Evaluation of Fluoxetine for Refractory Constipation With Somatic Symptom Disorder Features

This single-center, randomized, double-blind, placebo-controlled trial evaluates the efficacy and safety of fluoxetine (40 mg/day) versus placebo in 194 adults with refractory chronic constipation exhibiting Somatic Symptom Disorder (SSD) features diagnosed by SCID-5. After a 2-week screening period, participants are randomized 1:1 to fluoxetine or matching placebo for 12 weeks. The primary endpoint is the proportion of CSBM responders, defined as an increase of ≥1 CSBM per week from baseline in ≥50% of treatment weeks (Weeks 5-12). Key secondary endpoints include weekly SBM/CSBM frequency, Bristol Stool Form Scale, straining score, bloating severity, Patient Global Impression of Change (PGIC, 7-point), and changes in validated PRO scales (SSD-12, PHQ-15, PHQ-9, GAD-7, PAC-QOL, KESS). Mechanistic assessments include resting-state fMRI and high-resolution anorectal manometry (HRAM). Safety is monitored through adverse events, thyroid/liver/renal function tests, and ECG.

Inclusion Criteria: 1. Diagnosis of Functional Constipation (FC): Participants must meet the Rome IV diagnostic criteria for functional constipation. 2. Low CSBM Frequency: During the 2-week screening period, participants must have Complete Spontaneous Bowel Movements (CSBM) ≤ 2 times per week. 3. Refractory to Standard Laxatives: Participants must have documented failure of at least 3 classes of conventional laxatives (e.g., osmotic, stimulant, or prosecretory agents), each administered at standard doses for ≥4 weeks. 4. Diagnosis of Somatic Symptom Disorder (SSD): Participants must meet the DSM-5 diagnostic criteria for Somatic Symptom Disorder, confirmed by the Structured Clinical Interview for DSM-5 (SCID-5), conducted by trained professionals. 5. Age Range: Participants must be between 18 and 70 years of age. 6. No Concurrent Trial Participation: Participants must not be enrolled in any other interventional clinical trial during the study period. 7. Informed Consent: Participants must voluntarily provide written informed consent. Exclusion Criteria: 1. Organic or Secondary Causes: Participants with organic gastrointestinal diseases (e.g., colorectal cancer, Crohn's disease, congenital megacolon), endocrine disorders (e.g., hypothyroidism), metabolic diseases (e.g., diabetes), neurological disorders (e.g., Parkinson's disease), or prior major abdominal surgery (e.g., colectomy, cholecystectomy). 2. Medications Affecting Bowel Function: Participants requiring long-term use of medications known to affect gastrointestinal motility or induce constipation (e.g., antiparkinsonian drugs, opioids), except for routine laxatives. 3. Chronic Pain Requiring Opioids: Participants with chronic pain syndromes unrelated to functional gastrointestinal disorders (e.g., fibromyalgia, severe chronic back pain) who require long-term opioid therapy. 4. Recent Psychotropic Medication Use: Participants who have used any antidepressant, anxiolytic, or antipsychotic medication within 4 weeks prior to screening. 5. Severe Psychiatric Conditions: Participants at risk of self-harm or suicide, or with severe major depressive episode, severe anxiety disorder, bipolar disorder, or schizophrenia spectrum disorders, as assessed by a psychiatrist. 6. Contraindications to Fluoxetine: Participants with a history of hypersensitivity to fluoxetine or other SSRIs, hepatic or renal impairment, or ECG evidence of QTc prolongation. 7. Pregnancy, Lactation, or Planned Pregnancy: Women who are pregnant, breastfeeding, or planning to become pregnant during the study period. 8. Malignancy or Autoimmune Disease: Participants with active malignant or benign tumors, or autoimmune diseases. 9. Severe Comorbidities: Participants with cardiovascular diseases, coagulation disorders (requiring long-term anticoagulation), hepatic or renal failure, organ failure, cognitive impairment, or aphasia, where the chronic condition requires long-term medication affecting quality of life and treatment evaluation. 10. Recent Clinical Trial Participation: Participants who have participated in another interventional clinical trial within 3 months prior to screening.