An update on ketamine and its two enantiomers as rapid-acting antidepressants

Zhang, Kai; Hashimoto, Kenji

doi:10.1080/14737175.2019.1554434

Cited by 92 publications

(54 citation statements)

References 95 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, it is possible that side‐effects of ( S )‐norketamine in humans are significantly lower than ( S )‐ketamine (Table ). Taken all together, ( S )‐norketamine and its prodrugs would be safer antidepressants than ( S )‐ketamine in humans . Notably, unlike ( S )‐ketamine, it should be noted that ( S )‐norketamine is not a schedule compound.…”

Section: Enantiomers Of Ketamine and Its Metabolitesmentioning

confidence: 99%

“…However, the detrimental side‐effects (i.e., psychotomimetic effects and dissociation) were evident after a single injection. Therefore, predictable biomarkers that distinguish responders or non‐responders to ketamine are necessary …”

Section: Ketamine’s Antidepressant Effects In Humansmentioning

confidence: 99%

“…Accumulating evidence has revealed the robust antidepressant effects and anti‐suicidal effects of ketamine, the N ‐methyl‐D‐aspartate receptor (NMDAR) antagonist, in treatment‐resistant patients with MDD or BD . The discovery of the robust antidepressant actions of ketamine is regarded as the greatest advancement in mood disorder research in the past 60 years .…”

mentioning

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

Self Cite

264

193

View full text Add to dashboard Cite

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.

show abstract

Section: Enantiomers Of Ketamine and Its Metabolitesmentioning

confidence: 99%

Section: Ketamine’s Antidepressant Effects In Humansmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Hashimoto

2019

Psychiatry Clin Neurosci

Self Cite

264

193

View full text Add to dashboard Cite

show abstract

“…Next, we measured NKG2D expression in the parietal cortex and the spleen from postmortem tissues from both controls and patients with major psychiatric disorders, including MDD, schizophrenia (SZ), and bipolar disorder (BD). The N-methyl-D-aspartate receptor antagonist (R,S)-ketamine is well-known to have robust antidepressant effects in treatment-resistant patients with depression [22][23][24][25][26][27]. Finally, we investigated whether a more potent enantiomer of (R,S)-ketamine, the rapid-acting and sustained antidepressant (R)-ketamine [25][26][27][28][29][30][31][32][33][34], can ameliorate abnormal splenic functions (i.e., increased volume and splenic functions) in CSDS-susceptible mice.…”

Section: Introductionmentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Initial reports of a rapid and sustained antidepressant effect of ketamine, and subsequent studies showing its benefits in treatment refractory depression, anxiety, bipolar disorder, PTSD and suicidality [33,[36][37][38][39], has stimulated a great deal of interest in the potential mechanism of action. Briefly, ketamine is a 50-50 racemic mixture of Rand S-optical enantiomers that act as non-competitive N-methyl-Daspartate (NMDA) receptor antagonists.…”

Section: Direct Effects Of Ketaminementioning

confidence: 99%

Thermoregulatory Fear of Harm Mood Disorder: In Depth Exploration of a Unique Juvenile-Onset Phenotype That Provides a Parsimonious Clinical Description of Certain Youths with Highly Comorbid Treatment Refractory Psychiatric Disorders

Papolos¹,

Mattis²,

Lachman³

et al. 2019

J Psychiatry Brain Sci

View full text Add to dashboard Cite

Among aggressive youths with severe mood lability who frequently fail to benefit from mood stabilizers and antipsychotics there is a discrete subtype called 'Thermoregulatory Fear of Harm Mood Disorder' (FOH). This disorder is characterized by an underlying thermoregulatory deficit, a specific prodromal sequence and a unique constellation of symptoms.The underlying problem appears to be a deficit in thermoregulation resulting in excessive heat that manifests as thermal discomfort in neutral ambient temperatures and moderate to extreme cold tolerance, and produces REM sleep-related problems and parasomnias, such as night-terrors and hypnogogic hallucinations. Clinically, FOH is associated with the advent in childhood of frequent, recurrent, vivid nightmares with themes of pursuit and abandonment. The apparent psychological sequelae of exposure to this frightening imagery is fear sensitization and auto-traumatization. A developmental sequence of fear based defensive behaviors arises and includes obsessive bedtime rituals, fear of the dark, separation anxiety, contamination fears, hypervigilance, perfectionism, misperception of neutral stimuli as threatening, as well as reactive aggression in response to limit setting and perceived threat or loss. Ketamine, chosen as a potential treatment because of its effectiveness in reducing fear sensitization and dose-dependent lowering of body temperature in preclinical studies, has been associated with sustained Journal of Psychiatry and Brain Science 2 of 43 J Psychiatry Brain Sci. 2019;4:e190004. https://doi.org/10.20900/jpbs.20190004 improvement in otherwise refractory youths. We present a detailed description of this heritable disorder, link its clinical features to a potential disturbance in brain derived neurotropic factor (BDNF) and orexin, and indicate how ketamine rapidly affects BDNF through multiple mechanisms, to produce a dramatic beneficial response in youths with this disorder.

show abstract

An update on ketamine and its two enantiomers as rapid-acting antidepressants

Cited by 92 publications

References 95 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

Thermoregulatory Fear of Harm Mood Disorder: In Depth Exploration of a Unique Juvenile-Onset Phenotype That Provides a Parsimonious Clinical Description of Certain Youths with Highly Comorbid Treatment Refractory Psychiatric Disorders

Contact Info

Product

Resources

About