A Phase 4 interventional study of Intravenous Esketamine and Crisis Response Planning (CRP) in Suicide Prevention, Ketamine and Crisis Response Plan, sponsored by University of Sao Paulo. Recruiting at 1 site in Brazil. Open to participants aged 14 Years and older. Per ClinicalTrials.gov, last updated 2026-09-16.
Sponsored by University of Sao Paulo · Phase 4, Interventional, and Treatment
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:
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.
STUDY DESIGN AND OBJECTIVES:
SAVE is a single-municipality, pragmatic, three-arm, parallel-group, superiority randomized controlled trial with 1:1:1 allocation and a Hybrid Type 1 effectiveness-implementation approach. It compares a single intravenous esketamine infusion plus enhanced treatment as usual (eTAU), a single Crisis Response Planning (CRP) session plus eTAU, and eTAU alone.
The primary objective is to determine whether either active intervention reduces the hazard of a first suicide-related event during 12 months of follow-up compared with eTAU alone. The comparison between CRP and esketamine is exploratory. Secondary objectives concern suicidal ideation, associated symptoms, well-being, quality of life, service use, implementation, and costs. The pragmatic design integrates study procedures into municipal emergency care while retaining standardized eligibility, outcome assessment, and safety procedures. An independent Data and Safety Monitoring Board (DSMB) oversees safety.
PILOT COHORT AND CONFIRMATORY COHORT:
Recruitment began in June 2026. Following a temporary suspension for an internal data-quality and process audit, recruitment has resumed and the study is currently recruiting. The first 10 randomized participants constitute a pilot cohort enrolled before the current protocol procedures. The updated protocol has institutional ethics approval under CAAE 89878225.0.0000.0068 and specifies the revised substance-related eligibility criteria, visit windows, esketamine dose, EMA schedule, safety contact procedures, and external blinded endpoint adjudication.
Pilot participants continue scheduled clinical and safety follow-up through 12 months under the applicable consent arrangements. Their characteristics, clinical observations, and operational findings are reported descriptively, with the procedures and data cutoffs identified. Pilot data are excluded from confirmatory efficacy analyses, and the pilot cohort will be identified separately in participant-flow reporting. The target confirmatory cohort comprises 468 participants randomized subsequently, with 156 per arm. Anticipated total enrollment is therefore 478.
SETTING:
The study is conducted in the public health network of Indaiatuba, São Paulo, Brazil. Participating services include urgent and emergency units, the reference hospital emergency department, the Medical Specialties Center (CEEM), Psychosocial Care Centers (CAPS), and primary care units (UBS), linked through the municipal Psychosocial Care Network (RAPS). Randomization and allocated interventions take place in emergency care settings, with continuing care through the municipal network. The single-municipality setting will be considered when interpreting generalizability.
ELIGIBILITY AND STUDY FLOW:
After clinical stabilization, attending clinicians refer potentially eligible patients to the research team. Eligible participants are aged 14 years or older and have either a suicide attempt within the previous 30 days, including an actual, interrupted, or aborted attempt, or current severe suicidal ideation with intent, corresponding to C-SSRS screening items 4 or 5. Non-suicidal self-injury alone does not satisfy the inclusion criteria.
Participants must reside within the study catchment area, be able to maintain follow-up contact, and provide informed consent or, for participants aged 14-17 years, assent with guardian consent. A clinical decision that psychiatric inpatient admission is required after emergency evaluation precludes enrollment. Eligibility does not exclude participants on the basis of sex, gender identity, race/color, or socioeconomic status.
Exclusions include contraindications to esketamine, pregnancy or breastfeeding, medical instability incompatible with study participation, a primary psychotic disorder, acute psychosis or mania precluding informed participation, inability to maintain follow-up contact, and the substance-related criteria described below. Contraindications to esketamine include relevant aneurysmal vascular disease, arteriovenous malformation, intracerebral hemorrhage, and hypersensitivity.
Consent or assent and guardian consent are obtained before study-specific procedures. Screening includes sociodemographic, clinical, psychiatric, and substance-use assessments. Pregnancy testing is performed when applicable. Eligible participants complete baseline assessment on Day 0 before the allocated intervention and are randomized through REDCap. Interventions are delivered in the emergency department or urgent and emergency unit. Clinical treatment takes priority over research procedures.
SUBSTANCE USE SCREENING:
The Brazilian Portuguese ASSIST is administered during eligibility assessment. Substance-specific involvement scores follow WHO scoring rules: questions 2 through 7 contribute to each score, except that question 5 is omitted for tobacco. Questions 1 and 8 are excluded from these scores. Risk thresholds are 0-10, 11-26, and 27 or higher for alcohol, and 0-3, 4-26, and 27 or higher for other substance classes, corresponding to lower, moderate, and high risk.
Substance-related exclusion applies when any of the following is present:
A documented history of ketamine use disorder identified during baseline psychiatric assessment.
The ASSIST hallucinogen category does not identify ketamine exposure specifically. Relevant substance history is therefore also assessed clinically. The hallucinogen threshold is a conservative eligibility criterion and may exclude participants whose high-risk involvement concerns substances other than ketamine; exclusions and their reasons will be reported.
Other ASSIST scores do not automatically exclude participation. High-risk involvement with alcohol or other non-tobacco substances is recorded for exploratory moderation analyses and to inform clinical care.
RANDOMIZATION, ALLOCATION CONCEALMENT, AND BLINDING:
A statistician not involved in outcome assessment generates a computerized sequence using variable permuted blocks and stratification by age group, recorded sex, and index presentation. Allocation is implemented through the REDCap randomization module with role-based permissions and an audit trail. The allocation table and block details are inaccessible to personnel enrolling participants, who cannot view future assignments.
Participants and treating clinicians are unblinded. Outcome assessors, the external endpoint adjudicator, and confirmatory data analysts remain blinded to treatment allocation. Assessors do not ask about treatment received, and participants are asked not to disclose their allocation. Accidental disclosure is documented, and an alternative blinded assessor completes subsequent assessment when feasible. Confirmatory analysts receive coded treatment groups without treatment identifiers until the confirmatory analysis is finalized.
All T1 assessments are conducted remotely by telephone or video using a centralized blinded assessor in every arm, including participants still in the clinical unit. Assessors do not access treating-team records during these assessments. This standardizes assessment modality and reduces contextual unblinding.
Disclosure of allocation for urgent clinical management is limited to personnel who require that information. The reason, personnel involved, and timing are documented. Clinical safety procedures do not routinely disclose treatment allocation to blinded assessors or the adjudicator.
INTERVENTIONS:
Enhanced treatment as usual:
eTAU comprises two study-specified components: early outpatient psychiatric consultation and lethal means safety counseling. Both are offered to participants in every randomized group alongside routine emergency care. The outpatient psychiatric consultation is arranged to take place within seven days of randomization at CAPS or CEEM. Lethal means safety counseling is delivered during the index emergency attendance by a trained research team member, who collaborates with the participant on a plan to reduce access to potentially lethal means.
Treating clinicians retain responsibility for clinical decisions, and the municipal mental health network supports continuing care. Concomitant medication, psychotherapy, and service use are recorded. Suicide risk assessment and emergency procedures are applied consistently across groups.
Esketamine plus eTAU:
Participants allocated to this group receive one intravenous esketamine infusion at 0.375 mg/kg over 40 minutes. Administration takes place in a monitored clinical setting with pulse oximetry, non-invasive blood pressure measurement, and ECG monitoring. A physician is present, and an advanced cardiovascular life support-capable team is immediately available. Structured symptom and safety assessments occur during the infusion and for 240 minutes afterward. Clinical observation continues, with discharge after 24 hours if the participant is clinically stable.
Protocol-defined safety thresholds trigger clinical assessment and intervention. These include sustained systolic blood pressure of 180 mmHg or higher or 90 mmHg or lower, diastolic blood pressure of 105 mmHg or higher or 50 mmHg or lower, a blood pressure change of 25 mmHg in either direction, or clinically significant dissociation or agitation. Treatment modification or discontinuation and the reason are documented.
Crisis Response Planning plus eTAU:
Participants allocated to this group receive one 20-to-45-minute CRP session with a trained clinician. The plan is developed collaboratively and includes personal warning signs, internal coping strategies, reasons for living, social support contacts, and professional and emergency contacts. Participants receive a printed plan and a digital photograph.
Clinicians complete a standardized three-hour training program with didactic content, role-play, certification, and continuing supervision. Fidelity checklists are used, and a consented subset of sessions, approximately 10-20%, is audio-recorded for adherence and competence assessment. Fidelity audits target inter-rater agreement of kappa 0.80 or higher.
RESCUE TREATMENT AND CONTINUING FOLLOW-UP:
After a participant experiences an event meeting the primary endpoint, open-label rescue combining esketamine and CRP may be offered according to clinical eligibility and safety assessment. Participants remain in scheduled outcome and safety follow-up. Rescue does not remove a participant from the confirmatory intention-to-treat population or remove the first qualifying event from the primary analysis.
The first qualifying event is analyzed under the original randomized allocation. Subsequent events, rescue exposure, and reasons for incomplete or modified rescue delivery are recorded. Recurrent-event analyses describe burden under the assigned care strategy, including access to rescue, and do not isolate the effect of rescue treatment. Clinical management does not wait for endpoint adjudication.
PRIMARY ENDPOINT AND EXTERNAL BLINDED ADJUDICATION:
The primary endpoint is time from randomization to the first qualifying suicide-related event during 12 months of follow-up. Qualifying events are an actual, interrupted, or aborted suicide attempt; a suicide-preventive psychiatric admission; suicide death; or self-injury requiring emergency department care.
Events are identified through structured C-SSRS interviews, routine clinical surveillance, participant contacts, and medical record linkage. Suicidal intent and individual event components are recorded separately so that non-suicidal self-injury is distinguished from a suicide attempt. Multiple reports describing the same episode are linked rather than counted as independent events. Individual components are also analyzed separately.
An external adjudicator blinded to randomized allocation reviews suspected endpoint events using the study definitions and source documentation from interviews, clinical records, and event reports. A study-team member prepares dossiers with treatment-identifying information removed. The adjudicator determines whether each event meets the endpoint definition, its component and occurrence date, and whether multiple reports describe the same episode.
Event occurrence, study-team awareness, and adjudication dates are recorded separately. Requests for clarification, inconclusive decisions, and accidental unblinding are documented. Adjudication is separate from symptom assessment, clinical management, and adverse-event reporting. Safety reporting and necessary care proceed without awaiting an adjudication decision.
ASSESSMENT SCHEDULE AND VISIT WINDOWS:
Assessments occur at baseline (T0), 24 hours (T1), seven days (T2), and weeks 2, 4, 8, 16, 24, 32, 40, and 52 (T3-T10). Monthly event surveillance continues between scheduled visits.
Day 0 is the date of randomization and the time origin for the primary endpoint and nominal follow-up schedule. Baseline assessment, also called T0 or V0, is completed on Day 0 before the allocated intervention. T0/V0 has no additional day-level window.
T1 is the protocol-defined 24-hour contact after delivery of the assigned intervention. No additional day-level window or late replacement is permitted. An uncompleted T1 assessment is recorded as missing and is not administered retrospectively.
The remaining target days and allowed windows are anchored to randomization:
T2: Day 7, plus or minus 2 days. T3: Day 14, plus or minus 3 days. T4: Day 28, plus or minus 5 days. T5: Day 56, plus or minus 7 days. T6: Day 112, plus or minus 10 days. T7: Day 168, plus or minus 14 days. T8: Day 224, plus or minus 14 days. T9: Day 280, plus or minus 14 days. T10: Day 364, plus or minus 21 days.
Nominal visit labels, intervention timestamps, and actual assessment dates and times are retained. Later visit windows do not shift after a delayed assessment. Assessments outside their permitted windows are retained and identified for sensitivity analyses; uncompleted assessments are recorded as missing. Calendar-month EMA periods are scheduled separately from week-based visits.
CLINICAL AND PATIENT-REPORTED MEASURES:
Measures include the C-SSRS, Beck Scale for Suicide Ideation (BSI), Patient Health Questionnaire-9 (PHQ-9), Montgomery-Asberg Depression Rating Scale (MADRS), Generalized Anxiety Disorder-7 (GAD-7), Snaith-Hamilton Pleasure Scale Brazilian version (SHAPS-BR), 13-item short Pittsburgh Sleep Quality Index (shortPSQI; five components, global score 0-15), 12-Item Short Form Health Survey (SF-12), 7-item Beck Hopelessness Scale (BHS-7), Short Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS), and Clinical Global Impression scales (CGI-S and CGI-I). Instrument-specific administration follows the study assessment schedule; not every instrument is administered at every visit.
Baseline covariates and exploratory moderators include impulsivity (BIS-15), substance involvement (ASSIST), borderline personality features (MSI-BPD), religiosity and spirituality (DUREL), ADHD symptoms (ASRS-S), and manic symptoms (ASRM). ASRM is also repeated at T2 for symptom monitoring. Brazilian Portuguese versions are used, with adapted or abbreviated forms identified in the assessment materials. Sex and gender identity are recorded separately; self-reported race/color is not treated as genetic ancestry.
VERIFICATION OF eTAU DELIVERY:
Delivery of early outpatient psychiatric consultation and lethal means safety counseling is documented separately in every arm, including dates, completion status, and reasons for non-completion. At T2, structured questions record whether the consultation occurred, its date, and any reason for non-attendance. Municipal scheduling and attendance records from CAPS, CEEM, and UBS are reviewed monthly to verify service contacts. Appointment booking alone is not counted as consultation delivery. Time from randomization to the completed consultation is reported by randomized group as an implementation measure.
ECOLOGICAL MOMENTARY ASSESSMENT:
The MindLogger smartphone application delivers three prompts per day during each of three periods of 30 consecutive days beginning at baseline and at calendar months 4 and 8 of follow-up. Two prompts occur at fixed times, 09:00 and 21:00. The third occurs at a randomly selected time between 10:00 and 20:00. All times refer to local time in Indaiatuba.
Each period contains 90 scheduled prompts, giving 90 assessment days and 270 scheduled prompts per participant across the study. Each prompt has a 60-minute response window and one reminder. The month 4 and month 8 periods are not treated as exact equivalents of the week 16 and week 32 visits.
Brief surveys assess momentary affect, self-evaluative states, cognitive and emotional regulation, interpersonal context, recent substance use, wish to live or die, suicidal ideation intensity and controllability, perceived ability to resist acting on suicidal thoughts, and recent self-harm. Item-specific ordinal and categorical response formats are used. Scheduled and actual prompt and response times are recorded.
Completion is calculated as answered prompts divided by delivered prompts, with delivered prompts also reported against the planned schedule. Completion is described separately by sampling period and prompt type. Days outside the three sampling periods are planned non-observation days and are not counted as missed prompts.
EMA analyses are exploratory and account for repeated observations within participants, sampling period, prompt type, and actual response timing. They examine day-level trajectories and prospective associations with subsequent outcomes. A completion threshold of 50% of delivered prompts defines the main analyzable EMA sample, with completion and sensitivity analyses reported by period. EMA analyses are not included in confirmatory family-wise error control. Pilot EMA data collected under earlier schedules are described separately.
EMA SAFETY CONTACT AND ESCALATION:
Responses indicating the highest level of current suicidal ideation, self-harm since the previous prompt, or inability to resist acting on suicidal thoughts trigger a safety alert. The study team manages alerts through a dedicated mobile phone with WhatsApp and contacts the participant within 24 hours of the alert. The 24-hour interval refers to elapsed time, including weekends and holidays.
Contact includes clinical risk assessment and referral to emergency services when indicated. The alert, contact attempts, assessment, and resulting action are documented in REDCap. The application displays crisis contact information. Participants are informed that the application and study WhatsApp contact do not provide continuous emergency monitoring and that urgent care should be sought immediately when needed rather than awaiting the study response.
BIOMARKERS AND LABORATORY PROCEDURES:
Venous blood is collected at baseline for exploratory biomarker analyses. Collection tubes, sample handling, and processing follow assay-specific laboratory requirements. Samples are analyzed through the hospital laboratory and are not retained in a research biobank; residual samples are disposed of after reporting in accordance with the approved procedures.
The planned panel includes high-sensitivity C-reactive protein, homocysteine, vitamins B1, B2, B6, B12 and D, folate, magnesium, zinc, selenium, thyroid-stimulating hormone, free T3, free T4, testosterone, DHEA-S, prolactin, and sex hormone-binding globulin. Exploratory analyses examine associations between baseline biomarkers and subsequent outcomes, including potential moderation of treatment effects. These analyses are not powered to establish definitive biomarker-defined subgroup effects.
ENROLLMENT TARGET AND STATISTICAL PLANNING:
The target confirmatory sample is 468 participants, with 156 per group, in addition to the 10 pilot participants. For the primary time-to-first-event endpoint, statistical information depends on the number of participants experiencing a first qualifying event. Recurrent episodes in the same participant do not count as additional first events for sample-size planning.
Planning for the two active-versus-eTAU comparisons uses a conservative two-sided alpha of 0.025 per comparison, a nominal power target of 90%, and equal allocation within each pairwise comparison. Using Schoenfeld's method, target hazard ratios of 0.50 for esketamine and 0.39 for CRP correspond to approximately 103 and 56 required first events, respectively. These are assumed planning effects, not estimates from the pilot.
Initial planning assumptions include a 30% 12-month event risk in eTAU, 24 months of accrual, 12 months of individual follow-up, and allowance for 20% attrition. The enrollment target alone does not establish that the required event totals or nominal power will be achieved. The statistical planning documentation will specify the translation from required events to enrollment and examine sensitivity to control risk, accrual, follow-up, and loss to follow-up. Any change to the enrollment target will require a documented revised calculation and corresponding protocol and registry updates.
Pilot observations may inform recruitment, follow-up, and event-ascertainment assumptions. A pooled short-term event proportion from 10 participants is not substituted for the 12-month control-group risk and is not used to estimate the target treatment effect.
STATISTICAL ANALYSIS:
Confirmatory analyses include all participants randomized in the post-pilot cohort and follow the intention-to-treat principle, retaining participants in their assigned groups regardless of adherence, treatment discontinuation, or subsequent rescue. Pilot participants are reported descriptively and excluded from confirmatory efficacy analyses.
The two confirmatory comparisons are esketamine plus eTAU versus eTAU and CRP plus eTAU versus eTAU. Holm's sequential procedure controls the two-sided family-wise type I error at 0.05: the smaller P value is compared with 0.025 and, if that hypothesis is rejected, the remaining P value is compared with 0.05. Effect estimates are reported with 95% confidence intervals, with nominal intervals distinguished from multiplicity-adjusted inference. CRP versus esketamine is exploratory.
Primary analysis:
Cox proportional-hazards models estimate hazard ratios, adjusting for age group, recorded sex, index presentation, baseline suicidal ideation, and baseline PHQ-9 score. Kaplan-Meier curves describe event-free follow-up. Schoenfeld residuals are used to assess proportional hazards; time-varying effects or restricted mean survival time estimates over the specified follow-up horizon are considered when appropriate. No municipality-level covariate is included because the trial is conducted in one municipality. Death from a cause other than suicide is addressed as a competing event in sensitivity analyses.
Recurrent-event and component analyses:
An exploratory negative-binomial model with a person-time offset estimates incidence rate ratios for distinct suicide-related episodes, including recurrences, using the same covariate set. Episode definitions and adjudication rules are consistent with the primary analysis. Further exploratory analyses include recurrent-event models, mean cumulative event functions, and analyses of individual endpoint components. Competing-risk analyses explicitly distinguish the event of interest from competing events. These analyses are outside confirmatory family-wise error control.
Secondary outcomes:
Continuous symptom outcomes, including suicidal ideation, depression, anxiety, anhedonia, sleep, hopelessness, well-being, and quality of life, are analyzed using mixed-effects models with participant random intercepts and fixed effects for randomized group, time, and group-by-time interaction. Actual assessment timing is retained, and sensitivity analyses are restricted to assessments within permitted windows. Repeated binary outcomes are analyzed using generalized estimating equations with a logit link.
Economic evaluation:
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.
Sensitivity, moderation, and missing-data analyses:
Per-protocol analyses are supplementary to intention-to-treat analyses. Exploratory moderation analyses examine treatment interactions with prior attempts, baseline severity, ASSIST high-risk status, and biomarkers, with effect estimates and confidence intervals interpreted cautiously. These analyses do not establish definitive subgroup effects.
Participants without an observed endpoint event are censored at the last date on which endpoint status can be established, subject to the defined follow-up horizon. Inverse probability weighting assesses sensitivity to dropout, and multiple imputation addresses missing baseline covariates when appropriate. Longitudinal analyses examine missing-at-random assumptions and use sensitivity analyses, including pattern-mixture approaches, to assess departures from those assumptions. Missed assessments, discontinuation of an intervention, loss to follow-up, and withdrawal of consent are distinguished.
Analyses will use R and Stata. The detailed statistical analysis plan will be finalized before treatment identities are revealed to confirmatory analysts.
IMPLEMENTATION EVALUATION:
The implementation evaluation uses ImpRes-BR to organize planning and evaluation, CFIR 2.0 to assess contextual determinants, ERIC to specify implementation strategies, and a Power/Interest matrix for stakeholder mapping. The Acceptability of Intervention Measure, Intervention Appropriateness Measure, and Feasibility of Intervention Measure (AIM/IAM/FIM) are administered to participating professionals at weeks 4, 24, and 52 of service implementation. Formative assessments immediately after training are distinguished from these scheduled outcomes.
Strategies include clinician training and capacity building; stakeholder engagement with municipal managers, emergency services, and CAPS; audit and feedback using quarterly service reports; contextual adaptation through interviews and focus groups; and integration of study procedures into routine clinical workflows through safety checklists, documentation tools, and defined responsibilities.
The evaluation combines professional surveys, fidelity audits, service-use measures, and semi-structured interviews. Qualitative sampling is purposive, with an anticipated approximately 20 professionals per participating unit, adjusted according to thematic saturation. Qualitative analysis uses a documented coding framework and procedures for resolving coding disagreements.
DATA MANAGEMENT AND CONFIDENTIALITY:
Study data are captured in REDCap with role-based access, range checks, and audit trails. Direct identifiers are stored separately from analytic datasets. Treatment-identifying information is restricted according to study roles, and adjudication dossiers are prepared to preserve allocation blinding. Data handling follows applicable Brazilian data protection requirements, including the Lei Geral de Proteção de Dados. Participant reports and publications use aggregate or appropriately de-identified information.
SAFETY MONITORING AND OVERSIGHT:
Suicide risk assessment is incorporated into clinical contacts across all groups. Adverse events and serious adverse events, including suicide attempts, hospitalizations, and deaths, are documented and reported to the responsible ethics committee and other authorities as required. Clinical management, safety reporting, and endpoint adjudication serve distinct purposes; none of the required clinical responses is delayed pending research classification.
The independent DSMB reviews cumulative safety data quarterly and when additional review is needed. It may recommend continuation, modification, or suspension. Unblinded safety information is restricted to personnel with an oversight need and is not routinely shared with blinded assessors, the adjudicator, or confirmatory analysts.
ETHICS AND REGULATORY COMPLIANCE:
The study received approval from the Ethics Committee of the Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, under CAAE 89878225.0.0000.0068, approval number 7.723.561. The updated protocol has ethics approval under the same CAAE. Municipal authorizations were obtained for conduct within the Indaiatuba public health network.
The study follows the approved consent procedures, applicable Brazilian requirements for research involving human participants, and the Declaration of Helsinki. Participants receive updated information or renewed consent when required by approved procedures. Withdrawal from research does not restrict access to usual clinical care. Substantive protocol changes are communicated to the ethics committee, registry, and participating teams in accordance with applicable requirements.
186 studies on the registry are indexed under Suicide Prevention; 92 are open to participants now.
This study's planned enrollment of 478 is above the median of 140 across 167 interventional studies indexed under Suicide Prevention.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Participants must meet all of the following criteria:
Either of the following:
Non-suicidal self-injury alone does not satisfy this criterion.
Exclusion Criteria:
Participants meeting any of the following criteria are excluded:
Any of the following substance-related conditions:
Substance-use assessment:
The Brazilian Portuguese WHO ASSIST is administered during baseline eligibility assessment. Substance-specific involvement scores are calculated from questions 2 through 7, with question 5 omitted for tobacco. Questions 1 and 8 do not contribute to these scores. High risk is defined as a score of 27 or higher.
The ASSIST hallucinogen category does not identify ketamine exposure specifically; relevant substance history is also assessed clinically. Except for the high-risk hallucinogen criterion above, ASSIST scores do not automatically exclude participation. Among eligible participants, high-risk involvement with alcohol or other non-tobacco substances is recorded for exploratory moderation analyses and to inform clinical care.
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Participants receive a single intravenous esketamine infusion of 0.375 mg/kg over 40 minutes, together with enhanced treatment as usual (eTAU). eTAU comprises early outpatient psychiatric consultation within 7 days of randomization and lethal means safety counseling during the index emergency attendance, alongside routine emergency care. The outpatient consultation is arranged through CAPS or CEEM. Delivery of both eTAU components is documented separately, including completion dates and reasons for non-completion.
Drug: Intravenous Esketamine · Other: Enhanced Treatment as Usual (eTAU)
Participants receive a single 20-to-45-minute Crisis Response Planning (CRP) session with a trained clinician, together with enhanced treatment as usual (eTAU). eTAU comprises early outpatient psychiatric consultation within 7 days of randomization and lethal means safety counseling during the index emergency attendance, alongside routine emergency care. The outpatient consultation is arranged through CAPS or CEEM. Delivery of both eTAU components is documented separately, including completion dates and reasons for non-completion.
Other: Crisis Response Planning (CRP) · Other: Enhanced Treatment as Usual (eTAU)
Participants receive enhanced treatment as usual (eTAU) alone as their randomized intervention. eTAU comprises early outpatient psychiatric consultation within 7 days of randomization and lethal means safety counseling during the index emergency attendance, alongside routine emergency care. The outpatient consultation is arranged through CAPS or CEEM. Delivery of both components is documented separately, including completion dates and 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.
Other: Enhanced Treatment as Usual (eTAU)
A 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.
A 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.
eTAU 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.
Time frame: One year from randomization
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.
Time frame: 12 months from randomization
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.
Time frame: Baseline, 24 hours, 7 days, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 1 year
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.
Time frame: Baseline, 7 days, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 1 year
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.
Time frame: Baseline, 7 days, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 1 year
Depression Severity - Clinician-Rated (Montgomery-Åsberg Depression Rating Scale)
Change in clinician-rated depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS; 10 items, each scored 0-6, total score 0-60; higher scores indicate greater depression severity).
Time frame: Baseline, 24 hours, 7 days, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 1 year
Anxiety Symptoms (Generalized Anxiety Disorder-7)
Change in anxiety symptom severity measured by the Generalized Anxiety Disorder-7 (GAD-7; 7 items, total score 0-21; scores of 10 or above indicate clinically significant anxiety).
Time frame: Baseline, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 40 weeks, and 1 year
Anhedonia (Snaith-Hamilton Pleasure Scale - Brazilian Version)
Change in anhedonia severity measured by the Snaith-Hamilton Pleasure Scale - Brazilian version (SHAPS-BR; 14 items, 4-point Likert scale, total score 0-14; higher scores indicate greater anhedonia; scores of 3 or above considered clinically significant).
Time frame: Baseline, 4 weeks, 32 weeks, and 1 year
Sleep Quality (Short Pittsburgh Sleep Quality Index)
Change from baseline in self-reported sleep quality measured using the 13-item short Pittsburgh Sleep Quality Index (shortPSQI), with a one-month recall period. The instrument comprises five components: sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, and daytime dysfunction. Each component is scored from 0 to 3; component scores are summed to obtain a global score from 0 to 15. Higher scores indicate poorer sleep quality. A global score greater than 4 indicates poor sleep quality according to the original shortPSQI scoring convention. Negative changes from baseline indicate improvement.
Time frame: Baseline, 4 weeks, 16 weeks, 40 weeks, and 1 year
Mental Well-Being (Short Warwick-Edinburgh Mental Well-Being Scale)
Change in mental well-being measured by the Short Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS; 7 items scored 1-5; higher total or Rasch-transformed scores indicate greater well-being).
Time frame: Baseline, 4 weeks, 16 weeks, 32 weeks, and 1 year
Hopelessness (Beck Hopelessness Scale - 7-Item Version)
Change in hopelessness measured by the Beck Hopelessness Scale 7-item version (BHS-7; 7 dichotomous items, total score 0-7; higher scores indicate greater hopelessness).
Time frame: Baseline, 4 weeks, 32 weeks, and 1 year
Health-Related Quality of Life (12-Item Short Form Health Survey)
Change in health-related quality of life measured by the 12-Item Short Form Health Survey (SF-12), yielding Physical Component Summary (PCS-12) and Mental Component Summary (MCS-12) scores. Utility values for the cost-effectiveness analysis will be derived using the SF-6D algorithm.
Time frame: Baseline, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 40 weeks, and 1 year
Clinical Global Impression - Improvement (CGI-I)
Clinician-rated global improvement measured by the Clinical Global Impression - Improvement scale (CGI-I; single item scored 1-7; 1 = very much improved, 7 = very much worse).
Time frame: 24 hours, 7 days, and 2 weeks
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.
Time frame: 12 months from randomization
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.
Time frame: 4 weeks, 24 weeks, and 1 year
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).
Time frame: Continuously throughout study participation, up to 1 year
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.
Time frame: 4 weeks, 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 1 year
Exploratory Baseline Biomarker Moderators of Treatment Response
Exploratory analyses examining whether baseline biological markers moderate treatment response across intervention arms. The biomarker panel includes: high-sensitivity C-reactive protein (hs-CRP), homocysteine, vitamins (B1/thiamine, B2/riboflavin, B6/pyridoxine, B12/cobalamin, D/25-hydroxyvitamin D, folate), minerals (erythrocyte magnesium, erythrocyte zinc, selenium), complete thyroid panel (TSH, free T3, free T4), and hormonal markers (testosterone, DHEA-S, prolactin, SHBG). Moderation analyses will report treatment × biomarker interaction effects with 95% confidence intervals.
Time frame: Baseline biomarker collection; correlation with primary and secondary outcomes at 12 months
Plan to share: No — Individual participant data will not be shared to protect participant privacy and confidentiality, particularly given the sensitive nature of suicide-related data and the vulnerable population being studied. The study involves detailed mental health assessments, suicide risk evaluations, and personal crisis information that requires strict confidentiality protections under Brazilian data protection laws and research ethics guidelines. Aggregate, de-identified results and statistical analyses will be made available through peer-reviewed publications and conference presentations. Researchers interested in collaboration or secondary analyses may contact the principal investigator to discuss potential partnerships within appropriate ethical and regulatory frameworks. The study protocol, statistical analysis plan, and aggregate results will be made publicly available to support scientific transparency while maintaining participant confidentiality.
Started Jun 2026 (actual). Primary completion is estimated for Dec 2028, 30 months after the start.
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Studies of the drug tested here: Esketamine