Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine

Chang, Lijia; Zhang, Kai; Pu, Yaoyu; Qu, Youge; Wang, Siming; Xiong, Zhili; Ren, Qian; Dong, Chao; Fujita, Yūkō; Hashimoto, Kenji

doi:10.1016/j.pbb.2019.04.008

Cited by 129 publications

(72 citation statements)

References 58 publications

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“…Taken all together, these preclinical and clinical studies suggest a possibility that ( R )‐ketamine may be a safer antidepressant than ( S )‐ketamine and ( R,S )‐ketamine …”

Section: Enantiomers Of Ketamine and Its Metabolitesmentioning

confidence: 80%

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Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

Hashimoto

2019

Psychiatry Clin Neurosci

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264

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Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one‐third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with bipolar disorder (BD) is typically poorly responsive to antidepressants. Therefore, there exists an unmet medical need for rapidly acting antidepressants with beneficial effects in treatment‐resistant patients with MDD or BD. Accumulating evidence suggests that the N‐methyl‐D‐aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects in treatment‐resistant patients with MDD or BD. Ketamine is a racemic mixture comprising equal parts of (R)‐ketamine (or arketamine) and (S)‐ketamine (or esketamine). Because (S)‐ketamine has higher affinity for NMDAR than (R)‐ketamine, esketamine was developed as an antidepressant. On 5 March 2019, esketamine nasal spray was approved by the US Food and Drug Administration. However, preclinical data suggest that (R)‐ketamine exerts greater potency and longer‐lasting antidepressant effects than (S)‐ketamine in animal models of depression and that (R)‐ketamine has less detrimental side‐effects than (R,S)‐ketamine or (S)‐ketamine. In this article, the author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamine. Furthermore, the author discusses the other potential rapid‐acting antidepressant candidates (i.e., NMDAR antagonists and modulators, low‐voltage‐sensitive T‐type calcium channel inhibitor, potassium channel Kir4.1 inhibitor, negative modulators of γ‐aminobutyric acid, and type A [GABAA] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine’s antidepressant effects are discussed.

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“…Taken all together, these preclinical and clinical studies suggest a possibility that ( R )‐ketamine may be a safer antidepressant than ( S )‐ketamine and ( R,S )‐ketamine …”

Section: Enantiomers Of Ketamine and Its Metabolitesmentioning

confidence: 80%

“…Very recently, we compared antidepressant effects and side‐effects in mice after intranasal administration of ( R,S )‐ketamine and its two enantiomers . The order of potency of antidepressant effects was ( R )‐ketamine > ( R,S )‐ketamine > ( S )‐ketamine.…”

Section: Enantiomers Of Ketamine and Its Metabolitesmentioning

confidence: 99%

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

Hashimoto

2019

Psychiatry Clin Neurosci

Self Cite

264

193

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“…(R)-ketamine hydrochloride was prepared by recrystallizing (R,S)-ketamine and D-(−)-tartaric acid [28]. The dose (10 mg/kg as hydrochloride salt) of (R)-ketamine was selected as reported previously [29,[32][33][34][35]. Other reagents were purchased commercially.…”

Section: Compounds and Treatmentmentioning

confidence: 99%

“…The CSDS procedure was performed as reported previously [29,[32][33][34][35][36]. Each day, for a total of 10 days, the C57BL/6 mice underwent 10 min exposure to a different CD1 aggressor mouse.…”

Section: Csds Modelmentioning

confidence: 99%

Splenic NKG2D confers resilience versus susceptibility in mice after chronic social defeat stress: beneficial effects of (R)-ketamine

Zhang

Sakamoto

Chang

et al. 2019

Eur Arch Psychiatry Clin Neurosci

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The spleen is a large immune organ that plays a key role in the immune system. The precise molecular mechanisms underlying the relationship between the spleen and stress-related psychiatric disorders are unknown. Here we investigated the role of spleen in stress-related psychiatric disorders. FACS analysis was applied to determine the contribution of the spleen to susceptibility and resilience in mice that were subjected to chronic social defeat stress (CSDS). We found a notable increase in splenic volume and weight in CSDS-susceptible mice compared to control (no CSDS) mice and CSDS-resilient mice. The number of granulocytes, but not of T cells and B cells, in the spleen of susceptible mice was higher than in the spleen of both control and resilient mice. Interestingly, NKG2D (natural killer group 2, member D) expression in the spleen of CSDS-susceptible mice was higher than that in control mice and CSDS-resilient mice. In addition, NKG2D expression in the spleen of patients with depression was higher than that in controls. Both increased splenic weight and increased splenic NKG2D expression in CSDS-susceptible mice were ameliorated after a subsequent administration of (R)-ketamine. The present findings indicate a novel role of splenic NKG2D in stress susceptibility versus resilience in mice subjected to CSDS. Furthermore, abnormalities in splenic functions in CSDS-susceptible mice were ameliorated after subsequent injection of (R)-ketamine. Thus, the brain-spleen axis might, at least in part, contribute to the pathogenesis of stress-related psychiatric disorders such as depression.

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“…Whether the long‐lasting anti‐depressant effects of (R)‐ketamine is related to MERK‐ERK signalling is unknown. Besides, detrimental side effects of (R)‐ketamine are fewer than (R,S)‐ketamine and (S)‐ketamine 15,21 . It was observed that (S)‐ketamine caused a reduction in parvalbumin (PV)‐positive cells in the medial pre‐frontal cortex (mPFC) and DG, while (R)‐ketamine did not.…”

Section: Introductionmentioning

confidence: 99%

Rapid anti‐depressant‐like effects of ketamine and other candidates: Molecular and cellular mechanisms

Peng

Fan

et al. 2020

Cell Proliferation

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Major depressive disorder takes at least 3 weeks for clinical anti-depressants, such as serotonin selective reuptake inhibitors, to take effect, and only one-third of patients remit. Ketamine, a kind of anaesthetic, can alleviate symptoms of major depressive disorder patients in a short time and is reported to be effective to treatment-resistant depression patients. The rapid and strong anti-depressant-like effects of ketamine cause wide concern. In addition to ketamine, caloric restriction and sleep deprivation also elicit similar rapid anti-depressant-like effects. However, mechanisms about the rapid anti-depressant-like effects remain unclear. Elucidating the mechanisms of rapid anti-depressant effects is the key to finding new therapeutic targets and developing therapeutic patterns. Therefore, in this review we summarize potential molecular and cellular mechanisms of rapid anti-depressant-like effects based on the pre-clinical and clinical evidence, trying to provide new insight into future therapy.

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Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine

Cited by 129 publications

References 58 publications

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

Splenic NKG2D confers resilience versus susceptibility in mice after chronic social defeat stress: beneficial effects of (R)-ketamine

Rapid anti‐depressant‐like effects of ketamine and other candidates: Molecular and cellular mechanisms

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