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

Sattar, Yasar; Wilson, John A.; Khan, Ali Mahmood; Adnan, Mahwish; Larios, Daniel Azzopardi; Shrestha, Shristi; Rahman, Quazi Mehbubar; Mansuri, Zeeshan; Hassan, Ali; Patel, Nirav; Tariq, Nargis; Latchana, Sharaad; Pantoja, Stefany C Lopez; Vargas, Sadiasept; Shaikh, Naveed A; Syed, Fawaduzzaman; Mittal, Daaman; Rumesa, Fatima

doi:10.7759/cureus.2652

Cited by 30 publications

(26 citation statements)

References 48 publications

(47 reference statements)

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“…5). With respect to the "disease/religion" component, both ketamine and DMT (as part of the Amazonian concoction ayahuasca) have been explored for therapeutic uses, especially for the treatment of major depression (Kyzar et al, 2017;Palhano-Fontes et al, 2018;Sattar et al, 2018). The presence of words related to spiritual and religious contexts suggests that the potential therapeutic benefits of these substances appear intertwined with ceremonial use in the Erowid corpus (Dakwar et al, 2014;Niciu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports

Martial

Cassol

Charland‐Verville

et al. 2019

Consciousness and Cognition

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The real or perceived proximity to death often results in a non-ordinary state of consciousness characterized by phenomenological features such as the perception of leaving the body boundaries, feelings of peace, bliss and timelessness, life review, the sensation of traveling through a tunnel and an irreversible threshold. Near-death experiences (NDEs) are comparable among individuals of different cultures, suggesting an underlying neurobiological mechanism. Anecdotal accounts of the similarity between NDEs and certain drug-induced altered states of consciousness prompted us to perform a large-scale comparative analysis of these experiences. After assessing the semantic similarity between ≈15,000 reports linked to the use of 165 psychoactive substances and 625 NDE narratives, we determined that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine consistently resulted in reports most similar to those associated with NDEs. Ketamine was followed by Salvia divinorum (a plant containing a potent and selective κ receptor agonist) and a series of serotonergic psychedelics, including the endogenous serotonin 2A receptor agonist N,N-Dimethyltryptamine (DMT). This similarity was driven by semantic concepts related to consciousness of the self and the environment, but also by those associated with the therapeutic, ceremonial and religious aspects of drug use. Our analysis sheds light on the longstanding link between certain drugs and the experience of "dying", suggests that ketamine could be used as a safe and reversible experimental model for NDE phenomenology, and supports the speculation that endogenous NMDA antagonists with neuroprotective properties may be released in the proximity of death.

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Section: Discussionmentioning

confidence: 99%

Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports

Martial

Cassol

Charland‐Verville

et al. 2019

Consciousness and Cognition

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show abstract

“…In addition, DAO is a peroxisomal enzyme that is known to oxidize d-serine and may play a regulatory role in N-methyl-d-aspartate-type (NMDA) receptor function (Corvin et al, 2007). The NMDA receptor has a major role in the neurophysiology of depression (Sattar et al, 2018). Moreover, hypothyroidism was determined, and TPO levels were significantly decreased with a higher risk of depression, which was expressed during gestation as a marker for subsequent postpartum depression (Dama et al, 2016).…”

Section: Other Metabolites and Enzymesmentioning

confidence: 99%

Serum Metabolic Profiling Reveals the Antidepressive Effects of the Total Iridoids of Valeriana jatamansi Jones on Chronic Unpredictable Mild Stress Mice

Chang

et al. 2020

Front. Pharmacol.

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Background: Depression is a long-term complex psychiatric disorder, and its etiology remains largely unknown. Valeriana jatamansi Jones ex Roxb (V. jatamansi) is used in the clinic for the treatment of depression, but there are insufficient reports of its antidepressive mechanisms and a poor understanding of its endogenous substance-related metabolism. The objective of this study was to identify biomarkers related to depression in serum samples and evaluate the antidepressive effects of the iridoid-rich fraction of V. jatamansi (IRFV) in a chronic unpredictable mild stress (CUMS) mouse model. Methods: Here, CUMS was used to establish a mouse model of depression. Behavioral and biochemical indicators were investigated to evaluate the pharmacodynamic effects. A comprehensive serum metabolomics study by nuclear magnetic resonance (NMR) approach was applied to investigate the pharmacological mechanism of IRFV in CUMS mouse. Subsequently, we used multivariate statistical analysis to identify metabolic markers, such as principal component analysis (PCA) and orthogonal projection to latent structure with discriminant analysis (OPLS-DA), to distinguish between the CUMS mouse and the control group. Results: After IRFV treatment, the immobility time, sucrose preference, and monoamine neurotransmitter were improved. PCA scores showed clear differences in metabolism between the CUMS group and control group. The PLS-DA or OPLS-DA model exhibited 26 metabolites as biomarkers to distinguish between the CUMS mice and the control mouse. Moreover, IRFV could significantly return 21 metabolites to normal levels. Conclusion: The results confirmed that IRFV exerted an antidepressive effect by regulating multiple metabolic pathways, including the tricarboxylic acid cycle, the synthesis of neurotransmitters, and amino acid metabolism. These findings provide insights into the antidepressive mechanisms of IRFV.

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“…Accumulating evidence implies that N-methyl-D-aspartate (NMDA) receptor antagonism by ketamine produces rapid and sustained antidepressant activity in TRD patients (Sattar et al, 2018). Ketamine preparations (e.g., ketalar R , ketavet R ) are a mixture of two enantiomers, and were approved for any use by FDA in 1970.…”

Section: Esketamine: Clinical Use In Depressionmentioning

confidence: 99%

Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?

et al. 2021

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Repurposing ketamine in the therapy of depression could well represent a breakthrough in understanding the etiology of depression. Ketamine was originally used as an anesthetic drug and later its use was extended to other therapeutic applications such as analgesia and the treatment of addiction. At the same time, the abuse of ketamine as a recreational drug has generated a concern for its psychotropic and potential long-term effects; nevertheless, its use as a fast acting antidepressant in treatment-resistant patients has boosted the interest in the mechanism of action both in psychiatry and in the wider area of neuroscience. This article provides a comprehensive overview of the actions of ketamine and intends to cover: (i) the evaluation of its clinical use in the treatment of depression and suicidal behavior; (ii) the potential use of ketamine in pediatrics; (iii) a description of its mechanism of action; (iv) the involvement of specific brain areas in producing antidepressant effects; (v) the potential interaction of ketamine with the hypothalamic-pituitary-adrenal axis; (vi) the effect of ketamine on neuronal transmission in the bed nucleus of stria terminalis and on its output; (vii) the evaluation of any gender-dependent effects of ketamine; (viii) the interaction of ketamine with the inflammatory processes involved in depression; (ix) the evaluation of the effects observed with single or repeated administration; (x) a description of any adverse or cognitive effects and its abuse potential. Finally, this review attempts to assess whether ketamine’s use in depression can improve our knowledge of the etiopathology of depression and whether its therapeutic effect can be considered an actual cure for depression rather than a therapy merely aimed to control the symptoms of depression.

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

Cited by 30 publications

References 48 publications

Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports

Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports

Serum Metabolic Profiling Reveals the Antidepressive Effects of the Total Iridoids of Valeriana jatamansi Jones on Chronic Unpredictable Mild Stress Mice

Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?

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