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.

Eligibility

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.

Conditions3

Interventions2

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