Background: Adolescent depression is a public health crisis, with rates having increased significantly in recent years, and 20.1% of teens diagnosed with depression in 2021. Depression during this key developmental period places the adolescent at a 2-3 fold higher risk of developing adult depression, alongside numerous social impairments, illnesses and comorbidities. Current treatments for depression, such as Selective Serotonin Reuptake Inhibitors (SSRIs), have shown limited success in achieving clinical remission and are often hindered by undesirable side-effects. In recent years, the gut-brain axis has emerged as a potential mechanism that influences both the brain and behavior via biochemical signaling between the nervous system and the enteric nervous system, highlighting the potential benefit of probiotic treatments as a novel therapeutic approach. Importantly, no studies have examined the effects of probiotics on adolescent depression, and limited research exist on its impact on the adolescent gut-brain axis. However, studies have found gut microbiota differences in adolescents with high stress and emotional problems, such as decreased Bifidobacterium and imbalances in Firmicutes, Bacteroides, and other bacteria, suggesting a connection between the gut microbiome and adolescent mental health. Several studies suggest that higher levels of Lactobacillus and Bifidobacterium, bacteria commonly found in many probiotics, may help protect against adult depression. In our pilot randomized controlled trial (RCT) among adults >18 years,  administration of multi-strain probiotic Visbiome^® had a large effect on the left hippocampus-precuneus resting state functional connectivity (HP RSFC), increase in Lactobacillus (a protective bacteria), and improved depression scores.
Objectives: The objectives of the study are to examine: (1) changes in left HP RSFC in depressed adolescents after an 8-week probiotic trial, (2) how the gut microbiome composition and structure are modified by the treatment, and (3) the associations between microbiome changes and left HP RSFC.
Methods: This is a double-blind, placebo-controlled randomized clinical trial to assess the effects of the administration of multi-strain probiotic Visbiome^® 450 billion CFU twice daily and placebo twice daily for 8-weeks in adolescents (15-24 years old) with a clinically diagnosed DSM-5 depressive disorder. We will recruit 77 participants, with the aim of enrolling 3-4 participants per month. We expect a 25% dropout rate (n=19). Participants will be recruited through flyers posted in public places, online communication methods by the study team, and confirmed community outreach partners like emails/listservs, social media ads, etc. Interested participants will be screened via online surveys, telephone calls, and video meetings. Enrolled participants will self-collect stool samples for gut microbiome analysis (alpha diversity, beta diversity, abundance of strains, etc.) and undergo two functional MRIs for left HP RSFC measurement pre- and post-intervention. Participants will additionally be sent electronic questionnaires, including the Beck Depression Inventory-II (BDI-II) for the measurement of depressive symptoms. We will use linear mixed models to test for the increase in left HP RSFC. We will utilize generalized linear mixed models to test for differences in beta diversity, alpha diversity, representation of functional genes, and relative abundance. Lastly, we will use linear mixed models to test the relationships between the gut microbiome and left HP RSFC.
Results: The study received IRB approval in January 2025, and recruitment is expected to start in February 2025 and complete by February 2027. Clinicaltrials.gov registration is pending.
Conclusions: The goals of the study are to determine any significant changes in the gut microbiome and left HP RSFC following an 8-week administration of Visbiome^®. This study is not a fully-powered efficacy trial. If changes in one of these outcome measures are significant, future trials will assess dose-response and efficacy. The findings from this study will expand the range of treatment options available in clinical practice and inform healthcare providers on the use of probiotics for treating adolescent depression.
Keywords: probiotic; depression; adolescent; mental health; gut microbiome; gut-brain axis; brain.