Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine

https://doi.org/10.1016/j.pharmthera.2020.107741Get rights and content
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Abstract

Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid-acting antidepressant effects and summarize how diverse phenomena associated with ketamine’s antidepressant actions – such as cortical excitation, synaptogenesis, and involved molecular determinants – are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain.

Keywords

Sleep
Circadian
Plasticity
Depression
Rapid-acting antidepressant
Slow-wave sleep

Abbreviations

AMPAR
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
BDNF
brain-derived neurotrophic factor
BMAL1
brain and muscle ARNT-like protein 1
CREB
cAMP related element binding protein
CLOCK
Circadian Locomotor Output Cycles Kaput
CRY
cryptochrome
EEG
electroencephalography
ENCORE-D
encoding consolidation and renormalization in depression
ERK
extracellular-signal regulated kinase
GABA
gamma-aminobutyric acid
GSK3β
glycogen synthase kinase 3β
HNK
hydroxynorketamine
LTP
long-term potentiation
mPFC
medial prefrontal cortex
mRNA
messenger ribonucleic acid
mTOR
mammalian target of rapamycin
NMDAR
N-methyl-D-aspartate receptor
per
period
NREM
non-rapid-eye movement sleep
REM
rapid-eye movement sleep
SD
sleep deprivation
SHY
synaptic homeostasis hypothesis
RORα
retinal orphan receptor α
SCN
suprachiasmatic nucleus
SWA
slow wave activity
SWS
slow wave sleep;
TrkB
tropomyosin related receptor B.

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1

Equal contribution.