Abstract
Major depressive disorder (MDD) is a severe, debilitating medical illness that affects millions of individuals worldwide. The young age of onset and chronicity of the disorder has a significant impact on the long-term disability that affected individuals face. Most existing treatments have focused on the ‘monoamine hypothesis’ for rational design of compounds. However, patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and overall functional impairment.
In this context, growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of MDD, and discuss the efficacy of glutamatergic agents as novel therapeutics. Preliminary clinical evidence has been promising, particularly with regard to the N-methyl-D-aspartate (NMDA) antagonist ketamine as a ‘proof-of-concept’ agent. The review also highlights potential molecular and inflammatory mechanisms that may contribute to the rapid antidepressant response seen with ketamine.
Because existing pharmacological treatments for MDD are often insufficient for many patients, the next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications. There is extant evidence that the glutamatergic system holds considerable promise for developing the next generation of novel and mechanistically distinct agents for the treatment of MDD.
Similar content being viewed by others
References
Cole JO. Therapeutic efficacy of antidepressant drugs: a review. JAMA 1964; 190: 448–55
Davis JM. Efficacy of tranquilizing and antidepressant drugs. Arch Gen Psychiatry 1965; 13 (6): 552–72
Jensen K. Depressions in patients treated with reserpine for arterial hypertension. Acta Psychiatr Neurol Scand 1959; 34 (2): 195–204
Bunney Jr WE, Davis JM. Norepinephrine in depressive reactions: a review. Arch Gen Psychiatry 1965; 13 (6): 483–94
Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 1965; 122 (5): 509–22
Connolly KR, Thase ME. If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs 2011; 71 (1): 43–64
Schechter LE, Ring RH, Beyer CE, et al. Innovative approaches for the development of antidepressant drugs: current and future strategies. Neuro Rx 2005; 2 (4): 590–611
Murray CJ, Lopez AD. Evidence-based health policy: lessons from the Global Burden of Disease Study. Science 1996; 274 (5288): 740–3
Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163 (1): 28–40
Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008; 5 (2): e45
Horder J, Matthews P, Waldmann R. Placebo, prozac and PLoS: significant lessons for psychopharmacology. J Psy-chopharmacol 2011; 25 (10): 1277–88
Fountoulakis KN, Möller HJ. Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data. Int J Neuropsychopharmacol 2011; 14 (3): 405–12
Gueorguieva R, Mallinckrodt C, Krystal JH. Trajectories of depression severity in clinical trials of duloxetine: insights into antidepressant and placebo responses. Arch Gen Psychiatry 2011; 68 (12): 1227–37
Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 1990; 185 (1): 1–10
Skolnick P, Layer RT, Popik P, et al. Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry 1996; 29 (1): 23–6
Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47 (4): 351–4
Zarate Jr CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatmentresistant major depression. Arch Gen Psychiatry 2006; 63 (8): 856–64
Machado-Vieira R, Salvadore G, Luckenbaugh DA, et al. Rapid onset of antidepressant action: a new paradigm in the research and treatment of major depressive disorder. J Clin Psychiatry 2008; 69 (6): 946–58
Watkins JC, Jane DE. The glutamate story. Br J Pharmacol 2006; 147 Suppl. 1: S100–8
Evans RH, Francis AA, Hunt K, et al. Antagonism of excitatory amino acid-induced responses and of synaptic excitation in the isolated spinal cord of the frog. Br J Pharmacol 1979; 67 (4): 591–603
Verkhratsky A, Kirchhoff F. Glutamate-mediated neuronal-glial transmission. J Anat 2007; 210 (6): 651–60
Mathew SJ, Keegan K, Smith L. Glutamate modulators as novel interventions for mood disorders. Rev Bras Psiquiatr 2005; 27 (3): 243–8
Malenka RC, Nicoll RA. Long-term potentiation: a decade of progress?. Science 1999; 285 (5435): 1870–4
Parsons CG, Danysz W, Quack G. Glutamate in CNS disorders as a target for drug development: an update. Drug News Perspect 1998; 11 (9): 523–9
Francis PT. Glutamatergic systems in Alzheimer’s disease. Int J Geriatr Psychiatry 2003; 18 Suppl. 1: S15–21
Cortese BM, Phan KL. The role of glutamate in anxiety and related disorders. CNS Spectr 2005; 10 (10): 820–30
Fan MM, Raymond LA. N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington’s disease. Prog Neurobiol 2007; 81 (5–6): 272–93
Schoepp DD. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 2001; 299 (1): 12–20
Kim JS, Schmid-Burgk W, Claus D, et al. Increased serum glutamate in depressed patients. Arch Psychiatr Nervenkr 1982; 232 (4): 299–304
Altamura CA, Mauri MC, Ferrara A, et al. Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry 1993; 150 (11): 1731–3
Altamura CA, Mauri MC, Ferrara A, et al. Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment. Neuropsychobiology 1998; 37 (3): 124–9
Mitani H, Shirayama Y, Yamada T, et al. Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30 (6): 1155–8
Levine J, Panchalingam K, Rapoport A, et al. Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatry 2000; 47 (7): 586–93
Frye MA, Tsai GE, Huggins T, et al. Low cerebrospinal fluid glutamate and glycine in refractory affective disorder [published erratum appears in Biol Psychiatry 2007; 61 (10): 1221]. Biol Psychiatry 2007; 61 (2): 162–6
Francis PT, Poynton A, Lowe SL, et al. Brain amino acid concentrations and Ca2+-dependent release in intractable depression assessed antemortem. Brain Res 1989; 494 (2): 315–24
Nowak G, Ordway GA, Paul IA. Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res 1995; 675 (1–2): 157–64
Holemans S, De Paermentier F, Horton RW, et al. NMDA glutamatergic receptors, labelled with [3H]MK-801, in brain samples from drug-free depressed suicides. Brain Res 1993; 616 (1–2): 138–43
Altamura C, Maes M, Dai J, et al. Plasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depression. Eur Neuropsychopharmacol 1995; 5 Suppl.: 71–5
Maes M, Verkerk R, Vandoolaeghe E, et al. Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment-resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivity. Acta Psychiatr Scand 1998; 97 (4): 302–8
Frye MA, Watzl J, Banakar S, et al. Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression. Neuropsychopharmacology 2007; 32 (12): 2490–9
Hasler G, van der Veen JW, et al. Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 2007; 64 (2): 193–200
Sanacora G, Gueorguieva R, Epperson CN, et al. Subtypespecific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 2004; 61 (7): 705–13
Yildiz-Yesiloglu A, Ankerst DP. Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: a systematic review of the in vivo proton magnetic resonance spectroscopy findings. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30 (6): 969–95
Yuksel C, Ongur D. Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry 2010; 68 (9): 785–94
Salvadore G, Zarate CA Jr. Magnetic resonance spectroscopy studies of the glutamatergic system in mood disorders: a pathway to diagnosis, novel therapeutics, and personalized medicine?. Biol Psychiatry 2010 Nov 1; 68 (9): 780–2
Gorman JM, Docherty JP. A hypothesized role for dendritic remodeling in the etiology of mood and anxiety disorders. J Neuropsychiatry Clin Neurosci 2010; 22 (3): 256–64
Holmes A, Wellman CL. Stress-induced prefrontal reorganization and executive dysfunction in rodents. Neurosci Biobehav Rev 2009; 33 (6): 773–83
McEwen BS. Stress, sex, and neural adaptation to a changing environment: mechanisms of neuronal remodeling. Ann N Y Acad Sci 2010; 1204 Suppl.: E38–59
Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 2008; 33 (1): 88–109
Lee LJ, Lo FS, Erzurumlu RS. NMDA receptor-dependent regulation of axonal and dendritic branching. J Neurosci 2005; 25 (9): 2304–11
Bessa JM, Ferreira D, Melo I, et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry 2009; 14 (8): 764–73, 739
Ongur D, Haddad S, Prescot AP, et al. Relationship between genetic variation in the glutaminase gene GLS1 and brain glutamine/glutamate ratio measured in vivo. Biol Psychiatry 2011; 70 (2): 169–74
Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 2012; 62 (1): 63–77
Manji HK, Quiroz JA, Sporn J, et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry 2003; 53 (8): 707–42
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 Jr CA, 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): 939–46
Zarate Jr CA, 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): 153–5
Anand A, Gunn AD, Barkay G, et al. Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a doubleblind, randomized, placebo-controlled trial. Bipolar Disord 2012; 14 (1): 64–70
Lenze EJ, Skidmore ER, Begley AE, et al. 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. Epub 2011 Dec 16
Mathew SJ, Murrough JW, Rot M, et al. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharmacol 2010; 13 (1): 71–82
Ibrahim L, Diazgranados N, Franco-Chaves J, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs. add-on riluzole: results from a four-week, double-blind, placebo-controlled study. Neuropsychopharmacology 2012 May; 37 (6): 1526–33
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): 631–7
Ibrahim L, DiazGranados 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. Neuropsychopharmacology 2012 May; 37 (6): 1526–33
Machado-Vieira R, Manji HK, Zarate CA. The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders. Neuroscientist 2009; 15 (5): 525–39
Lesch KP, Schmitt A. Antidepressants and gene expression profiling: how to SNARE novel drug targets. Pharmacogenomics J 2002; 2 (6): 346–8
Meloni D, Gambarana C, De Montis MG, et al. Dizocilpine antagonizes the effect of chronic imipramine on learned helplessness in rats. Pharmacol Biochem Behav 1993; 46 (2): 423–6
Papp M, Moryl E. Antidepressant activity of noncompetitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Eur J Pharmacol 1994; 263 (1–2): 1–7
Layer RT, Popik P, Olds T, et al. Antidepressant-like actions of the polyamine site NMDA antagonist, eliprodil (SL-82.0715). Pharmacol Biochem Behav 1995; 52 (3): 621–7
Przegaliński E, Tatarczyńska E, Dereń-Wesolek A, et al. Antidepressant-like effects of a partial agonist at strychnine-insensitive glycine receptors and a competitive NMDA receptor antagonist. Neuropharmacology 1997; 36 (1): 31–7
Nowak G, Trullas R, Layer RT, et al. Adaptive changes in the N-methyl-D-aspartate receptor complex after chronic treatment with imipramine and 1-aminocyclopropane-carboxylic acid. J Pharmacol Exp Ther 1993; 265 (3): 1380–6
Paul IA, Layer RT, Skolnick P, et al. Adaptation of the NMDA receptor in rat cortex following chronic electroconvulsive shock or imipramine. Eur J Pharmacol 1993; 247 (3): 305–11
Paul IA, Nowak G, Layer RT, et al. Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments. J Pharmacol Exp Ther 1994; 269 (1): 95–102
Chaturvedi HK, Chandra D, Bapna JS. Interaction between N-methyl-D-aspartate receptor antagonists and imipramine in shock-induced depression. Indian J Exp Biol 1999; 37 (10): 952–8
Machado-Vieira R, Salvadore G, Ibrahim LA, et al. Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des 2009; 15 (14): 1595–611
Sanacora G, Zarate CA, Krystal JH, et al. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 2008; 7 (5): 426–37
Malinow R, Malenka RC. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 2002; 25: 103–26
Zhu JJ, Qin Y, Zhao M, et al. Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 2002; 110 (4): 443–55
Esteban JA. AMPA receptor trafficking: a road map for synaptic plasticity. Mol Interv 2003; 3 (7): 375–85
Anggono V, Huganir RL. Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol. Epub 2012 Jan 2
Bleakman D, Alt A, Witkin JM. AMPA receptors in the therapeutic management of depression. CNS Neurol Disord Drug Targets 2007; 6 (2): 117–26
Chourbaji S, Vogt MA, Fumagalli F, et al. AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression. FASEB J 2008; 22 (9): 3129–34
Gibbons AS, Brooks L, Scarr E, et al. AMPA receptor expression is increased post-mortem samples of the anterior cingulate from subjects with major depressive disorder. J Affect Disord 2012 Feb; 136 (3): 1232–7
Maeng S, Zarate Jr CA, 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): 349–52
Zarate Jr C, Machado-Vieira R, Henter I, et al. Glutamatergic modulators: the future of treating mood disorders?. Harv Rev Psychiatry 2010; 18 (5): 293–303
Alt A, Nisenbaum ES, Bleakman D, et al. A role for AMPA receptors in mood disorders. Biochem Pharmacol 2006; 71 (9): 1273–88
O’Neill MJ, Witkin JM. AMPA receptor potentiators: application for depression and Parkinson’s disease. Curr Drug Targets 2007; 8 (5): 603–20
Bleakman D, Lodge D. Neuropharmacology of AMPA and kainate receptors. Neuropharmacology 1998; 37 (10-11): 1187-204
Borges K, Dingledine R. AMPA receptors: molecular and functional diversity. Prog Brain Res 1998; 116: 153–70
Li X, Tizzano JP, Griffey K, et al. Antidepressant-like actions of an AMPA receptor potentiator (LY392098). Neuropharmacology 2001; 40 (8): 1028–33
Knapp RJ, Goldenberg R, Shuck C, et al. Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model. Eur J Pharmacol 2002; 440 (1): 27–35
Lindholm JS, Autio H, Vesa L, et al. The antidepressantlike effects of glutamatergic drugs ketamine and AMPA receptor potentiator LY 451646 are preserved in bdnf/heterozygous null mice. Neuropharmacology 2012; 62 (1): 391–7
Bursi R, Erdemli G, Campbell R, et al. Translational PK-PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576. Psychopharmacology (Berl) 2011; 218 (4): 713–24
Niciu MJ, Kelmendi B, Sanacora G. Overview of glutamatergic neurotransmission in the nervous system. Pharmacol Biochem Behav 2012; 100 (4): 656–64
Szewczyk B, Palucha-Poniewiera A, Poleszak E, et al. Investigational NMDA receptor modulators for depression. Expert Opin Investig Drugs 2012; 21 (1): 91–102
Krystal JH, Mathew SJ, D’Souza DC, et al. Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs 2010; 24 (8): 669–93
Harrison NL, Simmonds MA. Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex. Br J Pharmacol 1985; 84 (2): 381–91
Bolshakov KV, Gmiro VE, Tikhonov DB, et al. Determinants of trapping block of N-methyl-d-aspartate receptor channels. J Neurochem 2003; 87 (1): 56–65
Narita M, Yoshizawa K, Nomura M, et al. Role of the NMDA receptor subunit in the expression of the discriminative stimulus effect induced by ketamine. Eur J Pharmacol 2001; 423 (1): 41–6
De Vry J, Jentzsch KR. Role of the NMDA receptor NR2B subunit in the discriminative stimulus effects of ketamine. Behav Pharmacol 2003; 14 (3): 229–35
Maler JM, Esselmann H, Wiltfang J, et al. Memantine inhibits ethanol-induced NMDA receptor up-regulation in rat hippocampal neurons. Brain Res 2005; 1052 (2): 156–62
Maeng S, Zarate Jr CA. The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Curr Psychiatry Rep 2007; 9 (6): 467–74
Engin E, Treit D, Dickson CT. Anxiolytic- and antidepressant-like properties of ketamine in behavioral and neurophysiological animal models. Neuroscience 2009; 161 (2): 359–69
Garcia LS, Comim CM, Valvassori SS, et al. Chronic administration of ketamine elicits antidepressant-like effects in rats without affecting hippocampal brain-derived neurotrophic factor protein levels. Basic Clin Pharmacol Toxicol 2008; 103 (6): 502–6
Garcia LS, Comim CM, Valvassori SS, 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 (1): 140–4
Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329 (5994): 959–64
Yilmaz A, Schulz D, Aksoy A, et al. Prolonged effect of an anesthetic dose of ketamine on behavioral despair. Pharmacol Biochem Behav 2002; 71 (1–2): 341–4
Garcia LS, Comim CM, Valvassori SS, et al. Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33 (3): 450–5
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): 754–61
da Silva FC, do Carmo de Oliveira Cito M, da Silva MI, et al. Behavioral alterations and pro-oxidant effect of a single ketamine administration to mice. Brain Res Bull 2010; 83 (1–2): 9–15
Rosa AO, Lin J, Calixto JB, et al. Involvement of NMDA receptors and L-arginine-nitric oxide pathway in the antidepressant-like effects of zinc in mice. Behav Brain Res 2003; 144 (1–2): 87–93
Kos T, Popik P, Pietraszek M, et al. Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice. Eur Neuropsychopharmacol 2006; 16 (4): 297–310
Chindo BA, Adzu B, Yahaya TA, et al. Ketamineenhanced immobility in forced swim test: a possible animal model for negative symptoms of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2012; 26: 26
Moghaddam B, Adams B, Verma A, et al. 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 (8): 2921–7
Green SM, Rothrock SG, Lynch EL, et al. Intramuscular ketamine for pediatric sedation in the emergency department: safety profile in 1022 cases. Ann Emerg Med 1998; 31 (6): 688–97
Howes MC. Ketamine for paediatric sedation/analgesia in the emergency department. Emerg Med J 2004; 21 (3): 275–80
Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural sedation in adults. Am J Emerg Med 2008; 26 (9): 985–1028
Jevtovic-Todorovic V, Wozniak DF, Benshoff ND, et al. A comparative evaluation of the neurotoxic properties of ketamine and nitrous oxide. Brain Res 2001; 895 (1–2): 264–7
Valentine GW, Mason GF, Gomez R, et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res 2011; 191 (2): 122–7
Bunney BG, Bunney WE. Rapid-acting antidepressant strategies: mechanisms of action. Int J Neuropsychopharmacol 2011; 7: 1–19
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): 139–45
Phelps LE, Brutsche N, Moral JR, et al. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol Psychiatry 2009; 65 (2): 181–4
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): 522–6
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): 1605–11
Larkin GL, Beautrais AL. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharmacol 2011; 14 (8): 1127–31
Mathew SJ, Shah A, Lapidus K, et al. Ketamine for treatment-resistant unipolar depression: current evidence. CNS Drugs 2012; 26 (3): 189–204
Doble A. The pharmacology and mechanism of action of riluzole. Neurology 1996; 47 (6 Suppl. 4): S233-41
Du J, Suzuki K, Wei Y, et al. The anticonvulsants lamotrigine, riluzole, and valproate differentially regulate AMPA receptor membrane localization: relationship to clinical effects in mood disorders. Neuropsychopharmacology 2007; 32 (4): 793–802
Mizuta I, Ohta M, Ohta K, et al. Riluzole stimulates nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis in cultured mouse astrocytes. Neurosci Lett 2001; 310 (2-3): 117-20
Zarate CA, Manji HK. Riluzole in psychiatry: a systematic review of the literature. Expert Opin Drug Metab Toxicol 2008; 4 (9): 1223–34
Papazisis G, et al. Neuroprotection by lamotrigine in a rat model of neonatal hypoxic-ischaemic encephalopathy. Int J Neuropsychopharmacol 2008; 11 (3): 321–9
Goodnick PJ. Bipolar depression: a review of randomised clinical trials. Expert Opin Pharmacother 2007; 8 (1): 13–21
Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry 2009; 194 (1): 4–9
Anand A, Charney DS, Oren DA, et al. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry 2000; 57 (3): 270–6
Wang M, Yang Y, Dong Z, et al. NR2B-containing N-methyl-D-aspartate subtype glutamate receptors regulate the acute stress effect on hippocampal long-term potentiation/long-term depression in vivo. Neuroreport 2006; 17 (12): 1343–6
Loftis JM, Janowsky A. The N-methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications. Pharmacol Ther 2003; 97 (1): 55–85
Gogas KR. Glutamate-based therapeutic approaches: NR2B receptor antagonists. Curr Opin Pharmacol 2006; 6 (1): 68–74
Merchant RE, Bullock MR, Carmack CA, et al. A doubleblind, placebo-controlled study of the safety, tolerability and pharmacokinetics of CP-101, 606 in patients with a mild or moderate traumatic brain injury. Ann N Y Acad Sci 1999; 890: 42–50
Faries D, Herrera J, Rayamajhi J, et al. The responsiveness of the Hamilton Depression Rating Scale. J Psychiatr Res 2000; 34 (1): 3–10
Kemp AH, Gordon E, Rush AJ, et al. Improving the prediction of treatment response in depression: integration of clinical, cognitive, psychophysiological, neuroimaging, and genetic measures. CNS Spectr 2008; 13 (12): 1066–86; quiz 1087-8
Kornhuber J, Weller M, Schoppmeyer K, et al. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm Suppl 1994; 43: 91–104
Bormann J. Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels. Eur J Pharmacol 1989; 166 (3): 591–2
Kornhuber J, Bormann J, Retz W, et al. Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex. Eur J Pharmacol 1989; 166 (3): 589–90
Kornhuber J, Bormann J, Hübers M, et al. Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study. Eur J Pharmacol 1991; 206 (4): 297–300
Kornhuber J, Weller M. Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol Psychiatry 1997; 41 (2): 135–44
Muller WE, Mutschler E, Riederer P. Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimer’s dementia. Pharmacopsychiatry 1995; 28 (4): 113–24
Lo D, Grossberg GT. Use of memantine for the treatment of dementia. Expert Rev Neuroth er 2011; 11 (10): 1359–70
Parsons CG, Danysz W, Quack G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist: a review of preclinical data. Neuropharmacology 1999; 38 (6): 735–67
Tsai GE. Searching for rational anti N-methyl-D-aspartate treatment for depression. Arch Gen Psychiatry, 2007; 64 (9): 1099–100; author reply 1100-1
Muhonen LH, Lönnqvist 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): 392–9
Holter SM, Danysz W, Spanagel R. Evidence for alcohol anti-craving properties of memantine. Eur J Pharmacol 1996; 314 (3): R1–2
Bachteler D, Economidou D, Danysz W, et al. The effects of acamprosate and neramexane on cue-induced reinstatement of ethanol-seeking behavior in rat. Neuropsychopharmacology 2005; 30 (6): 1104–10
Piasecki J, Koros E, Dyr W, et al. Ethanol-reinforced behaviour in the rat: effects of uncompetitive NMDA receptor antagonist, memantine. Eur J Pharmacol 1998; 354 (2–3): 135–43
Escher T, Call SB, Blaha CD, et al. Behavioral effects of aminoadamantane class NMDA receptor antagonists on schedule-induced alcohol and self-administration of water in mice. Psychopharmacology (Berl) 2006; 187 (4): 424–34
Boden JM, Fergusson DM. Alcohol and depression. Addiction 2011; 106 (5): 906–14
Conner KR, Pinquart M, Gamble SA. Meta-analysis of depression and substance use among individuals with alcohol use disorders. J Subst Abuse Treat 2009; 37 (2): 127–37
Nagy J. Renaissance of NMDA receptor antagonists: do they have a role in the pharmacotherapy for alcoholism?. IDrugs 2004; 7 (4): 339–50
Petrakis IL, Limoncelli D, Gueorguieve R, et al. Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. Am J Psychiatry 2004; 161 (10): 1776–82
Bäckström P, Bachteler D, Koch S, et al. mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior. Neuropsychopharmacology 2004; 29 (5): 921–8
Krupitsky EM, Rudenko AA, Burakov AM, et al. Antiglutamatergic strategies for ethanol detoxification: comparison with placebo and diazepam. Alcohol Clin Exp Res 2007; 31 (4): 604–11
Rogóz Z, Skuza G, Maj J, et al. Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats. Neuropharmacology 2002; 42 (8): 1024–30
Huber TJ, Dietrich DE, Emrich HM. Possible use of amantadine in depression. Pharmacopsychiatry 1999; 32 (2): 47–55
Rogóz Z, Kubera M, Rogóz K, et al. Effect of coadministration of fluoxetine and amantadine on immunoendocrine parameters in rats subjected to a forced swimming test. Pharmacol Rep 2009; 61 (6): 1050–60
Kubera M, Basta-Kairn A, Budziszewska B, et al. Effect of amantadine and imipramine on immunological parameters of rats subjected to a forced swimming test. Int J Neuropsychopharmacol 2006; 9 (3): 297–305
Maj J, Rogoz Z. Synergistic effect of amantadine and imipramine in the forced swimming test. Pol J Pharmacol 2000; 52 (2): 111–4
Dietrich DE, Bode L, Spannhuth CW, et al. Amantadine in depressive patients with Borna disease virus (BDV) infection: an open trial. Bipolar Disord 2000; 2 (1): 65–70
Ferszt R, Kühl KP, Bode L, et al. Amantadine revisited: an open trial of amantadinesulfate treatment in chronically depressed patients with Borna disease virus infection. Pharmacopsychiatry 1999; 32 (4): 142–7
Stryjer R, Strous RD, Shaked G, et al. Amantadine as augmentation therapy in the management of treatmentresistant depression. Int Clin Psychopharmacol 2003; 18 (2): 93–6
Rogóz Z, Skuza G, Daniel WA, et al. Amantadine as an additive treatment in patients suffering from drugresistant unipolar depression. Pharmacol Rep 2007; 59 (6): 778–84
Autry AE, Adachi M, Nosyreva E, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011; 475 (7354): 91–5
Hoeffer CA, Klann E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 2010; 33 (2): 67–75
Duman RS, Li N, Liu RJ, et al. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 2012; 62 (1): 35–41
Cryan JF, O’eary OF. Neuroscience: a glutamate pathway to faster-acting antidepressants?. Science 2010; 329 (5994): 913–4
Ravikumar B, Rubinsztein DC. Can autophagy protect against neurodegeneration caused by aggregate-prone proteins?. Neuroreport 2004; 15 (16): 2443–5
Pickford F, Masliah E, Brtischgi M, et al. The autophagyrelated protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 2008; 118 (6): 2190–9
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 (11): 1068–70
Kaidanovich-Beilin O, Milman A, Weizman A, et al. Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on beta-catenin in mouse hippocampus. Biol Psychiatry 2004; 55 (8): 781–4
O’Brien WT, Harper AD, Jové F, et al. Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci 2004; 24 (30): 6791–8
Beaulieu JM, Sotnikova TD, Yao WD, et al. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci USA. 2004; 101 (14): 5099–104
Gould TD, Chen G, Manji HK. In vivo evidence in the brain for lithium inhibition of glycogen synthase kinase-3. Neuropsychopharmacology 2004; 29 (1): 32–8
Polter A, Beurel E, Yang S, et al. Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances. Neuropsychopharmacology 2010; 35 (8): 1761–74
Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 2004; 29 (2): 95–102
Rayasam GV, Tulasi VK, Sodhi R, et al. Glycogen synthase kinase 3: more than a namesake. Br J Pharmacol 2009; 156 (6): 885–98
Shimizu E, Hashimoto K, Iyo M. Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: the possibility to explain ethnic mental traits. Am J Med Genet B Neuropsychiatr Genet 2004; 126B (1): 122-3
Casey BJ, Glatt CE, Tottenham N, et al. Brain-derived neurotrophic factor as a model system for examining gene by environment interactions across development. Neuroscience 2009; 164 (1): 108–20
Egan MF, Kojima M, Callicott JH, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112 (2): 257–69
Neves-Pereira M, Mundo E, Muglia P, et al. The brainderived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet 2002; 71 (3): 651–5
Sklar P, Gabriel SB, McInnis MG, et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry 2002; 7 (6): 579–93
Sen S, Nesse RM, Stoltenberg SF, et al. A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology 2003; 28 (2): 397–401
Ribasés M, Gratacòs M, Fernández-Aranda F, et al. Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum Mol Genet 2004; 13 (12): 1205–12
Sun M, Liu L, Yang Y, et al. Association study of brainderived neurotrophic factor Val66Met polymorphism and clinical characteristics of first episode schizophrenia [in Chinese]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2012; 29 (2): 155–8
Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 2012; 64 (2): 238–58
Machado-Vieira R, Yuan P, Brutsche N, et al. Brainderived neurotrophic factor and initial antidepressant response to an N-methyl-D-aspartate antagonist. J Clin Psychiatry 2009; 70 (12): 1662–6
Ricci V, Martinotti G, Gelfo F, et al. Chronic ketamine use increases serum levels of brain-derived neurotrophic factor. Psychopharmacology (Berl) 2011; 215 (1): 143–8
Inamura N, Nawa H, Takei N. Enhancement of translation elongation in neurons by brain-derived neurotrophic factor: implications for mammalian target of rapamycin signaling. J Neurochem 2005; 95 (5): 1438–45
Slipczuk L, Bekinschtein P, Katche C, et al. BDNF activates mTOR to regulate GluR1 expression required for memory formation. PLoS ONE 2009; 4 (6): e6007
Takei N, Inamura N, Kawamura M, et al. Brain-derived neurotrophic factor induces mammalian target of rapamy-cin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci 2004; 24 (44): 9760–9
Laje G, Lally N, Mathews D, et al. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol Psychiatry. In press
Liu RJ, Lee FS, Li XY, et al. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketaminestimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 2012; 71 (11): 996–1005
Murrough JW. Ketamine as a novel antidepressant: from synapse to behavior. Clin Pharmacol Ther 2012; 91 (2): 303–9
Cornwell BR, Salvadore G, Furey M, et al. Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression. Biol Psychiatry. Epub 2012 Apr 20
Li X, Witkin JM, Need AB, et al. Enhancement of antidepressant potency by a potentiator of AMPA receptors. Cell Mol Neurobiol 2003; 23 (3): 419–30
Maes M, Bosmans E, Suy E, et al. Immune disturbances during major depression: upregulated expression of interleukin-2 receptors. Neuropsychobiology 1990; 24 (3): 115–20
Maes M, Bosmans E, Suy E, et al. Depression-related disturbances in mitogen-induced lymphocyte responses and interleukin-1 beta and soluble interleukin-2 receptor production. Acta Psychiatr Scand 1991; 84 (4): 379–86
Maes M, Lambrechts J, Bosmans E, et al. Evidence for a systemic immune activation during depression: results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody staining. Psychol Med 1992; 22 (1): 45–53
Bufalino C, Hepgul N, Aguglia E, et al. The role of immune genes in the association between depression and inflammation: a review of recent clinical studies. Brain Behav Immun. Epub 2012 May 8
Eyre H, Baune BT. Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology. Epub 2012 Apr 21
Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006; 59 (12): 1116–27
Catena-Dell’Osso M, Bellantuono C, Consoli G, et al. Inflammatory and neurodegenerative pathways in depression: a new avenue for antidepressant development?. Curr Med Chem 2011; 18 (2): 245–55
Gardner A, Boles RG. Beyond the serotonin hypothesis: mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35 (3): 730–43
Maes M, et al. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 2009; 24 (1): 27–53
Leonard B, Maes M. Mechanistic explanations how cellmediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 2012; 36 (2): 764–85
Moir AT, Eccleston D. The effects of precursor loading in the cerebral metabolism of 5-hydroxyindoles. J Neurochem 1968; 15 (10): 1093–108
Maes M, Leonard BE, Myint AM, et al. The new ‘5-HT’ hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35 (3): 702–21
Muller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry 2007; 12 (11): 988–1000
Moylan S, Maes M, Wray NR, et al. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry. Epub 2012 Apr 24
Koga K, Ogata M, Takenaka I, et al. Ketamine suppresses tumor necrosis factor-alpha activity and mortality in carrageenan-sensitized endotoxin shock model. Circ Shock 1994; 44 (3): 160–8
Taniguchi T, Shibata K, Yamamoto K. Ketamine inhibits endotoxin-induced shock in rats. Anesthesiology 2001; 95 (4): 928–32
Taniguchi T, Takemoto Y, Kanakura H, et al. The doserelated effects of ketamine on mortality and cytokine responses to endotoxin-induced shock in rats. Anesth Analg 2003; 97 (6): 1769–72
Suliburk JW, Helmer KS, Gonzalez EA, et al. Ketamine attenuates liver injury attributed to endotoxemia: role of cyclooxygenase-2. Surgery 2005; 138 (2): 134–40
Welters ID, Hafer G, Menzebach A, et al. Ketamine inhibits transcription factors activator protein 1 and nuclear factor-kappaB, interleukin-8 production, as well as CD11b and CD16 expression: studies in human leukocytes and leukocytic cell lines. Anesth Analg 2010; 110 (3): 934–41
Albensi BC, Mattson MP. Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse 2000; 35 (2): 151–9
Gutierrez H, Davies AM. Regulation of neural process growth, elaboration and structural plasticity by NF-kappaB. Trends Neurosci 2011; 34 (6): 316–25
Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 2009; 27: 693–733
Roytblat L, Talmor D, Rachinsky M, et al. Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth Analg 1998; 87 (2): 266–71
Bartoc C, Frumento RJ, Jalbout M, et al. A randomized, double-blind, placebo-controlled study assessing the antiinflammatory effects of ketamine in cardiac surgical patients. J Cardiothorac Vasc Anesth 2006; 20 (2): 217–22
Cho JE, Shim JK, Choi YS, et al. Effect of low-dose ketamine on inflammatory response in off-pump coronary artery bypass graft surgery. Br J Anaesth 2009; 102 (1): 23–8
Carlson PJ, Singh JB, Zarate Jr CA, et al. Neural circuitry and neuroplasticity in mood disorders: insights for novel therapeutic targets. NeuroRx 2006; 3 (1): 22–41
Javitt DC, Schoepp D, Kalivas PW, et al. Translating glutamate: from pathophysiology to treatment. Sci Transl Med 2011; 3 (102): 102mr2
Orloff J, Douglas F, Pinheiro J, et al. The future of drug development: advancing clinical trial design. Nat Rev Drug Discov 2009; 8 (12): 949–57
Acknowledgements
The authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; Bethesda, MD, USA), and thank the 7SE Research Unit of the NIMH-NIH for their support.
Role of funding source: This review was supported by the IRP-NIMH-NIH. The NIMH had no further role in the writing of this review, or in the decision to submit the paper for publication.
Financial disclosures: The authors gratefully acknowledge the support of the IRP-NIMH-NIH, and the NARSAD Independent Investigator Award and Brain and Behavior Foundation Bipolar Research Award (Dr Zarate). Dr Mathews and Ioline Henter have no conflict of interest to disclose, financial or otherwise. Dr Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. Dr Zarate has assigned his rights in the patent to the US Government but will share a percentage of any royalties that may be received by the Government.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mathews, D.C., Henter, I.D. & Zarate, C.A. Targeting the Glutamatergic System to Treat Major Depressive Disorder. Drugs 72, 1313–1333 (2012). https://doi.org/10.2165/11633130-000000000-00000
Published:
Issue Date:
DOI: https://doi.org/10.2165/11633130-000000000-00000