Esketamine With or Without Integration Therapy for Treatment-Resistant Depression

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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.
• Поведенческое 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.

Первичные конечные точки

• Change From Baseline in Depression Severity as Assessed by MADRS [Срок оценки: Baseline and end of acute treatment at 8 weeks]

Вторичные конечные точки (5)

• Proportion of Participants Achieving Treatment Response (≥50% Reduction in MADRS) [Срок оценки: From enrollment (baseline) to the end of acute treatment at 8 weeks]
• Proportion of Participants Achieving Remission (MADRS <10) [Срок оценки: At the end of acute treatment at 8 weeks]
• Proportion of Participants Experiencing Depressive Relapse Confirmed by SCID-5 [Срок оценки: From achievement of remission through 6 months after completion of acute treatment]
• Change From Baseline in Functional Impairment as Assessed by WSAS [Срок оценки: Baseline and end of acute treatment at 8 weeks]
• Change From Baseline in Suicidality as Assessed by C-SSRS [Срок оценки: Baseline and end of acute treatment at 8 weeks]

Критерии участия

Критерии включения

• 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).

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Пуэрто-Рико · 2 центра

• Pravan Foundation — San Juan
• University of Puerto Rico, Department of Psychiatry — San Juan

Публикации

• 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
• 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
• 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
• 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.2018.17 PMID 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 PMID 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 P PMID 31166571

Идентификаторы

NCT: NCT07369102 · 2507449648

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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