Skip to main content
Log in

Ketamine for Treatment-Resistant Unipolar Depression

Current Evidence

  • Leading Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action andsignificant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapid-onset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5 mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I

Similar content being viewed by others

References

  1. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163(1): 28–40

    Article  PubMed  Google Scholar 

  2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163(11): 1905–17

    Article  PubMed  Google Scholar 

  3. Gaynes BN, Warden D, Trivedi MH, et al. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for depression. Psych Services 2009; 60: 1439–45

    Article  Google Scholar 

  4. Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry 2006; 163(7): 1161–72

    Article  PubMed  Google Scholar 

  5. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry 2006; 163(9): 1519–30

    Article  PubMed  Google Scholar 

  6. aan het Rot M, Charney DS, Mathew SJ. Intravenous ketamine for treatment-resistant major depressive disorder. Primary Psychiatry 2008; 15(4): 39–47

    Google Scholar 

  7. Mathew SJ, Murrough J, aan het Rot M, et al. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharm 2010; 13(1): 71–82

    Article  CAS  Google Scholar 

  8. aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 2010; 67(2): 139–45

    Article  PubMed  CAS  Google Scholar 

  9. Price RB, Nock MT, Charney DS, et al. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry 2009; 66(5): 522–6

    Article  PubMed  CAS  Google Scholar 

  10. Murrough JW, Mathew SJ. Overcoming antidepressant treatment resistance: focus on glutamate. In: Cryan JF, Leonard BE, editors. Depression: from psychopathology to pharmacotherapy. Basel: Karger, 2010: 89–100

    Chapter  Google Scholar 

  11. Murrough JW, Perez AM, Mathew SJ, et al. A case of sustained remission following an acute course of ketamine in treatment-resistant depression [letter]. J Clin Psychiatry 2011; 72: 3

    Article  Google Scholar 

  12. Shelton RC. Therapeutic options for treatment-resistant depression. CNS Drugs 2010; 24(2): 131–61

    Article  PubMed  CAS  Google Scholar 

  13. Trivedi MH, Thase ME, Osuntokun O, et al. An integrated analysis of olanzapine/fluoxetine combination in clinical trials of treatment-resistant depression. J Clin Psychiatry 2009; 70(3): 387–96

    Article  PubMed  CAS  Google Scholar 

  14. Sackeim HA, Dillingham EM, Prudic J, et al. Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects. Arch Gen Psychiary 2009; 66(7): 729–37

    Article  CAS  Google Scholar 

  15. Sackeim HA, Prudic J, Fuller R, et al. The cognitive effects of electroconvulsive therapy in community settings. Neuropsychopharmacology 2007; 32(1): 244–54

    Article  PubMed  Google Scholar 

  16. Sackeim HA, Brannan SK, Rush AJ, et al. Durability of antidepressant response to vagus nerve stimulation (VNS). Int J Neuropsychopharmacol 2007; 10(6): 817–26

    Article  PubMed  CAS  Google Scholar 

  17. George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry 2010; 67(5): 507–16

    Article  PubMed  Google Scholar 

  18. Lisanby SH, Husain MM, Rosenquist PB, et al. Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: clinical predictors of outcome in a multisite, randomized controlled clinical trial. Neuropsychopharmacology 2009; 34(2): 522–34

    Article  PubMed  Google Scholar 

  19. Vialou V, Robison AJ, Laplant QC, et al. DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat Neurosci 2010; 13(6): 745–52

    Article  PubMed  CAS  Google Scholar 

  20. Koo JW, Russo SJ, Ferguson D, et al. Nuclear factor-kappaB is a critical mediator of stress-impaired neuro-genesis and depressive behavior. Proc Natl Acad Sci U S A 2010; 107(6): 2669–74

    Article  PubMed  Google Scholar 

  21. Mathew SJ. Treatment-resistant depression: recent developments and future directions. Depress Anxiety 2008; 25: 989–92

    Article  PubMed  Google Scholar 

  22. Mathew SJ, Manji HK, Charney DS. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology 2008; 33(9): 2080–92

    Article  PubMed  CAS  Google Scholar 

  23. Abbott A. The drug deadlock. Nature 2010; 468: 158–9

    Article  PubMed  CAS  Google Scholar 

  24. Sanacora G, Zarate CA, Krystal JH, et al. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discovery 2008; 7(5): 426–37

    Article  CAS  Google Scholar 

  25. Machado-Vieira R, Manji HK, Zarate CA. The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders. Neuroscientist 2009 Oct; 15(5): 525–39

    Article  PubMed  CAS  Google Scholar 

  26. Price RB, Shungu DC, Mao X, et al. Amino acid neuro-transmitter concentrations in anterior cingulate and occipital cortex in symptomatic patients with major depression: relationship to treatment resistance. Biol Psychiatry 2009; 65(9): 792–800

    Article  PubMed  CAS  Google Scholar 

  27. Preskorn SH, Baker B, Kolluri S, et al. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist: CP-101,606 in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 2008; 28(6): 631–7

    Article  PubMed  CAS  Google Scholar 

  28. Reich DL, Silvay G. Ketamine: an update on the first twentyfive years of clinical experience. Can J Anaesth 1989; 36(2): 186–97

    Article  PubMed  CAS  Google Scholar 

  29. Ketalar® (ketamine) hydrochloride injection [package insert]. Rochester (MI): JHP Pharmaceuticals, LLC, 2009 Feb

  30. Knox JW, Bovill JG, Clarke RS, et al. Clinical studies of induction agents: XXXVI. Ketamine. Br J Anaesth 1970; 42(10): 875–85

    Article  CAS  Google Scholar 

  31. Green SM, Johnson NE. Ketamine sedation for pediatric procedures: part 2, review and implications. Ann Emerg Med 1990; 19(9): 1033–46

    Article  PubMed  CAS  Google Scholar 

  32. Harrison NL, Simmonds MA. Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex. Br J Pharmacol 1985; 84(2): 381–91

    Article  PubMed  CAS  Google Scholar 

  33. Anis NA, Berry SC, Burton NR, et al. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol 1983; 79(2): 565–75

    Article  PubMed  CAS  Google Scholar 

  34. Parsons CG, Quack G, Bresink I, et al. Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo. Neuropharmacology 1995; 34(10): 1239–58

    Article  PubMed  CAS  Google Scholar 

  35. Cohen MG, Chan SL, Bhargava HN, et al. Inhibition of mammalian brain acetylcholinesterase by ketamine. Biochem Pharmacol 1974; 23(11): 1647–52

    Article  PubMed  CAS  Google Scholar 

  36. Lodge D, Anis NA, Burton NR. Effects of optical isomers of ketamine on excitation of cat and rat spinal neurones by amino acids and acetylcholine. Neurosci Lett 1982; 29(3): 281–6

    Article  PubMed  CAS  Google Scholar 

  37. Weber M, Motin L, Gaul S, et al. Intravenous anaesthetics inhibit nicotinic acetylcholine receptor-mediated currents and Ca2+ transients in rat intracardiac ganglion neurons. Br J Pharmacol 2005; 144(1): 98–107

    Article  PubMed  CAS  Google Scholar 

  38. Volle RL, Alkadhi KA, Branisteanu DD, et al. Ketamine and ditran block end-plate ion conductance and [3H]phencyclidine binding to electric organ membrane. J Pharmacol Exp Ther 1982; 221(3): 570–6

    PubMed  CAS  Google Scholar 

  39. Hirota K, Hashimoto Y, Lambert DG. Interaction of intravenous anesthetics with recombinant human M1-M3 muscarinic receptors expressed in Chinese hamster ovary cells. Anesth Analg 2002; 95(6): 1607–10

    Article  PubMed  CAS  Google Scholar 

  40. Morita T, Hitomi S, Saito S, et al. Repeated ketamine administration produces up-regulation of muscarinic acetylcholine receptors in the forebrain, and reduces behavioral sensitivity to scopolamine in mice. Psychopharmacology (Berl) 1995; 117(4): 396–402

    Article  CAS  Google Scholar 

  41. Bevan RK, Rose MA, Duggan KA. Evidence for direct interaction of ketamine with alpha 1- and beta 2-adrenoceptors. Clin Exp Pharmacol Physiol 1997; 24(12): 923–6

    Article  PubMed  CAS  Google Scholar 

  42. Smith DJ, Pekoe GM, Martin LL, et al. The interaction of ketamine with the opiate receptor. Life Sci 1980; 26(10): 789–95

    Article  PubMed  CAS  Google Scholar 

  43. Smith DJ, Bouchal RL, deSanctis CA, et al. Properties of the interaction between ketamine and opiate binding sites in vivo and in vitro. Neuropharmacology 1987; 26(9): 1253–60

    Article  PubMed  CAS  Google Scholar 

  44. Smith DJ, Azzaro AJ, Zaldivar SB, et al. Properties of the optical isomers and metabolites of ketamine on the high affinity transport and catabolism of monoamines. Neuropharmacology 1981; 20(4): 391–6

    Article  PubMed  CAS  Google Scholar 

  45. Rammes G, Rupprecht R, Ferrari U, et al. The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett 2001; 306(1–2): 81–4

    Article  PubMed  CAS  Google Scholar 

  46. Appadu BL, Lambert DG. Interaction of i.v. anaesthetic agents with 5-HT3 receptors. Br J Anaesth 1996; 76(2): 271–3

    CAS  Google Scholar 

  47. Barann M, Gothert M, Fink K, et al. Inhibition by anaesthetics of 14C-guanidinium flux through the voltage-gated sodium channel and the cation channel of the 5-HT3 receptor of N1E-115 neuroblastoma cells. Naunyn Schmiedebergs Arch Pharmacol 1993; 347(2): 125–32

    Article  PubMed  CAS  Google Scholar 

  48. Seeman P, Guan HC, Hirbec H. Dopamine D2high receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil. Synapse 2009; 63(8): 698–704

    Article  PubMed  CAS  Google Scholar 

  49. Seeman P, Ko K, Tallerico T. Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. Mol Psychiatry 2005; 10(9): 877–83

    Article  PubMed  CAS  Google Scholar 

  50. Micheletti G, Lannes B, Haby C, et al. Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat striatum. Brain Res Mol Brain Res 1992; 14(4): 363–8

    Article  PubMed  CAS  Google Scholar 

  51. Jordan S, Chen R, Fernalld R, et al. In vitro biochemical evidence that the psychotomimetics phencyclidine, ketamine and dizocilpine (MK-801) are inactive at cloned human and rat dopamine D2 receptors. Eur J Pharmacol 2006; 540(1–3): 53–6

    Article  PubMed  CAS  Google Scholar 

  52. Aalto S, Hirvonen J, Kajander J, et al. Ketamine does not decrease striatal dopamine D2 receptor binding in man. Psychopharmacology (Berl) 2002; 164(4): 401–6

    Article  CAS  Google Scholar 

  53. Momosaki S, Hatano K, Kawasumi Y, et al. Rat-PET study without anesthesia: anesthetics modify the dopamine D1 receptor binding in rat brain. Synapse 2004; 54(4): 207–13

    Article  PubMed  CAS  Google Scholar 

  54. Salmi E, Långsjö JW, Aalto S, et al. Subanesthetic ketamine does not affect 11C-flumazenil binding in humans. Anesth Analg 2005; 101(3): 722–5

    Article  PubMed  CAS  Google Scholar 

  55. Heinzel A, Steinke R, Poeppel TD, et al. S-ketamine and GABA-A-receptor interaction in humans: an exploratory study with I-123-iomazenil SPECT. Hum Psychopharmacol 2008; 23(7): 549–54

    Article  PubMed  CAS  Google Scholar 

  56. Lin LH, Chen LL, Zirrolli JA, et al. General anesthetics potentiate gamma-aminobutyric acid actions on gamma-aminobutyric acidA receptors expressed by Xenopus oocytes: lack of involvement of intracellular calcium. J Pharmacol Exp Ther 1992; 263(2): 569–78

    PubMed  CAS  Google Scholar 

  57. Allaoua H, Chicheportiche R. Anaesthetic properties of phencyclidine (PCP) and analogues may be related to their interaction with Na+ channels. Eur J Pharmacol 1989; 163(2–3): 327–35

    Article  PubMed  CAS  Google Scholar 

  58. Chen XS, Shu S, Bayliss DA. HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine. J Neurosci 2009; 29(3): 600–9

    Article  PubMed  CAS  Google Scholar 

  59. Vollenweider FX, Leenders KL, Oye I, et al. Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol 1997; 7(1): 25–38

    Article  PubMed  CAS  Google Scholar 

  60. Paul R, Schaaff N, Padberg F, et al. Comparison of racemic ketamine and S-ketamine in treatment-resistant major depression: report of two cases. World J Biol Psychiatry 2009; 10(3): 241–4

    Article  PubMed  Google Scholar 

  61. Finck AD, Ngai SH. Opiate receptor mediation of ketamine analgesia. Anesthesiology 1982; 56(4): 291–7

    Article  PubMed  CAS  Google Scholar 

  62. Pfenninger E, Baier C, Claus S, et al. Psychometric changes as well as analgesic action and cardiovascular adverse effects of ketamine racemate versus s-(+)-ketamine in subanesthetic doses [in German]. Anaesthesist 1994; 43(2): 68–75

    Google Scholar 

  63. Himmelseher S, Pfenninger E. The clinical use of S-(+)-ketamine: a determination of its place. Anasthesiol In-tensivmed Notfallmed Schmerzther 1998; 33(12): 764–70

    Article  CAS  Google Scholar 

  64. Langsjo J, Maksimow A, Salmi E, et al. S-ketamine anesthesia increases cerebral blood flow in excess of the metabolic needs in humans. Anesthesiology 2005; 103: 258–68

    Article  PubMed  Google Scholar 

  65. Piper SN, Beschmann R, Mengistu A, et al. Postoperative analgosedation with S(+)-ketamine decreases the incidences of postanesthetic shivering and nausea and vomiting after cardiac surgery. Med Sci Monit 2008; 14(12): 159–65

    Google Scholar 

  66. Proescholdt M, Heimann A, Kempski O. Neuroprotection of S(+) ketamine isomer in global forebrain ischemia. Brain Res 2001; 904: 245–51

    Article  PubMed  CAS  Google Scholar 

  67. Pfenninger E, Durieux M, Himmelseher S. Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers. Anesthesiology 2002; 96(2): 357–66

    Article  PubMed  CAS  Google Scholar 

  68. Blonk M, Koder BG, van den Bemt PM, et al. Use of oral ketamine in chronic pain management: a review. Eur J Pain 2010; 14(5): 466–72

    Article  PubMed  CAS  Google Scholar 

  69. Abrams R, Morrison JE, Villasenor A, et al. Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. Anesth Prog 1993; 40(3): 63–6

    PubMed  CAS  Google Scholar 

  70. Weksler N, Ovadia L, Muati G, et al. Nasal ketamine for paediatric premedication. Can J Anaesth 1993; 40(2): 119–21

    Article  PubMed  CAS  Google Scholar 

  71. Louon A, Reddy VG. Nasal midazolam and ketamine for paediatric sedation during computerised tomography. Acta Anaesthesiol Scand 1994; 38(3): 259–61

    Article  PubMed  CAS  Google Scholar 

  72. Diaz JH. Intranasal ketamine preinduction of paediatric outpatients. Paediatr Anaesth 1997; 7(4): 273–8

    Article  PubMed  CAS  Google Scholar 

  73. Weber FH, Wulf H, el Saeidi G. Premedication with nasal s-ketamine and midazolam provides good conditions for induction of anesthesia in preschool children. Can J Anaesth 2003; 50(5): 470–5

    Article  PubMed  Google Scholar 

  74. Roelofse JA, Shipton EA, de la Harpe CJ, et al. Intranasal sufentanil/midazolam versus ketamine/midazolam for analgesia/sedation in the pediatric population prior to undergoing multiple dental extractions under general anesthesia: a prospective, double-blind, randomized comparison. Anesth Prog 2004; 51(4): 114–21

    PubMed  CAS  Google Scholar 

  75. Kaube H, Herzog J, Käufer T, et al. Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 2000; 55(1): 139–41

    Article  PubMed  CAS  Google Scholar 

  76. Carr DB, Goudas LC, Denman WT, et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain 2004; 108(1–2): 17–27

    Article  PubMed  CAS  Google Scholar 

  77. Huge V, Lauchart M, Magerl W, et al. Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain. Eur J Pain 2010; 14(4): 387–94

    Article  PubMed  CAS  Google Scholar 

  78. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47(4): 351–4

    Article  PubMed  CAS  Google Scholar 

  79. White PF, Way WL, Trevor AJ. Ketamine: its pharmacology and therapeutic uses. Anesthesiology 1982; 56(2): 119–36

    Article  PubMed  CAS  Google Scholar 

  80. Noppers I, Niesters M, Aarts L, et al. Ketamine for the treatment of chronic non-cancer pain. Expert Opin Pharmacother 2010; 11(14): 2417–29

    Article  PubMed  CAS  Google Scholar 

  81. Subramanian K, Subramanian B, Steinbrook RA. Ketamine as adjunct analgesic to opiates: a quantitative and qualitative systematic review. Anesth Analg 2004; 99:482–95

    Article  Google Scholar 

  82. Bell RF, Dahl JB, Moore RA, et al. Perioperative ketamine for acute postoperative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand 2005; 49: 1405–28

    Article  PubMed  CAS  Google Scholar 

  83. McQueen A, Baroletti S. Adjuvant ketamine analgesia for the management of cancer pain. Ann Pharmacother 2002; 36: 1614–9

    Article  PubMed  CAS  Google Scholar 

  84. Hocking G, Cousins M. Ketamine in chronic pain management: an evidence-based review. Anesth Analges 2003; 97: 1730–9

    Article  CAS  Google Scholar 

  85. Correll GE, Maleki J, Gracely EJ, et al. Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med 2004; 5(3): 263–75

    Article  PubMed  Google Scholar 

  86. Goldberg ME, Domsky R, Scaringe D, et al. Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Pain Physician 2005; 8(2): 175–9

    PubMed  Google Scholar 

  87. Schwartzman RJ, Alexander GM, Grothusen JR, et al. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain 2009; 147: 107–15

    Article  PubMed  CAS  Google Scholar 

  88. Zarate Jr CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63(8): 856–64

    Article  PubMed  CAS  Google Scholar 

  89. Anand A, Charney DS, Oren DA, et al. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry 2000; 57(3): 270–6

    Article  PubMed  CAS  Google Scholar 

  90. Zarate Jr CA, Payne JL, Quiroz J, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry 2004; 161(1): 171–4

    Article  PubMed  Google Scholar 

  91. Zarate Jr CA, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry 2005; 57(4): 430–2

    Article  PubMed  CAS  Google Scholar 

  92. Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry 2007; 61: 822–5

    Article  PubMed  CAS  Google Scholar 

  93. Ibrahim L, Diazgranados N, Luckenbaugh DA, et al. Rapid decrease in depressive symptoms with an N-methyl-D-aspartate antagonist in ECT-resistant major depression. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35(4): 1155–9

    Article  PubMed  CAS  Google Scholar 

  94. Glue P, Gulati A, Le Nedelec M, et al. Dose- and exposure-response to ketamine in depression. Biol Psychiatry 2011; 70(4): e9–10

    Article  PubMed  Google Scholar 

  95. Murrough JW, Gallo JM, Collins KA, et al. Reply to: dose-and exposure-response to ketamine in depression. Biol Psychiatry 2011; 70(4): e11–2

    Article  Google Scholar 

  96. Nock MK, Banaji MR. Assessment of self-injurious thoughts using a behavioral test. Am J Psychiatry 2007; 164: 820–3

    Article  PubMed  Google Scholar 

  97. Diaz Granados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry 2010; 71(12): 1605–11

    Article  CAS  Google Scholar 

  98. Larkin GL, Beautrais AL. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharm 2011; 14(8): 1127–31

    Article  CAS  Google Scholar 

  99. Thangathurai D, Mogos M. Ketamine alleviates fear, depression, and suicidal ideation in terminally ill patients [letter]. J Palliat Med 2011; 14(4): 389

    Article  PubMed  Google Scholar 

  100. Curran HV, Monaghan L. In and out of the K-hole: a comparison of the acute residual effects of ketamine in frequent and infrequent ketamine users. Addiction 2001; 96: 749–60

    Article  PubMed  CAS  Google Scholar 

  101. Morgan CJA, Muetzelfeldt L, Curran HV. Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study. Addiction 2009; 105: 121–33

    Article  PubMed  Google Scholar 

  102. Rowland LM, Astur RS, Jung RE, et al. Selective cognitive impairments associated with NMDA receptor blockade in humans. Neuropsychopharmacology 2005; 30: 633–9

    Article  PubMed  CAS  Google Scholar 

  103. Morgan CJA, Mofeez A, Brandner B, et al. Ketamine impairs response inhibition and is positively reinforcing in healthy volunteers: a dose-response study. Psycho-pharmacology 2004; 172: 298–308

    CAS  Google Scholar 

  104. Malhotra AK, Pinals DA, Weingarter H, et al. NMDA receptor function and human cognition: the effects of ketamine and healthy volunteers. Neuropsychopharma-cology 1996; 14: 301–7

    Article  CAS  Google Scholar 

  105. Hetem LA, Danion JM, Diemunsch P, et al. Effect of subanesthetic dose of ketamine on memory and conscious awareness in healthy volunteers. Psychopharmacology (Berl)2000; 152:283–8

    Article  PubMed  CAS  Google Scholar 

  106. Curran HV, Morgan CJA. Cognitive, dissociative and psychogenetic effects of ketamine on recreational users on the night of drug use and three days later. Addiction 2000; 95: 575–90

    Article  PubMed  CAS  Google Scholar 

  107. Jevtovic-Todorovic V, Wozniak D, Bemshoff N, et al. A comparative evaluation of the neurotoxic properties of ketamine and nitrous oxide. Brain Res 2001; 895: 264–7

    Article  PubMed  CAS  Google Scholar 

  108. Morgan CJ, Curran HV. Acute and chronic effects of ketamine upon human memory: a review. Psychopharmacol (Berl) 2006; 188(4): 408–24

    Article  CAS  Google Scholar 

  109. Morgan CJ, Monaghan L, Curran HV. Beyond the K-hole: a 3-year longitudinal investigation of the cognitive and subjective effects of ketamine in recreational users who have substantially reduced their use of the drug. Addiction 2004; 99(11): 1450–61

    Article  PubMed  Google Scholar 

  110. Olney JW, Labruyere J, Wang G, et al. NMDA antagonist neurotoxicity: mechanism and prevention. Science 1991; 254(5037): 1515–8

    Article  PubMed  CAS  Google Scholar 

  111. Phillips ML, Drevets WC, Rauch SL, et al. Neurobiology of emotion perception I: the neural basis of normal emotion perception. Biol Psychiatry 2003; 54(5): 504–14

    Article  PubMed  Google Scholar 

  112. Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychopharmacology 2010; 35(1): 192–216

    Article  PubMed  Google Scholar 

  113. Krishnan V, Nestler EJ. Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry 2010; 167(11): 1305–20

    Article  PubMed  Google Scholar 

  114. Murrough JW, Iacoviello B, Neumeister A, et al. Cognitive dysfunction in depression: neurocircuitry and new therapeutic strategies. Neurobiol Learn Mem 2011; 96(4): 553–63

    Article  PubMed  CAS  Google Scholar 

  115. Erk S, Mikschl A, Stier S, et al. Acute and sustained effects of cognitive emotion regulation in major depression. J Neurosci 2010; 30(47): 15726–34

    Article  PubMed  CAS  Google Scholar 

  116. Vollenweider FX, Leenders KL, Scharfetter C, et al. Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Eur Neuropsychopharmacol 1997; 7(1): 9–24

    Article  PubMed  CAS  Google Scholar 

  117. Breier A, Malhotra AK, Pinals DA, et al. Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 1997; 154(6): 805–11

    PubMed  CAS  Google Scholar 

  118. Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 2010; 11(9): 642–51

    Article  PubMed  CAS  Google Scholar 

  119. Kennedy SH, Evans KR, Krüger S, et al. Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am J Psychiatry 2001; 158(6): 899–905

    Article  PubMed  CAS  Google Scholar 

  120. Breier A, Adler CM, Weisenfeld N, et al. Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach. Synapse 1998; 29(2): 142–7

    Article  PubMed  CAS  Google Scholar 

  121. Abel KM, Allin MP, Kucharska-Pietura K, et al. Ketamine alters neural processing of facial emotion recognition in healthy men: an fMRI study. Neuroreport 2003; 14(3): 387–91

    Article  PubMed  CAS  Google Scholar 

  122. Abel KM, Allin MP, Kucharska-Pietura K, et al. Ketamine and fMRI BOLD signal: distinguishing between effects mediated by change in blood flow versus change in cognitive state. Hum Brain Mapp 2003; 18(2): 135–45

    Article  PubMed  Google Scholar 

  123. Fu CH, Williams SC, Cleare AJ, et al. Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study. Arch Gen Psychiatry 2004; 61(9): 877–89

    Article  PubMed  Google Scholar 

  124. Salvadore G, Cornwell BR, Colon-Rosario V, et al. Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine. Biol Psychiatry 2009; 65(4): 289–95

    Article  PubMed  CAS  Google Scholar 

  125. Salvadore G, Cornwell BR, Sambataro F et al. Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine. Neuropsychopharmacology 2010; 35(7): 1415–22

    Article  PubMed  CAS  Google Scholar 

  126. Davidson RJ, Irwin W, Anderle MJ, et al. The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatry 2003; 160(1): 64–75

    Article  PubMed  Google Scholar 

  127. Pizzagalli DA. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology 2011; 36(1): 183–206

    Article  PubMed  Google Scholar 

  128. Kennedy SH, Giacobbe P, Rizvi SJ, et al. Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years. Am J Psychiatry 2011; 168(5): 502–10

    Article  PubMed  Google Scholar 

  129. Valentine GW, Mason GF, Gomez R, et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res 2011; 191(2): 122–7

    Article  PubMed  CAS  Google Scholar 

  130. Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329(5994): 959–64

    Article  PubMed  CAS  Google Scholar 

  131. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. BioPsychiatry 2006 Jun 15; 59(12): 1116–27

    Article  CAS  Google Scholar 

  132. Murrough JW, Charney DS. Cracking the moody brain: lifting the mood with ketamine. Nat Med 2010; 16(12): 1384–5

    Article  PubMed  CAS  Google Scholar 

  133. Maeng S, Zarate Jr CA, Du J, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 2008; 63(4): 349–52

    Article  PubMed  CAS  Google Scholar 

  134. Correll GE, Futter GE. Two case studies of patients with major depressive disorder given low-dose (subanesthetic) ketamine infusions. Pain Med 2006; 7(1): 92–5

    Article  PubMed  Google Scholar 

  135. Liebrenz M, Stohler R, Borgeat A. Repeated intravenous ketamine therapy in a patient with treatment-resistant major depression. World J Biol Psychiatry 2009; 10 (4 Pt 2): 640–3

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was generously supported by the Department of Veterans Affairs (via salary support for Drs Mathew and Clark), the National Institute of Mental Health (5R01MH81870 to Dr Mathew, 1K23MH094707-01 to Dr Murrough), NARSAD (awards to Drs Mathew, Lapidus and Murrough) and the Mount Sinai Clinical and Translational Sciences Award (UL1RR029887). The sponsors did not have a role in the preparation of this article.

Dr Mathew and Dr Charney (Dean of Mount Sinai School of Medicine) and the Mount Sinai School of Medicine have been named on a use patent application of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the FDA for this indication, Dr Charney and the Mount Sinai School of Medicine could benefit financially. Dr Mathew has relinquished his claim to any royalties and will not benefit financially if ketamine is approved for this use.

Dr Mathew has received grant/research support from Evotec, GlaxoSmithKline, NARSAD, NIMH, Novartis and Roche Pharmaceuticals during the last 5 years. Medication for a National Institutes of Health funded study has been provided by Sanofi. In 2010–11, Dr Mathew received consulting or lecture fees from AstraZeneca, Cephalon, Inc. and Roche.

Dr Shah has received grant/research support from PPD, Inc., Johnson & Johnson and Roche Pharmaceuticals.

Within the last 2 years, Dr Murrough has received salary support through a Mount Sinai School of Medicine research fellowship funded with an educational grant from AstraZeneca.

Drs Shah, Clark, Jarun, Lapidus, Ostermeyer and Murrough have no conflicts of interest that are directly relevant to the content of this review.

The authors wish to thank the following individuals for their significant contributions to this work: Mount Sinai School of Medicine: Dennis Charney, M.D., Dan Iosifescu, M.D., David Reich, M.D. and Andrew Perez, M.D.; Baylor College of Medicine: Rayan Al Jurdi, M.D., Lee Chang, M.D., Thomas Newton, M.D. and Richard de la Garza II, Ph.D.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sanjay J. Mathew MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mathew, S.J., Shah, A., Lapidus, K. et al. Ketamine for Treatment-Resistant Unipolar Depression. CNS Drugs 26, 189–204 (2012). https://doi.org/10.2165/11599770-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11599770-000000000-00000

Keywords

Navigation