Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

Newport, D. Jeffrey; Carpenter, Linda L.; McDonald, William M.; Potash, James B.; Tohen, Mauricio; Nemeroff, Charles B.; Treatments,

doi:10.1176/appi.ajp.2015.15040465

Cited by 501 publications

(413 citation statements)

References 172 publications

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“…In addition, most current antidepressants can take weeks before patients or animal models feel the full antidepressant effects (42,43). Recently, we reported that a single dose of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine (or R-ketamine) showed a rapid antidepressant effect in the social defeat stress model (37,39), consistent with rapid antidepressant effects of ketamine in treatmentresistant patients with depression (44)(45)(46). However, ketamine leads to psychotomimetic side effects and abuse liability that appears to be absent in the case of TPPU.…”

Section: Discussionmentioning

confidence: 71%

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Ren

Ishima

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

156

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Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depressionlike behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression.brain-derived neurotrophic factor | depression | epoxyeicosatrienoic acid | soluble epoxide hydrolase | resilience

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Section: Discussionmentioning

confidence: 71%

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Ren

Ishima

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

156

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“…123,124 Along with its rapid behavioral effects, ketamine increases synaptogenesis in rodents through rapid release of BDNF in an activity-dependent manner. 104,125 Furthermore, recent evidence suggests that the therapeutic effects of ketamine may be mediated through epigenetic mechanisms.…”

Section: Antidepressants Alter Cellular Functioning Through Epigenementioning

confidence: 99%

A role for activity‐dependent epigenetics in the development and treatment of major depressive disorder

Nagy

Vaillancourt

Turecki

2018

Genes Brain and Behavior

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Chronic stressors, during developmental sensitive periods and beyond, contribute to the risk of developing psychiatric conditions, including major depressive disorder (MDD). Epigenetic mechanisms including DNA methylation and histone modifications, at key stress response and neurotrophin genes, are increasingly implicated in mediating this risk. Although the exact mechanisms through which stressful environmental stimuli alter the epigenome are still unclear, research from the learning and memory fields indicates that epigenomic marks can be altered, at least in part, through calcium-dependent signaling cascades in direct response to neuronal activity. In this review, we highlight key findings from the stress, MDD, and learning and memory fields to propose a model where stress regulates downstream cellular functioning through activity-dependent epigenetic changes. Furthermore, we suggest that both typical and novel antidepressant treatments may exert positive influence through similar, activity-dependent pathways.

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“…The antidepressant effect of sub-anesthetic doses of ketamine has been demonstrated in several studies in mice (Maeng et al 2008, Popik et al 2008, Silva et al 2010, rats (Akinfiresoye and Tizabi 2013, Fraga et al 2013, Garcia et al 2008a, b, 2009, Li et al 2010, Parise et al 2013, Popik et al 2008, Reus et al 2011, Tizabi et al 2012, Yang et al 2012) and humans (Maeng and Zarate 2007, Rot et al 2010, Zarate et al 2006, and the investigation of its mechanism of action or even the involvement of active metabolites is an active field of research (Li et al 2010, Newport et al 2015, Zanos et al 2016). Contrary to our results, there are few works successfully describing the use of ketamine repeated treatment to mimic schizophrenia negative symptoms in the forced swimming.…”

Section: Discussionmentioning

confidence: 99%

Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects

Neves

Borsoi

Antonio

et al. 2017

An. Acad. Bras. Ciênc.

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Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine subanesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

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Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

Cited by 501 publications

References 172 publications

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

A role for activity‐dependent epigenetics in the development and treatment of major depressive disorder

Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects

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