Targeting glutamate signalling in depression: progress and prospects

Key Points

  • Depression is one of the leading causes of disability worldwide; however, no truly mechanistically novel compounds have come to the market in decades.

  • Ignited by the observation of a rapid antidepressant effect of the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, the glutamate system has emerged as a leading focus for novel drug discovery for depression and other mood disorders.

  • New basic and clinical research is clarifying the mechanistic relevance and therapeutic feasibility of multiple targets within the glutamate system for novel drug discovery, including NMDA and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, metabotropic glutamate receptors, and other key regulatory proteins such as glycine transporter 1 and excitatory amino acid transporters.

  • Encouragingly, multiple glutamate-based compounds have entered clinical testing, with some compounds recently advancing to phase III trials.

Abstract

Major depressive disorder (MDD) is severely disabling, and current treatments have limited efficacy. The glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine was recently repurposed as a rapidly acting antidepressant, catalysing the vigorous investigation of glutamate-signalling modulators as novel therapeutic agents for depressive disorders. In this Review, we discuss the progress made in the development of such modulators for the treatment of depression, and examine recent preclinical and translational studies that have investigated the mechanisms of action of glutamate-targeting antidepressants. Fundamental questions remain regarding the future prospects of this line of drug development, including questions concerning safety and tolerability, efficacy, dose–response relationships and therapeutic mechanisms.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Glutamate signalling in health and disease.
Figure 2: The antidepressant mechanism of action of NMDAR modulators.

References

  1. 1

    Collins, P. Y. et al. Grand challenges in global mental health. Nature 475, 27–30 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Whiteford, H. A. et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 382, 1575–1586 (2013).

    Article  PubMed  Google Scholar 

  3. 3

    Mrazek, D. A., Hornberger, J. C., Altar, C. A. & Degtiar, I. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996–2013. Psychiatr. Serv. 65, 977–987 (2014).

    Article  PubMed  Google Scholar 

  4. 4

    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).

    Article  PubMed  Google Scholar 

  5. 5

    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).

    Article  PubMed  Google Scholar 

  6. 6

    Abdallah, C. G., Sanacora, G., Duman, R. S. & Krystal, J. H. Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. Annu. Rev. Med. 66, 509–523 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. 7

    Papakostas, G. I. & Ionescu, D. F. Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder. Mol. Psychiatry 20, 1142–1150 (2015). This review provides a concise overview of new directions in treatment development for TRD, including treatments targeting the glutamate system, the opioid system, inflammatory signalling systems and others.

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Mathew, S. J. Glycine transporter-I inhibitors: a new class of antidepressant? Biol. Psychiatry 74, 710–711 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. 9

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

    Article  CAS  PubMed  Google Scholar 

  10. 10

    Duman, R. S. & Aghajanian, G. K. Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 68–72 (2012). This review integrates preclinical research related to the effects of both stress and antidepressant treatment on synaptic plasticity, and proposes normalization of synaptic function as a final common pathway for depression treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Morris, R. G., Anderson, E., Lynch, G. S. & Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319, 774–776 (1986).

    Article  CAS  PubMed  Google Scholar 

  12. 12

    Cole, A. J., Saffen, D. W., Baraban, J. M. & Worley, P. F. Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 340, 474–476 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. 13

    Hardingham, G. E., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414 (2002). This report describes opposing effects of synaptic compared with extrasynaptic NMDARs on BDNF expression and cell survival: the activation of synaptic NMDARs led to upregulation of BDNF expression and the activation of extra-synaptic NMDARs reduced BDNF expression.

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Stanika, R. I. et al. Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity. Proc. Natl Acad. Sci. USA 106, 9854–9859 (2009).

    Article  PubMed  Google Scholar 

  15. 15

    Hardingham, G. E. & Bading, H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11, 682–696 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Papouin, T. & Oliet, S. H. Organization, control and function of extrasynaptic NMDA receptors. Phil. Trans. R. Soc. B 369, 20130601 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Duman, R. S. & Monteggia, L. M. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59, 1116–1127 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. 18

    Krishnan, V. & Nestler, E. J. The molecular neurobiology of depression. Nature 455, 894–902 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Olney, J. W., Labruyere, J. & Price, M. T. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244, 1360–1362 (1989).

    Article  CAS  PubMed  Google Scholar 

  20. 20

    Olney, J. W. et al. NMDA antagonist neurotoxicity: mechanism and prevention. Science 254, 1515–1518 (1991).

    Article  CAS  PubMed  Google Scholar 

  21. 21

    Camacho, A. & Massieu, L. Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death. Arch. Med. Res. 37, 11–18 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. 22

    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).

    Article  CAS  PubMed  Google Scholar 

  23. 23

    Sanacora, G., Zarate, C. A., Krystal, J. H. & Manji, H. K. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat. Rev. Drug Discov. 7, 426–437 (2008). This comprehensive review brings together multiple lines of evidence for the dysfunction of the glutamate system in mood disorders, including genetic, post-mortem and in vivo neuroimaging data.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Smoller, J. W. The genetics of stress-related disorders: PTSD, depression, and anxiety disorders. Neuropsychopharmacology 41, 297–319 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. 25

    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).

    Article  CAS  PubMed  Google Scholar 

  26. 26

    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).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    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).

    Article  CAS  PubMed  Google Scholar 

  28. 28

    Karolewicz, B., Stockmeier, C. A. & Ordway, G. A. Elevated levels of the NR2C subunit of the NMDA receptor in the locus coeruleus in depression. Neuropsychopharmacology 30, 1557–1567 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    McCullumsmith, R. E. et al. Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder. Brain Res. 1127, 108–118 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Karolewicz, B. et al. Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression. Int. J. Neuropsychopharmacol. 12, 143–153 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. 31

    Feyissa, A. M., Chandran, A., Stockmeier, C. A. & Karolewicz, B. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 70–75 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. 32

    Chandley, M. J. et al. Elevated gene expression of glutamate receptors in noradrenergic neurons from the locus coeruleus in major depression. Int. J. Neuropsychopharmacol. 17, 1569–1578 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. 33

    Gray, A. L., Hyde, T. M., Deep-Soboslay, A., Kleinman, J. E. & Sodhi, M. S. Sex differences in glutamate receptor gene expression in major depression and suicide. Mol. Psychiatry 20, 1057–1068 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. 34

    Sanacora, G. & Banasr, M. From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders. Biol. Psychiatry 73, 1172–1179 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    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 study provides an early report of the loss of glial cells within the PFC of patients with mood disorders, consistent with the hypothesized glutamate abnormalities in these disorders.

    Article  CAS  PubMed  Google Scholar 

  36. 36

    Banasr, M. et al. Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol. Psychiatry 15, 501–511 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Duman, R. S., Aghajanian, G. K., Sanacora, G. & Krystal, J. H. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat. Med. 22, 238–249 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Popoli, M., Yan, Z., McEwen, B. S. & Sanacora, G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat. Rev. Neurosci. 13, 22–37 (2011). This comprehensive review summarizes the diverse mechanisms by which glutamate signalling is influenced by stress and by the functioning of the glucocorticoid system.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Manji, H. K. et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol. Psychiatry 53, 707–742 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. 40

    Kempton, M. J. et al. Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder. Arch. Gen. Psychiatry 68, 675–690 (2011).

    Article  PubMed  Google Scholar 

  41. 41

    Yuksel, C. & Ongur, D. Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol. Psychiatry 68, 785–794 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Kaiser, R. H., Andrews-Hanna, J. R., Wager, T. D. & Pizzagalli, D. A. Large-scale network dysfunction in major depressive disorder: a meta-analysis of resting-state functional connectivity. JAMA Psychiatry 72, 603–611 (2015). This recent meta-analysis provides a comprehensive examination of resting-state network alterations reported in patients with depression.

    Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Hasler, G. et al. Reduced prefrontal glutamate/glutamine and γ-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch. Gen. Psychiatry 64, 193–200 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. 44

    Sanacora, G. et al. Reduced cortical γ-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch. Gen. Psychiatry 56, 1043–1047 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. 45

    Sanacora, G. et al. Subtype-specific alterations of γ-aminobutyric acid and glutamate in patients with major depression. Arch. Gen. Psychiatry 61, 705–713 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. 46

    Deschwanden, A. et al. Reduced metabotropic glutamate receptor 5 density in major depression determined by [11C]ABP688 PET and postmortem study. Am. J. Psychiatry 168, 727–734 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Abdallah, C. G. et al. Glutamate metabolism in major depressive disorder. Am. J. Psychiatry 171, 1320–1327 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Hirota, K. & Lambert, D. G. Ketamine: its mechanism(s) of action and unusual clinical uses. Br. J. Anaesth. 77, 441–444 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    Zanos, P. et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481–486 (2016). This recent preclinical study showed that the metabolism of racemic ketamine to (2 R ,6 R )-HNK is necessary for the antidepressant effects of ketamine, and that this metabolite itself shows antidepressant-like effects in mice that seem to be independent of the NMDAR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Zhang, J. C., Li, S. X. & Hashimoto, K. R (–)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacol. Biochem. Behav. 116, 137–141 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Yang, C. et al. R-Ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry 5, e632 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    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).

    Article  CAS  PubMed  Google Scholar 

  53. 53

    Murrough, J. W. et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am. J. Psychiatry 170, 1134–1142 (2013). This first multi-site RCT using a psychoactive control condition demonstrated a rapid antidepressant effect of ketamine in patients with TRD.

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Newport, D. J. et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am. J. Psychiatry 172, 950–966 (2015).

    Article  PubMed  Google Scholar 

  55. 55

    McGirr, A. et al. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol. Med. 45, 693–704 (2015).

    Article  CAS  PubMed  Google Scholar 

  56. 56

    Caddy, C. et al. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst. Rev. 9, CD011612 (2015).

    Google Scholar 

  57. 57

    aan het Rot, M. et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol. Psychiatry 67, 139–145 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Murrough, J. W. et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol. Psychiatry 74, 250–256 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. 59

    Shiroma, P. R. et al. Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. J. Affect. Disord. 155, 123–129 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. 60

    Rasmussen, K. G. et al. Serial infusions of low-dose ketamine for major depression. J. Psychopharmacol. 27, 444–450 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Segmiller, F. et al. Repeated S-ketamine infusions in therapy resistant depression: a case series. J. Clin. Pharmacol. 53, 996–998 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. 62

    Cusin, C. et al. Ketamine augmentation for outpatients with treatment-resistant depression: preliminary evidence for two-step intravenous dose escalation. Aust. N. Z. J. Psychiatry 51, 55–64 (2017).

    Article  PubMed  Google Scholar 

  63. 63

    Singh, J. B. et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am. J. Psychiatry 173, 816–826 (2016). This is the first RCT of repeated ketamine dosing in patients with TRD, in which two- and three-times weekly treatment schedules over up to 4 weeks showed comparable efficacy that was superior to placebo.

    Article  PubMed  Google Scholar 

  64. 64

    Hu, Y. D. et al. Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study. Psychol. Med. 46, 623–635 (2016).

    Article  PubMed  Google Scholar 

  65. 65

    Lapidus, K. A. et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol. Psychiatry 76, 970–976 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Loo, C. K. et al. Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatr. Scand. 134, 48–56 (2016).

    Article  CAS  PubMed  Google Scholar 

  67. 67

    Schoevers, R. A., Chaves, T. V., Balukova, S. M., Rot, M. A. & Kortekaas, R. Oral ketamine for the treatment of pain and treatment-resistant depression. Br. J. Psychiatry 208, 108–113 (2016).

    Article  PubMed  Google Scholar 

  68. 68

    Lally, N. et al. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry 4, e469 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Lally, N. et al. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J. Psychopharmacol. 29, 596–607 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Saligan, L. N., Luckenbaugh, D. A., Slonena, E. E., Machado-Vieira, R. & Zarate, C. A. Jr. An assessment of the anti-fatigue effects of ketamine from a double-blind, placebo-controlled, crossover study in bipolar disorder. J. Affect. Disord. 194, 115–119 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Price, R. B., Nock, M. K., Charney, D. S. & Mathew, S. J. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol. Psychiatry 66, 522–526 (2009). This early study reported rapid effects of ketamine on patient reports of suicidal thinking, as well as on implicit cognitive measures that had been previously linked to suicide risk.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Price, R. B. et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress. Anxiety 31, 335–343 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Ballard, E. D. et al. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J. Psychiatr. Res. 58, 161–166 (2014).

    Article  PubMed  Google Scholar 

  74. 74

    Murrough, J. W. et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychol. Med. 45, 3571–3580 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. 75

    Murrough, J. W. et al. Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response. Psychopharmacology (Berl.) 231, 481–488 (2014).

    Article  CAS  Google Scholar 

  76. 76

    Murrough, J. W. et al. Neurocognitive effects of ketamine and association with antidepressant response in individuals with treatment-resistant depression: a randomized controlled trial. Neuropsychopharmacology 40, 1084–1090 (2015).

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Shiroma, P. R. et al. Neurocognitive performance and serial intravenous subanesthetic ketamine in treatment-resistant depression. Int. J. Neuropsychopharmacol. 17, 1805–1813 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. 78

    Lee, Y. et al. A new perspective on the anti-suicide effects with ketamine treatment: a procognitive effect. J. Clin. Psychopharmacol. 36, 50–56 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. 79

    Singh, J. B. et al. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol. Psychiatry 80, 424–431 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. 80

    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).

    Article  CAS  PubMed  Google Scholar 

  81. 81

    Papp, M. & Moryl, E. Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Eur. J. Pharmacol. 263, 1–7 (1994).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Li, N. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959–964 (2010). This landmark report demonstrates rapid-onset antidepressant effects of ketamine dependent on the activation of the mTOR pathway and increased number and function of new spine synapses in the PFC of rats.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Autry, A. E. et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95 (2011). This important preclinical study showed that ketamine and other NMDAR antagonists produce fast-acting antidepressant-like effects in mouse models that depend on the rapid synthesis of BDNF via a mechanism that includes the deactivation of eEF2 kinase.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Donahue, R. J., Muschamp, J. W., Russo, S. J., Nestler, E. J. & Carlezon, W. A. Jr. Effects of striatal ΔFosB overexpression and ketamine on social defeat stress-induced anhedonia in mice. Biol. Psychiatry 76, 550–558 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Gideons, E. S., Kavalali, E. T. & Monteggia, L. M. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc. Natl Acad. Sci. USA 111, 8649–8654 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Chowdhury, G. M. et al. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol. Psychiatry 22, 120–126 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    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).

    Article  CAS  PubMed  Google Scholar 

  88. 88

    Voleti, B. et al. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol. Psychiatry 74, 742–749 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    Liu, R. J. et al. GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. Neuropsychopharmacology http://dx.doi.org/10.1038/npp.2016.202 (2016).

  90. 90

    Jimenez-Sanchez, L. et al. Activation of AMPA receptors mediates the antidepressant action of deep brain stimulation of the infralimbic prefrontal cortex. Cereb. Cortex 26, 2778–2789 (2016).

    Article  PubMed  Google Scholar 

  91. 91

    Citri, A. & Malenka, R. C. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology 33, 18–41 (2008).

    Article  PubMed  Google Scholar 

  92. 92

    Turrigiano, G. Too many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement. Annu. Rev. Neurosci. 34, 89–103 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Popp, S. et al. In search of the mechanisms of ketamine's antidepressant effects: how robust is the evidence behind the mTor activation hypothesis. F1000Res. 5, 634 (2016).

    Article  Google Scholar 

  94. 94

    Beurel, E., Song, L. & Jope, R. S. Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol. Psychiatry 16, 1068–1070 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Liu, R. J. et al. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology 38, 2268–2277 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Beurel, E., Grieco, S. F., Amadei, C., Downey, K. & Jope, R. S. Ketamine-induced inhibition of glycogen synthase kinase-3 contributes to the augmentation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor signaling. Bipolar Disord. 18, 473–480 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Yang, J. J. et al. Serum interleukin-6 is a predictive biomarker for ketamine's antidepressant effect in treatment-resistant patients with major depression. Biol. Psychiatry 77, e19–e20 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Wesseling, H., Rahmoune, H., Tricklebank, M., Guest, P. C. & Bahn, S. A targeted multiplexed proteomic investigation identifies ketamine-induced changes in immune markers in rat serum and expression changes in protein kinases/phosphatases in rat brain. J. Proteome Res. 14, 411–421 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Park, M. et al. Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression. J. Psychiatr. Res. 84, 113–118 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Milak, M. S. et al. A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder. Mol. Psychiatry 21, 320–327 (2015). This in vivo1H-MRS study demonstrated that ketamine administration is associated with a transient rise in Glx and GABA levels in patients with depression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Stone, J. M. et al. Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology. Mol. Psychiatry 17, 664–665 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. 102

    Luckenbaugh, D. A. et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J. Affect. Disord. 159, 56–61 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Wan, L. L. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J. Clin. Psychiatry 76, 247–252 (2015).

    Article  PubMed  Google Scholar 

  104. 104

    Deakin, J. F. et al. Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Arch. Gen. Psychiatry 65, 154–164 (2008).

    Article  PubMed  Google Scholar 

  105. 105

    Downey, D. et al. Comparing the actions of lanicemine and ketamine in depression: key role of the anterior cingulate. Eur. Neuropsychopharmacol. 26, 994–1003 (2016).

    Article  CAS  PubMed  Google Scholar 

  106. 106

    Li, M. et al. Temporal dynamics of antidepressant ketamine effects on glutamine cycling follow regional fingerprints of AMPA and NMDA receptor densities. Neuropsychopharmacology http://dx.doi.org/10.1038/npp.2016.184 (2016).

  107. 107

    Murrough, J. W. et al. Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Transl Psychiatry 5, e509 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Scheidegger, M. et al. Ketamine administration reduces amygdalo-hippocampal reactivity to emotional stimulation. Hum. Brain Mapp. 37, 1941–1952 (2016).

    Article  PubMed  Google Scholar 

  109. 109

    Murrough, J. W. et al. Reduced global functional connectivity of the medial prefrontal cortex in major depressive disorder. Hum. Brain Mapp. 37, 3214–3223 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Abdallah, C. G. et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology http://dx.doi.org/10.1038/npp.2016.186 (2016).

  111. 111

    Carlson, P. J. et al. Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study. Biol. Psychiatry 73, 1213–1221 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Nugent, A. C. et al. Neural correlates of rapid antidepressant response to ketamine in bipolar disorder. Bipolar Disord. 16, 119–128 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Machado-Vieira, R. et al. Brain-derived neurotrophic factor and initial antidepressant response to an N-methyl-D-aspartate antagonist. J. Clin. Psychiatry 70, 1662–1666 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Haile, C. N. et al. Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression. Int. J. Neuropsychopharmacol. 17, 331–336 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Esser, S. K., Hill, S. L. & Tononi, G. Sleep homeostasis and cortical synchronization: I. modeling the effects of synaptic strength on sleep slow waves. Sleep 30, 1617–1630 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Duncan, W. C. et al. Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder. Int. J. Neuropsychopharmacol. 16, 301–311 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. 117

    Laje, G. et al. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol. Psychiatry 72, e27–28 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Preskorn, S. H. 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. 28, 631–637 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. 119

    Sanacora, G. et al. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol. Psychiatry 19, 978–985 (2014).

    Article  CAS  PubMed  Google Scholar 

  120. 120

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

    Article  CAS  PubMed  Google Scholar 

  121. 121

    Heresco-Levy, U. et al. A randomized add-on trial of high-dose D-Cycloserine for treatment-resistant depression. Int. J. Neuropsychopharmacol. 16, 501–506 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Kantrowitz, J. T., Halberstam, B. & Gangwisch, J. Single-dose ketamine followed by daily D-Cycloserine in treatment-resistant bipolar depression. J. Clin. Psychiatry 76, 737–738 (2015).

    Article  PubMed  Google Scholar 

  123. 123

    Zhang, X. L., Sullivan, J. A., Moskal, J. R. & Stanton, P. K. A. NMDA receptor glycine site partial agonist, GLYX-13, simultaneously enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in hippocampus. Neuropharmacology 55, 1238–1250 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Burgdorf, J. et al. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology 38, 729–742 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Preskorn, S. et al. Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J. Psychiatr. Pract. 21, 140–149 (2015).

    Article  PubMed  Google Scholar 

  126. 126

    Ibrahim, L. et al. A randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. J. Clin. Psychopharmacol. 32, 551–557 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Kemp, J. A. et al. 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex. Proc. Natl Acad. Sci. USA 85, 6547–6550 (1988).

    Article  CAS  PubMed  Google Scholar 

  128. 128

    Zanos, P. et al. The prodrug 4-chlorokynurenine causes ketamine-like antidepressant effects, but not side effects, by NMDA/glycineB-site inhibition. J. Pharmacol. Exp. Ther. 355, 76–85 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Mullard, A. Deuterated drugs draw heavier backing. Nat. Rev. Drug Discov. 15, 219–221 (2016).

    Article  CAS  PubMed  Google Scholar 

  130. 130

    Huang, C. C. et al. Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biol. Psychiatry 74, 734–741 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. 131

    Durr, K. L. et al. Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states. Cell 158, 778–792 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Ward, S. E., Bax, B. D. & Harries, M. Challenges for and current status of research into positive modulators of AMPA receptors. Br. J. Pharmacol. 160, 181–190 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Nations, K. R. et al. Maximum tolerated dose evaluation of the AMPA modulator Org 26576 in healthy volunteers and depressed patients: a summary and method analysis of bridging research in support of phase II dose selection. Drugs R. D. 12, 127–139 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Nations, K. R. et al. Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial. J. Psychopharmacol. 26, 1525–1539 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. 135

    Dwyer, J. M., Lepack, A. E. & Duman, R. S. mGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure. J. Mol. Psychiatry 1, 15 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  136. 136

    Witkin, J. M. et al. The rapidly acting antidepressant ketamine and the mGlu2/3 receptor antagonist LY341495 rapidly engage dopaminergic mood circuits. J. Pharmacol. Exp. Ther. 358, 71–82 (2016).

    Article  CAS  PubMed  Google Scholar 

  137. 137

    Hughes, Z. A. et al. Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression. Neuropharmacology 66, 202–214 (2013).

    Article  CAS  PubMed  Google Scholar 

  138. 138

    Quiroz, J. A. et al. Efficacy and safety of basimglurant as adjunctive therapy for major depression: a randomized clinical trial. JAMA Psychiatry 73, 675–684 (2016).

    Article  PubMed  Google Scholar 

  139. 139

    Jain, F. A., Hunter, A. M., Brooks, J. O. III & Leuchter, A. F. Predictive socioeconomic and clinical profiles of antidepressant response and remission. Depress. Anxiety 30, 624–630 (2013).

    Article  CAS  PubMed  Google Scholar 

  140. 140

    Miller, S. et al. Cognition-childhood maltreatment interactions in the prediction of antidepressant outcomes in major depressive disorder patients: results from the iSPOT-D trial. Depress. Anxiety 32, 594–604 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Williams, L. M. et al. Amygdala reactivity to emotional faces in the prediction of general and medication-specific responses to antidepressant treatment in the randomized iSPOT-D trial. Neuropsychopharmacology 40, 2398–2408 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Breitenstein, B. et al. ABCB1 gene variants and antidepressant treatment outcome: a meta-analysis. Am. J. Med. Genet. B Neuropsychiatr. Genet. 168B, 274–283 (2015).

    Article  CAS  Google Scholar 

  143. 143

    Zarate, C. A. Jr et al. A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biol. Psychiatry 74, 257–264 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. 144

    Tan, S., Lam, W. P., Wai, M. S., Yu, W. H. & Yew, D. T. Chronic ketamine administration modulates midbrain dopamine system in mice. PLoS ONE 7, e43947 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Williams, N. R. & Schatzberg, A. F. NMDA antagonist treatment of depression. Curr. Opin. Neurobiol. 36, 112–117 (2016).

    Article  CAS  PubMed  Google Scholar 

  146. 146

    Miller, A. H. Conceptual confluence: the kynurenine pathway as a common target for ketamine and the convergence of the inflammation and glutamate hypotheses of depression. Neuropsychopharmacology 38, 1607–1608 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Dale, O., Somogyi, A. A., Li, Y., Sullivan, T. & Shavit, Y. Does intraoperative ketamine attenuate inflammatory reactivity following surgery? A systematic review and meta-analysis. Anesth. Analg. 115, 934–943 (2012).

    Article  CAS  PubMed  Google Scholar 

  148. 148

    Choi, M. et al. Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats. Proc. Natl Acad. Sci. USA 112, 15755–15760 (2015).

    Article  CAS  PubMed  Google Scholar 

  149. 149

    Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000).

    Article  CAS  PubMed  Google Scholar 

  150. 150

    Kew, J. N. & Kemp, J. A. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl.) 179, 4–29 (2005).

    Article  CAS  Google Scholar 

  151. 151

    Schoepp, D. D. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J. Pharmacol. Exp. Ther. 299, 12–20 (2001).

    CAS  PubMed  Google Scholar 

  152. 152

    Trullas, R. & Skolnick, P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur. J. Pharmacol. 185, 1–10 (1990). This early preclinical report demonstrates proof-of-principle that NMDAR antagonists may represent a new class of antidepressants.

    Article  CAS  PubMed  Google Scholar 

  153. 153

    Shors, T. J., Seib, T. B., Levine, S. & Thompson, R. F. Inescapable versus escapable shock modulates long-term potentiation in the rat hippocampus. Science 244, 224–226 (1989).

    Article  CAS  PubMed  Google Scholar 

  154. 154

    Skolnick, P., Popik, P. & Trullas, R. Glutamate-based antidepressants: 20 years on. Trends Pharmacol. Sci. 30, 563–569 (2009).

    Article  CAS  PubMed  Google Scholar 

  155. 155

    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).

    Article  CAS  PubMed  Google Scholar 

  156. 156

    Papp, M. & Moryl, E. Antidepressant-like effects of 1-aminocyclopropanecarboxylic acid and D-Cycloserine in an animal model of depression. Eur. J. Pharmacol. 316, 145–151 (1996).

    Article  CAS  PubMed  Google Scholar 

  157. 157

    Sos, P. et al. Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol. Lett. 34, 287–293 (2013).

    CAS  PubMed  Google Scholar 

  158. 158

    Diazgranados, N. et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch. Gen. Psychiatry 67, 793–802 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Zarate, C. A. Jr et al. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol. Psychiatry 71, 939–946 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to James W. Murrough.

Ethics declarations

Competing interests

In the past 3 years, J.W.M. has provided consultation services for Novartis, Janssen Research and Development, Genentech, ProPhase and Impel Neuropharma, has received research support from Avanir Pharmaceuticals, Inc., and is named on a pending patient for lithium to extend the antidepressant effect of ketamine and for the combination of lithium and ketamine for the treatment of suicidal ideation. The Icahn School of Medicine at Mount Sinai (to which J.W.M. is affiliated) is named on a patent and has entered into a licensing agreement and will receive payments related to the use of ketamine if it is approved for the treatment of depression. J.W.M. is not named on the patent and will not receive any payments. C.G.A. has served as a consultant and/or on advisory boards for Genentech and Janssen. S.J.M. has been receiving consulting fees from Acadia, Cerecor, Otsuka and Valeant, and is on an advisory board for VistaGen Therapeutics. He has received research support from Janssen Research & Development. He is supported by the use of facilities and resources at the Michael E. Debakey VA Medical Center, Houston, Texas, USA.

Related links

FURTHER INFORMATION

ClinicalTrials.gov

PowerPoint slides

Glossary

Synaptic plasticity

Activity- or experience-dependent changes in synaptic structure and function that are relatively long-lasting (that is, persisting beyond the initial electrochemical event).

Long-term potentiation

A form of synaptic plasticity in which postsynaptic cellular responses are augmented as a function of recent neuronal activity.

Excitotoxicity

Neurotoxicity through a mechanism at least partially dependent on high Ca2+ influx and subsequent triggering of cell death mechanisms.

Bipolar disorder

A mood disorder that is characterized by episodes of depression alternating with episodes of mania or hypomania.

Glial cells

Non-neuronal central nervous system cells, including astrocytes and oligodendrocytes, that function to maintain homeostasis, support neurotransmission and neuronal health, and form myelin.

Glutamate–glutamine cycling

Biochemical pathway that describes the uptake and conversion of glutamate to glutamine by astrocytes and the subsequent transfer of glutamine back to neurons for conversion to glutamate.

Enantiomers

Stereoisomers that are mirror images of each other.

Escitalopram

The (S)-stereoisomer of citalopram; a serotonin-selective reuptake inhibitor (SSRI) approved in the United States for the treatment of major depressive disorder and generalized anxiety disorder.

Chronic variable stress

Procedure used to model depression in rodents that typically consists of subjecting the animal to daily bouts of mild-to-moderate environmental stressors over several weeks.

Chronic social defeat stress

Procedure used to model depression in rodents that consists of exposing a target rodent to an aggressor daily for 10 days.

Sucrose preference

Procedure used to assess anhedonia or lack of response to pleasure in rodents that involves measuring the degree to which an animal preferentially selects a solution sweetened with sucrose over a non-sweet solution.

Global brain connectivity

A seed-free, whole-brain approach to resting-state functional magnetic resonance imaging connectivity analysis.

Learned helplessness

Behavioural pattern that occurs when animals are repeatedly exposed to aversive stimuli that cannot be controlled or from which the animal cannot escape.

Forced swimming test

Behavioural despair test in which the degree to which a rodent swims when placed in a cylinder filled with water from which it cannot escape is taken as a measure of antidepressant activity.

Pseudobulbar affect

Type of affect characterized by episodes of uncontrollable crying or laughing and which typically occurs secondary to a neurological injury.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Murrough, J., Abdallah, C. & Mathew, S. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov 16, 472–486 (2017). https://doi.org/10.1038/nrd.2017.16

Download citation

Further reading

Search

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