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 oflife despite receiving conventional antidepressant therapy. Emerging evidence suggeststhat gut microbiota, intestinal permeability, immune activation, neuroplasticity, andinflammatory pathways contribute significantly to the pathophysiology of depression andtrauma‐related disorders.This study integrates two novel innovations. First, it will develop and validate theTrauma Anxiety Depression Emotion (TADE) management tool, a comprehensive instrumentdesigned to assess trauma exposure, PTSD symptoms, depression, anxiety, stress, emotionalfunctioning, and treatment priorities. Second, it will evaluate Structured IntegratedReframing Therapy (SIRT), a newly developed psychotherapy integrating CognitiveBehavioral Therapy (CBT), Dialectical Behavior Therapy (DBT), mindfulness, cognitivereframing, and communication‐focused therapeutic techniques.The study is designed as a prospective, four‐arm, parallel‐group randomized controlledtrial. Eligible participants with trauma‐related Major Depressive Disorder will berandomly 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 validatedpsychometric instruments including the Hamilton Depression Rating Scale (HAM‐D), PTSDChecklist for DSM‐5 (PCL‐5), and Generalized Anxiety Disorder‐7 (GAD‐7). Biologicaloutcomes will include measurement of gut‐brain axis and inflammatory biomarkers includingShort‐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 becollected at baseline, Week 4, Week 8, and Week 12.The primary objectives are to determine the effectiveness of psilocybin‐assisted SIRT inreducing depressive symptoms and to validate the TADE management tool. Secondaryobjectives include evaluating changes in gut‐brain axis biomarkers, determiningcorrelations between biomarker changes and clinical improvement, and identifyingbiological predictors of treatment response. This integrated approach aims to provideevidence for a personalized treatment strategy that combines innovative psychotherapeuticinterventions, psychedelic‐assisted therapy, and biomarker‐guided clinical management fortrauma‐related Major Depressive Disorder.