Translational Psychiatry
September 1, 2015
Chun Yang, Yukihiko Shirayama, J-C Zhang et al.
600 citations
R-ketamine, a stereoisomer of the anesthetic ketamine, produces a more potent and longer-lasting antidepressant effect than S-ketamine (esketamine) in mouse models of depression, without causing psychotomimetic side effects or abuse liability. In the social defeat stress and learned helplessness models, R-ketamine more effectively restored decreased dendritic spine density, brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in the prefrontal cortex, CA3, and dentate gyrus of the hippocampus. Neither isomer affected these measures in the nucleus accumbens. S-ketamine, but not R-ketamine, caused hyperlocomotion, prepulse inhibition deficits, rewarding effects, and loss of parvalbumin-positive cells in the medial prefrontal cortex and dentate gyrus. R-ketamine appears to be a safe, long-lasting antidepressant.
Psychiatry and Clinical Neurosciences
June 19, 2019
Kenji Hashimoto
325 citations
Ketamine, particularly its enantiomers (R)-ketamine and (S)-ketamine, shows rapid and sustained antidepressant effects in patients with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD). While (S)-ketamine (esketamine) was FDA-approved as a nasal spray in 2019 due to its higher affinity for the NMDA receptor, preclinical data suggest (R)-ketamine may have greater potency, longer-lasting effects, and fewer side effects. The author reviews the historical development of ketamine enantiomers and their metabolites, compares other rapid-acting antidepressant candidates, and discusses the molecular and cellular mechanisms underlying ketamine's effects.
Molecular Psychiatry
May 7, 2021
Wei Yan, Lijia Chang, Kenji Hashimoto
242 citations
The antidepressant effects of the drug (R,S)-ketamine, a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), are not primarily due to blocking the N-methyl-D-aspartate receptor (NMDAR), despite initial assumptions. Preclinical studies in rodents show arketamine has more potent and longer-lasting antidepressant-like effects than esketamine, even though arketamine binds less strongly to NMDAR. Clinical trials with other NMDAR-blocking compounds failed to produce robust antidepressant effects in humans, indicating rodent findings do not always translate. The exact molecular mechanisms remain unclear. This review covers recent findings on these mechanisms, the possible roles of the brain-gut-microbiota and brain-spleen axes, and arketamine's potential for treating cognitive impairment, Parkinson's disease, osteoporosis, inflammatory bowel diseases, and stroke.
Biochemical pharmacology
July 1, 2020
Kenji Hashimoto
232 citations
Ketamine, developed as an anesthetic in the 1960s, is also abused recreationally for its dissociative effects. It shows strong antidepressant effects in treatment-resistant depression. The racemic mixture contains (R)-ketamine and (S)-ketamine; (S)-ketamine nasal spray was approved by the US FDA in 2019 and in Europe later that year. Although (R)-ketamine has lower affinity for the NMDAR, it produces more potent and longer-lasting antidepressant-like effects in animal models with fewer side effects than (R,S)-ketamine or (S)-ketamine. BDNF and TrkB receptor involvement is suggested, and RNA-sequencing points to TGF-β1 in (R)-ketamine's effects. A pilot study showed rapid, sustained antidepressant effects of (R)-ketamine in treatment-resistant patients. This review covers mechanisms of ketamine enantiomers and metabolites and discusses the brain-gut-microbiota and brain-spleen axes in stress-related disorders.
Translational Psychiatry
December 15, 2017
Chun Yang, Youge Qu, Yuko Fujita et al.
231 citations
The gut microbiota-brain axis is implicated in depression, and (R)-ketamine shows more potent and longer-lasting antidepressant effects than (S)-ketamine. In a chronic social defeat stress mouse model of depression, fecal 16S ribosomal RNA gene sequencing revealed that both enantiomers attenuated increases in Deltaproteobacteria levels. (R)-ketamine, but not (S)-ketamine, also reversed reductions in Mollicutes levels. At the genus level, both enantiomers attenuated decreases in Butyricimonas, with (R)-ketamine being more potent. These findings suggest that the antidepressant actions of ketamine enantiomers may be partly mediated by restoring gut microbiota, with (R)-ketamine's specific effects on Mollicutes and Butyricimonas potentially explaining its superior efficacy.
Expert Review of Neurotherapeutics
December 4, 2018
Kai Zhang, Kenji Hashimoto
133 citations
Ketamine and its enantiomers show rapid-acting and sustained antidepressant effects in treatment-resistant patients with major depressive disorder and bipolar disorder. Clinical studies demonstrate that (R,S)-ketamine has rapid and sustained antidepressant activity in these populations. Preclinical data suggest that (R)-ketamine may exert longer-lasting antidepressant effects than (S)-ketamine in animal models, with potentially fewer side effects. (S)-norketamine also exhibits rapid and sustained antidepressant effects similar to (S)-ketamine but without causing behavioral and biochemical abnormalities, making it a potentially safer alternative.
Scientific Reports
November 10, 2017
Youge Qu, Chun Yang, Qian Ren et al.
126 citations
In a mouse model of depression induced by chronic social defeat stress, (R)-ketamine, but not the related NMDAR antagonist lanicemine, reversed depression-like behavior and partially restored the composition of gut bacteria, including Bacteroidales, Clostridiales, Ruminococcaceae, and Clostridium. The findings suggest that the antidepressant effects of (R)-ketamine may be partly mediated by its ability to normalize gut microbiota alterations.
European Archives of Psychiatry and Clinical Neuroscience
April 18, 2016
Kenji Hashimoto, Takeharu Kakiuchi, Hiroyuki Ohba et al.
125 citations
Esketamine, but not R-ketamine, reduces dopamine D2/3 receptor binding availability in the monkey striatum, indicating that esketamine triggers dopamine release in this brain region. This dopamine release may underlie the psychotomimetic side effects of esketamine. R-ketamine, in contrast, does not affect striatal dopamine D2/3 binding, consistent with its proposed safer profile as a rapid antidepressant. The findings suggest a neurochemical difference between the two ketamine enantiomers that could explain their distinct side-effect profiles.
The International Journal of Neuropsychopharmacology
October 7, 2016
Chao Dong, Ji-Chun Zhang, Wei Yao et al.
116 citations
MGS0039, a metabotropic glutamate 2/3 receptor antagonist, produces rapid and sustained antidepressant effects in mice subjected to social defeat stress, similar to the well-known antidepressant ketamine. A single dose of either drug reversed depression-like behaviors—reducing immobility in tail suspension and forced swimming tests within 1–2 days and restoring sucrose preference over 3–7 days. Both compounds also reversed reductions in brain-derived neurotrophic factor, TrkB signaling, glutamate receptor subunits, and spine density in the prefrontal cortex, dentate gyrus, and CA3 region of the hippocampus, but not in the nucleus accumbens. These findings suggest that MGS0039 may offer a novel antidepressant mechanism through lasting synaptic changes in specific brain regions.
PLoS ONE
February 4, 2013
Xiancang Ma, Yonghui Dang, Min Jia et al.
115 citations
A single dose of the NMDA receptor antagonist ketamine, but not the GSK-3 inhibitor SB216763, produced long-lasting antidepressant effects in a mouse model of chronic mild stress (CMS). In CMS mice, ketamine reversed the drop in sucrose intake and reduced immobility in the tail suspension and forced swimming tests, effects that persisted for 8 days after a single dose. The GSK-3 inhibitor did not produce these effects. Ketamine also reduced immobility in non-stressed control mice. These results suggest that ketamine's rapid and sustained antidepressant action may not depend on GSK-3 inhibition.
The International Journal of Neuropsychopharmacology
November 14, 2017
Yukihiko Shirayama, Kenji Hashimoto
113 citations
A single dose of (R)-ketamine (20 mg/kg) produced an antidepressant effect in a rat learned helplessness model of depression. In contrast, neither (R)-norketamine (20 mg/kg) nor (2R,6R)-hydroxynorketamine (20 and 40 mg/kg) showed such effects. These results indicate that the metabolism of ketamine to hydroxynorketamine is not essential for its antidepressant actions, contradicting previous claims.
Current Molecular Medicine
May 4, 2015
Yuta Ohgi, Takashi Futamura, Kenji Hashimoto
109 citations
Glutamate, a major excitatory neurotransmitter, is crucial for synaptic plasticity including long-term potentiation and new synapse formation. Evidence links glutamate signaling to psychiatric disorders like schizophrenia, major depressive disorder, and bipolar disorder. Postmortem brain studies show altered spine density in these conditions, suggesting remodeled neuronal circuits contribute to their pathobiology. Drugs targeting the glutamate system, particularly the NMDA receptor antagonist ketamine, show rapid and robust antidepressant effects in treatment-resistant patients, unlike conventional antidepressants. Animal studies indicate ketamine induces rapid synaptogenesis, implicating NMDA receptor signaling in depression treatment. This review summarizes glutamate's role in dendritic spine formation and remodeling, discusses abnormalities from postmortem and animal studies, and reviews potential benefits of NMDA receptor-acting drugs.
Progress in Neuro-Psychopharmacology and Biological Psychiatry
July 30, 2006
Eiji Shimizu, Hiroyuki Watanabe, Takashi Kojima et al.
103 citations
A 27-year-old man experienced substance intoxication after a single ingestion of what he believed was pure methylone powder purchased online. Chemical analysis revealed the powder contained about 60% methylone (120 mg) and 38% 5-MeO-MIPT (76 mg), a mixture not disclosed to the user. The case highlights that clinicians should be alert to intoxication from these agents and that substance-related mental disorders may be complicated by the combined use of multiple psychoactive drugs, especially when the actual composition of purchased drugs is unknown.
Psychopharmacology
August 3, 2016
Bangkun Yang, Ji-Chun Zhang, Mei Han et al.
93 citations
R-ketamine and rapastinel, both NMDA receptor antagonists, produced rapid antidepressant effects in mice susceptible to social defeat stress. A single injection of either compound (10 mg/kg) reduced immobility in the tail suspension and forced swimming tests and increased sucrose preference for up to seven days. R-ketamine, but not rapastinel, restored reduced BDNF-TrkB signaling, PSD-95, and GluA1 levels in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus. Neither compound altered the elevated levels of these proteins in the nucleus accumbens. A lower intravenous dose of R-ketamine (3 mg/kg) maintained antidepressant effects after seven days, whereas rapastinel did not, indicating R-ketamine produces a longer-lasting antidepressant effect.
The International Journal of Neuropsychopharmacology
July 16, 2019
Yukio Ago, Wataru Tanabe, Momoko Higuchi et al.
91 citations
Ketamine enantiomers and their metabolites differentially affect monoamine neurotransmitter release in the mouse prefrontal cortex. (R)-ketamine more strongly increases serotonin release than (S)-ketamine, while (S)-ketamine produces a larger increase in dopamine release. Both enantiomers increase noradrenaline release to a similar extent. The metabolite (2R,6R)-HNK slightly increases serotonin and noradrenaline but not dopamine release, whereas (S)-NK increases dopamine and noradrenaline but not serotonin. An AMPA receptor antagonist blocks (S)-ketamine-induced serotonin release and dopamine release by both enantiomers, but not (R)-ketamine-induced serotonin release, indicating (R)-ketamine acts through an AMPA receptor-independent mechanism. These findings reveal neurochemical differences underlying the pharmacological profiles of ketamine enantiomers and their metabolites.
Neuropharmacology
August 14, 2022
Ji-Chun Zhang, Wei Yao, Kenji Hashimoto
88 citations
The NMDAR antagonist (R,S)-ketamine produces rapid and sustained antidepressant effects in treatment-resistant major depressive disorder and other psychiatric conditions. (R,S)-ketamine is a racemic mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with esketamine having greater NMDAR affinity. An esketamine nasal spray was approved in 2019 for treatment-resistant depression. Preclinical studies indicate arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite lower NMDAR binding affinity, and causes fewer side effects such as psychotomimetic and dissociative effects and abuse liability. An open-label study showed rapid and sustained antidepressant effects of arketamine in treatment-resistant MDD patients, and a phase 2 trial is underway. This review covers the history, molecular mechanisms, and future directions of arketamine.
Translational Psychiatry
February 23, 2016
H-L Sun, Z-Q Zhou, G.-F. Zhang et al.
87 citations
Ketamine produces rapid (within 0.5 hour) and sustained (up to 72 hours) antidepressant effects in rats exposed to chronic unpredictable mild stress (CUMS), a model of depression. The antidepressant action is blocked by ANA-12, a TrkB antagonist, indicating involvement of TrkB signaling. Ketamine restores reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus and increases the ratio of phosphorylated TrkB to total TrkB. While ketamine does not affect p11 expression shortly after administration, it normalizes reduced p11 and BDNF levels 72 hours later. Knockdown of hippocampal p11 prevents ketamine's behavioral effects, suggesting p11 is essential for the sustained antidepressant response.
Scientific Reports
June 5, 2017
Ze-Min Xie, Xingming Wang, Ning Xu et al.
69 citations
Rats with neuropathic pain that also developed depression-like behaviors had higher levels of pro-inflammatory cytokines (interleukin-1β and interleukin-6) and an imbalance between pro- and anti-inflammatory cytokines, along with lower levels of brain-derived neurotrophic factor in the prefrontal cortex, compared to rats without depression-like behaviors and sham-operated controls. A single dose of ketamine reversed both the depression-like behaviors and the elevated serum levels of IL-1β and IL-6. These findings suggest that changes in inflammatory cytokines and BDNF may underlie depression caused by neuropathic pain, and that serum cytokines could serve as biomarkers for ketamine's antidepressant effects.
Expert Opinion on Therapeutic Targets
September 20, 2016
Kenji Hashimoto
68 citations
The NMDA receptor antagonist ketamine produces rapid and lasting antidepressant effects in people with treatment-resistant depression, but how it does so is not fully understood. A key metabolite of (R)-ketamine, called (2R,6R)-hydroxynorketamine (HNK), shows antidepressant effects in rodent models of depression. This suggests that the conversion of (R)-ketamine into (2R,6R)-HNK is crucial for its antidepressant action. The article discusses these findings and their broader significance.
The International Journal of Neuropsychopharmacology
August 28, 2019
Jiancheng Zhang, Youge Qu, Lijia Chang et al.
56 citations
A single injection of (R)-ketamine (10 mg/kg) rapidly reversed the loss of dendritic spines in the medial prefrontal cortex and hippocampus of mice that had become susceptible after chronic social defeat stress. Spine density was measured three hours after treatment and was significantly increased in the prelimbic area of the medial prefrontal cortex, the Cornu Ammonis3 region, and the dentate gyrus of the hippocampus. The findings suggest that (R)-ketamine's rapid restoration of spine density in these brain regions may underlie its fast-acting antidepressant effects.
European Archives of Psychiatry and Clinical Neuroscience
February 27, 2024
Kenji Hashimoto
51 citations
The relationship between mystical experiences and antidepressant effects of ketamine and classic psychedelics like psilocybin is debated. Ketamine can cause dissociative symptoms such as out-of-body experiences, while psychedelics often produce hallucinogenic experiences like a sense of unity. Clinical studies indicate that dissociative symptoms from ketamine or esketamine are not directly linked to their antidepressant properties. The antidepressant potential of arketamine, which lacks dissociative side effects, remains unproven in large-scale trials. Activation of the serotonin 5-HT2A receptor is crucial for psychedelics' hallucinogenic effects, but its role in antidepressant action is unclear. This article examines whether mystical experiences enhance antidepressant outcomes.
Pharmacology Biochemistry and Behavior
December 5, 2022
Youge Qu, Lijia Chang, Li Ma et al.
42 citations
In mice treated with lipopolysaccharide (LPS) to induce depression-like behavior, both lisuride (a non-hallucinogenic psychedelic analog) and (R)-ketamine (a novel antidepressant) reduced immobility in the forced swimming test and prevented loss of dendritic spine density in the prelimbic region of the medial prefrontal cortex, CA3, and dentate gyrus of the hippocampus. DOI, a hallucinogenic psychedelic with potent 5-HT2AR agonism, did not improve these measures. The findings suggest that the antidepressant-like effect of lisuride is not linked to 5-HT2AR-related psychedelic effects, and that 5-HT2AR may not play a major role in rapid antidepressant actions of psychedelics.
European Archives of Psychiatry and Clinical Neuroscience
February 14, 2023
Kenji Hashimoto
40 citations
Cognitive impairment is common in psychiatric disorders like schizophrenia, major depressive disorder, and bipolar disorder, and current medications do not improve it. The drug (R,S)-ketamine, a rapid antidepressant, may improve cognitive impairment in patients with these conditions, even though it causes cognitive impairment in healthy people. Its component arketamine shows more potent antidepressant-like effects than esketamine in rodents and may improve cognitive deficits induced by phencyclidine or maternal immune activation in mice. The article proposes arketamine as a potential treatment for cognitive impairment in psychiatric disorders and discusses the possible role of the gut-microbiome-brain axis.
Pharmacology, Biochemistry and Behavior
April 22, 2020
J. Witkin, J. Kranzler, K. Kaniecki et al.
33 citations
The (R)-ketamine enantiomer may offer a safer treatment for substance abuse disorder by reducing withdrawal symptoms and drug-seeking behavior without causing negative mood or anhedonia. In experiments with morphine-dependent rats, (R)-ketamine alleviated withdrawal signs and blocked morphine-induced place preference in mice without producing place preference itself. Unlike S-ketamine, (R)-ketamine did not induce anhedonia in rats. These findings suggest (R)-ketamine could dampen withdrawal and drug liking without the dissociative or mood-related side effects that limit current therapies, supporting further preclinical and clinical investigation.
Journal of Anesthesia and Translational Medicine
July 11, 2024
Kenji Hashimoto, Mingming Zhao, Tingting Zhu et al.
32 citations
Ketamine and its enantiomers have a long history in anesthesia and are now gaining attention for rapid-acting antidepressant effects in severe depression. Esketamine, the (S)-enantiomer, received approval in the U.S. and Europe in 2019 as a nasal spray for depression, but concerns about long-term efficacy, addiction, and suicide risk persist. In rodent models, arketamine, the (R)-enantiomer, shows superior and longer-lasting antidepressant effects with fewer side effects than esketamine, though human research on arketamine is limited. The article reviews the historical use of ketamine and its enantiomers in anesthesia and psychiatry and explores future directions.