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

This theory-building paper (2020) proposes that the circadian rhythm may be an important factor in the antidepressant effect of ketamine therapies.

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.”

Authors: S. Kohtala, O. Alitalo, M. Rosenholm, S. Rozov & T. Rantamäki

Summary

  1. Introduction

Ketamine, an NMDAR antagonist, has been shown to alleviate the core symptoms of depression and suicidal ideation within a few hours, and has also demonstrated rapid therapeutic efficacy in certain other psychiatric disorders. The S(+)-enantiomer of ketamine (esketamine) was approved by the US Food and Drug Administration and the European Medicines Agency as an adjunctive treatment for high-suicide-risk, depressed patients to provide faster symptomatic relief. However, a significant proportion of patients do not get sufficient benefit from ketamine.

We begin this review by outlining certain effects and mechanisms considered to be important for ketamine’s antidepressant action. We discuss the basic neurobiology and function of sleep and circadian rhythm, and discuss how recently proposed hypotheses of rapid antidepressant action may provide critical insights into the actions of rapid-acting antidepressants in the brain.

  1. Antidepressant mechanisms of ketamine

Ketamine blocks NMDARs, which are activated by glutamate, and inhibits monoamine reuptake. At lower subanesthetic doses, ketamine increases cortical excitation and energy metabolism, which contradicts the anticipated effects of an NMDAR-blocking agent.

The disinhibition hypothesis proposes that ketamine blocks NMDARs on GABA-ergic interneurons, leading to the disinhibition of pyramidal neurons, accompanied by enhanced glutamate release and burst. Moreover, animal studies suggest that ketamine exerts NMDAR inhibition-independent antidepressant actions via its hydroxynorketamine metabolites.

Most hypotheses about ketamine’s antidepressant action converge on its ability to activate postsynaptic AMPARs through a glutamate burst, and the ketamine metabolite HNK promotes glutamate release and AMPAR activation in mice.

Ketamine activates AMPARs, which are involved in several molecular pathways implicated in antidepressant actions. These effects are most prominent with high doses of ketamine, and are diminished in BDNFmet66met knock-in mice that exhibit compromised activity-dependent BDNF release.

Ketamine increases the transcription of immediate-early genes (IEGs), such as Homer-1a, which contribute to glutamatergic signaling and synaptic function. BDNF up-regulates Homer-1a mRNA and its protein accumulation at synapses in cultured neurons, presumably through the ERK pathway. Ketamine induces increased mTOR activity and increased synapse-associated proteins, which are causally associated with increased antidepressant-like behavioral responses. However, a recent clinical study suggests that rapamycin pretreatment prolongs the antidepressant effects of ketamine.

Ketamine is expected to affect synaptic plasticity, as demonstrated by its ability to restore hippocampal long-term potentiation in animal models of depression. Several studies support the notion that LTP-like plasticity is impaired in depressed patients, and that ketamine can enhance LTP-mediated neural plasticity. Ketamine induces antidepressant-like behavioral responses in rats, whereas prior neuronal inactivation with the GABAA agonist muscimol blocks these effects.

Ketamine’s many effects are increasing in knowledge at an astonishing rate, and many of these effects are physiological events that have a reciprocal connection with wake and sleep.

3.1. Introduction to circadian rhythms and sleep

Animals adjust their behavior according to the circadian rhythms generated by circadian oscillators throughout the body. These rhythms reflect the day/night cycle generated by the rotation of the Earth. Mammalian circadian regulation is hierarchical and comprises a master clock located in the hypothalamic suprachiasmatic nucleus (SCN), and peripheral clocks that are synchronized to the SCN through photic input from the retina and endocrine feedback loops mediated by melatonin. The circadian clock is a complex architecture of interlocking positive and negative feedback loops of circadian gene transcription and translation that enables the organism to anticipate the imminent rhythmic changes in the environment and match them with the appropriate local gene and protein output.

The sleep-wake cycle is a fundamental behavioral state preserved across phylogeny, and it is influenced by homeostatic and circadian components, Process S and Process C, respectively. Under high sleep pressure, the need for recovery sleep can override circadian regulation to promote sleep.

In the mammalian brain, sleep can be broadly divided into two discrete stages: rapid eye movement (REM) sleep and non-REM sleep. REM sleep consists of wake-like high-frequency, low-amplitude EEG activity, while NREM sleep is divided into three stages that are dominated by high-amplitude, synchronized, low-frequency EEG activity.

The electrophysiological rhythms of sleep are generated by the principal computational components of the brain – neural circuits and neurons. Glial cells are also important for sleep regulation.

3.2. Functions of sleep

Despite great advances in the understanding of sleep, its primary physiological functions remain unclear. However, it is possible that some of these functions can be addressed during wakefulness or quiet rest without the requirement for the evolutionarily risky disconnection from the external environment that occurs during sleep.

Sleep duration and intensity are closely associated with brain size across species, and NREM sleep peaks during brain growth spurt and declines during adolescence. Sleep serves as a suitable period for the regulation of synaptic strength, memory consolidation, and learning, and enhances both memory encoding and consolidation. However, the overall contribution to synaptic change and synaptic plasticity remains unclear.

Neuroplastic changes initiated during waking experience may trigger transient changes and prime circuits and synapses to undergo further processing in sleep. Sleep may also serve a role in the active system consolidation of memory by redistributing newly encoded memory engrams, for example, from the hippocampus to the cortex.

Many hypotheses examining the role of sleep in memory consolidation and facilitation of synaptic plasticity focus on sleep-wake patterns (SWA) and the connection between cortical activity and SWA. SWA increases during recovery sleep after short-term memory loss.

Synaptic potentiation increases and decreases during wake and sleep, respectively, which is one of the key arguments of the synaptic homeostasis hypothesis. The SHY suggests that sleep is an ideal time for the brain to downregulate synaptic strength, because the brain is disconnected from the external environment and can sample its inputs without external influence. SWA during sleep causes synaptic depression, which reduces synaptic strength, which in turn causes less SWA, which provides a self-limiting mechanism.

3.3. Association between depression and disturbances in sleep and circadian regulation

Major depression is associated with abnormalities in circadian regulation and sleep, including a reduction in the amount of slow wave sleep (SWS), a shorter latency to first REM sleep episode, and an increased intensity of REM sleep.

Many patients with depression show a diurnal pattern of mood variation, which is alleviated by time spent awake towards the evening. Moreover, depression is often modulated by seasonal change, perhaps due to the changing amount of daylight. In experiments on rodents, phases of temperature, locomotion, and sleep-wake cycles became decoupled from one another, which led to symptoms and changes characteristic for a depression-like state. In humans, circadian patterns of gene expression were markedly abnormal across six brain areas in MDD.

Monoaminergic antidepressants normalize sleep architecture of depressed patients by reducing the amount of REM sleep and increasing REM latency. This normalization of sleep architecture may play a role in the therapeutic action of these drugs. Sleep disruption (SD) can increase feelings of dysphoria in healthy controls, while in depressed patients SD can induce remarkably rapid amelioration of symptoms. However, the antidepressant effects of SD are highly transient and typically reappear after the next sleep episode. SD may be involved in the antidepressant effects of ketamine and other rapid-acting antidepressants through LTP-like synaptic plasticity and transcriptional regulation of circadian genes.

4.1. Rapid antidepressant effects and sleep homeostasis

Ketamine is a short-acting drug that achieves rapid, yet long lasting effects. Its effects are closely connected to the mechanisms of sleep regulation, and the neurobiological adaptations that emerge in response to ketamine treatment and its withdrawal.

Ketamine can improve depressive symptoms by increasing glutamate release, energy metabolism, and the secretion of BDNF, as well as by activating multiple molecular pathways that are thought to contribute to increased protein synthesis and synaptic plasticity. Ketamine induces dissociative and psychotomimetic effects, which are also connected to increased gamma oscillations. The sustained and elevated gamma power post-ketamine may be a potential biomarker for ketamine-induced synaptic potentiation. Several clinical studies have reported that the most robust action on depressed mood is often observed on the following day of the ketamine treatment, i.e., after a night of sleep. This suggests a possible connection between the effects of ketamine, glutamatergic neurotransmission, and the regulation of sleep homeostasis.

A net gain of synaptic potentiation takes place during treatment, which results in the increased emergence of slow wave amplitude during the subsequent sleep period. This result supports the idea that ketamine responders exhibit dysregulated synaptic homeostasis during sleep.

BDNF levels are increased and SWA is facilitated by cortical excitation induced by subanesthetic ketamine, and by rapid-acting treatments of depression affecting cortical excitation during wake. The close association between activity-dependent release of BDNF and synaptic homeostasis is further supported by animal studies. Moreover, the Val66Met BDNF polymorphism is associated with lower SWA intensity after SD than the Val66Val BDNF polymorphism.

BDNF is a key mediator of synaptic plasticity and strength, and SWA may represent the synaptic strength of cortical circuits. Ketamine and other excitatory treatments may increase SWA, thus increasing cortical microcircuit activity and synaptic strength.

In the recent years, several hypotheses have been formulated about the function of sleep in antidepressant effects. The ENCORE-D hypothesis views these effects as occurring in three consecutive phases.

Ketamine’s ability to transiently excite cortical neurocircuits by facilitating glutamatergic activity alters their computational properties and patterns of connectivity, and normalizes depressogenic cognitive processes. This leads to the homeostatic emergence of synaptic strength after ketamine withdrawal. The third phase of ketamine’s effects occurs during subsequent sleep, when cortical neurocircuits undergo synaptic renormalization, challenged by increased synaptic strength and synaptogenesis, which in turn allows ketamine-induced changes to be maintained, resulting in more persistent changes in circuit activity the following day. The synaptic plasticity model of SD as a treatment of depression focuses on synaptic homeostasis and sleep/wake-dependent shifts in synaptic plasticity particularly influenced by SD. This hypothesis proposes that prolonged wakefulness increases cortical excitability and compensates for the attenuated associative plasticity in depression. The notion that depressive symptoms are associated with dysregulated synaptic strength is supported by indirect evidence from a study that demonstrated increased cortical synaptic strength in association with time spent awake.

4.2. Antidepressant effects of ketamine and circadian regulation

The role of circadian dysregulation in the pathophysiology of depression and regulation of mood is being increasingly highlighted. Ketamine may also recruit circadian mechanisms in the rapid and sustained recovery of depressive symptoms.

Preclinical studies indicate that both SD and ketamine influence the function of the circadian molecular components, leading to altered clock gene transcriptional output levels, but the precise underlying mechanisms can only be speculated at this point.

Various excitatory stimuli converge on the CREB pathway, which in turn regulates the expression of IEGs and clock-controlled genes, resulting in the synchronization of the mammalian circadian clock. Ketamine’s effects on circadian rhythms can also be examined through its effects on energy expenditure and behavior, both strong non-photic entraining cues for circadian rhythms.

Ketamine may affect circadian regulation through alterations in both the homeostatic (S) and circadian (C) components of sleep. These alterations may explain how ketamine can improve mood by restoring the circadian misalignments present in depressed patients. Ketamine may affect the circadian clock, and may also alter the expression of non-centralclockgenes. Additionally, processes S and C complement each other, and the effects of ketamine cannot be isolated to either individually.

The lateral habenula (LHb) is a brain area connected with the suprachiasmatic nucleus (SCN) and may play a role in circadian effects induced by ketamine. Increased activity of the neurons in the LHb may promote stronger inhibitory control over connecting dopaminergic, noradrenergic, and serotonergic areas and have a negative influence on mood regulation.

Ketamine’s effects on circadian mechanisms and the timing of drug administration may differ depending on the phase of the circadian cycle. Circadian oscillations in physiological functions of the body result in considerable diurnal variations in the expression of drug targets and drug metabolizing enzymes. The synaptic function of the brain undergoes a distinct circadian variation. The circadian clock rhythm regulates the expression of genes in the SCN, and the phosphorylation status of proteins is also regulated. This may explain the circadian variations in the hypnotic efficacy of ketamine in rodents.

Ketamine’s distribution in the central nervous system may also be affected by circadian fluctuations and the wake-sleep cycle, and its metabolism may be affected by the time of administration.

4.3. Unforeseen consequences

Ketamine’s antidepressant effects are also interconnected with physiological circadian rhythmicity and/or the sleep-wake cycle, which regulates cognition, mood, and behavior at all levels ranging from molecular to cellular and on a scale ranging from electrophysiological to ultrastructural.

The cortical firing rates, synchrony, slope and amplitude of evoked cortical responses, synaptic AMPAR expression levels, miniature excitatory postsynaptic currents, spine density, and number of AMPARs are all increased during wakefulness. Conversely, they are decreased during sleep.

Ketamine’s effects may be modulated by homeostatic pressure and/or circadian time at the time of administration, and this may be particularly important for drugs that regulate excitatory neurotransmission. Timing may be important in antidepressant studies, as strong cues may advance or postpone the circadian rhythm depending on the time of day they are experienced.

Depressed patients have decreased brain glucose utilization, which undergoes significant diurnal variation. The effect of experiment timing in subanesthetic ketamine has not been clinically addressed.

The timing of ketamine treatments in animal models is important because the sleep-wake cycle is different in humans and widely used experimental animals. Humans are diurnal and sleep in one consolidated period during the dark phase, while rodents sleep in multiple shorter bouts throughout the 24 hours.

In rodents, lower doses of ketamine stimulate locomotor activity and inhibit REM sleep, and increase high-frequency gamma oscillations. Moreover, subanesthetic doses of ketamine alter the dynamics of theta-gamma phase-amplitude coupling. Subanesthetic ketamine can induce circadian phase shifts similar to bright light and electroconvulsive shocks, and may also cause increased sleep latency. However, there is a lack of research on the consequences of such disruptions in the context of ketamine for the interpretation of behavioral or molecular studies.

Ketamine’s ability to acutely suppress REM sleep and modulate circadian rhythms may be masked by its effect on activity-promoting systems, and this may be a major confounding factor in studies investigating the effects of ketamine on depressive-like behavior, associated molecular pathways, and electrophysiological changes.

  1. Closing remarks

This review aims to show how chronobiological processes, especially sleep, may be involved in the mechanisms of action of ketamine and other treatments capable of producing rapid and sustained antidepressant effects.

Declaration of Competing Interest

T.R. and S.K. are listed as co-inventors on a patent application that discloses new tools enabling the development of rapid-acting antidepressants.

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