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

Summary

Suicide is one of the leading causes of early death worldwide. In Brazil, suicide rates have been rising steadily over the past two decades, and most suicides occur in low- and middle-income countries where access to specialized care is limited. There is an urgent need for fast-acting, practical interventions that can be delivered in public emergency settings. Two promising approaches have emerged: esketamine, a medication that can rapidly reduce suicidal thoughts within hours, and Crisis Response Planning (CRP), a brief session in which a trained clinician works with the person to create a personalized written plan for managing future suicidal crises.

The goal of this clinical trial is to learn if esketamine or Crisis Response Planning (CRP), each added to enhanced treatment as usual (eTAU), can prevent future suicide-related events compared to eTAU alone in adolescents and adults aged 14 years or older who recently attempted suicide or have severe suicidal thoughts. The main questions it aims to answer are:

Does a single esketamine infusion plus eTAU lower the risk of a new suicide-related event compared to eTAU alone over 12 months? Does a single session of Crisis Response Planning plus eTAU lower the risk of a new suicide-related event compared to eTAU alone over 12 months? Which approach leads to faster or more lasting improvements in suicidal thoughts, depression, anxiety, sleep, well-being, hopelessness, and quality of life? Are these interventions feasible, acceptable, and cost-effective within a public health system?

Researchers will compare three groups to see which approach works best to prevent suicide attempts, suicide-related hospitalizations, and suicide deaths over one year.

A total of 468 participants will be randomly assigned in equal numbers (156 per group) to one of three groups:

Esketamine group: receive a single intravenous esketamine infusion (0.50 mg/kg given over 40 minutes) in a monitored medical setting with continuous heart rate, blood pressure, and oxygen monitoring, plus eTAU. A physician will be present throughout. Participants will be observed for up to 24 hours before discharge.

Crisis Response Planning group: complete one 20-to-45-minute session with a trained clinician to build a personal crisis plan that includes warning signs, coping strategies, reasons for living, support contacts, and emergency resources. Participants will leave with a written and digital copy of their plan, plus eTAU.

Enhanced treatment as usual (eTAU) group: receive standard emergency care, safety counseling about access to lethal means, connection to the local mental health network (including Psychosocial Care Centers and primary care), and a scheduled psychiatric follow-up appointment within 7 days.

Participants will:

Complete health questionnaires about suicidal thoughts, depression, anxiety, sleep, well-being, hopelessness, and quality of life at 11 time points over one year (at enrollment, 24 hours, 7 days, 2 weeks, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 1 year) Provide a blood sample at the start of the study for exploratory analyses of biological markers that may be related to treatment response Use a smartphone app to report their mood, thoughts, and emotions four times a day for four weeks after enrollment Be monitored for safety and adverse events throughout the entire study period

The study takes place in the public emergency network of Indaiatuba, São Paulo, Brazil (population approximately 256,000), and is designed to reflect real-world clinical conditions. Participants who experience a new suicide-related event during the study will be offered an open-label rescue treatment combining esketamine and Crisis Response Planning, and will continue to be followed for the remainder of the year. The study also includes an evaluation of how well these interventions can be adopted and sustained within Brazil's public mental health system, including assessments of acceptability, feasibility, and cost-effectiveness.

Conditions

• Suicide Prevention
• Ketamine
• Crisis Response Plan

Interventions

DRUG

Intravenous Esketamine

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.

OTHER

Crisis Response Planning intervention (structures safety planning)

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.

Sponsors & Collaborators

• Yale University

  collaborator OTHER

• University of Vermont

  collaborator OTHER

• University of Pittsburgh

  collaborator OTHER

• University of Sao Paulo

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

14 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-05-31

Primary Completion

2028-12-31

Completion

2029-12-31