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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

Recent studies indicate that nitrous oxide (N 2 O), a gaseous anesthetic and an NMDA (N -methyl-D-aspartate) receptor antagonist, produces rapid antidepressant effect in patients suffering from treatment-resistant depression. Our recent work implies that hypothermia and reduced energy expenditure are connected with antidepressant-induced activation of TrkB neurotrophin receptors — a key regulator of synaptic plasticity. In this study, we demonstrate that a brief exposure to N 2 O leads to a drop in body temperature following the treatment, which is linked to decreased locomotor activity; enhanced slow-wave electroencephalographic activity; reduced brain glucose utilization; and increased phosphorylation of TrkB, GSK3β (glycogen synthase kinase 3β), and p70S6K (a kinase downstream of mTor (mammalian target of rapamycin)) in the medial prefrontal cortex of adult male mice. Moreover, preventing the hypothermic response in a chronic corticosterone stress model of depression attenuated the antidepressant-like behavioral effects of N 2 O in the saccharin preference test. These findings indicate that N 2 O treatment modulates TrkB signaling and related neurotrophic signaling pathways in a temperature-dependent manner, suggesting that the phenomenon driving TrkB activation — altered thermoregulation and energy expenditure — is linked to antidepressant-like behavioral responses. [Display omitted] • N 2 O activates TrkB in mouse prefrontal cortex after its delivery is ceased. • Body temperature drop and brain glucose utilization coincide with N 2 O-induced pTrkB. • Maintaining normothermia post-N 2 O mitigates antidepressant-like behavioral effects. [ABSTRACT FROM AUTHOR]

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i. p.) 1 h prior to ketamine or HNKs (10 mg/kg, i. p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Glu ext , GABA ext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R , S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 h post-injection (t24 h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients. • Ketamine, as a non-competitive NMDAR antagonist, increases the overall excitability of the medial prefrontal cortex (mPFC), which is presumed to be essential for its fast-acting antidepressant activity. • Pre-treatment with fluconazole, an inhibitor of hepatic cytochrome P450 enzymes, altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R , S)-norketamine, while robustly reducing those of (6)-HNKs. • Fluconazole pretreatment attenuated the antidepressant-like behavioral actions of ketamine that appeared at the same time (t24 h), and the ketamine-induced neuronal release of GABA in the mPFC. • A single (2R,6R)-HNK administration selectively rescued the antidepressant-like activity of ketamine in mice pretreated with fluconazole within 24 h of treatment. • These findings emphasize the key role of ketamine metabolism in its sustained actions and suggest that the dosage of ketamine should be reduced in MDD patients receiving CYPI such as fluconazole. [ABSTRACT FROM AUTHOR]

Introduction: Major depressive disorder is often associated with suicidal tendencies, and this condition accentuates the need for rapid-acting antidepressants. We previously reported that Alkaloids (ALK) from Trichilia monadelpha possess antidepressant action in acute animal models of depression and that this effect is mediated through the monoamine and L-arginine-NO-cGMP pathways. This study investigated the possible rapid-onset antidepressant effect of ALK from T. monadelpha and its connection with the glycine/NMDA receptor pathway. Methods: The onset of ALK action from T. monadelpha was evaluated using the Open Space Swim Test (OSST), a chronic model of depression. The modified forced swimming and tail suspension tests were used to assess the effect of the ALK on the glycine/NMDA receptor pathway. The Instutute of Cancer Research (ICR) mice were treated with either ALK (30–300 mg/kg, orally [PO]), imipramine (3–30 mg/kg, PO), fluoxetine (3–30 mg/kg, PO), or saline. To identify the role of glycine/NMDA receptor pathway in the effect of ALK, we pretreated mice with a partial agonist of the glycine/NMDA receptor, D-cycloserine (2.5 mg/kg, intraperitoneally [IP]), and an agonist of glycine/NMDA receptor, D-serine (600 mg/kg, IP), before ALK administration. Results: ALK reversed immobility in mice after the second day of drug treatment in the OSST. In contrast, there was a delay in the effects induced by fluoxetine and imipramine. ALK also increased mean swimming and climbing scores in mice. ALK was more efficacious than imipramine and fluoxetine in reducing immobility and increasing distance traveled. It is noteworthy that ALK was less potent than fluoxetine and imipramine. D-cycloserine potentiated mobility observed in the ALK- and fluoxetine-treated mice. In contrast, D-serine decreased mobility in the ALK-treated mice. Conclusion: The study results suggest that ALK from T. monadelpha exhibits rapid antidepressant action in mice, and the glycine/NMDA receptor pathway possibly mediates the observed effect.

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 (N2O) 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. [ABSTRACT FROM AUTHOR]

Introduction: Major depressive disorder is often associated with suicidal tendencies, and this condition accentuates the need for rapid-acting antidepressants. We previously reported that Alkaloids (ALK) from Trichilia monadelpha possess antidepressant action in acute animal models of depression and that this effect is mediated through the monoamine and L-arginine-NO-cGMP pathways. This study investigated the possible rapid-onset antidepressant effect of ALK from T. monadelpha and its connection with the glycine/NMDA receptor pathway. Methods: The onset of ALK action from T. monadelpha was evaluated using the Open Space Swim Test (OSST), a chronic model of depression. The modified forced swimming and tail suspension tests were used to assess the effect of the ALK on the glycine/NMDA receptor pathway. The Instutute of Cancer Research (ICR) mice were treated with either ALK (30-300 mg/kg, orally [PO]), imipramine (3-30 mg/kg, PO), fluoxetine (3-30 mg/kg, PO), or saline. To identify the role of glycine/NMDA receptor pathway in the effect of ALK, we pretreated mice with a partial agonist of the glycine/NMDA receptor, D-cycloserine (2.5 mg/kg, intraperitoneally [IP]), and an agonist of glycine/NMDA receptor, D-serine (600 mg/kg, IP), before ALK administration. Results: ALK reversed immobility in mice after the second day of drug treatment in the OSST. In contrast, there was a delay in the effects induced by fluoxetine and imipramine. ALK also increased mean swimming and climbing scores in mice. ALK was more efficacious than imipramine and fluoxetine in reducing immobility and increasing distance traveled. It is noteworthy that ALK was less potent than fluoxetine and imipramine. D-cycloserine potentiated mobility observed in the ALK-and fluoxetine-treated mice. In contrast, D-serine decreased mobility in the ALK-treated mice. Conclusion: The study results suggest that ALK from T. monadelpha exhibits rapid antidepressant action in mice, and the glycine/NMDA receptor pathway possibly mediates the observed effect. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Recent research into the rapid antidepressant effect of subanesthetic doses of ketamine have identified a series of relevant protein cascades activated within hours of administration. Prior to, or concurrent with, these activation cascades, ketamine treatment generates dissociative and psychotomimetic side effects along with an increase in circulating glucocorticoids. In rats, we observed an over 3-fold increase in corticosterone levels in both serum and brain tissue, within an hour of administration of low dose ketamine (10 mg/kg), but not with (2R, 6R)-hydroxynorketamine (HNK) (10 mg/kg), a ketamine metabolite shown to produce antidepressant-like action in rodents without inducing immediate side-effects. Hippocampal tissue from ketamine, but not HNK, injected animals displayed a significant increase in the expression of sgk1, a downstream effector of glucocorticoid receptor signaling. To examine the role conscious sensation of ketamine’s side effects plays in the release of corticosterone, we assessed serum corticosterone levels after ketamine administration while under isoflurane anesthesia. Under anesthesia, ketamine failed to increase circulating corticosterone levels relative to saline controls. Concurrent with its antidepressant effects, ketamine generates a release of glucocorticoids potentially linked to disturbing cognitive side effects and the activation of distinct molecular pathways which should be considered when attempting to delineate the molecular mechanisms of its antidepressant function.

Rationale: Reward-related impairments are common in major depressive disorder (MDD) and may contribute to the loss of interest in pleasurable activities. A novel approach to studying reward-related decision-making are effort-based tasks; however, direct comparisons between delayed-onset and rapid-acting antidepressants (ADs) have not yet been carried out. Objectives: To investigate the effects of conventional delayed-onset ADs versus rapid-acting ADs, ketamine and scopolamine, on effort-related choice behaviour. Methods: Female Lister hooded rats were trained in an operant effort for reward task (EfRT) where animals choose between working for a high value-high effort reward and consuming low value-low effort chow. Using a within-subject study design, animals were then tested following acute treatment with different monoaminergic ADs, and the rapid-acting ADs ketamine or scopolamine. Results: Consistent with previous findings, we found choice behaviour was sensitive to dopaminergic manipulations. We observed that pre-feeding altered choice behaviour and that the use of high or low value reward differentially affected behaviour. Monoamine re-uptake inhibitors and rapid-acting ADs resulted in similar, general patterns of reduced motivation without any evidence for specific effects, and we did not observe any clear differences between these classes of antidepressant. Conclusions: Motivational changes induced by dopaminergic manipulations and pre-feeding differentially affect effort choice behaviour. However, both conventional delayed-onset ADs and ketamine and scopolamine appear to have detrimental effects on motivation in this task at the higher doses tested without any evidence of specificity for effort-related choice behaviour, in contrast to their specificity in tasks which look at more cognitive aspects of reward processing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Posttraumatic stress disorder (PTSD) is a debilitating disorder with limited medication treatment options. Recent reports have described the dearth of research on new drug development as a crisis in the pharmacotherapy of PTSD. There are only two PTSD medications approved by the U.S. Food and Drug Administration, and both are serotonergic antidepressants. Therefore, there is a tremendous need to identify more effective and more rapidly acting pharmacotherapies for PTSD that work through novel neural mechanisms. Pilot evidence and case reports provided preliminary evidence supporting the safety and utility of investigating the therapeutic effects of ketamine in PTSD. However, the efficacy of this drug for PTSD has not yet been tested in active duty military or veteran populations. Here, we report the design and methods of a study funded under the Consortium to Alleviate PTSD. The study is a multisite, placebo-controlled, double–blind, randomized clinical trial to examine the dose-related efficacy of ketamine, as compared to placebo, in producing a rapid and sustained reduction in PTSD symptomatology in veterans and active duty military populations with antidepressant-resistant PTSD. Approximately 198 eligible participants who meet criteria for PTSD will be randomized to the study drug (i.e., ketamine 0.5 mg/kg, ketamine 0.2 mg/kg, or placebo). The study drug will be administered intravenously twice per week for 4 weeks, followed by a 4-week follow-up period. This ongoing study is the only trial of therapeutic effects of ketamine for PTSD and the first placebo-controlled trial to determine the dose-related effects of repeated ketamine on PTSD. [ABSTRACT FROM AUTHOR]

Rapid antidepressant effects of ketamine become most evident when its psychotomimetic effects subside, but the neurobiological basis of this "lag" remains unclear. Laughing gas (N2O), another NMDA-R (N-methyl-d-aspartate receptor) blocker, has been reported to bring antidepressant effects rapidly upon drug discontinuation. We took advantage of the exceptional pharmacokinetic properties of N2O to investigate EEG (electroencephalogram) alterations and molecular determinants of antidepressant actions during and immediately after NMDA-R blockade. Effects of the drugs on brain activity were investigated in C57BL/6 mice using quantitative EEG recordings. Western blot and qPCR were used for molecular analyses. Learned helplessness (LH) was used to assess antidepressant-like behavior. Immediate-early genes (e.g., bdnf) and phosphorylation of mitogen-activated protein kinase—markers of neuronal excitability—were upregulated during N2O exposure. Notably, phosphorylation of BDNF receptor TrkB and GSK3β (glycogen synthase kinase 3β) became regulated only gradually upon N2O discontinuation, during a brain state dominated by slow EEG activity. Subanesthetic ketamine and flurothyl-induced convulsions (reminiscent of electroconvulsive therapy) also evoked slow oscillations when their acute pharmacological effects subsided. The correlation between ongoing slow EEG oscillations and TrkB-GSK3β signaling was further strengthened utilizing medetomidine, a hypnotic-sedative agent that facilitates slow oscillations directly through the activation of α2-adrenergic autoreceptors. Medetomidine did not, however, facilitate markers of neuronal excitability or produce antidepressant-like behavioral changes in LH. Our results support a hypothesis that transient cortical excitability and the subsequent regulation of TrkB and GSK3β signaling during homeostatic emergence of slow oscillations are critical components for rapid antidepressant responses. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Depression is one of the most disabling diseases worldwide. Approximately one-third of depressed patients are treatment-resistant to the currently available antidepressants and there is a significant therapeutic time lag of weeks to months. There is a clear unmet need for rapid-acting and more efficacious treatments. (R,S)-ketamine, an old anesthetic drug, appears now to be going through a renaissance. Areas covered: This paper reviews recent literature describing the antidepressant effects of ketamine and its enantiomer (S)-ketamine in patients with major depressive disorder (MDD) and bipolar disorder (BD). Furthermore, the authors discuss the therapeutic potential of (R)-ketamine, another enantiomer of (R,S)-ketamine, and (S)-norketamine. Expert commentary: A number of clinical studies have demonstrated that (R,S)-ketamine has rapid-acting and sustained antidepressant activity in treatment-resistant patients with MDD, BD, and other psychiatric disorders. Off-label use of ketamine for mood disorders is proving popular in the United States. Meanwhile, preclinical data suggests that (R)-ketamine can exert longer-lasting antidepressant effects than (S)-ketamine in animal models of depression, and (R)-ketamine may have less detrimental side effects than (R,S)-ketamine and (S)-ketamine. Additionally, (S)-norketamine exhibits rapid and sustained antidepressant effects, with a potency similar to that of (S)-ketamine. Unlike (S)-ketamine, (S)-norketamine does not cause behavioral and biochemical abnormalities and could be a safer than (S)-ketamine too. [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

Classical psychedelics with 5-hydroxytryptamine-2A receptor (5-HT 2A R) agonism have rapid antidepressant actions in patients with depression. However, there is an ongoing debate over the role of 5-HT 2A R 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-HT 2A R agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT 2A R and 5-HT 1A R 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-HT 2A R-related psychedelic effects. It is, therefore, unlikely that 5-HT 2A R may play a major role in rapid-acting antidepressant actions of psychedelics although further detailed study is needed. • Psychedelic drug DOI did not show antidepressant-like effect in LPS-treated mice. • Non-hallucinogenic psychedelic analog lisuride shows antidepressant-like effect in LPS-treated mice. • DOI did not ameliorate the decreased dendritic spine density in the brain of LPS-treated mice. • Lisuride ameliorated the decreased dendritic spine density in the brain of LPS-treated mice. • Antidepressant effect of lisuride is not associated with 5-HT 2A R-related psychedelic effects. [ABSTRACT FROM AUTHOR]

ABSTRACT [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Recent research has seen low-dose ketamine emerge as a novel, rapid-acting antidepressant. Ketamine, an N-methy-d-aspartate (NMDA) receptor antagonist, leads to effects on the glutamatergic system and abnormalities in this neurotransmittor system are present in depression. This article aims to (1) review the clinical literature on low-dose ketamine as a rapid-acting antidepressant in affective disorders, (2) provide a critical overview of the limitations of ketamine and research attempts to overcome these (3) discuss the proposed mechanisms of action of ketamine and (4) point towards future research directions. Method: The electronic database Pubmed, Web of Science and sciencedirect were searched using the keywords: ketamine, N-methyl-d-aspartate receptor antagonist, rapid-acting antidepressant, depression, treatment-resistant depression, bipolar depression, suicidal ideation, electroconvulsive therapy, mechanism of action. Result: The literature demonstrates evidence supporting a rapid-acting antidepressant effect of low-dose intravenous ketamine in major depressive disorder, in bipolar depression and in depression with suicidal ideation. There are mixed results as to whether ketamine leads to a reduction in time to remission in patients undergoing electroconvulsive therapy (ECT). Efforts to unravel ketamine′s therapeutic mechanism of action have implicated the mammalian target of rapamycin (mTOR)-dependent synapse formation in the rat prefrontal cortex, eukaryotic elongation factor 2 phosphorylation (p-eEF2) and glycogen synthase kinase (GSK-3). Ketamine′s limiting factors are the transient nature of its antidepressant effect and concerns regarding abuse, and research efforts to overcome these are reviewed. Conclusion: Current and future research studies are using ketamine as a promising tool to evaluate the glutamatergic neurotransmittor system to learn more about the pathophysiology of depression and develop more specific rapid-acting antidepressant treatments. [Copyright &y& Elsevier]

Rapid antidepressant effects have been connected with specific neurobiological mechanisms that are thought to be controlled by drugs like ketamine (A). A more physiological perspective that acknowledges the impact of sleep and chronobiology in the complex effects triggered by ketamine and related antidepressants (B) may be the last piece for a more holistic understanding of the rapid and sustained antidepressant actions. [Display omitted] • Ketamine influences processes related to sleep-wake neurobiology. • Sleep is often ignored in studies addressing ketamine's antidepressant effects. • Key sleep variables are undisclosed in majority of the most cited papers on ketamine. • Ketamine is commonly administered during the inactive period in animal studies. • Routine practice in the clinic is to administer ketamine during "office hours". 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. [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

Recent research into the rapid antidepressant effect of subanesthetic doses of ketamine have identified a series of relevant protein cascades activated within hours of administration. Prior to, or concurrent with, these activation cascades, ketamine treatment generates dissociative and psychotomimetic side effects along with an increase in circulating glucocorticoids. In rats, we observed an over 3-fold increase in corticosterone levels in both serum and brain tissue, within an hour of administration of low dose ketamine (10 mg/kg), but not with (2R, 6R)-hydroxynorketamine (HNK) (10 mg/kg), a ketamine metabolite shown to produce antidepressant-like action in rodents without inducing immediate side-effects. Hippocampal tissue from ketamine, but not HNK, injected animals displayed a significant increase in the expression of sgk1 , a downstream effector of glucocorticoid receptor signaling. To examine the role conscious sensation of ketamine's side effects plays in the release of corticosterone, we assessed serum corticosterone levels after ketamine administration while under isoflurane anesthesia. Under anesthesia, ketamine failed to increase circulating corticosterone levels relative to saline controls. Concurrent with its antidepressant effects, ketamine generates a release of glucocorticoids potentially linked to disturbing cognitive side effects and the activation of distinct molecular pathways which should be considered when attempting to delineate the molecular mechanisms of its antidepressant function. [ABSTRACT FROM AUTHOR]