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Ruin Moaddel, Michelle Shardell, Mohammed Khadeer, Jacqueline Lovett, Bashkim Kadriu, Sarangan Ravichandran, Patrick J Morris, Peixiong Yuan, Craig J Thomas, Todd D Gould, Luigi Ferrucci, Carlos A Zarate
(R,S)-Ketamine produces rapid, robust, and sustained antidepressant effects in major depressive disorder. Specifically, its pharmacological efficacy in treatment refractory depression is considered a major breakthrough in the field. However, the mechanism of action of ketamine's rapid effect remains to be determined. In order to identify pathways that are responsible for ketamine's effect, a targeted metabolomic approach was carried out using a double-blind, placebo-controlled crossover design, with infusion order randomized with medication-free patients with treatment-resistant major depressive disorder (29 subjects) and healthy controls (25 subjects)...
August 16, 2018: Psychopharmacology
Muhammad W Ashraf, Marko A Peltoniemi, Klaus T Olkkola, Pertti J Neuvonen, Teijo I Saari
Low dose oral S-ketamine is increasingly used in chronic pain therapy, but extensive cytochrome P450 mediated metabolism makes it prone to pharmacokinetic drug-drug interactions. In our study, concentration-time data from five studies was used to develop a semi-mechanistic model that describes the ticlopidine-mediated inhibition of S-ketamine biotransformation. A mechanistic model was implemented to account for reversible and time dependent hepatic CYP2B6 inactivation by ticlopidine, which causes elevated S-ketamine exposure in vivo...
August 9, 2018: CPT: Pharmacometrics & Systems Pharmacology
Pan-Fen Wang, Alicia Neiner, Evan D Kharasch
WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Human ketamine N-demethylation to norketamine in vitro at therapeutic concentrations is catalyzed predominantly by the cytochrome P4502B6 isoform (CYP2B6). The CYP2B6 gene is highly polymorphic. CYP2B6.6, the protein encoded by the common variant allele CYP2B6*6, exhibits diminished ketamine metabolism in vitro compared with wild-type CYP2B6.1. The gene for cytochrome P450 oxidoreductase (POR), an obligatory P450 coenzyme, is also polymorphic...
August 7, 2018: Anesthesiology
Jasper van der Aart, Sandeep S V Golla, Marieke van der Pluijm, Lothar A Schwarte, Robert C Schuit, Pieter J Klein, Athanasios Metaxas, Albert D Windhorst, Ronald Boellaard, Adriaan A Lammertsma, Bart N M van Berckel
BACKGROUND: Efforts to develop suitable positron emission tomography (PET) tracers for the ion channel site of human N-methyl-D-aspartate (NMDA) receptors have had limited success. [18 F]PK-209 is a GMOM derivative that binds to the intrachannel phencyclidine site with high affinity and selectivity. Primate PET studies have shown that the volume of distribution in the brain was reduced by administration of the NMDA receptor antagonist MK-801, consistent with substantial specific binding...
July 27, 2018: EJNMMI Research
Lucie Bartova, Konstantinos Papageorgiou, Ivan Milenkovic, Markus Dold, Ana Weidenauer, Matthaeus Willeit, Dietmar Winkler, Siegfried Kasper
Rapid anti-suicidal and antidepressant effects of ketamine have repeatedly been confirmed in unipolar and bipolar depression. Although meaningful antidepressant efficacy of ketamine has also been shown in depressed patients with a history of psychotic symptoms, its administration in psychotic disorders has largely been neglected due to its potential to exacerbate dissociative or psychotic symptoms. Presenting a case of a young female inpatient suffering from schizophrenia with a severe post-psychotic depression, we demonstrate a robust anti-suicidal and antidepressant effect of S-ketamine infusions administered thrice weekly for 3 weeks in total...
July 2, 2018: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Kai Zhang, Min Ma, Chao Dong, Kenji Hashimoto
Background: A recent study demonstrated that inflammatory bone markers play a role in the antidepressant functions of (R,S)-ketamine in treatment-resistant patients with depression. We examined the effect of inflammatory bone markers in the antidepressant functions of (R)-ketamine and (S)-ketamine in a chronic social defeat stress (CSDS) model. Methods: Behavioral tests for antidepressant actions were performed after a single administration of (R)-ketamine or (S)-ketamine...
July 19, 2018: International Journal of Neuropsychopharmacology
Zheng Tian, Chao Dong, Atsuhiro Fujita, Yuko Fujita, Kenji Hashimoto
The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-ketamine has robust antidepressant effects in depressed patients although it has detrimental side effects such as psychotomimetic and dissociative symptoms. (R,S)-Ketamine is known to cause the expression of heat shock protein HSP-70 (a marker for neuronal injury) in the retrosplenial cortex of rat brain, suggesting that the neuropathological changes may play a role in the detrimental side effects of (R,S)-ketamine. This study was undertaken to examine whether (R,S)-ketamine and its two enantiomers, (R)-ketamine and (S)-ketamine, causes the expression of HSP-70 in the rat retrosplenial cortex after a single administration...
September 2018: Pharmacology, Biochemistry, and Behavior
Tineke Grent-'t-Jong, Davide Rivolta, Joachim Gross, Ruchika Gajwani, Stephen M Lawrie, Matthias Schwannauer, Tonio Heidegger, Michael Wibral, Wolf Singer, Andreas Sauer, Bertram Scheller, Peter J Uhlhaas
Hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning...
July 17, 2018: Brain: a Journal of Neurology
Felix Mueller, Francesco Musso, Markus London, Peter de Boer, Norman Zacharias, Georg Winterer
Background: Subanesthetic dosages of the NMDAR antagonist, S-Ketamine, can cause changes in behavior in healthy subjects, which are similar to the state acute psychosis and are relevant in translational schizophrenia research. Functional magnetic resonance imaging (fMRI) can be used for non-hypothesis-driven analysis of brain connectivity. The correlation between clinical behavioral scores and neuroimaging can help to characterize ketamine effects on healthy brains in resting state. Method: seventeen healthy, male subjects (mean: 27...
2018: NeuroImage: Clinical
Benedikt Büttner, Ashham Mansur, Matthias Kalmbach, José Hinz, Thomas Volk, Karoly Szalai, Markus Roessler, Ingo Bergmann
BACKGROUND: Out-of-hospital analgosedation in trauma patients is challenging for emergency physicians due to associated complications. We compared peripheral nerve block (PNB) with analgosedation (AS) as an analgetic approach for patients with isolated extremity injury, assuming that prehospital required medical interventions (e.g. reduction, splinting of dislocation injury) using PNB are less painful and more feasible compared to AS. METHODS: Thirty patients (aged 18 or older) were randomized to receive either ultrasound-guided PNB (10 mL prilocaine 1%, 10 mL ropivacaine 0...
2018: PloS One
H Trimmel, R Helbok, T Staudinger, W Jaksch, B Messerer, H Schöchl, R Likar
Correction to: Wien Klin Wochenschr 2017 The article S(+)-ketamine Current trends in emergency and intensive caremedicine, written by Helmut Trimmel, Raimund Helbok, Thomas Staudinger, Wolfgang Jaksch, Brigitte Messerer, Herbert Schöchl and Rudolf Likar, was ….
June 29, 2018: Wiener Klinische Wochenschrift
Chun Yang, Shizuka Kobayashi, Kazuhito Nakao, Chao Dong, Mei Han, Youge Qu, Qian Ren, Ji-Chun Zhang, Min Ma, Hidetoh Toki, Jun-Ichi Yamaguchi, Shigeyuki Chaki, Yukihiko Shirayama, Kazu Nakazawa, Toshiya Manabe, Kenji Hashimoto
BACKGROUND: Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts robust antidepressant effects in patients with treatment-resistant depression. The precise mechanisms underlying ketamine's antidepressant actions remain unclear, although previous research suggests that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) activation plays a role. We investigated whether (S)-norketamine and (R)-norketamine, the two main metabolites of (R,S)-ketamine, also play a significant role in ketamine's antidepressant effects and whether the effects are mediated by AMPAR...
May 14, 2018: Biological Psychiatry
L Laaksonen, M Kallioinen, J Långsjö, T Laitio, A Scheinin, J Scheinin, K Kaisti, A Maksimow, R E Kallionpää, V Rajala, J Johansson, O Kantonen, M Nyman, S Sirén, K Valli, A Revonsuo, O Solin, T Vahlberg, M Alkire, H Scheinin
INTRODUCTION: The highly selective α2 -agonist dexmedetomidine has become a popular sedative for neurointensive care patients. However, earlier studies have raised concern that dexmedetomidine might reduce cerebral blood flow without a concomitant decrease in metabolism. Here, we compared the effects of dexmedetomidine on the regional cerebral metabolic rate of glucose (CMRglu ) with three commonly used anaesthetic drugs at equi-sedative doses. METHODS: One hundred and sixty healthy male subjects were randomised to EC50 for verbal command of dexmedetomidine (1...
July 2018: British Journal of Anaesthesia
Ulrich J Spreng, Vegard Dahl, Johan Ræder
Background and objective Perioperative low-dose ketamine has been useful for postoperative analgesia. In this study we wanted to assess the analgesic effect and possible side-effects of perioperative low-dose S (+) ketamine when added to a regime of non-opioid multimodal pain prophylaxis. Methods Seventy-seven patients scheduled for haemorrhoidectomy were enrolled in this randomized, double-blind, controlled study. They received oral paracetamol 1-2 g, total intravenous anaesthesia, intravenous 8 mg dexamethasone, 30 mg ketorolac and local infiltration with bupivacaine/epinephrine...
April 1, 2010: Scandinavian Journal of Pain
Lijia Chang, Hidetoh Toki, Youge Qu, Yuko Fujita, Akiko Mizuno-Yasuhira, Jun-Ichi Yamaguchi, Shigeyuki Chaki, Kenji Hashimoto
Background: Although previous reports suggest sex-specific differences in the antidepressant actions of (R,S)-ketamine, these differences in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown. Methods: Saline or (R)-ketamine was administered 23 hours post lipopolysaccharide (LPS) administration to adult male or female mice. Subsequently, antidepressant effects were assessed using a forced swimming test (FST). Furthermore, the concentration of (R)-ketamine and its two major metabolites, (R)-norketamine and (2R,6R)-hydroxynorketamine (HNK), was measured in the plasma and brain after the administration of (R)-ketamine in the mice...
June 9, 2018: International Journal of Neuropsychopharmacology
Jun-Ichi Yamaguchi, Hidetoh Toki, Youge Qu, Chun Yang, Hiroyuki Koike, Kenji Hashimoto, Akiko Mizuno-Yasuhira, Shigeyuki Chaki
(R,S)-Ketamine has rapid and sustained antidepressant effects in depressed patients. Although the metabolism of (R,S)-ketamine to (2 R,6 R)-hydroxynorketamine (HNK), a metabolite of (R)-ketamine, has been reported to be essential for its antidepressant effects, recent evidence suggests otherwise. The present study investigated the role of the metabolism of (R)-ketamine to (2 R,6 R)-HNK in the antidepressant actions of (R)-ketamine. Antidepressant effects were evaluated using the forced swimming test in the lipopolysaccharide (LPS)-induced inflammation model of mice and the tail suspension test in naive mice...
August 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
P Molero, J A Ramos-Quiroga, R Martin-Santos, E Calvo-Sánchez, L Gutiérrez-Rojas, J J Meana
Ketamine and its enantiomer S-ketamine (esketamine) are promising candidates to produce a rapid-onset antidepressant effect in treatment-resistant depression. Ketamine causes continued blockade of the glutamate N-methyl-D-aspartate (NMDA) receptor, though this might not primarily mediate the antidepressant effect. Alternative hypotheses include selectivity for the NMDA receptor subtype containing the NMDA receptor subunit 2B (NR2B), inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase, increased expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrKB), and activation of the mammalian target of rapamycin (mTOR) signaling pathway, alongside other independent actions attributed to the ketamine metabolism to R-hydroxynorketamine (R-HNK)...
May 7, 2018: CNS Drugs
Rafaela Claudino, Carina Nones, Erika Araya, Juliana Chichorro
AIMS: To assess the analgesic effect of intranasal administration of S-ketamine in different rat models of facial pain. METHODS: Nociceptive responses induced by formalin injected into the upper lip and facial hyperalgesia induced by capsaicin or carrageenan injected into the upper lip were used to evaluate the analgesic effect of intranasal ketamine in acute facial pain models in rats (n = 173). The effect of intranasal ketamine on heat and mechanical hyperalgesia induced by constriction of the infraorbital nerve (CION) was also evaluated...
2018: Journal of Oral & Facial Pain and Headache
Basant Pradhan, Ludmil Mitrev, Ruin Moaddell, Irving W Wainer
Post-traumatic stress disorder (PTSD) is a chronic and debilitating condition that is often refractory to standard frontline antidepressant therapy. A promising new approach to PTSD therapy is administration of a single sub-anesthetic dose of (R,S)-ketamine (Ket). The treatment produces rapid and significant therapeutic response, which lasts for only 4-7 days. In one of our studies, the mean duration of response was increased to 33 days when Ket administration was combined with a mindfulness-based cognitive therapy, Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER)...
July 2018: Biochimica et Biophysica Acta
Andréa T Faccio, Francisco J Ruperez, Nagendra S Singh, Santiago Angulo, Marina F M Tavares, Michel Bernier, Coral Barbas, Irving W Wainer
BACKGROUND: Impairment in mitochondrial biogenesis and function plays a key role in depression and anxiety, both of which being associated with changes in fatty acid and phospholipid metabolism. The antidepressant effects of (R,S)-ketamine have been linked to its conversion into (2S,6S;2R,6R)-hydroxynorketamine (HNK); however, the connection between structure and stereochemistry of ketamine and HNK in the mitochondrial homeostatic response has not yet been fully elucidated at a metabolic level...
June 2018: Biochimica et Biophysica Acta
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