Cognitive-behavioral Therapy for the Diseases Associated With Esophageal-brain-gut Axis Communication Abnormalities.

Esophageal Visceral Hypersensitivity and Hypervigilance in Disorders of Gut-brain Interaction: the Roles of Cognitive-behavioral Therapy

Gastroesophageal reflux disease (GERD) is a challenging gastrointestinal disorder, and proton pump inhibitors (PPIs) are typically the first line of treatment. However, up to 40% of GERD patients experience little to no relief or only partial relief of their symptoms after receiving PPI therapy. Among these patients, who do not respond to high-dose PPIs taken twice daily, more than 90% exhibit conditions related to brain-gut axis communication disorders, such as esophageal hypersensitivity and functional heartburn. Visceral hypersensitivity and esophageal hypervigilance are the two key causes of esophageal symptoms in this group of patients. According to the Rome IV consensus on esophageal disorders, five categories are identified: functional chest pain, functional heartburn, globus sensation, functional dysphagia, and esophageal hypersensitivity. The diagnostic criteria state that patients must have chronic esophageal symptoms, and any structural, inflammatory, or motility abnormalities must be excluded. Therefore, diagnosing brain-gut axis communication disorders in the esophagus requires upper gastrointestinal endoscopy, esophageal pH-impedance testing, and high-resolution esophageal manometry. Neuromodulators, which regulate peripheral and central pain sensitivity, are a cornerstone of pharmacological treatment for brain-gut axis communication disorders and associated symptoms. Additionally, growing evidence supports the use of brain-gut axis behavioral therapies, such as gut-directed hypnotherapy and cognitive behavioral therapy (CBT), to effectively treat these disorders. However, research on neuromodulators and CBT in brain-gut axis communication disorders remains limited, and their efficacy is still unclear. The aim of this study is to investigate the effectiveness and role of CBT in treating brain-gut axis communication disorders. The information gained from this research will help clarify the pathophysiological mechanisms related to brain-gut axis communication abnormalities and refractory GERD symptoms. Furthermore, the findings will guide the development of effective treatment strategies for patients with brain-gut axis communication disorders who do not respond to PPI therapy in clinical practice.

Study Overview

• Status: Recruiting
• Conditions: GERD Without Erosive Esophagitis; Gut-Brain Disorders
• Intervention / Treatment: Behavioral: Cognitive Behavioral Therapy (CBT); Behavioral: Lifestyle management (sham control)

Detailed Description

All participants will undergo questionnaire assessments and heart rate variability (HRV) measurements prior to treatment. The questionnaires include the Gastroesophageal Reflux Disease Questionnaire (GERDQ), PROMIS GERD, DSI & GSS, RSI, the Brief Esophageal Dysphagia Questionnaire (BEDQ), the Esophageal Hypersensitivity and Anxiety Scale (EHAS), Visceral Sensitivity Index (VSI), Sleep and Psychosocial Questionnaires (Pittsburgh Sleep Quality Index [PSQI], Taiwan Depression Questionnaire [TDQ], State-Trait Anxiety Inventory [STAI], Functional Dyspepsia [FD] Questionnaire, Irritable Bowel Syndrome [IBS] Questionnaire, and Quality of Life Questionnaire [SF-12, Northwestern Esophageal Quality of Life Questionnaire NEQOL]). HRV measurements will be conducted using a non-invasive "MindTech" physiological feedback system (Ministry of Health and Welfare Medical Device License No. 011374).

Afterwards, a single-blind trial with computer-generated random allocation will be conducted. Participants will undergo either six weeks of cognitive behavioral therapy (CBT) led by a therapist or six weeks of lifestyle management (sham control). Each group will receive one session per week, with each session lasting one hour. After six weeks of counseling, participants will undergo another round of questionnaire assessments and HRV measurements at the 12th week of the study. The questionnaire assessment and HRV measurements will take approximately 20 to 30 minutes to complete.

Cognitive behavioral therapy (CBT) will follow these steps in sequence: (1) education and tracking initiation, (2) introduction to heart rate variability and breathing, (3) cognitive restructuring and breathing techniques, (4) cognitive diffusion and behavioral experiments, (5) problem-focused and emotion-focused coping strategies, (6) conclusion of therapy and relapse prevention.

Lifestyle management (sham control) will follow these steps in sequence: (1) education and tracking initiation, (2) dietary habits: what, when, where, why, (3) changing my diet: strategies and obstacles, (4) lifestyle factors: alcohol, smoking, and sugar, (5) lifestyle factors: sleep and exercise, (6) conclusion of therapy and relapse prevention.

In this study, we will use a non-invasive physiological signal sensor connected to the physiological feedback system to measure participants' physiological signals, including electrocardiogram (ECG) and respiration. Prior to measurement, participants will be attached with ECG electrodes for a two-lead ECG, which will be converted into heart rate variability indicators. Additionally, a non-invasive respiratory sensor will measure the participant's breaths per minute. Except for a very small percentage of participants who may experience allergic reactions to ECG electrodes, the likelihood of adverse effects is less than 1%.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Wei-Yi Lei Gastroenterology attending physician; Phone Number: +88638561825; Email: hlmweb@tzuchi.com.tw

Study Locations

• Taiwan
  • Hualien City, Taiwan
    • Recruiting
    • Hualien Tzu Chi Hospital,Buddhist Tzu Chi Medical Foundation
    • Contact: Wei-Yi Lei Gastroenterology attending physician; Phone Number: +88638561825; Email: hlmweb@tzuchi.com.tw

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age between 18 and 75 years, with clear consciousness and willingness to sign the informed consent form.
2. Subjects with chronic esophageal symptoms related to disorders of the brain-gut axis communication (such as heartburn, acid reflux, sensation of a foreign body in the throat, difficulty swallowing, and chest pain or discomfort).

Exclusion Criteria:

1. Esophageal strictures, or history of surgery on the esophagus, gastrointestinal tract, or throat.
2. Structural esophageal diseases (such as diverticula, esophageal rings, etc.), infectious esophagitis, erosive esophagitis, eosinophilic esophagitis.
3. Non-erosive gastroesophageal reflux disease or significant esophageal motility disorders.
4. History of or current diagnosis of malignancies in the esophagus, gastrointestinal tract, or other organs.
5. Significant endocrine or rheumatic immune diseases that may affect gastrointestinal motility.
6. Continuous use of medications that may affect esophageal motility within the past month (such as anticholinergics, opioid-like agents, nitrates, calcium channel blockers, etc.).
7. Use of or currently taking antidepressants, selective serotonin reuptake inhibitors, or other psychotropic medications within the past three months.
8. Pregnant or breastfeeding women.
9. Individuals with mental illness or those who are unable to cooperate.
10. Known allergy to tricyclic antidepressants.
11. Known allergy to selective serotonin reuptake inhibitors.
12. Known allergy to any component of proton pump inhibitors.

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
Active Comparator: Cognitive behavioral therapy (CBT); Cognitive Behavioral Therapy (CBT) will be implemented according to the following steps: (1) Psychoeducation and beginning of tracking; (2) Introduction to heart rate variability and breathing; (3) Cognitive restructuring and breathing application; (4) Cognitive defusion and behavioral experiments; (5) Coping strategies for problem-focused and emotion-focused approaches; (6) Conclusion of therapy and relapse prevention.	Behavioral: Cognitive Behavioral Therapy (CBT); The participants will undergo a 6-week cognitive behavioral therapy (CBT) guided by a psychologist, with one session per week, each lasting 1 hour.
Sham Comparator: Lifestyle management (sham control); Lifestyle management (sham control) will be implemented according to the following steps: (1) Psychoeducation and beginning of tracking; (2) Dietary habits: What, when, where, and why; (3) Changing my diet: Strategies and barriers; (4) Lifestyle factors: Alcohol, smoking, and sugar; (5) Lifestyle factors: Sleep and exercise; (6) Conclusion of therapy and relapse prevention.	Behavioral: Lifestyle management (sham control); The participants will undergo a 6-week lifestyle management (sham control) guided by a psychologist, with one session per week, each lasting 1 hour.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate variability(HRV)	Participants will undergo heart rate variability measurement before receiving treatment, and another heart rate variability measurement will be conducted after week 12 of the study.	Participants will undergo heart rate variability measurement before receiving treatment, and another heart rate variability measurement will be conducted after week 12 of the study.
Gastroesophageal Reflux Disease Questionnaire（GERDQ）	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The minimum score of the questionnaire is 0 and the maximum score is 18. The higher the score, the worse the gastroesophageal reflux symptoms.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
PROMIS Gastroesophageal Reflux Disease Questionnaire（PROMIS GERD）	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The minimum score of the questionnaire is 0 and the maximum score is 52. The higher the score, the worse the gastroesophageal reflux symptoms.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
Disease symptom index(DSI)	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The minimum score of the questionnaire is 0 and the maximum score is 16. The higher the score, the worse the gastroesophageal reflux symptoms.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
Reflux Symptom Index(RSI)	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The minimum score of the questionnaire is 0 and the maximum score is 45. The higher the score, the worse the gastroesophageal reflux symptoms.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
The Brief Esophageal Dysphagia Questionnaire(BEDQ)	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The lowest score of the questionnaire is 0 and the highest score is 40. The higher the score, the more severe the dysphagia.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
Esophageal Hypervigilance and Anxiety Scale(EHAS)	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The lowest score of the questionnaire is 0 and the highest score is 60. The higher the score, the more severe the esophageal hypervigilance and anxiety.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
Visceral sensitivity index(VSI)	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The lowest score of the questionnaire is 0 and the highest score is 75. The higher the score, the higher the visceral sensitivity.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
Pittsburgh Sleep Quality Index(PSQI)	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The lowest score of the questionnaire is 0 and the highest score is 21. The higher the score, the worse the sleep quality.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
Taiwanese Depression Questionnaire(TDQ)	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The lowest score of the questionnaire is 0 and the highest score is 54. The higher the score, the higher the depression index.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
The State-Trait Anxiety Inventory(STAI)	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The lowest score of the questionnaire is 1 and the highest score is 80. The higher the score, the more obvious the anxiety trait.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
Illness Cognition Questionnaire (ICQ)	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The lowest score of the questionnaire is 1 and the highest score is 72. The higher the score, the higher the level of disease awareness.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
Short-form-12-health-survey-questionnaire(SF-12)	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The results of the SF-12 health scale mainly include two total scores: physical health total score (PCS) and mental health total score (MCS). These two scores are used to measure an individual's health status in these two aspects.; **Physical Health Score (PCS) and Mental Health Score (MCS)** are usually expressed as standardized scores with a mean of 50 and a standard deviation of 10.; A higher score indicates better health, whereas a lower score indicates worse health.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
Northwest Esophageal Quality of Life Scale(NEQOL)	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The lowest score of the questionnaire is 0 and the highest score is 56. The higher the score, the worse the esophageal quality of life.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.
Global Symptom Severity Questionnaire(GSS)	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period. The minimum score of the questionnaire is 0 and the maximum score is 100. The higher the score, the worse the gastroesophageal reflux symptoms.	Each participant will undergo a questionnaire assessment upon entering the study, and another questionnaire assessment will be conducted at the end of the 12-week treatment period.

Collaborators and Investigators

• Sponsor: Hualien Tzu Chi General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 2, 2024
• Primary Completion (Actual): April 24, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: April 15, 2025
• First Submitted That Met QC Criteria: April 15, 2025
• First Posted (Actual): April 22, 2025

Study Record Updates

• Last Update Posted (Actual): April 29, 2025
• Last Update Submitted That Met QC Criteria: April 24, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: gastroesophageal reflux disease; cognitive behavior therapy; disorders of gut-brain interaction
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Digestive System Diseases; Gastrointestinal Diseases; Esophageal Diseases; Gastroenteritis; Brain Diseases; Esophagitis
• Other Study ID Numbers: TCRD113-042

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