The influence of ketamine on drug discovery in depression

Kraus, Christoph; Wasserman, Daniel; Henter, Ioline D.; Acevedo-Diaz, Elia E.; Kadriu, Bashkim; Zarate, Carlos A.

doi:10.1016/j.drudis.2019.07.007

Cited by 62 publications

(84 citation statements)

References 95 publications

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“…The relatively recent discovery 52 and replication of ketamine's antidepressant properties [53][54][55][56][57][58] have provided a major breakthrough towards advancing more effective interventions for TRD. However, both the molecular mechanisms, which appear to extend beyond NMDA receptor antagonism, and the brain systems-level mechanisms accounting for changes in behavior linked with therapeutic response remain unclear 59,60 . The current investigation thus sought to address how ketamine modulates inhibitory control networks in the brain in relation to antidepressant response.…”

Section: Discussionmentioning

confidence: 99%

Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression

et al. 2020

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Subanesthetic ketamine is found to induce fast-acting and pronounced antidepressant effects, even in treatment resistant depression (TRD). However, it remains unclear how ketamine modulates neural function at the brain systemslevel to regulate emotion and behavior. Here, we examined treatment-related changes in the inhibitory control network after single and repeated ketamine therapy in TRD. Forty-seven TRD patients (mean age = 38, 19 women) and 32 healthy controls (mean age = 35, 18 women) performed a functional magnetic resonance imaging (fMRI) response inhibition task at baseline, and 37 patients completed the fMRI task and symptom scales again 24 h after receiving both one and four 0.5 mg/kg intravenous ketamine infusions. Analyses of fMRI data addressed effects of diagnosis, time, and differences between treatment remitters and non-remitters. Significant decreases in brain activation were observed in the inhibitory control network, including in prefrontal and parietal regions, and visual cortex following serial ketamine treatment, p < 0.05 corrected. Remitters were distinguished from non-remitters by having lower functional activation in the supplementary motor area (SMA) prior to treatment, which normalized towards controls following serial ketamine treatment. Results suggest that ketamine treatment leads to neurofunctional plasticity in executive control networks including the SMA during a response-inhibitory task. SMA changes relate to reductions in depressive symptoms, suggesting modulation of this network play an important role in therapeutic response. In addition, early changes in the SMA network during response inhibition appear predictive of overall treatment outcome, and may serve as a biomarker of treatment response.

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Section: Discussionmentioning

confidence: 99%

Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression

et al. 2020

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“…Recent studies reported that a single infusion of sub-anesthetic dose of ketamine, a non-competitive NMDA receptor antagonist, induces rapid and sustained antidepressant effect in treatment-resistant patients (Kraus et al, 2017;Lener et al, 2017;Kraus et al, 2019). In preclinical studies, ketamine was shown to rapidly reverse the dendritic retraction and spine loss induced by chronic stress in pyramidal neurons of prefrontal cortex and HPC (Anggono and Huganir, 2012;Moda-Sava et al, 2019;Tornese et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Modulation by chronic stress and ketamine of ionotropic AMPA/NMDA and metabotropic glutamate receptors in the rat hippocampus

Elhussiny

Carini

Mingardi

et al. 2021

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Converging clinical and preclinical evidence has shown that dysfunction of the glutamate system is a core feature of major depressive disorder. In this context, the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has raised growing interest as fast acting antidepressant. Using the chronic mild stress (CMS) rat model of depression, performed in male rats, we aimed at analyzing whether hippocampal specific changes in subunit expression and regulation of α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) or NMDA ionotropic receptors and in metabotropic glutamate receptors could be associated with behavioral vulnerability/resilience to CMS. We also assessed whether acute ketamine (10 mg/ kg) was able to dampen the alterations in CMS vulnerable animals. Although chronic stress and ketamine had no effect on ionotropic glutamate receptors mRNAs (expression, RNA editing and splicing), we found selective modulations in their protein expression, phosphorylation and localization at synaptic membranes. AMPA GluA2 expression at synaptic membranes was significantly increased only in CMS resilient rats (although a trend was found also in vulnerable animals), while its phosphorylation at Ser 880 was higher in both CMS resilient and vulnerable rats, a change partially dampened by ketamine. In the hippocampus from all stressed groups, despite NMDA receptor expression levels were reduced in total extract, the levels of GluN2B-containing NMDA receptors were remarkably increased in synaptic membranes. Finally, mGlu2 underwent a selective downregulation in stress vulnerable animals, which was completely restored by acute ketamine. Overall, these results are in line with a hypofunction of activity-dependent glutamatergic synaptic transmission induced by chronic stress exposure in all the animals, as suggested by the alterations of ionotropic glutamate receptors expression and localization at synaptic level. At the same time, the selective modulation of mGlu2 receptor, confirms its previously hypothesized functional role in regulating stress vulnerability and, for the first time here, suggests a mGlu2 involvement in the fast antidepressant effect of ketamine. 2013). The stress response is aimed at reaching a new equilibrium through adaptation, the so called "allostasis", allowing to activate coping strategies for survival. However, physical or psychological stress, especially when repeated, particularly intense, and affecting genetically susceptible subjects, is also recognized as main risk and precipitating factor for a number of systemic and neuropsychiatric

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“…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: 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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The influence of ketamine on drug discovery in depression

Cited by 62 publications

References 95 publications

Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression

Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression

Modulation by chronic stress and ketamine of ionotropic AMPA/NMDA and metabotropic glutamate receptors in the rat hippocampus

Ketamine: A tale of two enantiomers

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