Mechanistic Target of Rapamycin–Independent Antidepressant Effects of ( R )-Ketamine in a Social Defeat Stress Model

Yang, Chun; Ren, Qian; Qu, Youge; Zhang, Ji-Chun; Ma, Min; Dong, Chao; Hashimoto, Kenji

doi:10.1016/j.biopsych.2017.05.016

Cited by 197 publications

(128 citation statements)

References 62 publications

(93 reference statements)

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“…The finding that (2R,6R)-HNK is more potent in inducing antidepressant-relevant behavioural actions compared to (2S,6S)-HNK (Chou et al, 2018;Zanos et al, 2016) is in line with the greater antidepressant-relevant potency of (R)-ketamine compared with the (S)-ketamine enantiomer in rodents (Fukumoto et al, 2017;Yang, Qu, Fujita, et al, 2017;Yang et al, 2018;Yang et al, 2015;Zanos et al, 2016). Although there is evidence that (R)-ketamine exerts antidepressant-relevant actions independent of its conversion to (2R,6R)-HNK in some animal tests (Shirayama & Hashimoto, 2017;Shirayama & Hashimoto, 2018;Yamaguchi et al, 2018;Zhang, Toki, et al, 2018), whether metabolism of (R)-ketamine contributes to the actions of the drug is unclear.…”

Section: Introductionmentioning

confidence: 58%

(R)‐Ketamine exerts antidepressant actions partly via conversion to (2R,6R)‐hydroxynorketamine, while causing adverse effects at sub‐anaesthetic doses

Zanos

Highland

Liu

et al. 2019

British J Pharmacology

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Background and Purpose (R)‐Ketamine (arketamine) may have utility as a rapidly acting antidepressant. While (R)‐ketamine has lower potency than (R,S)‐ketamine to inhibit NMDA receptors in vitro, the extent to which (R)‐ketamine shares the NMDA receptor‐mediated adverse effects of (R,S)‐ketamine in vivo has not been fully characterised. Furthermore, (R)‐ketamine is metabolised to (2R,6R)‐hydroxynorketamine (HNK), which may contribute to its antidepressant‐relevant actions. Experimental Approach Using mice, we compared (R)‐ketamine with a deuterated form of the drug (6,6‐dideutero‐(R)‐ketamine, (R)‐d2‐ketamine), which hinders its metabolism to (2R,6R)‐HNK, in behavioural tests predicting antidepressant responses. We also examined the actions of intracerebroventricularly infused (2R,6R)‐HNK. Further, we quantified putative NMDA receptor inhibition‐mediated adverse effects of (R)‐ketamine. Key Results (R)‐d2‐Ketamine was identical to (R)‐ketamine in binding to and functionally inhibiting NMDA receptors but hindered (R)‐ketamine's metabolism to (2R,6R)‐HNK. (R)‐Ketamine exerted greater potency than (R)‐d2‐ketamine in several antidepressant‐sensitive behavioural measures, consistent with a role of (2R,6R)‐HNK in the actions of (R)‐ketamine. There were dose‐dependent sustained antidepressant‐relevant actions of (2R,6R)‐HNK following intracerebroventricular administration. (R)‐Ketamine exerted NMDA receptor inhibition‐mediated behaviours similar to (R,S)‐ketamine, including locomotor stimulation, conditioned‐place preference, prepulse inhibition deficits, and motor incoordination, with approximately half the potency of the racemic drug. Conclusions and Implications Metabolism of (R)‐ketamine to (2R,6R)‐HNK increases the potency of (R)‐ketamine to exert antidepressant‐relevant actions in mice. Adverse effects of (R)‐ketamine require higher doses than those necessary for antidepressant‐sensitive behavioural changes in mice. However, our data revealing that (R)‐ketamine's adverse effects are elicited at sub‐anaesthetic doses indicate a potential risk for sensory dissociation and abuse liability.

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Section: Introductionmentioning

confidence: 58%

(R)‐Ketamine exerts antidepressant actions partly via conversion to (2R,6R)‐hydroxynorketamine, while causing adverse effects at sub‐anaesthetic doses

Zanos

Highland

Liu

et al. 2019

British J Pharmacology

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“…For instance, S-ketamine has about a 2-4-fold greater affinity for the NMDA and opioid receptors, higher anesthetic potency and maybe fewer adverse effects than R-ketamine (Andrade, 2017;Domino, 2010;Kohrs and Durieux, 1998;Muller et al, 2016;White et al, 1980). In constrast, R-ketamine seems to have a longer lasting antidepressantlike effect than S-ketamine possibly mediated by different molecular mechanisms (Fukumoto et al, 2017;Yang et al, 2018Yang et al, , 2015Zhang et al, 2014). Surprisingly, most of the selected studies in this review were inaccurate in identifying the type of ketamine that was used and some of them did not even describe the manufacturer.…”

Section: Literature Reviewmentioning

confidence: 99%

Ketamine effects on anxiety and fear-related behaviors: current literature evidence and new findings

Silote

Oliveira

Ribeiro

et al. 2019

Preprint

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Highlights  Ketamine induces mixed effects in animal anxiety tests  Few studies investigated the individual effects of S-ketamine in anxiety/fear tests  None study evaluated the effects of R-Ketamine on anxiety/fear-related behaviors  Systemic ketamine does not affect panic-like behaviors in the elevated T-maze Abstract Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, presents rapid and sustained antidepressant effect in clinical and preclinical studies.Regarding ketamine effects on anxiety, there is a widespread discordance among preclinical studies. To address this issue, the present study reviewed the literature (electronic database MEDLINE) to summarize the profile of ketamine effects in animal tests of anxiety/fear. We found that ketamine anxiety/fear-related effects may depend on the anxiety paradigm, schedule of ketamine administration and tested species.Moreover, there was no report of ketamine effects in animal tests of fear related to panic disorder (PD). Based on that finding, we evaluated if treatment with ketamine and another NMDA antagonist, MK-801, would induce acute and sustained (24 hours later) anxiolytic and/or panicolytic-like effects in animals exposed to the elevated T-maze (ETM). The ETM evaluates, in the same animal, conflict-evoked and fear behaviors, which are related, respectively, to generalized anxiety disorder and PD. Male Wistar rats were systemically treated with racemic ketamine (10, 30 and 80 mg/kg) or MK-801 (0.05 and 0.1 mg/kg) and tested in the ETM in the same day or 24 hours after their administration. Ketamine did not affect the behavioral tasks performed in the ETM acutely or 24 h later. MK-801 impaired inhibitory avoidance in the ETM only at 45 min post-injection, suggesting a rapid but not sustained anxiolytic-like effect. Altogether our results suggest that ketamine might have mixed effects in anxiety tests while it does not affect panic-related behaviors.

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“…However, there has yet to be a comprehensive investigation of ( R )-ketamine in clinical trials, studies that are critical for validating the efficacy and side effect profile of this enantiomer. Interestingly, a recent study found that ( S )-ketamine’s antidepressant effects are mTOR-dependent whereas ERK signaling appears to be key to the antidepressant effects of ( R )-ketamine [46]. The observed divergence in signaling pathways may explain the differential efficacy and side effect profiles reported in rodent studies.…”

Section: Rapid-acting Antidepressants Reverse Stress-induced Deficitsmentioning

confidence: 99%

Rapid-Acting Antidepressants: Mechanistic Insights and Future Directions

Gerhard

Duman

2018

Curr Behav Neurosci Rep

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Purpose of Review Ketamine produces rapid (within hours) antidepressant actions, even in patients considered treatment resistant, and even shows promise for suicidal ideation. Here, we review current research on the molecular and cellular mechanisms of ketamine and other novel rapid-acting antidepressants, and briefly explore gender differences in the pathophysiology and treatment of MDD. Recent Findings Ketamine, an NMDA receptor antagonist, increases BDNF release and synaptic connectivity, opposing the deficits caused by chronic stress and depression. Efforts are focused on the development of novel rapid agents that produce similar synaptic and rapid antidepressant actions, but without the side effects of ketamine. The impact of gender on the response to ketamine and other rapid-acting antidepressants is in early stages of investigation. Summary The discovery that ketamine produces rapid therapeutic actions for depression and suicidal ideation represents a major breakthrough and much needed alternative to currently available medications. However, novel fast acting agents with fewer side effects are needed, as well as elucidation of the efficacy of these rapid-acting antidepressants for depression in women.

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Mechanistic Target of Rapamycin–Independent Antidepressant Effects of ( R )-Ketamine in a Social Defeat Stress Model

Cited by 197 publications

References 62 publications

(R)‐Ketamine exerts antidepressant actions partly via conversion to (2R,6R)‐hydroxynorketamine, while causing adverse effects at sub‐anaesthetic doses

(R)‐Ketamine exerts antidepressant actions partly via conversion to (2R,6R)‐hydroxynorketamine, while causing adverse effects at sub‐anaesthetic doses

Ketamine effects on anxiety and fear-related behaviors: current literature evidence and new findings

Rapid-Acting Antidepressants: Mechanistic Insights and Future Directions

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