1932

Abstract

For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of ()-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal ideation, occurring within hours following a single administration, with relief from symptoms typically lasting up to a week. The discovery of these actions of ketamine has resulted in a reconceptualization of how depression could be more effectively treated in the future. In this review, we discuss clinical data pertaining to ketamine and other rapid-acting antidepressant drugs, as well as the current state of pharmacological knowledge regarding their mechanism of action. Additionally, we discuss the neurobiological circuits that are engaged by this drug class and that may be targeted by a future generation of medications, for example, hydroxynorketamine; metabotropic glutamate receptor 2/3 antagonists; and -methyl--aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor modulators.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010617-052811
2019-01-06
2024-04-13
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/59/1/annurev-pharmtox-010617-052811.html?itemId=/content/journals/10.1146/annurev-pharmtox-010617-052811&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Kessler RC, Berglund P, Demler O, Jin R, Koretz D et al. 2003. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 289:3095–105
    [Google Scholar]
  2. 2.  Duman RS, Heninger GR, Nestler EJ 1997. A molecular and cellular theory of depression. Arch. Gen. Psychiatry 54:597–606
    [Google Scholar]
  3. 3.  Gould TD, Manji HK 2002. Signaling networks in the pathophysiology and treatment of mood disorders. J. Psychosom. Res. 53:687–97
    [Google Scholar]
  4. 4.  Hyman SE, Nestler EJ 1996. Initiation and adaptation: a paradigm for understanding psychotropic drug action. Am. J. Psychiatry 153:151–62
    [Google Scholar]
  5. 5.  Thompson SM, Kallarackal AJ, Kvarta MD, Van Dyke AM, LeGates TA, Cai X 2015. An excitatory synapse hypothesis of depression. Trends Neurosci 38:279–94
    [Google Scholar]
  6. 6.  Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW et al. 2006. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am. J. Psychiatry 163:1905–17
    [Google Scholar]
  7. 7.  UK ECT Rev. Group 2003. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet 361:799–808
    [Google Scholar]
  8. 8.  Segman RH, Shapira B, Gorfine M, Lerer B 1995. Onset and time course of antidepressant action: psychopharmacological implications of a controlled trial of electroconvulsive therapy. Psychopharmacology 119:440–48
    [Google Scholar]
  9. 9.  Wu JC, Bunney WE 1990. The biological basis of an antidepressant response to sleep deprivation and relapse: review and hypothesis. Am. J. Psychiatry 147:14–21
    [Google Scholar]
  10. 10.  Kellner CH, Greenberg RM, Murrough JW, Bryson EO, Briggs MC, Pasculli RM 2012. ECT in treatment-resistant depression. Am. J. Psychiatry 169:1238–44
    [Google Scholar]
  11. 11.  Reich DL, Silvay G 1989. Ketamine: an update on the first twenty-five years of clinical experience. Can. J. Anaesth. 36:186–97
    [Google Scholar]
  12. 12.  Green SM, Rothrock SG, Lynch EL, Ho M, Harris T et al. 1998. Intramuscular ketamine for pediatric sedation in the emergency department: safety profile in 1,022 cases. Ann. Emerg. Med. 31:688–97
    [Google Scholar]
  13. 13.  Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR et al. 2000. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47:351–54
    [Google Scholar]
  14. 14.  Iadarola ND, Niciu MJ, Richards EM, Vande Voort JL, Ballard ED et al. 2015. Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. Ther. Adv. Chronic Dis. 6:97–114
    [Google Scholar]
  15. 15.  Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M et al. 2015. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am. J. Psychiatry 172:950–66
    [Google Scholar]
  16. 16.  Kishimoto T, Chawla JM, Hagi K, Zarate CA, Kane JM et al. 2016. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol. Med. 46:1459–72
    [Google Scholar]
  17. 17.  Zarate CA Jr., Singh JB, Carlson PJ, Brutsche NE, Ameli R et al. 2006. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63:856–64
    [Google Scholar]
  18. 18.  Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K et al. 2016. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am. J. Psychiatry 173:816–26
    [Google Scholar]
  19. 19.  Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE et al. 2013. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am. J. Psychiatry 170:1134–42
    [Google Scholar]
  20. 20.  Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P et al. 2010. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch. Gen. Psychiatry 67:793–802
    [Google Scholar]
  21. 21.  Zarate CA, Brutsche N, Ibrahim L, Franco-Chaves J, Diazgranados N et al. 2012. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol. Psychiatry 71:939–46
    [Google Scholar]
  22. 22.  Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M et al. 2015. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am. J. Psychiatry 172:950–66
    [Google Scholar]
  23. 23.  Diazgranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID et al. 2010. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-d-aspartate antagonist in patients with treatment-resistant major depressive disorder. J. Clin. Psychiatry 71:1605–11
    [Google Scholar]
  24. 24.  Price RB, Nock MK, Charney DS, Mathew SJ 2009. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol. Psychiatry 66:522–26
    [Google Scholar]
  25. 25.  Price RB, Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK et al. 2014. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depression Anxiety 31:335–43
    [Google Scholar]
  26. 26.  Murrough JW, Soleimani L, DeWilde KE, Collins KA, Lapidus KA et al. 2015. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychol. Med. 45:3571–80
    [Google Scholar]
  27. 27.  Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW et al. 2017. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am. J. Psychiatry 175:150–58
    [Google Scholar]
  28. 28.  Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM et al. 2014. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J. Psychiatr. Res. 58:161–66
    [Google Scholar]
  29. 29.  Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA Jr. 2014. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl. Psychiatry 4:e469
    [Google Scholar]
  30. 30.  Lally N, Nugent AC, Luckenbaugh DA, Niciu MJ, Roiser JP, Zarate CA Jr. 2015. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J. Psychopharmacol. 29:596–607
    [Google Scholar]
  31. 31.  Ballard ED, Wills K, Lally N, Richards EM, Luckenbaugh DA et al. 2017. Anhedonia as a clinical correlate of suicidal thoughts in clinical ketamine trials. J. Affect. Disord. 218:195–200
    [Google Scholar]
  32. 32.  Wilkinson ST, Toprak M, Turner MS, Levine SP, Katz RB, Sanacora G 2017. A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders. Am. J. Psychiatry 174:695–96
    [Google Scholar]
  33. 33.  Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS et al. 2017. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry 74:399–405
    [Google Scholar]
  34. 34.  Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R et al. 1994. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry 51:199–214
    [Google Scholar]
  35. 35.  Singh JB, Fedgchin M, Daly E, Xi L, Melman C et al. 2015. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol. Psychiatry 80:424–31
    [Google Scholar]
  36. 36.  Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P et al. 2018. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 75:139–48
    [Google Scholar]
  37. 37.  Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN et al. 2018. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol. Rev. 70:621–60
    [Google Scholar]
  38. 38.  Zarate CA Jr., Singh JB, Quiroz JA, De Jesus G, Denicoff KK et al. 2006. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am. J. Psychiatry 163:153–55
    [Google Scholar]
  39. 39.  Lee SY, Chen SL, Chang YH, Chen PS, Huang SY et al. 2013. Add-on memantine to valproate treatment increased HDL-C in bipolar II disorder. J. Psychiatr. Res. 47:1343–48
    [Google Scholar]
  40. 40.  Smith EG, Deligiannidis KM, Ulbricht CM, Landolin CS, Patel JK, Rothschild AJ 2013. Antidepressant augmentation using the N-methyl-d-aspartate antagonist memantine: a randomized, double-blind, placebo-controlled trial. J. Clin. Psychiatry 74:966–73
    [Google Scholar]
  41. 41.  Omranifard V, Shirzadi E, Samandari S, Afshar H, Maracy MR 2014. Memantine add on to citalopram in elderly patients with depression: a double-blind placebo-controlled study. J. Res. Med. Sci. 19:525–30
    [Google Scholar]
  42. 42.  Zarate CA Jr., Mathews D, Ibrahim L, Chaves JF, Marquardt C et al. 2013. A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biol. Psychiatry 74:257–64
    [Google Scholar]
  43. 43.  Sanacora G, Smith MA, Pathak S, Su HL, Boeijinga PH et al. 2014. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol. Psychiatry 19:978–85
    [Google Scholar]
  44. 44.  Sanacora G, Johnson MR, Khan A, Atkinson SD, Riesenberg RR et al. 2017. Adjunctive lanicemine (AZD6765) in patients with major depressive disorder and history of inadequate response to antidepressants: a randomized, placebo-controlled study. Neuropsychopharmacology 42:844–53
    [Google Scholar]
  45. 45.  Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW 2008. 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. 28:631–37
    [Google Scholar]
  46. 46.  Ibrahim L, Diazgranados N, Jolkovsky L, Brutsche N, Luckenbaugh D et al. 2012. 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. 32:551–57
    [Google Scholar]
  47. 47. Cerecor. 2016. Cerecor reports top-line data from CERC-301 phase 2 study for major depressive disorder Press Release, Nov. 29. https://ir.cerecor.com/press-releases/detail/30/cerecor-reports-top-line-data-from-cerc-301-phase-2-study
  48. 48.  Paterson B, Fraser H, Wang C, Marcus R 2015. A randomized, double-blind, placebo-controlled, sequential parallel study of CERC-301 in the adjunctive treatment of subjects with severe depression and recent active suicidal ideation despite antidepressant treatment Poster presented at National Network of Depression Centers Annual Conference Ann Arbor, MI: Nov. 5
  49. 49.  Moskal JR, Burch R, Burgdorf JS, Kroes RA, Stanton PK et al. 2014. GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists. Expert Opin. Invest. Drugs 23:243–54
    [Google Scholar]
  50. 50.  Preskorn S, Macaluso M, Mehra DO, Zammit G, Moskal JR et al. 2015. 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. 21:140–49
    [Google Scholar]
  51. 51.  Murrough JW, Abdallah CG, Mathew SJ 2017. Targeting glutamate signalling in depression: progress and prospects. Nat. Rev. Drug Discov. 16:472–86
    [Google Scholar]
  52. 52.  Gillin JC, Sutton L, Ruiz C, Darko D, Golshan S et al. 1991. The effects of scopolamine on sleep and mood in depressed patients with a history of alcoholism and a normal comparison group. Biol. Psychiatry 30:157–69
    [Google Scholar]
  53. 53.  Furey ML, Drevets WC 2006. Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch. Gen. Psychiatry 63:1121–29
    [Google Scholar]
  54. 54.  Drevets WC, Furey ML 2010. Replication of scopolamine's antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biol. Psychiatry 67:432–38
    [Google Scholar]
  55. 55.  Khajavi D, Farokhnia M, Modabbernia A, Ashrafi M, Abbasi SH et al. 2012. Oral scopolamine augmentation in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled study. J. Clin. Psychiatry 73:1428–33
    [Google Scholar]
  56. 56.  Park L, Furey ML, Nugent AC, Farmer C, Ellis J et al. 2018. Neurophysiological changes associated with antidepressant response to ketamine not observed in a negative trial of scopolamine in major depressive disorder. Int. J. Neuropsychopharmacol. In press
  57. 57.  Domino EF, Chodoff P, Corssen G 1965. Pharmacologic effects of Ci-581, a new dissociative anesthetic, in man. Clin. Pharmacol. Ther. 6:279–91
    [Google Scholar]
  58. 58.  Anis NA, Berry SC, Burton NR, Lodge D 1983. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br. J. Pharmacol. 79:565–75
    [Google Scholar]
  59. 59.  Domino EF 2010. Taming the ketamine tiger. Anesthesiology 113:678–84
    [Google Scholar]
  60. 60.  Hansen KB, Yi F, Perszyk RE, Menniti FS, Traynelis SF 2017. NMDA receptors in the central nervous system. Methods in Molecular Biology, Vol. 1677 N Burnashev, P Szepetowski 1–80 New York: Humana Press
    [Google Scholar]
  61. 61.  Kotermanski SE, Johnson JW 2009. Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine. J. Neurosci. 29:2774–79
    [Google Scholar]
  62. 62.  Dravid SM, Erreger K, Yuan H, Nicholson K, Le P et al. 2007. Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block. J. Physiol. 581:107–28
    [Google Scholar]
  63. 63.  Yamakura T, Mori H, Masaki H, Shimoji K, Mishina M 1993. Different sensitivities of NMDA receptor channel subtypes to non-competitive antagonists. Neuroreport 4:687–90
    [Google Scholar]
  64. 64.  Irifune M, Shimizu T, Nomoto M, Fukuda T 1992. Ketamine-induced anesthesia involves the N-methyl-d-aspartate receptor-channel complex in mice. Brain Res 596:1–21–9
    [Google Scholar]
  65. 65.  Petrenko AB, Yamakura T, Sakimura K, Baba H 2014. Defining the role of NMDA receptors in anesthesia: Are we there yet?. Eur. J. Pharmacol. 723:29–37
    [Google Scholar]
  66. 66.  Chen X, Shu S, Bayliss DA 2009. HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine. J. Neurosci. 29:600–9
    [Google Scholar]
  67. 67.  Rocha BA, Ward AS, Egilmez Y, Lytle DA, Emmett-Oglesby MW 1996. Tolerance to the discriminative stimulus and reinforcing effects of ketamine. Behav. Pharmacol. 7:160–68
    [Google Scholar]
  68. 68.  Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J et al. 2016. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533:481–86
    [Google Scholar]
  69. 69.  Moghaddam B, Adams B, Verma A, Daly D 1997. 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. 17:2921–27
    [Google Scholar]
  70. 70.  Homayoun H, Moghaddam B 2007. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J. Neurosci. 27:11496–500
    [Google Scholar]
  71. 71.  Li N, Lee B, Liu RJ, Banasr M, Dwyer JM et al. 2010. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–64
    [Google Scholar]
  72. 72.  Duman RS 2014. Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections. Dialogues Clin. Neurosci. 16:11–27
    [Google Scholar]
  73. 73.  Monteggia LM, Gideons E, Kavalali ET 2013. The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine. Biol. Psychiatry 73:1199–203
    [Google Scholar]
  74. 74.  Autry AE, Adachi M, Nosyreva E, Na ES, Los MF et al. 2011. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475:91–95
    [Google Scholar]
  75. 75.  Miller OH, Yang L, Wang CC, Hargroder EA, Zhang Y et al. 2014. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. eLife 3:e03581
    [Google Scholar]
  76. 76.  Miller OH, Moran JT, Hall BJ 2016. Two cellular hypotheses explaining the initiation of ketamine's antidepressant actions: direct inhibition and disinhibition. Neuropharmacology 100:17–26
    [Google Scholar]
  77. 77.  Zanos P, Gould TD 2018. Mechanisms of ketamine action as an antidepressant. Mol. Psychiatry 23:801–11
    [Google Scholar]
  78. 78.  Yang Y, Cui Y, Sang K, Dong Y, Ni Z et al. 2018. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554:317–22
    [Google Scholar]
  79. 79.  Yang Y, Wang H, Hu J, Hu H 2018. Lateral habenula in the pathophysiology of depression. Curr. Opin. Neurobiol. 48:90–96
    [Google Scholar]
  80. 80.  Zhang JC, Li SX, Hashimoto K 2014. R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacol. Biochem. Behav. 116:137–41
    [Google Scholar]
  81. 81.  Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W et al. 2015. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl. Psychiatry 5:e632
    [Google Scholar]
  82. 82.  Fukumoto K, Toki H, Iijima M, Hashihayata T, Yamaguchi JI et al. 2017. Antidepressant potential of (R)-ketamine in rodent models: comparison with (S)-ketamine. J. Pharmacol. Exp. Ther. 361:9–16
    [Google Scholar]
  83. 83.  Zanos P, Gould TD 2018. Intracellular signaling pathways involved in (S)- and (R)-ketamine antidepressant actions. Biol. Psychiatry 83:2–4
    [Google Scholar]
  84. 84.  Maeng S, Zarate CA Jr., Du J, Schloesser RJ, McCammon J et al. 2008. Cellular mechanisms underlying the antidepressant effects of ketamine: role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol. Psychiatry 63:349–52
    [Google Scholar]
  85. 85.  Li N, Liu RJ, Dwyer JM, Banasr M, Lee B et al. 2011. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol. Psychiatry 69:754–61
    [Google Scholar]
  86. 86.  Jimenez-Sanchez L, Campa L, Auberson YP, Adell A 2014. The role of GluN2A and GluN2B subunits on the effects of NMDA receptor antagonists in modeling schizophrenia and treating refractory depression. Neuropsychopharmacology 39:2673–80
    [Google Scholar]
  87. 87.  Kiselycznyk C, Jury NJ, Halladay LR, Nakazawa K, Mishina M et al. 2015. NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism. Behav. Brain Res. 287:89–95
    [Google Scholar]
  88. 88.  Zanos P, Piantadosi SC, Wu HQ, Pribut HJ, Dell MJ et al. 2015. 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
    [Google Scholar]
  89. 89.  Shaffer CL, Osgood SM, Smith DL, Liu J, Trapa PE 2014. Enhancing ketamine translational pharmacology via receptor occupancy normalization. Neuropharmacology 86:174–80
    [Google Scholar]
  90. 90.  Can A, Zanos P, Moaddel R, Kang HJ, Dossou KS et al. 2016. Effects of ketamine and ketamine metabolites on evoked striatal dopamine release, dopamine receptors, and monoamine transporters. J. Pharmacol. Exp. Ther. 359:159–70
    [Google Scholar]
  91. 91.  Zarate CA Jr., Brutsche N, Laje G, Luckenbaugh DA, Venkata SL et al. 2012. Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression. Biol. Psychiatry 72:331–38
    [Google Scholar]
  92. 92.  Hirota K, Lambert DG 2011. Ketamine: new uses for an old drug?. Br. J. Anaesth. 107:123–26
    [Google Scholar]
  93. 93.  Singh NS, Zarate CA Jr., Moaddel R, Bernier M, Wainer IW 2014. What is hydroxynorketamine and what can it bring to neurotherapeutics?. Expert Rev. Neurother. 14:1239–42
    [Google Scholar]
  94. 94.  Leung LY, Baillie TA 1986. Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine. J. Med. Chem. 29:2396–99
    [Google Scholar]
  95. 95.  Pham TH, Defaix C, Xu X, Deng SX, Fabresse N et al. 2017. Common neurotransmission recruited in (R,S)-ketamine and (2R,6R)-hydroxynorketamine-induced sustained antidepressant-like effects. Biol. Psychiatry 84:e3–6
    [Google Scholar]
  96. 96.  Chou D, Peng HY, Lin TB, Lai CY, Hsieh MC et al. 2018. (2R,6R)-hydroxynorketamine rescues chronic stress-induced depression-like behavior through its actions in the midbrain periaqueductal gray. Neuropharmacology 139:1–12
    [Google Scholar]
  97. 97.  Morris PJ, Moaddel R, Zanos P, Moore CE, Gould T et al. 2017. Synthesis and N-methyl-d-aspartate (NMDA) receptor activity of ketamine metabolites. Org. Lett. 19:4572–75
    [Google Scholar]
  98. 98.  Moaddel R, Abdrakhmanova G, Kozak J, Jozwiak K, Toll L et al. 2013. Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors. Eur. J. Pharmacol. 698:228–34
    [Google Scholar]
  99. 99.  Suzuki K, Nosyreva E, Hunt KW, Kavalali ET, Monteggia LM 2017. Effects of a ketamine metabolite on synaptic NMDAR function. Nature 546:E1–3
    [Google Scholar]
  100. 100.  Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J et al. 2017. Reply to: Effects of a ketamine metabolite on synaptic NMDAR function. Nature 546:E4–5
    [Google Scholar]
  101. 101.  Paul RK, Singh NS, Khadeer M, Moaddel R, Sanghvi M et al. 2014. (R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function. Anesthesiology 121:149–59
    [Google Scholar]
  102. 102.  Singh NS, Rutkowska E, Plazinska A, Khadeer M, Moaddel R et al. 2016. Ketamine metabolites enantioselectively decrease intracellular D-serine concentrations in PC-12 cells. PLOS ONE 11:e0149499
    [Google Scholar]
  103. 103.  Wray NH, Schappi JM, Singh H, Senese NB, Rasenick MM 2018. NMDAR-independent, cAMP-dependent antidepressant actions of ketamine. Mol. Psychiatry. In press
  104. 104.  Yao N, Skiteva O, Zhang X, Svenningsson P, Chergui K 2018. Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit. Mol. Psychiatry. In press
  105. 105.  Cavalleri L, Merlo Pich E, Millan MJ, Chiamulera C, Kunath T et al. 2018. Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling. Mol. Psychiatry 23:812–23
    [Google Scholar]
  106. 106.  Kroin J, Das V, Moric M, Buvanendran A 2018. Efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain. Reg. Anesth. Pain Manag. In press
  107. 107.  Liu RJ, Duman C, Kato T, Hare B, Lopresto D et al. 2017. GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. Neuropsychopharmacology 42:1231–42
    [Google Scholar]
  108. 108.  Lepack AE, Bang E, Lee B, Dwyer JM, Duman RS 2016. Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures. Neuropharmacology 111:242–52
    [Google Scholar]
  109. 109.  Burgdorf J, Zhang XL, Nicholson KL, Balster RL, Leander JD et al. 2013. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology 38:729–42
    [Google Scholar]
  110. 110.  Kato T, Fogaca MV, Deyama S, Li XY, Fukumoto K, Duman RS 2018. BDNF release and signaling are required for the antidepressant actions of GLYX-13. Mol. Psychiatry. In press
  111. 111.  Burgdorf J, Zhang XL, Weiss C, Gross A, Boikess SR et al. 2015. The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus. Neuroscience 308:202–11
    [Google Scholar]
  112. 112.  Rajagopal L, Burgdorf JS, Moskal JR, Meltzer HY 2016. GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice. Behav. Brain Res. 299:105–10
    [Google Scholar]
  113. 113.  Witkin JM, Overshiner C, Li X, Catlow JT, Wishart GN et al. 2014. M1 and M2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine. J. Pharmacol. Exp. Ther. 351:448–56
    [Google Scholar]
  114. 114.  Navarria A, Wohleb ES, Voleti B, Ota KT, Dutheil S et al. 2015. Rapid antidepressant actions of scopolamine: role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors. Neurobiol. Dis. 82:254–61
    [Google Scholar]
  115. 115.  Voleti B, Navarria A, Liu RJ, Banasr M, Li N et al. 2013. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol. Psychiatry 74:742–49
    [Google Scholar]
  116. 116.  Wohleb ES, Wu M, Gerhard DM, Taylor SR, Picciotto MR et al. 2016. GABA interneurons mediate the rapid antidepressant-like effects of scopolamine. J. Clin. Investig. 126:2482–94
    [Google Scholar]
  117. 117.  Pittenger C, Duman RS 2008. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33:88–109
    [Google Scholar]
  118. 118.  Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC 2012. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 487:183–89
    [Google Scholar]
  119. 119.  Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z 2012. Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron 73:962–77
    [Google Scholar]
  120. 120.  Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X et al. 2013. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J. Neurosci. 33:15669–74
    [Google Scholar]
  121. 121.  Hong LE, Summerfelt A, Buchanan RW, O'Donnell P, Thaker GK et al. 2010. Gamma and delta neural oscillations and association with clinical symptoms under subanesthetic ketamine. Neuropsychopharmacology 35:632–40
    [Google Scholar]
  122. 122.  Zanos P, Thompson SM, Duman RS, Zarate CA Jr., Gould TD 2018. Convergent mechanisms underlying rapid antidepressant action. CNS Drugs 32:197–227
    [Google Scholar]
  123. 123.  Hare BD, Ghosal S, Duman RS 2018. Rapid acting antidepressants in chronic stress models: molecular and cellular mechanisms. Chronic Stress In press
  124. 124.  Sohal VS, Zhang F, Yizhar O, Deisseroth K 2009. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459:698–702
    [Google Scholar]
  125. 125.  Widman AJ, McMahon LL 2018. Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. PNAS 115:E3007–16
    [Google Scholar]
  126. 126.  Pozzi L, Pollak Dorocic I, Wang X, Carlen M, Meletis K 2014. Mice lacking NMDA receptors in parvalbumin neurons display normal depression-related behavior and response to antidepressant action of NMDAR antagonists. PLOS ONE 9:e83879
    [Google Scholar]
  127. 127.  Koike H, Chaki S 2014. Requirement of AMPA receptor stimulation for the sustained antidepressant activity of ketamine and LY341495 during the forced swim test in rats. Behav. Brain Res. 271:111–15
    [Google Scholar]
  128. 128.  Koike H, Iijima M, Chaki S 2011. Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav. Brain Res. 224:107–11
    [Google Scholar]
  129. 129.  Yu H, Li M, Zhou D, Lv D, Liao Q et al. 2018. Vesicular glutamate transporter 1 (VGLUT1)-mediated glutamate release and membrane GluA1 activation is involved in the rapid antidepressant-like effects of scopolamine in mice. Neuropharmacology 131:209–22
    [Google Scholar]
  130. 130.  Dwyer JM, Lepack AE, Duman RS 2012. mTOR activation is required for the antidepressant effects of mGluR2/3 blockade. Int. J. Neuropsychopharmacol. 15:429–34
    [Google Scholar]
  131. 131.  Autry AE, Monteggia LM 2012. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol. Rev. 64:238–58
    [Google Scholar]
  132. 132.  Castren E, Kojima M 2017. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments. Neurobiol. Dis. 97:119–26
    [Google Scholar]
  133. 133.  Nibuya M, Morinobu S, Duman RS 1995. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J. Neurosci. 15:7539–47
    [Google Scholar]
  134. 134.  Ghosal S, Bang E, Yue W, Hare BD, Lepack AE et al. 2018. Activity-dependent brain-derived neurotrophic factor release is required for the rapid antidepressant actions of scopolamine. Biol. Psychiatry 83:29–37
    [Google Scholar]
  135. 135.  Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS 2014. BDNF release is required for the behavioral actions of ketamine. Int. J. Neuropsychopharmacol. 18:pyu033
    [Google Scholar]
  136. 136.  Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ 2014. Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur. Psychiatry 29:419–23
    [Google Scholar]
  137. 137.  Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS 2002. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22:3251–61
    [Google Scholar]
  138. 138.  Park H, Poo MM 2013. Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci. 14:7–23
    [Google Scholar]
  139. 139.  Fischell J, Van Dyke AM, Kvarta MD, LeGates TA, Thompson SM 2015. Rapid antidepressant action and restoration of excitatory synaptic strength after chronic stress by negative modulators of alpha5-containing GABAA receptors. Neuropsychopharmacology 40:2499–509
    [Google Scholar]
  140. 140.  Manji HK, Drevets WC, Charney DS 2001. The cellular neurobiology of depression. Nat. Med. 7:541–47
    [Google Scholar]
  141. 141.  McEwen BS, Nasca C, Gray JD 2016. Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology 41:3–23
    [Google Scholar]
  142. 142.  Chaki S 2017. mGlu2/3 receptor antagonists as novel antidepressants. Trends Pharmacol. Sci. 38:569–80
    [Google Scholar]
  143. 143.  Gu G, Lorrain DS, Wei H, Cole RL, Zhang X et al. 2008. Distribution of metabotropic glutamate 2 and 3 receptors in the rat forebrain: implication in emotional responses and central disinhibition. Brain Res 1197:47–62
    [Google Scholar]
  144. 144.  Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F et al. 2011. Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60:1017–41
    [Google Scholar]
  145. 145.  Ago Y, Yano K, Araki R, Hiramatsu N, Kita Y et al. 2013. Metabotropic glutamate 2/3 receptor antagonists improve behavioral and prefrontal dopaminergic alterations in the chronic corticosterone-induced depression model in mice. Neuropharmacology 65:29–38
    [Google Scholar]
  146. 146.  Koike H, Iijima M, Chaki S 2013. Effects of ketamine and LY341495 on the depressive-like behavior of repeated corticosterone-injected rats. Pharmacol. Biochem. Behav. 107:20–23
    [Google Scholar]
  147. 147.  Dong C, Zhang JC, Yao W, Ren Q, Ma M et al. 2017. Rapid and sustained antidepressant action of the mGlu2/3 receptor antagonist MGS0039 in the social defeat stress model: comparison with ketamine. Int. J. Neuropsychopharmacol. 20:228–36
    [Google Scholar]
  148. 148.  Dwyer JM, Lepack AE, Duman RS 2013. mGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure. J. Mol. Psychiatry 1:15
    [Google Scholar]
  149. 149.  Ahnaou A, Ver Donck L, Drinkenburg WHIM 2014. Blockade of the metabotropic glutamate (mGluR2) modulates arousal through vigilance states transitions: evidence from sleep–wake EEG in rodents. Behav. Brain Res. 270:56–67
    [Google Scholar]
  150. 150.  Henter ID, de Sousa RT, Zarate CA Jr. 2018. Glutamatergic modulators in depression. Harv. Rev. Psychiatry. In press
  151. 151.  Karasawa J, Shimazaki T, Kawashima N, Chaki S 2005. AMPA receptor stimulation mediates the antidepressant-like effect of a group II metabotropic glutamate receptor antagonist. Brain Res 1042:92–98
    [Google Scholar]
  152. 152.  Wolak M, Siwek A, Szewczyk B, Poleszak E, Pilc A et al. 2013. Involvement of NMDA and AMPA receptors in the antidepressant-like activity of antidepressant drugs in the forced swim test. Pharmacol. Rep. 65:991–97
    [Google Scholar]
  153. 153.  Alt A, Nisenbaum ES, Bleakman D, Witkin JM 2006. A role for AMPA receptors in mood disorders. Biochem. Pharmacol. 71:1273–88
    [Google Scholar]
  154. 154.  O'Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES 2004. AMPA receptor potentiators for the treatment of CNS disorders. Curr. Drug Targets CNS Neurol. Disord. 3:181–94
    [Google Scholar]
  155. 155.  O'Neill MJ, Witkin JM 2007. AMPA receptor potentiators: application for depression and Parkinson's disease. Curr. Drug Targets 8:603–20
    [Google Scholar]
  156. 156.  Fukumoto K, Iijima M, Chaki S 2014. Serotonin-1A receptor stimulation mediates effects of a metabotropic glutamate 2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and an N-methyl-D-aspartate receptor antagonist, ketamine, in the novelty-suppressed feeding test. Psychopharmacology 231:2291–98
    [Google Scholar]
  157. 157.  Li X, Tizzano JP, Griffey K, Clay M, Lindstrom T, Skolnick P 2001. Antidepressant-like actions of an AMPA receptor potentiator (LY392098). Neuropharmacology 40:1028–33
    [Google Scholar]
  158. 158.  Abdallah CG, Sanacora G, Duman RS, Krystal JH 2018. The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?. Pharmacol. Ther. 190:148–58
    [Google Scholar]
  159. 159.  Atack JR, Maubach KA, Wafford KA, O'Connor D, Rodrigues AD et al. 2009. In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)- pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA receptor α5 subtype-selective inverse agonist. J. Pharmacol. Exp. Ther. 331:470–84
    [Google Scholar]
  160. 160.  Lingford-Hughes A, Hume SP, Feeney A, Hirani E, Osman S et al. 2002. Imaging the GABA-benzodiazepine receptor subtype containing the α5-subunit in vivo with [11C]Ro15 4513 positron emission tomography. J. Cereb. Blood Flow Metab. 22:878–89
    [Google Scholar]
  161. 161.  Zanos P, Nelson ME, Highland JN, Krimmel SR, Georgiou P et al. 2017. A negative allosteric modulator for α5 subunit-containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in mice. eNeuro 4:ENEURO.0285–16.2017
    [Google Scholar]
  162. 162.  Prenosil GA, Schneider Gasser EM, Rudolph U, Keist R, Fritschy JM, Vogt KE 2006. Specific subtypes of GABAA receptors mediate phasic and tonic forms of inhibition in hippocampal pyramidal neurons. J. Neurophysiol. 96:846–57
    [Google Scholar]
  163. 163.  Carreno FR, Collins GT, Frazer A, Lodge DJ 2017. Selective pharmacological augmentation of hippocampal activity produces a sustained antidepressant-like response without abuse-related or psychotomimetic effects. Int. J. Neuropsychopharmacol. 20:504–9
    [Google Scholar]
  164. 164.  Xu NZ, Ernst M, Treven M, Cerne R, Wakulchik M et al. 2018. Negative allosteric modulation of alpha 5-containing GABAA receptors engenders antidepressant-like effects and selectively prevents age-associated hyperactivity in tau-depositing mice. Psychopharmacology 235:1151–61
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010617-052811
Loading
/content/journals/10.1146/annurev-pharmtox-010617-052811
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error