A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression

Zarate, Carlos A.; Singh, Jaskaran; Carlson, Paul J.; Brutsché, Nancy E.; Ameli, Rezvan; Luckenbaugh, David A.; Charney, Dennis S.; Manji, Husseini K.

doi:10.1001/archpsyc.63.8.856

Cited by 3,282 publications

(2,444 citation statements)

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“…Preclinical and clinical studies have reported that low doses of the noncompetitive NMDAR antagonist and psychotomimetic ketamine have a rapid antidepressant action: a rapid (within hours) and sustained (up to 1 week) antidepressant effect on core symptoms can be induced by a single subanesthetic dose of intravenously-infused ketamine in patients with treatment-resistant depression [7,8,14,111] .…”

Section: Ketamine Has Rapid-onset Antidepressant Effi Cacymentioning

confidence: 99%

“…Thus, the mechanisms underlying the clinical response to antidepressants may include effects on neural plasticity. This point of view is strongly supported by the rapid onset of antidepressant efficacy of ketamine in clinical trials, because NMDAR activation is critical for both LTP and hippocampusdependent memory [8,13,14] . These developments suggest an alternative etiology for depression due to functional disturbances of neural plasticity in the glutamatergic system.…”

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confidence: 94%

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Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

et al. 2014

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Depression is a devastating psychiatric disorder widely attributed to defi cient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4−8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplifi cation. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant effi cacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modifi ed indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.Keywords: depression; stress; neural plasticity; glutamatergic transmission; monoamine-based antidepressant; ketamine IntroductionDepression is a common psychiatric disorder, with prevalence rates of 19% in Beirut and 16.2% in the UnitedStates [1] . Depression is also one of the leading causes of severe mental disability, suicide, and socioeconomic burden, and its diagnosis sometimes relies on selfreported symptoms in the major depressive inventory [2,3] .The pathogenesis of depression is still not clear, and currently available antidepressants are far from satisfactory.Most antidepressants target the monoaminergic system [4] ; however, 30%-40% of patients are resistant to monoaminebased antidepressants (remittance rates of 13% to 36.8% with citalopram [5] ), and a clinically significant reduction of depressive symptoms in responders usually requires 4−8 weeks of daily treatment [6] . These limitations result in a large proportion of patients at high risk of suicide even after diagnosis. Thus, it is necessary to search for new antidepressants outside the monoaminergic system. R ecent clinical studies have demonstrated that a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has rapid antidepressant efficacy within 2 h that can be sustained for over 7 days in patients with treatment-resistant depression [7,8] . This finding suggests that depression could be directly associated with defi cits in glutamatergic synaptic transmission and plasticity. The monoaminergic hypothesis of depression, based on the efficacy of antidepressants that enhance monoaminergic transmission and signaling, has dominated the field of depression research for nearly half a century.However, the primacy of monoaminergic dysfunction in depression is inconsistent with the delay between enhancement of synaptic monoamines confer...

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Section: Ketamine Has Rapid-onset Antidepressant Effi Cacymentioning

confidence: 99%

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confidence: 94%

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

et al. 2014

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“…Response rates for initial treatment are estimated to be about 50%, while remission, considered to be the goal of treatment, ranges from 15–40% 1. The metabotropic glutamate receptor 5 (mGlu5) receptor has emerged as an attractive target for the treatment of anxiety and depressive disorders based on its expression pattern in the brain and the efficacy of mGlu5 antagonists in various animal models 2, 3. Glutamate is the main excitatory neurotransmitter that mediates its effects via ionotropic glutamate receptors (i.e., N‐methyl‐D‐aspartate (NMDA), α‐amino‐3‐hydroxy‐5‐methylisoazol‐4‐priopionate (AMPA) or kainate receptors) and G‐protein‐coupled receptors (e.g., mGlu receptors).…”

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confidence: 99%

Population Pharmacokinetic and Exposure–dizziness Modeling for a Metabotropic Glutamate Receptor Subtype 5 Negative Allosteric Modulator in Major Depressive Disorder Patients

Cosson

Schaedeli‐Stark

Arab‐Alameddine

et al. 2018

Clinical Translational Sci

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Dizziness, the most frequently observed adverse event in patients with major depressive disorder, was observed with basimglurant, a selective, orally active metabotropic glutamate receptor subtype 5 negative allosteric modulator. The potential relationship between dizziness and basimglurant exposure was explored. The pharmacokinetics of basimglurant was characterized with nonlinear mixed effects modeling using data from 288 trial participants enrolled in five clinical trials. The pharmacokinetics of basimglurant after daily oral administration of a modified release formulation was best described by a two‐compartment disposition model with a transit compartment, lag time for the absorption, and first‐order elimination. The largest covariate effects were the effect of smoking and male gender on apparent clearance followed by the effect of body weight on distribution volumes. Clearance was twofold higher in smokers and 40% higher in males. A logistic regression model showed a statistically significant correlation between basimglurant Cmax and incidence of dizziness. An increased risk of dizziness is predicted with increasing doses.

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“…Ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist that has attracted widespread attention for its rapid-onset antidepressant effects, especially in individuals with treatment-resistant depression and suicidal ideation [1][2][3]. Compared with the traditional antidepressants that take weeks, if not months, to benefit patients and are associated with a high rate of relapse, ketamine exerts its antidepressant effects within several hours.…”

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confidence: 99%

“…Compared with the traditional antidepressants that take weeks, if not months, to benefit patients and are associated with a high rate of relapse, ketamine exerts its antidepressant effects within several hours. These clinical benefits can last for 2 weeks after a single injection [1,2,4]. However, ketamine still has limited clinical application, mainly because of its psychotomimetic side-effects and liability of abuse.…”

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confidence: 99%

On the Eve of Upgrading Antidepressants: (R)-Ketamine and Its Metabolites

et al. 2016

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A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression

Abstract: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.

Cited by 3,282 publications

References 55 publications

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

Population Pharmacokinetic and Exposure–dizziness Modeling for a Metabotropic Glutamate Receptor Subtype 5 Negative Allosteric Modulator in Major Depressive Disorder Patients

On the Eve of Upgrading Antidepressants: (R)-Ketamine and Its Metabolites

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