R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects
Chun Yang, Yukihiko Shirayama, J-C Zhang, Qian Ren, Wei Yao, Min Ma, Chao Dong, Kenji Hashimoto
Translational Psychiatry September 1, 2015 DOI: 10.1038/tp.2015.136 (opens in new tab)
The journal has published a correction to this paper. Read the correction (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | R-ketamine S-ketamine |
| Topics | Ketamine Esketamine |
| Keywords | Psychotomimetic Antidepressant Nucleus accumbens Pharmacology Prefrontal cortex Brain-derived neurotrophic factor Hippocampus Nmda receptor Neurotrophic factors Central nervous system Cognition |
| Citations | 600 |
| Post-publication review | 3 comments on PubPeer (opens in new tab) · last active February 2023 |
| Key findings | R-ketamine shows greater antidepressant potency and longer-lasting effects than S-ketamine, without psychotomimetic side effects, mediated by increased BDNF-TrkB signaling and synaptogenesis in the prefrontal cortex and hippocampus. |
Abstract
Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF-TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF-TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase Mice | 2007 | Experimental study |
Citations in the library
Cited by 267
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects ACS Pharmacology & Translational Science December 10, 2020
and 262 more in the library
Cites 19
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- Recent advances in the phencyclidine model of schizophrenia American Journal of Psychiatry October 1, 1991
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression Archives of General Psychiatry August 1, 2010
- Ketamine use: a review Addiction July 21, 2011
and 14 more in the library