Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression

Daly, Ella; Singh, Jaskaran; Fedgchin, Maggie; Cooper, Kevin; Lim, Pilar; Shelton, Richard C.; Thase, Michael E.; Winokur, Andrew; Nueten, Luc Van; Manji, Husseini K.; Drevets, Wayne C.

doi:10.1001/jamapsychiatry.2017.3739

Cited by 483 publications

(416 citation statements)

References 45 publications

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“…In addition, in patients with depression, intravenous, 40-min infusion of ( S )-ketamine (0.2 and 0.4 mg/kg) has been reported to exert antidepressant responses within 2 hours following administration, an effect that was sustained for at least 3 days, with some patients reporting beneficial effects for up to a period of two weeks following a single administration 18 . In addition, intranasal administration of 28–84 mg ( S )-ketamine twice a week for a total period of two weeks induced antidepressant actions in treatment-resistant depressed patients as an adjunct treatment 119 . To date, there is no human clinical trial directly comparing the antidepressant efficacy of ( S )- and ( R )-ketamine enantiomers, or assessing antidepressant actions of ( R )-ketamine in depressed patients.…”

Section: Nmdar Inhibition-independent Mechanismsmentioning

confidence: 99%

Mechanisms of ketamine action as an antidepressant

2018

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Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions in treatment-resistant patients. Although this finding has been met with enthusiasm, ketamine’s widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the unique antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine’s antidepressant actions but lack its undesirable effects. Here, we review hypotheses for the mechanism of action of ketamine as an antidepressant, including direct synaptic or extra-synaptic (GluN2B-selective) NMDAR inhibition, selective inhibition of NMDARs localized on GABAergic interneurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) activation. We also discuss links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR), and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine’s (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine’s action are not mutually exclusive and may act in a complementary fashion to exert the acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine’s antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression.

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Section: Nmdar Inhibition-independent Mechanismsmentioning

confidence: 99%

Mechanisms of ketamine action as an antidepressant

2018

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“…In a randomized, double-blind placebo-controlled trial, intravenous infusion of the ( S )-ketamine enantiomer (40-min infusion, 0.2 and 0.4 mg/kg) exerted antidepressant responses one day post-administration, which was sustained for three days, and in some patients lasted for up to two weeks following a single infusion [35]. In addition, a randomized controlled clinical trial indicated dose-dependent antidepressant actions of intranasally-administered ( S )-ketamine (administration regimen: 28–84 mg, twice a week for a total of 2 weeks) in treatment-resistant depressed patients under oral classical antidepressant treatment [63]. Pre-clinical rodent studies have also indicated rapid-acting antidepressant behavioral actions of ( S )-ketamine following chronic social defeat stress, where the drug reduced behavioral despair (i.e.…”

Section: Ketamine: the Prototype Rapid-acting Antidepressantmentioning

confidence: 99%

Convergent Mechanisms Underlying Rapid Antidepressant Action

et al. 2018

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Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal and anti-anhedonic actions following a single administration to depressed patients. Proposed mechanisms of ketamine’s antidepressant action include N-methyl-D-aspartate receptor (NMDAR) modulation, GABAergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergoing pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine - pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists (i.e. GLYX-13 (rapastinel)), metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.

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“…A subset of patients who received 4 more open-label infusions spaced 3–4 days apart continued to respond. In a phase 2, industry-sponsored study of 67 patients with treatment-resistant depression (64% of whom had not responded to a single antidepressant during the current episode) [59] intranasal esketamine added to ongoing antidepressant therapy was significantly superior to placebo in reducing depressive symptoms during a 2-week double-blind phase. Subsequently, 5 weeks of open-label treatment twice a week followed by open administration once a week and then once every other week resulted in increasing improvement that was maintained at 8 weeks of follow-up without further treatment.…”

Section: Ketamine Derivatives and Related Drugsmentioning

confidence: 99%