Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders

Key Points

  • Mood disorders are common, chronic, recurrent mental illnesses that affect the lives of millions of individuals worldwide. There is growing evidence that the glutamatergic system is central to the treatment, and potentially the neurobiology of these disorders.

  • Abnormal function of the glutamatergic system has been implicated in the pathophysiology of many psychiatric and neurological disorders. Glutamatergic abnormalities have been reported in plasma, serum, cerebrospinal fluid and brain tissue of individuals afflicted with mood disorders.

  • There is mounting evidence of alterations in NMDA (N-methyl-D-aspartate) and AMPA/KA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate) receptor function in mood disorders, and several studies have found differences related to NMDA receptor expression and binding affinities between individuals with and without mood disorders.

  • Therapeutics used in the treatment of mood disorders affect many facets of the glutamatergic system. These include both antidepressants and mood stabilizers such as lithium, valproate and lamotrigine.

  • Several agents that act on the glutamatergic system have been explored as potential treatments in mood disorders. These include inhibitors of glutamate release (such as lamotrigine and riluzole), partial NMDA antagonists (for example, D-cycloserine) and NMDA antagonists (such as memantine and ketamine).

  • Ketamine has been shown to have anxiolytic and antidepressant effects in animal models of anxiety and depression as well as antidepressant effects in humans. A double-blind placebo-controlled crossover study found that a single intravenous dose of ketamine resulted in rapid and significant antidepressant effects in patients with treatment-resistant major depressive disorder within 2 hours, an effect that remained significant for 7 days.

  • Other agents that affect the glutamatergic system are also being explored as potential novel therapeutics. These include AMPA potentiators, subunit selective NMDA receptor subunit 2B (NR2B) antagonists, glial glutamate transporter enhancers, group I metabotropic receptor modulators and presynaptic packaging and glutamate-release inhibitors.

Abstract

Mood disorders are common, chronic, recurrent mental illnesses that affect the lives of millions of individuals worldwide. To date, the monoaminergic systems (serotonergic, noradrenergic and dopaminergic) in the brain have received the greatest attention in neurobiological studies of mood disorders, and most therapeutics target these systems. However, there is growing evidence that the glutamatergic system is central to the neurobiology and treatment of these disorders. Here, we review data supporting the involvement of the glutamatergic system in mood-disorder pathophysiology as well as the efficacy of glutamatergic agents in mood disorders. We also discuss exciting new prospects for the development of improved therapeutics for these devastating disorders.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Glutamatergic neurotransmission and potential targets for drug development.
Figure 2: Antidepressants converge to regulate AMPA- and NMDA-mediated synaptic plasticity in critical neuronal circuits.

Similar content being viewed by others

References

  1. Kessler, R. C. et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 593–602 (2005).

    Article  PubMed  Google Scholar 

  2. Fagiolini, A. et al. Functional impairment in the remission phase of bipolar disorder. Bipolar Disord. 7, 281–285 (2005).

    PubMed  Google Scholar 

  3. Huxley, N. & Baldessarini, R. J. Disability and its treatment in bipolar disorder patients. Bipolar Disord. 9, 183–196 (2007).

    PubMed  Google Scholar 

  4. Tohen, M. et al. The McLean-Harvard First-Episode Mania Study: prediction of recovery and first recurrence. Am. J. Psychiatry 160, 2099–2107 (2003).

    PubMed  Google Scholar 

  5. Murray, C. J. & Lopez, A. D. Evidence-based health policy — lessons from the Global Burden of Disease Study. Science 274, 740–743 (1996).

    CAS  PubMed  Google Scholar 

  6. Rush, A. J. et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am. J. Psychiatry 163, 1905–1917 (2006).

    PubMed  Google Scholar 

  7. Trivedi, M. H. et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am. J. Psychiatry 163, 28–40 (2006).

    PubMed  Google Scholar 

  8. Judd, L. L. et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch. Gen. Psychiatry 59, 530–537 (2002).

    PubMed  Google Scholar 

  9. Nierenberg, A. A. et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am. J. Psychiatry 163, 210–216 (2006).

    PubMed  Google Scholar 

  10. Drevets, W. C. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr. Opin. Neurobiol. 11, 240–249 (2001).

    CAS  PubMed  Google Scholar 

  11. Dunlop, B. W. & Nemeroff, C. B. The role of dopamine in the pathophysiology of depression. Arch. Gen. Psychiatry 64, 327–337 (2007).

    CAS  PubMed  Google Scholar 

  12. Manji, H. K., Drevets, W. C. & Charney, D. S. The cellular neurobiology of depression. Nature Med. 7, 541–547 (2001). This article reviews the data demonstrating that severe mood disorders arise from abnormalities in synaptic and neural-plasticity cascades.

    CAS  PubMed  Google Scholar 

  13. Berman, R. M., Krystal, J. H. & Charney, D. S. in Biology of Schizophrenia and Affective Disease (ed. Watson, S. J.) 295–368 (American Psychiatric Press, Washington, D.C., 1996).

    Google Scholar 

  14. Manji, H. K., Moore, G. J., Rajkowska, G. & Chen, G. Neuroplasticity and cellular resilience in mood disorders. Millennium Article. Mol. Psychiatry 5, 578–593 (2000).

    CAS  PubMed  Google Scholar 

  15. Payne, J. L., Quiroz, J. A., Zarate, C. A. & Manji, H. K. Timing is everything: does the robust upregulation of noradrenergically regulated plasticity genes underlie the rapid antidepressant effects of sleep deprivation? Biol. Psychiatry 52, 921–926 (2002).

    CAS  PubMed  Google Scholar 

  16. Orrego, F. & Villanueva, S. The chemical nature of the main central excitatory transmitter: a critical appraisal based upon release studies and synaptic vesicle localization. Neuroscience 56, 539–555 (1993).

    CAS  PubMed  Google Scholar 

  17. Krystal, J. H. et al. NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders. Harv. Rev. Psychiatry 7, 125–143 (1999).

    CAS  PubMed  Google Scholar 

  18. Erecinska, M. & Silver, I. A. Metabolism and role of glutamate in mammalian brain. Prog. Neurobiol. 35, 245–296 (1990).

    CAS  PubMed  Google Scholar 

  19. Varoqui, H., Schafer, M. K., Zhu, H., Weihe, E. & Erickson, J. D. Identification of the differentiation-associated Na+/PI transporter as a novel vesicular glutamate transporter expressed in a distinct set of glutamatergic synapses. J. Neurosci. 22, 142–155 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Herzog, E. et al. Localization of VGLUT3, the vesicular glutamate transporter type 3, in the rat brain. Neuroscience 123, 983–1002 (2004).

    CAS  PubMed  Google Scholar 

  21. Peng, J. et al. Semiquantitative proteomic analysis of rat forebrain postsynaptic density fractions by mass spectrometry. J. Biol. Chem. 279, 21003–21011 (2004).

    CAS  PubMed  Google Scholar 

  22. Rothstein, J. D., Jin, L., Dykes-Hoberg, M. & Kuncl, R. W. Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proc. Natl Acad. Sci. USA 90, 6591–6595 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Tanaka, K. et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276, 1699–1702 (1997).

    CAS  PubMed  Google Scholar 

  24. Pitt, D., Nagelmeier, THAT IS, Wilson, H. C. & Raine, C. S. Glutamate uptake by oligodendrocytes: Implications for excitotoxicity in multiple sclerosis. Neurology 61, 1113–1120 (2003).

    CAS  PubMed  Google Scholar 

  25. Parsons, C. G., Danysz, W. & Quack, G. Glutamate in CNS disorders as a target for drug development: an update. Drug News Perspect. 11, 523–569 (1998).

    CAS  PubMed  Google Scholar 

  26. Francis, P. T. Glutamatergic systems in Alzheimer's disease. Int. J. Geriatr Psychiatry 18, S15–S21 (2003).

    PubMed  Google Scholar 

  27. Cortese, B. M. & Phan, K. L. The role of glutamate in anxiety and related disorders. CNS Spectr. 10, 820–830 (2005).

    PubMed  Google Scholar 

  28. Fan, M. M. & Raymond, L. A. N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease. Prog. Neurobiol. 81, 272–293 (2007).

    CAS  PubMed  Google Scholar 

  29. Kim, J. S., Schmid-Burgk, W., Claus, D. & Kornhuber, H. H. Increased serum glutamate in depressed patients. Arch. Psychiatr. Nervenkr. 232, 299–304 (1982).

    CAS  PubMed  Google Scholar 

  30. Altamura, C. A. et al. Plasma and platelet excitatory amino acids in psychiatric disorders. Am. J. Psychiatry 150, 1731–1733 (1993).

    CAS  PubMed  Google Scholar 

  31. Mauri, M. C. et al. Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment. Neuropsychobiology 37, 124–129 (1998).

    CAS  PubMed  Google Scholar 

  32. Mitani, H. et al. Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 1155–1158 (2006).

    CAS  PubMed  Google Scholar 

  33. Levine, J. et al. Increased cerebrospinal fluid glutamine levels in depressed patients. Biol. Psychiatry 47, 586–593 (2000).

    CAS  PubMed  Google Scholar 

  34. Frye, M. A., Tsai, G. E., Huggins, T., Coyle, J. T. & Post, R. M. Low cerebrospinal fluid glutamate and glycine in refractory affective disorder. Biol. Psychiatry 61, 162–166 (2006).

    PubMed  Google Scholar 

  35. Francis, P. T. et al. Brain amino acid concentrations and Ca2+-dependent release in intractable depression assessed antemortem. Brain Res. 494, 315–324 (1989).

    CAS  PubMed  Google Scholar 

  36. Altamura, C., Maes, M., Dai, J. & Meltzer, H. Y. Plasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depression. Eur. Neuropsychopharmacol. 5, 71–75 (1995).

    CAS  PubMed  Google Scholar 

  37. Maes, M., Verkerk, R., Vandoolaeghe, E., Lin, A. & Scharpe, S. 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. 97, 302–308 (1998).

    CAS  PubMed  Google Scholar 

  38. Hashimoto, K., Sawa, A. & Iyo, M. Increased levels of glutamate in brains from patients with mood disorders. Biol. Psychiatry 62, 1310–1316 (2007).

    CAS  PubMed  Google Scholar 

  39. de Graaf, R. A., Mason, G. F., Patel, A. B., Behar, K. L. & Rothman, D. L. In vivo1H-[13C]-NMR spectroscopy of cerebral metabolism. NMR Biomed. 16, 339–357 (2003).

    CAS  PubMed  Google Scholar 

  40. Nowak, G., Ordway, G. A. & Paul, I. A. Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res. 675, 157–164 (1995).

    CAS  PubMed  Google Scholar 

  41. Scarr, E., Pavey, G., Sundram, S., MacKinnon, A. & Dean, B. Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. Bipolar Disord. 5, 257–264 (2003).

    CAS  PubMed  Google Scholar 

  42. McCullumsmith, R. E. et al. Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder. Brain Res. 1127, 108–118 (2007). In this article, the authors describe alterations in NMDA receptor complex in post-mortem brain tissue of patients with BPD.

    CAS  PubMed  Google Scholar 

  43. Law, A. J. & Deakin, J. F. Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses. Neuroreport 12, 2971–2974 (2001).

    CAS  PubMed  Google Scholar 

  44. Nudmamud-Thanoi, S. & Reynolds, G. P. The NR1 subunit of the glutamate/NMDA receptor in the superior temporal cortex in schizophrenia and affective disorders. Neurosci. Lett. 372, 173–177 (2004).

    CAS  PubMed  Google Scholar 

  45. Mundo, E. et al. Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder. Mol. Psychiatry 8, 241–245 (2003).

    CAS  PubMed  Google Scholar 

  46. Martucci, L. et al. N-methyl-D-aspartate receptor NR2B subunit gene GRIN2B in schizophrenia and bipolar disorder: polymorphisms and mRNA levels. Schizophr. Res. 84, 214–221 (2006).

    PubMed  Google Scholar 

  47. Woo, T. U., Walsh, J. P. & Benes, F. M. Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch. Gen. Psychiatry 61, 649–657 (2004). This article shows that there are alterations in neurons that express NMDA NR2A receptor subunits in post-mortem brain tissue of patients with BPD.

    CAS  PubMed  Google Scholar 

  48. Meador-Woodruff, J. H., Hogg, A. J. Jr., & Smith, R. E. Striatal ionotropic glutamate receptor expression in schizophrenia, bipolar disorder, and major depressive disorder. Brain Res. Bull. 55, 631–640 (2001).

    CAS  PubMed  Google Scholar 

  49. Beneyto, M. & Meador-Woodruff, J. H. Lamina-specific abnormalities of AMPA receptor trafficking and signaling molecule transcripts in the prefrontal cortex in schizophrenia. Synapse 60, 585–598 (2006).

    CAS  PubMed  Google Scholar 

  50. Kristiansen, L. V. & Meador-Woodruff, J. H. Abnormal striatal expression of transcripts encoding NMDA interacting PSD proteins in schizophrenia, bipolar disorder and major depression. Schizophr. Res. 78, 87–93 (2005).

    PubMed  Google Scholar 

  51. Clinton, S. M. & Meador-Woodruff, J. H. Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder. Neuropsychopharmacology 29, 1353–1362 (2004).

    CAS  PubMed  Google Scholar 

  52. Toro, C. & Deakin, J. F. NMDA receptor subunit NRI and postsynaptic protein PSD-95 in hippocampus and orbitofrontal cortex in schizophrenia and mood disorder. Schizophr. Res. 80, 323–330 (2005).

    PubMed  Google Scholar 

  53. Hamidi, M., Drevets, W. C. & Price, J. L. Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biol. Psychiatry 55, 563–569 (2004).

    PubMed  Google Scholar 

  54. Rajkowska, G. & Miguel-Hidalgo, J. J. Gliogenesis and glial pathology in depression. CNS Neurol. Disord. Drug Targets. 6, 219–233 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Ongur, D., Drevets, W. C. & Price, J. L. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc. Natl Acad. Sci. USA 95, 13290–13295 (1998). This article demonstrates that there is a reduction in the number of frontal cortex glia cells in mood disorders.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Rajkowska, G. et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol. Psychiatry 45, 1085–1098 (1999).

    CAS  PubMed  Google Scholar 

  57. Miguel-Hidalgo, J. J. et al. Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder. Biol. Psychiatry 48, 861–873 (2000).

    CAS  PubMed  Google Scholar 

  58. Rajkowska, G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol. Psychiatry 48, 766–777 (2000).

    CAS  PubMed  Google Scholar 

  59. Cotter, D., Mackay, D., Landau, S., Kerwin, R. & Everall, I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch. Gen. Psychiatry 58, 545–553 (2001).

    CAS  PubMed  Google Scholar 

  60. Rajkowska, G., Halaris, A. & Selemon, L. D. Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol. Psychiatry 49, 741–752 (2001).

    CAS  PubMed  Google Scholar 

  61. Webster, M. J. et al. Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression. Brain Behav. Immunity 15, 388–400 (2001).

    CAS  Google Scholar 

  62. Bowley, M. P., Drevets, W. C., Ongur, D. & Price, J. L. Low glial numbers in the amygdala in major depressive disorder. Biol. Psychiatry 52, 404–412 (2002).

    PubMed  Google Scholar 

  63. Choudary, P. V. et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc. Natl Acad. Sci. USA 102, 15653–15658 (2005). A microarray study showing that there are alterations in glutamatergic and GABAergic systems in depression.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. McCullumsmith, R. E. & Meador-Woodruff, J. H. Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder. Neuropsychopharmacology 26, 368–375 (2002).

    CAS  PubMed  Google Scholar 

  65. Zarate, C. A., Quiroz, J., Payne, J. & Manji, H. K. Modulators of the glutamatergic system: implications for the development of improved therapeutics in mood disorders. Psychopharmacol. Bull. 36, 35–83 (2002).

    PubMed  Google Scholar 

  66. Kugaya, A. & Sanacora, G. Beyond monoamines: glutamatergic function in mood disorders. CNS Spectr. 10, 808–819 (2005).

    PubMed  Google Scholar 

  67. Toro, C. T., Hallak, J. E., Dunham, J. S. & Deakin, J. F. Glial fibrillary acidic protein and glutamine synthetase in subregions of prefrontal cortex in schizophrenia and mood disorder. Neurosci. Lett. 404, 276–281 (2006).

    CAS  PubMed  Google Scholar 

  68. Trullas, R. & Skolnick, P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur. J. Pharmacol. 185, 1–10 (1990). This article discusses the antidepressant-like activity of NMDA antagonists in preclinical models.

    CAS  PubMed  Google Scholar 

  69. Sernagor, E., Kuhn, D., Vyklicky, L. Jr., & Mayer, M. L. Open channel block of NMDA receptor responses evoked by tricyclic antidepressants. Neuron 2, 1221–1227 (1989).

    CAS  PubMed  Google Scholar 

  70. Pittaluga, A. et al. Antidepressant treatments and function of glutamate ionotropic receptors mediating amine release in hippocampus. Neuropharmacology 53, 27–36 (2007).

    CAS  PubMed  Google Scholar 

  71. Nowak, G., Trullas, R., Layer, R. T., Skolnick, P. & Paul, I. A. Adaptive changes in the N-methyl-D-aspartate receptor complex after chronic treatment with imipramine and 1-aminocyclopropanecarboxylic acid. J. Pharmacol. Exp. Ther. 265, 1380–1386 (1993).

    CAS  PubMed  Google Scholar 

  72. Paul, I. A., Layer, R. T., Skolnick, P. & Nowak, G. Adaptation of the NMDA receptor in rat cortex following chronic electroconvulsive shock or imipramine. Eur. J. Pharmacol. 247, 305–311 (1993).

    CAS  PubMed  Google Scholar 

  73. Paul, I. A., Nowak, G., Layer, R. T., Popik, P. & Skolnick, P. Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments. J. Pharmacol. Exp. Ther. 269, 95–102 (1994).

    CAS  PubMed  Google Scholar 

  74. Skolnick, P. et al. Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry 29, 23–26 (1996).

    CAS  PubMed  Google Scholar 

  75. Nowak, G., Legutko, B., Skolnick, P. & Popik, P. Adaptation of cortical NMDA receptors by chronic treatment with specific serotonin reuptake inhibitors. Eur. J. Pharmacol. 342, 367–370 (1998).

    CAS  PubMed  Google Scholar 

  76. Wong, M. L. et al. Differential effects of kindled and electrically induced seizures on a glutamate receptor (GluR1) gene expression. Epilepsy Res. 14, 221–227 (1993).

    CAS  PubMed  Google Scholar 

  77. Naylor, P., Stewart, C. A., Wright, S. R., Pearson, R. C. & Reid, I. C. Repeated ECS induces GluR1 mRNA but not NMDAR1A-G mRNA in the rat hippocampus. Mol. Brain Res. 35, 349–353 (1996).

    CAS  PubMed  Google Scholar 

  78. Svenningsson, P. et al. Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac). Proc. Natl Acad. Sci. USA 99, 3182–3187 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Martinez-Turrillas, R., Del Rio, J. & Frechilla, D. Neuronal proteins involved in synaptic targeting of AMPA receptors in rat hippocampus by antidepressant drugs. Biochem. Biophys. Res. Commun. 353, 750–755 (2007).

    CAS  PubMed  Google Scholar 

  80. Barbon, A. et al. Regulation of editing and expression of glutamate α-amino-propionic-acid (AMPA)/kainate receptors by antidepressant drugs. Biol. Psychiatry 59, 713–720 (2006).

    CAS  PubMed  Google Scholar 

  81. Zarate, C. A. Jr, et al. Regulation of cellular plasticity cascades in the pathophysiology and treatment of mood disorders: role of the glutamatergic system. Ann. NY Acad. Sci. 1003, 273–291 (2003).

    CAS  PubMed  Google Scholar 

  82. Bowden, C. L. et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch. Gen. Psychiatry 57, 481–489 (2000).

    CAS  PubMed  Google Scholar 

  83. Hokin, L. E., Dixon, J. F. & Los, G. V. A novel action of lithium: stimulation of glutamate release and inositol 1,4,5 trisphosphate accumulation via activation of the N-methyl D-aspartate receptor in monkey and mouse cerebral cortex slices. Adv. Enzyme Regul. 36, 229–244 (1996).

    CAS  PubMed  Google Scholar 

  84. Nonaka, S., Hough, C. J. & Chuang, D. M. Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx. Proc. Natl Acad. Sci. USA 95, 2642–2647 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Hashimoto, R., Hough, C., Nakazawa, T., Yamamoto, T. & Chuang, D. M. Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation. J. Neurochem. 80, 589–597 (2002).

    CAS  PubMed  Google Scholar 

  86. Du, J. et al. Structurally dissimilar antimanic agents modulate synaptic plasticity by regulating AMPA glutamate receptor subunit GluR1 synaptic expression. Ann. NY Acad. Sci. 1003, 378–380 (2003).

    CAS  PubMed  Google Scholar 

  87. Du, J. et al. The role of hippocampal GluR1 and GluR2 receptors in manic-like behaviors. J. Neurosci. 28, 68–79 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Ahmad, S., Fowler, L. J. & Whitton, P. S. Effects of combined lamotrigine and valproate on basal and stimulated extracellular amino acids and monoamines in the hippocampus of freely moving rats. Naunyn Schmiedebergs Arch. Pharmacol. 371, 1–8 (2005).

    CAS  PubMed  Google Scholar 

  89. Du, J. et al. The anticonvulsants lamotrigine, riluzole, and valproate differentially regulate AMPA receptor membrane localization: relationship to clinical effects in mood disorders. Neuropsychopharmacology 32, 793–802 (2007).

    CAS  PubMed  Google Scholar 

  90. Mizuta, I. 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. 310, 117–120 (2001).

    CAS  PubMed  Google Scholar 

  91. Frizzo, M. E., Dall'Onder, L. P., Dalcin, K. B. & Souza, D. O. Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell. Mol. Neurobiol. 24, 123–128 (2004).

    CAS  PubMed  Google Scholar 

  92. Debono, M. W., Le Guern, J., Canton, T., Doble, A. & Pradier, L. Inhibition by riluzole of electrophysiological responses mediated by rat kainate and NMDA receptors expressed in Xenopus oocytes. Eur. J. Pharmacol. 235, 283–289 (1993).

    CAS  PubMed  Google Scholar 

  93. Jehle, T. et al. Effects of riluzole on electrically evoked neurotransmitter release. Br. J. Pharmacol. 130, 1227–1234 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Zarate, C. A. Jr, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am. J. Psychiatry 161, 171–174 (2004).

    PubMed  Google Scholar 

  95. Zarate, C. A. Jr, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol. Psychiatry 57, 430–432 (2005).

    CAS  PubMed  Google Scholar 

  96. Sanacora, G. et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol. Psychiatry 61, 822–825 (2007).

    CAS  PubMed  Google Scholar 

  97. Crane, G. Cycloserine as an antidepressant agent. Am. J. Psychiatry 115, 1025–1026 (1959).

    CAS  PubMed  Google Scholar 

  98. Crane, G. The psychotropic effect of cycloserine: a new use of an antibiotic. Comp. Psychiatry 2, 51–59 (1961).

    Google Scholar 

  99. Heresco-Levy, U. et al. Controlled trial of D-cycloserine adjuvant therapy for treatment-resistant major depressive disorder. J. Affect Disord. 93, 239–243 (2006).

    CAS  Google Scholar 

  100. van Berckel, B. N. et al. The partial NMDA agonist D-cycloserine stimulates LH secretion in healthy volunteers. Psychopharmacology (Berl.) 138, 190–197 (1998).

    CAS  Google Scholar 

  101. van Berckel, B. N. et al. Behavioral and neuroendocrine effects of the partial NMDA agonist D-cycloserine in healthy subjects. Neuropsychopharmacology 16, 317–324 (1997).

    CAS  PubMed  Google Scholar 

  102. Davis, M., Ressler, K., Rothbaum, B. O. & Richardson, R. Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol. Psychiatry 60, 369–375 (2006).

    CAS  PubMed  Google Scholar 

  103. Ressler, K. J. et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch. Gen. Psychiatry 61, 1136–1144 (2004).

    PubMed  Google Scholar 

  104. Guastella, A. J. et al. A randomized controlled trial of D-cycloserine enhancement of exposure therapy for social anxiety disorder. Biol. Psychiatry 63, 544–549 (2008).

    CAS  PubMed  Google Scholar 

  105. Kushner, M. G. et al. D-Cycloserine augmented exposure therapy for obsessive-compulsive disorder. Biol. Psychiatry 62, 835–838 (2007).

    CAS  PubMed  Google Scholar 

  106. Reisberg, B. et al. A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch. Neurol. 63, 49–54 (2006).

    PubMed  Google Scholar 

  107. Reisberg, B. et al. Memantine in moderate-to-severe Alzheimer's disease. N. Engl. J. Med. 348, 1333–1341 (2003).

    CAS  PubMed  Google Scholar 

  108. Teng, C. T. & Demetrio, F. N. Memantine may acutely improve cognition and have a mood stabilizing effect in treatment-resistant bipolar disorder. Rev. Bras. Psiquiatr. 28, 252–254 (2006).

    PubMed  Google Scholar 

  109. Zarate, C. A. Jr, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856–864 (2006). In this randomized, placebo-controlled, double-blind crossover study, ketamine, an NMDA receptor antagonist, was found to have long-lasting and sustained antidepressant effects that began minutes after its administration.

    CAS  PubMed  Google Scholar 

  110. Ferguson, J. M. & Shingleton, R. N. An open-label, flexible-dose study of memantine in major depressive disorder. Clin. Neuropharmacol. 30, 136–144 (2007).

    CAS  PubMed  Google Scholar 

  111. Harrison, N. L. & Simmonds, M. A. Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex. Br. J. Pharmacol. 84, 381–391 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Zarate, C. A., Charney, D. S. & Manji, H. K. Searching for rational anti-N-methyl-D-aspartate treatment for depression. Arch. Gen. Psychiatry 64, 1100–1101 (2007).

    Google Scholar 

  113. 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. 17, 2921–2927 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Maeng, S. et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol. Psychiatry 63, 349–352 (2008).

    CAS  PubMed  Google Scholar 

  115. Green, S. M. et al. Intravenous ketamine for pediatric sedation in the emergency department: safety profile with 156 cases. Acad. Emerg. Med. 5, 971–976 (1998).

    CAS  PubMed  Google Scholar 

  116. Britt, G. C. & McCance-Katz, E. F. A brief overview of the clinical pharmacology of “club drugs”. Subst. Use Misuse 40, 1189–1201 (2005).

    PubMed  Google Scholar 

  117. Perry, E. B. Jr, et al. Psychiatric safety of ketamine in psychopharmacology research. Psychopharmacology (Berl.) 192, 253–260 (2007).

    CAS  Google Scholar 

  118. Carpenter, W. T. J. The schizophrenia ketamine challenge study debate. Biol. Psychiatry 46, 1081–1091 (1999).

    PubMed  Google Scholar 

  119. Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351–354 (2000).

    CAS  PubMed  Google Scholar 

  120. Bleakman, D. & Lodge, D. Neuropharmacology of AMPA and kainate receptors. Neuropharmacology 37, 1187–1204 (1998).

    CAS  PubMed  Google Scholar 

  121. Borges, K. & Dingledine, R. AMPA receptors: molecular and functional diversity. Prog. Brain Res. 116, 153–170 (1998).

    CAS  PubMed  Google Scholar 

  122. Black, M. D. Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data. Psychopharmacology (Berl.) 179, 154–163 (2005).

    CAS  Google Scholar 

  123. Knapp, R. J. et al. Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model. Eur. J. Pharmacol. 440, 27–35 (2002).

    CAS  PubMed  Google Scholar 

  124. Li, X. et al. Antidepressant-like actions of an AMPA receptor potentiator (LY392098). Neuropharmacology 40, 1028–1033 (2001).

    CAS  PubMed  Google Scholar 

  125. Bai, F., Bergeron, M. & Nelson, D. L. Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus. Neuropharmacology 44, 1013–1021 (2003).

    CAS  PubMed  Google Scholar 

  126. Lauterborn, J., Lynch, G., Vanderklish, P., Arai, A. & CM., G. Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J. Neurosci. 20, 8–21 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Lauterborn, J. et al. Chronic elevation of brain-derived neurotrophic factor by ampakines. J. Pharmacol. Exp. Ther. 307, 297–305 (2003).

    CAS  PubMed  Google Scholar 

  128. Suetake-Koga, S. et al. In vitro and antinociceptive profile of HON0001, an orally active NMDA receptor NR2B subunit antagonist. Pharmacol. Biochem. Behav. 84, 134–141 (2006).

    CAS  PubMed  Google Scholar 

  129. Borza, I. et al. Selective NR1/2B N-methyl-D-aspartate receptor antagonists among indole-2-carboxamides and benzimidazole-2-carboxamides. J. Med. Chem. 50, 901–914 (2007).

    CAS  PubMed  Google Scholar 

  130. Liverton, N. J. et al. Identification and characterization of 4-methylbenzyl 4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate, an orally bioavailable, brain penetrant NR2B selective N-methyl-D-aspartate receptor antagonist. J. Med. Chem. 50, 807–819 (2007).

    CAS  PubMed  Google Scholar 

  131. Preskorn, S. et al. A placebo-controlled trial of the NR2B subunit specific NMDA antagonist CP-101,606 plus paroxetine for treatment resistant depression (TRD). Annual Conference of the American Psychological Association (San Francisco, California) 154 (2007).

    Google Scholar 

  132. Brown, R. H.,Jr. Amyotrophic lateral sclerosis — a new role for old drugs. N. Engl. J. Med. 352, 1376–1378 (2005).

    CAS  PubMed  Google Scholar 

  133. Miller, T. M. & Cleveland, D. W. Medicine. Treating neurodegenerative diseases with antibiotics. Science 307, 361–362 (2005).

    CAS  PubMed  Google Scholar 

  134. Rothstein, J. D. et al. β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433, 73–77 (2005).

    CAS  PubMed  Google Scholar 

  135. Mineur, Y. S., Picciotto, M. R. & Sanacora, G. Antidepressant-like effects of ceftriaxone in male C57BL/6J mice. Biol. Psychiatry 61, 250–252 (2006).

    PubMed  Google Scholar 

  136. D'Ascenzo, M. et al. mGluR5 stimulates gliotransmission in the nucleus accumbens. Proc. Natl Acad. Sci. USA 104, 1995–2000 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Haydon, P. G. & Carmignoto, G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol. Rev. 86, 1009–1031 (2006).

    CAS  PubMed  Google Scholar 

  138. Lee, Y., Gaskins, D., Anand, A. & Shekhar, A. Glia mechanisms in mood regulation: a novel model of mood disorders. Psychopharmacology (Berl.) 191, 55–65 (2007).

    Google Scholar 

  139. Palucha, A. & Pilc, A. Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol. Ther. 115, 116–147 (2007).

    CAS  PubMed  Google Scholar 

  140. Witkin, J. M., Marek, G. J., Johnson, B. G. & Schoepp, D. D. Metabotropic glutamate receptors in the control of mood disorders. CNS Neurol. Disord. Drug Targets. 6, 87–100 (2007).

    CAS  PubMed  Google Scholar 

  141. Karasawa, J., Shimazaki, T., Kawashima, N. & Chaki, S. AMPA receptor stimulation mediates the antidepressant-like effect of a group II metabotropic glutamate receptor antagonist. Brain Res. 1042, 92–98 (2005).

    CAS  PubMed  Google Scholar 

  142. Patil, S. T. et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nature Med. 13, 1102–1107 (2007).

    CAS  PubMed  Google Scholar 

  143. Dunayevich, E. et al. Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology 22 Aug 2007 (doi:10.1038/sj.npp.1301531).

    PubMed  Google Scholar 

  144. Bonanno, G. et al. Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus. J. Neurosci. 25, 3270–3279 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Wang, M., Yang, Y., Dong, Z., Cao, J. & Xu, L. 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 17, 1343–1346 (2006).

    CAS  PubMed  Google Scholar 

  146. Lesch, K. P. & Schmitt, A. Antidepressants and gene expression profiling: how to SNARE novel drug targets. Pharmacogenomics J. 2, 346–348 (2002).

    CAS  PubMed  Google Scholar 

  147. Thompson, C. M. et al. Inhibitor of the glutamate vesicular transporter (VGLUT). Curr. Med. Chem. 12, 2041–2056 (2005).

    CAS  PubMed  Google Scholar 

  148. Baker, D. A., Xi, Z. X., Shen, H., Swanson, C. J. & Kalivas, P. W. The origin and neuronal function of in vivo nonsynaptic glutamate. J. Neurosci. 22, 9134–9141 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Moran, M. M., McFarland, K., Melendez, R. I., Kalivas, P. W. & Seamans, J. K. Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. J. Neurosci. 25, 6389–6393 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Lafleur, D. L. et al. N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl.) 184, 254–256 (2006).

    CAS  Google Scholar 

  151. LaRowe, S. D. et al. Is cocaine desire reduced by N-acetylcysteine? Am. J. Psychiatry 164, 1115–1117 (2007).

    PubMed  Google Scholar 

  152. Carlson, P. J., Singh, J. B., Zarate, C. A. Jr, Drevets, W. C. & Manji, H. K. Neural circuitry and neuroplasticity in mood disorders: insights for novel therapeutic targets. NeuroRx 3, 22–41 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Du, J. et al. Modulation of synaptic plasticity by antimanic agents: the role of AMPA glutamate receptor subunit 1 synaptic expression. J. Neurosci. 24, 6578–6589 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Conn, P. J. Physiological roles and therapeutic potential of metabotropic glutamate receptors. Ann. NY Acad. Sci. 1003, 12–21 (2003).

    CAS  PubMed  Google Scholar 

  155. Balazs, R., Bridges, R. J. & Cotman, C. W. Excitatory Amino Acid Transmission in Health and Disease (Oxford University Press, USA, New York, 2005).

    Google Scholar 

  156. Hardingham, G. E., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nature Neurosci. 5, 405–414 (2002).

    CAS  PubMed  Google Scholar 

  157. Ivanov, A. et al. Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of the extracellular signal-regulated kinases (ERK) activity in cultured rat hippocampal neurons. J. Physiol. 572, 789–798 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Agid, Y. et al. How can drug discovery for psychiatric disorders be improved? Nature Rev. Drug Discov. 6, 189–201 (2007).

    CAS  Google Scholar 

  159. Michael-Titus, A. T., Bains, S., Jeetle, J. & Whelpton, R. Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex — a possible mechanism of neuroprotection in major depression? Neuroscience 100, 681–684 (2000).

    CAS  PubMed  Google Scholar 

  160. White, G., Lovinger, D. M., Peoples, R. W. & Weight, F. F. Inhibition of N-methyl-D-aspartate activated ion current by desmethylimipramine. Brain Res. 537, 337–339 (1990).

    CAS  PubMed  Google Scholar 

  161. Boyer, P. A., Skolnick, P. & Fossom, L. H. Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain. A quantitative in situ hybridization study. J. Mol. Neurosci. 10, 219–233 (1998).

    CAS  PubMed  Google Scholar 

  162. Song, I. et al. Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors. Neuron 21, 393–400 (1998).

    CAS  PubMed  Google Scholar 

  163. Stoll, L., Seguin, S. & Gentile, L. Tricyclic antidepressants, but not the selective serotonin reuptake inhibitor fluoxetine, bind to the S1S2 domain of AMPA receptors. Arch. Biochem. Biophys. 458, 213–219 (2007).

    CAS  PubMed  Google Scholar 

  164. Moutsimilli, L. et al. Selective cortical VGLUT1 increase as a marker for antidepressant activity. Neuropharmacology 49, 890–900 (2005).

    CAS  PubMed  Google Scholar 

  165. Tordera, R. M., Pei, Q. & Sharp, T. Evidence for increased expression of the vesicular glutamate transporter, VGLUT1, by a course of antidepressant treatment. J. Neurochem. 94, 875–883 (2005).

    CAS  PubMed  Google Scholar 

  166. Dixon, J. F., Los, G. V. & Hokin, L. E. Lithium stimulates glutamate “release” and inositol 1,4,5-trisphosphate accumulation via activation of the N-methyl-D-aspartate receptor in monkey and mouse cerebral cortex slices. Proc. Natl Acad. Sci. USA 91, 8358–8362 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Dixon, J. F. & Hokin, L. E. Lithium stimulates accumulation of second-messenger inositol 1,4,5-trisphosphate and other inositol phosphates in mouse pancreatic minilobules without inositol supplementation. Biochem. J. 304, 251–258 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Ma, J. & Zhang, G. Y. Lithium reduced N-methyl-D-aspartate receptor subunit 2A tyrosine phosphorylation and its interactions with Src and Fyn mediated by PSD-95 in rat hippocampus following cerebral ischemia. Neurosci. Lett. 348, 185–189 (2003).

    CAS  PubMed  Google Scholar 

  169. Karkanias, N. B. & Papke, R. L. Lithium modulates desensitization of the glutamate receptor subtype gluR3 in Xenopus oocytes. Neurosci. Lett. 277, 153–156 (1999).

    CAS  PubMed  Google Scholar 

  170. Kang, T. C. et al. Valproic acid reduces enhanced vesicular glutamate transporter immunoreactivities in the dentate gyrus of the seizure prone gerbil. Neuropharmacology 49, 912–921 (2005).

    CAS  PubMed  Google Scholar 

  171. Cunningham, M. O., Woodhall, G. L. & Jones, R. S. Valproate modifies spontaneous excitation and inhibition at cortical synapses in vitro. Neuropharmacology 45, 907–917 (2003).

    CAS  PubMed  Google Scholar 

  172. Ueda, Y. & Willmore, L. J. Molecular regulation of glutamate and GABA transporter proteins by valproic acid in rat hippocampus during epileptogenesis. Exp. Brain Res. 133, 334–339 (2000).

    CAS  PubMed  Google Scholar 

  173. Hassel, B., Iversen, E. G., Gjerstad, L. & Tauboll, E. Up-regulation of hippocampal glutamate transport during chronic treatment with sodium valproate. J. Neurochem. 77, 1285–1292 (2001).

    CAS  Google Scholar 

  174. Loscher, W. Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain. Neurochem. Res. 18, 485–502 (1993).

    CAS  PubMed  Google Scholar 

  175. Zeise, M. L., Kasparow, S. & Zieglgansberger, W. Valproate suppresses N-methyl-D-aspartate-evoked, transient depolarizations in the rat neocortex in vitro. Brain Res. 544, 345–348 (1991).

    CAS  PubMed  Google Scholar 

  176. Ko, G. Y., Brown-Croyts, L. M. & Teyler, T. J. The effects of anticonvulsant drugs on NMDA-EPSP, AMPA-EPSP, and GABA-IPSP in the rat hippocampus. Brain Res. Bull. 42, 297–302 (1997).

    CAS  PubMed  Google Scholar 

  177. Turski, L. The N-methyl-D-aspartate receptor complex. Various sites of regulation and clinical consequences. Arzneimittelforschung 40, 511–514 (1990) (in German).

    CAS  PubMed  Google Scholar 

  178. Steppuhn, K. G. & Turski, L. Modulation of the seizure threshold for excitatory amino acids in mice by antiepileptic drugs and chemoconvulsants. J. Pharmacol. Exp. Ther. 265, 1063–1070 (1993).

    CAS  PubMed  Google Scholar 

  179. Kunig, G. et al. Inhibition of [3H]α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA] binding by the anticonvulsant valproate in clinically relevant concentrations: an autoradiographic investigation in human hippocampus. Epilepsy Res. 31, 153–157 (1998).

    CAS  PubMed  Google Scholar 

  180. Basselin, M., Chang, L., Bell, J. M. & Rapoport, S. I. Chronic lithium chloride administration attenuates brain NMDA receptor-initiated signaling via arachidonic acid in unanesthetized rats. Neuropsychopharmacology 31, 1659–1674 (2006).

    CAS  PubMed  Google Scholar 

  181. Zarate, C. A. J. et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am. J. Psychiatry 163, 153–155 (2006).

    PubMed  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the support of the Intramural Research Program of the National Institute of Mental Heath, the Stanley Medical Research Institute and NARSAD. NIMH K02MH076222 (GS). I. Henter provided outstanding editorial assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Husseini K. Manji.

Ethics declarations

Competing interests

Gerard Sanacora and John Krystal are co-sponsors of a patent application (PCTWO06108055A1) that was filed by Yale University related to the use of drugs that modulate glutamate neurotransmission for the treatment of depression. A patent application for the use of ketamine in depression has been submitted listing Husseini K. Manji and Carlos A. Zarate among the inventors. H.K.M. and C.A.Z. have assigned their rights on the patent to the US government.

Related links

Related links

DATABASES

OMIM

Alzheimer's disease

amyotrophic lateral sclerosis

bipolar disorder

Huntington's chorea

major depressive disorder

schizophrenia

Glossary

Major depressive disorder

(MDD). A chronic mood disorder that is characterized by a long-lasting depressed mood or marked loss of interest or pleasure in all or nearly all activities. MDD often affects mental efficiency, memory, appetite and sleep habits.

Bipolar disorder

(BPD). A mood disorder whereby affected individuals alternate between states of deep depression and mania. Whereas depression is characterized by persistent and long-term sadness or despair, mania is a mental state that is characterized by great excitement, flight of ideas, a decreased need for sleep, and, sometimes, uncontrollable behaviour, hallucinations or delusions.

Synaptic plasticity

The cellular processes that result in lasting changes in the efficacy of neurotransmission. Changes in neurotransmitter levels, receptor subunit phosphorylation, surface/cellular levels of receptors and conductance changes all regulate the strength of signal transmission at the synapse.

Neural plasticity

Changes in intracellular signalling cascades and gene regulation that lead to modifications of synapse number and strength, variations in neurotransmitter release, remodelling of axonal and dendritic architecture and, in some areas of the CNS, the generation of new neurons. These modifications can be of short duration or long lasting.

Glutamate/glutamine cycle

Process through which most brain glutamate is recycled. Glutamate released by neurons is converted to glutamine in astrocytes. Glutamine is then transported out for re-uptake by neurons, which convert it back into glutamate via the action of glutaminase.

RNA editing

Molecular processes in which the information content is altered in a RNA molecule through a chemical change in the base make-up.

Montgomery–Asberg Depression Rating Scale

An 11-item clinician-administered questionnaire that is used to rate the severity of a patient's depression.

Hamilton Depression Rating Scale

A 21-item, clinician-administered questionnaire that is used to rate the severity of a patient's depression.

Psychotomimetic

Refers to a drug or substance that produces psychological or behavioural changes that resemble those of a psychotic state.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sanacora, G., Zarate, C., Krystal, J. et al. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 7, 426–437 (2008). https://doi.org/10.1038/nrd2462

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2462

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing