Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression

Farmer, Cristan; Gilbert, Jessica R.; Moaddel, Ruin; George, Jomy; Adeojo, Lilian W; Lovett, Jacqueline; Nugent, Allison C.; Kadriu, Bashkim; Yuan, Peixiong; Gould, Todd D.; Park, Lawrence T.; Zarate, Carlos A.

doi:10.1038/s41386-020-0663-6

Cited by 59 publications

(76 citation statements)

References 67 publications

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“…Another proposed mechanism suggests that ketamine's antidepressant effects are NMDAR-independent and occur through ketamine's metabolites; of these, (2R,6R)-hydroxynorketamine (HNK) is of particular interest 34,67 . Intriguingly, a recent study from our laboratory found that ketamine and NK plasma levelsbut not (2R,6R)-HNK levels-were uniquely related to increased dissociative symptoms (as assessed via CADSS score) in participants with TRD 68 . Furthermore, the (2R,6R)-HNK metabolite may be particularly dependent on AMPARs and, thus, would not have dissociative side effects or abuse potential.…”

Section: Dissociation or Other Psychotomimetic Effects Associated Witmentioning

confidence: 80%

The role of dissociation in ketamine’s antidepressant effects

2020

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Ketamine produces immediate antidepressant effects and has inspired research into next-generation treatments. Ketamine also has short term dissociative effects, in which individuals report altered consciousness and perceptions of themselves and their environment. However, whether ketamine’s dissociative side effects are necessary for its antidepressant effects remains unclear. This perspective examines the relationship between dissociative effects and acute and longer-lasting antidepressant response to ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists. Presently, the literature does not support the conclusion that dissociation is necessary for antidepressant response to ketamine. However, further work is needed to explore the relationship between dissociation and antidepressant response at the molecular, biomarker, and psychological levels.

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Section: Dissociation or Other Psychotomimetic Effects Associated Witmentioning

confidence: 80%

The role of dissociation in ketamine’s antidepressant effects

2020

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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%

“…There is, however, some recent clinical evidence that found no relationship between norketamine concentration (neither (S)-norketamine nor (R)-norketamine) and antidepressant response, following administration of (R,S)-ketamine to individuals with TRD (Farmer et al, 2020).…”

Section: Mechanistic Considerationsmentioning

confidence: 96%

“…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%

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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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“…This might be explained by the persistent reduction of neuronal firing of interneurons, i.e., GABAergic neurons, in the cortex, which might directly influence the mode of action through which gamma oscillation develops in ASSR. Thus, moderate NMDA receptor blockade biases the excitatory/ inhibitory balance toward increased excitability, which could yield beneficial effects on brain function, similar to the antidepressive effect of ketamine (47). However, the effect of NMDA receptor antagonists on gamma power may not be explained solely by the disinhibition of GABAergic activity, as higher exposure of ketamine (and accordingly higher receptor occupancy) reduces ASSR signaling, which may reflect a collapse of cortical neuronal synchrony (20,21).…”

Section: Gamma Oscillations In Drug Developmentmentioning

confidence: 99%

Enhancing Clinical Trials Through Synergistic Gamma Power Analysis

Honda

Matsumoto²,

Tajinda³

et al. 2020

Front. Psychiatry

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While the etiology of many neuropsychiatric disorders remains unknown, increasing evidence suggests that aberrant sensory processing plays a central role. For this class of disorders, which are characterized by affective, cognitive, and behavioral symptoms, electroencephalography remains the dominant tool for providing insight into the physiological and molecular underpinnings of the disease state and predicting the effectiveness of investigational new drugs. Within the spectrum of electrical activity present in the CNS, high-frequency oscillations in the gamma band are frequently altered in these patient populations. Measurement of gamma oscillation can be further classified into baseline and evoked, each of which offers a specific commentary on disease state. Baseline gamma analysis provides a surrogate of pharmacodynamics and predicting the time course effects of clinical candidate drugs, while alterations in evoked (time-locked) gamma power may serve as a disease biomarker and have utility in assessing patient response to new drugs. Together, these techniques offer complimentary methods of analysis for discrete realms of clinical and translational medicine. In terms of drug development, comprehensive analysis containing aspects of both baseline and evoked gamma oscillations may prove more useful in establishing better workflow and more accurate criteria for the testing of investigational new drugs.

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Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression

Cited by 59 publications

References 67 publications

The role of dissociation in ketamine’s antidepressant effects

The role of dissociation in ketamine’s antidepressant effects

Ketamine: A tale of two enantiomers

Enhancing Clinical Trials Through Synergistic Gamma Power Analysis

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