Ketamine metabolite pilot study in a suicidal depression trial

Grunebaum, Michael F.; Galfalvy, Hanga; Choo, Tse‐Hwei; Parris, Michelle S.; Burke, Ainsley K.; Suckow, Raymond F.; Cooper, Thomas B.; Mann, J. John

doi:10.1016/j.jpsychires.2019.08.005

Cited by 33 publications

(25 citation statements)

References 39 publications

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“…This topic is subject to active ongoing work and debate in the preclinical domain, while patient studies are still underway (Collingridge et al, 2017;Zanos et al, 2018a;Hashimoto, 2019). However, a recent study did find a correlation between plasma 2R,6R-HNK levels and the antidepressant and antisuicidal effects of ketamine in patients (Grunebaum et al, 2019), but higher rather than lower levels correlated with less clinical improvement.…”

Section: Examining Rapid Antidepressant Effects Through Encodingmentioning

confidence: 99%

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Rantamäki

Kohtala

2020

Pharmacol Rev

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Brain and Mind Doctoral Program (S.K.), the Orion Research Foundation (S.K.), and the Emil Aaltonen foundation (S.K.). T.R. and S.K. are listed as coinventors on a patent application, wherein new tools enabling the development of rapid-acting antidepressants and the efficacy monitors thereof are disclosed based on the basic principles of ENCORE-D. T.R. and S.K. have assigned their patent rights to the University of Helsinki but will share a percentage of any royalties that may be received by the University of Helsinki.

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Section: Examining Rapid Antidepressant Effects Through Encodingmentioning

confidence: 99%

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Rantamäki

Kohtala

2020

Pharmacol Rev

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“… 65 Some studies have proposed that one of the primary metabolites of ketamine, hydroxynorketamine, plays a significant role in mediating antidepressant effects independent of NMDAR antagonism via direct AMPAR activation. 66 Since the initial controversial finding, further studies 67 , 68 have questioned the veracity of these findings. At present, the full activity of ketamine metabolites and their clinical significance is not well understood.…”

Section: Resultsmentioning

confidence: 99%

Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action

Irwin

VandenBerg

2021

Mental Health Clinician

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Introduction MDD represents a significant burden worldwide, and while a number of approved treatments exist, there are high rates of treatment resistance and refractoriness. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, is a novel, rapid-acting antidepressant, however the mechanisms underlying the efficacy of ketamine are not well understood and many other mechanisms outside of NMDAR antagonism have been postulated based on preclinical data. This focused review aims to present a summary of the proposed mechanisms of action by which ketamine functions in depressive disorders supported by preclinical data and clinical studies in humans. Methods A literature search was completed using the PubMed and Google Scholar databases. Results were limited to clinical trials and case studies in humans that were published in English. The findings were used to compile this article. Results The antidepressant effects associated with ketamine are mediated via a complex interplay of mechanisms; key steps include NMDAR blockade on γ-aminobutyric acid interneurons, glutamate surge, and subsequent activation and upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Discussion Coadministration of ketamine for MDD with other psychotropic agents, for example benzodiazepines, may attenuate antidepressant effects. Limited evidence exists for these effects and should be evaluated on a case-by-case basis.

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“…Clinical trials have not yet examined the utility of (2R,6R)-HNK as a rapid-acting antidepressant. However, clinical studies investigating ketamine metabolite plasma levels as biomarkers have found that higher (2R,6R)-HNK levels were associated with less improvement in depressive symptoms ( Farmer et al, 2020 ; Grunebaum et al, 2019 ), which is counterintuitive considering preclinical findings. Regardless, (2R,6R)-HNK, with its potential to modulate mGlu2 and AMPA receptor function, remains a promising candidate antidepressant and work to validate this compound for clinical use is ongoing at the United States National Institute for Mental Health ( Kraus et al., 2019 ).…”

Section: Mechanistic Considerationsmentioning

confidence: 95%

“…Until there is a clearer understanding of target engagement, it is difficult to interpret dose-related effects of (2R,6R)-HNK and (R)-ketamine. In clinical studies, (2R,6R)-HNK levels are a poor predictor of antidepressant response (Farmer et al, 2020;Grunebaum et al, 2019;Zarate et al, 2012a). Is that because (2R,6R)-HNK levels are too low to produce clinical benefit?…”

Section: Declaration Of Conflicting Interestsmentioning

confidence: 99%

Ketamine: A tale of two enantiomers

2020

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The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate receptor antagonist, is arguably the most important breakthrough in depression research in the last 50 years. Ketamine remains an off-label treatment for treatment-resistant depression with factors that limit widespread use including its dissociative effects and abuse potential. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. An (S)-ketamine nasal spray has been developed and approved for use in treatment-resistant depression in the United States and Europe; however, some concerns regarding efficacy and side effects remain. Although (R)-ketamine is a less potent N-Methyl-D-Aspartate receptor antagonist than (S)-ketamine, increasing preclinical evidence suggests (R)-ketamine may have more potent and longer lasting antidepressant effects than (S)-ketamine, alongside fewer side effects. Furthermore, a recent pilot trial of (R)-ketamine has demonstrated rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research is ongoing to determine the specific cellular and molecular mechanisms underlying the antidepressant actions of ketamine and its component enantiomers in an effort to develop future rapid-acting antidepressants that lack undesirable effects. Here, we briefly review findings regarding the antidepressant effects of ketamine and its enantiomers before considering underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling, inhibition of glycogen synthase kinase-3 and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems.

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Ketamine metabolite pilot study in a suicidal depression trial

Cited by 33 publications

References 39 publications

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects

Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action

Ketamine: A tale of two enantiomers

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