(R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders.

NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). (S)-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, (R)-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of (R)-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than (S)-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of (R)-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with (R)-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications.

Treating bipolar depression with esketamine: Safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment-resistant depression.

BACKGROUND: Bipolar depression accounts for most of the disease duration in type I and type II bipolar disorder (BD), with few treatment options, often poorly tolerated. Many individuals do not respond to first-line therapeutic options, resulting in treatment-resistant bipolar depression (B-TRD). Esketamine, the S-enantiomer of ketamine, has recently been approved for treatment-resistant depression (TRD), but no data are available on its use in B-TRD. OBJECTIVES: To compare the efficacy of esketamine in two samples of unipolar and bipolar TRD, providing preliminary indications of its effectiveness in B-TRD. Secondary outcomes included the evaluation of the safety and tolerability of esketamine in B-TRD, focusing on the average risk of an affective switch. METHODS: Thirty-five B-TRD subjects treated with esketamine nasal spray were enrolled and compared with 35 TRD patients. Anamnestic data and psychometric assessments (Montgomery-Asberg Depression Rating Scale/MADRS, Hamilton-depression scale/HAM-D, Hamilton-anxiety scale/HAM-A) were collected at baseline (T0), at one month (T1), and three months (T2) follow up. RESULTS: A significant reduction in depressive symptoms was found at T1 and T2 compared to T0, with no significant differences in response or remission rates between subjects with B-TRD and TRD. Esketamine showed a greater anxiolytic action in subjects with B-TRD than in those with TRD. Improvement in depressive symptoms was not associated with treatment-emergent affective switch. CONCLUSIONS: Our results supported the effectiveness and tolerability of esketamine in a real-world population of subjects with B-TRD. The low risk of manic switch in B-TRD patients confirmed the safety of this treatment.

Molecular mechanisms of rapid-acting antidepressants: New perspectives for developing antidepressants.

Major depressive disorder (MDD) is a chronic relapsing psychiatric disorder. Conventional antidepressants usually require several weeks of continuous administration to exert clinically significant therapeutic effects, while about two-thirds of the patients are prone to relapse of symptoms or are completely ineffective in antidepressant treatment. The recent success of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine as a rapid-acting antidepressant has propelled extensive research on the action mechanism of antidepressants, especially in relation to its role in synaptic targets. Studies have revealed that the mechanism of antidepressant action of ketamine is not limited to antagonism of postsynaptic NMDA receptors or GABA interneurons. Ketamine produces powerful and rapid antidepressant effects by affecting α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors, adenosine A1 receptors, and the L-type calcium channels, among others in the synapse. More interestingly, the 5-HT2A receptor agonist psilocybin has demonstrated potential for rapid antidepressant effects in depressed mouse models and clinical studies. This article focuses on a review of new pharmacological target studies of emerging rapid-acting antidepressant drugs such as ketamine and hallucinogens (e.g., psilocybin) and briefly discusses the possible strategies for new targets of antidepressants, with a view to shed light on the direction of future antidepressant research.

The Neurobiology and Pharmacotherapy of Posttraumatic Stress Disorder.

New approaches to the neurobiology of posttraumatic stress disorder (PTSD) are needed to address the reported crisis in PTSD drug development. These new approaches may require the field to move beyond a narrow fear-based perspective, as fear-based medications have not yet demonstrated compelling efficacy. Antidepressants, particularly recent rapid-acting antidepressants, exert complex effects on brain function and structure that build on novel aspects of the biology of PTSD, including a role for stress-related synaptic dysconnectivity in the neurobiology and treatment of PTSD. Here, we integrate this perspective within a broader framework-in other words, a dual pathology model of ( a) stress-related synaptic loss arising from amino acid-based pathology and ( b) stress-related synaptic gain related to monoamine-based pathology. Then, we summarize the standard and experimental (e.g., ketamine) pharmacotherapeutic options for PTSD and discuss their putative mechanism of action and clinical efficacy.

Intravenous arketamine for treatment-resistant depression: open-label pilot study.

We aimed to analyze the efficacy and safety of arketamine, the R(-)-enantiomer of ketamine, for treatment-resistant depression (TRD) in humans. Open-label pilot trial, seven subjects with TRD received a single intravenous infusion of arketamine (0.5 mg/kg); primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) 24 h after. Mean MADRS dropped from 30.7 before infusion to 10.4 after one day, a mean difference of 20.3 points [CI 95% 13.6-27.0; p < 0.001]; dissociation was nearly absent. Arketamine might produce fast-onset and sustained antidepressant effects in humans with favorable safety profile, like previously reported with animals; further controlled-trials are needed.

Ketamine and the Future of Rapid-Acting Antidepressants.

The therapeutic onset of traditional antidepressants is delayed by several weeks and many depressed patients fail to respond to treatment altogether. In contrast, subanesthetic ketamine can rapidly alleviate symptoms of depression within hours of a single administration, even in patients who are considered treatment-resistant. Ketamine is thought to exert these effects by restoring the integrity of neural circuits that are compromised in depression. This hypothesis stems in part from preclinical observations that ketamine can strengthen synaptic connections by increasing glutamate-mediated neurotransmission and promoting rapid neurotrophic factor release. An improved understanding of how ketamine, and other novel rapid-acting antidepressants, give rise to these processes will help foster future therapeutic innovation. Here, we review the history of antidepressant treatment advances that preceded the ketamine discovery, critically examine mechanistic hypotheses for how ketamine may exert its antidepressant effects, and discuss the impact this knowledge has had on ongoing drug discovery efforts.

(R)-Ketamine Rapidly Ameliorates the Decreased Spine Density in the Medial Prefrontal Cortex and Hippocampus of Susceptible Mice After Chronic Social Defeat Stress.

BACKGROUND: A recent study demonstrated that spine formation rates by ketamine in the prefrontal cortex (PFC) were not altered at 3-6 h following a single injection, but were markedly altered at 12-24 h. Here, we investigated the acute (3 h post-treatment) effects of (R)-ketamine in the decreased spine density in the medial PFC (mPFC) and hippocampus in susceptible mice after chronic social defeat stress (CSDS). METHODS: (R)-ketamine (10 mg/kg) or saline was administered intraperitoneally to CSDS-susceptible mice. Dendritic spine density in the mPFC and hippocampus was measured 3 h after a single injection. RESULTS: (R)-ketamine significantly ameliorated the decreased spine density in the prelimbic area of mPFC, Cornu Ammonis3, and dentate gyrus of the hippocampus of CSDS-susceptible mice. CONCLUSIONS: This study suggests that (R)-ketamine rapidly ameliorates the decreased spine density in the mPFC and hippocampus of CSDS-susceptible mice, resulting in its rapid-acting antidepressant effects.

Molecular Mechanism and Clinical Relevance of Ketamine as Rapid-Acting Antidepressant.

Preclinical Research The emergence of rapid-acting antidepressants such as ketamine has motivated studies aiming to reveal the molecular mechanism of the ketamine antidepressant effect and to enable the clinical application of rapid-acting antidepressants. Here, we provide an overview of studies addressing the antidepressant effects of ketamine in depressed patients and animal models of depression and we compare the reduction of depressive symptoms in humans with the reduction in immobility time in the forced swim test in rodents after acute ketamine treatment. We also discuss different theories and potential biochemical pathways involved in the rapid antidepressant response to ketamine including the modulation of glutamatergic neurotransmission and intracellular hub-kinase activation. Finally, we summarize recent brain-region specific studies and we suggest that the activation of the ventral hippocampus-medial prefrontal cortex-dorsal raphae nuclei (vHC-mPFC-DRN) neuronal pathway may mediate the antidepressant effect of ketamine. Although substantial progress has been made, further brain-region specific animal studies and longitudinal clinical trials are necessary for the understanding and successful application of novel rapid-acting antidepressants. Drug Dev Res 77 : 414-422, 2016. © 2016 Wiley Periodicals, Inc.

Linking Hypothermia and Altered Metabolism with TrkB Activation.

Many mechanisms have been proposed to explain acute antidepressant drug-induced activation of TrkB neurotrophin receptors, but several questions remain. In a series of pharmacological experiments, we observed that TrkB activation induced by antidepressants and several other drugs correlated with sedation, and most importantly, coinciding hypothermia. Untargeted metabolomics of pharmacologically dissimilar TrkB activating treatments revealed effects on shared bioenergetic targets involved in adenosine triphosphate (ATP) breakdown and synthesis, demonstrating a common perturbation in metabolic activity. Both activation of TrkB signaling and hypothermia were recapitulated by administration of inhibitors of glucose and lipid metabolism, supporting a close relationship between metabolic inhibition and neurotrophic signaling. Drug-induced TrkB phosphorylation was independent of electroencephalography slow-wave activity and remained unaltered in knock-in mice with the brain-derived neurotrophic factor (BDNF) Val66Met allele, which have impaired activity-dependent BDNF release, alluding to an activation mechanism independent from BDNF and neuronal activity. Instead, we demonstrated that the active maintenance of body temperature prevents activation of TrkB and other targets associated with antidepressants, including p70S6 kinase downstream of the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3ß (GSK3ß). Increased TrkB, GSK3ß, and p70S6K phosphorylation was also observed during recovery sleep following sleep deprivation, when a physiological temperature drop is known to occur. Our results suggest that the changes in bioenergetics and thermoregulation are causally connected to TrkB activation and may act as physiological regulators of signaling processes involved in neuronal plasticity.

Neuropsychological Effects of Antidepressants: Translational Studies.

Pharmacological treatments that improve mood were first identified serendipitously, but more than half a century later, how these drugs induce their antidepressant effects remains largely unknown. With the help of animal models, a detailed understanding of their pharmacological targets and acute and chronic effects on brain chemistry and neuronal function has been achieved, but it remains to be elucidated how these effects translate to clinical efficacy. Whilst the field has been dominated by the monoamine and neurotrophic hypotheses, the idea that the maladaptive cognitive process plays a critical role in the development and perpetuation of mood disorders has been discussed since the 1950s. Recently, studies using objective methods to quantify changes in emotional processing found acute effects with conventional antidepressants in both healthy volunteers and patients. These positive effects on emotional processing and cognition occur without a change in the subjective ratings of mood. Building from these studies, behavioural methods for animals that quantify similar cognitive affective processes have been developed. Integrating these behavioural approaches with pharmacology and targeted brain manipulations, a picture is beginning to emerge of the underlying mechanisms that may link the pharmacology of antidepressants, these neuropsychological constructs and clinical efficacy. In this chapter, we discuss findings from animal studies, experimental medicine and patients investigating the neuropsychological effects of antidepressant drugs. We discuss the possible neural circuits that contribute to these effects and discuss whether a neuropsychological model of antidepressant effects could explain the temporal differences in clinical benefits observed with conventional delayed-onset antidepressants versus rapid-acting antidepressants.

Rapid antidepressant-like effect of non-hallucinogenic psychedelic analog lisuride, but not hallucinogenic psychedelic DOI, in lipopolysaccharide-treated mice.

Classical psychedelics with 5-hydroxytryptamine-2A receptor (5-HT2AR) agonism have rapid antidepressant actions in patients with depression. However, there is an ongoing debate over the role of 5-HT2AR in the antidepressant-like actions of psychedelics. In this study, we compared the effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT2AR and 5-HT1AR agonisms), and the novel antidepressant (R)-ketamine on depression-like behavior and the decreased dendritic spine density in the brain of lipopolysaccharide (LPS)-treated mice. Saline (10 ml/kg), DOI (2.0 mg/kg), lisuride (1.0 mg/kg), or (R)-ketamine (10 mg/kg) was administered intraperitoneally to LPS (0.5 mg/kg, 23 h before)-treated mice. Both lisuride and (R)-ketamine significantly ameliorated the increased immobility time of forced swimming test, and the decreased dendritic spine density in the prelimbic region of medial prefrontal cortex, CA3 and dentate gyrus of hippocampus of LPS-treated mice. In contrast, DOI did not improve these changes produced after LPS administration. This study suggests that antidepressant-like effect of lisuride in LPS-treated mice is not associated with 5-HT2AR-related psychedelic effects. It is, therefore, unlikely that 5-HT2AR may play a major role in rapid-acting antidepressant actions of psychedelics although further detailed study is needed.

The potential of ketamine for posttraumatic stress disorder: a review of clinical evidence.

Posttraumatic stress disorder (PTSD) is a devastating condition, for which there are few pharmacological agents, often with a delayed onset of action and poor efficacy. Trauma-focused psychotherapies are further limited by few trained providers and low patient engagement. This frequently results in disease chronicity as well as psychiatric and medical comorbidity, with considerable negative impact on quality of life. As such, off-label interventions are commonly used for PTSD, particularly in chronic refractory cases. Ketamine, an N-methyl-D-aspartate (NDMA) receptor antagonist, has recently been indicated for major depression, exhibiting rapid and robust antidepressant effects. It also shows transdiagnostic potential for an array of psychiatric disorders. Here, we synthesize clinical evidence on ketamine in PTSD, spanning case reports, chart reviews, open-label studies, and randomized trials. Overall, there is high heterogeneity in clinical presentation and pharmacological approach, yet encouraging signals of therapeutic safety, efficacy, and durability. Avenues for future research are discussed.

[Elucidation of the Mechanisms Underlying the Rapid Antidepressant Actions of Ketamine and Search for Possible Candidates for Novel Rapid-acting Antidepressants].

Ketamine, an N-methyl-D-aspartate receptor antagonist, elicits swift antidepressant effects even in subjects with treatment-resistant depression. Nonetheless, owing to the serious adverse effects associated with ketamine, including psychotomimetic effects, the development of safer rapid-acting antidepressants is imperative. The elucidation of the mechanisms underlying the antidepressant effects of ketamine will facilitate the advancement of these alternative treatments. Previous preclinical studies have indicated that the antidepressant properties of ketamine are mediated by the activity-dependent release of brain-derived neurotrophic factor (BDNF) and the subsequent activation of mechanistic target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex (mPFC). Our research has demonstrated that ketamine exerts antidepressant-like effects by inducing the release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) in the mPFC. Furthermore, our recent findings have revealed that resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), which are bioactive lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, exhibit antidepressant-like effects in rodent models. Notably, the antidepressant-like effects of RvD1, RvD2, and RvE1 require mTORC1 activation. Moreover, the intranasal administration of RvE1 elicits rapid antidepressant-like effects through the release of BDNF and VEGF in the mPFC and hippocampal dentate gyrus (DG), as well as mTORC1 activation in the mPFC, albeit not in the DG. These findings strongly suggest that resolvins, particularly RvD1, RvD2, and RvE1, hold promise as prospective candidates for novel, safer, and rapid-acting antidepressants.

Storm on predictive brain: A neurocomputational account of ketamine antidepressant effect.

For the past decade, ketamine, an N-methyl-D-aspartate receptor (NMDAr) antagonist, has been considered a promising treatment for major depressive disorder (MDD). Unlike the delayed effect of monoaminergic treatment, ketamine may produce fast-acting antidepressant effects hours after a single administration at subanesthetic dose. Along with these antidepressant effects, it may also induce transient dissociative (disturbing of the sense of self and reality) symptoms during acute administration which resolve within hours. To understand ketamine's rapid-acting antidepressant effect, several biological hypotheses have been explored, but despite these promising avenues, there is a lack of model to understand the timeframe of antidepressant and dissociative effects of ketamine. In this article, we propose a neurocomputational account of ketamine's antidepressant and dissociative effects based on the Predictive Processing (PP) theory, a framework for cognitive and sensory processing. PP theory suggests that the brain produces top-down predictions to process incoming sensory signals, and generates bottom-up prediction errors (PEs) which are then used to update predictions. This iterative dynamic neural process would relies on N-methyl-D-aspartate (NMDAr) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic receptors (AMPAr), two major component of the glutamatergic signaling. Furthermore, it has been suggested that MDD is characterized by over-rigid predictions which cannot be updated by the PEs, leading to miscalibration of hierarchical inference and self-reinforcing negative feedback loops. Based on former empirical studies using behavioral paradigms, neurophysiological recordings, and computational modeling, we suggest that ketamine impairs top-down predictions by blocking NMDA receptors, and enhances presynaptic glutamate release and PEs, producing transient dissociative symptoms and fast-acting antidepressant effect in hours following acute administration. Moreover, we present data showing that ketamine may enhance a delayed neural plasticity pathways through AMPAr potentiation, triggering a prolonged antidepressant effect up to seven days for unique administration. Taken together, the two sides of antidepressant effects with distinct timeframe could constitute the keystone of antidepressant properties of ketamine. These PP disturbances may also participate to a ketamine-induced time window of mental flexibility, which can be used to improve the psychotherapeutic process. Finally, these proposals could be used as a theoretical framework for future research into fast-acting antidepressants, and combination with existing antidepressant and psychotherapy.

New investigational agents for the treatment of major depressive disorder.

INTRODUCTION: Pharmacotherapy of depression is characterized by the delayed onset of action, chronic treatment requirements, and insufficient effectiveness. Ketamine, with its rapid action and long-lasting effects, represents a breakthrough in the modern pharmacotherapy of depression. AREAS COVERED: The current review summarizes the latest findings on the mechanism of the antidepressant action of ketamine and its enantiomers and metabolites. Furthermore, the antidepressant potential of psychedelics, non-hallucinogenic serotonergic modulators, and metabotropic glutamate receptor ligands was discussed. EXPERT OPINION: Recent data indicated that to achieve fast and long-acting antidepressant-like effects, compounds must induce durable effects on the architecture and density of dendritic spines in brain regions engaged in mood regulation. Such mechanisms underlie the actions of ketamine and psychedelics. These compounds trigger hallucinations; however, it is thought that these effects might be essential for their antidepressant action. Behavioral studies with serotonergic modulators affecting 5-HT1A (biased agonists), 5-HT4 (agonists), and 5-HT-7 (antagonists) receptors exert rapid antidepressant-like activity, but they seem to be devoid of these effects. Another way to avoid psychomimetic effects and achieve the desired rapid antidepressant-like effects is combined therapy. In this respect, ligands of metabotropic receptors show some potential.

A systematic review of studies investigating the acute effects of N-methyl-D-aspartate receptor antagonists on behavioural despair in normal animals suggests poor predictive validity.

The ability of the N-methyl-D-aspartate receptor antagonist ketamine to induce a rapid and sustained antidepressant effect has led to a surge in pre-clinical studies investigating underlying mechanisms and seeking novel treatments. Animal models are key to this research as they can provide a behavioural readout linking underlying mechanisms to clinical benefits. However, quantifying depression-related behaviours in rodents represents a major challenge with the validity of traditional methods such as models of behavioural despair (forced swim test and tail suspension test) a topic of debate. While there is good evidence to support the value of using these behavioural readouts to study the effects of stress, these approaches have largely failed to detect reliable phenotypic effects in other disease models. In this systematic review, we identified publications which had tested N-methyl-D-aspartate receptor antagonists in normal animals using either the forced swim test or tail suspension test. We compared findings for different doses and time points and also drugs with different clinical profiles to investigate how well the outcomes in the rodent model predicted their effects in the clinic. Despite clear evidence that N-methyl-D-aspartate receptor antagonists reduce immobility time and hence exhibit an antidepressant profile in these tasks, we found similar effects with both clinically effective drugs as well as those which have failed to show efficacy in clinical trials. These findings suggest that behavioural despair tests in normal animals do not provide a good method to predict clinical efficacy of N-methyl-D-aspartate receptor antagonists.

Ketamine-50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanisms.

Over the past 50 years, ketamine has solidified its position in both human and veterinary medicine as an important anesthetic with many uses. More recently, ketamine has been studied and used for several new indications, ranging from chronic pain to drug addiction and post-traumatic stress disorder. The discovery of the rapid-acting antidepressant effects of ketamine has resulted in a surge of interest towards understanding the precise mechanisms driving its effects. Indeed, ketamine may have had the largest impact for advancements in the research and treatment of psychiatric disorders in the past few decades. While intense research efforts have been aimed towards uncovering the molecular targets underlying ketamine's effects in treating depression, the underlying neurobiological mechanisms remain elusive. These efforts are made more difficult by ketamine's complex dose-dependent effects on molecular mechanisms, multiple pharmacologically active metabolites, and a mechanism of action associated with the facilitation of synaptic plasticity. This review aims to provide a brief overview of the different uses of ketamine, with an emphasis on examining ketamine's rapid antidepressant effects spanning molecular, cellular, and network levels. Another focus of the review is to offer a perspective on studies related to the different doses of ketamine used in antidepressant research. Finally, the review discusses some of the latest hypotheses concerning ketamine's action.

Targeting metabotropic glutamate receptors for rapid-acting antidepressant drug discovery.

INTRODUCTION: Depression is a highly debilitating psychiatric disorder and a worldwide health issue. Functional deficits in glutamatergic cortico-limbic areas are hypothesized to play a key role in the pathogenesis of the disease. Consistently, the clinical antidepressant efficacy of the N-Methyl-D-aspartate (NMDA) receptor antagonist ketamine gives hope for a new class of glutamatergic rapid-acting antidepressants. In this context, metabotropic glutamate (mGlu) receptors have received attention as interesting targets for new antidepressants. AREAS COVERED: The present review summarizes the preclinical evidence supporting the antidepressant effect of the pharmacological modulation of mGlu receptors. Antidepressant properties in animal models of mGlu1 antagonists, mGlu5 negative allosteric modulators (NAMs) and positive allosteric modulators (PAMs), mGlu2/3 agonists, PAMs, orthosteric antagonists and NAMs, mGlu4 and mGlu7 PAMs are reviewed. To date, orthosteric mGlu2/3 antagonists are the most promising compounds in development as antidepressants. EXPERT OPINION: Although accumulating clinical and preclinical evidence concur to confirm a primary role of glutamate transmission modulation for the induction of a rapid antidepressant effect, very little is still known about the cellular mechanisms involved. More mechanistic studies are required to understand the role of glutamate in depression and the therapeutic potential of drugs directly targeting the glutamate synapse.

A wake-up call: Sleep physiology and related translational discrepancies in studies of rapid-acting antidepressants.

Depression is frequently associated with sleep problems, and clinical improvement often coincides with the normalization of sleep architecture and realignment of circadian rhythm. The effectiveness of treatments targeting sleep in depressed patients, such as sleep deprivation, further demonstrates the confluence of sleep and mood. Moreover, recent studies showing that the rapid-acting antidepressant ketamine influences processes related to sleep-wake neurobiology have led to novel hypotheses explaining rapid and sustained antidepressant effects. Despite the available evidence, studies addressing ketamine's antidepressant effects have focused on pharmacology and often overlooked the role of physiology. To explore this discrepancy in research on rapid-acting antidepressants, we examined articles published between 2009-2019. A keyword search algorithm indicated that vast majority of the articles completely ignored sleep. Out of the 100 most frequently cited preclinical and clinical research papers, 89 % and 71 %, respectively, did not mention sleep at all. Furthermore, only a handful of these articles disclosed key experimental variables, such as the times of treatment administration or behavioral testing, let alone considered the potential association between these variables and experimental observations. Notably, in preclinical studies, treatments were preferentially administered during the inactive period, which is the polar opposite of clinical practice and research. We discuss the potential impact of this practice on the results in the field. Our hope is that this perspective will serve as a wake-up call to (re)-examine rapid-acting antidepressant effects with more appreciation for the role of sleep and chronobiology.

Rapid-acting antidepressants and the regulation of TrkB neurotrophic signalling-Insights from ketamine, nitrous oxide, seizures and anaesthesia.

Increased glutamatergic neurotransmission and synaptic plasticity in the prefrontal cortex have been associated with the rapid antidepressant effects of ketamine. Activation of BDNF (brain-derived neurotrophic factor) receptor TrkB is considered a key molecular event for antidepressant-induced functional and structural synaptic plasticity. Several mechanisms have been proposed to underlie ketamine's effects on TrkB, but much remains unclear. Notably, preliminary studies suggest that besides ketamine, nitrous oxide (N2 O) can rapidly alleviate depressive symptoms. We have shown nitrous oxide to evoke TrkB signalling preferentially after the acute pharmacological effects have dissipated (ie after receptor disengagement), when slow delta frequency electroencephalogram (EEG) activity is up-regulated. Our findings also demonstrate that various anaesthetics and sedatives activate TrkB signalling, further highlighting the complex mechanisms underlying TrkB activation. We hypothesize that rapid-acting antidepressants share the ability to regulate TrkB signalling during homeostatically evoked slow-wave activity and that this mechanism is important for sustained antidepressant effects. Our observations urge the examination of rapid and sustained antidepressant effects beyond conventional receptor pharmacology by focusing on brain physiology and temporally distributed signalling patterns spanning both wake and sleep. Potential implications of this approach for the improvement of current therapies and discovery of novel antidepressants are discussed.