NCT07369102

Esketamine With or Without Integration Therapy for Treatment-Resistant Depression

Esketamine With or Without Psychedelic Preparation and Integration for Treatment-Resistant Depression: A Randomized Controlled Trial

• Status: Recruiting
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 20 (estimated)
• Sponsor: University of Puerto Rico · Academic / Other
• Sex: All
• Age: 21 Years – 65 Years
• Healthy volunteers: Not accepted

Summary

This study will explore the effects of esketamine (Spravato®), an FDA-approved nasal spray, on adults diagnosed with treatment-resistant depression (TRD). All participants will receive esketamine as prescribed by a healthcare professional in a clinical setting. The purpose of this research is to understand whether adding therapeutic support in the form of preparation and integration sessions - before and after the esketamine doses - can enhance the treatment experience and lead to longer-lasting improvements in mood and functioning. Participants will be randomly assigned to one of two groups: Esketamine with therapeutic support sessions (integration group) Esketamine without additional support (standard care group) Both groups will receive standard monitoring and psychiatric evaluation during the study. The support sessions offered in the integration group are designed to help participants prepare for their treatment sessions and make sense of their experiences afterward, using a structured, evidence-based approach. The study will last approximately 8 weeks per participant, with follow-up assessments. The goal is to learn whether integration therapy can improve treatment outcomes, safety, and satisfaction for individuals with depression that hasn't responded to other treatments.

Detailed description

This is a single-site, randomized, controlled trial evaluating the effects of therapeutic preparation and integration on the clinical outcomes and subjective experience of intranasal esketamine treatment in adults with treatment-resistant depression (TRD). All participants will receive FDA-approved intranasal esketamine (Spravato®) twice weekly in accordance with current clinical guidelines. Participants will be randomly assigned to one of two arms: Integration Arm: Esketamine with brief, structured preparation and integration sessions conducted by a trained clinician Control Arm: Esketamine without additional psychotherapeutic support beyond standard care Therapeutic support in the integration arm is informed by existing psychedelic-assisted therapy frameworks and consists of brief, manualized sessions designed to enhance safety, emotional processing, and meaning-making. These sessions aim to help participants prepare psychologically for their esketamine experiences and to integrate insights or emotional responses afterward. The primary outcome is change in depression severity, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes include measures of emotional regulation, therapeutic alliance, treatment acceptability, and dissociative experiences. Exploratory measures will examine participants' engagement with integration, perceived coherence of their experience, and overall satisfaction. This study seeks to address a current gap in the literature by evaluating the role of structured psychological support in esketamine treatment for depression. While esketamine has demonstrated rapid antidepressant effects, the variability in subjective response and relapse rates suggests that adjunctive support may be beneficial. By including both quantitative and qualitative measures, the study aims to generate data to inform more holistic and patient-centered models of esketamine treatment. All study procedures will be conducted at a licensed clinical site under the supervision of qualified healthcare professionals. The protocol has received ethical approval from an institutional review board (IRB), and all participants will provide informed consent prior to participation.

Conditions

• Treatment-resistant Depression (TRD)

Interventions

Type	Name	Description
DRUG	Esketamine hydrochloride (intranasal)	Intranasal esketamine (Spravato®), administered under medical supervision in accordance with FDA guidelines for treatment-resistant depression. Dosing schedule includes twice-weekly administration during weeks 1-4 (acute phase), followed by weekly or biweekly administration during weeks 5-8 (maintenance phase), based on clinical response and tolerability. All dosing occurs in a clinical setting with standard monitoring for at least two hours post-administration.
BEHAVIORAL	Integration Therapy	Brief, structured psychotherapeutic sessions delivered before and after each esketamine dose, based on psychedelic-assisted therapy principles. Sessions are designed to support emotional safety, preparation for the treatment experience, and integration of psychological content that may arise. Conducted by trained clinicians following a standardized framework developed for this study. Only participants in the experimental arm receive this intervention.

Timeline

• Start date: 2026-02-01
• Primary completion: 2026-12-01
• Completion: 2026-12-01
• First posted: 2026-01-27
• Last updated: 2026-01-27

Locations

2 sites across 1 country: Puerto Rico

Regulatory

• FDA-regulated drug study