Ketamine's Mechanism Research Articles

La découverte des propriétés antidépressives de la kétamine

BackgroundDepression is a frequent disease with a significant medico-economic impact. Conventional antidepressants have a delayed action and are ineffective in one third of cases. Discovery of ketamine's antidepressant effects these last years opens new perspectives for treatment-resistant depression. MethodThis article reviews the discovery of the antidepressant effect of ketamine, the current state of knowledge on its use and the mechanisms underlying these properties. ResultsMany studies now show a robust and rapid but transient antidepressant effect of a subanesthesic dose of ketamine in patients with treatment-resistant depression. To maintain the initial benefits, limited published data pinpoint the interest of repeated administrations of ketamine while relay with glutamatergic modulators seem to be inefficient as well as the combination with electroconvulsive therapy. Ketamine's mechanisms of action are strongly explored. Evidences indicate that ketamine antagonism of the NMDA receptor with a subsequent activation of AMPA receptor are mandatory for the antidepressant effect. Intracellular signalling pathways play a key role. An anti-inflammatory effect of ketamine would also be at stake. ConclusionThe demonstration of ketamine antidepressant effects is a major discovery in psychopharmacology. If studies are still required to evaluate efficacy and safety of ketamine, especially in the long-term exposure and if data remains too limited to use ketamine in routine practice, the discovery of the potent antidepressant effect of ketamine strongly stimulates research for a better understanding of the pathophysiology of depression and for new therapeutic strategies, particularly in the field of modulation of the glutamate pathway in depressive disorders.

What is the mechanism of Ketamine's rapid-onset antidepressant effect? A concise overview of the surprisingly large number of possibilities.

Abundant clinical data now confirm that ketamine produces a remarkable rapid-onset antidepressant effect - hours or days - in contrast to the delayed onset (typically weeks) of current antidepressant drugs. This surprising and revolutionary finding may lead to the development of life-saving pharmacotherapy for depressive illness by reducing the high suicide risk associated with the delayed onset of effect of current drugs. As ketamine has serious self-limiting drawbacks that restrict its widespread use for this purpose, a safer alternative is needed. Our objective is to review the proposed mechanism(s) of ketamine's rapid-onset antidepressant action for new insights into the physiological basis of depressive illness that may lead to new and novel targets for antidepressant drug discovery. A search was conducted on published literature (e.g. PubMed) and Internet sources to identify information relevant to ketamine's rapid-acting antidepressant action and, specifically, to the possible mechanism(s) of this action. Key search words included 'ketamine', 'antidepressant', 'mechanism of action', 'depression' and 'rapid acting', either individually or in combination. Information was sought that would include less well-known, as well as well-known, basic pharmacologic properties of ketamine and that identified and evaluated the several hypotheses about ketamine's mechanism of antidepressant action. Whether the mechanistic explanation for ketamine's rapid-onset antidepressant action is related to its well-known antagonism of the NMDA (N-Methyl-d-aspartate) subtype of glutamate receptor or to something else has not yet been fully elucidated. The evidence from pharmacologic, medicinal chemistry, animal model and drug-discovery sources reveals a wide variety of postulated mechanisms. The surprising discovery of ketamine's rapid-onset antidepressant effect is a game-changer for the understanding and treatment of depressive illness. There is some convergence on NMDA receptor antagonism as a likely, but to date unproven, common mechanism. The surprising number of other mechanisms, and the several novel biochemical aetiologies of depression proposed, suggests exciting new drug-discovery targets.

Temporal Dynamics of Antidepressant Ketamine Effects on Glutamine Cycling Follow Regional Fingerprints of AMPA and NMDA Receptor Densities.

The anterior cingulate cortex (ACC) has shown decreased glutamate levels in patients with major depressive disorder. Subanesthetic doses of ketamine were repeatedly shown to improve depressive symptoms within 24 h after infusion and this antidepressant effect was attributed to increased α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) throughput. To elucidate ketamine's mechanism of action, we tested whether the clinical time course of the improvement is mirrored by the change of glutamine/glutamate ratio and if such effects show a regional and temporal specificity in two distinct subdivisions of ACC with different AMPA/N-methyl-D-aspartate receptor profiles. In a double-blind, placebo-controlled intravenous infusion study of ketamine, we measured glutamate and glutamine in the pregenual ACC (pgACC) and the anterior midcingulate cortex at 1 and 24 h post infusion with magnetic resonance spectroscopy at 7 T. A significant interaction of time, region, and treatment was found for the glutamine/glutamate ratios (placebo, n=14; ketamine, n=12). Post-hoc analyses revealed that the glutamine/glutamate ratio increased significantly in the ketamine group, compared with placebo, specifically in the pgACC after 24 h. The glutamine/glutamate increase in the pgACC caused by ketamine at 24 h post infusion was reproduced in an enlarged sample (placebo, n=24; ketamine, n=20). Our results support a significant temporal and regional response in glutamine/glutamate ratios to a single subanesthetic dose of ketamine, which mirrors the time course of the antidepressant response and reversal of the molecular deficits in patients and which may be associated with the histoarchitectonical receptor fingerprints of the ACC subregions.

Ketamine Inhalation Ameliorates Ovalbumin-Induced Murine Asthma by Suppressing the Epithelial-Mesenchymal Transition.

BackgroundAsthma accounts for 0.4% of all deaths worldwide, a figure that increases annually. Ketamine induces bronchial smooth muscle relaxation, and increasing evidence suggests that its anti-inflammatory properties might protect against lung injury and ameliorate asthma. However, there is a lack of evidence of the usefulness and mechanism of ketamine in acute asthma exacerbation. This study aimed to analyze the therapeutic effects and mechanism of action of ketamine on acute ovalbumin (OVA)-induced murine asthma.Material/MethodsIn vivo, BALB/c mice with OVA-induced asthma were treated with or without ketamine (25 or 50 mg/mL). Serum, lung sections, and mononuclear cell suspensions from the lung were collected for histological, morphometric, immunofluorescence, microRNA, quantitative polymerase chain reaction, regulatory T cell identification, cytokine, and Western blotting analyses. In vitro, bronchial epithelial cells were cultured to analyze the effect and mechanism of ketamine on epithelial-mesenchymal transition (EMT) and transforming growth factor-β (TGF-β) signaling.ResultsThe inhalation of ketamine 25 or 50 mg/mL markedly suppressed OVA-induced airway hyper-responsiveness and airway inflammation, significantly increased the percentage of CD4+CD25+ T cells, and significantly decreased OVA-induced up-regulation of TGF-β1 and the EMT. MiR-106a was present at higher amounts in OVA-induced lung samples and was suppressed by ketamine treatment. The in vitro results showed that TGF-β1-induced EMT was suppressed by ketamine via miR-106a level regulation.ConclusionsKetamine ameliorates lung fibrosis in OVA-induced asthmatic mice by suppressing EMT and regulating miR-106a level, while ketamine inhalation might be a new therapeutic approach to the treatment of allergic asthma.

KETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID-ACTING ANTIDEPRESSANTS.

Major depressive disorder (MDD) is a common and debilitating psychiatric disorder. Traditional antidepressants are of limited efficacy and take weeks to months to yield full therapeutic effects. Thus, there is a clear need for effective rapid-acting antidepressant medications. The N-methyl-d-aspartate receptor (NMDA-R) antagonist, ketamine, has received a great deal of attention over the last 20 years due to the discovery that a single subanesthetic dose leads to a rapid antidepressant effect in individuals with treatment-resistant depression. Animal and human research suggest that ketamine's antidepressant effects are mediated by a glutamate surge that leads to a cascade of events that result in synaptogenesis and reversal of the negative effects of chronic stress and depression, particularly within the prefrontal cortex (PFC). Preclinical and clinical data have provided compelling insights into the mechanisms underlying the rapid-acting antidepressant effects of ketamine. This review discusses stress-related neurobiology of depression and the safety, tolerability, and efficacy of ketamine for MDD, along with a review of ketamine's mechanism of action and prospective predictors of treatment response. Research limitations and future clinical prospects are also discussed.

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression.

The authors conducted a systematic review and meta-analysis of ketamine and other N-methyl-d-aspartate (NMDA) receptor antagonists in the treatment of major depression. Searches of MEDLINE, PsycINFO, and other databases were conducted for placebo-controlled, double-blind, randomized clinical trials of NMDA antagonists in the treatment of depression. Primary outcomes were rates of treatment response and transient remission of symptoms. Secondary outcomes included change in depression symptom severity and the frequency and severity of dissociative and psychotomimetic effects. Results for each NMDA antagonist were combined in meta-analyses, reporting odds ratios for dichotomous outcomes and standardized mean differences for continuous outcomes. Ketamine (seven trials encompassing 147 ketamine-treated participants) produced a rapid, yet transient, antidepressant effect, with odds ratios for response and transient remission of symptoms at 24 hours equaling 9.87 (4.37-22.29) and 14.47 (2.67-78.49), respectively, accompanied by brief psychotomimetic and dissociative effects. Ketamine augmentation of ECT (five trials encompassing 89 ketamine-treated participants) significantly reduced depressive symptoms following an initial treatment (Hedges' g=0.933) but not at the conclusion of the ECT course. Other NMDA antagonists failed to consistently demonstrate efficacy; however, two partial agonists at the NMDA coagonist site, d-cycloserine and rapastinel, significantly reduced depressive symptoms without psychotomimetic or dissociative effects. The antidepressant efficacy of ketamine, and perhaps D-cycloserine and rapastinel, holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine's mechanism of action. The fleeting nature of ketamine's therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.

Ketamine for depression: evidence, challenges and promise.

Major depressive disorder and bipolar depression are among the most prevalent and disabling mental disorders worldwide. Real-world effectiveness trials in major depressive disorder have underscored that most pharmacological options target monoamines, which are involved in a minority (15-20%) of synaptic contacts in the mammalian brain. Most synapses (∼50%) use the amino acid glutamate as their primary neurotransmitter, and preclinical models of depression have implicated aberrant glutamatergic neurotransmission for 25 years (1). More recently, the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine was shown to produce rapid and robust antidepressant effects in patients with treatment-resistant major depressive disorder and bipolar depression (2–7).

Antidepressant mechanism of ketamine: perspective from preclinical studies.

A debilitating mental disorder, major depressive disorder is a leading cause of global disease burden. Existing antidepressant drugs are not adequate for the majority of depressed patients, and large clinical studies have demonstrated their limited efficacy and slow response onset. Growing evidence of low-dose ketamine's rapid and potent antidepressant effects offers strong potential for future antidepressant agents. However, ketamine has considerable drawbacks such as its abuse potential, psychomimetic effects, and increased oxidative stress in the brain, thus limiting its widespread clinical use. To develop superior antidepressant drugs, it is crucial to better understand ketamine's antidepressant mechanism of action. Recent preclinical studies indicate that ketamine's antidepressant mechanism involves mammalian target of rapamycin pathway activation and subsequent synaptogenesis in the prefrontal cortex, as well as glycogen synthase kinase-3 beta (GSK-3β) inactivation. Adjunct GSK-3β inhibitors, such as lithium, can enhance ketamine's efficacy by augmenting and prolonging its antidepressant effects. Given the potential for depressive relapses, lithium in addition to ketamine is a promising solution for this clinical issue.

Glutamate NMDA receptor modulators for the treatment of depression: trials and tribulations.

Glutamate NMDA receptor modulators for the treatment of depression: trials and tribulations.

Glutamate Receptor Antagonists as Fast-Acting Therapeutic Alternatives for the Treatment of Depression: Ketamine and Other Compounds

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression. These effects are in direct contrast to the more modest effects seen after weeks of treatment with classic monoaminergic antidepressants. Numerous open-label and case studies similarly validate ketamine's antidepressant properties. These clinical findings have been reverse-translated into preclinical models in an effort to elucidate ketamine's antidepressant mechanism of action, and three important targets have been identified: mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3 (GSK-3). Current clinical and preclinical research is focused on (a) prolonging/maintaining ketamine's antidepressant effects, (b) developing more selective NMDA receptor antagonists free of ketamine's adverse effects, and (c) identifying predictor, mediator/moderator, and treatment response biomarkers of ketamine's antidepressant effects.

Neural correlates of rapid antidepressant response to ketamine in bipolar disorder

Ketamine, an N-methyl d-aspartate (NMDA) antagonist, has rapid antidepressant effects in depressed subjects with bipolar disorder (BD). Evidence supports a role for the glutamatergic system in the pathophysiology of BD. This double-blind, randomized, cross-over study sought to determine cerebral metabolic correlates of antidepressant response to ketamine. Twenty-one subjects with BD currently in a depressed state underwent [(18) F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging after receiving a placebo infusion as well as after receiving a ketamine infusion. Metabolism was compared between ketamine and placebo infusions, and correlated with clinical response. Regional metabolic rate of glucose (rMRGlu) in regions of interest (ROIs) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were the main outcome measures. The study found that change in metabolism between sessions was significantly correlated with percentage change in MADRS scores in the right ventral striatum; subjects who showed the greatest improvement had the largest metabolic increase after ketamine infusion compared to placebo. In a voxel-wise analysis, subjects with BD had significantly lower glucose metabolism in the left hippocampus following the ketamine infusion than following the placebo infusion. In addition, metabolism in the subgenual anterior cingulate cortex (ACC) following the placebo infusion was positively correlated with percentage improvement in MADRS score following the ketamine infusion. Taken together, the results suggest that higher activity in the subgenual ACC may predict antidepressant response to ketamine. Ketamine administration altered glucose metabolism in areas known to be involved in mood disorders; these alterations may partially underlie ketamine's mechanism of action.

Synaptic Mechanisms Underlying Rapid Antidepressant Action of Ketamine

Recent clinical studies have demonstrated that a single subpsychotomimetic dose of ketamine, an ionotropic glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist, produces a rapid antidepressant response in patients with major depressive disorder, with effects lasting up to 2 weeks. Despite enthusiasm about this unexpected efficacy of ketamine, its widespread use as a fast-acting antidepressant in routine clinical settings is curtailed by its abuse potential as well as possible psychotomimetic effects. However, the ability of ketamine to produce a rapid and long-lasting antidepressant response in patients with depression provides a unique opportunity for investigation of mechanisms that mediate these clinically relevant behavioral effects. From a mechanistic perspective, it is easy to imagine how activation of NMDA receptors may trigger cellular and behavioral responses; it is relatively more difficult, however, to envision how transient blockade of one of the key pathways for neuronal communication produces a persistent beneficial effect. The authors discuss recent work linking ketamine's mechanism of action to homeostatic synaptic plasticity processes activated after suppression of NMDA-mediated glutamatergic neurotransmission. They focus on their recent work demonstrating that ketamine-mediated blockade of NMDA receptors at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and desuppression of rapid dendritic protein translation, including BDNF (brain-derived neurotrophic factor), which then contributes to synaptic plasticity mechanisms that mediate longterm effects of the drug. The authors also explore possible molecular strategies to target spontaneous neurotransmitter release selectively to help uncover novel presynaptic avenues for the development of fast-acting antidepressants and possibly psychoactive compounds with effectiveness against other neuropsychiatric disorders.

Ketamine as a Novel Antidepressant: From Synapse to Behavior

Recent reports of a rapid antidepressant effect of the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, even in treatment-resistant populations, have spurred translational therapeutic and neuroscience research aimed at elucidating ketamine's mechanism of action. This article provides a concise overview of research findings that pertain to the effects of low-dose ketamine at the cellular, neurocircuitry, and behavioral levels and describes an integrated model of the action of ketamine in the treatment of depression.

Suicidal Ideation Abates After Ketamine Infusion

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessSuicidal Ideation Abates After Ketamine InfusionJun YanJun YanSearch for more papers by this authorPublished Online:16 Oct 2009https://doi.org/10.1176/pn.44.20.0021Research conducted in the past few years shows that ketamine leads to a rapid antidepressant effect within hours of administration. A recent study has demonstrated how this mood change translates into a tangible protection against suicidal ideation in treatment-resistant patients with depression (see Original article: Ketamine Leaves BDNF Unchanged for more on ketamine treatment).Ketamine is an anesthetic given intravenously that is often used in surgery and in veterinary medicine. It is known to cause psychosis and has raised abuse concerns. In a paper published in the September 1 Biological Psychiatry, researchers at Mount Sinai School of Medicine, Rutgers University, and Harvard University conducted two clinical studies in which they assessed suicidal ideation in patients with treatment-resistant depression. The study was funded by the National Institutes of Health.Twenty-six patients participated in the first study, in which each received a single infusion of ketamine at a dose of 0.5 mg/kg and was then kept in the hospital for 28 hours. Outcomes were measured 24 hours after the infusion using the single suicide-related item in the Montgomery-Asberg Depression Rating Scale (MADRS-SI). Scores ranged from 0 to 6, with a score of 6 indicating “explicit plans for suicide when there is an opportunity” or “active preparations for suicide.”Subjects' mean score on the MADRS-SI scale decreased from 2.85 before the ketamine infusion to 0.77 at 24 hours after the infusion, which was statistically significant. Before the infusion, 13 patients had a score of 4 or above on the scale. Twenty-four hours after the infusion, eight of the 13 patients had a score of 0 or 1 and three had a score of 2 or 3; two remained at or above a score of 4.Ten of the 26 patients also completed the Implicit Association Test, a behavioral-assessment instrument the researchers used to measure the implicit suicidal intention before and after the infusion. The implicit and explicit suicidal association scores also decreased significantly after the ketamine infusion.Ten of the patients who had been deemed responders in the first study participated in the second study and received repeated ketamine infusions three times a week in a period of 12 days for up to six infusions. Their average MADRS-SI score was 3.0 at baseline. Nine patients scored 0 on the MADRS-SI scale after every repeated infusion. One patient had a score of 2 after the first infusion (baseline score 4). The patient was dropped from further infusion because of lack of response in overall depressive symptoms, defined as at least 50 percent reduction in MADRS total score.The effect of ketamine on suicidal ideation was likely an indirect result of the antidepressant effect of the drug, the authors concluded after they analyzed the correlation between the total score of the nonsuicide-related items in the MADRS and the suicide-related item score. The 26 patients in the single-dose study had an average preinfusion MADRS total score of 37 (scale range 0-60), which decreased to 15 at 24 hours after the infusion. Seventeen of these patients had a 50 percent reduction in MADRS total score.All study participants had moderate to severe depression as indicated by an Inventory of Depression Symptomatology score of 32 or above at baseline and had failed at least two adequate antidepressant trials in the current depressive episode. They had been suffering from major depressive disorder for a mean of 29 years. All had been in the current depressive episode for at least two years and failed an average of six antidepressants in the current episode. Five of the 26 participants had a history of suicide attempts.No patient experienced hallucinations during the studies, Rebecca Price, M.S., a Ph.D. candidate in psychology at Rutgers University and the lead author of the article, told Psychiatric News. The psychotomimetic side effects observed in the studies were “minimal” at this low dose of ketamine, she said, and additional results and analyses are pending publication.The rapid antidepressant effect of ketamine infusion has previously been reported in small clinical trials conducted by researchers at the Mood and Anxiety Disorders Program at the National Institute of Mental Health (NIMH). The NIMH researchers also demonstrated that ketamine's mechanism of action may lie in its antagonism of the NMDA (N-methyl d-aspartate) receptors and subsequent activation of the AMPA (amino-3-hydroxy-5 methylisoxazole-4-propionic acid) receptors; both are biologically activated by the neurotransmitter glutamate (Psychiatric News, September 7, 2007).An abstract of “Effects of Intravenous Ketamine on Explicit and Implicit Measures of Suicidality in Treatment-Resistant Depression” is posted at<www.journals.elsevierhealth.com/periodicals/bps/article/S0006-3223(09)00519-8/abstract>.▪ ISSUES NewArchived

Protective mechanisms of ketamine on ischemia induced cerebral damage

众多研究显示,氯胺酮对脑缺血缺氧性损伤具有保护作用.主要通过调节神经细胞凋亡;与NMDA受体结合,抑制兴奋性氨基酸毒性及钙离子内流;抑制炎性因子生成和蛋白激酶表达等几个方面发挥脑保护作用。

Mechanisms involved in the antiplatelet activity of ketamine in human platelets

The aim of this study was to systematically examine the inhibitory mechanisms of ketamine in platelet aggregation. In this study, ketamine concentration-dependently (100-350 microM) inhibited platelet aggregation both in washed human platelet suspensions and platelet-rich plasma stimulated by agonists. Ketamine inhibited phosphoinositide breakdown and intracellular Ca2+ mobilization in human platelets stimulated by collagen. Ketamine (200 and 350 microM) significantly inhibited thromboxane (Tx) A2 formation stimulated by collagen. Moreover, ketamine (200 and 350 microM) increased the fluorescence of platelet membranes tagged with diphenylhexatriene. Rapid phosphorylation of a platelet protein of Mr 47,000 (P47), a marker of protein kinase C activation, was triggered by phorbol-12,13-dibutyrate (100 nM). This phosphorylation was markedly inhibited by ketamine (350 microM). These results indicate that the antiplatelet activity of ketamine may be involved in the following pathways. Ketamine may change platelet membrane fluidity, with a resultant influence on activation of phospholipase C, and subsequent inhibition of phosphoinositide breakdown and phosphorylation of P47, thereby leading to inhibition of intracellular Ca2+ mobilization and TxA2 formation, ultimately resulting in inhibition of platelet aggregation.

Different Inhibitory Mechanisms of Ketamine and Midazolam on Nitric Oxide-Mediated Lower Esophageal Sphincter Relaxation in Rabbits

Different Inhibitory Mechanisms of Ketamine and Midazolam on Nitric Oxide-Mediated Lower Esophageal Sphincter Relaxation in Rabbits