Beneficial effects of (R)-ketamine, but not its metabolite (2R,6R)-hydroxynorketamine, in the depression-like phenotype, inflammatory bone markers, and bone mineral density in a chronic social defeat stress model

Xiong, Zhili; Fujita, Yūkō; Zhang, Kai; Pu, Yaoyu; Chang, Lijia; Ma, Min; Chen, Jincao; Hashimoto, Kenji

doi:10.1016/j.bbr.2019.111904

Cited by 40 publications

(33 citation statements)

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“…There was also a positive correlation between ketamine‐induced behavioral outcome (i.e., anhedonia) and OPG/RANKL ratio. In addition, ( R )‐ketamine, but not (2 R ,6 R )‐HNK, significantly improved the decreased bone mineral density of CSDS‐susceptible mice . Collectively, it is likely that the bone turnover markers might be involved in the antidepressant effects of ( R )‐ketamine .…”

Section: Ketamine’s Antidepressant Effects In Humansmentioning

confidence: 95%

“…In addition, ( R )‐ketamine, but not (2 R ,6 R )‐HNK, significantly improved the decreased bone mineral density of CSDS‐susceptible mice . Collectively, it is likely that the bone turnover markers might be involved in the antidepressant effects of ( R )‐ketamine . Furthermore, ( R )‐ketamine would be a potential therapeutic drug for abnormalities in bone metabolism in depressed patients …”

Section: Ketamine’s Antidepressant Effects In Humansmentioning

confidence: 99%

“…reported increased blood levels of osteoprotegerin (OPG)/receptor activator of nuclear factor kB Ligand (RANKL) ratio and osteopontin after ketamine infusion, suggesting that the OPG/RANK/RANKL system might be implicated in ketamine’s antidepressant effects. Unlike ( S )‐ketamine and (2 R ,6 R )‐hydroxynorketamine (HNK), ( R )‐ketamine attenuated the higher blood levels of RANKL in a chronic social‐defeat stress (CSDS) model . There was also a positive correlation between ketamine‐induced behavioral outcome (i.e., anhedonia) and OPG/RANKL ratio.…”

Section: Ketamine’s Antidepressant Effects In Humansmentioning

confidence: 99%

“…Collectively, it is likely that the bone turnover markers might be involved in the antidepressant effects of ( R )‐ketamine . Furthermore, ( R )‐ketamine would be a potential therapeutic drug for abnormalities in bone metabolism in depressed patients …”

Section: Ketamine’s Antidepressant Effects In Humansmentioning

confidence: 99%

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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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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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Section: Ketamine’s Antidepressant Effects In Humansmentioning

confidence: 95%

Section: Ketamine’s Antidepressant Effects In Humansmentioning

confidence: 99%

Section: Ketamine’s Antidepressant Effects In Humansmentioning

confidence: 99%

Section: Ketamine’s Antidepressant Effects In Humansmentioning

confidence: 99%

See 2 more Smart Citations

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

Hashimoto

2019

Psychiatry Clin Neurosci

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272

193

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“…To date, four different research groups have published data demonstrating that (2R,6R)-HNK produces rapid and/or sustained antidepressant-like effects across a number of preclinical models that include forced swim test (FST), learned helplessness, novelty suppressed feeding, chronic restraint stress, and chronic social defeat stress (CSDS; Chou et al, 2018;Fukumoto et al, 2019;Highland et al, 2018;Lumsden et al, 2019;Pham et al, 2018;Zanos et al, 2016;Zanos, Highland, Liu, et al, 2019;Zanos, Highland, Stewart, et al, 2019). The Hashimoto and Chaki research group, however, has failed to replicate these antidepressant-like effects of (2R,6R)-HNK but have demonstrated antidepressant-like effects of (R)-ketamine in their studies (Shirayama & Hashimoto, 2018;Xiong et al, 2019;Yamaguchi et al, 2018;Yang et al, 2017;Zhang, Fujita, & Hashimoto, 2018). One possible explanation for these findings may be related to the limited dose range (typically a single dose) and behavioural assays used by the Hashimoto/Chaki group.…”

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confidence: 99%

What role does the (2R,6R)‐hydronorketamine metabolite play in the antidepressant‐like and abuse‐related effects of (R)‐ketamine?

Hillhouse

Rice

Porter

2019

British J Pharmacology

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Major depressive disorder (MDD) is a major health concern in which approximately 30% of patients do not response to currently approved antidepressant medications and are classified as treatment-resistant patients. The noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine produces both rapid (<24 hr) and sustained (up to several weeks) antidepressant effects in treatmentresistant patients following acute or repeated i.v. infusions of ketamine (0.5 mg·kg −1 ), a finding that has been replicated across several clinical studies. Ketamine also has demonstrated abuse liability among illicit drug users and concerns regarding the possible neurotoxic, and psychotomimetic effects have limited ketamine's clinical use (see Hillhouse & Porter, 2015). These concerns have led to the development and evaluation of ketamine's isomers and their biologically active metabolites to assess safety concerns (i.e., reduced abuse concern), and to elucidate ketamine's mechanism of action.The recent paper by Zanos, Highland, Liu, et al. (2019) aims to fill these gaps in understanding ketamine's therapeutic potential by first examining if ketamine-associated abuse liability can be reduced. The (S)-ketamine enantiomer has higher affinity for NMDA receptors and is thought to be more responsible for the abuse-related effects of ketamine, in that preclinical data have found that (S)-ketamine produces antidepressant-like effects and abuse-related effects at comparable doses. For example, while (S)-ketamine produces antidepressantlike effects across several behavioral models at 10 mg·kg −1 ; (S)-ketamine also produces conditioned place preference (CPP), increases locomotor activity (LMA), and disrupts the startle reflex at 10 mg·kg −1 (Yang et al., 2015;Yang et al., 2017;Zanos et al., 2016;Zhang, Li, & Hashimoto, 2014). Conversely, (R)-ketamine appears to have reduced abuse liability as it failed to produce CPP, increased LMA, or disruption of the startle reflex response, although it should be noted that a limited dose range (10-20 mg·kg −1 ) was tested (Yang et al., 2015). Furthermore, results indicated that (R)-ketamine produces more potent and longer acting antidepressant-like effects, producing antidepressant-like effects as low as 5 mg·kg −1 (Zanos et al., 2016; Zanos, Highland, Liu, et al., 2019). The present study (Zanos, Highland, Liu, et al., 2019) builds upon these findings by demonstrating that (R)-ketamine produces abuse-related effects at doses four to 18 times higher than the antidepressant dose (5 mg·kg −1 ), including hyperactivity (40 mg·kg −1 ), CPP (40 mg·kg −1 ), motor impairments (20-40 mg·kg −1 ), and disrupted started reflex (90 mg·kg −1 ). In sum, the (R)-and (S)-ketamine enantiomers produce both antidepressantlike and abuse-related effects; however, the therapeutic window (i.e., antidepressant-like effects vs. abuse liability) is larger, and the antidepressant-like effects are sustained for longer periods of time for (R)ketamine, compared to (S)-ketamine. Taken together, with evidence which indic...

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Decreased bone mineral density in ovariectomized mice is ameliorated after subsequent repeated intermittent administration of (R)‐ketamine, but not (S)‐ketamine

Fujita

Hashimoto

2020

Neuropsychopharm Rep

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Osteoporosis is the common chronic disease characterized by low bone mass and structural deterioration of bone tissue, leading to fragility of the bone. Depression is common in people with osteoporosis. A meta-analysis demonstrated that bone mineral density (BMD) in patients with depression is reduced compared to subjects without depression, 1 indicating depression as a risk factor for low BMD. 2-4 Furthermore, the use of antidepressants is associated with osteoporotic fracture in elderly peoples. 5,6 Importantly, the use of selective serotonin reuptake inhibitors (SSRIs) is associated with decreased BMD and increased fracture risk in humans. 7 Therefore, the development of the novel antidepressants which also have beneficial effects for osteoporosis is an unmet medical need.

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Beneficial effects of (R)-ketamine, but not its metabolite (2R,6R)-hydroxynorketamine, in the depression-like phenotype, inflammatory bone markers, and bone mineral density in a chronic social defeat stress model

Cited by 40 publications

References 50 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

What role does the (2R,6R)‐hydronorketamine metabolite play in the antidepressant‐like and abuse‐related effects of (R)‐ketamine?

Decreased bone mineral density in ovariectomized mice is ameliorated after subsequent repeated intermittent administration of (R)‐ketamine, but not (S)‐ketamine

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