Major Depressive Disorder, Post-Traumatic Stress Disorder (PTSD)
Conditions
Keywords
Psilocybin, TADE Tool, Trauma, Biomarkers, Randomized Controlled Trial
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.
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.
Interventions
DRUGPsilocybin
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.
BEHAVIORALStructured 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.
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
Khyber Medical University Peshawar
Hayatabad Medical Complex
KMU Institute of Health Science, Islamabad
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
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.
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Depression Severity | 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. |
| Trauma-Related Symptoms | 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. |
| Anxiety Severity | 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. |
| Gut-Brain Axis and Neuroinflammatory Biomarkers | 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). |
Countries
Pakistan
Contacts
CONTACTBushra Riaz, PhD*
CONTACTDr Owais Qaiser, PhD*
PRINCIPAL_INVESTIGATORDr Omer Malik, PhD
Khyber Medical University Peshawar, Pakistan
STUDY_CHAIRDr Inayat Shah, PhD*
Khyber Medical University
PRINCIPAL_INVESTIGATORNaveeda Sarwar, PhD
Khyber Medical University
Outcome results
None listed