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A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression
Open accessAbstract
CONTEXT: Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects-for instance, within a few hours or days-would have an enormous impact on patient care and public health. OBJECTIVE: To determine whether an N-methyl-D-aspartate-receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression. DESIGN: A randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009. SETTING: Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland. Patients Eighteen subjects with DSM-IV bipolar depression (treatment-resistant). INTERVENTIONS: Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The Montgomery-Asberg Depression Rating Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 postinfusion. MAIN OUTCOME MEASURES: Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores. RESULTS: Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d = 0.52, 95% confidence interval [CI], 0.28-0.76); this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d = 0.80, 95% CI, 0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms, only at the 40-minute point. CONCLUSION: In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist.
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In the citing paper
“Recently, ketamine has been shown to have a rapid effect on depressive symptoms and suicidal ideation after a single dose.8 9 10 11”
From Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial (2022) · cites this paper as [8]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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 [5]
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In the citing paper
“Intravenous ketamine (level 3)477, 478 has rapid onset of efficacy”
The cited source says what the claim attributes to it.
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 [12]
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 [12]
In the citing paper
“Firstly, the suicidal risk was often poorly measured (eg, with one single item of a depression scale).”
From Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial (2022) · cites this paper as [8]
In the citing paper
“Thirdly, samples were usually small.”
From Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial (2022) · cites this paper as [8]
In the citing paper
“Secondly, response (usually defined as a 50% score reduction on a scale) was the most common outcome rather than remission (that is, complete absence of suicidal ideas).”
From Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial (2022) · cites this paper as [8]
In the citing paper
“Results in bipolar disorder—a disorder associated with a high suicidal risk and limited options to treat depression27—are highly encouraging and support two previous small studies.8 28”
From Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial (2022) · cites this paper as [8]
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 [149]
In the citing paper
“In addition to the therapeutic effects of ketamine in major depressed patients, ketamine exerts antidepressant actions in patients suffering with bipolar depression, with a similar response rate 20, 21.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [20]
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Citations
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A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
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Yatham, L. N., Kennedy, S. H., Parikh, S. V., Schaffer, A., Bond, D. J., Frey, B. N., Sharma, V., Goldstein, B. I., Rej, S., Beaulieu, S., et al. (2018) · Bipolar Disorders · doi:10.1111/bdi.12609 · Cited by 1,852
Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants
Duman, R. S., Aghajanian, G. K., Sanacora, G., & Krystal, J. H. (2016) · Nature Medicine · doi:10.1038/nm.4050 · Cited by 1,750
NMDAR inhibition-independent antidepressant actions of ketamine metabolites
Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. I., Alkondon, M., Yuan, P., Pribut, H. J., Singh, N. S., et al. (2016) · Nature · doi:10.1038/nature17998 · Cited by 1,609
Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders
Autry, A. E., & Monteggia, L. M. (2012) · Pharmacological Reviews · doi:10.1124/pr.111.005108 · Cited by 1,390
Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms
Zanos, P., Moaddel, R., Morris, P. J., Riggs, L. M., Highland, J. N., Georgiou, P., Pereira, E. F. R., Albuquerque, E. X., Thomas, C. J., Zarate, C. A., et al. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.015198 · Cited by 1,260
Self-citation
Metadata
- Authors
- Diazgranados, N., Ibrahim, L., Brutsche, N. E., Newberg, A., Kronstein, P., Khalife, S., Kammerer, W. A., Quezado, Z., Luckenbaugh, D. A., Salvadore, G., Machado-Vieira, R., Manji, H. K., & Zarate, C. A.
- Affiliations
- National Institutes of Health (US)
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2010-08-01
- Volume
- 67
- Issue
- 8
- Pages
- 793
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC3000408
- OpenAlex
- W2108403304
- Cited by
- 963
- References
- 50
- Citations by year
- 2026: 14 · 2025: 45 · 2024: 31 · 2023: 40 · 2022: 56 · 2021: 68 · 2020: 76 · 2019: 52 · 2018: 66 · 2017: 55 · 2016: 81 · 2015: 96 · 2014: 73 · 2013: 80 · 2012: 73
- FWCI
- 48.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 MH999999)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Keywords
- bipolar depression, treatment-resistant depression, ketamine, NMDA receptor antagonists, rapid antidepressant effects, intravenous infusion, lithium, valproic acid, manic symptoms
- MeSH terms
- Adolescent, Adult, Aged, Bipolar Disorder, Double-Blind Method, Drug Resistance, Drug Therapy, Combination, Female, Humans, Ketamine, Male, Middle Aged, Placebos, Psychiatric Status Rating Scales, Valproic Acid, N-Methylaspartate, Treatment Outcome, Lithium Compounds, Excitatory Amino Acid Antagonists, Diagnostic and Statistical Manual of Mental Disorders
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