Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder.
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.
Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Wallace C
WC
Duncan
Simone
S
Sarasso
Fabio
F
Ferrarelli
Jessica
J
Selter
Brady A
BA
Riedner
Nadia S
NS
Hejazi
Peixiong
P
Yuan
Nancy
N
Brutsche
Husseini K
HK
Manji
Giulio
G
Tononi
Carlos A
CA
Zarate
D000328:Adult; D000704:Analysis of Variance; D058256:Brain Waves / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood*; D003865:Major Depressive Disorder / Q000097:blood / Q000188:drug therapy*; D004569:Electroencephalography; D004797:Enzyme-Linked Immunosorbent Assay; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D019782:Riluzole / Q000627:therapeutic use; D016037:Single-Blind Method; D012894:Sleep Stages / Q000187:drug effects*; D013223:Statistics as Topic; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D019782:Riluzole