Gut Feeling: Understanding the Mechanisms Underlying the Antidepressant Properties of Probiotics

Study Overview
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Brief Summary
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Previous research has suggested that probiotics can improve depressive symptoms in patients with Major Depressive Disorder (MDD), particularly when used in addition to antidepressants. The aim of this exploratory pilot study is to improve the investigator's understanding of the mechanisms underlying these effects. This study will assess the effects of an 8-week double-blind placebo-controlled probiotic intervention on the gut microbiome, inflammatory marker levels, brain activity and neurotransmitter levels in patients with MDD and their relationship to changes in mood. This study will also recruit a group of demographically-matched healthy controls for gut microbiome comparison with the MDD group (non-interventional).

Official Title
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Gut Feeling: Understanding the Mechanisms Underlying the Antidepressant Properties of Probiotics

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Dietary Supplement: Multi-strain probiotic
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria for MDD participants: aged 18-55; currently in a depressive episode according to DSM-5 criteria, who are currently on antidepressant treatment but remain symptomatic (HAM-D17 score >13); on stable treatment regimen of an approved treatment for at least 6 weeks; non-smokers; for participants willing to take part in the neuroimaging component: right-handed, no contraindications, non-claustrophobic, weight <126kg; Exclusion criteria for MDD participants: eating disorder, bipolar disorder, schizophrenia or psychotic symptoms; substance dependence in the past year, except for caffeine; active suicidal ideation; use of probiotic supplements in the past 2 weeks, or regular use of a probiotic; use of antibiotics in the past 12 weeks; history of allergic reaction to any of the components of BioKult; history of history of a systemic medical illness; current presence of significant GI problems or disease or history of major GI surgery; pregnancy or breastfeeding; following a dietary regimen unrepresentative of the general population (e.g. fasting or following a specific diet); regular/current use of antacids, proton pump inhibitors, laxatives, antidiarrheals; Inclusion criteria for Healthy Volunteers: Aged 18-55; No current or historic presence of depression, other psychiatric disorder or substance dependence No history of a systemic medical illness; No family history of psychiatric disorder; Non-smoker; Not used probiotic supplements in the past 2 weeks, nor regular use of a probiotic; Not used antibiotics in the past 12 weeks; No current presence of gastrointestinal disease, or history of major GI surgery; No reported regular/current use of antacids, proton pump inhibitors, laxatives, antidiarrheals; pregnancy or breastfeeding; not currently following a dietary regimen or dietary restrictions unrepresentative of the general population (e.g. fasting or following a specific diet);

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multi-strain probiotic BioKult<br>4 capsules daily for 8 weeks | Dietary Supplement: Multi-strain probiotic<br>* The intervention in this study is a multi-strain probiotic which contains: Bacillus subtilis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus delbrueckii ssp. bulgaricus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus helveticus, Lactobacillus salivarius, Lactococcus lactis ssp. lactis, Streptococcus thermophilus. Each capsule contains minimum 2 billion live microorganisms per capsule, equivalent to 10 billion live microorganisms per gram.<br>* Other names: BioKult;|
| Placebo Comparator: Placebo<br>4 capsules daily for 8 weeks | Other: Placebo<br>* Visually identical capsules in identical packaging containing no active bacteria.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| gut microbiota in MDD | species diversity and abundance at the level of organisational taxonomic units (OTUs) will be measured with 16S ribosomal RNA (rRNA) sequencing | baseline | 
| differences in gut microbiota between MDD and healthy volunteers | species diversity and abundance at the level of OTUs will be measured with 16SrRNA-based sequencing and compared between the two groups | baseline | 
| gut microbiota changes in MDD following probiotic intervention and their correlation to change in depressive symptoms | species diversity and abundance at the level of OTUs will be measured with 16SrRNA-based sequencing and depressive symptoms will be measured with the Inventory of Depressive Symptomatology Self-Report (IDS-SR) and the Hamilton Depression Rating Scale (HAM-D17) | change from baseline to week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurotransmitters | levels of glutamate and gamma-aminobutyric acid (GABA) will be measured with Magnetic Resonance Imaging (MRS) | change from baseline to week 8 | 
| Blood | levels of tumor necrosis factor (TNF-a), interleukins IL-1β, IL-6, IL-17, and C-reactive protein (CRP) will be measured | change from baseline to week 8 | 
| Brain activity | measured with functional magnetic resonance imaging (fMRI) | change from baseline to week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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probiotic, depression, microbiome, bacteria