A Phase 4 interventional study of Esketamine hydrochloride (intranasal) and Integration Therapy in Treatment-resistant Depression (TRD), sponsored by University of Puerto Rico. Recruiting at 2 sites in Puerto Rico. Open to participants aged 21 Years to 65 Years. Per ClinicalTrials.gov, last updated 2026-01-27.
Sponsored by University of Puerto Rico · Phase 4, Interventional, and Treatment
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.
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.
448 studies on the registry are indexed under Depressive Disorder, Treatment-Resistant; 147 are open to participants now.
This study's planned enrollment of 20 is below the median of 59 across 372 interventional studies indexed under Depressive Disorder, Treatment-Resistant.
Browse Depressive Disorder, Treatment-Resistant studies →University of Puerto Rico is the lead sponsor of 46 studies on the registry; 15 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Able to have children. For women this usually means from the first period until menopause, unless permanently unable to through surgery; for men, unless permanently sterile. Read who the line is about — participants, women, men, or their partners.
Criteria about it usually ask for contraception during the study and for a time after it.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Reproductive potential
Able to have children. For women this usually means from the first period until menopause, unless permanently unable to through surgery; for men, unless permanently sterile. Read who the line is about — participants, women, men, or their partners.
Criteria about it usually ask for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Participants in this arm will receive FDA-approved intranasal esketamine (Spravato®) twice weekly during the acute phase (weeks 1-4), followed by weekly or biweekly dosing during the maintenance phase (weeks 5-8), based on clinical response. In addition, participants will receive brief, structured therapeutic sessions for preparation and integration before and after each dosing session. These sessions are designed to support emotional processing, meaning-making, and therapeutic engagement.
Drug: Esketamine hydrochloride (intranasal) · Behavioral: Integration Therapy
Participants in this arm will receive FDA-approved intranasal esketamine (Spravato®) twice weekly during the acute phase (weeks 1-4), followed by weekly or biweekly dosing during the maintenance phase (weeks 5-8), based on clinical response. No additional psychotherapeutic support will be provided beyond standard clinical monitoring and psychiatric care.
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.
Also known as: Spravato
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.
Change From Baseline in Depression Severity as Assessed by MADRS
Change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to the end of acute treatment. The MADRS is a clinician-rated scale assessing depressive symptom severity, with scores ranging from 0 to 60. Higher scores indicate more severe depression; lower scores indicate symptom improvement.
Time frame: Baseline and end of acute treatment at 8 weeks
Proportion of Participants Achieving Treatment Response (≥50% Reduction in MADRS)
Number of participants achieving treatment response, defined as a ≥50% reduction in MADRS total score from baseline. MADRS scores range from 0 to 60, with higher scores indicating greater depression severity.
Time frame: From enrollment (baseline) to the end of acute treatment at 8 weeks
Proportion of Participants Achieving Remission (MADRS <10)
Number of participants achieving remission, defined as a MADRS total score below 10 at the end of acute treatment. MADRS scores range from 0 to 60, with lower scores indicating fewer depressive symptoms.
Time frame: At the end of acute treatment at 8 weeks
Proportion of Participants Experiencing Depressive Relapse Confirmed by SCID-5
Number of participants meeting DSM-5 criteria for a new major depressive episode after achieving remission, as assessed using the Structured Clinical Interview for DSM-5 (SCID-5). This is a categorical diagnostic outcome (yes/no).
Time frame: From achievement of remission through 6 months after completion of acute treatment
Change From Baseline in Functional Impairment as Assessed by WSAS
Change in Work and Social Adjustment Scale (WSAS) total score from baseline to the end of acute treatment. WSAS scores range from 0 to 40, with higher scores indicating greater functional impairment and lower scores indicating better functioning.
Time frame: Baseline and end of acute treatment at 8 weeks
Change From Baseline in Suicidality as Assessed by C-SSRS
Change in suicidal ideation and behavior severity as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS). The scale includes ordinal severity categories, with higher scores indicating greater suicidality risk.
Time frame: Baseline and end of acute treatment at 8 weeks
Subjective Experience Following Esketamine Administration (Qualitative Reflections)
Subjective experiences assessed through semi-structured interviews and written reflections exploring emotional, perceptual, and psychological experiences following esketamine sessions. Data will be analyzed using thematic qualitative analysis. This outcome does not use a numeric score.
Time frame: Within 72 hours after dosing sessions occurring at Weeks 4 and 8
Engagement With Psychedelic Integration as Assessed by Integration Scales
Engagement with preparation and integration processes assessed using Psychedelic Integration Scales. Scores reflect perceived meaning-making, insight, and behavioral integration. Scale scores range from lowest possible score (minimal engagement) to highest possible score (high engagement and integration); higher scores indicate greater integration.
Time frame: Within 72 hours after each integration session and at the end of acute treatment at 8 weeks
Treatment Credibility and Expectancy as Assessed by the CEQ
Treatment credibility and expectancy assessed using the Credibility/Expectancy Questionnaire (CEQ). CEQ items are scored on Likert scales, with higher scores indicating greater perceived credibility and expectancy of benefit.
Time frame: Baseline: after the first preparation session and prior to the first esketamine dosing session
Therapeutic Alliance as Assessed by the Working Alliance Inventory-Short Form (WAI-SF)
Therapeutic alliance assessed using the Working Alliance Inventory-Short Form (WAI-SF), which measures agreement on goals, tasks, and therapeutic bond. Scores range from 12 to 84, with higher scores indicating stronger therapeutic alliance.
Time frame: At Week 4 of acute treatment
Dissociative Symptoms as Assessed by the CADSS
Dissociative symptoms assessed using the Clinician-Administered Dissociative States Scale (CADSS). Total scores range from 0 to 92, with higher scores indicating greater dissociative symptom severity.
Time frame: Immediately after each esketamine dosing session during the acute treatment phase
Mystical-Type Experience as Assessed by the MEQ-30
Mystical-type experiences assessed using the Mystical Experience Questionnaire-30 (MEQ-30), including total and subscale scores. Scores range from 0 to 5 per item, with higher scores indicating greater intensity of mystical-type experiences.
Time frame: Within 24 hours after dosing sessions 2 and 4 during the acute treatment phase
Altered States of Consciousness as Assessed by the 5D-ASC
Altered states of consciousness assessed using the Five-Dimensional Altered States of Consciousness (5D-ASC) questionnaire. Subscale scores range from 0 to 100, with higher scores indicating greater intensity of altered states.
Time frame: Within 24 hours after dosing sessions 2 and 4 during the acute treatment phase
Change From Baseline in Emotion Regulation Difficulties as Assessed by DERS
Change in Difficulties in Emotion Regulation Scale (DERS) total score from baseline to the end of acute treatment. Total scores range from 36 to 180, with higher scores indicating greater difficulty with emotion regulation.
Time frame: Baseline and end of acute treatment at 8 weeks
Patient Satisfaction as Assessed by the Client Satisfaction Questionnaire-8 (CSQ-8)
Patient satisfaction assessed using the Client Satisfaction Questionnaire-8 (CSQ-8). Total scores range from 8 to 32, with higher scores indicating greater satisfaction with care.
Time frame: At the end of acute treatment at 8 weeks and 6 months after completion of acute treatment
Negative Treatment Effects as Assessed by the Negative Effects Questionnaire (NEQ)
Negative treatment effects assessed using the Negative Effects Questionnaire (NEQ), including total and subscale scores. Higher scores indicate greater perceived negative effects of treatment.
Time frame: At the end of acute treatment at 8 weeks and 6 months after completion of acute treatment
Plan to share: Undecided — The investigators may consider sharing de-identified individual participant data upon study completion, subject to IRB approval, institutional policy, and data use agreements.
Start is estimated for Feb 2026; primary completion for Dec 2026, 10 months later.
Of 18 phase 4 interventional studies under Depressive Disorder, Treatment-Resistant, half reached primary completion within 38 months of starting (the median), counting those still running; a quarter within 27 and three quarters within 59. This study's planned 10 months is below that.
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Depressive Disorder, Treatment-Resistant →
University of Puerto Rico