Esketamine Versus Crisis Response Planning Versus Enhanced Treatment as Usual for Suicide Prevention: A Pragmatic Randomized Trial in a Brazilian Municipality (SAVE)

Inclusion Criteria: Participants must meet all of the following criteria: 1. Age 14 years or older. 2. Presentation to a participating public emergency service (ED/UEU) in Indaiatuba, São Paulo, Brazil. 3. Either of the following: 1. A suicide attempt within the previous 30 days, including an actual, interrupted, or aborted attempt; OR 2. 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). Non-suicidal self-injury alone does not satisfy this criterion. 4. Residence within the study catchment area in Indaiatuba, enabling completion of follow-up assessments. 5. Ability to provide written informed consent for participants aged 18 years or older, or written assent with written informed consent from a parent or legal guardian for participants aged 14-17 years. 6. No clinical decision for voluntary or involuntary admission to a psychiatric inpatient unit following the index emergency evaluation. Exclusion Criteria: Participants meeting any of the following criteria are excluded: 1. A contraindication to esketamine, including aneurysmal vascular disease, arteriovenous malformation, a history of intracerebral hemorrhage, or known hypersensitivity to esketamine or ketamine. 2. Current pregnancy or breastfeeding. Pregnancy testing is performed in the emergency setting for participants with pregnancy potential; breastfeeding status is established by clinical history. 3. Medical instability requiring intensive care unit admission without feasible study follow-up. 4. A primary psychotic disorder, such as schizophrenia or schizoaffective disorder; or current acute psychosis or an acute manic episode that precludes informed participation. 5. Any of the following substance-related conditions: 1. Acute intoxication at assessment that precludes valid informed consent, reliable administration of the C-SSRS, or safe delivery of the assigned intervention, as determined by the attending physician. Re-screening is permitted after clinical recovery if all other eligibility criteria remain satisfied. For participants qualifying on the basis of a recent suicide attempt, that attempt must still fall within the preceding 30 days. 2. High-risk hallucinogen involvement, defined as a WHO ASSIST substance-specific involvement score of 27 or higher for the hallucinogen category, item (h). 3. A documented history of ketamine use disorder identified during baseline psychiatric assessment. 6. Inability to maintain contact for follow-up assessments. 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.