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A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Open accessAbstract
CONTEXT: Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. OBJECTIVE: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. DESIGN: A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. SETTING: Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects with DSM-IV major depression (treatment resistant). INTERVENTIONS: After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. RESULTS: Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. CONCLUSIONS: 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.
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“Shortly thereafter, ketamine's robust antidepressant effects were confirmed in treatmentresistant depression (TRD) and bipolar disorder (BD) [5][6][7]”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Not only do they produce sustained therapeutic effects following a single administration, they also appear to have broad therapeutic potential”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [38]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Unlike traditional antidepressants, psychoplastogens produce both fast-acting and sustained beneficial behavioral effects after a single administration (Figure 1) (38–42).”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [38]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The rapid-acting dissociative agent ketamine, which has shown its efficacy in treating depression, is known to increase BDNF levels (37, 38).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [37]
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“However, other NMDAR antagonists do not show antidepressant effects (Zarate et al., 2006)”
From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Zarate et al., 2006
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“Ketamine's half-life in the body is ;2 h (Autry et al., 2011), yet a single low-dose treatment elicits sustained (.1 week) antidepressant effects in patients (Berman et al., 2000;Zarate et al., 2006;Price et al., 2009), strongly suggesting it induces neuroplasticity (Duman, 2018).”
From Psychedelics and Neural Plasticity: Therapeutic Implications (2022) · cites this paper as Zarate et al., 2006
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“A single dose of ketamine alleviates depressive symptoms within hours in patients who have failed to respond to two or more conventional antidepressants, and the effects are sustained for 7 to 10 days.”
From Synaptic Dysfunction in Depression: Potential Therapeutic Targets (2012) · cites this paper as [5]
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“Ketamine's anxiolytic effects have also been supported by placebo-controlled trials which demonstrated that the psychic anxiety item on the 21item HAM-D significantly improved after ketamine infusion (compared to saline); the psychic anxiety item was one of only four items to improve (Zarate et al, 2006).”
From Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial (2018) · cites this paper as Zarate et al, 2006
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“A power analysis based on ketamine's antidepressant effects was used to determine the sample size of 18 (Murrough et al, 2013a;Zarate et al, 2006).”
From Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial (2018) · cites this paper as Zarate et al, 2006
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“which induce similar immediate antidepressant response rates (71% at 28 hours for ketamine vs. 69% at 48 hours for psilocybin) 94”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [94]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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“A notable recent discovery shows that ketamine, a N-methyl-D-aspartate receptor antagonist, produces rapid (within hours) antidepressant responses in patients who are resistant to typical antidepressants.”
From Synaptic Dysfunction in Depression: Potential Therapeutic Targets (2012) · cites this paper as [5]
The cited source says what the claim attributes to it.
In the citing paper
“Ketamine, an antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor (an ionotropic glutamate receptor), was shown to exhibit rapid onset and robust, short-term antidepressant effect in patients with treatment-resistant depression (TRD) [1–3].”
From Cardiac Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: Results from the Clinical Development Program (2020) · cites this paper as [2]
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In the citing paper
“Racemic ketamine was obtained from the Yale-New Haven Hospital Pharmacy and administered intravenously by constant infusion over 40 minutes at a dose of 0.5mg/kg, which has consistently been shown to have robust and rapid antidepressant effects 7,8 , and is typically used clinically.”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [7]
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In the citing paper
“Several clinical studies suggest that ketamine may also have significant anxiolytic effects.”
From Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial (2018) · cites this paper as Zarate et al, 2006
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In the citing paper
“The results of the study are consistent with previous work suggesting that ketamine has anxiolytic effects in patients with major depression (Salvadore et al, 2009;Zarate et al, 2006).”
From Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial (2018) · cites this paper as Zarate et al, 2006
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In the citing paper
“Several studies have demonstrated the efficacy of ketamine for treatment-resistant depression (Zarate et al, 2006).”
From Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial (2018) · cites this paper as Zarate et al, 2006
The cited source says what the claim attributes to it.
In the citing paper
“The lack of efficacy in our trial is likely due the fact that in our study most patients had mild to moderate depression as opposed to the more severe treatment-resistant major depression studied in ketamine clinical trials (Murrough et al, 2013a;Murrough et al, 2013b;Zarate et al, 2006).”
From Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial (2018) · cites this paper as Zarate et al, 2006
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“Intravenous ketamine administered at subanesthetic doses was found to exhibit robust and rapid onset of efficacy in patients with treatment-resistant depression (9).”
The cited source says what the claim attributes to it.
In the citing paper
“whereas it typically does not produce the sustained antidepressant response of psilocybin (35% at week 1 for ketamine vs. 71% at 1 month for psilocybin). 73,94,95”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [94]
In the citing paper
“Subsequent randomized controlled trials (RCTs) replicated this finding, demonstrating a 60–70% response rate of ketamine in TRD populations.10–14”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [11]
In the citing paper
“However, ketamine’s antidepressant properties are also transient, lasting an average of 1 week following a single infusion10–14 and 18–19 days following repeated infusions.15,16”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [11]
In the citing paper
“Diverse NMDA receptor antagonism has demonstrated rapid antidepressant efficacy in preclinical depression paradigms [24,29,70,71] and in some clinical trials [72,73].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [73]
In the citing paper
“Comparable results have been replicated in several similarly designed RDBPCTs examining single administration of sub-anesthetic dose ketamine in patients with MDD and TRD [73,91,92,93].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [73]
In the citing paper
“Extensive experience with human patients has established that ketamine exerts rapid, robust antidepressant, antianhedonic, and antisuicidal actions within two hours of administration that are sustained for at least seven days in patients with major depression following a single infusion or intranasal administration [129-133].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [130]
In the citing paper
“Ketamine’s therapeutic effects occur within hours, with the strongest effect sizes observed at one day post-administration (Zarate et al., 2006).”
From Clinical indicators of the suicide crisis and response to ketamine (2025) · cites this paper as Zarate et al., 2006
In the citing paper
“A single, intravenous or intranasal sub-anesthetic dose of ketamine, a non-competitive NMDA glutamate receptor channel blocker, produces a rapid onset of antidepressant response that can last several days in the majority of treatment resistant unipolar and bipolar depressed patients participating in a growing number of clinical trials148–150.”
From Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants (2016) · cites this paper as [150]
In the citing paper
“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.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [5]
In the citing paper
“A subsequent double-blind randomized clinical trial demonstrated the efficacy of ketamine in treatment-resistant major depressed patients, who failed at least two conventional antidepressant treatments 5.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [5]
In the citing paper
“The antidepressant effects of ketamine manifested within 2 hours post-infusion and 35% of patients maintained response for at least 7 days 5.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [5]
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Metadata
- Authors
- Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K.
- Affiliations
- National Institutes of Health (US)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2006-08-01
- Volume
- 63
- Issue
- 8
- Pages
- 856
- ISSN
- 0003-990X (ISSN-L)
- OpenAlex
- W2109334244
- Semantic Scholar
- 3e83c317059846d97106b64a4befc4c24b87e3d1
- Cited by
- 3,766
- References
- 62
- Citations by year
- 2026: 125 · 2025: 186 · 2024: 240 · 2023: 197 · 2022: 222 · 2021: 249 · 2020: 404 · 2019: 229 · 2018: 233 · 2017: 202 · 2016: 237 · 2015: 223 · 2014: 190 · 2013: 206 · 2012: 159
- FWCI
- 48.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- ketamine, NMDA receptor antagonists, treatment-resistant depression, major depressive disorder, rapid antidepressant effects, intravenous infusion, glutamatergic system, antidepressant onset of action, remission
- MeSH terms
- Adult, Antidepressive Agents, Major Depressive Disorder, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Drug Resistance, Female, Humans, Infusions, Intravenous, Ketamine, Male, Middle Aged, Placebos, Psychiatric Status Rating Scales, Receptors, N-Methyl-D-Aspartate, Treatment Outcome, Cross-Over Studies, Excitatory Amino Acid Antagonists
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