Intravenous Ketamine for Acute Suicidal Crisis and Psychiatric Hospital Length of Stay

Acute suicidal crises frequently require psychiatric hospitalization and are associated with substantial morbidity, mortality, and healthcare utilization. Conventional antidepressant treatments may require several weeks to achieve clinically meaningful effects, creating an important therapeutic gap during periods of acute suicide risk. Rapid-acting glutamatergic interventions may therefore provide an important therapeutic option during this critical period.

This is a single-center, randomized, double-blind, active placebo-controlled superiority trial conducted at the Institute of Psychiatry, Hospital das Clínicas, University of São Paulo Medical School (IPq-HCFMUSP), São Paulo, Brazil. Adults hospitalized because of suicide risk and presenting with acute suicidal ideation will be randomized in a 1:1 ratio using permuted blocks stratified by psychiatric diagnosis.

Participants assigned to the experimental group will receive eight intravenous infusions of esketamine at a dose of 0.5 mg/kg administered over 40 minutes twice weekly. Participants assigned to the control group will receive intravenous midazolam 0.045 mg/kg as an active placebo. Participants, investigators, and outcome assessors will remain blinded to treatment allocation.

Eligible participants must be enrolled within 72 hours after hospital admission. Following written informed consent and baseline assessments, the first study infusion will be administered within 24 hours after randomization. For the primary analysis, time zero will be defined as the first study infusion.

The primary objective is to determine whether intravenous esketamine reduces time to psychiatric hospital discharge compared with active placebo. Secondary objectives include evaluating remission and severity of suicidal ideation, suicidal behavior, depressive symptoms, psychological pain, hopelessness, global clinical improvement, safety and tolerability, dissociative symptoms, and healthcare costs. Clinical follow-up will continue through Week 12. Exploratory analyses will assess inflammatory biomarkers, BDNF, and genetic markers as potential predictors or mediators of treatment response.

• Esketamine (Drug): ntravenous esketamine 0.5 mg/kg diluted in 100 mL of 0.9% saline, administered over 40 minutes twice weekly for a total of eight infusions.
• Midazolam (Intravenous) (Drug): Intravenous midazolam 0.045 mg/kg diluted in 0.9% saline and administered as an active placebo.

Primary outcomes

• Time to Psychiatric Hospital Discharge [From the first study infusion until discharge from the index psychiatric hospitalization, assessed up to 6 months.]: Time, in days, from the first study infusion to discharge from the index psychiatric hospitalization. Hospital discharge will be considered the event of interest. Participants who do not experience the event during the observation period will be censored at the last date for which outcome information is available. Time to discharge will be compared between participants randomized to intravenous esketamine and participants randomized to active placebo.

Secondary outcomes

• Remission of Suicidal Ideation at 72 Hours [72 hours after the first study infusion]: Proportion of participants achieving complete remission of suicidal ideation, defined as a Scale for Suicide Ideation (SSI) score ≤3.
• Change in Suicidal Ideation Severity [Baseline through Week 12]: Change in clinician-rated and self-rated Scale for Suicide Ideation (SSI) scores from baseline across treatment and follow-up assessments. Higher scores indicate greater severity of suicidal ideation.
• Suicidal Ideation and Behavior During Follow-up [Baseline through Week 12]: Change in suicidal ideation and occurrence of suicidal behavior assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).
• Suicide Attempts During Follow-up [From the first study infusion through Week 12]: Number and proportion of participants experiencing at least one suicide attempt during clinical follow-up.
• Change in Depressive Symptoms Assessed by PHQ-9 [Baseline through Week 12]: Change in Patient Health Questionnaire-9 total score from baseline. Higher scores indicate greater severity of depressive symptoms.
• Change in Depressive Symptoms Assessed by QIDS-SR [Baseline through Week 12]: Change in Quick Inventory of Depressive Symptomatology-Self-Report total score from baseline.
• Change in Clinician-Rated Depressive Symptoms [Baseline through Week 12]: Change in Inventory of Depressive Symptomatology-Clinician Rated (IDS-C30) total score from baseline.
• Change in Psychological Pain [Baseline through Week 12]: Change in Psychological Pain Visual Analog Scale (PPP-VAS) score from baseline.
• Change in Hopelessness [Baseline through Week 12]: Change in Beck Hopelessness Scale (BHS) total score from baseline. Higher scores indicate greater hopelessness.
• Clinical Global Improvement [Through Week 12]: Overall clinical improvement assessed using the Clinical Global Impression-Improvement (CGI-I) scale.
• Change in Manic Symptoms [Baseline through Week 12]: Change in Young Mania Rating Scale (YMRS) total score during treatment and follow-up.
• Change in General Psychiatric Symptoms [Baseline through Week 12]: Change in Brief Psychiatric Rating Scale (BPRS) total score during treatment and follow-up.
• Dissociative Symptoms [After the first study infusion and at weeks 1, 2, 4, 6 and 12.]: Severity of dissociative symptoms assessed using the Clinician-Administered Dissociative States Scale (CADSS) after the first study infusion and at weeks 1, 2, 4, 6 and 12.
• Treatment-Emergent Adverse Events [From the first study infusion through Week 12]: Incidence and severity of adverse events occurring during study treatment and clinical follow-up.
• Treatment-Related Healthcare Costs [From the first study infusion through Week 12]: Healthcare costs associated with the index psychiatric hospitalization, medications, and psychotherapeutic treatments.

Other outcomes

• Change in Plasma Brain-Derived Neurotrophic Factor (BDNF) Levels [Baseline, 24-72 hours after the first infusion, Week 2, and Week 6.]: Change from baseline in plasma brain-derived neurotrophic factor (BDNF) concentrarion, measured using a luminex-based multiplex assay and expressed in ng/ml.
• Change in Plasma Interleukin-6 (IL-6) Concentration [Baseline, 24-72 hours after the first study infusion, Week 2, and Week 6.]: Change from baseline in plasma interleukin-6 (IL-6) concentration, measured using a Luminex-based multiplex assay and expressed in pg/mL.
• Change in Plasma Tumor Necrosis Factor-Alpha (TNF-α) Concentration [Baseline, 24-72 hours after the first study infusion, Week 2, and Week 6.]: Change from baseline in plasma tumor necrosis factor-alpha (TNF-α) concentration, measured using a Luminex-based multiplex assay and expressed in pg/mL.
• Change in Plasma Interleukin-1 Beta (IL-1β) Concentration [Baseline, 24-72 hours after the first study infusion, Week 2, and Week 6.]: Change from baseline in plasma interleukin-1 beta (IL-1β) concentration, measured using a Luminex-based multiplex assay and expressed in pg/mL.
• Change in Plasma Interleukin-10 (IL-10) Concentration [Baseline, 24-72 hours after the first study infusion, Week 2, and Week 6.]: Change from baseline in plasma interleukin-10 (IL-10) concentration, measured using a Luminex-based multiplex assay and expressed in pg/mL
• Odds Ratio for Week 4 Suicidal Ideation Remission per Standard Deviation Increase in Major Depressive Disorder Polygenic Risk Score [Baseline genetic assessment; remission of suicidal ideation assessed at the end of Week 4, after completion of eight study infusions.]: The baseline major depressive disorder polygenic risk score (PRS) will be calculated using large-scale GWAS summary statistics and standardized as a z-score. Remission of suicidal ideation will be defined as a Scale for Suicide Ideation (SSI) score ≤3 at the end of Week 4, after eight study infusions. Logistic regression will estimate the odds ratio (OR) per one-standard-deviation increase in PRS, adjusting for the first 10 principal components of genetic ancestry.
• Odds Ratio for Week 4 Suicidal Ideation Remission per Standard Deviation Increase in Suicidal Behavior Polygenic Risk Score [Baseline genetic assessment; remission of suicidal ideation assessed at the end of Week 4, after completion of eight study infusions.]: The baseline suicidal behavior polygenic risk score (PRS) will be calculated using large-scale GWAS summary statistics and standardized as a z-score. Remission of suicidal ideation will be defined as a Scale for Suicide Ideation (SSI) score ≤3 at the end of Week 4, after eight study infusions. Logistic regression will estimate the odds ratio (OR) per one-standard-deviation increase in PRS, adjusting for the first 10 principal components of genetic ancestry.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age ≥18 years.
* Psychiatric hospitalization because of suicide risk.
* Acute suicidal ideation, defined as a Scale for Suicide Ideation (SSI) score >3.
* Ability to understand the study procedures and provide written informed consent.
* Willingness to participate in the study.

Exclusion Criteria:

* Current diagnosis of schizophrenia or another psychotic disorder.
* Active substance use disorder within the previous 6 months, except caffeine or nicotine.
* Known contraindication to esketamine, including severe hypertension, previous stroke, intracranial hypertension, porphyria, or known hypersensitivity to the study drug.
* Pregnancy or breastfeeding.
* Unstable medical condition or clinically relevant cardiovascular risk.
* Participation in another clinical trial within the previous 3 months.

• Results publication: Sajid S, Mann JJ, Grunebaum MF. Clinical trials since 2020 of rapid anti-suicidal ideation effects of ketamine and its enantiomers: a systematic review. Transl Psychiatry. 2025 Feb 6;15(1):44. doi: 10.1038/s41398-025-03255-0. PMID 39915491
• Results publication: Jollant F, Colle R, Nguyen TML, Corruble E, Gardier AM, Walter M, Abbar M, Wagner G. Ketamine and esketamine in suicidal thoughts and behaviors: a systematic review. Ther Adv Psychopharmacol. 2023 Feb 7;13:20451253231151327. doi: 10.1177/20451253231151327. eCollection 2023. PMID 36776623
• Results publication: Grunebaum MF, Galfalvy HC, Choo TH, Keilp JG, Moitra VK, Parris MS, Marver JE, Burke AK, Milak MS, Sublette ME, Oquendo MA, Mann JJ. Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial. Am J Psychiatry. 2018 Apr 1;175(4):327-335. doi: 10.1176/appi.ajp.2017.17060647. Epub 2017 Dec 5. PMID 29202655
• Results publication: Abbar M, Demattei C, El-Hage W, Llorca PM, Samalin L, Demaricourt P, Gaillard R, Courtet P, Vaiva G, Gorwood P, Fabbro P, Jollant F. Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. BMJ. 2022 Feb 2;376:e067194. doi: 10.1136/bmj-2021-067194. PMID 35110300