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

Phase 4Not Yet RecruitingNCT07120477

University of Sao Paulo500 enrolled

Overview

1. Background Suicide is a major public health challenge with over 800,000 deaths annually worldwide. Brazil experienced a concerning 57% increase in suicide rates between 2000-2019, highlighting urgent need for effective prevention strategies. This study evaluates two promising interventions: esketamine (rapid-acting pharmacological treatment) and Crisis Response Planning (CRP, evidence-based psychological safety planning approach) in a real-world Brazilian public health setting. 2. Study Design Pragmatic randomized controlled trial with hybrid implementation-effectiveness design comparing three approaches in emergency departments across two Brazilian cities with combined population of 310,000: * Group A: Single esketamine infusion (0.5 mg/kg over 40 minutes) + optimized usual treatment (OUT) * Group B: Crisis Response Planning + OUT * Group C: OUT alone (enhanced control) 3. Participants Adults and adolescents (≥14 years) presenting with high suicide risk defined as: * Recent suicide attempts within 30 days (actual, interrupted, or aborted) * Severe suicidal ideation (Columbia-Suicide Severity Rating Scale questions 4-5 positive) * Non-suicidal self-harm requiring emergency medical attention 4. Target enrollment: \~272 participants per group (816 total). Key exclusions: esketamine contraindications (cardiovascular disease, aneurysms), psychotic disorders, severe substance use disorders, pregnancy/lactation, inability to consent. 5. Interventions 1. Esketamine Group: IV infusion administered in medical setting with continuous 4-hour monitoring (pulse, blood pressure, ECG, oxygen saturation). Trained medical staff and emergency protocols available. 2. Crisis Response Planning: Collaborative intervention delivered by trained clinical psychologists. 20-45 minute sessions creating personalized, written safety plans identifying warning signs, internal coping strategies, social support contacts, professional resources, and means restriction. 3. Optimized Usual Treatment: Enhanced standard care including guaranteed psychiatric follow-up appointment within one week through municipal mental health services (CAPS - Psychosocial Care Centers). 6. Primary Outcome Repeated suicide-related events over one year including suicide attempts, interrupted attempts, suicide-prevention hospitalizations, deaths by suicide, and non-suicidal self-harm requiring medical attention. 7. Comprehensive Data Collection 1. Biomarkers: 10mL venous blood samples (2 EDTA tubes) collected at baseline by senior clinical nurses. Comprehensive laboratory analysis including complete blood count, metabolic panel, vitamins (B1, B2, B6, B12, B9, D, K), hormones (TSH, T3, T4, testosterone, DHEA, prolactin), inflammatory markers (CRP), brain-derived neurotrophic factor (BDNF), platelet monoamine oxidase (MAO), minerals (iron, ferritin, magnesium, zinc, selenium), and lipid profiles. Samples processed within 24 hours and stored at -80°C for analysis. 2. Clinical Assessments: Comprehensive evaluations at 11 time points (baseline, 24 hours, 7 days, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, 1 year) using validated instruments: Columbia-Suicide Severity Rating Scale (C-SSRS), depression scales (PHQ-9, MADRS), anxiety (GAD-7), quality of life (SF-36v2), impulsivity (BIS-11), trauma history (MACE), substance use (ASSIST), sleep quality (PSQI), and additional psychosocial measures. 3. Ecological Momentary Assessment: Real-time data collection via smartphone application for consenting participants. Six daily prompts assessing mood, suicidal thoughts, and emotional states using validated scales. Previous research demonstrates safety and high compliance rates in suicide research populations. 8. Secondary Outcomes * Time to new suicidal crisis or psychiatric emergency * Changes in depression and anxiety severity scores * Quality of life and functional outcome improvements * Treatment response variability by demographic factors (age, gender, socioeconomic status) * Comprehensive cost-effectiveness analysis including direct medical costs and indirect productivity losses * Patient and clinician satisfaction with treatment modalities * Implementation barriers and facilitators using Consolidated Framework for Implementation Research (CFIR) * Biomarker predictors of treatment response 9. Clinical Significance This represents the first large-scale, real-world direct comparison of rapid-acting pharmacological (esketamine) versus evidence-based psychological (CRP) interventions for suicide prevention within a public health system. Results will provide crucial evidence for clinical practice guidelines and inform implementation of these interventions in Brazil and similar global contexts. The pragmatic design ensures findings are directly applicable to routine emergency department practice, while comprehensive biomarker analysis may identify biological predictors of treatment response to personalize suicide prevention approaches.

Interventions

Intravenous EsketamineDRUG

Single-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

Collaborative 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.

Eligibility

Sex: ALLMin age: 14 Years

Medical Language ↔ Plain English

* Inclusion Criteria: * Age ≥ 14 years * Recent suicide attempt within 30 days (actual, interrupted, or aborted) * Severe suicidal ideation (positive response to questions 4 or 5 on Columbia-Suicide Severity Rating Scale screening version) * Non-suicidal self-harm requiring medical attention in emergency department setting * Resident of Jaguariúna, Indaiatuba, or surrounding areas * Able to provide informed consent (or assent with guardian consent for minors) * Not requiring long-term psychiatric hospitalization after emergency evaluation * Exclusion Criteria: * Medical conditions contraindicated for esketamine use (aneurysmal vascular disease, arteriovenous malformation, intracerebral hemorrhage, known hypersensitivity to esketamine) * Need for intensive care unit admission without possibility of later study participation * Severe substance use disorders interfering with protocol adherence * Psychotic disorders * Lack of stable housing or inability to be contacted for follow-up assessments * History of non-response to esketamine or previous enrollment in esketamine studies * Pregnancy or breastfeeding * Inability to provide informed consent due to cognitive impairment or explicit refusal to participate

Outcomes

Primary Outcomes

Repeated Suicide-Related Events at One Year

Composite outcome including repeated suicide attempts (actual, interrupted, aborted), hospitalizations for suicide prevention, deaths by suicide, and non-suicidal self-harm requiring medical attention in emergency settings. Based on validated definitions from the Columbia-Suicide Severity Rating Scale and previous suicide prevention studies. Events assessed through medical records review, participant self-report, and contact with emergency services in both study municipalities.

Time frame: One year from baseline enrollment

Secondary Outcomes

Changes in Depressive Symptoms and Depression Prevalence

Changes in mental health scores measured by Patient Health Questionnaire-9 (PHQ-9), assessed at multiple time points to evaluate treatment impact on overall mental health status.

Time frame: Baseline, 7 days, 1 month, 3 months, 6 months, and 1 year

Changes in Depressive Symptoms and Depression Prevalence

Changes in mental health scores measured by Montgomery-Asberg Depression Rating Scale (MADRS), assessed at multiple time points to evaluate treatment impact on overall mental health status.

Time frame: Baseline, 7 days, 1 month, 3 months, 6 months, and 1 year

Changes in Depression, Anxiety, and Mood Disorder Severity

Changes in mental health scores measured by Generalized Anxiety Disorder-7 (GAD-7), assessed at multiple time points to evaluate treatment impact on overall mental health status.

Time frame: Baseline, 7 days, 1 month, 3 months, 6 months, and 1 year

Changes in Depression, Anxiety, and Mood Disorder Severity

Changes in mental health scores measured by the Hypomania Checklist (HCL-32) Questionnaire, assessed at multiple time points to evaluate treatment impact on overall mental health status.

Time frame: Baseline, 7 days, 1 month, 3 months, 6 months, and 1 year

Time to Next Suicidal Crisis or Emergency

Time elapsed between initial intervention and occurrence of any new suicidal crisis, including suicide attempts, hospitalization, or emergency department visits related to suicidal behavior. Measured using survival analysis methods with censoring at study completion.

Time frame: Up to one year from baseline

Demographic Variability in Treatment Response

Analysis of treatment outcome differences across demographic subgroups including age, gender, socioeconomic status, and other baseline characteristics. Identifies which populations may benefit most from specific interventions.

Time frame: One year from baseline

Changes in Patient-Reported Quality of Life

Changes in quality of life measured by SF-36v2 questionnaire, assessed at multiple timepoints.

Time frame: Baseline, 1 month, 3 months, 6 months, and 1 year

Frequency and Nature of Treatment-Related Adverse Events

Documentation of all adverse events, complications, and safety concerns associated with each treatment arm, including physical symptoms after esketamine infusion, psychological distress during crisis planning sessions, and any serious adverse events.

Time frame: Throughout study participation, up to one year

Comparative Cost-Effectiveness of Treatment Approaches

Economic evaluation comparing direct medical costs, indirect productivity losses, healthcare utilization, and cost per quality-adjusted life year (QALY) across treatment groups. Includes medication costs, therapy sessions, hospitalizations, and lost productivity.

Time frame: One year from baseline enrollment

Patients' Treatment Satisfaction and Acceptability Ratings

Patients' satisfaction scores evaluating perceived effectiveness, feasibility, and acceptability of each treatment modality, assessed through qualitative interviews.

Time frame: 1 month, 6 months, and 1 year post-treatment

Healthcare Providers' Treatment Satisfaction and Acceptability Ratings

Healthcare Providers' satisfaction scores evaluating perceived effectiveness, feasibility, and acceptability of each treatment modality, assessed through qualitative interviews.

Time frame: 1 month, 6 months, and 1 year post-treatment

Implementation Science Outcomes for Clinical Integration

Identification of barriers and facilitators for implementing esketamine therapy and crisis response planning in emergency department settings, evaluated using the Consolidated Framework for Implementation Research (CFIR).

Time frame: Throughout study conduct, analyzed at study completion

Post-Treatment Healthcare Service Utilization

Comparison of readmission rates, additional mental health service needs, emergency department visits, and psychiatric consultations across treatment groups during follow-up period.

Time frame: Six months and one year post-treatment

Healthcare Professional Engagement with Implementation Strategies

Rate of healthcare professional adherence to implementation strategies, engagement with training programs, and adoption of study interventions in routine clinical practice within the emergency department settings.

Time frame: Throughout study conduct, up to one year

Serum Brain-derived neurotrophic factor (BDNF) Predictor of Treatment Outcome

Analysis of baseline serum Brain-derived neurotrophic factor (BDNF) as a predictor of treatment response and resistance. Identifies biological factors that may guide personalized treatment selection.