Esketamine Versus Crisis Response Planning Versus Optimized Treatment as Usual for Suicide Prevention: A Pragmatic Controlled Trial in Two Brazilian Cities
- Conditions
- Suicide PreventionKetamineCrisis Response Plan
- Interventions
- Other: Crisis Response Planning intervention (structures safety planning)
- Registration Number
- NCT07120477
- Lead Sponsor
- University of Sao Paulo
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 500
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Esketamine plus optimized usual treatment Intravenous Esketamine Single esketamine infusion (0.5 mg/kg over 40 minutes) plus optimized usual treatment (early psychiatric follow-up within one week) Crisis Response Planning plus Optimized Usual Treatment Crisis Response Planning intervention (structures safety planning) Crisis Response Planning intervention (structured safety planning) plus optimized usual treatment (early psychiatric follow-up within one week) Optimized Usual Treatment Only Intravenous Esketamine Optimized usual treatment alone (enhanced standard care with early psychiatric follow-up within one week) Optimized Usual Treatment Only Crisis Response Planning intervention (structures safety planning) Optimized usual treatment alone (enhanced standard care with early psychiatric follow-up within one week)
- Primary Outcome Measures
Name Time Method Repeated Suicide-Related Events at One Year One year from baseline enrollment 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.
- Secondary Outcome Measures
Name Time Method Changes in Patient-Reported Quality of Life Baseline, 1 month, 3 months, 6 months, and 1 year Changes in quality of life measured by SF-36v2 questionnaire, assessed at multiple timepoints.
Frequency and Nature of Treatment-Related Adverse Events Throughout study participation, up to one year 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.
Comparative Cost-Effectiveness of Treatment Approaches One year from baseline enrollment 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.
Patients' Treatment Satisfaction and Acceptability Ratings 1 month, 6 months, and 1 year post-treatment Patients' satisfaction scores evaluating perceived effectiveness, feasibility, and acceptability of each treatment modality, assessed through qualitative interviews.
Healthcare Providers' Treatment Satisfaction and Acceptability Ratings 1 month, 6 months, and 1 year post-treatment Healthcare Providers' satisfaction scores evaluating perceived effectiveness, feasibility, and acceptability of each treatment modality, assessed through qualitative interviews.
Implementation Science Outcomes for Clinical Integration Throughout study conduct, analyzed at study completion 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).
Changes in Depressive Symptoms and Depression Prevalence Baseline, 7 days, 1 month, 3 months, 6 months, and 1 year 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.
Changes in Depression, Anxiety, and Mood Disorder Severity Baseline, 7 days, 1 month, 3 months, 6 months, and 1 year 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 to Next Suicidal Crisis or Emergency Up to one year from baseline 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.
Demographic Variability in Treatment Response One year from baseline 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.
Post-Treatment Healthcare Service Utilization Six months and one year post-treatment Comparison of readmission rates, additional mental health service needs, emergency department visits, and psychiatric consultations across treatment groups during follow-up period.
Healthcare Professional Engagement with Implementation Strategies Throughout study conduct, up to one year 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.
Serum Brain-derived neurotrophic factor (BDNF) Predictor of Treatment Outcome Baseline biomarker collection with outcome correlation at 6 months and 1 year 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.
Monoamine oxidase (MAO) Predictor of Treatment Outcome Baseline biomarker collection with outcome correlation at 6 months and 1 year Analysis of baseline platelet Monoamine oxidase (MAO) as a predictor of treatment response and resistance. Identifies biological factors that may guide personalized treatment selection.
Hormones (TSH, T3, Free T3 and Free T4, Total Testosterone, SHBG, S-DHEA, Prolactin) Predictors of Treatment Outcome Baseline biomarker collection with outcome correlation at 6 months and 1 year Analysis of baseline hormones (TSH, T3, Free T3 and Free T4, Total Testosterone, SHBG, S-DHEA, Prolactin) as predictors of treatment response and resistance. Identifies biological factors that may guide personalized treatment selection.
Vitamins and Minerals Biomarkers Predictors of Treatment Outcome Baseline biomarker collection with outcome correlation at 6 months and 1 year Analysis of baseline vitamins and minerals (25-hydroxy-vitamin D, Vitamin B1, Vitamin B12, Vitamin B6, and Folic Acid (B9), Vitamin K, Magnesium, and Red Blood Cell/Erythrocyte Zinc) as predictors of treatment response and resistance. Identifies biological factors that may guide personalized treatment selection.
Iron Profile (Iron, Ferritin and Transferrin Saturation) Predictors of Treatment Outcome Baseline biomarker collection with outcome correlation at 6 months and 1 year Analysis of baseline Iron Profile (Iron, Ferritin, and Transferrin Saturation) as predictors of treatment response and resistance. Identifies biological factors that may guide personalized treatment selection.
Homocysteine Predictor of Treatment Outcome Baseline biomarker collection with outcome correlation at 6 months and 1 year Analysis of baseline Homocysteine as a predictor of treatment response and resistance. Identifies biological factors that may guide personalized treatment selection.
Ultrasensitive C-Reactive Protein Predictor of Treatment Outcome Baseline biomarker collection with outcome correlation at 6 months and 1 year Analysis of baseline Ultrasensitive C-Reactive Protein as a predictor of treatment response and resistance. Identifies biological factors that may guide personalized treatment selection.
25-hydroxy-vitamin D Predictor of Treatment Outcome Baseline biomarker collection with outcome correlation at 6 months and 1 year Analysis of baseline 25-hydroxy-vitamin D as a predictor of treatment response and resistance. Identifies biological factors that may guide personalized treatment selection.