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Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial
Open accessAbstract
OBJECTIVE: Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. The authors tested the acute effect of adjunctive subanesthetic intravenous ketamine on clinically significant suicidal ideation in patients with major depressive disorder. METHOD: In a randomized clinical trial, adults (N=80) with current major depressive disorder and a score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomly assigned to receive ketamine or midazolam infusion. The primary outcome measure was SSI score 24 hours after infusion (at day 1). RESULTS: The reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI=2.33, 7.59; Cohen's d=0.75). The proportion of responders (defined as having a reduction ≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio=2.85, 95% CI=1.14, 7.15; number needed to treat=4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate=7.65, 95% CI=1.36, 13.94), and this effect mediated 33.6% of ketamine's effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up. CONCLUSIONS: Adjunctive ketamine demonstrated a greater reduction in clinically significant suicidal ideation in depressed patients within 24 hours compared with midazolam, partially independently of antidepressant effect.
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In the citing paper
“Ketamine, an NMDA glutamate receptor antagonist, reduced suicidal ideation within 1–4 hours in major depression(71–75) and bipolar disorder.(76, 77)”
From Improving Suicide Prevention Through Evidence-Based Strategies: A Systematic Review (2021) · cites this paper as [72]
In the citing paper
“Furthermore, ketamine has been reported to also have anti-suicidal and anti-anhedonic actions.14,19,20”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [19]
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 [10]
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 [10]
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 [10]
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 [10]
In the citing paper
“The persistence of the ketamine effect at six weeks of intake is not in line with previous studies10 11 31 and the related meta-analysis,12 but those three studies together analysed only 63 patients.”
From Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial (2022) · cites this paper as [10]
In the citing paper
“Altered expression of glutamate receptor N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainite glutamate receptors is linked to suicidal behavior (129) and may play a role in the rapid-onset antidepressant and antisuicidal effects of ketamine (130-135).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [132]
In the citing paper
“The anti–suicidal ideation effect of ketamine is only partly explained by its antidepressant action, and effects on memory and cognition may also play a role (131-133).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [132]
In the citing paper
“Intravenous ketamine is a rapidly acting treatment that robustly reduces depressive symptoms and suicidal ideation in hours instead of weeks (130-133).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [132]
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“Medications with the potential of lowering risk of suicide include lithium in patients with bipolar disorder (95, 96), ketamine in patients with severe major depression (95, 97), and clozapine in patients with schizophrenia (95, 98).”
Background
Metadata
- Authors
- Grunebaum, M. F., Galfalvy, H. C., Choo, T.-H., Keilp, J. G., Moitra, V. K., Parris, M. S., Marver, J. E., Burke, A. K., Milak, M. S., Sublette, M. E., Oquendo, M. A., & Mann, J. J.
- Affiliations
- Columbia University Irving Medical Center (US)
- From the Molecular Imaging and Neuropathology Division, Department of Psychiatry, and the Department of Anesthesiology, Columbia University Medical Center and New York State Psychiatric Institute, New York.
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2018-04-01
- Volume
- 175
- Issue
- 4
- Pages
- 327-335
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC5880701
- OpenAlex
- W2771797851
- Cited by
- 431
- References
- 47
- Citations by year
- 2026: 31 · 2025: 45 · 2024: 52 · 2023: 57 · 2022: 62 · 2021: 54 · 2020: 55 · 2019: 43 · 2018: 31
- FWCI
- 24.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH096784)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Keywords
- ketamine, midazolam, suicidal ideation, major depressive disorder, rapid-acting antidepressants, adjunctive pharmacotherapy, suicide risk reduction, antidepressant effects, mediation analysis
- MeSH terms
- Behavior Rating Scale, Suicide Prevention, Adult, Depressive Disorder, Major, Major Depressive Disorder, Double-Blind Method, Female, Humans, Infusions, Intravenous, Ketamine, Male, Midazolam, Middle Aged, Suicide, Young Adult, Suicidal Ideation
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