71(6):681–688.
  • Lally N, Nugent AC, Luckenbaugh DA, et al. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry. 2014;4(10):e469. mGluR.
  • Rodriguez CI, Kegeles LS, Levinson A, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. 2013;38(12):2475–2483.
  • Aan Het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67(2):139–145.
  • Rasmussen KG, Lineberry TW, Galardy CW, et al. Serial infusions of low-dose ketamine for major depression. J Psychopharmacol. 2013;27(5):444–450.
  • Diamond PR, Farmery AD, Atkinson S, et al. Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic. J Psychopharmacol. 2014;28(6):536–544.
  • Kadriu B, Musazzi L, Henter ID, et al. Glutamatergic neurotransmission: pathway to developing novel rapid-acting antidepressant treatments. Int J Neuropsychopharmacol. 2019;22(2):119–135.
  • Short B, Fong J, Galvez V, et al. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5(1):65–78.
  • Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013;19(6):370–380.
  • Yamaguchi JI, Toki H, Qu Y, et al. (2R,6R)-Hydroxynorketamine is not essential for the antidepressant actions of (R)-ketamine in mice. Neuropsychopharmacology. 2018;43(9):1900–1907.
  • Zhang K, Toki H, Fujita Y, et al. Lack of deuterium isotope effects in the antidepressant effects of (R)-ketamine in a chronic social defeat stress model. Psychopharmacology (Berl). 2018;235(11):3177–3185.
  • [cited 2019 Jan 3]. Available from:https://www.realwire.com/releases/ATAI-Life-ScienceS-acquireS-majority-stake-in-Perception-Neuroscience
  • FDA briefing document psychopharmacologic drugs advisory committee (PDAC)and drug safety and risk management (DSaRM) advisory committee meeting, 2019 Feb 12; Available from:https://www.fda.gov/media/121376/download
  • Singh JB, Fedgchin M, Daly E, et al. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol Psychiatry. 2016;80(6):424–431.
  • [cited 2016 Aug 16]. Available from:https://www.jnj.com/media-center/presS-releases/esketamine-recieveS-breakthrough-therapy-designation-from-uS-food-and-drug-administration-foR-majoR-depressive-disordeR-with-imminent-risk-of-suicide
  • Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):139–148.
  • Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2018;175(7):620–630.
  • Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428–438.
  • Parsons CG, Stoffler A, Danysz W. Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system–too little activation is bad, too much is even worse. Neuropharmacology. 2007;53(6):699–723.
  • Amidfar M, Khiabany M, Kohi A, et al. Effect of memantine combination therapy on symptoms in patients with moderate-to-severe depressive disorder: randomized, double-blind, placebo-controlled study. J Clin Pharm Ther. 2017;42(1):44–50.
  • Omranifard V, Shirzadi E, Samandari S, et al. Memantine add on to citalopram in elderly patients with depression: A double-blind placebo-controlled study. J Res Med Sci. 2014;19(6):525–530.
  • Smith EG, Deligiannidis KM, Ulbricht CM, et al. Antidepressant augmentation using the N-methyl-D-aspartate antagonist memantine: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2013;74(10):966–973.
  • Zarate CA Jr., Singh JB, Quiroz JA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163(1):153–155.
  • Ferguson JM, Shingleton RN. An open-label, flexible-dose study of memantine in major depressive disorder. Clin Neuropharmacol. 2007;30(3):136–144.
  • Muhonen LH, Lonnqvist J, Juva K, et al. Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence. J Clin Psychiatry. 2008;69(3):392–399.
  • Amidfar M, Reus GZ, Quevedo J, et al. The role of memantine in the treatment of major depressive disorder: clinical efficacy and mechanisms of action. Eur J Pharmacol. 2018;827:103–111.
  • Zarate CA Jr., Mathews D, Ibrahim L, et al. A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biol Psychiatry. 2013;74(4):257–264.
  • Sanacora G, Smith MA, Pathak S, et al. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol Psychiatry. 2014;19(9):978–985.
  • Sanacora G, Johnson MR, Khan A, 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(4):844–853.
  • Sanacora G, Schatzberg AF. Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders? Neuropsychopharmacology. 2015;40(2):259–267.
  • Preskorn SH, Baker B, Kolluri S, et al. 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(6):631–637.
  • Ibrahim L, Diaz Granados N, Jolkovsky L, 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(4):551–557.
  • Bruning JB, Murillo AC, Chacon O, et al. Structure of the Mycobacterium tuberculosis D-alanine: D-alanineligase, a target of the antituberculosis drug D-cycloserine. Antimicrob Agents Chemother. 2011;55(1):291–301.
  • Lench AM, Robson E, Jones RS. differential effects of D-cycloserine and ACBC at NMDA receptors in the rat entorhinal cortex are related to efficacy at the Co-agonist binding site. PLoS One. 2015;10(7):e0133548.
  • Heresco-Levy U, Javitt DC, Gelfin Y, et al. Controlled trial of D-cycloserine adjuvant therapy for treatment-resistant major depressive disorder. J Affect Disord. 2006;93(1–3):239–243.
  • Heresco-Levy U, Gelfin G, Bloch B, et al. A randomized add-on trial of high-dose D-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol. 2013;16(3):501–506.
  • Kantrowitz JT, Halberstam B, Gangwisch J. Single-dose ketamine followed by daily D-Cycloserine in treatment-resistant bipolar depression. J Clin Psychiatry. 2015;76(6):737–738.
  • Huang CC, Wei IH, Huang CL, et al. Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biol Psychiatry. 2013;74(10):734–741.
  • Salituro FG, Tomlinson RC, Baron BM, et al. Enzyme-activated antagonists of the strychnine-insensitive glycine/NMDA receptor. J Med Chem. 1994;37(3):334–336.
  • Ragguett RM, Rong C, Kratiuk K, et al. Rapastinel - an investigational NMDA-R modulator for major depressive disorder: evidence to date. Expert Opin Investig Drugs. 2019;28(2):113–119.
  • Allergan’s rapastinel receives FDA breakthrough therapy designation for adjunctive treatment of major depressive disorder (MDD). 2016. Available from:https://www.allergan.com/news/news/thomsonreuters/allergan-S-rapastinel-receiveS-fda-breakthrough-th.
  • Available from[cited 2019 Mar 6].:https://www.allergan.com/news/news/thomson-reuters/allergan-announceS-phase-3-resultS-foR-rapastinel.
  • Szewczyk B, Szopa A, Serefko A, et al. The role of magnesium and zinc in depression: similarities and differences. Magnes Res. 2018;31(3):78–89.
  • Mrazek DA, Hornberger JC, Altar CA, et al. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996–2013. Psychiatr Serv. 2014;65(8):977–987.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.