A Phase 2 interventional study of Esketamine and Midazolam (Intravenous) in Suicidal Ideation and Suicidal Behavior, sponsored by University of Sao Paulo. Not yet recruiting at 1 site in Brazil. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-10-22.
Sponsored by University of Sao Paulo · Phase 2, Interventional, and Treatment
This randomized, double-blind, active placebo-controlled superiority trial will evaluate whether intravenous esketamine reduces time to psychiatric hospital discharge in adults hospitalized because of acute suicide risk. A total of 106 participants will be randomized in a 1:1 ratio to receive intravenous esketamine or midazolam as an active placebo. Participants assigned to esketamine will receive eight 40-minute intravenous infusions at a dose of 0.5 mg/kg administered twice weekly. The primary outcome is time from the first study infusion to psychiatric hospital discharge. Secondary outcomes include suicidal ideation and behavior, depressive symptoms, psychological pain, hopelessness, global clinical improvement, safety, tolerability, dissociative symptoms, and healthcare costs. Exploratory analyses will investigate peripheral inflammatory markers, BDNF, and polygenic risk scores as potential predictors or mediators of treatment response. Clinical follow-up will continue through Week 12.
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.
530 studies on the registry are indexed under Suicidal Ideation; 198 are open to participants now.
This study's planned enrollment of 106 is above the median of 80 across 440 interventional studies indexed under Suicidal Ideation.
Browse Suicidal Ideation studies →University of Sao Paulo is the lead sponsor of 1,030 studies on the registry; 92 are open to participants now.
Of its 8 completed or terminated interventional studies of FDA-regulated products, 0 (0%) have results posted.
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Exclusion Criteria:
Participants will receive eight intravenous esketamine infusions at a dose of 0.5 mg/kg administered over 40 minutes twice weekly. Esketamine will be diluted in 100 mL of 0.9% saline and administered using a volumetric infusion pump. Blood pressure, heart rate, oxygen saturation, and cardiac rhythm will be monitored during and after each infusion.
Drug: Esketamine
Participants will receive intravenous midazolam at a dose of 0.045 mg/kg diluted in 0.9% saline. Midazolam is used as an active placebo to improve maintenance of masking. Blood pressure, heart rate, oxygen saturation, and cardiac rhythm will be monitored during and after the infusion.
Drug: Midazolam (Intravenous)
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.
Intravenous midazolam 0.045 mg/kg diluted in 0.9% saline and administered as an active placebo.
Time to Psychiatric Hospital Discharge
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.
Time frame: From the first study infusion until discharge from the index psychiatric hospitalization, assessed up to 6 months.
Remission of Suicidal Ideation at 72 Hours
Proportion of participants achieving complete remission of suicidal ideation, defined as a Scale for Suicide Ideation (SSI) score ≤3.
Time frame: 72 hours after the first study infusion
Change in Suicidal Ideation Severity
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.
Time frame: Baseline through Week 12
Suicidal Ideation and Behavior During Follow-up
Change in suicidal ideation and occurrence of suicidal behavior assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).
Time frame: Baseline through Week 12
Suicide Attempts During Follow-up
Number and proportion of participants experiencing at least one suicide attempt during clinical follow-up.
Time frame: From the first study infusion through Week 12
Change in Depressive Symptoms Assessed by PHQ-9
Change in Patient Health Questionnaire-9 total score from baseline. Higher scores indicate greater severity of depressive symptoms.
Time frame: Baseline through Week 12
Change in Depressive Symptoms Assessed by QIDS-SR
Change in Quick Inventory of Depressive Symptomatology-Self-Report total score from baseline.
Time frame: Baseline through Week 12
Change in Clinician-Rated Depressive Symptoms
Change in Inventory of Depressive Symptomatology-Clinician Rated (IDS-C30) total score from baseline.
Time frame: Baseline through Week 12
Change in Psychological Pain
Change in Psychological Pain Visual Analog Scale (PPP-VAS) score from baseline.
Time frame: Baseline through Week 12
Change in Hopelessness
Change in Beck Hopelessness Scale (BHS) total score from baseline. Higher scores indicate greater hopelessness.
Time frame: Baseline through Week 12
Clinical Global Improvement
Overall clinical improvement assessed using the Clinical Global Impression-Improvement (CGI-I) scale.
Time frame: Through Week 12
Change in Manic Symptoms
Change in Young Mania Rating Scale (YMRS) total score during treatment and follow-up.
Time frame: Baseline through Week 12
Change in General Psychiatric Symptoms
Change in Brief Psychiatric Rating Scale (BPRS) total score during treatment and follow-up.
Time frame: Baseline through Week 12
Dissociative Symptoms
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.
Time frame: After the first study infusion and at weeks 1, 2, 4, 6 and 12.
Treatment-Emergent Adverse Events
Incidence and severity of adverse events occurring during study treatment and clinical follow-up.
Time frame: From the first study infusion through Week 12
Treatment-Related Healthcare Costs
Healthcare costs associated with the index psychiatric hospitalization, medications, and psychotherapeutic treatments.
Time frame: From the first study infusion through Week 12
Change in Plasma Brain-Derived Neurotrophic Factor (BDNF) Levels
Change from baseline in plasma brain-derived neurotrophic factor (BDNF) concentrarion, measured using a luminex-based multiplex assay and expressed in ng/ml.
Time frame: Baseline, 24-72 hours after the first infusion, Week 2, and Week 6.
Change in Plasma Interleukin-6 (IL-6) Concentration
Change from baseline in plasma interleukin-6 (IL-6) concentration, measured using a Luminex-based multiplex assay and expressed in pg/mL.
Time frame: Baseline, 24-72 hours after the first study infusion, Week 2, and Week 6.
Change in Plasma Tumor Necrosis Factor-Alpha (TNF-α) Concentration
Change from baseline in plasma tumor necrosis factor-alpha (TNF-α) concentration, measured using a Luminex-based multiplex assay and expressed in pg/mL.
Time frame: Baseline, 24-72 hours after the first study infusion, Week 2, and Week 6.
Change in Plasma Interleukin-1 Beta (IL-1β) Concentration
Change from baseline in plasma interleukin-1 beta (IL-1β) concentration, measured using a Luminex-based multiplex assay and expressed in pg/mL.
Time frame: Baseline, 24-72 hours after the first study infusion, Week 2, and Week 6.
Change in Plasma Interleukin-10 (IL-10) Concentration
Change from baseline in plasma interleukin-10 (IL-10) concentration, measured using a Luminex-based multiplex assay and expressed in pg/mL
Time frame: Baseline, 24-72 hours after the first study infusion, Week 2, and Week 6.
Odds Ratio for Week 4 Suicidal Ideation Remission per Standard Deviation Increase in Major Depressive Disorder Polygenic Risk Score
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.
Time frame: Baseline genetic assessment; remission of suicidal ideation assessed at the end of Week 4, after completion of eight study infusions.
Odds Ratio for Week 4 Suicidal Ideation Remission per Standard Deviation Increase in Suicidal Behavior Polygenic Risk Score
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.
Time frame: Baseline genetic assessment; remission of suicidal ideation assessed at the end of Week 4, after completion of eight study infusions.
Plan to share: Undecided
Start is estimated for Apr 2027; primary completion for Jan 2029, 21 months later.
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Studies of the drug tested here: Esketamine