A Review of the Mechanism of Antagonism of N-methyl-D-aspartate Receptor by Ketamine in Treatment-resistant Depression

A lack of effective treatment for patients with treatment-resistant depression (TRD) has led to the evaluation of ketamine, an N-methyl- D-aspartate receptor antagonist. Despite the demonstrated short-term benefits of using intravenous (IV) ketamine, side effects and the difficulty in administering ketamine outside the health-care setting has raised interest in alternative dosage forms. Research articles evaluating oral or intranasal (IN) ketamine were retrieved from the PubMed database. Patients who received oral or IN ketamine experienced a similar reduction in depressive symptoms within 24 hours of treatment and fewer side effects compared to patients who received IV ketamine. Novel administration forms of ketamine provide an opportunity for patients with TRD to achieve remission with fewer adverse side effects. Future studies should continue to evaluate these administration strategies in the hope of promoting ketamine’s use outside health-care settings and for longer time periods.

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Esketamine in Treatment Resistant Depression: The Way to Remission

Revista Portuguesa de Psiquiatria e Saúde Mental ◽

10.51338/rppsm.2021.v.i1.174 ◽

2021 ◽

pp. 35-39

Author(s):

João Facucho-Oliveira ◽

Daniel Esteves-Sousa ◽

Bruno Prates ◽

Rui Neves ◽

Pedro Varandas

Keyword(s):

Depressive Symptoms ◽

Behavioral Therapy ◽

Symptomatic Relief ◽

European Medicines Agency ◽

Caucasian Woman ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Major Depressive ◽

Aspartate Receptor ◽

Resistant Depression

Major depressive disorder affects an estimate of 5% of the population with nearly 1‑third of patients failing to achieve remission with conventional pharmacological treatment. Esketamine, a novel rapid‑acting antidepressant, with a noncompetitive antagonism on N‑methyl‑D‑Aspartate receptor, have been recently approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treatment‑resistant depression. Here, we report a clinical case of a 42‑year‑old Caucasian woman who endured many years with severe depressive symptoms and high functional impairment. Previous treatments included cognitive behavioral therapy, numerous pharmacological trials with antidepressants and augmentation agents, and neurostimulation approaches. Upon treatment with esketamine, the patient presented remarkable clinical recovery. Psychometric assessments determined an acute reduction on the MADRS score after 1 week and progressive recovery of the depressive symptoms on the following weeks. Likewise, PHQ‑9 scale assessments, evaluating the relative frequency of depressive symptoms. and the Sheehan scale, assessing functional recovery, also determined a pronounced symptomatic relief.

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Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature

Mental Health Clinician ◽

10.9740/mhc.2017.01.016 ◽

2017 ◽

Vol 7 (1) ◽

pp. 16-23 ◽

Cited By ~ 19

Author(s):

Sarah E. Grady ◽

Travis A. Marsh ◽

Allison Tenhouse ◽

Kelsey Klein

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Bipolar Depression ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Major Depressive ◽

Randomized Controlled ◽

The Past ◽

Aspartate Receptor ◽

Resistant Depression

Abstract Introduction: Over the past decade, ketamine has been studied for major depressive disorder and bipolar depression. Ketamine is believed to exert its antidepressant properties through N-methyl-D-aspartate receptor antagonism. Methods: Study authors completed a literature review of seven randomized controlled trials of ketamine usage in major depressive disorder and bipolar depression. Results: Ketamine demonstrated a statistically significant improvement over placebo or midazolam in major depressive disorder. Ketamine also exhibited a statistically significant improvement over placebo in bipolar depression. Discussion: Ketamine has shown promise in quickly reducing symptoms in patients with treatment resistant depression and bipolar depression. Using ketamine may be helpful for patients that have exhausted other therapeutic options.

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Ketamine: A tale of two enantiomers

Journal of Psychopharmacology ◽

10.1177/0269881120959644 ◽

2020 ◽

pp. 026988112095964

Author(s):

Luke A Jelen ◽

Allan H Young ◽

James M Stone

Keyword(s):

Side Effects ◽

Receptor Antagonist ◽

The United States ◽

Receptor Activation ◽

Racemic Mixture ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Aspartate Receptor ◽

Antidepressant Effects ◽

Resistant Depression

The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate receptor antagonist, is arguably the most important breakthrough in depression research in the last 50 years. Ketamine remains an off-label treatment for treatment-resistant depression with factors that limit widespread use including its dissociative effects and abuse potential. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. An (S)-ketamine nasal spray has been developed and approved for use in treatment-resistant depression in the United States and Europe; however, some concerns regarding efficacy and side effects remain. Although (R)-ketamine is a less potent N-Methyl-D-Aspartate receptor antagonist than (S)-ketamine, increasing preclinical evidence suggests (R)-ketamine may have more potent and longer lasting antidepressant effects than (S)-ketamine, alongside fewer side effects. Furthermore, a recent pilot trial of (R)-ketamine has demonstrated rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research is ongoing to determine the specific cellular and molecular mechanisms underlying the antidepressant actions of ketamine and its component enantiomers in an effort to develop future rapid-acting antidepressants that lack undesirable effects. Here, we briefly review findings regarding the antidepressant effects of ketamine and its enantiomers before considering underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling, inhibition of glycogen synthase kinase-3 and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems.

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Dextromethorphan/Bupropion: A Novel Oral NMDA (N-methyl-d-aspartate) Receptor Antagonist with Multimodal Activity

CNS Spectrums ◽

10.1017/s1092852919001470 ◽

2019 ◽

Vol 24 (5) ◽

pp. 461-466 ◽

Cited By ~ 3

Author(s):

Stephen M. Stahl

Keyword(s):

Rapid Onset ◽

Mechanisms Of Action ◽

Second Line ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Major Depressive ◽

Therapeutic Benefits ◽

Aspartate Receptor ◽

Adequate Response ◽

Resistant Depression

Although currently available antidepressants increase monoamine levels soon after the start of treatment, therapeutic benefits are often delayed by several weeks and the majority of patients with major depressive disorder fail to achieve an adequate response to first- or second-line therapies targeting monoamines. The recent approval of the NMDA (N-methyl-d-aspartate) antagonist esketamine given intranasally for treatment-resistant depression has reinforced the need for agents with rapid onset with alternate mechanisms of action. Dextromethorphan/bupropion, an investigational medicine currently in development, is one such candidate.

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A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyaa025 ◽

2020 ◽

Vol 23 (7) ◽

pp. 417-425 ◽

Cited By ~ 6

Author(s):

Lawrence T Park ◽

Bashkim Kadriu ◽

Todd D Gould ◽

Panos Zanos ◽

Deanna Greenstein ◽

...

Keyword(s):

Magnetic Resonance ◽

Adverse Effects ◽

Rating Scale ◽

Secondary Outcome ◽

Treatment Resistant Depression ◽

Glycine Site ◽

Treatment Resistant ◽

Aspartate Receptor ◽

Antidepressant Effects ◽

Resistant Depression

Abstract Background Ketamine has rapid-acting antidepressant effects but is associated with psychotomimetic and other adverse effects. A 7-chlorokynurenic acid is a potent and specific glycine site N-methyl-d-aspartate receptor antagonist but crosses the blood-brain barrier inefficiently. Its prodrug, L-4-chlorokynurenine (4-Cl-KYN), exerts acute and sustained antidepressant-like effects in rodents and has no reported psychotomimetic effects in either rodents or healthy volunteers. This study examined whether 4-Cl-KYN has rapid antidepressant effects in individuals with treatment-resistant depression. Methods After a 2-week drug-free period, 19 participants with treatment-resistant depression were randomized to receive daily oral doses of 4-Cl-KYN monotherapy (1080 mg/d for 7 days, then 1440 mg/d for 7 days) or placebo for 14 days in a randomized, placebo-controlled, double-blind, crossover manner. The primary outcome measure was the Hamilton Depression Rating Scale score, assessed at several time points over a 2-week period; secondary outcome measures included additional rating scale scores. Pharmacokinetic measures of 7-chlorokynurenic acid and 4-Cl-KYN and pharmacodynamic assessments were obtained longitudinally and included 1H-magnetic resonance spectroscopy brain glutamate levels, resting-state functional magnetic resonance imaging, and plasma and cerebrospinal fluid measures of kynurenine metabolites and neurotrophic factors. Results Linear mixed models detected no treatment effects, as assessed by primary and secondary outcome measures. No difference was observed for any of the peripheral or central biological indices or for adverse effects at any time between groups. A 4-Cl-KYN was safe and well-tolerated, with generally minimal associated adverse events. Conclusions In this small crossover trial, 4-Cl-KYN monotherapy exerted no antidepressant effects at the doses and treatment duration studied. ClinicalTrials.gov identifier: NCT02484456.

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