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

July 12, 2026 updated by: Khyber Medical University Peshawar

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

60

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Pakistan
    • Capital
      • Islamabad, Capital, Pakistan, 25000
        • Active, not recruiting
        • Institute of Health Science, Khyber Medical University
    • KPK
      • Peshawar, KPK, Pakistan, 25000
        • Recruiting
        • Hayatabad Medical Complex Peshawar
        • Contact:
        • Contact:
        • Principal Investigator:
          • Dr Owais Qaiser, PhD*
      • Peshawar, KPK, Pakistan
        • Active, not recruiting
        • Khyber Medical University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Conventional Therapy (Control)
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)
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.
Other Names:
  • Standard antidepressant therapy
Experimental: Psilocybin Therapy
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: 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.
Other Names:
  • Standard antidepressant therapy
Drug: 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.
Experimental: Structured Integrated Reframing Therapy (SIRT)
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.
Drug: 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.
Other Names:
  • Standard antidepressant therapy
Behavioral: 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.
Experimental: Psilocybin-Assisted Structured Integrated Reframing Therapy
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: 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.
Other Names:
  • Standard antidepressant therapy
Drug: 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.
Behavioral: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Depression Severity
Time Frame: Baseline, Week 4, Week 8, and Week 12
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
Time Frame: Baseline, Week 4, Week 8, and Week 12
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
Time Frame: Baseline, Week 4, Week 8, and Week 12
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
Time Frame: Baseline, Week 4, Week 8, and Week 12

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Khyber Medical University Peshawar

Collaborators

Hayatabad Medical Complex
KMU Institute of Health Science, Islamabad

Investigators

  • Principal Investigator: Dr Omer Malik, PhD, Khyber Medical University Peshawar, Pakistan
  • Study Chair: Dr Inayat Shah, PhD*, Khyber Medical University
  • Principal Investigator: Naveeda Sarwar, PhD, Khyber Medical University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2026

Primary Completion (Estimated)

October 22, 2027

Study Completion (Estimated)

November 22, 2027

Study Registration Dates

First Submitted

July 6, 2026

First Submitted That Met QC Criteria

July 12, 2026

First Posted (Actual)

July 14, 2026

Study Record Updates

Last Update Posted (Actual)

July 14, 2026

Last Update Submitted That Met QC Criteria

July 12, 2026

Last Verified

July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • KMU/DIR/CTU/2026/6

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual Participant Data (IPD) that underlie the results reported in publications, including de-identified demographic, clinical, psychometric, and biomarker data, will be made available to qualified researchers upon reasonable request. Data will be shared after publication of the primary study results, subject to approval by the Principal Investigator and Khyber Medical University Institutional Research Ethics Board. All shared data will be de-identified to protect participant confidentiality.

IPD Sharing Time Frame

Data will become available within 6 months after publication of the primary study results and will remain available for 5 years thereafter.

IPD Sharing 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.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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