Effect of Psilocybin and Structured Integrated Reframing Therapy on Gut-Brain Axis Biomarkers and Depression in Major Depressive Disorder

Официальное название

Effect of Psilocybin and Structured Integrated Reframing Therapy on Gut-Brain Axis Biomarkers and Depression in Trauma-Related Major Depressive Disorder: Randomized Controlled Trial

Обзор

Trauma-related Major Depressive Disorder (MDD) is frequently associated with poor response to conventional antidepressants, persistent psychological distress, and alterations in gut-brain axis function. Existing assessment tools primarily diagnose depression or PTSD but provide limited guidance for integrated clinical management. This study aims to develop and validate the Trauma Anxiety Depression Emotion (TADE) management tool while simultaneously evaluating the effectiveness of psilocybin-assisted Structured Integrated Reframing Therapy (SIRT) in improving clinical and biological outcomes. This prospective, four-arm randomized controlled trial will compare conventional therapy, psilocybin therapy, SIRT, and psilocybin-assisted SIRT. Participants will undergo assessment using the newly developed TADE tool together with established psychometric scales including HAM-D, PCL-5, and GAD-7. Biological outcomes will include serum gut-brain axis and inflammatory biomarkers, including Short-Chain Fatty Acids (SCFAs), Interleukin-6 (IL-6), Interleukin-10 (IL-10), Zonulin, Occludin, and Glial Cell Line-Derived Neurotrophic Factor (GDNF). Assessments will be performed at baseline, during treatment, and at 12-week follow-up. The study aims to determine whether combining psilocybin with SIRT provides superior clinical improvement and favorable biological changes compared with either intervention alone while establishing the validity and clinical utility of the TADE management tool.

Подробное описание

Major Depressive Disorder (MDD) is among the leading causes of disability worldwide. Individuals with trauma-related MDD frequently experience persistent depressive symptoms, anxiety, emotional dysregulation, post-traumatic stress symptoms, and impaired quality of life despite receiving conventional antidepressant therapy. Emerging evidence suggests that gut microbiota, intestinal permeability, immune activation, neuroplasticity, and inflammatory pathways contribute significantly to the pathophysiology of depression and trauma-related disorders.

This study integrates two novel innovations. First, it will develop and validate the Trauma Anxiety Depression Emotion (TADE) management tool, a comprehensive instrument designed to assess trauma exposure, PTSD symptoms, depression, anxiety, stress, emotional functioning, and treatment priorities. Second, it will evaluate Structured Integrated Reframing Therapy (SIRT), a newly developed psychotherapy integrating Cognitive Behavioral Therapy (CBT), Dialectical Behavior Therapy (DBT), mindfulness, cognitive reframing, and communication-focused therapeutic techniques.

The study is designed as a prospective, four-arm, parallel-group randomized controlled trial. Eligible participants with trauma-related Major Depressive Disorder will be randomly allocated to one of four intervention groups: (1) conventional therapy, (2) psilocybin therapy, (3) Structured Integrated Reframing Therapy (SIRT), or (4) psilocybin-assisted SIRT.

Clinical outcomes will be evaluated using the TADE tool together with validated psychometric instruments including the Hamilton Depression Rating Scale (HAM-D), PTSD Checklist for DSM-5 (PCL-5), and Generalized Anxiety Disorder-7 (GAD-7). Biological outcomes will include measurement of gut-brain axis and inflammatory biomarkers including Short-Chain Fatty Acids (SCFAs), Interleukin-6 (IL-6), Interleukin-10 (IL-10), Zonulin, Occludin, and Glial Cell Line-Derived Neurotrophic Factor (GDNF). Blood samples will be collected at baseline, Week 4, Week 8, and Week 12.

The primary objectives are to determine the effectiveness of psilocybin-assisted SIRT in reducing depressive symptoms and to validate the TADE management tool. Secondary objectives include evaluating changes in gut-brain axis biomarkers, determining correlations between biomarker changes and clinical improvement, and identifying biological predictors of treatment response. This integrated approach aims to provide evidence for a personalized treatment strategy that combines innovative psychotherapeutic interventions, psychedelic-assisted therapy, and biomarker-guided clinical management for trauma-related Major Depressive Disorder.

Вмешательства

• Препарат Psilocybin
  Oral psilocybin administered under medical supervision in a controlled clinical setting. Participants assigned to psilocybin-containing arms will receive two supervised dosing sessions during the 8-week intervention period in addition to stable standard antidepressant therapy. The dosage and administration procedures will follow the approved study protocol.
• Поведенческое Structured Integrated Reframing Therapy (SIRT)
  Structured Integrated Reframing Therapy (SIRT) is a trauma-informed psychotherapy integrating evidence-based components of Cognitive Behavioral Therapy (CBT), Dialectical Behavior Therapy (DBT), mindfulness, cognitive reframing, emotional regulation, coping skills training, and communication-focused therapeutic techniques. Therapy is delivered once weekly for 8 weeks by trained therapists.
• Препарат Selective Serotonin Reuptake Inhibitor (SSRI)
  Participants in all study arms will continue a stable prescribed selective serotonin reuptake inhibitor (SSRI) regimen throughout the study. Participants must have been receiving the same antidepressant for at least 6 weeks before enrollment with adequate treatment adherence. Medication adjustments will be made only if clinically indicated.

Первичные конечные точки

• Depression Severity [Срок оценки: Baseline, Week 4, Week 8, and Week 12]
• Trauma-Related Symptoms [Срок оценки: Baseline, Week 4, Week 8, and Week 12]
• Anxiety Severity [Срок оценки: Baseline, Week 4, Week 8, and Week 12]
• Gut-Brain Axis and Neuroinflammatory Biomarkers [Срок оценки: Baseline, Week 4, Week 8, and Week 12]

Критерии участия

Критерии включения

• Adults aged 18-60 years.
• Diagnosis of Major Depressive Disorder (MDD) according to DSM-5 criteria.
• Trauma-related depression with clinically significant trauma symptoms.
• Hamilton Depression Rating Scale (HAM-D) score >16.
• PTSD Checklist for DSM-5 (PCL-5) score >33.
• Generalized Anxiety Disorder-7 (GAD-7) score >10.
• Receiving a stable single SSRI antidepressant regimen for at least 6 weeks before enrollment with adequate treatment adherence.
• Able and willing to provide written informed consent.
• Willing to comply with all study procedures and follow-up visits.
• Women of childbearing potential must agree to use effective contraception throughout the study.

Критерии исключения

• Significant cardiovascular disease.
• Clinically significant hepatic or renal impairment.
• Significant neurological disorders.
• Current or past psychotic disorder or bipolar disorder.
• Current substance or alcohol use disorder, including ketamine or psychedelic drug use.
• Use of more than one antidepressant medication.
• Pregnancy, planned pregnancy, or breastfeeding.
• Known hypersensitivity or contraindication to psilocybin.
• Participation in another interventional clinical trial within the previous 30 days.
• Inability or unwillingness to provide informed consent.
• Any medical or psychiatric condition that, in the investigator's opinion, would interfere with safe participation or study assessments.

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

Открытое

Основная цель

Лечение

Центры проведения

Пакистан · 3 центра

• Institute of Health Science, Khyber Medical University — Islamabad
• Hayatabad Medical Complex Peshawar — Peshawar
• Khyber Medical University — Peshawar

Публикации

• Cui L, Li S, Wang S, Wu X, Liu Y, Yu W, Wang Y, Tang Y, Xia M, Li B. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal Transduct Target Ther. 2024 Feb 9;9(1):30. doi: 10.1038/s41392-024-01738-y. PMID 38331979
• Ahern E, White J, Slattery E. Change in Cognitive Function over the Course of Major Depressive Disorder: A Systematic Review and Meta-analysis. Neuropsychol Rev. 2025 Mar;35(1):1-34. doi: 10.1007/s11065-023-09629-9. Epub 2024 Feb 5. PMID 38315296
• Martire G, Sipple D, Baron D, Gold MS, Lewandowski KU, Dennen CA, Sharafshah A, Elman I, Thanos PK, Modestino EJ, Badgaiyan RD, Pinhasov A, Bowirrat A, Makale M, Roy AK, Sunder K, Murphy KT, Mahajan S, Mahajan Y, Levin C, Blum K. Theorizing that Psychedelic Assisted Therapy May Play a Role in the Treatment of Trauma-Induced Personality Disorders. J Addict Psychiatry. 2024;8(2):161-165. Epub 2024 N PMID 39634920
• Rosenblat JD, Meshkat S, Doyle Z, Kaczmarek E, Brudner RM, Kratiuk K, Mansur RB, Schulz-Quach C, Sethi R, Abate A, Ali S, Bawks J, Blainey MG, Brietzke E, Cronin V, Danilewitz J, Dhawan S, Di Fonzo A, Di Fonzo M, Drzadzewski P, Dunlop W, Fiszter H, Gomes FA, Grewal S, Leon-Carlyle M, McCallum M, Mofidi N, Offman H, Riva-Cambrin J, Schmidt J, Smolkin M, Quinn JM, Zumrova A, Marlborough M, McIntyre PMID 38359838
• Euteneuer F, Neubert M, Salzmann S, Fischer S, Ehlert U, Rief W. Biomarkers as predictors of CBT responsiveness in major depressive disorder: The role of heart rate variability and inflammation. J Psychosom Res. 2024 Nov;186:111885. doi: 10.1016/j.jpsychores.2024.111885. Epub 2024 Aug 13. PMID 39180963
• Dziedzic A, Maciak K, Blizniewska-Kowalska K, Galecka M, Kobierecka W, Saluk J. The Power of Psychobiotics in Depression: A Modern Approach through the Microbiota-Gut-Brain Axis: A Literature Review. Nutrients. 2024 Apr 4;16(7):1054. doi: 10.3390/nu16071054. PMID 38613087

Идентификаторы

NCT: NCT07703722 · KMU/DIR/CTU/2026/6

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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