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

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.