The antidepressant actions of ketamine and its enantiomers

Johnston, Jamie; Henter, Ioline D.; Zarate, Carlos A.

doi:10.1016/j.pharmthera.2023.108431

Cited by 33 publications

(17 citation statements)

References 138 publications

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“…The (R)-enantiomer has not been approved for clinical use; however, preclinical studies report a more favorable side-effect profile than that of (S)-ketamine ( Yang et al, 2015 ). However, (R)-ketamine failed to show a significant antidepressant effect compared with placebo according to recently published clinical studies ( Johnston et al, 2023 ; Leal et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

(S)-Ketamine but Not (R)-Ketamine Shows Acute Effects on Depression-Like Behavior and Sleep-Wake Architecture in Rats

Koncz

Papp

Pothorszki

et al. 2023

International Journal of Neuropsychopharmacology

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Background Racemic ketamine consists of two enantiomers, namely (R)ketamine and (S)ketamine, with distinguishable pharmacological properties. Both enantiomers have been reported to show rapid antidepressant effects in rodents. Currently, the (S)enantiomer has been approved for the treatment of major depression, while (R)ketamine failed to show antidepressant effect in recent clinical studies. Major depressive disorder is frequently characterized by disinhibition of rapid eye movement (REM) sleep and disruption of nonREM (NREM) sleep. Racemic ketamine and most conventional antidepressants affect these parameters. However, it remains largely unknown which enantiomer is responsible for these effects. Methods Here, we compared acute effects of the two ketamine enantiomers (15 mg/kg i.p.) on different sleepwake stages in freely moving, EEGequipped rats. We also evaluated the antidepressant-like activity of the enantiomers in a chronic restraint stress model of depression. Results (S)ketamine, but not (R)ketamine increased REM sleep latency and decreased REM sleep time at 2h and 3h, and increased EEG delta power during NREM sleep. In addition, only (S)-ketamine increased wakefulness and decreased NREM sleep in the first 2 hours. In the forced swimming test only (S)-ketamine decreased the immobility time of chronically stressed rats. Conclusion Effects of the two ketamine enantiomers on rat sleepwake architecture and behavior are markedly different when administered in the same dose. (S)ketamine remarkably affects sleepwake cycle and very likely sleeprelated neuroplasticity, which may be relevant for its antidepressant efficacy. Our results regarding (R)-ketamine’s lack of effect on vigilance and behavior are in line with the recent clinical studies.

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Section: Introductionmentioning

confidence: 99%

(S)-Ketamine but Not (R)-Ketamine Shows Acute Effects on Depression-Like Behavior and Sleep-Wake Architecture in Rats

Koncz

Papp

Pothorszki

et al. 2023

International Journal of Neuropsychopharmacology

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“…Chang et al (Chang et al, 2019) showed in their comparative study that in the mouse chronic social defeat stress (CSDS) model, the antidepressant potency of ketamine and its two enantiomers was in the order of (R)-ketamine > (R, S)-ketamine > (S)ketamine. What's more, in other animal models of depression, researchers similarly confirmed that the antidepressant effect of (R)-ketamine was observed to be more effective and prolonged than that of (R, S)-ketamine and its other metabolites, such as (S)ketamine and (2R,6R)-hydroxynorketamine (HNK) (Zhang et al, 2014;Yang et al, 2015;Fukumoto et al, 2017;Shirayama and Hashimoto, 2018;Yang et al, 2018;Johnston et al, 2023). However, a recent small-scale clinical trial indicated that the effects of (R)-ketamine on TRD patients were not superior to those of the placebo group (Leal et al, 2023).…”

Section: Introductionmentioning

confidence: 84%

“…Furthermore, ketamine, administered through intraperitoneal injection 30 min after MCAO, demonstrated significant reductions in infarct volume, edema ratio, and neurological deficit, providing neuroprotection against ischemic brain injury ( Shu et al, 2012 ). Given that both ketamine and ( S )-ketamine have shown improvements and neuroprotective effects against ischemic stroke ( Shu et al, 2012 ; Zhang et al, 2023 ), ( R )-ketamine, compared to ketamine and ( S )-ketamine, has a stronger, more lasting antidepressant effect with fewer side effects ( Johnston et al, 2023 ). Thus ( Xiong et al, 2020 ), further confirmed that ( R )-ketamine is also significant in ischemic stroke through animal experiments.…”

Section: Research On Non-depressive Conditionsmentioning

confidence: 99%

Exploring the multifaceted potential of (R)-ketamine beyond antidepressant applications

Zhang,

Pu,

Liu

et al. 2024

Front. Pharmacol.

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(R, S)- and (S)-ketamine have made significant progress in the treatment of treatment-resistant depression (TRD) and have become a research focus in recent years. However, they both have risks of psychomimetic effects, dissociative effects, and abuse liability, which limit their clinical use. Recent preclinical and clinical studies have shown that (R)-ketamine has a more efficient and lasting antidepressant effect with fewer side effects compared to (R, S)- and (S)-ketamine. However, a recent small-sample randomized controlled trial found that although (R)-ketamine has a lower incidence of adverse reactions in adult TRD treatment, its antidepressant efficacy is not superior to the placebo group, indicating its antidepressant advantage still needs further verification and clarification. Moreover, an increasing body of research suggests that (R)-ketamine might also have significant applications in the prevention and treatment of medical fields or diseases such as cognitive disorders, perioperative anesthesia, ischemic stroke, Parkinson’s disease, multiple sclerosis, osteoporosis, substance use disorders, inflammatory diseases, COVID-19, and organophosphate poisoning. This article briefly reviews the mechanism of action and research on antidepressants related to (R)-ketamine, fully revealing its application potential and development prospects, and providing some references and assistance for subsequent expanded research.

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“…Furthermore, (S)-ketamine has been shown to bind to the mu-opioid receptor (MOR) (Ki: 7 ± 3 μM) and kappa-opioid receptor (KOR) (Ki: 14 ± 7 μM) with higher affinity than (R)-ketamine (Ki: 19 ± 5 μM, 40 ± 10 μM, respectively), while (R)-ketamine showed greater affinity for sigma-1 and sigma-2 receptors (Ki = 27 ± 3 µM, Ki = 0.5 ± 0.1 mM, respectively) than (S)-ketamine (131 ± 15 µM, 2.8 ± 0.7 mM, respectively) [ 3 ]. (S)-ketamine has recently been approved for treatment-resistant depression by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), while (R)-ketamine had no significant antidepressant effect compared to placebo in recent clinical studies, suggesting caution when interpreting its therapeutic potential [ 4 ]. In animal models, the racemic mixture and both enantiomers have been shown to cause rapid-onset antidepressant effects, with the addition of (R)-ketamine having a more favorable side-effect profile than (S)-ketamine since it does not cause psychotomimetic effects [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Unique Effects of (R)-Ketamine Compared to (S)-Ketamine on EEG Theta Power in Rats

Pothorszki,

Koncz,

Török

et al. 2024

Pharmaceuticals

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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.

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The antidepressant actions of ketamine and its enantiomers

Cited by 33 publications

References 138 publications

(S)-Ketamine but Not (R)-Ketamine Shows Acute Effects on Depression-Like Behavior and Sleep-Wake Architecture in Rats

(S)-Ketamine but Not (R)-Ketamine Shows Acute Effects on Depression-Like Behavior and Sleep-Wake Architecture in Rats

Exploring the multifaceted potential of (R)-ketamine beyond antidepressant applications

Unique Effects of (R)-Ketamine Compared to (S)-Ketamine on EEG Theta Power in Rats

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