Cognitive Behavioral Therapy for Functional Dyspepsia (Epigastric Pain Syndrome and Postprandial Distress Syndrome Subtypes) (FD-CBT)

Multimodal Phenotyping of Functional Dyspepsia: Controlled Trial on Response to Cognitive-Behavioral Therapy in Subtypes of Epigastric Pain Syndrome and Postprandial Discomfort Syndrome

The goal of this clinical trial is to learn whether adding Cognitive Behavioral Therapy (CBT) to standard medical treatment can improve symptoms in adults with Functional Dyspepsia. The study includes adults aged 18 to 65 years diagnosed with Functional Dyspepsia, classified as Epigastric Pain Syndrome or Postprandial Distress Syndrome.

The main questions it aims to answer are:

Does Cognitive Behavioral Therapy added to standard treatment reduce gastrointestinal symptoms compared with standard treatment alone? Do patients with Postprandial Distress Syndrome and Epigastric Pain Syndrome respond differently to Cognitive Behavioral Therapy? Researchers will compare optimized standard medical treatment alone to optimized standard treatment combined with Cognitive Behavioral Therapy to see if the addition of CBT leads to greater symptom improvement and better quality of life.

Participants will:

Be randomly assigned to receive either standard medical treatment alone or standard treatment plus Cognitive Behavioral Therapy Take part in clinical visits and complete questionnaires about gastrointestinal symptoms, psychological well-being, and quality of life Provide blood, saliva, and stool samples at several time points over a 12-month follow-up period

Study Overview

• Status: Not yet recruiting
• Conditions: Functional Dyspepsia; Epigastric Pain Syndrome; Postprandial Distress Syndrome
• Intervention / Treatment: Drug: Optimized Standard Treatment (OPT); Behavioral: Cognitive Behavioral Therapy + Optimized Standard Treatment (CBT + OPT)

Detailed Description

Functional Dyspepsia is a chronic disorder of gut-brain interaction characterized by persistent upper gastrointestinal symptoms in the absence of structural disease. It is commonly classified into Epigastric Pain Syndrome and Postprandial Distress Syndrome, which may reflect partially distinct underlying mechanisms. Standard medical treatments often provide incomplete symptom relief, and growing evidence supports a role for psychological factors and gut-brain axis dysregulation in symptom generation and persistence.

This randomized controlled trial investigates the effectiveness of adding a manualized Cognitive Behavioral Therapy program to optimized standard medical treatment in adults with Functional Dyspepsia. Participants are stratified by dyspepsia subtype and randomly assigned in a 1:1 ratio to receive either optimized standard treatment alone or optimized standard treatment combined with Cognitive Behavioral Therapy. Outcome assessors are blinded to treatment allocation.

The Cognitive Behavioral Therapy intervention is delivered individually by trained therapists and focuses on psychoeducation, cognitive restructuring, stress management, coping strategies, and behavioral and interoceptive exposure. The intervention is designed to target symptom-related cognitions, emotional responses, and behavioral patterns that may contribute to symptom persistence.

In addition to evaluating clinical efficacy, the study adopts a multimodal approach to characterize biological, psychological, and clinical factors associated with treatment response. Data collection includes clinical and psychological assessments and the collection of biological samples to explore markers related to inflammation, stress regulation, gut barrier function, and gut microbiota composition and activity. Measurements are obtained at baseline and during follow-up to assess changes over time and their relationship with symptom improvement.

The study aims to identify predictors of response to Cognitive Behavioral Therapy and to explore differences between Epigastric Pain Syndrome and Postprandial Distress Syndrome. By integrating clinical, psychological, and biological data, the trial seeks to support a more personalized treatment approach for Functional Dyspepsia and to improve the targeting of psychological interventions in clinical practice.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Francesco Russo, MD; Phone Number: +390804994129; Email: francesco.russo@irccsdebellis.it
• Study Contact Backup: Name: Laura Prospero, Psychologist; Phone Number: +390804994274; Email: laura.prospero@irccsdebellis.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18-65 years
• Diagnosis of Functional Dyspepsia according to Rome IV criteria
• Classification as Epigastric Pain Syndrome (EPS) or Postprandial Distress Syndrome (PDS)
• Active symptoms within the last month
• Willingness to participate in Cognitive Behavioral Therapy and provide biological samples for research
• Ability to provide written informed consent

Exclusion Criteria:

• Presence of structural gastrointestinal disease (e.g., peptic ulcer, malignancy)
• History of major abdominal surgery affecting the stomach or small intestine
• Severe psychiatric disorders (e.g., psychosis, bipolar disorder) interfering with participation
• Current participation in other interventional clinical trials
• Use of medications that may confound study outcomes (e.g., chronic corticosteroids, immunosuppressants)
• Pregnancy or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Optimized Standard Treatment (OPT); Participants receive standard medical treatment for Functional Dyspepsia, including proton pump inhibitors, antiacids, and prokinetics at standard doses, according to clinical guidelines. No additional psychological intervention is provided.	Drug: Optimized Standard Treatment (OPT); Participants receive guideline-based standard medical treatment for Functional Dyspepsia, including proton pump inhibitors, antiacids, and prokinetics at recommended doses. This intervention does not include any psychological or behavioral therapy.
Experimental: Cognitive Behavioral Therapy + Optimized Standard Treatment (CBT + OPT); Participants receive the same optimized standard medical treatment as the OPT arm, plus a manualized Cognitive Behavioral Therapy program. CBT consists of 10 individual sessions (60 minutes each) over 12 weeks, with a 6-month booster session. Sessions include psychoeducation, cognitive restructuring, stress management, coping strategies, interoceptive and behavioral exposure, relaxation, and nutritional integration. Adherence and engagement are monitored throughout the study.	Drug: Optimized Standard Treatment (OPT); Participants receive guideline-based standard medical treatment for Functional Dyspepsia, including proton pump inhibitors, antiacids, and prokinetics at recommended doses. This intervention does not include any psychological or behavioral therapy.; Behavioral: Cognitive Behavioral Therapy + Optimized Standard Treatment (CBT + OPT); Participants receive the same optimized standard medical treatment as the OPT arm, plus a manualized Cognitive Behavioral Therapy program. CBT consists of 10 individual sessions (60 minutes each) over 12 weeks, with a 6-month booster session. Sessions cover psychoeducation, cognitive restructuring, stress management, coping strategies, interoceptive/behavioral exposure, relaxation, and nutritional integration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in gastrointestinal symptom severity as assessed by the Leeds Dyspepsia Questionnaire - Short Form (LDQ-SF)	The primary outcome is a statistically significant reduction in total LDQ-SF score in patients treated with CBT + optimized pharmacological treatment (OPT) compared to OPT alone, with an expected greater benefit in the Postprandial Distress Syndrome (PDS) subtype compared to the Epigastric Pain Syndrome (EPS) subtype. The LDQ-SF assesses the frequency and severity of dyspeptic symptoms (epigastric pain, heartburn, nausea, vomiting, early satiety, bloating, regurgitation, postprandial discomfort); scores range from 0 to 32, with higher scores indicating greater symptom severity. Responder status is defined as a ≥30-50% reduction in total LDQ-SF score from baseline.	Baseline (T0), 3 months (T1 - end of intervention), 6 months (T2 - intermediate follow-up), 12 months (T3 - final follow-up)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anxiety and Depression - Hospital Anxiety and Depression Scale (HADS)	Change from baseline in HADS total score and subscales (anxiety and depression) in CBT + OPT vs OPT alone. The HADS consists of 14 items divided into two subscales (anxiety and depression, 7 items each); each subscale ranges from 0 to 21, with higher scores indicating greater psychological distress. The total score ranges from 0 to 42.	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)
Perceived Stress - Perceived Stress Scale (PSS)	Change from baseline in perceived stress levels in CBT + OPT vs OPT alone. The PSS-10 consists of 10 items; scores range from 0 to 40, with higher scores indicating greater perceived stress.	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)
Somatic Symptom Burden - Patient Health Questionnaire (PHQ-15)	A 15-item measure of somatic symptom severity (range: 0-30). Higher scores indicate greater somatic symptom burden.	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)
Patient Global Impression of Change (PGIC)	Patient-reported subjective perception of overall improvement at each follow-up time point. A 7-point Likert scale assessing the patient's overall perception of improvement (range: 1-7). Higher scores indicate greater perceived improvement.	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)
Visceral Anxiety - Visceral Sensitivity Index (VSI)	A 15-item scale assessing gastrointestinal-specific anxiety (range: 0-75). Higher scores indicate greater anxiety and hypervigilance toward gastrointestinal sensations.	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)
Serum Interleukin-6 (IL-6)	Change from baseline in serum IL-6 levels (pg/mL) in CBT + OPT vs. OPT alone, as a marker of systemic inflammation.	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)
Serum Interleukin-8 (IL-8)	Change from baseline in serum IL-8 levels (pg/mL) in CBT + OPT vs. OPT alone, as a marker of systemic inflammation.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Serum Interleukin-10 (IL-10)	Change from baseline in serum IL-10 levels (pg/mL) in CBT + OPT vs. OPT alone, as a marker of anti-inflammatory response.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Serum Tumor Necrosis Factor-alpha (TNF-α)	Change from baseline in serum TNF-α levels (pg/mL) in CBT + OPT vs. OPT alone, as a marker of systemic inflammation.	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)
High-sensitivity C-Reactive Protein (hs-CRP)	Change from baseline in serum hs-CRP levels (mg/L) in CBT + OPT vs. OPT alone, as a marker of systemic low-grade inflammation.	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)
Diurnal Salivary Cortisol Profile	Change from baseline in diurnal salivary cortisol levels (nmol/L), measured at 4 time points across the day, in CBT + OPT vs. OPT alone, as a marker of hypothalamic-pituitary-adrenal (HPA) axis activity and stress regulation.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Plasma Ghrelin	Change from baseline in plasma ghrelin levels (pg/mL) in CBT + OPT vs. OPT alone, as a marker of appetite regulation and gut-brain axis signaling.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Plasma Cholecystokinin (CCK)	Change from baseline in plasma CCK levels (pg/mL) in CBT + OPT vs. OPT alone, as a marker of postprandial satiety signaling and gastrointestinal motility.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Plasma Glucagon-Like Peptide-2 (GLP-2)	Change from baseline in plasma GLP-2 levels (pg/mL) in CBT + OPT vs. OPT alone, as a marker of intestinal barrier integrity and mucosal growth.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Plasma Peptide YY (PYY)	Change from baseline in plasma PYY levels (pg/mL) in CBT + OPT vs. OPT alone, as a marker of postprandial satiety and gut motility regulation.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Plasma Gastrin	Change from baseline in plasma gastrin levels (pg/mL) in CBT + OPT vs. OPT alone, as a marker of gastric acid secretion and mucosal function.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Plasma Motilin	Change from baseline in plasma motilin levels (pg/mL) in CBT + OPT vs. OPT alone, as a marker of gastric motility and interdigestive motor activity.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Plasma Leptin	Change from baseline in plasma leptin levels (ng/mL) in CBT + OPT vs. OPT alone, as a marker of energy homeostasis and neuroendocrine regulation.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Plasma Serotonin (5-HT)	Change from baseline in plasma serotonin levels (ng/mL) in CBT + OPT vs. OPT alone, as a marker of enteric nervous system signaling and gut-brain communication.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Plasma Brain-Derived Neurotrophic Factor (BDNF)	Change from baseline in plasma BDNF levels (pg/mL) in CBT + OPT vs. OPT alone, as a marker of neuroplasticity and gut-brain axis modulation.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Plasma Cortisol	Change from baseline in plasma cortisol levels (nmol/L) in CBT + OPT vs. OPT alone, as a marker of hypothalamic-pituitary-adrenal (HPA) axis activation and physiological stress response.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Fecal Zonulin	Change from baseline in fecal zonulin levels (ng/mL) in CBT + OPT vs. OPT alone, as a marker of intestinal barrier permeability and tight junction regulation.	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)
Fecal Calprotectin	Change from baseline in fecal calprotectin levels (µg/g) in CBT + OPT vs. OPT alone, as a marker of intestinal mucosal inflammation.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Gut Microbiota Alpha Diversity - Observed Species	Change from baseline in observed species richness (count). Higher values indicate greater microbial richness.	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)
Gut Microbiota Beta Diversity - UniFrac Distance	Change from baseline in UniFrac distance (unitless), reflecting phylogenetic dissimilarity between microbial communities. Higher values indicate greater dissimilarity.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Gut Microbiota Beta Diversity - Bray-Curtis Dissimilarity	Change from baseline in Bray-Curtis dissimilarity index (unitless). Higher values indicate greater compositional differences.	Baseline (T0), 3 months (T1 - end of intervention), 6 months (T2 - intermediate follow-up), 12 months (T3 - final follow-up)
Relative Abundance of Faecalibacterium prausnitzii	Change from baseline in relative abundance (%) assessed by 16S rRNA sequencing in CBT + OPT vs. OPT alone.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Relative Abundance of Bifidobacterium spp.	Change from baseline in relative abundance (%) assessed by 16S rRNA sequencing.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Predicted Butyrate Production Pathway Abundance	Change from baseline in predicted abundance (arbitrary units) derived from 16S rRNA data in CBT + OPT vs. OPT alone.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Fecal Acetate	Change from baseline in fecal acetate concentration (µmol/g) in CBT + OPT vs. OPT alone	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)
Fecal Propionate	Change from baseline in fecal propionate concentration (µmol/g).	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)
Fecal Butyrate	Change from baseline in fecal butyrate concentration (µmol/g).	Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weekly Symptom Diary - Frequency and Intensity of Gastrointestinal Symptoms	Self-reported daily frequency and intensity of gastrointestinal symptoms and medication use, recorded in a structured weekly diary throughout the study period using a numeric rating scale (range: 0-10). Higher scores indicate greater symptom severity.	Weekly from baseline through 12 months (T3)
CBT Adherence Rate	Proportion of participants who complete the planned cognitive behavioral therapy (CBT) sessions (10 individual sessions and a booster session at 6 months), expressed as a percentage. Higher values indicate greater adherence to the intervention.	3 months (T1) and 6 months (T2 - booster session)
CBT Drop-out Rate	Proportion of participants who discontinue the CBT intervention before completion, expressed as a percentage (%). Higher values indicate lower acceptability of the intervention.	3 months (T1) and 6 months (T2 - booster session)
Medication Use - Consumption of PPIs, Antacids, and Prokinetics	Change from baseline in the use of pharmacological treatments (proton pump inhibitors, antacids, prokinetics) as a proxy measure of clinical improvement and healthcare resource utilization.	Baseline (T0), 3 months (T1), 6 months (T2), 12 months (T3)
Automatic Thoughts and Cognitive Triggers (CBT group only)	Exploratory analysis of CBT-specific cognitive variables, including automatic thoughts and behavioral triggers recorded on structured CBT sheets, as potential mediators of symptom improvement in the CBT + OPT group.	Throughout the intervention (Months 3-6) and at 6 months (T2)
Per-Protocol Subgroup Analysis	Pre-specified per-protocol analysis was restricted to participants who completed at least 80% of the CBT sessions and all biological sampling time points to assess treatment efficacy under optimal adherence conditions.	12 months (T3)

Collaborators and Investigators

• Sponsor: Azienda Ospedaliera Specializzata in Gastroenterologia Saverio de Bellis

Publications and helpful links

General Publications

• Huang Q, You F, Liang F, Ma C. Dietary microbes and functional dyspepsia: modulating the gut microecology for therapeutic benefit. Front Nutr. 2025 Aug 19;12:1625987. doi: 10.3389/fnut.2025.1625987. eCollection 2025.
• Cheng M, Zhou XE, Xu YC, Dou HM. The efficacy of cognitive behavior stress management on functional dyspepsia: A protocol for systematic review and meta-analysis. Medicine (Baltimore). 2022 May 13;101(19):e29157. doi: 10.1097/MD.0000000000029157.
• Sun E, Zhang X, Zhao Y, Li J, Sun J, Mu Z, Wang R. Beverages containing Lactobacillus paracasei LC-37 improved functional dyspepsia through regulation of the intestinal microbiota and their metabolites. J Dairy Sci. 2021 Jun;104(6):6389-6398. doi: 10.3168/jds.2020-19882. Epub 2021 Mar 11.
• Singh V, Lee G, Son H, Koh H, Kim ES, Unno T, Shin JH. Butyrate producers, "The Sentinel of Gut": Their intestinal significance with and beyond butyrate, and prospective use as microbial therapeutics. Front Microbiol. 2023 Jan 12;13:1103836. doi: 10.3389/fmicb.2022.1103836. eCollection 2022.
• Brown G, Hoedt EC, Keely S, Shah A, Walker MM, Holtmann G, Talley NJ. Role of the duodenal microbiota in functional dyspepsia. Neurogastroenterol Motil. 2022 Nov;34(11):e14372. doi: 10.1111/nmo.14372. Epub 2022 Apr 11.
• Wei Z, Xing X, Tantai X, Xiao C, Yang Q, Jiang X, Hao Y, Liu N, Wang Y, Wang J. The Effects of Psychological Interventions on Symptoms and Psychology of Functional Dyspepsia: A Systematic Review and Meta-Analysis. Front Psychol. 2022 Apr 8;13:827220. doi: 10.3389/fpsyg.2022.827220. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: February 11, 2026
• First Submitted That Met QC Criteria: May 5, 2026
• First Posted (Actual): May 11, 2026

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Inflammation; Functional Dyspepsia; Microbiota; Randomized Controlled Trial; Biomarkers; Cognitive Behavioral Therapy; Precision Medicine; Gastrointestinal Symptoms; Gut-Brain Axis; Epigastric Pain Syndrome; Postprandial Distress Syndrome; Disorders of Gut-Brain Interaction
• Additional Relevant MeSH Terms: Pathologic Processes; Pathological Conditions, Signs and Symptoms; Inflammation; Behavior Therapy; Psychotherapy; Behavioral Disciplines and Activities; Cognitive Behavioral Therapy
• Other Study ID Numbers: RC2026-22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No