Fecal Microbiota Transplantation in Depression

Study Overview
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Brief Summary
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The prevalence of psychiatric disorders such as major depression disorder (MDD) is increasing rapidly. Despite advancements in the development of therapeutics, current treatment options have not reached optimal efficacy. Recent interest has been drawn towards the importance of the biochemical signalling between the gastrointestinal tract and the central nervous system also known as the microbiome-gut-brain axis. The pathogenesis of gut microbiota in extra intestinal diseases was inspired by massive studies in germ free (GF) animals, which indicated that the gut microbiota plays a role in the normal regulation of behaviour that are relevant to mood, anxiety and stress. However, the exact mechanisms by which intestinal dysbiosis are involved in the development of psychiatric diseases are not completely clarified. A new method to alter the composition of the gastrointestinal microbiota involves fecal microbiota transplantation (FMT). The goal of FMT is to introduce or restore a stable microbial community in the gut by transplanting intestinal microbiota from a healthy donor to the patient. FMT, as a microbiota-target therapy, is arguably very effective for curing recurrent Clostridium difficile infection and has good outcomes in other intestinal diseases. At the same time, applications in previously unexpected areas, including metabolic diseases, neuropsychiatric disorders, autoimmune diseases, allergic disorders, and tumors have shown health enhancing results. FMT has initially been conducted using colonoscopy. However, recent evidence has shown that treatment with frozen FMT capsules (to be taken orally) is also safe and beneficial in restoring the gut microbiota in patients with various diseases As FMT capsules may be an effective, pragmatical adjuvant therapy (in addition to standard treatment) for depression, this project is aimed at (1) investigating for the first time if single administration of FMT capsules ameliorates depressive symptoms in patients with moderate to severe MDD 4 weeks after treatment and (2) establishing the safety profile of encapsulated FMT in MDD. Furthermore, we will also test if (3) FMT capsules modulates immune signalling and inflammatory processes, (4) Hypothalamic-pituitary-adrenal (HPA) axis responses, (5) neurogenesis, (6) energy balance hormones, (7) gut microbiota composition and (8) brain perfusion, structure and activation.

Official Title
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Oral Frozen Fecal Microbiota Transplantation (FMT) Capsules for Depression: a Double-blind, Placebo-controlled, Randomized Parallel Group Study

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Fecal microbiota capsules
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18, body mass index 20-30 kg/m² Able to provide signed and dated informed consent Patients with moderate to severe depression (as expressed by a Hamilton Depression Rating Scale (HAMD-17) > 17) Treatment as usual for depression In- and outpatients at the UPK Basel Exclusion Criteria: Patients with mild MDD (HAMD-17 < 17) Comorbid psychiatric disturbances such as substance abuse disorder, bipolar disorder, schizophrenia, eating disorders. Current medical conditions such as acute infectious disease, Dietary restrictions (vegetarian, vegan, gluten-free, PEG/TPN feeding, and any kind of deviation from the UPK standard catering) Recent use of medications besides their anti-depressant medication (within 3 months, mainly antibiotics or probiotic consumption within last six weeks). Pregnancy (tested before both MRI scans using the AlereTM TestPack +Plus hCG Urine Test), breast-feeding Body Mass Index (BMI) > 30 Current or recent use of antibiotics (within 3 months before inclusion) Anticipated antibiotic use in upcoming 4 weeks Inability to read and understand the participant's information and informed consent form Inability (e.g. dysphagia) to or unwilling to swallow capsules Active vomiting Known or suspected toxic megacolon and/or known small bowel ileus Major gastrointestinal surgery (e.g. significant bowel resection) within 3 months before enrolment. This does not include appendectomy or cholecystectomy. History of total colectomy or bariatric surgery. Concurrent intensive induction chemotherapy, radiation therapy or biological treatment for active malignancy. Patients on maintenance chemotherapy may be enrolled only after consultation with a medical monitor. Life expectancy < 6 months Patients with a history of severe anaphylactic or anaphylactoid food allergy Solid organ transplant recipients ≤ 90 days post-transplant or on active treatment for rejection Neuropenia (≤500 neutrophils/mL) or other severe immunosuppression. Anti-TNF will be permitted. Patients on monoclonal antibodies to B and T cells, glucocorticoids, antimetabolites (azathioprine, 6-mercaptopurine, methotrexate), calcineurin inhbitors (tacrolimus, cyclosporine) and mycophenolate mofetil may be enrolled only after consultation with the medical monitor. A condition that would jeopardize the safety or rights of the subject, would make it unlikely for the subject to complete the study, or would confound the results of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FMT group<br>Patient group receiving active FMT capsules | Drug: Fecal microbiota capsules<br>* Patients will receive FMT capsules DE containing the fecal microbiota drug substance within a gelatin capsule shell. The drug substance is fecal microbiota from a single donor.<br>|
| Placebo Comparator: Placebo group<br>Patient group receiving placebo capsules | Drug: Placebo oral capsule<br>* The control condition is a placebo FMT capsule. The FMT placebo capsule is identical in appearance to active capsules, but does not contain human feces, the active pharmaceutical ingredient. Placebo capsules will contain an autoclaved solution of glycerol and saline, contained in an identical gelatin capsule as the active product, including the same enteric polymer coating<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depressive symptoms as measured with the Hamilton Rating Scale for Depression | Efficacy measure | Change from baseline score to follow-up measurements at 1, 2 and 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gut microbiota composition as assessed by 16-S-rRNA sequencing of stool samples | Efficacy measure | Change from baseline score to follow-up measurement after 1 month | 
| Cerebral blood flow (measured with arterial spin labeling, mL/100 g/min^10) | Efficacy measure | Change from baseline score to follow-up measurement after 1 month | 
| Brain structure (measured with structural magnetic resonance imaging to assess gray matter volume in mm^3, and diffusion tensor imaging to assess fractional anisotropy (dimensionless) and mean diffusivity (m2/s)) | Efficacy measure | Change from baseline score to follow-up measurement after 1 month | 
| Brain function (measured Blood-oxygen-level dependent contrast imaging) | Efficacy measure | Change from baseline score to follow-up measurement after 1 month | 
| HPA axis function (measured with salivary cortisol awakening responses). | Efficacy measure | Change from baseline score to follow-up measurement after 1 month | 
| Neurogenesis (measured with blood levels of BDNF). | Efficacy measure | Change from baseline score to follow-up measurement after 1 month | 
| Appetite-regulating hormones (measured with blood levels of ghrelin and leptin). | Efficacy measure | Change from baseline score to follow-up measurement after 1 month | 
| Immunoregulation and inflammation (measured with blood levels of macrophage migration inhibitory factor and interleukin 1 beta). | Efficacy measure | Change from baseline score to follow-up measurement after 1 month | 
| Cognition (measured with the Trail Making Test) | Efficacy measure | Change from baseline score to follow-up measurement after 1 month | 
| Physical activity (measured with a portable wristwatch). | Efficacy measure | Change from baseline score to follow-up measurement after 1 month | 
| Sleep quality (measured with 28-channel electroencephalography) | Efficacy measure | Change from baseline score to follow-up measurement after 1 month |