Safety and Efficacy of Fecal Microbiota Transplantation in a Population With Bipolar Disorder

A Randomized Controlled Trial of the Safety and Efficacy of Fecal Microbiota Transplantation in a Population With Bipolar Disorder

Every human harbors complex microbial communities (collectively, the human 'microbiome') that cover the skin and the body's mucosal surfaces. There is mounting evidence of an interaction between the intestinal microbiota, the gut, and the central nervous system (CNS) in what is recognized as the microbiome-gut-brain axis. Based on this compelling body of evidence, there is growing enthusiasm for work that is focused on translating this emerging association into novel therapies for psychiatric illness. Fecal microbiota transplantation(FMT) is a technique in which gut bacteria are transferred from a healthy screened donor to a patient, with the goal to introduce or restore a stable microbial community in the gut.There are no clinical trials examining the impact of FMT on Bipolar Disorder (BD). However, there is biological rationale to support this type of treatment, given the known inflammatory underpinnings of this illness. The objective of this study is to assess the effectiveness of this very novel therapy targeting the gut-brain axis, FMT, to treat bipolar depression. Study Hypotheses: Main hypothesis: FMT from healthy donors to patients with BD depression will improve depression symptoms as an adjunct to approved medication. Secondary hypotheses: FMT will also reduce anxiety and global function FMT is safe and will be well tolerated by the patients Improvements in clinical parameters will be associated with specific changes in the intestinal microbiome and/or metabolites in stool and serum

The primary goals of this proof of concept study are to determine the effectiveness, safety and tolerability of FMT in adults with BD depression. Objective 1: To evaluate the effectiveness of the combination of a currently accepted approved therapy for BD depression + FMT in individuals with BD depression. This will be assessed through a change in the Montgomery-Ãsberg Depression Rating Scale (MADRS) total score from baseline (pre-intervention) to the final visit (week 24). The investigators will also assess the proportion of patients withdrawing from study due to inadequate control of depressive symptoms. Secondary objective 2: To evaluate the effectiveness of FMT on anxiety symptoms and global function/overall improvement in participants with BD depression. Secondary objective 3: To determine the safety and tolerability of FMT in individuals with BD depression. Safety will be evaluated by solicited and unsolicited adverse events, including serious adverse events, throughout the study period. Tolerability will be assessed using the Toronto Side Effect Scale (TSES). This is a 32-item instrument that is designed to establish incidence, frequency, and severity of CNS, gastrointestinal, and sexual side effects. Secondary objective 4: To assess the effect of FMT on microbiome profile (community structure and functional metagenome) and fecal metabolome. Changes in fecal microbiome profile and fecal metabolome from baseline to the final visit will be assessed using next generation sequencing and nuclear magnetic resonance (NMR) spectrometry, respectively. Changes in mood rating scales will be correlated with a specific microbiome and metabolome signature. Intestinal microbiome and metabolome of healthy donors will also be assessed.

Adults with BD depression being treated with an approved medication will be assigned to either allogenic FMT (from a healthy, screened individual with no personal or family history of an Axis 1 disorder) or autologous FMT (re-infusion of own feces)

Both the patient and the study team (clinical team, study coordinator, data analyst) will be blinded to group assignments.

Participants Randomized to this arm will receive FMT (Fecal Microbiota Transplantation) from a healthy, screened individual with no personal or family history of an Axis 1 disorder.

Participants Randomized to this arm will receive FMT (Fecal Microbiota Transplantation) by re-infusion of their own feces donated earlier in the study.

Fifty (50) g of screened donor feces will be weighed and homogenized with 30 mL of sterile 0.9 N NaCl + 10% glycerol using a sterile 330 micron micro-filter-separated double-compartment polyethylene bag in the Stomacher® Paddle Blender. 2.The volume of fecal filtrate corresponding to fifty (50) g of donor stools will be transferred into a 50 mL Falcon tube with screw top and frozen at -80oC. 3. For colonoscopy administration, three (3) Falcon tubes of thawed FMT concentrated will be diluted to a total volume of 300 mL with 0.9N NaCl and will be transported to the endoscopy suite. In the endoscopy suite, the FMT product will be packaged into 6 x 50 ml syringes for patient delivery by colonoscopy.

1. Fifty (50) g of the participant's feces will be weighed and homogenized with 30 mL of sterile 0.9 N NaCl + 10% glycerol using a sterile 330 micron micro-filter-separated double-compartment polyethylene bag in the Stomacher® Paddle Blender. 3.The volume of fecal filtrate corresponding to fifty (50) g of participant's stools will be transferred into a 50 mL Falcon tube with screw top and frozen at -80oC. 3. For colonoscopy administration, three (3) Falcon tubes of thawed FMT concentrated will be diluted to a total volume of 300 mL with 0.9N NaCl and will be transported to the endoscopy suite. In the endoscopy suite, the FMT product will be packaged into 6 x 50 ml syringes for patient delivery by colonoscopy.

The MADRS score will be used to assess the effectiveness of the combination of a currently accepted approved therapy plus FMT on depression symptoms. The MADRS score will also help assess the percentage of patients who show inadequate control of depressive symptoms

The effectiveness of Approved treatment + FMT in controlling anxiety symptoms and global function/Overall improvement will be assessed through the CGI

The effectiveness of Approved treatment + FMT in improving the quality of life of bipolar depression patients will be assessed through the World Health Organization Quality of life (WHOQOL-BREF) questionnaire.

Stool samples will be collected and analysed using next generation sequencing to examine changes in Changes in fecal microbiome profile

Inclusion Criteria: Between 18-65 years of age Outpatient status Have a diagnosis of bipolar disorder (BD) (type I or II) according to the Mini International Neuropsychiatric Interview (MINI) Have been on a stable first line treatment for BD depression at an adequate dose for at least 8 weeks prior to study entry Suffer from a current depressive episode (Montgomery-Åsberg Depression Rating Scale (MADRS) score at screening and baseline of ≥ 12) Exclusion Criteria: DSM-IV criteria for substance abuse within the last 6 months or lifetime dependency Active eating disorders Schizophrenia or schizoaffective disorder Current psychotic symptoms A Young Mania Rating Scale (YMRS) score of ≥12 at screening Active suicidality Regular intake of non-steroidal anti-inflammatory drugs or iron supplements in the 3 months prior to study entry Use of prebiotics or probiotics for medical purposes, use of antibiotics or any experimental drug in the 3 months prior to study entry Chronic gastrointestinal diseases Conditions causing immunosuppression A significant bleeding disorder Any contraindication to colonoscopy Pregnancy or breastfeeding

both the descriptive and analyzed data, including individual patient data, will be submitted to the National Database for Clinical Trials related to Mental Illness (NDCT), which is part of the National Institute of Mental Health Data Archive (NDA). The data are de-identified and will be made available to qualified researchers, who have to request access to the dataset.

Researchers approved for access to NDCT have the ability to download shared data from all clinical trials available in the repository

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