Esketamine Versus Crisis Response Planning Versus Optimized Treatment as Usual for Suicide Prevention: A Pragmatic Controlled Trial in Two Brazilian Cities

STUDY DESIGN AND CONCEPTUAL FRAMEWORK The SAVE Study (Esketamine Versus Crisis Response Planning Versus Enhanced Treatment as Usual for Suicide Prevention) 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. The pragmatic design embeds interventions within routine emergency-department workflows, uses broad inclusion criteria, flexible delivery, and minimal exclusion criteria to maximize real-world generalizability and scalability across low- and middle-income country (LMIC) public health networks. The protocol adheres to the SPIRIT 2025 guidelines (Chan et al., 2025), and reporting will follow the CONSORT 2025 Statement (Hopewell et al., 2025). An independent Data and Safety Monitoring Board (DSMB) oversees safety throughout the trial.

SETTING The trial is conducted in Indaiatuba, São Paulo State, Brazil (population approximately 256,000), which integrates urgent and emergency units (UPA/UEU), a reference hospital emergency department (ED), a Medical Specialties Center (CEEM), a Psychosocial Care Center (CAPS), and primary care units (UBS) within the municipal Psychosocial Care Network (RAPS). Randomization and interventions occur in the ED/UEU; linkage to CAPS and primary care ensures continuity of treatment. This setting was selected because it represents a typical mid-sized Brazilian municipality with a functional but resource-constrained public mental health infrastructure, enhancing the transferability of findings to similar contexts nationally and internationally.

STUDY FLOW Once clinical stabilization is achieved, potentially eligible patients-based on clinical and psychiatric evaluations conducted by attending physicians in the emergency setting-are referred to study researchers for further evaluation. The presence of a primary psychotic disorder, acute psychosis, or acute mania is assessed by the attending physician before referral to the research team. Study researchers then visit the site to conduct additional assessments and invite eligible individuals to participate. Those who provide informed consent (or assent, for minors aged 14-17, with guardian consent) complete further evaluations to confirm eligibility, including sociodemographic, clinical, and psychiatric assessments, as well as the ASSIST for substance use disorder screening, which also serves as an exclusion criterion. Female participants additionally undergo a rapid pregnancy test within the emergency setting. Eligible participants proceed to baseline assessments (T0) and are randomized in a 1:1:1 ratio. Interventions are delivered immediately in the ED/UEU.

RANDOMIZATION, CONCEALMENT, AND BLINDING A statistician not involved in outcome assessments generates a computer-randomized sequence with permuted, variable block sizes and stratification by three factors: (1) age group (≥18 vs. 14-17 years), (2) sex (male vs. female/other), and (3) index presentation (suicide attempt \[actual, interrupted, or aborted\] vs. severe suicidal ideation vs. non-suicidal self-injury). Allocation is implemented via REDCap's automated randomization module, which features role-based access and audit-trail logging, ensuring concealment.

While participants and treating clinicians are necessarily unblinded due to the nature of the interventions, outcome assessors and data analysts are kept blinded to treatment allocation. Assessors are trained not to inquire about treatment received and to terminate assessments if participants voluntarily reveal their allocation, with reassignment to an alternative blinded assessor. Data analysts receive coded datasets (Groups A, B, and C) without treatment identification until completion of the primary analyses. Emergency unblinding is limited to serious safety concerns requiring knowledge of allocation for appropriate clinical management, following a pre-specified protocol approved by the Ethics Committee. All unblinding events are documented with detailed justification and reported to the Ethics Committee.

INTERVENTION DETAILS Arm A - Enhanced Treatment as Usual (eTAU, control): Routine ED care augmented by a structured linkage across RAPS, booked psychiatric follow-up within 7 days (CAPS/CEEM) after the index event, and a lethal means safety counseling intervention delivered at the emergency department by a research team member. The lethal means counseling consists of developing a plan to limit the participant's access to potentially lethal suicide attempt methods. Risk assessment and emergency procedures are standardized and identical across all three arms. Researchers have no interference with eTAU clinical decisions.

Arm B - Esketamine + eTAU: One intravenous esketamine infusion at 0.50 mg/kg over 40 minutes, administered in a monitored clinical setting with continuous pulse oximetry, non-invasive blood pressure, and ECG monitoring. A physician is present throughout; an ACLS-capable team is immediately available. Structured symptom ratings occur during infusion and for 240 minutes afterward. Discharge can occur after 24 hours if clinically stable. Pre-specified safety thresholds trigger intervention, including: sustained systolic blood pressure ≥180 or ≤90 mmHg, diastolic blood pressure ≥105 or ≤50 mmHg, blood pressure shift of ±25 mmHg, or clinically significant dissociation or agitation. The esketamine infusion protocol follows established safety guidelines from long-term extension studies.

Arm C - Crisis Response Planning (CRP) + eTAU: A 20-to-45-minute single-session Crisis Response Plan delivered by trained clinicians, comprising collaborative identification of personal warning signs, internal self-regulation strategies, reasons for living, social support contacts, and professional and emergency contacts. Participants leave with a written plan (printed card plus digital photograph). Therapists complete a standardized 3-hour training program, which includes didactic content, role-plays, certification, and weekly supervision. Sessions utilize fidelity checklists, and 10-20% of sessions are audio-recorded for adherence and competence coding, with a target inter-rater reliability of κ ≥ 0.80 across fidelity audits.

RESCUE TREATMENT FOR RECURRENT EVENTS Participants who experience a recurrent suicide-related event (i.e., meet the primary endpoint) during follow-up are offered an open-label rescue treatment combining esketamine and CRP while remaining in scheduled follow-up assessments. The rescue phase is analyzed descriptively and does not contribute to the primary intention-to-treat (ITT) analysis of the endpoint.

ASSESSMENT SCHEDULE Follow-up assessments are conducted at 11 time points: baseline (T0), 24 hours (T1), 7 days (T2), 2 weeks (T3), 4 weeks (T4), 8 weeks (T5), 16 weeks (T6), 24 weeks (T7), 32 weeks (T8), 40 weeks (T9), and 1 year (T10), with monthly event surveillance between scheduled visits. Core instruments include the Columbia-Suicide Severity Rating Scale (C-SSRS), Beck Scale for Suicide Ideation (BSI), Patient Health Questionnaire-9 (PHQ-9), Montgomery-Åsberg Depression Rating Scale (MADRS), Generalized Anxiety Disorder-7 (GAD-7), Snaith-Hamilton Pleasure Scale-Brazilian version (SHAPS-BR), Pittsburgh Sleep Quality Index abbreviated version (Short PSQI), 12-Item Short Form Health Survey (SF-12), Barratt Impulsiveness Scale Short Form (BIS-15), Beck Hopelessness Scale 7-item version (BHS-7), Short Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS), Alcohol, Smoking and Substance Involvement Screening Test (ASSIST), McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD), Duke University Religion Index (DUREL), Adult ADHD Self-Report Scale Short Form (ASRS-S), Altman Self-Rating Mania Scale (ASRM), and Clinical Global Impression scales (CGI-S and CGI-I). All psychometric instruments are validated Brazilian Portuguese versions. The assessment battery was streamlined following expert consultation to reduce participant burden in this high-acuity population.

Baseline-only measures serving as covariates and potential moderators include impulsivity (BIS-15), substance use (ASSIST), borderline personality features (MSI-BPD), religiosity/spirituality (DUREL), ADHD symptoms (ASRS-S), and manic symptoms (ASRM).

ECOLOGICAL MOMENTARY ASSESSMENT (EMA) A smartphone application (MindLogger) collects four daily ratings for four consecutive weeks following the index event. Each brief survey assesses momentary affect (e.g., happiness, sadness, loneliness, anger, anxiety, stress, hopefulness, calmness, boredom), self-evaluative states (e.g., self-worth, perceived purpose, forgiveness, hopelessness), and cognitive-emotional regulation strategies (e.g., distraction, rumination, reappraisal, emotional acceptance, seeking social support). Participants also report on contextual factors, including current company (e.g., alone, with family, partner, friends), interpersonal events (e.g., recent conflicts), and substance use within the past two hours (alcohol, cannabis, opioids, stimulants, sedatives, hallucinogens, nicotine).

The EMA further captures momentary suicidal processes through items evaluating the wish to live and to die, current suicidal ideation intensity, controllability over suicidal thoughts, perceived ability to resist acting on them, and recent self-harm behaviors. Responses are rated on brief ordinal scales reflecting real-time intensity or frequency. This approach enables high-frequency, real-world sampling of emotional, cognitive, behavioral, and contextual dynamics during the critical post-index period, enhancing temporal resolution and ecological validity for modeling short-term risk fluctuations.

BIOMARKERS AND LABORATORY PROCEDURES At baseline, venous blood samples (10 mL in EDTA tubes) are collected and immediately analyzed at the hospital laboratory. Samples are destroyed after report release (no biobank storage). The biomarker panel includes: high-sensitivity C-reactive protein (hs-CRP), homocysteine, comprehensive vitamin assessment (B1/thiamine, B2/riboflavin, B6/pyridoxine, B12/cobalamin, D/25-hydroxyvitamin D, folate), essential minerals (magnesium and zinc in erythrocytes, selenium), complete thyroid panel (TSH, free T3, free T4), and hormonal markers (testosterone, DHEA-S, prolactin, SHBG). Exploratory analyses will examine whether baseline inflammatory and nutritional markers moderate treatment response.

SAMPLE SIZE JUSTIFICATION Sample size determination followed an event-driven design appropriate for the time-to-first-event primary endpoint, analyzed using Cox proportional hazards models. Statistical power depends primarily on the number of observed events.

For the two co-primary pairwise comparisons (esketamine + eTAU vs. eTAU, and CRP + eTAU vs. eTAU), the family-wise type I error rate was controlled at αFWER = 0.05 using the Holm-Bonferroni sequential procedure, corresponding to α = 0.025 (two-sided) for each comparison. Required numbers of events were computed using Schoenfeld's proportional hazards method. Assuming equal allocation (p = 0.5), 90% power, and target hazard ratios of 0.50 for esketamine and 0.39 for CRP, this yielded approximately 103 and 56 required events, respectively.

The expected 12-month cumulative event risk in the control group was set at 30%, with a 24-month accrual period and 12-month follow-up period, accounting for 20% attrition/censoring. Under these assumptions, the corresponding two-arm totals were approximately 312 participants (156 per group) for the esketamine comparison and 182 participants (91 per group) for the CRP comparison. For the three-arm (1:1:1) design, the study was powered to the limiting contrast (esketamine vs. eTAU), yielding a total sample size of 468 participants (156 per arm). The CRP vs. esketamine comparison will be analyzed as a key secondary, exploratory outcome.

STATISTICAL ANALYSIS PLAN All analyses follow the intention-to-treat

• Total Suicide-Related Events (Count) [Срок оценки: 12 months from randomization]
• Suicidal Ideation Severity (Beck Scale for Suicide Ideation) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: Baseline, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 40 weeks, and 1 year]
• Anhedonia (Snaith-Hamilton Pleasure Scale - Brazilian Version) [Срок оценки: Baseline, 4 weeks, 32 weeks, and 1 year]
• Sleep Quality (Pittsburgh Sleep Quality Index - Abbreviated Version) [Срок оценки: Baseline, 4 weeks, 16 weeks, 40 weeks, and 1 year]
• Mental Well-Being (Short Warwick-Edinburgh Mental Well-Being Scale) [Срок оценки: Baseline, 4 weeks, 16 weeks, 32 weeks, and 1 year]
• Hopelessness (Beck Hopelessness Scale - 7-Item Version) [Срок оценки: Baseline, 4 weeks, 32 weeks, and 1 year]
• Health-Related Quality of Life (12-Item Short Form Health Survey) [Срок оценки: Baseline, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 40 weeks, and 1 year]
• Clinical Global Impression - Improvement (CGI-I) [Срок оценки: 24 hours, 7 days, and 2 weeks]