Suicide is one of the leading causes of early death worldwide. In Brazil, suicide rates have been rising steadily over the past two decades, and most suicides occur in low- and middle-income countries where access to specialized care is limited. There is an urgent need for fast-acting, practical interventions that can be delivered in public emergency settings. Two promising approaches have emerged: esketamine, a medication that can rapidly reduce suicidal thoughts within hours, and Crisis Response Planning (CRP), a brief session in which a trained clinician works with the person to create a personalized written plan for managing future suicidal crises.
The goal of this clinical trial is to learn if esketamine or Crisis Response Planning (CRP), each added to enhanced treatment as usual (eTAU), can prevent future suicide-related events compared to eTAU alone in adolescents and adults aged 14 years or older who recently attempted suicide or have severe suicidal thoughts. The main questions it aims to answer are:
Does a single esketamine infusion plus eTAU lower the risk of a new suicide-related event compared to eTAU alone over 12 months? Does a single session of Crisis Response Planning plus eTAU lower the risk of a new suicide-related event compared to eTAU alone over 12 months? Which approach leads to faster or more lasting improvements in suicidal thoughts, depression, anxiety, sleep, well-being, hopelessness, and quality of life? Are these interventions feasible, acceptable, and cost-effective within a public health system?
Researchers will compare three groups to see which approach works best to prevent suicide attempts, suicide-related hospitalizations, and suicide deaths over one year.
A total of 468 participants will be randomly assigned in equal numbers (156 per group) to one of three groups:
Esketamine group: receive a single intravenous esketamine infusion (0.50 mg/kg given over 40 minutes) in a monitored medical setting with continuous heart rate, blood pressure, and oxygen monitoring, plus eTAU. A physician will be present throughout. Participants will be observed for up to 24 hours before discharge.
Crisis Response Planning group: complete one 20-to-45-minute session with a trained clinician to build a personal crisis plan that includes warning signs, coping strategies, reasons for living, support contacts, and emergency resources. Participants will leave with a written and digital copy of their plan, plus eTAU.
Enhanced treatment as usual (eTAU) group: receive standard emergency care, safety counseling about access to lethal means, connection to the local mental health network (including Psychosocial Care Centers and primary care), and a scheduled psychiatric follow-up appointment within 7 days.
Participants will:
Complete health questionnaires about suicidal thoughts, depression, anxiety, sleep, well-being, hopelessness, and quality of life at 11 time points over one year (at enrollment, 24 hours, 7 days, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 1 year) Provide a blood sample at the start of the study for exploratory analyses of biological markers that may be related to treatment response Use a smartphone app to report their mood, thoughts, and emotions four times a day for four weeks after enrollment Be monitored for safety and adverse events throughout the entire study period
The study takes place in the public emergency network of Indaiatuba, São Paulo, Brazil (population approximately 256,000), and is designed to reflect real-world clinical conditions. Participants who experience a new suicide-related event during the study will be offered an open-label rescue treatment combining esketamine and Crisis Response Planning, and will continue to be followed for the remainder of the year. The study also includes an evaluation of how well these interventions can be adopted and sustained within Brazil's public mental health system, including assessments of acceptability, feasibility, and cost-effectiveness.
Age 14 years or older
Presentation to a public emergency service (ED/UEU) within the study municipality
Recent suicide attempt within the past 30 days (actual, interrupted, or aborted attempt)
Current severe suicidal ideation, defined as endorsement of items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) screening version, indicating active suicidal ideation with specific plan and/or method, or active suicidal ideation with intent to act
Contraindications to esketamine, including: aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage, or known hypersensitivity to esketamine or ketamine
Current pregnancy or breastfeeding (confirmed by rapid pregnancy test in the emergency setting for female participants of childbearing potential)
Medical instability requiring intensive care unit (ICU) admission without feasible study follow-up
Primary psychotic disorder (e.g., schizophrenia, schizoaffective disorder), current acute psychosis, or current acute manic episode precluding informed participation
Parallel
Intravenous Esketamine
DrugSingle-session intravenous esketamine infusion (0.5 mg/kg) administered over 40 minutes in a medical setting with continuous monitoring of vital signs, blood pressure, ECG, and oxygen saturation for 4 hours post-infusion. Administration supervised by trained medical staff with emergency protocols available. Participants will be discharged 24 hours post-infusion if no clinical complications arise, with ambulatory evaluations at 48 hours, 72 hours, and 7 days post-infusion.
Crisis Response Planning intervention (structures safety planning)
Other interventionCollaborative safety planning intervention delivered by trained clinical psychologists in 20-45 minute sessions. Participants create personalized, written crisis response plans identifying warning signs of emotional distress, internal coping strategies, social support contacts, professional resources, and means restriction methods. The intervention follows a structured format focusing on practical crisis management tools that participants can implement during suicidal crises.
Time to first event
Time from randomization to the first occurrence of a composite suicide-related event, defined as any suicide attempt (actual, interrupted, or aborted) assessed via the Columbia-Suicide Severity Rating Scale (C-SSRS), suicide-preventive psychiatric admission, suicide death, or self-injury requiring emergency department care. Events are ascertained through structured C-SSRS interviews at each follow-up visit, medical record linkage, and routine clinical surveillance. Analysis uses Cox proportional-hazards models with Holm-Bonferroni family-wise error control for two co-primary comparisons (esketamine + eTAU vs. eTAU; CRP + eTAU vs. eTAU).
Total Suicide-Related Events (Count)
Total number of suicide-related events per participant over the follow-up period, including recurrent suicide attempts (actual, interrupted, or aborted), suicide-preventive psychiatric admissions, suicide deaths, and self-injury requiring emergency department care. This pre-specified supplementary analysis captures cumulative event burden including recurrences, complementary to the time-to-first-event primary endpoint. Analyzed using negative-binomial regression models with person-time offsets, estimating incidence rate ratios (IRRs) and 95% confidence intervals, adjusted for prespecified covariates. Not included in family-wise error control.
Suicidal Ideation Severity (Beck Scale for Suicide Ideation)
Change in suicidal ideation severity measured by the Beck Scale for Suicide Ideation (BSI; 21 items, 3-point Likert scale, total score 0-38; higher scores indicate greater ideation severity; scores above 6 considered clinically significant). Analyzed using linear mixed-effects models with random intercepts and fixed effects for group, time, and group × time interaction.
Suicidal Ideation and Behavior (Columbia-Suicide Severity Rating Scale)
Trajectories of suicidal ideation severity level and presence of suicidal behaviors assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) structured clinician-administered interview. Captures the highest ideation level (1-5) and occurrence of suicidal behaviors since the last assessment.
Depressive Symptoms - Self-Reported (Patient Health Questionnaire-9)
Change in self-reported depressive symptom severity measured by the Patient Health Questionnaire-9 (PHQ-9; 9 items, total score 0-27; severity cutoffs: 5 mild, 10 moderate, 15 moderately severe, 20 severe). Validated Brazilian Portuguese version with population norms.
Cost-Effectiveness Analysis
Incremental cost-effectiveness ratios (ICERs) comparing each active intervention to eTAU from a societal perspective. Includes direct medical costs (medication, monitoring, hospitalizations, emergency visits, outpatient mental health services) and indirect productivity losses. Cost per quality-adjusted life year (QALY) gained calculated using SF-6D utility values derived from SF-12, with 3% annual discounting and a willingness-to-pay threshold below 3 times Brazilian GDP per capita per QALY gained.
Implementation Outcomes - Acceptability, Appropriateness, and Feasibility (AIM/IAM/FIM)
Clinician-reported implementation outcomes measured by the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM). Administered to clinicians involved in CRP delivery and esketamine implementation. Supplemented by qualitative semi-structured interviews analyzed through thematic analysis.
Frequency and Severity of Adverse Events
Documentation of all adverse events (AEs) and serious adverse events (SAEs) across treatment arms, including cardiovascular and dissociative effects during and after esketamine infusion, psychological distress, hospitalizations, suicide attempts, and deaths. Reported following CONSORT Harms guidelines. Reviewed quarterly by the independent Data and Safety Monitoring Board (DSMB).
Healthcare Service Utilization
Comparison of healthcare service use across treatment arms, including psychiatric hospitalizations, emergency department visits, outpatient mental health consultations (CAPS, CEEM, UBS), and medication use. Data collected via participant report and medical record linkage, used as input for the cost-effectiveness analysis.
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University of Sao Paulo
Lead sponsor
Yale University
Collaborator
University of Vermont
Collaborator
University of Pittsburgh
Collaborator
