Cognitive and Psychiatric Effects of Linaclotide on Patients With Constipation

August 30, 2021 updated by: Paul Moayyedi, McMaster University

Cognitive and Psychiatric Effects of Linaclotide on Patients With Irritable Bowel Syndrome-Constipation Predominant and Chronic Idiopathic Constipation

Irritable Bowel syndrome - constipation predominant (IBS-C) is a chronic and disabling,disorder of the gut that is characterized by abdominal pain or discomfort. Approximately 50% of patients with IBS-C will also meet criteria for anxiety or depression.

Anti depressant medication is widely used in the treatment of IBS. Linaclotide is a novel medication for IBS that is also effective at relieving pain associated with IBS, which may be in part to signalling between the gut and the brain. However, the impact of Linaclotide on the psychiatric symptoms of anxiety and depression on IBS has not been investigated.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Irritable bowel syndrome (IBS) is a chronic, disabling functional gastrointestinal disorder that is characterized by abdominal pain or discomfort and a disturbance in bowel habit. It has long been recognized that psychological factors can be important in IBS, and that bi-directional signaling between the gut and the brain is likely involved in the pathophysiology of the syndrome. Approximately 50% of patients with IBS at a tertiary center will also meet criteria for anxiety or depression. Anti-depressant medications are widely used in the treatment of IBS, even without psychiatric comorbidity, with good evidence for both tricyclic antidepressants and selective serotonin reuptake inhibitors. Unfortunately both classes of anti-depressants have significant gastrointestinal side effects and a large number of patients cannot tolerate the medications.

Linaclotide, a guanylate cyclase agonist, has emerged as an important, novel treatment for patients with constipation-predominant IBS (IBS-C) and Chronic Idiopathic Constipation (CIC). Linaclotide is effective at relieving pain associated with IBS, which may be in part mediated by modulation of signaling between the gut and the brain. In this study the investigators will study the effect of Linaclotide on anxiety, depression and cognitive functioning in patients with IBS-C and CIC. If Linaclotide is also effective in treating anxiety and depression and improving cognitive functioning in patients with IBS-C and CIC, this will be an important therapeutic advance for the 50% of IBS patients with psychiatric comorbidity.

The investigators also propose to investigate the mechanisms by which Linaclotide may effect psychiatric symptoms and neuropsychological functioning by measuring changes in the gut microbiome and inflammatory biomarkers. The gut and the brain are intimately connected by several, bidirectional, signaling pathways including neural, humoral and immune mechanisms. The concept of the "gut-brain axis" has recently been supplanted by the "microbiota-gut-brain axis," emphasizing the important role the gut microbiota plays in mediating brain responses. The gut microbiota communicate with the brain through immune and neuronal pathways and some microbiota can directly secrete neurotransmitters such as serotonin, dopamine and gamma-aminobutyric acid (GABA) . In true bidirectional fashion, the brain can also influence the microbiota through the secretion of cortisol and sympathetic neurotransmission, changing gut motility, secretion and mucin production, which can affect the habitat of the resident microbiota and thereby alter the composition of the microbiota. Alterations in gut microbiota have been associated with irritable bowel syndrome in multiple studies.

Given the importance of the gut microbiota in mediating gut-brain responses, the investigators propose that the gut microbiota may play a direct role in the pathophysiology of anxiety and depression in patients with IBS. If Linaclotide is effective in reducing psychiatric and neuropsychological symptoms in patients with IBS, this may occur through changes in the gut microbiota, perhaps as a result of altered colonic motility and altered habitat of resident microbiota.

Study Type

Observational

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Hamilton, Ontario, Canada, L8N3Z5
        • McMaster University Medical Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Patients with IBS-C or CIC starting on Linaclotide

Description

Inclusion Criteria:

  • IBS-C or CIC as defined by Rome III criteria
  • able to provide and sign informed consent
  • age 18-65 years

Exclusion Criteria:

  • Previous diagnosis of bipolar, schizophrenia, or schizoaffective disorder
  • psychosis
  • active suicidal thoughts
  • presence of a major neurocognitive disorder, delirium or other cognitive disorder
  • active substance dependence ( including the use of cannabis more than 3 times per week
  • active eating disorder
  • pregnant or breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To measure anxiety and depression using the Depression, Anxiety and Stress Scale (DASS) in patients with IBS-C and CIC before and after treatment with Linaclotide
Time Frame: Change from baseline to week 8
Change from baseline to week 8

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To measure neuropsychological performance in Patients with IBS-C and CIC using a standardized neuropsychological assessment in patients (CNS vital signs) before and after treatment with Linaclotide
Time Frame: Change from baseline to week 8
Neuropsychological testing will be performed using the standardized and validated CNS vital signs evaluation platform.
Change from baseline to week 8
To determine changes in fecal microbiome profile before and after treatment with Linaclotide and whether these changes correlate with changes in psychiatric symptoms and cognition.
Time Frame: Change from baseline to week 8
Fecal microbiome profile will be characterized using our in-house bioinformatics pipelines that provide measures of diversity between time points as well as differences in taxa between time points. Measurements will be aggregated to arrive at one reported value including diversity measures for microbiome analysis.
Change from baseline to week 8
To determine changes in inflammatory biomarker profile before and after treatment with Linaclotide and whether these changes correlate with changes in psychiatric symptoms and cognition.
Time Frame: Change from baseline to week 8
Inflammatory biomarkers measured will include IL-1, IL-6, TNF-alpha, IFN-gamma. Measurements will be aggregated to arrive at one reported value for average inflammatory biomarker levels.
Change from baseline to week 8

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

McMaster University

Investigators

  • Principal Investigator: Paul Moayyedi, MD, PhD, McMaster University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2016

Primary Completion (ANTICIPATED)

December 1, 2020

Study Completion (ANTICIPATED)

March 1, 2021

Study Registration Dates

First Submitted

March 1, 2016

First Submitted That Met QC Criteria

November 9, 2017

First Posted (ACTUAL)

November 14, 2017

Study Record Updates

Last Update Posted (ACTUAL)

August 31, 2021

Last Update Submitted That Met QC Criteria

August 30, 2021

Last Verified

August 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1088

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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