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

NCT07703722 | Recruiting Phase 3 DMC

• 1 other identifier: KMU/DIR/CTU/2026/6
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Major Depressive Disorder; Post-Traumatic Stress Disorder (PTSD)

Keywords

Psilocybin; TADE Tool; Trauma; Biomarkers; Randomized Controlled Trial

Outcome Measures

Primary Outcomes (4)

• Depression Severity

  Change in depression severity measured using the Hamilton Depression Rating Scale (HAM-D-17). The HAM-D-17 is a clinician-administered scale with a total score ranging from 0 to 52, where higher scores indicate more severe depressive symptoms. The outcome will be reported as the change in total HAM-D-17 score from baseline.

  Baseline, Week 4, Week 8, and Week 12

• Trauma-Related Symptoms

  Change in trauma-related symptoms measured using the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5). The PCL-5 is a self-report questionnaire with a total score ranging from 0 to 80, where higher scores indicate more severe PTSD symptoms. The outcome will be reported as the change in total PCL-5 score from baseline.

  Baseline, Week 4, Week 8, and Week 12

• Anxiety Severity

  Change in anxiety severity measured using the Generalized Anxiety Disorder 7-item Scale (GAD-7). The GAD-7 is a self-report questionnaire with a total score ranging from 0 to 21, where higher scores indicate more severe anxiety symptoms. The outcome will be reported as the change in total GAD-7 score from baseline.

  Baseline, Week 4, Week 8, and Week 12

• Gut-Brain Axis and Neuroinflammatory Biomarkers

  Change in serum concentrations of gut-brain axis and neuroinflammatory biomarkers, including: Short-Chain Fatty Acids (SCFAs) Interleukin-6 (IL-6) Interleukin-10 (IL-10) Zonulin Occludin Glial Cell Line-Derived Neurotrophic Factor (GDNF) Biomarkers will be quantified using validated laboratory assays and reported in their respective concentration units (e.g., pg/mL or ng/mL, as appropriate).

  Baseline, Week 4, Week 8, and Week 12

Study Arms (4)

Conventional Therapy (Control)

ACTIVE COMPARATOR

Participants will receive standard conventional treatment for trauma-related Major Depressive Disorder, consisting of a stable selective serotonin reuptake inhibitor (SSRI) regimen prescribed by the treating psychiatrist. No psilocybin or Structured Integrated Reframing Therapy (SIRT) will be administered. Treatment will continue for 8 weeks with routine clinical follow-up.

Drug: Selective Serotonin Reuptake Inhibitor (SSRI)

Psilocybin Therapy

EXPERIMENTAL

Participants will continue standard SSRI therapy and receive oral psilocybin administered under medical supervision in a controlled clinical setting. Two supervised dosing sessions will be conducted during the 8-week intervention period according to the study protocol. No SIRT will be provided.

Drug: Psilocybin; Drug: Selective Serotonin Reuptake Inhibitor (SSRI)

Structured Integrated Reframing Therapy (SIRT)

EXPERIMENTAL

Participants will continue standard SSRI therapy and receive Structured Integrated Reframing Therapy (SIRT), a trauma-informed psychotherapy integrating Cognitive Behavioral Therapy (CBT), Dialectical Behavior Therapy (DBT), mindfulness, cognitive reframing, and communication-focused therapeutic techniques. Therapy will be delivered once weekly for 8 weeks by trained therapists.

Behavioral: Structured Integrated Reframing Therapy (SIRT); Drug: Selective Serotonin Reuptake Inhibitor (SSRI)

Psilocybin-Assisted Structured Integrated Reframing Therapy

EXPERIMENTAL

Participants will continue standard SSRI therapy and receive both supervised oral psilocybin administration and Structured Integrated Reframing Therapy (SIRT). Psilocybin will be administered in two supervised dosing sessions during the 8-week intervention period, while SIRT will be delivered once weekly for 8 weeks. The combined intervention is intended to evaluate the synergistic effects of psychedelic-assisted psychotherapy on clinical outcomes and gut-brain axis biomarkers.

Drug: Psilocybin; Behavioral: Structured Integrated Reframing Therapy (SIRT); Drug: Selective Serotonin Reuptake Inhibitor (SSRI)

Interventions

Psilocybin DRUG

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.

Psilocybin Therapy; Psilocybin-Assisted Structured Integrated Reframing Therapy

Structured Integrated Reframing Therapy (SIRT) BEHAVIORAL

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.

Psilocybin-Assisted Structured Integrated Reframing Therapy; Structured Integrated Reframing Therapy (SIRT)

Selective Serotonin Reuptake Inhibitor (SSRI) DRUG

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.

Also known as: Standard antidepressant therapy

Conventional Therapy (Control); Psilocybin Therapy; Psilocybin-Assisted Structured Integrated Reframing Therapy; Structured Integrated Reframing Therapy (SIRT)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hayatabad Medical Complex: collaborator
• Khyber Medical University Peshawar: lead
• KMU Institute of Health Science, Islamabad: collaborator

Study Sites (3)

Institute of Health Science, Khyber Medical University

Islamabad, Capital, 25000, Pakistan

ACTIVE NOT RECRUITING

Hayatabad Medical Complex Peshawar

Peshawar, KPK, 25000, Pakistan

RECRUITING

Khyber Medical University

Peshawar, KPK, Pakistan

ACTIVE NOT RECRUITING

Related Publications (6)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 Nov 15.

  PMID: 39634920 BACKGROUND

• 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 RS. Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin. Med. 2024 Mar 8;5(3):190-200.e5. doi: 10.1016/j.medj.2024.01.005. Epub 2024 Feb 14.

  PMID: 38359838 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major; Stress Disorders, Post-Traumatic; Wounds and Injuries

Interventions

Psilocybin; Selective Serotonin Reuptake Inhibitors

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Stress Disorders, Traumatic; Trauma and Stressor Related Disorders

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Neurotransmitter Agents; Serotonin Agents; Physiological Effects of Drugs

Study Officials

• Dr Omer Malik, PhD

  Khyber Medical University Peshawar, Pakistan

  PRINCIPAL INVESTIGATOR

• Dr Inayat Shah, PhD*

  Khyber Medical University

  STUDY CHAIR

• Naveeda Sarwar, PhD

  Khyber Medical University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bushra Riaz, PhD*

CONTACT

+92 3338000744; bushrariaz098@gmail.com

Dr Owais Qaiser, PhD*

CONTACT

+92 3139625788; drowaisqaisar.ibms@kmu.edu.pk

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: This is an open-label study. Participants and treating clinicians will know the assigned intervention because psychotherapy and psilocybin administration cannot be practically blinded. Outcome measures will be collected using standardized validated instruments according to the study protocol.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants will be randomly assigned in a 1:1:1:1 ratio to one of four parallel groups: (1) Conventional Therapy, (2) Psilocybin Therapy, (3) Structured Integrated Reframing Therapy (SIRT), or (4) Psilocybin-assisted SIRT. Participants remain in their assigned group throughout the study.

Study Record Dates

• First Submitted: July 6, 2026
• First Posted: July 14, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): October 22, 2027
• Study Completion (Estimated): November 22, 2027
• Last Updated: July 14, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will become available within 6 months after publication of the primary study results and will remain available for 5 years thereafter.
• Access Criteria: Qualified researchers may request access by submitting a methodologically sound research proposal. Requests will be reviewed by the Principal Investigator and the Khyber Medical University Institutional Research Ethics Board. A data access agreement may be required before de-identified data are released.

Locations

PA (3)