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Pharmaceuticals
Special Issues
Ketamine and Ketamine Metabolite Pharmacology
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Ketamine and Ketamine Metabolite Pharmacology

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (15 December 2023) | Viewed by 24791

Special Issue Editors

Prof. Dr. Ana Lúcia S. Rodrigues

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Guest Editor
Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis 88040-900, SC, Brazil
Interests: animal models; neuroscience; behavioral pharmacology; neuropsychopharmacology; biological psychiatry; antidepressant agents
Dr. Anderson Camargo

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Guest Editor
Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis 88040-900, SC, Brazil
Interests: biological psychiatry; behavioral pharmacology; fast-acting antidepressants; ketamine; molecular psychiatry; neuroscience; neuropsychopharmacology

Special Issue Information

Dear Colleagues,

The discovery that a single sub-anesthetic dose of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, elicits rapid and sustainable antidepressant actions in patients with major depressive disorder, even in those considered treatment-resistant, has led to new avenues in the pharmacotherapy of this psychiatric disorder. Ketamine metabolites are also reported to trigger fast and persistent antidepressant responses. Compelling findings obtained in animal models of depression also revealed that ketamine and its metabolites may trigger synaptic protein synthesis, the rapid and robust proliferation of dendritic spines, and synaptogenesis, providing a mechanistic link with antidepressant effects. Some intracellular signaling pathways that may underlie these effects have been investigated, particularly the mechanistic target of rapamycin (mTOR) pathway, mainly in the prefrontal cortex and hippocampus. In addition, groundbreaking evidence also suggests the potential benefits of ketamine in the management of anxiety, bipolar disorder and post-traumatic stress disorder. However, the pharmacology of ketamine and ketamine metabolites remains to be fully resolved. Within this scenario, this Special Issue focuses on this timely topic, aiming to explore the pharmacology of ketamine and ketamine metabolites, providing new methods for treating these psychiatric disorders.

Prof. Dr. Ana Lúcia S. Rodrigues
Dr. Anderson Camargo
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antidepressants
  • depression
  • ketamine
  • ketamine metabolites
  • pharmacology

Published Papers (7 papers)

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Research

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11 pages, 4031 KiB  
Article
Unique Effects of (R)-Ketamine Compared to (S)-Ketamine on EEG Theta Power in Rats
by Dóra Pothorszki, Szabolcs Koncz, Dóra Török, Noémi Papp and György Bagdy
Pharmaceuticals 2024, 17(2), 194; https://doi.org/10.3390/ph17020194 - 01 Feb 2024
Cited by 1 | Viewed by 874
Abstract
Differences in the pharmacological effects of (S)-ketamine and (R)-ketamine are at the focus of research. Clinical data and our rat studies confirmed the antidepressant effect of (S)- but not (R)-ketamine, with similar differences in quantitative electroencephalogram (EEG) and sleep effects. In contrast, studies [...] Read more.
Differences in the pharmacological effects of (S)-ketamine and (R)-ketamine are at the focus of research. Clinical data and our rat studies confirmed the antidepressant effect of (S)- but not (R)-ketamine, with similar differences in quantitative electroencephalogram (EEG) and sleep effects. In contrast, studies mainly on mice showed some stronger, preferable effects of (R)-ketamine. EEG theta (5–9 Hz) rhythm originates from the hippocampus, and its power is associated with cognitive functions, attention, and decreased anxiety. To find a brain parameter that is not associated with the antidepressant effect of drugs and may confirm potent in vivo effects of (R)-ketamine in rats, theta EEG power-inducing effects of the two enantiomers were measured and compared for 23 h. EEG-equipped Wistar rats were treated with (R)-ketamine (7.5, 15, 30 mg/kg i.p.), (S)-ketamine (7.5 and 15 mg/kg i.p.), or vehicle at the beginning of the passive phase. Frontoparietal EEG, electromyogram, and motor activity were recorded. (R)-ketamine but not (S)-ketamine dose-dependently increased EEG theta power during wakefulness and rapid eye movement (REM) sleep for 23 h. These results suggest that (R)-ketamine has an effect on a hippocampal function that was not affected by (S)-ketamine and may be associated with neural plasticity and memory encoding. Full article
(This article belongs to the Special Issue Ketamine and Ketamine Metabolite Pharmacology)
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21 pages, 7891 KiB  
Article
Exploring the Molecular Targets for the Antidepressant and Antisuicidal Effects of Ketamine Enantiomers by Using Network Pharmacology and Molecular Docking
by Glorister A. Altê and Ana Lúcia S. Rodrigues
Pharmaceuticals 2023, 16(7), 1013; https://doi.org/10.3390/ph16071013 - 17 Jul 2023
Cited by 2 | Viewed by 1760
Abstract
Ketamine, a racemic mixture of esketamine (S-ketamine) and arketamine (R-ketamine), has received particular attention for its rapid antidepressant and antisuicidal effects. NMDA receptor inhibition has been indicated as one of the main mechanisms of action of the racemic mixture, but other pharmacological targets [...] Read more.
Ketamine, a racemic mixture of esketamine (S-ketamine) and arketamine (R-ketamine), has received particular attention for its rapid antidepressant and antisuicidal effects. NMDA receptor inhibition has been indicated as one of the main mechanisms of action of the racemic mixture, but other pharmacological targets have also been proposed. This study aimed to explore the possible multiple targets of ketamine enantiomers related to their antidepressant and antisuicidal effects. To this end, targets were predicted using Swiss Target Prediction software for each ketamine enantiomer. Targets related to depression and suicide were collected by the Gene Cards database. The intersections of targets were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Network pharmacology analysis was performed using Gene Mania and Cytoscape software. Molecular docking was used to predict the main targets of the network. The results indicated that esketamine and arketamine share some biological targets, particularly NMDA receptor and phosphodiesterases 3A, 7A, and 5A but have specific molecular targets. While esketamine is predicted to interact with the GABAergic system, arketamine may interact with macrophage migration inhibitory factor (MIF). Both ketamine enantiomers activate neuroplasticity-related signaling pathways and show addiction potential. Our results identified novel, poorly explored molecular targets that may be related to the beneficial effects of esketamine and arketamine against depression and suicide. Full article
(This article belongs to the Special Issue Ketamine and Ketamine Metabolite Pharmacology)
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8 pages, 507 KiB  
Article
Impact of Repeated Doses of Subcutaneous Esketamine on Acute Dissociative Symptoms in Treatment-Resistant Depression
by Lorena Catarina Del Sant, Luciana Maria Sarin, Ana Cecília Lucchese, Eduardo Jorge Muniz Magalhães, Marco Aurélio Tuena, Carolina Nakahira, José Alberto Del Porto, Acioly Luiz Tavares De Lacerda and Jair de Jesus Mari
Pharmaceuticals 2023, 16(1), 31; https://doi.org/10.3390/ph16010031 - 26 Dec 2022
Cited by 2 | Viewed by 1890
Abstract
Background: Esketamine has been approved by the US Food and Drug Administration (FDA) as an adjunctive treatment for use in conjunction with an oral antidepressant for patients with treatment-resistant depression (TRD), but dissociative symptoms are common adverse effects. Methods: A retrospective analysis of [...] Read more.
Background: Esketamine has been approved by the US Food and Drug Administration (FDA) as an adjunctive treatment for use in conjunction with an oral antidepressant for patients with treatment-resistant depression (TRD), but dissociative symptoms are common adverse effects. Methods: A retrospective analysis of 394 subcutaneous esketamine injections given to 70 patients with TRD that were administered once a week during a six-week trial in conjunction with oral antidepressant therapy. Doses between 0.5 to 1.0 mg/kg were administered according to the patient’s response. Dissociative symptoms were assessed using the Clinician-Administered Dissociative States Scale (CADSS) 30 and 60 min after every weekly treatment (day 1, 8, 15, 22, 29 and 36). Results: Seventy patients received a total of 394 subcutaneous esketamine injections over six weeks. Over time, the evolution of CADSS scores demonstrated a significant mean difference of CADSS at 60 min post-injection (p = 0.010) throughout the six infusions. The mean CADSS scores at 60 min on day 22, 29 and 36 were similar. There were no differences between mean CADSS scores 30 min after the injections, no clinical correlation between response and dissociative symptoms, no correlation between time and demographic and clinical characteristics and no interactions between time and combined medication. Conclusions: Our results suggest that repeated subcutaneous esketamine doses are safe and well-tolerated regarding their acute dissociative and psychotomimetic symptoms. Symptoms usually peak at 30 min and decrease at 60 min post-injection, returning to their pretreatment levels at 120 min. Dissociative symptoms do not correlate with antidepressant response. Full article
(This article belongs to the Special Issue Ketamine and Ketamine Metabolite Pharmacology)
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Review

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16 pages, 354 KiB  
Review
Ketamine, an Old–New Drug: Uses and Abuses
by Katarina Savić Vujović, Ana Jotić, Branislava Medić, Dragana Srebro, Aleksandar Vujović, Janko Žujović, Ana Opanković and Sonja Vučković
Pharmaceuticals 2024, 17(1), 16; https://doi.org/10.3390/ph17010016 - 21 Dec 2023
Cited by 1 | Viewed by 1641
Abstract
Ketamine as an old–new drug has a variety of clinical implications. In the last 30 years, ketamine has become popular for acute use in humans. Ketamine in standard doses is principally utilized for the induction and maintenance of surgical procedures. Besides its use [...] Read more.
Ketamine as an old–new drug has a variety of clinical implications. In the last 30 years, ketamine has become popular for acute use in humans. Ketamine in standard doses is principally utilized for the induction and maintenance of surgical procedures. Besides its use in anesthesia and analgesia, recent studies have shown that ketamine has found a place in the treatment of asthma, epilepsy, depression, bipolar affective disorders, alcohol and heroin addiction. Ketamine primarily functions as a noncompetitive antagonist targeting the N-methyl-D-aspartate (NMDA) receptor, but its mechanism of action is complex. It is generally regarded as safe, with low doses and short-term use typically not leading to significant adverse effects. Also, ketamine is known as a powerful psychostimulant. During the past decade, ketamine has been one of the commonly abused drugs. Full article
(This article belongs to the Special Issue Ketamine and Ketamine Metabolite Pharmacology)
19 pages, 1292 KiB  
Review
Ketamine and the Disinhibition Hypothesis: Neurotrophic Factor-Mediated Treatment of Depression
by Philip Borsellino, Reese I. Krider, Deanna Chea, Ryan Grinnell and Thomas A. Vida
Pharmaceuticals 2023, 16(5), 742; https://doi.org/10.3390/ph16050742 - 12 May 2023
Cited by 5 | Viewed by 3910
Abstract
Ketamine is a promising alternative to traditional pharmacotherapies for major depressive disorder, treatment-resistant depression, and other psychiatric conditions that heavily contribute to the global disease burden. In contrast to the current standard of care medications for these disorders, ketamine offers rapid onset, enduring [...] Read more.
Ketamine is a promising alternative to traditional pharmacotherapies for major depressive disorder, treatment-resistant depression, and other psychiatric conditions that heavily contribute to the global disease burden. In contrast to the current standard of care medications for these disorders, ketamine offers rapid onset, enduring clinical efficacy, and unique therapeutic potential for use in acute, psychiatric emergencies. This narrative presents an alternative framework for understanding depression, as mounting evidence supports a neuronal atrophy and synaptic disconnection theory, rather than the prevailing monoamine depletion hypothesis. In this context, we describe ketamine, its enantiomers, and various metabolites in a range of mechanistic actions through multiple converging pathways, including N-methyl-D-aspartate receptor (NMDAR) inhibition and the enhancement of glutamatergic signaling. We describe the disinhibition hypothesis, which posits that ketamine’s pharmacological action ultimately results in excitatory cortical disinhibition, causing the release of neurotrophic factors, the most important of which is brain-derived neurotrophic factor (BDNF). BDNF-mediated signaling along with vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF-1) subsequently give rise to the repair of neuro-structural abnormalities in patients with depressive disorders. Ketamine’s efficacious amelioration of treatment-resistant depression is revolutionizing psychiatric treatment and opening up fresh vistas for understanding the underlying causes of mental illness. Full article
(This article belongs to the Special Issue Ketamine and Ketamine Metabolite Pharmacology)
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21 pages, 422 KiB  
Review
Pharmacological Mechanism of Ketamine in Suicidal Behavior Based on Animal Models of Aggressiveness and Impulsivity: A Narrative Review
by Thi Mai Loan Nguyen, Fabrice Jollant, Laurent Tritschler, Romain Colle, Emmanuelle Corruble and Alain M. Gardier
Pharmaceuticals 2023, 16(4), 634; https://doi.org/10.3390/ph16040634 - 21 Apr 2023
Cited by 4 | Viewed by 2274
Abstract
Around 700,000 people die from suicide each year in the world. Approximately 90% of suicides have a history of mental illness, and more than two-thirds occur during a major depressive episode. Specific therapeutic options to manage the suicidal crisis are limited and measures [...] Read more.
Around 700,000 people die from suicide each year in the world. Approximately 90% of suicides have a history of mental illness, and more than two-thirds occur during a major depressive episode. Specific therapeutic options to manage the suicidal crisis are limited and measures to prevent acting out also remain limited. Drugs shown to reduce the risk of suicide (antidepressants, lithium, or clozapine) necessitate a long delay of onset. To date, no treatment is indicated for the treatment of suicidality. Ketamine, a glutamate NMDA receptor antagonist, is a fast-acting antidepressant with significant effects on suicidal ideation in the short term, while its effects on suicidal acts still need to be demonstrated. In the present article, we reviewed the literature on preclinical studies in order to identify the potential anti-suicidal pharmacological targets of ketamine. Impulsive–aggressive traits are one of the vulnerability factors common to suicide in patients with unipolar and bipolar depression. Preclinical studies in rodent models with impulsivity, aggressiveness, and anhedonia may help to analyze, at least in part, suicide neurobiology, as well as the beneficial effects of ketamine/esketamine on reducing suicidal ideations and preventing suicidal acts. The present review focuses on disruptions in the serotonergic system (5-HTB receptor, MAO-A enzyme), neuroinflammation, and/or the HPA axis in rodent models with an impulsive/aggressive phenotype, because these traits are critical risk factors for suicide in humans. Ketamine can modulate these endophenotypes of suicide in human as well as in animal models. The main pharmacological properties of ketamine are then summarized. Finally, numerous questions arose regarding the mechanisms by which ketamine may prevent an impulsive–aggressive phenotype in rodents and suicidal ideations in humans. Animal models of anxiety/depression are important tools to better understand the pathophysiology of depressed patients, and in helping develop novel and fast antidepressant drugs with anti-suicidal properties and clinical utility. Full article
(This article belongs to the Special Issue Ketamine and Ketamine Metabolite Pharmacology)

Other

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14 pages, 1002 KiB  
Systematic Review
Effect of Ketamine on Sleep in Treatment-Resistant Depression: A Systematic Review
by Aleksander Kwaśny, Adam Włodarczyk, Damian Ogonowski and Wiesław Jerzy Cubała
Pharmaceuticals 2023, 16(4), 568; https://doi.org/10.3390/ph16040568 - 10 Apr 2023
Cited by 5 | Viewed by 10630
Abstract
Background: Depression is a debilitating disease with a high socioeconomic burden. Regular antidepressants usually require several weeks to ameliorate symptoms; however, numerous patients do not achieve remission. What is more, sleep disturbances are one of the most common residual symptoms. Ketamine is a [...] Read more.
Background: Depression is a debilitating disease with a high socioeconomic burden. Regular antidepressants usually require several weeks to ameliorate symptoms; however, numerous patients do not achieve remission. What is more, sleep disturbances are one of the most common residual symptoms. Ketamine is a novel antidepressant with rapid onset of action with a proven antisuicidal effect. Little is known about its impact on sleep–wake and circadian rhythm alterations. The aim of this systematic review is to research the impact ketamine has on sleep disturbances in depression. Methods: PubMed, Web of Science, and APA PsycINFO were searched for relevant studies on ketamine’s impact on sleep disturbances in depression. Preferred Reporting Items for Systematic Reviews and Meta-Analyses PRISMA2020 methodology was applied. The systematic review protocol was registered in the PROSPERO Registry (CRD42023387897). Results: Five studies were included in this review. Two studies reported significant improvement in sleep measured by MADRS (Montgomery–Åsberg Depression Rating Scale) and QIDS-SR16 (Quick Inventory of Depressive Symptomatology Self-Report (16-item)) scales after intravenous ketamine and intranasal esketamine administration. One case report showed mitigation of symptoms in PSQI (Pittsburgh Sleep Quality Index) and ISI (Insomnia Severity Index) during 3-month treatment with esketamine. In two studies, sleep was objectively measured by nocturnal EEG (electroencephalography) and showed a decrease in nocturnal wakefulness accompanied by an increase in slow wave (SWS) and rapid eye movement (REM) sleep. Conclusion: Ketamine reduces the severity of sleep insomnia in depression. Robust data are lacking. More research is needed. Full article
(This article belongs to the Special Issue Ketamine and Ketamine Metabolite Pharmacology)
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