Hashimoto R Ketamine Shows Greater Potency And Longer Lasting Pdf
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- R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine
- Intravenous arketamine for treatment-resistant depression: open-label pilot study
Arketamine appears to be more effective as a rapid-acting antidepressant than esketamine in preclinical research. In rodent studies , esketamine produced hyperlocomotion , prepulse inhibition deficits, and rewarding effects , while arketamine did not, in accordance with its lower potency as an NMDA receptor antagonist and dopamine reuptake inhibitor. A study conducted in mice found that ketamine's antidepressant activity is not caused by ketamine inhibiting NMDAR, but rather by sustained activation of a different glutamate receptor, the AMPA receptor , by a metabolite, 2R,6R - hydroxynorketamine ; as of it was unknown if this was happening in humans.
R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine
Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites is not fully understood. The extracellular monoamine levels in the prefrontal cortex were measured by in vivo microdialysis.
R -Ketamine and S -ketamine acutely increased serotonin release in a dose-dependent manner, and the effect of R -ketamine was greater than that of S -ketamine. In contrast, S -ketamine caused a robust increase in dopamine release compared with R -ketamine. Both ketamine enantiomers increased noradrenaline release, but these effects did not differ.
S -NK increased dopamine and noradrenaline but not serotonin release. Differential effects between R -ketamine and S -ketamine were also observed in a lipopolysaccharide-induced model of depression. Local application of R -ketamine into the prefrontal cortex caused a greater increase in prefrontal serotonin release than that of S -ketamine. R -Ketamine strongly activates the prefrontal serotonergic system through an AMPA receptor-independent mechanism.
These findings provide a neurochemical basis for the underlying pharmacological differences between ketamine enantiomers and their metabolites. Several molecular mechanisms underlying the antidepressant-like effects of R,S -ketamine have been proposed, which focus on the glutamatergic system. However, R -ketamine has been reported to possess greater potency and longer-lasting antidepressant effects than S -ketamine in several animal models of depression despite R -ketamine having lower affinity for the N -methyl-D-aspartate receptor than S -ketamine.
The present study demonstrates the differences between ketamine enantiomers in inducing prefrontal serotonin 5-HT and dopamine but not noradrenaline release. S -Ketamine caused a robust increase in dopamine release compared with R -ketamine via an AMPA receptor-dependent mechanism. A ketamine metabolite 2R,6R -hydroxynorketamine induced a slight increase in 5-HT and noradrenaline release and S -norketamine increased dopamine and noradrenaline release.
These findings provide a neurochemical basis for understanding the pharmacological differences and mechanisms of R -ketamine, S -ketamine, and their metabolites. Accumulating evidence has indicated that the N -methyl-D-aspartate NMDA receptor antagonist ketamine racemic ketamine; R,S -ketamine has rapid and potent antidepressant effects in major depressive disorder including treatment-resistant depression Berman et al.
R,S -Ketamine also produces antisuicidal effects in treatment-resistant depression Price et al. However, other NMDA antagonists, including memantine and lanicemine, which bind to the receptor at the same site as ketamine, do not exhibit consistent evidence for clinical antidepressant efficacy Zarate et al. Moreover, several animal studies have demonstrated that R -ketamine has greater potency and longer lasting antidepressant effects than S -ketamine Zhang et al.
Therefore, mechanisms other than the NMDA receptor also play an important role in mediating the antidepressant effects of ketamine. In addition to the glutamatergic system, recent preclinical studies indicate the potential involvement of the monoaminergic system in the antidepressant actions of ketamine du Jardin et al.
Furthermore, the monoaminergic system has been implicated in the antidepressant effects of numerous currently used drugs. Regarding the antidepressant-like effects of ketamine, a serotonin 5-HT synthesis inhibitor, p -chlorophenylalanine PCPA , attenuated the acute Fukumoto et al. Additionally, a recent study shows that activation of Drd1 the dopamine [DA]-D 1 receptor -expressing pyramidal cells in the medial PFC produces rapid and long-lasting antidepressant responses, and the disruption of Drd1 activity blocked the rapid antidepressant effects of R,S -ketamine Hare et al.
These findings suggest that the monoaminergic system is involved at least partly in the acute and sustained antidepressant-like effects of ketamine. Previous microdialysis studies have shown that acute administration of R,S -ketamine in the dose range showing antidepressant activity increased the extracellular levels of 5-HT and DA in the PFC Lorrain et al.
Witkin et al. However, the neurochemical effects of R -ketamine are not fully understood, and there is no comparative study to our knowledge of ketamine enantiomers. In this study, we aimed to clarify the effects of R -ketamine and S -ketamine on the in vivo release of monoamines in the PFC of both normal mice and a lipopolysaccharide LPS -induced mouse model of depression Zhang et al.
Since the AMPA receptor is suggested to be involved in the antidepressant-like effects of ketamine Maeng et al. All experimental procedures were conducted in accordance with the guidelines of the Guide for the Care and Use of Laboratory Animals National Research Council, Every effort was made to minimize animal suffering and to reduce the number of animals used.
R -Ketamine hydrochloride and S -ketamine hydrochloride were prepared by recrystallization of R,S -ketamine Ketalar, ketamine hydrochloride, Daiichi Sankyo Pharmaceutical Ltd. Louis, MO , respectively. All drugs were dissolved in saline 0. All drugs except NBQX were administered i. NBQX was s. The doses of R -ketamine, S -ketamine, and their metabolites used here were selected according to previous studies Zhang et al.
To induce depression-like models, mice were i. Microdialysis experiments were performed as previously reported Ago et al. Briefly, each mouse was anesthetized with a mixture of medetomidine 0. The cannula was cemented in place with dental acrylic, and the animal was kept warm and allowed to recover from anesthesia.
Postoperative analgesia was performed with a single injection of buprenorphine 0. The active probe membranes were 3 mm long. A stabilization period of 3 hours was established before the onset of the experiment. After the experiments, Evans Blue dye was microinjected through the cannula to histologically verify the position of the probe, and only data from animals with correct probe placement were used in the analysis.
Data were analyzed using 2- or 3-way ANOVA for treatment or dosage as the inter-subject factor and repeated measures with time as the intra-subject factor, followed by the Tukey-Kramer post hoc test when the interaction was significant.
Statistical analyses were performed using the Statview 5. Mice were i. The effects of local application of R -ketamine and S -ketamine on extracellular monoamine levels in the prefrontal cortex PFC of mice.
Both R -ketamine and S -ketamine caused an increase in 5-HT release, and the effect of R -ketamine was significantly greater than that of S -ketamine. In contrast, S -ketamine caused a robust increase in DA release compared with R -ketamine.
Both R -ketamine and S -ketamine increased NA release, but these have similar effects. Although it is unclear exactly how these differences would contribute to the pharmacological differences between R -ketamine and S -ketamine, several reports show differences in the effects of ketamine enantiomers on antidepressant-like activity and psychosis- or addiction-related behaviors.
R -Ketamine exhibits more potent and longer acting antidepressant-like effects than S -ketamine Zhang et al. Pham et al. These findings suggest that enhanced prefrontal serotonergic activity by R -ketamine could contribute to its potent and sustained antidepressant-like effect. Thus, the serotonergic system might not be involved mainly in the antidepressant-like effects of ketamine metabolites, except for 2R,6R -HNK.
These findings raise the possibility that increases in NA and DA release in the PFC might contribute at least partly to the antidepressant-like effects of ketamine and its metabolites. The prefrontal DA system has been implicated in playing a pivotal role in depression and antidepressant actions Ago et al. Therefore, the enhanced activity of the prefrontal dopaminergic system by S -ketamine would contribute to its antidepressant-like activity, whereas DA-D 1 receptors might not play a major role in the antidepressant actions of R -ketamine Chang et al.
Conversely, S -ketamine might have a higher potential for inducing psychotomimetic effects such as hyperactivity, pre-pulse inhibition deficits, and rewarding effects compared with R -ketamine Yang et al.
Similar to this observation, in this study, S -ketamine caused a robust increase in DA release in the PFC, while R -ketamine had a small effect. Thus, the exact role of DA release induced by ketamine enantiomers and their metabolites remains unclear.
Further studies investigating the effects of ketamine and its metabolites in other brain regions such as the striatum, nucleus accumbens, and hippocampus are required for full elucidation. Previous studies have suggested the involvement of AMPA receptor activation in the antidepressant-like action of R -ketamine, S -ketamine, and R,S -ketamine Maeng et al.
These observations suggest that AMPA receptors might be involved in the behavioral and neurochemical effects of ketamine. A positron emission tomography study showed that subanesthetic doses of ketamine transiently decrease 5-HT transporter SERT binding in conscious monkeys, and ketamine infusion transiently increased 5-HT but not DA levels in the extracellular fluid of the PFC of conscious monkeys Yamamoto et al.
These findings suggest that subanesthetic ketamine might enhance serotonergic transmission by the inhibition of SERT activity.
We also observed that local application of R -ketamine and S -ketamine into the PFC induced increases in prefrontal 5-HT release, and the effect of R -ketamine was significantly greater than that of S -ketamine. Therefore, the mechanism of R -ketamine-induced prefrontal 5-HT release remains unknown.
Although the reasons for these discrepancies are currently unknown, several factors such as different animal models used normal vs stress-induced or genetic models of depression , behavioral tests, and different doses and isomers of ketamine could account for them. Thus, the role of 5-HT in the acute and sustained antidepressant effects of R,S -ketamine and its enantiomers might differ depending on the experimental conditions.
In this regard, it might be important to see whether the differential effects of R -ketamine and S -ketamine on prefrontal monoaminergic transmission in normal animals are also observed in depression-like models. LPS is known to cause depression-like behaviors in the forced swim and tail-suspension tests Zhang et al.
Both R -ketamine and S -ketamine show antidepressant-like effects in an LPS-induced depression model, but the potency of R -ketamine is higher than that of S -ketamine Yang et al. In this study, we found that R -ketamine and S -ketamine enhanced serotonergic and dopaminergic neurotransmission, respectively, in LPS-treated mice as seen in normal mice.
This finding implies that R -ketamine would produce pronounced 5-HT release, leading to antidepressant effects under some conditions of depression. In conclusion, our study showed that R -ketamine and S -ketamine differentially affect serotonergic and dopaminergic neurotransmission in the PFC in particular. These findings provide a neurochemical basis for understanding the pharmacological differences and the mechanisms of action of R -ketamine, S -ketamine, and their metabolites.
The other authors declare no conflicts of interest. Ago Y , Nakamura S , Baba A , Matsuda T Sulpiride in combination with fluvoxamine increases in vivo dopamine release selectively in rat prefrontal cortex. Neuropsychopharmacology 30 : 43 — Google Scholar. Neuropsychopharmacology 38 : — Eur J Pharmacol : — Int J Neuropsychopharmacol 17 : — Biol Psychiatry 47 : — Am J Psychiatry : — Chaki S Beyond ketamine: new approaches to the development of safer antidepressants.
Curr Neuropharmacol 15 : — Eur Arch Psychiatry Clin Neurosci. Epub ahead of print. Neuropharmacology : 1 — JAMA Psychiatry 75 : — Psychopharmacology : — Prog Neuropsychopharmacol Biol Psychiatry 71 : 27 — Mol Psychiatry.
Intravenous arketamine for treatment-resistant depression: open-label pilot study
Background: Postoperative depression is a common complication after surgery that profoundly affects recovery and prognosis. New research indicates that R , S -ketamine is a potent antidepressant that exerts a rapid and sustained antidepressive effect. However, there is no consensus on whether intraoperative low-dose R , S -ketamine prevents postoperative depression. Objectives: This study aimed to investigate the safety, feasibility, and short-term complications of intraoperative low-dose R , S -ketamine in preventing postoperative depressive symptoms. Sensitivity and metaregression analyses were performed to identify potential confounders. The meta-analysis was performed using Review Manager 5. Results: A total of 13 studies seven in Chinese and six in English representing 1, cases of patients who were treated with R , S -ketamine and cases of patients who received other treatments were included in the meta-analysis.
Open-label pilot trial, seven subjects with TRD received a single intravenous infusion of arketamine 0. Arketamine might produce fast-onset and sustained antidepressant effects in humans with favorable safety profile, like previously reported with animals; further controlled-trials are needed. In the last two decades the approach to the pharmacological treatment of major depressive disorder MDD has markedly changed with the demonstration of the antidepressant properties of ketamine. Despite this evidence, a wider use of ketamine and esketamine is limited by concerns surrounding the associated potential for abuse, psychotomimetic and cardiovascular side-effects, and the relatively short-lived antidepressant effect of these treatments. Arketamine was tested in humans in the past as an anesthetic in patients undergoing surgery, with no serious adverse effects, but, as it proved to have weaker hypnotic and analgesic actions than the racemate and esketamine [ 22 , 23 ], it did not become commercially available. Also regarding safety, Vollenweider et al.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Electronic address: [email protected]
Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites is not fully understood. The extracellular monoamine levels in the prefrontal cortex were measured by in vivo microdialysis. R -Ketamine and S -ketamine acutely increased serotonin release in a dose-dependent manner, and the effect of R -ketamine was greater than that of S -ketamine. In contrast, S -ketamine caused a robust increase in dopamine release compared with R -ketamine. Both ketamine enantiomers increased noradrenaline release, but these effects did not differ.
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 model. Behavioral tests for antidepressant actions were performed after a single administration of R -ketamine or S -ketamine.
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