Skip to main content

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

  • Article
  • Published:

Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects

Molecular Psychiatry volume 24, pages 1040–1052 (2019)Cite this article

Subjects

Abstract

Ketamine’s mechanism of action was assessed using gamma power from magnetoencephalography (MEG) as a proxy measure for homeostatic balance in 35 unmedicated subjects with major depressive disorder (MDD) and 25 healthy controls enrolled in a double-blind, placebo-controlled, randomized cross-over trial of 0.5 mg/kg ketamine. MDD subjects showed significant improvements in depressive symptoms, and healthy control subjects exhibited modest but significant increases in depressive symptoms for up to 1 day after ketamine administration. Both groups showed increased resting gamma power following ketamine. In MDD subjects, gamma power was not associated with the magnitude of the antidepressant effect. However, baseline gamma power was found to moderate the relationship between post-ketamine gamma power and antidepressant response; specifically, higher post-ketamine gamma power was associated with better response in MDD subjects with lower baseline gamma, with an inverted relationship in MDD subjects with higher baseline gamma. This relationship was observed in multiple regions involved in networks hypothesized to be involved in the pathophysiology of MDD. This finding suggests biological subtypes based on the direction of homeostatic dysregulation and has important implications for inferring ketamine’s mechanism of action from studies of healthy controls alone.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. 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.

    Article  PubMed  Google Scholar 

  2. Zarate CA Jr., 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.

    Article  CAS  PubMed  Google Scholar 

  3. Valentine GW, Mason GF, Gomez R, Fasula M, Watzl J, Pittman B, 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;191:122–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170:1134–42.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016;173:816–26.

    Article  PubMed  Google Scholar 

  6. Zarate CA Jr., Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71:939–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, 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;71:1605–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Murrough JW, Soleimani L, DeWilde KE, Collins KA, Lapidus KA, Iacoviello BM, et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychol Med. 2015;45:3571–80.

    Article  CAS  PubMed  Google Scholar 

  9. Maeng S, Zarate CA Jr. 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.

    Article  PubMed  Google Scholar 

  10. Maeng S, Zarate CA Jr., Du J, Schloesser RJ, McCammon J, Chen G, 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;63:349–52.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pinault D. N-methyl d-aspartate receptor antagonists ketamine and MK-801 induce wake-related aberrant gamma oscillations in the rat neocortex. Biol Psychiatry. 2008;63:730–5.

    Article  CAS  PubMed  Google Scholar 

  14. Anderson PM, Pinault D, O’Brien TJ, Jones NC. Chronic administration of antipsychotics attenuates ongoing and ketamine-induced increases in cortical gamma oscillations. Int J Neuropsychopharmacol. 2014;17:1895–904.

    Article  CAS  PubMed  Google Scholar 

  15. Jones NC, Anderson P, Rind G, Sullivan C, van den Buuse M, O’Brien TJ. Effects of aberrant gamma frequency oscillations on prepulse inhibition. Int J Neuropsychopharmacol. 2014;17:1671–81.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang Y, Yoshida T, Katz DB, Lisman JE. NMDAR antagonist action in thalamus imposes delta oscillations on the hippocampus. J Neurophysiol. 2012;107:3181–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rivolta D, Heidegger T, Scheller B, Sauer A, Schaum M, Birkner K, et al. Ketamine dysregulates the amplitude and connectivity of high-frequency oscillations in cortical-subcortical networks in humans: evidence from resting-state magnetoencephalography-recordings. Schizophr Bull. 2015;41:1105–14.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Shaw AD, Saxena N, E Jackson L, Hall JE, Singh KD, Muthukumaraswamy SD. Ketamine amplifies induced gamma frequency oscillations in the human cerebral cortex. Eur Neuropsychopharmacol. 2015;25:1136–46.

    Article  CAS  PubMed  Google Scholar 

  19. Ren Z, Pribiag H, Jefferson SJ, Shorey M, Fuchs T, Stellwagen D, et al. Bidirectional homeostatic regulation of a depression-related brain state by gamma-aminobutyric acidergic deficits and ketamine treatment. Biol Psychiatry. 2016;80:457–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci. 2007;27:11496–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Carlen M, Meletis K, Siegle JH, Cardin JA, Futai K, Vierling-Claassen D, et al. A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior. Mol Psychiatry. 2012;17:537–48.

    Article  CAS  PubMed  Google Scholar 

  22. Miller OH, Moran JT, Hall BJ. Two cellular hypotheses explaining the initiation of ketamine’s antidepressant actions: direct inhibition and disinhibition. Neuropharmacology. 2016;100:17–26.

    Article  CAS  PubMed  Google Scholar 

  23. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDA receptor inhibition-independent antidepressant actions of a ketamine metabolite. Nature. 2016;533:481–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bartos M, Vida I, Jonas P. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci. 2007;8:45–56.

    Article  CAS  PubMed  Google Scholar 

  25. Fries P. Neuronal gamma-band synchronization as a fundamental process in cortical computation. Annu Rev Neurosci. 2009;32:209–24.

    Article  CAS  PubMed  Google Scholar 

  26. Debener S, Herrmann CS, Kranczioch C, Gembris D, Engel AK. Top-down attentional processing enhances auditory evoked gamma band activity. Neuroreport. 2003;14:683–6.

    Article  PubMed  Google Scholar 

  27. Mulert C, Leicht G, Hepp P, Kirsch V, Karch S, Pogarell O, et al. Single-trial coupling of the gamma-band response and the corresponding BOLD signal. Neuroimage. 2010;49:2238–47.

    Article  CAS  PubMed  Google Scholar 

  28. Niessing J, Ebisch B, Schmidt KE, Niessing M, Singer W, Galuske RA. Hemodynamic signals correlate tightly with synchronized gamma oscillations. Science. 2005;309:948–51.

    Article  CAS  PubMed  Google Scholar 

  29. Shmuel A, Leopold DA. Neuronal correlates of spontaneous fluctuations in fMRI signals in monkey visual cortex: implications for functional connectivity at rest. Hum Brain Mapp. 2008;29:751–61.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kann O, Hollnagel JO, Elzoheiry S, Schneider J. Energy and potassium ion homeostasis during gamma oscillations. Front Mol Neurosci. 2016;9:47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Gandal MJ, Sisti J, Klook K, Ortinski PI, Leitman V, Liang Y, et al. GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction. Transl Psychiatry. 2012;2:e142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kehrer C, Maziashvili N, Dugladze T, Gloveli T. Altered excitatory-inhibitory balance in the NMDA-hypofunction model of schizophrenia. Front Mol Neurosci. 2008;1:6.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338:68–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Turrigiano GG. The self-tuning neuron: synaptic scaling of excitatory synapses. Cell. 2008;135:422–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Smith KS, Rudolph U. Anxiety and depression: mouse genetics and pharmacological approaches to the role of GABA(A) receptor subtypes. Neuropharmacology. 2012;62:54–62.

    Article  CAS  PubMed  Google Scholar 

  36. Thompson SM, Kallarackal AJ, Kvarta MD, Van Dyke AM, LeGates TA, Cai X. An excitatory synapse hypothesis of depression. Trends Neurosci. 2015;38:279–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Drevets WC. Neuroplasticity in mood disorders. Dialogues Clin Neurosci. 2004;6:199–216.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Drevets WC, Gadde KM, Krishnan KR. Neuroimaging studies of mood disorders. In: Charney DS, editor. Neurobiology of mental illness. 2nd ed. Oxford: Oxford University Press; 2004. p. 461–90.

    Chapter  Google Scholar 

  39. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. First MB, Spitzer RL, Gibbon M, Williams AR. Structured clinical interview for DSM-IV TR axis I disorders, research version, patient edition (SCID-I/P). New York: State Psychiatric Institute, Biometrics Research; 2001.

    Google Scholar 

  41. Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001;62:10–17.

    CAS  PubMed  Google Scholar 

  42. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bech P, Boyer P, Germain JM, Padmanabhan K, Haudiquet V, Pitrosky B, et al. HAM-D17 and HAM-D6 sensitivity to change in relation to desvenlafaxine dose and baseline depression severity in major depressive disorder. Pharmacopsychiatry. 2010;43:271–6.

    Article  CAS  PubMed  Google Scholar 

  44. Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995;167:99–103.

    Article  CAS  PubMed  Google Scholar 

  45. Gard DE, Gard MG, Kring AM, John OP. Anticipatory and consummatory components of the experience of pleasure: a scale development study. J Res Personal. 2006;40:1086–102.

    Article  Google Scholar 

  46. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32:50–5.

    Article  CAS  PubMed  Google Scholar 

  47. Beck AT, Beamesderfer A. Assessment of depression: the depression inventory. Mod Probl Pharm. 1974;7:151–69.

    CAS  Google Scholar 

  48. Blanchard EB, Jones-Alexander J, Buckley TC, Forneris CA. Psychometric properties of the PTSD checklist (PCL). Behav Res Ther. 1996;34:669–73.

    Article  CAS  PubMed  Google Scholar 

  49. Endicott J, Nee J, Harrison W, Blumenthal R. Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull. 1993;29:321–6.

    CAS  PubMed  Google Scholar 

  50. Guy W. Clinical global impressions. In: Guy W, editor. ECDEU assessment manual for psychopharmacology. National Institute of Mental Health; Rockville, MD, 1976.

  51. Beck AT, Kovacs M, Weissman A. Assessment of suicidal intention: the scale for suicide ideation. J Consult Clin Psychol. 1979;47:343–52.

    Article  CAS  PubMed  Google Scholar 

  52. McNair DM, Lorr M, Droppleman LF. EITS manual for the profile of mood states. Educational and Testing Service; San Diego, CA, 1971.

  53. Aitken RC. Measurement of feelings using visual analogue scales. Proc R Soc Med. 1969;62:989–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, et al. Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress. 1998;11:125–36.

    Article  CAS  PubMed  Google Scholar 

  55. Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep. 1962;10:799–812.

    Article  Google Scholar 

  56. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–35.

    Article  CAS  PubMed  Google Scholar 

  57. Lopes da Silva F. EEG and MEG: relevance to neuroscience. Neuron. 2013;80:1112–28.

    Article  CAS  PubMed  Google Scholar 

  58. Gramfort A, Luessi M, Larson E, Engemann DA, Strohmeier D, Brodbeck C, et al. MEG and EEG data analysis with MNE-Python. Front Neurosci. 2013;7:267.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Cox RW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res. 1996;29:162–73.

    Article  CAS  PubMed  Google Scholar 

  60. Robinson SE, Vrba J. Functional neuroimaging by synthetic aperture magnetometry (SAM). Biomag. Sendai: Tohoku University Press; 1999. p. 302–5.

  61. Chen G, Saad ZS, Britton JC, Pine DS, Cox RW. Linear mixed-effects modeling approach to FMRI group analysis. Neuroimage. 2013;73:176–90.

    Article  PubMed  Google Scholar 

  62. Perry EB Jr., Cramer JA, Cho HS, Petrakis IL, Karper LP, Genovese A, et al. Psychiatric safety of ketamine in psychopharmacology research. Psychopharmacol. 2007;192:253–60.

    Article  CAS  Google Scholar 

  63. Taylor MJ, Tiangga ER, Mhuircheartaigh RN, Cowen PJ. Lack of effect of ketamine on cortical glutamate and glutamine in healthy volunteers: a proton magnetic resonance spectroscopy study. J Psychopharmacol. 2012;26:733–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51:199–214.

    Article  CAS  PubMed  Google Scholar 

  65. Stone JM, Erlandsson K, Arstad E, Squassante L, Teneggi V, Bressan RA, et al. Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy: a [(123)I]CNS-1261 SPET study. Psychopharmacol. 2008;197:401–8.

    Article  CAS  Google Scholar 

  66. Mason OJ, Morgan CJ, Stefanovic A, Curran HV. The psychotomimetic states inventory (PSI): measuring psychotic-type experiences from ketamine and cannabis. Schizophr Res. 2008;103:138–42.

    Article  PubMed  Google Scholar 

  67. Pollak TA, De Simoni S, Barimani B, Zelaya FO, Stone JM, Mehta MA. Phenomenologically distinct psychotomimetic effects of ketamine are associated with cerebral blood flow changes in functionally relevant cerebral foci: a continuous arterial spin labelling study. Psychopharmacol. 2015;232:4515–24.

    Article  CAS  Google Scholar 

  68. Muthukumaraswamy SD, Shaw AD, Jackson LE, Hall J, Moran R, Saxena N. Evidence that subanesthetic doses of ketamine cause sustained disruptions of NMDA and AMPA-mediated frontoparietal connectivity in humans. J Neurosci. 2015;35:11694–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Scheidegger M, Walter M, Lehmann M, Metzger C, Grimm S, Boeker H, et al. Ketamine decreases resting state functional network connectivity in healthy subjects: implications for antidepressant drug action. PLoS ONE. 2012;7:e44799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Li M, Demenescu LR, Colic L, Metzger CD, Heinze HJ, Steiner J, et al. Temporal dynamics of antidepressant ketamine effects on glutamine cycling follow regional fingerprints of AMPA and NMDA receptor densities. Neuropsychopharmacology. 2017;42:1201–9.

    Article  CAS  PubMed  Google Scholar 

  71. Haegens S, Cousijn H, Wallis G, Harrison PJ, Nobre AC. Inter- and intra-individual variability in alpha peak frequency. Neuroimage. 2014;92:46–55.

    Article  PubMed  Google Scholar 

  72. Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med. 2017;23:28–38.

    Article  CAS  PubMed  Google Scholar 

  73. Duncan NW, Wiebking C, Tiret B, Marjanska M, Hayes DJ, Lyttleton O, et al. Glutamate concentration in the medial prefrontal cortex predicts resting-state cortical-subcortical functional connectivity in humans. PLoS ONE. 2013;8:e60312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kapogiannis D, Reiter DA, Willette AA, Mattson MP. Posteromedial cortex glutamate and GABA predict intrinsic functional connectivity of the default mode network. Neuroimage. 2013;64:112–9.

    Article  CAS  PubMed  Google Scholar 

  75. Nugent AC, Martinez A, D’Alfonso A, Zarate CA, Theodore WH. The relationship between glucose metabolism, resting-state fMRI BOLD signal, and GABA-binding potential: a preliminary study in healthy subjects and those with temporal lobe epilepsy. J Cereb Blood Flow Metab. 2015;35:583–91.

    Article  CAS  Google Scholar 

  76. Tomasi D, Wang GJ, Volkow ND. Energetic cost of brain functional connectivity. Proc Natl Acad Sci USA. 2013;110:13642–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Niciu MJ, Ionescu DF, Richards EM, Zarate CA Jr. Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder. J Neural Transm. 2014;121:907–24.

    Article  CAS  PubMed  Google Scholar 

  78. Menon V. Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn Sci. 2011;15:483–506.

    Article  PubMed  Google Scholar 

  79. Zheng H, Xu L, Xie F, Guo X, Zhang J, Yao L, et al. The altered triple networks interaction in depression under resting state based on graph theory. Biomed Res Int. 2015;2015:386326.

    PubMed  PubMed Central  Google Scholar 

  80. Manoliu A, Meng C, Brandl F, Doll A, Tahmasian M, Scherr M, et al. Insular dysfunction within the salience network is associated with severity of symptoms and aberrant inter-network connectivity in major depressive disorder. Front Hum Neurosci. 2013;7:930.

    Article  PubMed  Google Scholar 

  81. Hoflich A, Hahn A, Kublbock M, Kranz GS, Vanicek T, Windischberger C, et al. Ketamine-induced modulation of the thalamo-cortical network in healthy volunteers as a model for schizophrenia. Int J Neuropsychopharmacol. 2015;18, https://doi.org/10.1093/ijnp/pyv040.

    Article  PubMed Central  CAS  Google Scholar 

  82. Driesen NR, McCarthy G, Bhagwagar Z, Bloch M, Calhoun V, D’Souza DC, et al. Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. Mol Psychiatry. 2013;18:1199–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ribary U, Ioannides AA, Singh KD, Hasson R, Bolton JP, Lado F, et al. Magnetic field tomography of coherent thalamocortical 40-Hz oscillations in humans. Proc Natl Acad Sci USA. 1991;88:11037–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Luo Q, Holroyd T, Jones M, Hendler T, Blair J. Neural dynamics for facial threat processing as revealed by gamma band synchronization using MEG. Neuroimage. 2007;34:839–47.

    Article  PubMed  Google Scholar 

  85. Nugent AC, Davis RM, Zarate CA Jr., Drevets WC. Reduced thalamic volumes in major depressive disorder. Psychiatry Res. 2013;213:179–85.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. A functional anatomical study of unipolar depression. J Neurosci. 1992;12:3628–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Greicius MD, Flores BH, Menon V, Glover GH, Solvason HB, Kenna H, et al. Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol Psychiatry. 2007;62:429–37.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the 7SE research unit and staff for their support. Ioline Henter (NIMH) provided invaluable editorial assistance.

Author information

Authors and Affiliations

  1. Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    Allison C. Nugent, Elizabeth D. Ballard, Lawrence T. Park, Nancy E. Brutsche & Carlos A. Zarate Jr.

  2. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

    Todd D. Gould

  3. Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, USA

    Ruin Moaddel

Authors
  1. Allison C. Nugent
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth D. Ballard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Todd D. Gould
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lawrence T. Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ruin Moaddel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nancy E. Brutsche
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carlos A. Zarate Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Allison C. Nugent.

Ethics declarations

Conflict of interest

Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; NCT00088699/04-M-0222/ZIA MH002857), by a NARSAD Independent Investigator Award to C.A.Z., and by a Brain and Behavior Mood Disorders Research Award to C.A.Z. C.A.Z. is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation. C.A.Z. is listed as a co-inventor on a patent for the use of (2 R,6 R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. C.A.Z. is listed as co-inventor on a patent application for the use of (2 R,6 R)-hydroxynorketamine and (2 S,6 S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and PTSDs; he has assigned his patent rights to the US government, but will share a percentage of any royalties that may be received by the government. The remaining authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nugent, A.C., Ballard, E.D., Gould, T.D. et al. Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Mol Psychiatry 24, 1040–1052 (2019). https://doi.org/10.1038/s41380-018-0028-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-018-0028-2

This article is cited by

Search

Advanced search

Quick links