Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study
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OBJECTIVE: The authors compared the efficacy of standard-of-care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among individuals at imminent suicide risk. METHOD: In a double-blind, multicenter, proof-of-concept study, 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment. The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the Montgomery-Åsberg Depression Rating Scale (MADRS). Clinician global judgment of suicide risk (from the Suicide Ideation and Behavior Assessment Tool) was also assessed. Secondary endpoints included these measures at 24 hours and double-blind endpoint at day 25. RESULTS: A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours (least-square mean difference=-5.3, SE=2.10; effect size=0.61) and at ∼24 hours (least-square mean difference=-7.2, SE=2.85; effect size=0.65), but not at day 25 (least-square mean difference=-4.5, SE=3.14; effect size=0.35). Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours (effect size=0.67), but not at 24 hours (effect size=0.35) or at day 25 (effect size=0.29). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point. The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache. CONCLUSIONS: These preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide.
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Antidepressants reduced suicidal ideation in 9 of 12 studies that reported effects on suicidal ideation.
“More promisingly, antidepressants reduced suicidal ideation in 9/12 studies that reported effects on suicidal ideation.(55, 57, 59–65)”
From Improving Suicide Prevention Through Evidence-Based Strategies: A Systematic Review (2021) · cites this paper as [63]
The Efficacy Results (p. 625) report reduced suicidal thoughts with esketamine versus placebo at 4 hours, so this paper supports one instance of the claimed effect. It is a single trial, however, and does not report that antidepressants reduced suicidal ideation in 9 of 12 studies. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe effects of ketamine on suicidal ideation may be linked to improvements in insomnia, a clinical variable that has been linked to suicidal behaviour.
“Of interest, the effects of ketamine on suicidal ideation may be linked to improvements in insomnia 313 , a clinical variable that has been linked to suicidal behaviour 314 .”
From Suicide and suicide risk (2019) · cites this paper as [314]
The Efficacy Results report improved suicidal-thought scores after esketamine, supporting the treatment-effect portion of the clause cited as 313. The paper does not link that effect to improvements in insomnia; searches for insomnia and sleep disturbance found no such analysis. The separate claim about insomnia and suicidal behaviour is attached to citation 314, not this source. (LLM, conf=0.81)
Experimental — accuracy not yet measuredEarlier studies of esketamine in patients with treatment-resistant depression and major depression at imminent risk for suicide, which demonstrated greater magnitude of early response, applied a less stringent definition for response onset and employed site-based raters for efficacy evaluation.
“Earlier studies of esketamine in patients with treatmentresistant depression (10,11) and major depression at imminent risk for suicide (12), which demonstrated greater magnitude of early response, applied a less stringent definition for response onset and employed site-based raters for efficacy evaluation.”
From Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study (2019) · cites this paper as [12]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn the major esketamine trials, significantly increased rates of somnolence versus placebo have been reported, especially in relapse-prevention studies, but this has not been seen consistently.
“However, when reviewing the major esketamine trials, significantly increased rates of somnolence versus placebo have been reported, especially in relapse-prevention studies,74,152 but this has not been seen consistently.153”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [153]
Altered expression of NMDA, AMPA, and kainite glutamate receptors is linked to suicidal behavior and may play a role in the rapid-onset antidepressant and antisuicidal effects of ketamine.
“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 [134]
Intranasal ketamine or esketamine shows promise as anti-suicidal ideation treatment and is less invasive, but absorption is more erratic and it must be administered in medical settings.
“Intranasal ketamine (or esketamine) also shows promise as anti–suicidal ideation treatment (134) and is less invasive, but its absorption is more erratic, and, like intravenous ketamine, it must be administered in medical settings.”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [134]
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Esketamine combined with SSRI or SNRI for treatment-resistant depression
Del Casale, A., Spirito, S., Arena, J. F., Preissner, S., Borro, M., Gentile, G., Modesti, M. N., Preissner, R., Ferracuti, S., & Simmaco, M. (2025) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2025.0200 · Cited by 23 · see citing works
Surjan, J., Grossi, J. D., Del Porto, J. A., Delfino, R. S., de Oliveira Cerqueira, R., Lucchese, A. C., Magalhães, E., Del Sant, L. C., Tuena, M. A., Nakahira, C., et al. (2022) · Clinical Drug Investigation · doi:10.1007/s40261-022-01193-z · Cited by 19 · see citing works
Sackeim, H. A., Dibué, M., Bunker, M. T., & Rush, A. J. (2020) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s286977 · Cited by 15 · see citing works
Clinical trials for rapid changes in suicidal ideation: lessons from ketamine
Ballard, E. D., Fields, J., Farmer, C. A., & Zarate, C. A. (2021) · Suicide and Life-Threatening Behavior · doi:10.1111/sltb.12663 · Cited by 10 · see citing works
Yadav, A., Dogra, S., Boda, A. K., Kumari, P., Kumar, A., Dash, M. K., & Yadav, P. N. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.4c00175 · Cited by 9 · see citing works
Bloomfield-Clagett, B., Ballard, E. D., Greenstein, D. K., Wilkinson, S. T., Grunebaum, M. F., Murrough, J. W., Mathew, S. J., Phillips, J. L., Fava, M., Sanacora, G., et al. (2022) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyac055 · Cited by 8 · see citing works
Self-citationLi, J., Ma, L., Sun, H., Li, M., Cao, Y., Peng, Y., & Xu, J. (2025) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-024-01920-x · Cited by 5 · see citing works
From psychache to neuroplasticity: A unified rescue-repair model of Ketamine’s anti-suicidal action
Domany, Y., & Solomon-Shashua, A. (2026) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2026.106804 · Cited by 2 · see citing works
- Authors
- Canuso, C. M., Singh, J. B., Fedgchin, M., Alphs, L., Lane, R., Lim, P., Pinter, C., Hough, D., Sanacora, G., Manji, H., & Drevets, W. C.
- Affiliations
- Yale University (US)
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2018-07-01
- Volume
- 175
- Issue
- 7
- Pages
- 620-630
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- OpenAlex
- W2796940952
- Cited by
- 676
- References
- 33
- Citations by year
- 2026: 38 · 2025: 55 · 2024: 69 · 2023: 58 · 2022: 67 · 2021: 84 · 2020: 232 · 2019: 55 · 2018: 17
- FWCI
- 62.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- AstraZeneca
- Sanofi
- Yale University
- Janssen Scientific Affairs
- Vistagen Therapeutics
- Servier
- National Institutes of Health
- Allergan
- Janssen Research and Development
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
- Keywords
- intranasal esketamine, major depressive disorder, suicidal ideation, suicide risk, rapid-acting antidepressants, antidepressant efficacy, adverse events, dissociation, standard of care treatment
- MeSH terms
- Suicide Prevention, Administration, Intranasal, Adult, Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Double-Blind Method, Female, Humans, Ketamine, Male, Psychiatric Status Rating Scales, Risk Factors
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