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

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)

Interventions

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.

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.

Sponsors & Collaborators

• Hayatabad Medical Complex

  collaborator OTHER_GOV

• KMU Institute of Health Science, Islamabad

  collaborator UNKNOWN

• Khyber Medical University Peshawar

  lead OTHER

Principal Investigators

• Dr Omer Malik, PhD · Khyber Medical University Peshawar, Pakistan

• Dr Inayat Shah, PhD* · Khyber Medical University

• Naveeda Sarwar, PhD · Khyber Medical University

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

60 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-04-01

Primary Completion

2027-10-22

Completion

2027-11-22

Countries

• Pakistan

Study Locations