key: cord-0023068-onnxqmcq
authors: Chinna Meyyappan, Arthi; Sgarbossa, Cassandra; Vazquez, Gustavo; Bond, David J; Müller, Daniel J; Milev, Roumen
title: The Safety and Efficacy of Microbial Ecosystem Therapeutic-2 in People With Major Depression: Protocol for a Phase 2, Double-Blind, Placebo-Controlled Study
date: 2021-09-22
journal: JMIR Res Protoc
DOI: 10.2196/31439
sha: a2ce3b5c24bb3435bc4aa7dbd40dd7746e3f344d
doc_id: 23068
cord_uid: onnxqmcq

BACKGROUND: The gut-brain axis is a bidirectional signaling pathway between the gastrointestinal tract and the brain; it is being studied because of its potential influence in mediating mood, anxiety, and other neuropsychiatric symptoms. Previous research examining the effects of gut microbiota on neuropsychiatric disorders suggests that gut repopulation treatments such as probiotics, microbe therapy, and fecal microbiota transplantation show promising results in treating symptoms of anxiety and depression. This study explores the use of an alternative gut repopulation treatment to fecal microbiota transplantation, known as Microbial Ecosystem Therapeutic (MET)-2, as an intervention against symptoms of depression. MET-2 is a daily, orally administered capsule containing 40 bacterial strains purified from a single healthy donor. OBJECTIVE: The primary aim of this study is to assess changes in mood in people with major depression that occur pre-, post-, and during the administration of MET-2. The secondary aims are to assess changes in anxiety symptoms, blood biomarker concentrations, and the level of repopulation of healthy gut bacteria as a response to treatment. METHODS: In this study, we will recruit 60 adults aged between 18 and 45 years old with major depression and randomly assign them to treatment or placebo groups. Patients in the treatment group will receive MET-2 once a day for 6 weeks, whereas patients in the placebo group will receive a matching placebo for 6 weeks. Participants will complete biweekly visits during the treatment period and a follow-up visit at 2 weeks post treatment. As a primary outcome measure, participants’ mood will be assessed using the Montgomery-Asberg Depression Rating Scale. Secondary outcome measures include changes in mood, anxiety, early stress, gastrointestinal symptoms, and tolerability of MET-2 treatment using a series of clinical scales and changes in blood markers, particularly immunoglobulins (Igs; IgA, IgG, and IgM) and inflammatory markers (C-reactive protein, tumor necrosis factor-α, transforming growth factor-β, interleukin-6, and interleukin-10). Changes in the relative abundance, diversity, and level of engraftment in fecal samples will be assessed using 16S rRNA sequencing. All data will be integrated to identify biomarkers that could indicate disease state or predict improvement in depressive symptoms in response to MET-2 treatment. RESULTS: Given the association between the gut microbiome and depression, we hypothesized that participants receiving MET-2 would experience greater improvement in depressive symptoms than those receiving placebo owing to the recolonization of the gut microbiome with healthy bacteria modulating the gut-brain axis connection. CONCLUSIONS: This study is the first of its kind to evaluate the safety and efficacy of a microbial therapy such as MET-2 in comparison with placebo for major depressive disorder. We hope that this study will also reveal the potential capabilities of microbial therapies to treat other psychiatric illnesses and mood disorders. TRIAL REGISTRATION: ClinicalTrials.gov NCT04602715; https://clinicaltrials.gov/ct2/show/NCT04602715 INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31439

Week 4

Week 8

Albumin

Hematocrit x

x Hemoglobin x x Platelet count x x Red blood cell count x x White blood cell count and differential (neutrophils, eosinophils, basophils, lymphocytes, and monocytes)

x x

This is a Multimedia Appendix to a full manuscript published in the J Med Internet Res. For full copyright and citation information see http://dx.doi.org/10.2196/jmir.31439

x x a alanine aminotransferase b alkaline phosphatase c aspartate aminotransferase d interleukin e c-reactive protein f transforming growth factor g tumour necrosis factor h immunoglobulin i high-density lipoprotein j low-density lipoprotein 

Able to understand and comply with the requirements of the study

Exclusion Criteria 1. History of chronic diarrhea 2. Need for regular use of agents that affect GI motility (narcotics such as codeine or morphine, agents such as loperamide or metoclopramide)

Elective surgery that will require preoperative antibiotics planned within 6 months of enrolment

History of bariatric surgery

Pregnant, breastfeeding, or planning to get pregnant in the next 6 months 7. Any condition for which

Current use of any antidepressant/antianxiety drug

Currently participating in a structured psychotherapy program 10. More than three depressive episodes throughout lifetime 11. Having failed an antidepressant or psychotherapeutic treatment during current depressive episode

Use of any antibiotic drug in the past 4 weeks (may be eligible to participate after a 1-month washout period)

Daily use of probiotic product in the past 2 weeks

Consumption of products fortified in probiotics

High suicidal risk, as measured by MADRS item 10 score equal to or higher than 4

Immunodeficiency (immuno-compromised and immuno-suppressed participants

acquired immune deficiency syndrome [AIDS], lymphoma, participants undergoing long-term corticosteroid treatment

Unstable medical conditions or serious diseases/conditions (e.g. cancer, cardiovascular, renal, lung, diabetes, psychiatric illness, bleeding disorders, etc.) 23. The use of natural health products

This is a Multimedia Appendix to a full manuscript published in the J Med Internet Res. For full copyright and citation information see http://dx.doi.org/10.2196/jmir.31439Textbox S1: Inclusion/Exclusion Criteria Inclusion Criteria