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Major Depressive DisorderPhase 3NCT07703722

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

A Phase 3 study testing Psilocybin, Structured Integrated Reframing Therapy (SIRT) and Selective Serotonin Reuptake Inhibitor (SSRI) in people with Major Depressive Disorder and Post-Traumatic Stress Disorder (PTSD), run by Khyber Medical University Peshawar at 3 sites in Pakistan.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 60 years
What is being tested?
Psilocybin, Structured Integrated Reframing Therapy (SIRT) and Selective Serotonin Reuptake Inhibitor (SSRI)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
60 participants
Where
3 sitesPakistan
Study dates
1 Apr 2026to 22 Nov 2027
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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.
Show all 10Show fewer
  • 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.

Who cannot join

  • 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.
Show all 11Show fewer
  • 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.

Trial locations and contacts

3 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Bushra Riaz, PhD* contact

+92 3338000744

bushrariaz098@gmail.com

Dr Owais Qaiser, PhD* contact

+92 3139625788

drowaisqaisar.ibms@kmu.edu.pk

Pakistan3 sites, 1 recruiting

  • Institute of Health Science, Khyber Medical University

    Islamabad, Capital, 25000

    Active, not recruiting

  • Hayatabad Medical Complex Peshawar

    Peshawar, KPK, 25000

    Dr Owais Qaiser, PhD*, +92 313 9625788, drowaisqaisar.ibms@kmu.edu.pk

    Dr Omer Malik, PhD, +92 333 5196243, omermalik@kmu.edu.pk

    Recruiting

  • Khyber Medical University

    Peshawar, KPK

    Active, not recruiting

Other trials in Pakistan

About this study

Official title: 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.

Read the 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.

Being tested
Psilocybin, Structured Integrated Reframing Therapy (SIRT), Selective Serotonin Reuptake Inhibitor (SSRI)
Keywords
Psilocybin, TADE Tool, Trauma, Biomarkers, Randomized Controlled Trial
Medical subject headings
Depressive Disorder, Major, Stress Disorders, Post-Traumatic, Wounds and Injuries

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PsilocybinDrug

    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.

  • Structured Integrated Reframing Therapy (SIRT)Behavioural

    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.

  • Selective Serotonin Reuptake Inhibitor (SSRI)Drug

    Also called Standard antidepressant therapy

    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.

Study groups in NCT07703722
Study groupRoleWhat they receive
Conventional Therapy (Control)Active comparatorParticipants 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.
Receives: Drug: Selective Serotonin Reuptake Inhibitor (SSRI)
Psilocybin TherapyExperimentalParticipants 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.
Receives: Drug: Psilocybin; Drug: Selective Serotonin Reuptake Inhibitor (SSRI)
Structured Integrated Reframing Therapy (SIRT)ExperimentalParticipants 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.
Receives: Behavioral: Structured Integrated Reframing Therapy (SIRT); Drug: Selective Serotonin Reuptake Inhibitor (SSRI)
Psilocybin-Assisted Structured Integrated Reframing TherapyExperimentalParticipants 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.
Receives: Drug: Psilocybin; Behavioral: Structured Integrated Reframing Therapy (SIRT); Drug: Selective Serotonin Reuptake Inhibitor (SSRI)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline, Week 4, Week 8, and Week 12

  2. 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.

    Measured: Baseline, Week 4, Week 8, and Week 12

  3. 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.

    Measured: Baseline, Week 4, Week 8, and Week 12

  4. 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).

    Measured: Baseline, Week 4, Week 8, and Week 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jul 2026
  2. Study start1 Apr 2026
  3. Primary completion22 Oct 2027 (estimated)
  4. Study completion22 Nov 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
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.
Masking
None (open label)
Enrolment
60 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07703722
Sponsor's protocol ID
KMU/DIR/CTU/2026/6
Status last verified
Jul 2026
First submitted
6 Jul 2026
Last updated
14 Jul 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: 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.

Publications

  • 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.

    PubMed 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.

    PubMed 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 Nov 15.

    PubMed 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 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.

    PubMed 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.

    PubMed 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.

    PubMed 38613087

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Psilocybin, Structured Integrated Reframing Therapy (SIRT) and Selective Serotonin Reuptake Inhibitor (SSRI) in people with Major Depressive Disorder and Post-Traumatic Stress Disorder (PTSD), run by Khyber Medical University Peshawar at 3 sites in Pakistan.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 14 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Pakistan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Bushra Riaz, PhD* (+92 3338000744, bushrariaz098@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Depression Severity (time frame: Baseline, Week 4, Week 8, and Week 12). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07703722, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jul 2026; AzTrials last refreshed its copy on 6 Nov 2026.

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