Current Psychiatry Reports

, 15:394 | Cite as

Ketamine, Sleep, and Depression: Current Status and New Questions

  • Wallace C. DuncanJr.
  • Carlos A. ZarateJr.Email author
Sleep Disorders (RM Benca, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Sleep Disorders


Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has well-described rapid antidepressant effects in clinical studies of individuals with treatment-resistant major depressive disorder (MDD). Preclinical studies investigating the effects of ketamine on brain-derived neurotrophic factor (BDNF) and on sleep slow wave activity (SWA) support its use as a prototype for investigating the neuroplastic mechanisms presumably involved in the mechanism of rapidly acting antidepressants. This review discusses human EEG slow wave sleep parameters and plasma BDNF as central and peripheral surrogate markers of plasticity, and their use in assessing ketamine’s effects. Acutely, ketamine elevates BDNF levels, as well as early night SWA and high-amplitude slow waves; each of these measures correlates with change in mood in depressed patients who respond to ketamine. The slow wave effects are limited to the first night post-infusion, suggesting that their increase is part of an early cascade of events triggering improved mood. Increased total sleep and decreased waking occur during the first and second night post infusion, suggesting that these measures are associated with the enduring treatment response observed with ketamine.


Ketamine NMDA antagonist Sleep Major depressive disorder MDD Synaptic plasticity Slow wave sleep Slow wave activity SWA AMPA Mood Rapid antidepressant response Neurotrophic factors Brain-derived neurotrophic factor BDNF Treatment-resistant depression Bipolar depression Sleep disorders Psychiatry 


Compliance with Ethics Guidelines

Conflict of Interest

Wallace C. Duncan, Jr., declares that he has no conflict of interest.

Carlos A. Zarate, Jr., is listed as a coinventor on a patent application for the use of ketamine and its metabolites in major depression. Dr. Zarate has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government.

Human Rights and Informed Consent

The MDD and BP patients that are discussed in this review were part of studies that were approved by the Combined Neuroscience Institutional Review Board of the National Institutes of Health. All subjects provided written informed consent before entry into the studies.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Rush AJ, Trivedi MH, Stewart JW, Nierenberg AA, Fava M, Kurian BT, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry. 2011;168:689–701.PubMedCrossRefGoogle Scholar
  2. 2.
    Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.PubMedCrossRefGoogle Scholar
  3. 3.
    Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28–40.PubMedCrossRefGoogle Scholar
  4. 4.
    Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry. 2006;63:1121–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Hemmeter UM, Hemmeter-Spernal J, Krieg JC. Sleep deprivation in depression. Expert Rev Neurother. 2010;10:1101–15.PubMedCrossRefGoogle Scholar
  7. 7.
    Husain MM, Rush AJ, Fink M, Knapp R, Petrides G, Rummans T, et al. Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report. J Clin Psychiatry. 2004;65:485–91.PubMedCrossRefGoogle Scholar
  8. 8.
    Pagnin D, de Queiroz V, Pini S, Cassano GB. Efficacy of ECT in depression: a meta-analytic review. J ECT. 2004;20:13–20.PubMedCrossRefGoogle Scholar
  9. 9.
    Faraguna U, Vyazovskiy VV, Nelson AB, Tononi G, Cirelli C. A causal role for brain-derived neurotrophic factor in the homeostatic regulation of sleep. J Neurosci. 2008;28:4088–95.PubMedCrossRefGoogle Scholar
  10. 10.
    Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793–802.PubMedCrossRefGoogle Scholar
  11. 11.
    Zarate Jr CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64.PubMedCrossRefGoogle Scholar
  12. 12.
    Machado-Vieira R, Ibrahim L, Henter ID, Zarate Jr CA. Novel glutamatergic agents for major depressive disorder and bipolar disorder. Pharmacol, Biochem Behav. 2012;100:678–87.CrossRefGoogle Scholar
  13. 13.
    Maeng S, Zarate Jr CA. The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Curr Psychiatry Rep. 2007;9:467–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Yilmaz A, Schulz D, Aksoy A, Canbeyli R. Prolonged effect of an anesthetic dose of ketamine on behavioral despair. Pharmacol, Biochem Behav. 2002;71:341–4.CrossRefGoogle Scholar
  15. 15.
    Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17:2921–7.PubMedGoogle Scholar
  16. 16.
    •• Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. This study shows that in rats, ketamine rapidly activates the mTOR pathway, thereby increasing synaptic signaling proteins, spine density, and function. Blocking the mTOR pathway negated these effects as well as ketamine’s antidepressant-like effects.PubMedCrossRefGoogle Scholar
  17. 17.
    • Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338:68–72. This review summarizes preclinical work showing that ketamine rapidly induces synaptogenesis and reverses synaptic deficits caused by chronic stress.PubMedCrossRefGoogle Scholar
  18. 18.
    Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, et al. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci. 2004;24:4401–11.PubMedCrossRefGoogle Scholar
  19. 19.
    Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112:257–69.PubMedCrossRefGoogle Scholar
  20. 20.
    Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69:754–61.PubMedCrossRefGoogle Scholar
  21. 21.
    •• Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475:91–5. This study shows that NMDA antagonists cause fast-acting antidepressant-like effects in mouse models and that such effects depend on rapid synthesis of BDNF. Spontaneous neurotransmission effects on protein synthesis are viable targets of fast-acting antidepressants.PubMedCrossRefGoogle Scholar
  22. 22.
    Kavalali ET, Monteggia LM. Synaptic mechanisms underlying rapid antidepressant action of ketamine. Am J Psychiatry. 2012;169:1150–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Huber R, Ghilardi MF, Massimini M, Tononi G. Local sleep and learning. Nature. 2004;430:78–81.PubMedCrossRefGoogle Scholar
  24. 24.
    Huber R, Ghilardi MF, Massimini M, Ferrarelli F, Riedner BA, Peterson MJ, et al. Arm immobilization causes cortical plastic changes and locally decreases sleep slow wave activity. Nat Neurosci. 2006;9:1169–76.PubMedCrossRefGoogle Scholar
  25. 25.
    Esser SK, Hill SL, Tononi G. Sleep homeostasis and cortical synchronization: I. Modeling the effects of synaptic strength on sleep slow waves. Sleep. 2007;30:1617–30.PubMedGoogle Scholar
  26. 26.
    Vyazovskiy VV, Riedner BA, Cirelli C, Tononi G. Sleep homeostasis and cortical synchronization: II. A local field potential study of sleep slow waves in the rat. Sleep. 2007;30:1631–42.PubMedGoogle Scholar
  27. 27.
    Vyazovskiy VV, Cirelli C, Pfister-Genskow M, Faraguna U, Tononi G. Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep. Nat Neurosci. 2008;11:200–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Huber R, Tononi G, Cirelli C. Exploratory behavior, cortical BDNF expression, and sleep homeostasis. Sleep. 2007;30:129–39.PubMedGoogle Scholar
  29. 29.
    Aeschbach D, Cutler AJ, Ronda JM. A role for non-rapid-eye-movement sleep homeostasis in perceptual learning. J Neurosci. 2008;28:2766–72.PubMedCrossRefGoogle Scholar
  30. 30.
    Bachmann V, Klein C, Bodenmann S, Schafer N, Berger W, Brugger P, et al. The BDNF Val66Met polymorphism modulates sleep intensity: EEG frequency- and state-specificity. Sleep. 2012;35:335–44.PubMedGoogle Scholar
  31. 31.
    Laje G, Lally N, Mathews D, Brutsche N, Chemerinski A, Akula N, et al. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol Psychiatry. 2012;72:e27–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Ostenfeld I. Abstinence from night sleep as a treatment for endogenous depressions. The earliest observations in a Danish mental hospital (1954) and the analysis of the causal mechanism. Dan Med Bull. 1986;33:45–9.PubMedGoogle Scholar
  33. 33.
    Schulte W. Sequelae of sleep deprivation. Medizinische Klinik (Munich). 1959;54:969–73.Google Scholar
  34. 34.
    Borbely AA, Wirz-Justice A. Sleep, sleep deprivation and depression. A hypothesis derived from a model of sleep regulation. Hum Neurobiol. 1982;1:205–10.PubMedGoogle Scholar
  35. 35.
    Tononi G, Cirelli C. Sleep function and synaptic homeostasis. Sleep Med Rev. 2006;10:49–62.PubMedCrossRefGoogle Scholar
  36. 36.
    Borbely AA. A two process model of sleep regulation. Hum Neurobiol. 1982;1:195–204.PubMedGoogle Scholar
  37. 37.
    Gorgulu Y, Caliyurt O. Rapid antidepressant effects of sleep deprivation therapy correlates with serum BDNF changes in major depression. Brain Res Bull. 2009;80:158–62.PubMedCrossRefGoogle Scholar
  38. 38.
    Ibrahim L, Duncan W, Luckenbaugh DA, Yuan P, Machado-Vieira R, Zarate Jr CA. Rapid antidepressant changes with sleep deprivation in major depressive disorder are associated with changes in vascular endothelial growth factor (VEGF): a pilot study. Brain Res Bull. 2011;86:129–33.PubMedCrossRefGoogle Scholar
  39. 39.
    Baxter Jr LR. Can lithium carbonate prolong the antidepressant effect of sleep deprivation? Arch Gen Psychiatry. 1985;42:635.PubMedCrossRefGoogle Scholar
  40. 40.
    Bunney BG, Bunney WE. Rapid-acting antidepressant strategies: mechanisms of action. Int J Neuropsychopharmacol. 2011;1-19.Google Scholar
  41. 41.
    Wu JC, Kelsoe JR, Schachat C, Bunney BG, DeModena A, Golshan S, et al. Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder. Biol Psychiatry. 2009;66:298–301.PubMedCrossRefGoogle Scholar
  42. 42.
    aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67:139–45.CrossRefGoogle Scholar
  43. 43.
    Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, Aan Het Rot M, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74:250–256.Google Scholar
  44. 44.
    Rasmussen KG, Lineberry TW, Galardy CW, Kung S, Lapid MI, Palmer BA, et al. Serial infusions of low-dose ketamine for major depression. J Psychopharmacol. 2013;27:444–50.PubMedCrossRefGoogle Scholar
  45. 45.
    Ibrahim L, Diazgranados N, Franco-Chaves J, Brutsche N, Henter ID, Kronstein P, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology. 2012;37:1526–33.Google Scholar
  46. 46.
    Mathew SJ, Murrough JW, aan het Rot M, Collins KA, Reich DL, Charney DS. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharmacol. 2010;13:71–82.PubMedCrossRefGoogle Scholar
  47. 47.
    Hemmeter U, Bischof R, Hatzinger M, Seifritz E, Holsboer-Trachsler E. Microsleep during partial sleep deprivation in depression. Biol Psychiatry. 1998;43:829–39.PubMedCrossRefGoogle Scholar
  48. 48.
    Van Bemmel A, van den Hoofdakker R. Maintenance of therapeutic effects of total sleep deprivation by limitation of subsequent sleep. A pilot study. Acta Psychiatr Scand. 1981;63:453–62.PubMedCrossRefGoogle Scholar
  49. 49.
    Hefti K, Holst SC, Sovago J, Bachmann V, Buck A, Ametamey SM, et al. Increased metabotropic glutamate receptor subtype 5 availability in human brain after one night without sleep. Biol Psychiatry. 2013;73:161–8.PubMedCrossRefGoogle Scholar
  50. 50.
    John J, Ramanathan L, Siegel JM. Rapid changes in glutamate levels in the posterior hypothalamus across sleep-wake states in freely behaving rats. Am J Physiol Regul Integr Comp Physiol. 2008;295:R2041–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Feinberg I, Campbell IG. Ketamine administration during waking increases delta EEG intensity in rat sleep. Neuropsychopharmacology. 1993;9:41–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Campbell IG, Feinberg I. NREM delta stimulation following MK-801 is a response of sleep systems. J Neurophysiol. 1996;76:3714–20.PubMedGoogle Scholar
  53. 53.
    • Duncan WC, Sarasso S, Ferrarelli F, Selter J, Riedner BA, Hejazi NS, et al. Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder. Int J Neuropsychopharmacol. 2013;16:301–11. This clinical study of ketamine’s antidepressant effects in treatment-resistant depression shows that ketamine acutely increases BDNF, slow wave activity, the occurrence of high amplitude waves, and slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels are proportional to changes in EEG parameters in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity is part of the rapid antidepressant.PubMedCrossRefGoogle Scholar
  54. 54.
    Duncan Jr WC, Selter J, Brutsche N, Sarasso S, Zarate Jr CA. Baseline delta sleep ratio predicts acute ketamine mood response in major depressive disorder. J Affect Disord. 2013;145:115–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Cornwell BR, Salvadore G, Furey M, Marquardt CA, Brutsche NE, Grillon C, et al. Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression. Biol Psychiatry. 2012;72:555–61.PubMedCrossRefGoogle Scholar
  56. 56.
    Selter J, Duncan WC, Luckenbaugh D, Chen G, Zarate C. Differential slow wave sleep response to ketamine in MDD versus BP Disorder. Abstracts of the Society for Neuroscience, Washington DC, November 12-16, 2011; 2011Google Scholar
  57. 57.
    Landsness EC, Goldstein MR, Peterson MJ, Tononi G, Benca RM. Antidepressant effects of selective slow wave sleep deprivation in major depression: a high-density EEG investigation. J Psychiatr Res. 2011;45:1019–26.PubMedCrossRefGoogle Scholar
  58. 58.
    Friston KJ, Sharpley AL, Solomon RA, Cowen PJ. Lithium increases slow wave sleep: possible mediation by brain 5-HT2 receptors? Psychopharmacology (Berl). 1989;98:139–40.CrossRefGoogle Scholar
  59. 59.
    Kupfer DJ, Reynolds 3rd CF, Weiss BL, Foster FG. Lithium carbonate and sleep in affective disorders. Further considerations. Arch Gen Psychiatry. 1974;30:79–84.PubMedCrossRefGoogle Scholar
  60. 60.
    Lanoir J, Lardennois D. The action of lithium carbonate on the sleep-waking cycle in the cat. Electroencephalogr Clin Neurophysiol. 1977;42:676–90.PubMedCrossRefGoogle Scholar
  61. 61.
    Son H, Yu IT, Hwang SJ, Kim JS, Lee SH, Lee YS, et al. Lithium enhances long-term potentiation independently of hippocampal neurogenesis in the rat dentate gyrus. J Neurochem. 2003;85:872–81.PubMedCrossRefGoogle Scholar
  62. 62.
    Gray NA, Zhou R, Du J, Moore GJ, Manji HK. The use of mood stabilizers as plasticity enhancers in the treatment of neuropsychiatric disorders. J Clin Psychiatry. 2003;64 Suppl 5:3–17.PubMedGoogle Scholar
  63. 63.
    Harding GF, Alford CA, Powell TE. The effect of sodium valproate on sleep, reaction times, and visual evoked potential in normal subjects. Epilepsia. 1985;26:597–601.PubMedCrossRefGoogle Scholar
  64. 64.
    Beaulieu JM. Not only lithium: regulation of glycogen synthase kinase-3 by antipsychotics and serotonergic drugs. Int J Neuropsychopharmacol. 2007;10:3–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Beurel E, Song L, Jope RS. Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry. 2011;16:1068–70.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2013

Authors and Affiliations

  1. 1.Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental HealthNational Institutes of HealthBethesdaUSA

Personalised recommendations