Lack of Opioid System in the Antidepressant Actions of Ketamine

Zhang, Kai; Hashimoto, Kenji

doi:10.1016/j.biopsych.2018.11.006

Cited by 55 publications

(38 citation statements)

References 10 publications

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“…Recently, we reported that naltrexone did not block the rapid‐acting and sustained antidepressant effects of ketamine in a CSDS model or LPS‐induced inflammation model . If opioid receptors are implicated in the antidepressant actions of ketamine, ( S )‐ketamine must be more potent than ( R )‐ketamine in animal models of depression.…”

Section: Molecular and Cellular Mechanisms Of Ketamine’s Antidepressamentioning

confidence: 98%

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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: Molecular and Cellular Mechanisms Of Ketamine’s Antidepressamentioning

confidence: 98%

“…If opioid receptors are implicated in the antidepressant actions of ketamine, ( S )‐ketamine must be more potent than ( R )‐ketamine in animal models of depression. Therefore, the opioid receptor system might not play a role in ketamine’s antidepressant actions …”

Section: Molecular and Cellular Mechanisms Of Ketamine’s Antidepressamentioning

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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“…Inflammation model by lipopolysaccharide (LPS) was performed as previously reported [51][52][53] . Saline (10 ml/kg) or LPS (0.5 mg/kg) was administered i.p.…”

Section: Antidepressant Effects Of Tgf-β1 In a Lps-induced Inflammatimentioning

confidence: 99%

Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1

et al. 2020

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In rodent models of depression, (R)-ketamine has greater potency and longer-lasting antidepressant effects than (S)ketamine; however, the precise molecular mechanisms underlying the antidepressant actions of (R)-ketamine remain unknown. Using RNA-sequencing analysis, we identified novel molecular targets that contribute to the different antidepressant effects of the two enantiomers. Either (R)-ketamine (10 mg/kg) or (S)-ketamine (10 mg/kg) was administered to susceptible mice after chronic social defeat stress (CSDS). RNA-sequencing analysis of prefrontal cortex (PFC) and subsequent GSEA (gene set enrichment analysis) revealed that transforming growth factor (TGF)-β signaling might contribute to the different antidepressant effects of the two enantiomers. (R)-ketamine, but not (S)-ketamine, ameliorated the reduced expressions of Tgfb1 and its receptors (Tgfbr1 and Tgfbr2) in the PFC and hippocampus of CSDS susceptible mice. Either pharmacological inhibitors (i.e., RepSox and SB431542) or neutralizing antibody of TGF-β1 blocked the antidepressant effects of (R)-ketamine in CSDS susceptible mice. Moreover, depletion of microglia by the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 blocked the antidepressant effects of (R)-ketamine in CSDS susceptible mice. Similar to (R)-ketamine, the recombinant TGF-β1 elicited rapid and long-lasting antidepressant effects in animal models of depression. Our data implicate a novel microglial TGF-β1-dependent mechanism underlying the antidepressant effects of (R)-ketamine in rodents with depression-like phenotype. Moreover, TGF-β1 and its receptor agonists would likely constitute a novel rapid-acting and sustained antidepressant in humans.

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“…CSDS-susceptible mice were administered either saline (10 ml/kg) or (R)-ketamine (10 mg/kg) intraperitoneally (i.p.). Then, behavioral tests, including locomotion, a tail suspension test (TST), a forced swimming test (FST), and a one % sucrose preference test (SPT) were carried out as reported previously [29,[32][33][34][35][37][38][39].…”

Section: Antidepressant Effects Of (Rs)-ketamine and (R)-ketamine Inmentioning

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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Lack of Opioid System in the Antidepressant Actions of Ketamine

Cited by 55 publications

References 10 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

Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1

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

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