The SAVE study will test whether a single esketamine infusion or a single Crisis Response Planning session, each added to enhanced treatment as usual, reduces future suicide-related events compared with enhanced treatment as usual alone. The study takes place in the public emergency care network of Indaiatuba, São Paulo, Brazil, and includes adolescents and adults aged 14 years or older who have attempted suicide within the previous 30 days or currently have severe suicidal thoughts with intent to act.
The main questions are whether either intervention reduces suicide-related events over 12 months and whether the interventions improve suicidal thoughts, depression, anxiety, sleep, well-being, hopelessness, and quality of life. Researchers will also evaluate acceptability, feasibility, use of health services, and costs.
Anticipated total enrollment is 478 participants: 10 participants in a separate pilot cohort and 468 in the main cohort used to test the study hypotheses. The main cohort will be assigned by chance, in equal numbers of 156 participants, to one of three groups:
1. Esketamine plus enhanced treatment as usual: one intravenous infusion of esketamine at 0.375 mg/kg over 40 minutes, with medical supervision and monitoring of heart rhythm, blood pressure, and oxygen levels. Participants remain under clinical observation, with discharge after 24 hours if clinically stable. 2. Crisis Response Planning plus enhanced treatment as usual: one 20-to-45-minute session with a trained clinician to develop a personalized plan covering warning signs, coping strategies, reasons for living, support contacts, and emergency resources. Participants receive a printed plan and a digital copy. 3. Enhanced treatment as usual alone: early outpatient psychiatric consultation, arranged to take place within seven days of randomization, plus lethal means safety counseling to reduce access to potentially lethal means. Both components are offered to participants in all three groups, alongside routine emergency care. The study records whether each component was delivered; booking a consultation alone does not count as receiving it.
Participants will complete assessments at enrollment, 24 hours, seven days, and weeks 2, 4, 8, 16, 24, 32, 40, and 52. Blood samples will be collected at enrollment for exploratory analyses of biological factors that may be associated with treatment response. Safety monitoring and contact to identify new events will continue throughout follow-up.
Participants will also use a smartphone application to answer brief questions about their mood, thoughts, and experiences during three periods of 30 consecutive days, beginning at enrollment and at calendar months 4 and 8. There will be three prompts each day: two at fixed times, 09:00 and 21:00, and one at a randomly selected time between 10:00 and 20:00, using local time in Indaiatuba. This represents 90 assessment days and 270 scheduled prompts over the study. The study team will contact participants within 24 hours of a safety alert through a dedicated study mobile phone with WhatsApp. Participants will be instructed to seek emergency care immediately when needed rather than wait for a study response.
The main outcome is the time to the first qualifying event: a suicide attempt, including an attempt stopped by the person or interrupted by someone else; a psychiatric admission to prevent suicide; death by suicide; or self-injury requiring emergency department care. An external adjudicator who does not know the assigned treatment will review suspected events and determine whether they meet the study definition. Outcome assessors will also be unaware of treatment allocation.
Participants who experience a qualifying event may be offered rescue treatment combining esketamine and Crisis Response Planning, depending on clinical eligibility and safety. They will remain in follow-up and in analyses according to their original randomized group. The first qualifying event will still count in the main analysis. Pilot data will be described separately and will not be included in confirmatory efficacy analyses.
Age 14 years or older.
Presentation to a participating public emergency service (ED/UEU) in Indaiatuba, São Paulo, Brazil.
A suicide attempt within the previous 30 days, including an actual, interrupted, or aborted attempt; OR
Current severe suicidal ideation, defined as endorsement of item 4 or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) screening version: active suicidal ideation with intent to act, without a specific plan (item 4), or with a specific plan (item 5).
A contraindication to esketamine, including aneurysmal vascular disease, arteriovenous malformation, a history of intracerebral hemorrhage, or known hypersensitivity to esketamine or ketamine.
Current pregnancy or breastfeeding. Pregnancy testing is performed in the emergency setting for participants with pregnancy potential; breastfeeding status is established by clinical history.
Medical instability requiring intensive care unit admission without feasible study follow-up.
A primary psychotic disorder, such as schizophrenia or schizoaffective disorder; or current acute psychosis or an acute manic episode that precludes informed participation.
Parallel
Intravenous Esketamine
DrugA single intravenous esketamine infusion of 0.375 mg/kg is administered over 40 minutes in a monitored medical setting. Monitoring includes blood pressure, ECG, and oxygen saturation, with structured safety assessments during the infusion and for 4 hours afterward. Administration is supervised by trained medical staff with emergency support available. Clinical observation continues, with discharge after 24 hours if clinically stable. Subsequent assessments follow the study assessment schedule.
Crisis Response Planning (CRP)
Other interventionA single 20-to-45-minute Crisis Response Planning (CRP) session is delivered by a trained clinician. The clinician and participant collaboratively develop a personalized plan identifying warning signs, internal coping strategies, reasons for living, social support contacts, and professional and emergency resources. Participants receive a printed plan and a digital copy. Clinicians receive standardized training and supervision, and intervention delivery is documented using a fidelity checklist.
Enhanced Treatment as Usual (eTAU)
Other interventioneTAU comprises early outpatient psychiatric consultation within 7 days of randomization and lethal means safety counseling during the index emergency attendance. Both components are offered in every randomized arm alongside routine emergency care. The consultation is arranged through CAPS or CEEM. During lethal means safety counseling, a trained team member collaborates with the participant on a plan to reduce access to potentially lethal means. Completion and dates of both components are recorded separately, together with reasons for non-completion. Consultation attendance is verified at the Day 7 assessment (T2) and through municipal service records; appointment booking alone is not counted as consultation delivery. Treating clinicians remain responsible for clinical care.
Time to first event
Time from randomization to the first suicide-related event: an actual, interrupted, or aborted suicide attempt; suicide-preventive psychiatric admission; suicide death; or self-injury requiring emergency department care. Events are identified through structured C-SSRS interviews, medical record linkage, and routine clinical surveillance. An external adjudicator blinded to treatment allocation reviews treatment-redacted source documentation to confirm whether each event meets the endpoint definition, its component and date, and whether multiple reports refer to the same episode. Suicidal intent and event components are recorded separately. The confirmatory analysis uses Cox proportional-hazards models, with Holm family-wise error control for esketamine plus eTAU versus eTAU and CRP plus eTAU versus eTAU. The 10 pilot participants are excluded from confirmatory efficacy analyses and reported descriptively.
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 costs and quality-adjusted life years (QALYs) will be compared between each active intervention and eTAU from a societal perspective. Costs include direct medical expenditure and productivity losses. QALYs will be estimated using SF-6D utility values derived from SF-12. Incremental cost-effectiveness ratios and uncertainty analyses will be reported, with interpretation across a range of willingness-to-pay thresholds specified in the economic analysis plan.
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
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