Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 27(1), P. 559 - 573

Published: May 7, 2021

The discovery of robust antidepressant actions exerted by the N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine has been a crucial breakthrough in mood disorder research. is racemic mixture equal amounts (R)-ketamine (arketamine) and (S)-ketamine (esketamine). In 2019, an esketamine nasal spray from Johnson & was approved United States America Europe for treatment-resistant depression. However, increasing number preclinical studies show that arketamine greater potency longer-lasting antidepressant-like effects than rodents, despite lower binding affinity NMDAR. clinical trials, non-ketamine NMDAR-related compounds did not exhibit ketamine-like patients with depression, these showing rodents. Thus, rodent data do necessarily translate to humans due complexity human psychiatric disorders. Collectively, available indicate it unlikely NMDAR plays major role action its enantiomers, although precise molecular mechanisms underlying enantiomers remain unclear. this paper, we review recent findings on potent enantiomer arketamine. Furthermore, discuss possible brain-gut-microbiota axis brain-spleen stress-related disorders Finally, potential as treatment cognitive impairment disorders, Parkinson's disease, osteoporosis, inflammatory bowel diseases, stroke.

Language: Английский

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Ketamine treatment for depression: a review

Discover Mental Health, Journal Year: 2022, Volume and Issue: 2(1)

Published: April 15, 2022

Abstract This manuscript reviews the clinical evidence regarding single-dose intravenous (IV) administration of novel glutamatergic modulator racemic ( R,S )-ketamine (hereafter referred to as ketamine) well its S -enantiomer, intranasal esketamine, for treatment major depressive disorder (MDD). Initial studies found that a single subanesthetic-dose IV ketamine infusion rapidly (within one day) improved symptoms in individuals with MDD and bipolar depression, antidepressant effects lasting three seven days. In 2019, esketamine received FDA approval an adjunctive treatment-resistant depression (TRD) adults. Esketamine was approved under risk evaluation mitigation strategy (REMS) requires medical supervision. Both are currently viable options TRD offer possibility rapid symptom improvement. The also ketamine’s use other psychiatric diagnoses—including suicidality, obsessive–compulsive disorder, post-traumatic stress substance abuse, social anxiety disorder—and potential adverse effects. Despite limited data, side antidepressant-dose ketamine—including dissociative symptoms, hypertension, confusion/agitation—appear be tolerable around time treatment. Relatively little is known about longer-term effects, including increased risks abuse and/or dependence. Attempts prolong combined therapy or repeat-dose reviewed, current guidelines use. addition presenting valuable option, studying has transform our understanding mechanisms underlying mood disorders development therapeutics.

Language: Английский

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The antidepressant actions of ketamine and its enantiomers

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 246, P. 108431 - 108431

Published: May 4, 2023

Language: Английский

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Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: July 3, 2023

Abstract Stroke and late-onset Alzheimer’s disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge basic research clinical practice. The similarities differences between stroke AD terms pathogenesis pathophysiology, however, have rarely been comparably reviewed. Here, we discuss background recent progresses that important informative related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity NMDAR-mediated Ca 2+ influx essential neuronal function cell survival. An ischemic insult, can cause rapid increases glutamate concentration excessive activation NMDARs, leading to swift overload cells acute excitotoxicity within hours days. On other hand, mild upregulation NMDAR activity, commonly seen animal models patients, is not immediately cytotoxic. Sustained hyperactivity dysregulation lasting from months years, nevertheless, be pathogenic slowly evolving events, i.e. degenerative excitotoxicity, development AD/ADRD. Specifically, mediated by extrasynaptic NMDARs (eNMDARs) downstream pathway transient potential cation channel subfamily M member (TRPM) primarily responsible excitotoxicity. subunit GluN3A plays “gatekeeper” role neuroprotective against both chronic Thus, share an NMDAR- -mediated mechanism provides common target preventive possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs was approved Federal Drug Administration (FDA) symptomatic treatment moderate-to-severe with variable efficacy. According eNMDARs, it conceivable MEM eNMDAR antagonists should administered much earlier, preferably during presymptomatic phases This anti-AD could simultaneously serve as preconditioning strategy attacks ≥ 50% patients. Future on regulation enduring control homeostasis, events will provide promising opportunity understand treat AD/ADRD stroke.

Language: Английский

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Are “mystical experiences” essential for antidepressant actions of ketamine and the classic psychedelics?

European Archives of Psychiatry and Clinical Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 27, 2024

The growing interest in the rapid and sustained antidepressant effects of dissociative anesthetic ketamine classic psychedelics, such as psilocybin, is remarkable. However, both psychedelics are known to induce acute mystical experiences; can cause symptoms out-of-body experience, while typically bring about hallucinogenic experiences, like a profound sense unity with universe or nature. role these experiences enhancing outcomes for patients depression currently an area ongoing investigation debate. Clinical studies have shown that following administration (S)-ketamine (esketamine) not directly linked their properties. In contrast, potential (R)-ketamine (arketamine), thought lack side effects, has yet be conclusively proven large-scale clinical trials. Moreover, although activation serotonin 5-HT

Language: Английский

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Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial

BMJ, Journal Year: 2024, Volume and Issue: unknown, P. e078218 - e078218

Published: April 10, 2024

Abstract Objective To determine whether a single low dose of esketamine administered after childbirth reduces postpartum depression in mothers with prenatal depression. Design Randomised, double blind, placebo controlled trial two parallel arms. Setting Five tertiary care hospitals China, 19 June 2020 to 3 August 2022. Participants 364 aged ≥18 years who had at least mild as indicated by Edinburgh postnatal scale scores ≥10 (range 0-30, higher indicating worse depression) and were admitted hospital for delivery. Interventions randomly assigned 1:1 receive either 0.2 mg/kg or infused intravenously over 40 minutes once the umbilical cord been clamped. Main outcome measures The primary was prevalence major depressive episode 42 days post partum, diagnosed using mini-international neuropsychiatric interview. Secondary outcomes included score seven partum 17 item Hamilton rating 0-52, depression). Adverse events monitored until 24 hours childbirth. Results A total (mean age 31.8 (standard deviation 4.1) years) enrolled randomised. At observed 6.7% (12/180) participants group compared 25.4% (46/181) (relative risk 0.26, 95% confidence interval (CI) 0.14 0.48; P<0.001). lower (median difference −3, CI −4 −2; P<0.001) (−3, also (−4, −6 −3; overall incidence adverse (45.1% (82/182) v 22.0% (40/182); P<0.001); however, symptoms lasted less than day none required drug treatment. Conclusions For depression, decreases episodes about three quarters. Neuropsychiatric more frequent but transient did not require intervention. Trial registration ClinicalTrials.gov NCT04414943 .

Language: Английский

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Targeting metaplasticity mechanisms to promote sustained antidepressant actions

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(4), P. 1114 - 1127

Published: Jan. 4, 2024

Language: Английский

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Uncovering Psychedelics: From Neural Circuits to Therapeutic Applications

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(1), P. 130 - 130

Published: Jan. 19, 2025

Psychedelics, historically celebrated for their cultural and spiritual significance, have emerged as potential breakthrough therapeutic agents due to profound effects on consciousness, emotional processing, mood, neural plasticity. This review explores the mechanisms underlying psychedelics’ effects, focusing ability modulate brain connectivity circuit activity, including default mode network (DMN), cortico-striatal thalamo-cortical (CSTC) loops, relaxed beliefs under psychedelics (REBUS) model. Advanced neuroimaging techniques reveal capacity enhance functional between sensory cerebral areas while reducing connections associative areas, decreasing rigidity rendering more plastic susceptible external changings, offering insights into outcome. The most relevant clinical trials of 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, lysergic acid diethylamide (LSD) demonstrate significant efficacy in treating treatment-resistant psychiatric conditions such post-traumatic stress disorder (PTSD), depression, anxiety, with favorable safety profiles. Despite these advancements, critical gaps remain linking molecular actions efficacy. highlights need further research integrate mechanistic optimize tools both therapy understanding human cognition.

Language: Английский

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Folate metabolism: a re-emerging therapeutic target in haematological cancers

Leukemia, Journal Year: 2021, Volume and Issue: 35(6), P. 1539 - 1551

Published: March 11, 2021

Abstract Folate-mediated one carbon (1C) metabolism supports a series of processes that are essential for the cell. Through number interlinked reactions happening in cytosol and mitochondria cell, folate contributes to de novo purine thymidylate synthesis, methionine cycle redox defence. Targeting gave rise modern chemotherapy, through introduction antifolates treat paediatric leukaemia. Since then, antifolates, such as methotrexate pralatrexate have been used blood cancers clinic. However, traditional many deleterious side effects normal proliferating tissue, highlighting urgent need novel strategies more selectively target 1C metabolism. Notably, mitochondrial enzymes shown be significantly upregulated various cancers, making them attractive targets development new chemotherapeutic agents. In this article, we present detailed overview folate-mediated metabolism, its importance on cellular level discuss how targeting has exploited cancers. Additionally, explore possible therapeutic could overcome limitations antifolates.

Language: Английский

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Ketamine and its metabolites: Potential as novel treatments for depression

Neuropharmacology, Journal Year: 2022, Volume and Issue: 222, P. 109305 - 109305

Published: Oct. 30, 2022

Language: Английский

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