Hostname: page-component-848d4c4894-xfwgj Total loading time: 0 Render date: 2024-06-16T07:48:55.188Z Has data issue: false hasContentIssue false

Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy volunteers: implications for antidepressant effect

Published online by Cambridge University Press:  09 December 2009

J. Horacek*
Prague Psychiatric Centre, Prague, Czech Republic Centre of Neuropsychiatric Studies, Prague, Czech Republic Third Medical Faculty of Charles University, Prague, Czech Republic
M. Brunovsky
Prague Psychiatric Centre, Prague, Czech Republic Centre of Neuropsychiatric Studies, Prague, Czech Republic
T. Novak
Centre of Neuropsychiatric Studies, Prague, Czech Republic
B. Tislerova
Third Medical Faculty of Charles University, Prague, Czech Republic
T. Palenicek
Centre of Neuropsychiatric Studies, Prague, Czech Republic Third Medical Faculty of Charles University, Prague, Czech Republic
V. Bubenikova-Valesova
Prague Psychiatric Centre, Prague, Czech Republic Centre of Neuropsychiatric Studies, Prague, Czech Republic
F. Spaniel
Prague Psychiatric Centre, Prague, Czech Republic Third Medical Faculty of Charles University, Prague, Czech Republic
J. Koprivova
Centre of Neuropsychiatric Studies, Prague, Czech Republic Third Medical Faculty of Charles University, Prague, Czech Republic
P. Mohr
Prague Psychiatric Centre, Prague, Czech Republic
M. Balikova
Institute of Forensic Medicine and Toxicology, First Medical Faculty, Charles University, Prague, Czech Republic
C. Hoschl
Prague Psychiatric Centre, Prague, Czech Republic Centre of Neuropsychiatric Studies, Prague, Czech Republic Third Medical Faculty of Charles University, Prague, Czech Republic
*Address for correspondence: Prof. Dr J. Horacek, Ph.D., Prague Psychiatric Centre, Ustavni 91, 181 03Prague 8, Czech Republic. (Email:



Theta cordance is a novel quantitative electroencephalography (QEEG) measure that correlates with cerebral perfusion. A series of clinical studies has demonstrated that the prefrontal theta cordance value decreases after 1 week of treatment in responders to antidepressants and that this effect precedes clinical improvement. Ketamine, a non-competitive antagonist of N-methyl-d-aspartate (NMDA) receptors, has a unique rapid antidepressant effect but its influence on theta cordance is unknown.


In a double-blind, cross-over, placebo-controlled experiment we studied the acute effect of ketamine (0.54 mg/kg within 30 min) on theta cordance in a group of 20 healthy volunteers.


Ketamine infusion induced a decrease in prefrontal theta cordance and an increase in the central region theta cordance after 10 and 30 min. The change in prefrontal theta cordance correlated with ketamine and norketamine blood levels after 10 min of ketamine infusion.


Our data indicate that ketamine infusion immediately induces changes similar to those that monoamineric-based antidepressants induce gradually. The reduction in theta cordance could be a marker and a predictor of the fast-acting antidepressant effect of ketamine, a hypothesis that could be tested in depressive patients treated with ketamine.

Original Articles
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Asada, H, Fukuda, Y, Tsunoda, S, Yamaguchi, M, Tonoike, M (1999). Frontal midline theta rhythms reflect alternative activation of prefrontal cortex and anterior cingulate cortex in humans. Neuroscience Letters 274, 2932.CrossRefGoogle ScholarPubMed
Bares, M, Brunovsky, M, Kopecek, M, Novak, T, Stopkova, P, Kozeny, J, Sos, P, Krajca, V, Hoschl, C (2008). Early reduction in prefrontal theta QEEG cordance value predicts response to venlafaxine treatment in patients with resistant depressive disorder. European Psychiatry 23, 350355.CrossRefGoogle ScholarPubMed
Bares, M, Brunovsky, M, Kopecek, M, Stopkova, P, Novak, T, Kozeny, J, Hoschl, C (2007). Changes in QEEG prefrontal cordance as a predictor of response to antidepressants in patients with treatment resistant depressive disorder: a pilot study. Journal of Psychiatric Research 41, 319325.CrossRefGoogle ScholarPubMed
Berman, RM, Cappiello, A, Anand, A, Oren, DA, Heninger, GR, Charney, DS, Krystal, JH (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 47, 351354.CrossRefGoogle ScholarPubMed
Bubenikova-Valesova, V, Horacek, J, Vrajova, M, Hoschl, C (2008). Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neuroscience and Biobehavioral Reviews 32, 10141023.CrossRefGoogle ScholarPubMed
Cook, IA, Leuchter, AF, Morgan, ML, Stubbeman, W, Siegman, B, Abrams, M (2005). Changes in prefrontal activity characterize clinical response in SSRI nonresponders: a pilot study. Journal of Psychiatric Research 39, 461466.CrossRefGoogle ScholarPubMed
Cook, IA, Leuchter, AF, Morgan, M, Witte, E, Stubbeman, WF, Abrams, M, Rosenberg, S, Uijtdehaage, SH (2002). Early changes in prefrontal activity characterize clinical responders to antidepressants. Neuropsychopharmacology 27, 120131.CrossRefGoogle ScholarPubMed
Cook, IA, Leuchter, AF, Uijtdehaage, SH, Osato, S, Holschneider, DH, Abrams, M, Rosenberg-Thompson, S (1998). Altered cerebral energy utilization in late life depression. Journal of Affective Disorders 49, 8999.CrossRefGoogle ScholarPubMed
Cook, IA, Leuchter, AF, Witte, E, Abrams, M, Uijtdehaage, SH, Stubbeman, W, Rosenberg-Thompson, S, Anderson-Hanley, C, Dunkin, JJ (1999). Neurophysiologic predictors of treatment response to fluoxetine in major depression. Psychiatry Research 85, 263273.CrossRefGoogle ScholarPubMed
Deakin, JF, Lees, J, McKie, S, Hallak, JE, Williams, SR, Dursun, SM (2008). Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Archives of General Psychiatry 65, 154164.CrossRefGoogle ScholarPubMed
Du, J, Machado-Vieira, R, Maeng, S, Martinowich, K, Manji, HK, Zarate, J (2006). Enhancing AMPA to NMDA throughput as a convergent mechanism for antidepressant action. Drug Discovery Today: Therapeutic Strategies 3, 519526.Google ScholarPubMed
Ebert, B, Mikkelsen, S, Thorkildsen, C, Borgbjerg, FM (1997). Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. European Journal of Pharmacology 333, 99–104.CrossRefGoogle ScholarPubMed
Hetem, LA, Danion, JM, Diemunsch, P, Brandt, C (2000). Effect of a subanesthetic dose of ketamine on memory and conscious awareness in healthy volunteers. Psychopharmacology (Berlin) 152, 283288.CrossRefGoogle ScholarPubMed
Hunter, AM, Cook, IA, Leuchter, AF (2007). The promise of the quantitative electroencephalogram as a predictor of antidepressant treatment outcomes in major depressive disorder. Psychiatric Clinics of North America 30, 105124.CrossRefGoogle ScholarPubMed
Ishii, R, Shinosaki, K, Ukai, S, Inouye, T, Ishihara, T, Yoshimine, T, Hirabuki, N, Asada, H, Kihara, T, Robinson, SE, Takeda, M (1999). Medial prefrontal cortex generates frontal midline theta rhythm. Neuroreport 10, 675679.CrossRefGoogle ScholarPubMed
Kennedy, SH, Konarski, JZ, Segal, ZV, Lau, MA, Bieling, PJ, McIntyre, RS, Mayberg, HS (2007). Differences in brain glucose metabolism between responders to CBT and venlafaxine in a 16-week randomized controlled trial. American Journal of Psychiatry 164, 778788.CrossRefGoogle Scholar
Knott, V, Mahoney, C, Kennedy, S, Evans, K (2000). Pre-treatment EEG and its relationship to depression severity and paroxetine treatment outcome. Pharmacopsychiatry 33, 201205.CrossRefGoogle ScholarPubMed
Krystal, JH, Sanacora, G, Blumberg, H, Anand, A, Charney, DS, Marek, G, Epperson, CN, Goddard, A, Mason, GF (2002). Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Molecular Psychiatry 7 (Suppl. 1), S71S80.CrossRefGoogle ScholarPubMed
Leuchter, AF, Cook, IA, DeBrota, DJ, Hunter, AM, Potter, WZ, McGrouther, CC, Morgan, ML, Abrams, M, Siegman, B (2008) Changes in brain function during administration of venlafaxine or placebo to normal subjects. Clinical EEG and Neuroscience Journal 39, 175181.CrossRefGoogle ScholarPubMed
Leuchter, AF, Cook, IA, Hunter, A, Korb, A (2009) Use of clinical neurophysiology for the selection of medication in the treatment of major depressive disorder: the state of the evidence. Clinical EEG and Neuroscience 40, 7883.CrossRefGoogle ScholarPubMed
Leuchter, AF, Cook, IA, Lufkin, RB, Dunkin, J, Newton, TF, Cummings, JL, Mackey, JK, Walter, DO (1994). Cordance: a new method for assessment of cerebral perfusion and metabolism using quantitative electroencephalography. NeuroImage 1, 208219.CrossRefGoogle ScholarPubMed
Leuchter, AF, Cook, IA, Uijtdehaage, SH, Dunkin, J, Lufkin, RB, Anderson-Hanley, C, Abrams, M, Rosenberg-Thompson, S, O'Hara, R, Simon, SL, Osato, S, Babaie, A (1997). Brain structure and function and the outcomes of treatment for depression. Journal of Clinical Psychiatry 58 (Suppl. 16), 2231.Google ScholarPubMed
Leuchter, AF, Cook, IA, Witte, EA, Morgan, M, Abrams, M (2002). Changes in brain function of depressed subjects during treatment with placebo. American Journal of Psychiatry 159, 122129.CrossRefGoogle ScholarPubMed
Leuchter, AF, Uijtdehaage, SH, Cook, IA, O'Hara, R, Mandelkern, M (1999). Relationship between brain electrical activity and cortical perfusion in normal subjects. Psychiatry Research 90, 125140.CrossRefGoogle ScholarPubMed
Maeng, S, Zarate, CA Jr., Du, J, Schloesser, RJ, McCammon, J, Chen, G, Manji, HK (2008). Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biological Psychiatry 63, 349352.CrossRefGoogle ScholarPubMed
Mathew, SJ, Keegan, K, Smith, L (2005). Glutamate modulators as novel interventions for mood disorders. Revista Brasileira de Psiquiatria 27, 243248.CrossRefGoogle ScholarPubMed
Mayberg, HS (2003). Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. British Medical Bulletin 65, 193207.CrossRefGoogle ScholarPubMed
Mayberg, HS, Liotti, M, Brannan, SK, McGinnis, S, Mahurin, RK, Jerabek, PA, Silva, JA, Tekell, JL, Martin, CC, Lancaster, JL, Fox, PT (1999). Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. American Journal of Psychiatry 156, 675682.CrossRefGoogle ScholarPubMed
Nuwer, MR, Lehmann, D, da Silva, FL, Matsuoka, S, Sutherling, W, Vibert, JF (1999). IFCN guidelines for topographic and frequency analysis of EEGs and EPs. The International Federation of Clinical Neurophysiology. Electroencephalography and Clinical Neurophysiology. Supplement 52, 1520.Google ScholarPubMed
Penders, J, Verstraete, A (2006). Laboratory guidelines and standards in clinical and forensic toxicology. Accreditation and quality assurance. Accreditation and Quality Assurance 11, 284290.CrossRefGoogle Scholar
Pizzagalli, D, Pascual-Marqui, RD, Nitschke, JB, Oakes, TR, Larson, CL, Abercrombie, HC, Schaefer, SM, Koger, JV, Benca, RM, Davidson, RJ (2001). Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical tomography analysis. American Journal of Psychiatry 158, 405415.CrossRefGoogle ScholarPubMed
Rowland, LM, Bustillo, JR, Mullins, PG, Jung, RE, Lenroot, R, Landgraf, E, Barrow, R, Yeo, R, Lauriello, J, Brooks, WM (2005). Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. American Journal of Psychiatry 162, 394396.CrossRefGoogle ScholarPubMed
Salvadore, G, Cornwell, BR, Colon-Rosario, V, Coppola, R, Grillon, C, Zarate, CA Jr., Manji, HK (2009). Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine. Biological Psychiatry 65, 289295.CrossRefGoogle Scholar
Szabo, ST, Hado-Vieira, R, Yuan, P, Wang, Y, Wei, Y, Falke, C, Cirelli, C, Tononi, G, Manji, HK, Du, J (2009). Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of mania. Neuropharmacology 56, 4755.CrossRefGoogle ScholarPubMed
Tishler, LC, Gordon, LB (1999). Ethical parameters of challenge studies inducing psychosis with ketamine. Ethics and Behavior 9, 211217.CrossRefGoogle ScholarPubMed
Tsujimoto, T, Shimazu, H, Isomura, Y (2006). Direct recording of theta oscillations in primate prefrontal and anterior cingulate cortices. Journal of Neurophysiology 95, 29873000.CrossRefGoogle ScholarPubMed
Zarate, CA Jr., Singh, JB, Carlson, PJ, Brutsche, NE, Ameli, R, Luckenbaugh, DA, Charney, DS, Manji, HK (2006). A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry 63, 856864.CrossRefGoogle ScholarPubMed