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Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder

  • Wallace C. Duncan (a1), Simone Sarasso (a2), Fabio Ferrarelli (a2), Jessica Selter (a1), Brady A. Riedner (a2), Nadia S. Hejazi (a1), Peixiong Yuan (a3), Nancy Brutsche (a1), Husseini K. Manji (a4), Giulio Tononi (a2) and Carlos A. Zarate (a1)...

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery–Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity – as reflected by increased SWA, individual slow wave parameters and plasma BDNF – is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.

Corresponding author
Address for correspondence: Dr C. A. Zarate Jr. 10 Center Dr. CRC, Unit 7 Southeast, Room 7-3445, Bethesda, Maryland 20892, USA. Tel.: (301) 451-0861Fax: (301) 402-9360Email:
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M aan het Rot , KA Collins , JW Murrough , AM Perez , . (2010). Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biological Psychiatry 67, 139145.

I Allaman , H Fiumelli , PJ Magistretti , JL Martin (2011). Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes. Psychopharmacology (Berlin) 216, 7584.

CA Altar , RE Whitehead , R Chen , G Wortwein , . (2003). Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biological Psychiatry 54, 703709.

AE Autry , M Adachi , E Nosyreva , ES Na , . (2011). NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 9195.

RM Berman , A Cappiello , A Anand , DA Oren , . (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 47, 351354.

N Diazgranados , L Ibrahim , NE Brutsche , A Newberg , . (2010). A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of General Psychiatry 67, 793802.

U Faraguna , VV Vyazovskiy , AB Nelson , G Tononi , . (2008). A causal role for brain-derived neurotrophic factor in the homeostatic regulation of sleep. Journal of Neuroscience 28, 40884095.

I Feinberg , IG Campbell (1993). Ketamine administration during waking increases delta EEG intensity in rat sleep. Neuropsychopharmacology 9, 4148.

Y Gorgulu , O Caliyurt (2009). Rapid antidepressant effects of sleep deprivation therapy correlates with serum BDNF changes in major depression. Brain Research Bulletin 80, 158162.

UM Hemmeter , J Hemmeter-Spernal , JC Krieg (2010). Sleep deprivation in depression. Expert Reviews of Neurotherapeutics 10, 11011115.

JR Hughes (1996). A review of the usefulness of the standard EEG in psychiatry. Clinical Electroencephalography 27, 3539.

SS Husain , IM Kevan , R Linnell , AI Scott (2004). Electroconvulsive therapy in depressive illness that has not responded to drug treatment. Journal of Affective Disorders 83, 121126.

L Ibrahim , N DiazGranados , J Franco-Chaves , N Brutsche , . (2012). Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs. add-on riluzole: results from a four-week, double-blind, placebo-controlled study. Neuropsychopharmacology 37, 15261533.

LC Johnson , K Hanson , RG Bickford (1976). Effect of flurazepam on sleep spindles and K-complexes. Electroencephalography and Clinical Neurophysiology 40, 6777.

F Karege , G Perret , G Bondolfi , M Schwald , . (2002 a). Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Research 109, 143148.

F Karege , M Schwald , M Cisse (2002 b). Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets. Neuroscience Letters 328, 262264.

V Knott , J McIntosh , A Millar , D Fisher , . (2006). Nicotine and smoker status moderate brain electric and mood activation induced by ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist. Pharmacology, Biochemistry, and Behavior 85, 228242.

V Knott , A Millar , J McIntosh , DK Shah , . (2011). Separate and combined effects of low dose ketamine and nicotine on behavioural and neural correlates of sustained attention. Biological Psychiatry 88, 8393.

AH Kossel , SB Cambridge , U Wagner , T Bonhoeffer (2001). A caged Ab reveals an immediate/instructive effect of BDNF during hippocampal synaptic potentiation. Proceedings of the National Academy of Sciences USA 98, 1470214707.

N Li , B Lee , RJ Liu , M Banasr , . (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959964.

B Lu (2003). BDNF and activity-dependent synaptic modulation. Learning and Memory 10, 8698.

R Machado-Viera , P Yuan , N Brutsche , N DiazGranados , . (2009). Brain-derived neurotrophic factor and initial antidepressant response to an N-methyl-D-aspartate antagonist. Journal of Clinical Psychiatry 70, 16621666.

S Maeng , CA Zarate Jr. ( 2007). The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Current Psychiatry Reports 9, 467474.

E Messaoudi , T Kanhema , J Soule , A Tiron , . (2007). Sustained Arc/Arc3.1 synthesis controls long-term potentiation consolidation through regulation of local actin polymerization of the dentate gyrus in vivo. Journal of Neuroscience 27, 1044510455.

SA Montgomery , M Asberg (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry 134, 382389.

W Pan , WA Banks , MB Fasold , J Bluth , . (1998). Transport of brain derived neurotrophic factor across the blood-brain barrier. Neuropharmacology 37, 15531561.

C Pittenger , V Coric , M Banasr , M Bloch , . (2008). Riluzole in the treatment of mood and anxiety disorders. CNS Drugs 22, 761786.

SH Preskorn , B Baker , S Kolluri , FS Menniti , . (2008). 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. Journal of Clinical Psychopharmacology 28, 631637.

GZ Reus , RB Stringari , KF Ribeiro , AK Ferraro , . (2011). Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behavioural Brain Research 221, 166171.

RJ Schloesser , LD Huang , PS Klein , HK Manji (2008). Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacolgy 33, 110113.

S Sen , R Duman , G Sanacora (2008). Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biological Psychiatry 64, 527532.

GW Valentine , GF Mason , R Gomez , M Fasula , . (2011). The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Research 191, 122127.

VV Vyazovskiy , C Cirelli , M Pfister-Genskow , U Faraguna , . (2008). Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep. Nature Neuroscience 11, 200208.

CA Zarate Jr., JL Payne , J Quiroz , J Sporn , . ( 2004). An open-label trial of riluzole in patients with treatment-resistant major depression. American Journal of Psychiatry 161, 171174.

CA Zarate Jr., JB Singh , PJ Carlson , NE Brutsche , . ( 2006 a). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry 63, 856864.

CA Zarate Jr., JB Singh , JA Quiroz , G De Jesus , . ( 2006 b). A double-blind, placebo-controlled study of memantine in the treatment of major depression. American Journal of Psychiatry 163, 153155.

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The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
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