Esketamine With or Without Integration Therapy for Treatment-Resistant Depression

NCT07369102 | Recruiting Phase 4 FDA Drug

• 1 other identifier: 2507449648
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Treatment-resistant Depression (TRD)

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

Outcome Measures

Primary Outcomes (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.

  Baseline and end of acute treatment at 8 weeks

Secondary Outcomes (5)

• Proportion of Participants Achieving Treatment Response (≥50% Reduction in MADRS)

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

• Proportion of Participants Achieving Remission (MADRS <10)

  At the end of acute treatment at 8 weeks

• Proportion of Participants Experiencing Depressive Relapse Confirmed by SCID-5

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

• Change From Baseline in Functional Impairment as Assessed by WSAS

  Baseline and end of acute treatment at 8 weeks

• Change From Baseline in Suicidality as Assessed by C-SSRS

  Baseline and end of acute treatment at 8 weeks

Other Outcomes (10)

• Subjective Experience Following Esketamine Administration (Qualitative Reflections)

  Within 72 hours after dosing sessions occurring at Weeks 4 and 8

• Engagement With Psychedelic Integration as Assessed by Integration Scales

  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

  Baseline: after the first preparation session and prior to the first esketamine dosing session

Study Arms (2)

Esketamine With Integration Therapy

EXPERIMENTAL

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

Esketamine Without Integration Therapy

ACTIVE COMPARATOR

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)

Interventions

Esketamine hydrochloride (intranasal) DRUG

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

Esketamine With Integration Therapy; Esketamine Without Integration Therapy

Integration Therapy BEHAVIORAL

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.

Esketamine With Integration Therapy

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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).

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• University of Puerto Rico: lead

Study Sites (2)

Pravan Foundation

San Juan, 00909, Puerto Rico

RECRUITING

University of Puerto Rico, Department of Psychiatry

San Juan, 00936, Puerto Rico

RECRUITING

Related Publications (7)

• 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.

  PMID: 34186531 BACKGROUND

• 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.

  PMID: 30917760 BACKGROUND

• 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.

  PMID: 33796055 BACKGROUND

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

  BACKGROUND

• 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.

  PMID: 29656663 BACKGROUND

• 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.

  PMID: 31109201 BACKGROUND

• 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.

  PMID: 31166571 BACKGROUND

Related Links

• Institutional Site
• Study Site
• Janssen Pharmaceuticals press release announcing FDA approval of Spravato® (esketamine) for treatment-resistant depression

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant; Depression; Psychological Well-Being; Dissociative Disorders

Interventions

Esketamine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior; Personal Satisfaction

Study Officials

• Karen G Gonzalez-Martinez, MD, MSc

  University of Puerto Rico, Medical Sciences Campus, Department of Psychiatry

  STUDY CHAIR

Central Study Contacts

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

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Independent clinician raters administering primary outcome measures (e.g., MADRS) will be blinded to participant group allocation.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: August 22, 2025
• First Posted: January 27, 2026
• Study Start: February 1, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: January 27, 2026

Record last verified: 2026-01

Locations

PR (2)