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Treatment-resistant Depression (TRD)Phase 4KIND-PRNCT07369102

Esketamine With or Without Integration Therapy for Treatment-Resistant Depression

A Phase 4 study testing Esketamine hydrochloride (intranasal) and Integration Therapy in people with Treatment-resistant Depression (TRD), run by University of Puerto Rico at 2 sites in Puerto Rico.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 21 to 65 years
Conditions the study is for
Treatment-resistant Depression (TRD)
What is being tested?
Esketamine hydrochloride (intranasal) and Integration Therapy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
2 sitesPuerto Rico
Study dates
1 Feb 2026to 1 Dec 2026
Phase
Phase 4
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age: Adults aged 21 to 65 years.
  • Diagnosis: Current Major Depressive Disorder (MDD) as confirmed by Structured Clinical Interview for DSM5 (SCID-5).
  • Treatment Resistance: Failure to achieve remission with at least two antidepressants of adequate dose and duration (TRD criteria) as confirmed by SCID-5.
  • Symptom Severity: Baseline Montgomery-Åsberg Depression Rating Scale (MADRS) ≥30.
  • Suicidal Ideation: Participants with baseline passive or active suicidal ideation may be included, provided they do not meet criteria for inpatient admission and are deemed clinically stable for outpatient care. This will be measured with the Columbia Suicide Severity Rating Scale (C-SSRS).
  • Consent: Ability to understand and voluntarily provide written informed consent.
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  • Contraception: For participants of reproductive potential, willingness to use at least one highly effective method of contraception (e.g., intrauterine device, hormonal contraception, sterilization) or two effective methods (e.g., barrier method plus spermicide) during the study and for at least one month after the final esketamine dose. Contraceptive method(s) will be documented at baseline via self-report on a standardized form and reaffirmed at each esketamine session by research staff. Participants who become pregnant or are unable to confirm adequate contraception will be withdrawn from the study for safety reasons.
  • Availability: Willingness and ability to attend all scheduled sessions and complete study procedures.
  • Motivation for Engagement: Demonstrates willingness and psychological readiness to engage in guided reflective work before and after esketamine dosing (as assessed during clinical intake).

Who cannot join

  • Acute Suicide Risk: Immediate need for inpatient psychiatric hospitalization due to suicidal ideation with plan or intent as identified through the C-SSRS.
  • Psychotic or Bipolar Disorders: Current diagnosis of bipolar I disorder (manic phase), schizophrenia, schizoaffective disorder, or other primary psychotic disorders if stated by participants as a past diagnosis or identified during the SCID-5.
  • Substance Use Disorder: Active moderate to severe substance use disorder (except nicotine) in the past 6 months as self-identified by participant or during the SCID-5.
  • Cognitive/Developmental Impairments: Intellectual disability, dementia, or other cognitive/developmental disorders that impair ability to engage meaningfully in structured psychotherapeutic sessions such as preparation or integration, per clinician judgment.
  • Medical Contraindications: Any medical condition judged to pose undue risk during esketamine administration (e.g., aneurysmal vascular disease, arteriovenous malformation, history of intracerebral hemorrhage, or hypersensitivity to esketamine/ketamine).
  • Pregnancy/Breastfeeding: Current pregnancy or breastfeeding.
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  • Ongoing Structured Psychotherapy Likely to Confound Outcomes: Participation in any formal psychotherapy within the past 3 months that involves structured, weekly sessions focused on behavioral change or emotional processing (e.g., CBT, ACT, psychodynamic therapy), unless the therapy was completed or stabilized at a low-intensity level for at least 8 weeks prior to enrollment.
  • Prior Non-Response to Esketamine: Six or more prior esketamine (≥56 mg) or IV ketamine sessions (0.4-0.7 mg/kg) without clinical response.
  • Recent Ketamine Use: Use of ketamine/esketamine in the past 12 weeks.
  • Inability to Consent: Any condition rendering the participant unable to provide informed consent.
  • Prior Enrollment: Previous participation in this study.

Trial locations and contacts

2 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Paulina D Rullan-Farinacci, MD contact

787-414-3571

paulina.rullan@upr.edu

Karen G Martinez-Gonzalez, MD, MSc contact

787-617-5557

karen.martinez4@upr.edu

Puerto Rico2 sites, 2 recruiting

  • Pravan Foundation

    San Juan, 00909

    David Melchor, 787-427-7000, david.melchor@pravanfoundation.org

    Recruiting

  • University of Puerto Rico, Department of Psychiatry

    San Juan, 00936

    Karen G Martinez-Gonzalez, MD, MSc, 787-617-5557, karen.martinez4@upr.edu

    Recruiting

Other trials in Puerto Rico

About this study

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

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.

Read more

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.

Read the 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.

Being tested
Esketamine hydrochloride (intranasal), Integration Therapy
Keywords
esketamine, Treatment-Resistant Depression, Spravato, Ketamine-Assisted Psychotherapy, Psychedelic Integration, Depression, Integration Therapy, Preparation and Integration, Mental Health, Dissociation, Intranasal Esketamine, Randomized Controlled Trial, Psychiatric Treatment, Therapeutic Support, Psychedelic Medicine
Medical subject headings
Depressive Disorder, Treatment-Resistant, Depression, Psychological Well-Being, Dissociative Disorders

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Esketamine hydrochloride (intranasal)Drug

    Also called Spravato

    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.

  • Integration TherapyBehavioural

    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.

Study groups in NCT07369102
Study groupRoleWhat they receive
Esketamine With Integration TherapyExperimentalParticipants 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.
Receives: Drug: Esketamine hydrochloride (intranasal); Behavioral: Integration Therapy
Esketamine Without Integration TherapyActive comparatorParticipants 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.
Receives: Drug: Esketamine hydrochloride (intranasal)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline and end of acute treatment at 8 weeks

Secondary outcomes (5)

  1. 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.

    Measured: From enrollment (baseline) to the end of acute treatment at 8 weeks

  2. 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.

    Measured: At the end of acute treatment at 8 weeks

  3. 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).

    Measured: From achievement of remission through 6 months after completion of acute treatment

  4. 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.

    Measured: Baseline and end of acute treatment at 8 weeks

  5. 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.

    Measured: Baseline and end of acute treatment at 8 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jan 2026
  2. Study start1 Feb 2026 (estimated)
  3. Primary completion1 Dec 2026 (estimated)
  4. Study completion1 Dec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
This is a two-arm, parallel assignment, randomized controlled trial comparing esketamine treatment with and without integration therapy sessions in adults with treatment-resistant depression.
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
20 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07369102
Sponsor's protocol ID
2507449648
Acronym
KIND-PR
Status last verified
Jan 2026
First submitted
22 Aug 2025
Last updated
27 Jan 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Undecided: The investigators may consider sharing de-identified individual participant data upon study completion, subject to IRB approval, institutional policy, and data use agreements.

Publications

  • Wilkinson ST, Rhee TG, Joormann J, Webler R, Ortiz Lopez M, Kitay B, Fasula M, Elder C, Fenton L, Sanacora G. Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial. Psychother Psychosom. 2021;90(5):318-327. doi: 10.1159/000517074. Epub 2021 Jun 29.

    PubMed 34186531

  • Dore J, Turnipseed B, Dwyer S, Turnipseed A, Andries J, Ascani G, Monnette C, Huidekoper A, Strauss N, Wolfson P. Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy. J Psychoactive Drugs. 2019 Apr-Jun;51(2):189-198. doi: 10.1080/02791072.2019.1587556. Epub 2019 Mar 27.

    PubMed 30917760

  • Gorman I, Nielson EM, Molinar A, Cassidy K, Sabbagh J. Psychedelic Harm Reduction and Integration: A Transtheoretical Model for Clinical Practice. Front Psychol. 2021 Mar 15;12:645246. doi: 10.3389/fpsyg.2021.645246. eCollection 2021.

    PubMed 33796055

  • Aixalà M. Psychedelic Integration: Psychotherapy for Non-Ordinary States of Consciousness. Santa Cruz, CA: MAPS; 2021.

  • Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, Pinter C, Hough D, Sanacora G, Manji H, Drevets WC. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018 Jul 1;175(7):620-630. doi: 10.1176/appi.ajp.2018.17060720. Epub 2018 Apr 16.

    PubMed 29656663

  • Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, Mazzucco C, Hough D, Thase ME, Shelton RC, Molero P, Vieta E, Bajbouj M, Manji H, Drevets WC, Singh JB. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry. 2019 Jun 1;176(6):428-438. doi: 10.1176/appi.ajp.2019.19020172. Epub 2019 May 21.

    PubMed 31109201

  • Daly EJ, Trivedi MH, Janik A, Li H, Zhang Y, Li X, Lane R, Lim P, Duca AR, Hough D, Thase ME, Zajecka J, Winokur A, Divacka I, Fagiolini A, Cubala WJ, Bitter I, Blier P, Shelton RC, Molero P, Manji H, Drevets WC, Singh JB. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2019 Sep 1;76(9):893-903. doi: 10.1001/jamapsychiatry.2019.1189.

    PubMed 31166571

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Esketamine hydrochloride (intranasal) and Integration Therapy in people with Treatment-resistant Depression (TRD), run by University of Puerto Rico at 2 sites in Puerto Rico.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 27 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Puerto Rico. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Paulina D Rullan-Farinacci, MD (787-414-3571, paulina.rullan@upr.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change From Baseline in Depression Severity as Assessed by MADRS (time frame: Baseline and end of acute treatment at 8 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07369102, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jan 2026.

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