Skip to main content Accessibility help

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

  • J. Horacek (a1) (a2) (a3), M. Brunovsky (a1) (a2), T. Novak (a2), B. Tislerova (a3), T. Palenicek (a2) (a3), V. Bubenikova-Valesova (a1) (a2), F. Spaniel (a1) (a3), J. Koprivova (a2) (a3), P. Mohr (a1), M. Balikova (a4) and C. Hoschl (a1) (a2) (a3)...



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.


Corresponding author

*Address for correspondence: Prof. Dr J. Horacek, Ph.D., Prague Psychiatric Centre, Ustavni 91, 181 03Prague 8, Czech Republic. (Email:


Hide All
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Mathew, SJ, Keegan, K, Smith, L (2005). Glutamate modulators as novel interventions for mood disorders. Revista Brasileira de Psiquiatria 27, 243248.
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.
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.
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.
Penders, J, Verstraete, A (2006). Laboratory guidelines and standards in clinical and forensic toxicology. Accreditation and quality assurance. Accreditation and Quality Assurance 11, 284290.
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.
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.
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.
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.
Tishler, LC, Gordon, LB (1999). Ethical parameters of challenge studies inducing psychosis with ketamine. Ethics and Behavior 9, 211217.
Tsujimoto, T, Shimazu, H, Isomura, Y (2006). Direct recording of theta oscillations in primate prefrontal and anterior cingulate cortices. Journal of Neurophysiology 95, 29873000.
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.


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

  • J. Horacek (a1) (a2) (a3), M. Brunovsky (a1) (a2), T. Novak (a2), B. Tislerova (a3), T. Palenicek (a2) (a3), V. Bubenikova-Valesova (a1) (a2), F. Spaniel (a1) (a3), J. Koprivova (a2) (a3), P. Mohr (a1), M. Balikova (a4) and C. Hoschl (a1) (a2) (a3)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed