Ketamine: translating mechanistic discoveries into the next generation of glutamate modulators for mood disorders

Zarate, Carlos A.; Machado‐Vieira, Rodrigo

doi:10.1038/mp.2016.249

Cited by 27 publications

(37 citation statements)

References 40 publications

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“…This may contribute to increased glutamatergic transmission by insertion of AMPARs at synapses in the hippocampus and medial prefrontal cortex. 3,11,38 In the NAc, we found that LTP in saline-treated mice is blocked by an mTOR inhibitor, rapamycin, suggesting a role for mTOR in this form of synaptic plasticity. In line with this possibility, an LTP induction protocol was shown to increase mTOR phosphorylation in the medial prefrontal cortex.…”

Section: Discussionmentioning

confidence: 80%

“…Unfortunately, the usefulness of ketamine for the treatment of depression is limited because of the dissociative, psychotic and abuse properties of this drug. [1][2][3][4] The antidepressant mechanism of action of ketamine has been proposed to be mediated through non-competitive antagonism at N-methyl-Daspartate receptors (NMDARs) and subsequent activation of AMPA receptors (AMPARs). 5 Furthermore, a recent study demonstrated antidepressant efficacy, with reduced side effects, of a metabolite of ketamine, (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), through stimulation of AMPARs, independently of NMDAR antagonism.…”

Section: Introductionmentioning

confidence: 99%

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Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

et al. 2017

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Low doses of ketamine trigger rapid and lasting antidepressant effects after one injection in treatment-resistant patients with major depressive disorder. Modulation of AMPA receptors (AMPARs) in the hippocampus and prefrontal cortex is suggested to mediate the antidepressant action of ketamine and of one of its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK). We have examined whether ketamine and (2R,6R)-HNK affect glutamatergic transmission and plasticity in the mesolimbic system, brain regions known to have key roles in reward-motivated behaviors, mood and hedonic drive. We found that one day after the injection of a low dose of ketamine, long-term potentiation (LTP) in the nucleus accumbens (NAc) was impaired. Loss of LTP was maintained for 7 days and was not associated with an altered basal synaptic transmission mediated by AMPARs and N-methyl-D-aspartate receptors (NMDARs). Inhibition of mammalian target of rapamycin signaling with rapamycin did not prevent the ketamine-induced loss of LTP but inhibited LTP in saline-treated mice. However, ketamine blunted the increase in the phosphorylation of the GluA1 subunit of AMPARs at a calcium/calmodulin-dependent protein kinase II/protein kinase C site induced by an LTP induction protocol. Moreover, ketamine caused a persistent increased phosphorylation of GluA1 at a protein kinase A site. (2R,6R)-HNK also impaired LTP in the NAc. In dopaminergic neurons of the ventral tegmental area from ketamine-or (2R,6R)-HNK-treated mice, AMPAR-mediated responses were depressed, while those mediated by NMDARs were unaltered, which resulted in a reduced AMPA/NMDA ratio, a measure of long-term synaptic depression. These results demonstrate that a single injection of ketamine or (2R,6R)-HNK induces enduring alterations in the function of AMPARs and synaptic plasticity in brain regions involved in reward-related behaviors.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

et al. 2017

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“…In 2000, a pilot study reported that intravenous infusion of a subanesthetic dose (0.5 mg/kg) of the NMDAR antagonist ketamine (0.5 mg/kg) produced a rapid and robust antidepressant effect in patients with depression [2]. These observations raised the possibility of an alternative to available biogenic amine-based antide pressants that often take weeks to months to produce a clinically meaningful therapeutic effect, leaving patients at increased risk of suicide [1,3,4]. …”

mentioning

confidence: 99%

“…Between 15% and 30% of patients who have a major depressive disorder (MDD) do not respond satisfactorily to two successive courses of antidepressant treatment (‘treatment-resistant depression’;TRD) [1,3,4]. In 2006, a randomized controlled trial (RCT) conducted by the National Institute of Health (NIH) [5] clearly demonstrated a rapid and robust effect of subanesthetic ketamine in TRD.…”

mentioning

confidence: 99%

“…In 2006, a randomized controlled trial (RCT) conducted by the National Institute of Health (NIH) [5] clearly demonstrated a rapid and robust effect of subanesthetic ketamine in TRD. This study was a milestone because of the profound impact of TRD on public health: patients with TRD experience a reduced quality of life, severe impairment in social functioning and workplace performance, and are at increased risk of suicide, all contributing to a significant healthcare burden [1,3,4]. Although growing in popularity, the use of intravenous subanesthetic ketamine in TRD remains off-label, limited to a medical setting, and is burdened by other significant challenges [3].…”

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confidence: 99%

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The development of glutamate-based antidepressants is taking longer than expected

Garay¹,

Zarate

Cavero³

et al. 2018

Drug Discovery Today

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Effects of ketamine on circadian rhythm and synaptic homeostasis in patients with treatment‐resistant depression: A protocol for mechanistic studies of its rapid and sustained antidepressant actions in humans

Zhuo

Tian

et al. 2019

Brain and Behavior

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BackgroundThe breakthrough discovery has been made that a single dose of ketamine, an N‐methyl‐D‐aspartate receptor antagonist, achieves rapid and sustained (~7 days) antidepressant activity in patients with major depressive disorder (MDD). This discovery has ushered in an exciting era of research and brought new hope for patients with MDD. However, the mechanisms underlying the specific antidepressant actions of ketamine in humans remain to be elucidated.ObjectivesThis study protocol was designed to test the main hypothesis that ketamine could rapidly reverse depression‐ and stress‐associated synaptic loss and deficits in resting‐state functional connectivity and that this action could be affected by circadian rhythm, in patients with treatment‐resistant depression.Methods/Study DesignIn this clinical study, adults (aged 18–65 years) with treatment‐resistant depression will be randomized to intravenous administration of placebo (control group) or ketamine (0.5 mg/kg body weight) at 11 a.m. (daytime group), or 6 p.m. (nighttime group) for 24 weeks. The primary outcome will be the change from baseline to 24 weeks in the total Montgomery‐Asberg Depression Rating Scale score. Brain imaging, sleep, and genetic studies, including functional magnetic resonance imaging, positron emission tomography, polysomnography, and genetic analyses, will be performed to examine whether and how ketamine can rapidly reverse deficits in synaptic function and to identify objective markers for the assessment of ketamine infusion therapy for treatment‐resistant depression.ConclusionsThis clinical study protocol is the first, to our knowledge, to describe the prospective testing of the hypothesis that daytime and nighttime administrations of ketamine would have different antidepressant effects. The brain imaging, sleep, and genetic findings from patients with treatment‐resistant depression are expected to shed new light on the mechanisms of ketamine and its interaction with target sites in the brain, which can be used for objective evaluation of the efficacy of ketamine.

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Ketamine: translating mechanistic discoveries into the next generation of glutamate modulators for mood disorders

Cited by 27 publications

References 40 publications

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

The development of glutamate-based antidepressants is taking longer than expected

Effects of ketamine on circadian rhythm and synaptic homeostasis in patients with treatment‐resistant depression: A protocol for mechanistic studies of its rapid and sustained antidepressant actions in humans

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