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

The extracted text does not present a formal Methods section or a systematic search strategy; the paper is a narrative review synthesising preclinical and clinical literature. The authors integrate evidence from molecular, electrophysiological, imaging, behavioural and chronobiological studies in both animals and humans to build conceptual links between ketamine pharmacology and sleep–circadian mechanisms. The narrative approach brings together varied types of evidence: animal pharmacology and genetic models (NMDAR manipulations, optogenetics, sleep-deprivation paradigms), human clinical and electrophysiological studies (sleep EEG, slow-wave activity, gamma power, BDNF measurements), and mechanistic studies of intracellular signalling relevant to both synaptic plasticity and clock function (CREB, ERK1/2, GSK3β, mTOR). Where available, the authors report correlations between physiological measures (for example SWA or BDNF) and clinical response. Several recently formulated theoretical frameworks (notably ENCORE-D and synaptic-plasticity accounts of sleep deprivation) are presented and compared. Because the review is conceptual rather than systematic, explicit inclusion/exclusion criteria, databases searched, or quantitative synthesis methods are not reported in the extracted text.

The review summarises accumulated evidence linking ketamine's known pharmacology to sleep and circadian biology. At the pharmacological level, subanesthetic ketamine paradoxically increases cortical excitation and energy metabolism, an effect explained by the disinhibition hypothesis—preferential NMDAR blockade on GABAergic interneurons leads to pyramidal cell disinhibition and glutamate bursts. Most mechanistic models converge on AMPAR activation, activity-dependent release of BDNF, and downstream signalling through TrkB, mTOR, ERK1/2 and GSK3β, with consequent changes in immediate-early genes (e.g. Homer-1a), synapse-associated proteins and dendritic spine dynamics. The role of hydroxynorketamine (2R,6R-HNK) metabolites is discussed as contested: some preclinical work suggests NMDAR-independent effects, but clinical studies report a negative correlation between plasma 2R,6R-HNK and antidepressant/antisuicidal outcomes. The authors highlight chronobiological findings that help reconcile the temporal dissociation between ketamine's brief pharmacology and its delayed clinical peak. Across rodent and human studies, ketamine and related excitatory interventions are associated with increased slow-wave activity (SWA) during the subsequent NREM sleep period, and in clinical series increases in SWS/SWA and total sleep time the night after ketamine correlated with mood improvement and with post-infusion rises in plasma BDNF. One cited figure is that approximately 70% of synaptic transcripts in mouse forebrain show circadian rhythmicity, demonstrating pervasive daily regulation of synaptic machinery. Clinical observations with sleep deprivation (SD) are also summarised: SD produces rapid but transient antidepressant effects in up to 50–60% of severely depressed patients, and SD similarly increases circulating BDNF and SWA after recovery sleep. These parallels support a link between activity-dependent synaptic potentiation during wake, homeostatic SWA during subsequent sleep, and antidepressant outcomes. Two specific conceptual models are reviewed. ENCORE-D (encoding, consolidation and renormalization in depression) proposes three phases: an encoding phase during acute drug-induced cortical excitation that alters network function; a consolidation phase during the withdrawal period when wake-associated homeostatic processes and molecular signalling (e.g. TrkB, GSK3β, p70S6K) occur and SWA emerges; and a renormalization phase during subsequent SWS when synaptic renormalization allows ketamine-induced advantageous synaptic changes to be maintained while depressogenic processes are downregulated. A complementary synaptic-plasticity model of SD posits that depression involves deficient associative plasticity and that extending wakefulness raises synaptic strength into a more LTP-favourable zone, transiently relieving symptoms. Both frameworks tie increases in cortical excitability, synaptic potentiation and sleep-dependent processing to clinical benefit. The authors also describe circadian intersections: key signalling pathways activated by ketamine (Ca2+ influx, CREB, ERK1/2, GSK3β, PKA/PKG and CaMKs) are the same pathways that shift circadian clocks and regulate clock gene transcription. Ketamine may therefore influence circadian timing directly or via non-photic cues such as increased locomotor activity and energy expenditure. Post-translational regulation and phosphorylation of synaptic plasticity proteins exhibit sleep–wake and circadian variation, and basic pharmacokinetics (hepatic metabolism to HNKs, blood–brain barrier permeability) may also vary with time of day. Animal experimental practices are discussed as a potential confound: most rodent work occurs during the animals' inactive (light) phase, when acute activation may interact with high sleep pressure, complicating interpretation and translation to human, diurnal physiology. Taken together, the reviewed data suggest that sleep homeostasis and circadian timing plausibly modulate both the emergence and maintenance of ketamine's antidepressant effects, but key elements remain correlative and hypotheses are presented as speculative and in need of experimental validation.

The authors interpret their synthesis as evidence that chronobiological processes—sleep homeostasis and circadian regulation—are integral to understanding ketamine's rapid and sustained antidepressant actions. They argue that viewing ketamine solely through classic pharmacological principles neglects pervasive, time-dependent physiological processes that could explain why transient receptor engagement yields delayed and lasting changes in mood and brain networks. ENCORE-D and related sleep-centric hypotheses are presented as useful frameworks that bridge molecular, network and behavioural observations by situating drug action within the daily cycle of encoding during wake, consolidation on withdrawal and synaptic renormalization during SWS. Kohtala and colleagues position these ideas relative to earlier work by noting convergent evidence: ketamine, sleep deprivation and other excitatory interventions similarly increase cortical excitability, BDNF and SWA, and SD produces robust though transient antidepressant effects. They also emphasise mechanistic overlap, since intracellular signalling implicated in ketamine's effects (CREB, ERK1/2, GSK3β, mTOR) is central to clock function and activity-dependent gene expression. Importantly, the authors acknowledge several uncertainties: much of the evidence is correlational, species differences in sleep architecture and diurnality complicate translation from rodent models to humans, and the role of ketamine metabolites (HNKs) remains unresolved. They further note that many preclinical studies may be confounded by timing of administration relative to the animal sleep–wake cycle, and that hypotheses such as ENCORE-D remain speculative and require rigorous experimental proof. Implications discussed by the authors include the need for chronobiologically informed research: experimentally testing time-of-day effects on ketamine efficacy and metabolism, incorporating sleep and circadian measures into clinical trials, and exploring how manipulating sleep (for example controlled sleep deprivation, light therapy or phase shifts) might stabilise or augment ketamine's antidepressant benefits. The review calls for multidisciplinary approaches—bringing together pharmacologists, molecular neurobiologists and sleep researchers—to experimentally probe the interactions between rapid-acting antidepressants and intrinsic temporal physiology.