Schaub AC, Schneider E, Vazquez-Castellanos JF, et al. Clinical, gut microbial and neural effects of a probiotic add-on therapy in depressed patients: a randomized controlled trial. Transl Psychiatry. 2022;12(1):227.
Double-blind, randomized, controlled trial (RCT) of 4 weeks duration
To determine if the addition of a multistrain, high-dose probiotic combination, in addition to usual care, affects symptoms in those with major depressive disorder (MDD)
High-dose, multistrain probiotic combinations designed to target the microbiota-gut-brain axis ameliorated depressive symptoms when used as add-on therapy in those with depressive disorder.
Investigators recruited 60 patients with current depressive episodes; 47 finished the 4-week study (21 in the probiotic group; 26 in the placebo group). The high dropout rate of 30% is not unexpected when studying depressed individuals. Both the study participants and staff were blinded to who was in each group.
Initially, the intention was to recruit only patients with severe depression, but investigators relaxed this requirement to include mild depression (Hamilton Depression Rating Scale [HAM-D score] >7) to increase enrollment during recruitment. In the final analysis, participants in the trial who received probiotics had a mean HAM-D score of 18.93 (SD=4.78). (Typically, a cut-off score of 20 or greater is used when recruiting individuals for clinical trials of depression.1)
Patients were randomized into 2 groups and tested at 3 different time points: before, during, and then 4 weeks after a 4-week intervention.
Study Medication and Dosage
During the trial, all patients continued treatment as usual (TAU), which was composed of antidepressants and antipsychotics as indicated. In addition to TAU, patients took a specific probiotic supplement made in Switzerland under the brand name Vivomixx® (sold in the US as Visbiome). This supplement contains 8 different strains of bacteria that each contain 450 billion colony-forming units (CFU):
- Streptococcus thermophilus
- Bifidobacterium breve
- Bifidobacterium longum
- Bifidobacterium infantis
- Lactobacillus acidophilus NCIMB
- Lactobacillus plantarum
- Lactobacillus paracasei
- Lactobacillus delbrueckii subsp. Bulgaricus
Investigators instructed the participants to mix this powder into cold, noncarbonated drinks and take 900 billion CFU/day.
Participants in the control group received a placebo indistinguishable from the active intervention.
In the baseline assessment, patients completed a battery of tests consisting of demographics, clinical measures, brain imaging, and stool sampling. The primary outcome measure used in the study was the HAM-D, a standard measure of depression. Additionally, investigators used German versions of the Beck Depression Inventory (BDI), the Gastrointestinal Symptom Rating Scale (GSRS), and the State-Trait Anxiety Inventory 1 to assess self-reported depressive symptoms, gastrointestinal symptoms, and anxiety.
In addition, stool samples were collected and analyzed, allowing enterotyping, calculation of diversity measures, and the determination of bacterial taxa associated with clinical changes.
Participants underwent brain scans to assess structural brain changes due to probiotic intervention and also functional magnetic resonance imaging (fMRI) in order to examine emotional face processing.
Depressive symptoms decreased in all participants. These general improvements are likely due to the antidepressant treatments that they all received.
There was a significantly greater improvement in the subjects taking probiotics than in the placebo group. In addition, the composition of their intestinal flora changed, at least temporarily: In the probiotic group, an analysis of stool samples revealed an increase in lactic acid bacteria at the end of treatment, and the amount of this increase correlated with the degree of reduction in depressive symptoms.
Alpha-diversity measures showed no significant changes over time, neither in the probiotics group nor in the placebo. However, when investigators compared the 2 study groups at postintervention and follow-up, the probiotic group maintained diversity while the placebo group’s diversity was reduced in inversed Simpson, Pielou’s evenness, and Shannon index but not in observed richness.
Taking the probiotic did increase the presence of the genus Lactobacillus present in the intervention group. This increase in abundance of Lactobacillus showed an inverse association with the HAM-D and BDI scores of the participants. In contrast, Lactobacilli counts also showed a significant positive association with the GSRS, suggesting greater levels of gastric discomfort from taking high-dose probiotics. However, the GSRS decreased over time, suggesting that as the Lactobacillus population increased, gastric distress symptoms decreased.
Taking probiotics changed brain activity on fMRI. When patients are shown images of neutral or fearful faces, there is a discernable difference in depressed patients on fMRI. Probiotic treatment of the depressed people in this study normalized their scan results.
Treatment of depression is challenging. Only about a third of patients with major depressive disorders respond to initial drug treatment.2 A 2005 paper reported that about a fifth of the US population will suffer from depression in their lifetimes, and 29% from anxiety disorders; nearly half will fit the criteria of some disorder listed in the DSM-IV. These numbers increased over time, appearing to be higher in younger cohorts.3 Few people will argue that people have gotten happier or less anxious in recent years. Given how common a disorder depression is, there could be clinically significant advantages to improving efficacy of treatment, even minimally.
In recent years evidence has mounted that the gut microbiome affects brain function and depressive behaviors. A full decade has passed since John Cryan and Timothy Dinan first published their paper “suggest[ing] a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain.”4 In 2013 Foster and Neufield reported that “bacteria, including commensal, probiotic, and pathogenic bacteria, in the gastrointestinal (GI) tract can activate neural pathways and central nervous system (CNS) signaling systems.” And they suggested that “understanding the microbiota-gut-brain axis may provide novel approaches for prevention and treatment of mental illness, including anxiety and depression.”5
In 2014 Naseribafrouei et al reported that analysis of fecal samples from 55 individuals found potential correlations between fecal microbiota and depression.6
In a 2015 paper, Jiang et al comparing fecal samples from 46 patients with depression and 30 healthy controls, reported increased fecal bacteria in the depressed individuals.7 At that time, researchers were already aware that elevated hypothalamic-pituitary-adrenal (HPA) axis responses and depression in rats could be reversed by giving them Bifidobacterium infantis.8
Perhaps the regularity of exposure is the key to benefit more than dose intensity?
In animals, probiotics increase plasma tryptophan levels and reduce concentrations of serotonin in the frontal cortex and cortical dopamine metabolites; this appears to ameliorate depressive symptoms.9
Messaoudi et al reported in 2010 that a combination of Lactobacillus helveticus R0052 and Bifidobacterium longum given to rats or healthy humans reduced measures of psychological stress.10
In 2007 Benton et al found that consuming a yogurt drink for a 3-week period improved the mood of those who started off in poor mood.11
By 2015 Luna and Foster were explaining how dietary changes might impact the gut biome and change stress-related behaviors including anxiety and depression.12 In 2018 Lach and Schellekens, along with Cryan and Dinan, elaborated further on this gut-brain axis, providing greater detail on how the various gut peptides produced by bacteria impact brain function:
“It is important to understand the contribution of bidirectional interactions between peptide hormones released from the gut and intestinal bacteria in the context of this axis. Indeed, the gastrointestinal tract is the largest endocrine organ in mammals, secreting dozens of different signaling molecules, including peptides. Gut peptides in the systemic circulation can bind cognate receptors on immune cells and vagus nerve terminals thereby enabling indirect gut-brain communication. Gut peptide concentrations are not only modulated by enteric microbiota signals, but also vary according to the composition of the intestinal microbiota. In this review, we will discuss the gut microbiota as a regulator of anxiety and depression, and explore the role of gut-derived peptides as signaling molecules in microbiome-gut-brain communication. Here, we summarize the potential interactions of the microbiota with gut hormones and endocrine peptides, including neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, and ghrelin in microbiome-to-brain signaling. Together, gut peptides are important regulators of microbiota-gut-brain signaling in health and stress-related psychiatric illnesses.”12
Akkasheh’s 2016 paper may be the earliest RCT that assessed the effect of probiotics on major depression. Forty individuals diagnosed with major depression were randomly assigned to 2 groups. The intervention group took daily doses that totaled just 6 billion CFUs of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum. Eight weeks of treatment was associated with improvements in BDI scores.14
That same year, Huang’s meta-analysis, which compiled existing data on probiotic use, reported a nearly 30% reduction in symptoms in subjects diagnosed with major depressive disorder (MDD; mean difference = –0.73, 95% CI [–1.37 to 0.09], P=0.03).15
In recent years multiple reviews have discussed the role probiotics might play in treating depression: Ansari et al in 2020 and Chudzik et al in 2021 are among the most recent.16,17
Perhaps the most interesting aspect of the study reviewed here is the demonstration that fMRI changes in association with probiotic use. The fact that fMRI can “perceive” the shifts in recognition of emotions caused by depression may have first been reported by Cynthia Fu in 2007.18
The idea that probiotics might lessen the emotional alarm triggered by hostile facial images reminds me of an explanation I once offered patients to explain the benefits of probiotics. The explanation centered on the ability of Lactobacilli and other probiotics to convince the immune system to not see them as a threat. All those billions of probiotic bacteria must somehow in chemical unison chant a message that is heard as, “We’re your friend. We’re here to help.” Admittedly this is inappropriately anthropomorphic, and we are not supposed to impose human emotions and behavior on one-celled organisms. Yet, there is much talk of conservation of biological pathways in evolution these days, and perhaps it isn’t that great a stretch to theorize that some chemical signal that turns down threat alarms on a cellular level is still functional in far more complex organisms such as humans?
It is fascinating to contemplate how deep an effect probiotic therapy may have. Still, it is uncertain how we might translate these fMRI changes into clinical practice. Maybe, and this is a stretch, we might extrapolate and say that patients who are more sensitive to threatening faces may also respond more positively to probiotics. We could then assess such characteristics during our interviews. I admit that I’ve never used this reported symptom as a reason to advise probiotic treatment.
The Schaub paper under discussion in this review may be easily misinterpreted on first reading as it describes itself as: “the first randomized controlled trial to determine whether short-term, high-dose probiotic supplementation reduces depressive symptoms along with gut microbial and neural changes in depressed patients.”
Clearly there have been prior RCTs involving probiotics given to depressed patients. PubMed.gov offers a citation list of 68 human RCTs. Nor is Schaub’s current work unique in using brain imaging to monitor changes associated with probiotic use and comparing those shifts with changing depression scores. Pinto-Sanchez et al reported such findings in 2017.19
What appears unique to this trial is simply the use of a specific probiotic product line. Recall that the specific product used in this study supplies 900 billion CFU/day and contains multiple types of Lactobaccilli, in contrast to the 6 billion CFUs/day in Akkasheh’s study. Few competing products match this dosage, so the investigators’ claim may technically be true: “the first randomized controlled trial to determine whether short-term, high-dose probiotic supplementation reduces depressive symptoms” (bold underline added).
While the results of using this high-dose product were statistically significant, the study does not answer the key clinical questions we want to know: “Which strains work better?” and “Does high dose work better than low dose?”
Our reflex assumption that more is better does not always prove predictive for evaluating natural therapies, whose dose responses often exhibit the U-shaped curves of hormetic responses.
The product used in the study under discussion is expensive. It is available online for $180 for a 30-day supply at the dosage used in the trial. Before suggesting such an expenditure to a patient, many health practitioners would like confirmation that it is worth the cost.
Could eating yogurt work as well? Dunlap reported in 2009 that commercial yogurts contain between 4.8 billion and 95 billion CFUs per 100 mL,20 so an 8-ounce serving of yogurt may contain a dozen to circa 200 billion CFUs or a decent fraction of the colony yield used in the Schaub study. Yogurt could be well within the dose range used in the Akkasheh study.
Since as far back as 2017, Iranian researchers Mohammadi et al have been reporting that combinations of yogurt plus probiotic capsules and yogurt plus placebo capsules have measurable impact on mental health.21
One would assume that, like many other natural agents, probiotics will exhibit a hormesis effect, and response will change with dosing. It is easy to imagine that the body will regard/respond to high-dose supplementation differently than to lower doses. It’s conceivable that the body might see high doses as an invading organism rather than a benign bit of normal flora. Schaub’s findings may suggest that even these high doses are still within the range of effectiveness.
While the manufacturers of the specific product tested in this study may use these data to market their product, it remains unclear how best to use this information in clinical practice. Some practitioners may suggest to their depressed patients that they order this product and take it. Others may suggest that their patients eat a daily serving of yogurt. Until someone conducts a direct comparison of these competing interventions, we do not know which will be more effective.
Schaub et al make another noteworthy point:
“Notably, in our study probiotic effects were only significant in a subsample with high compliance and accentuated in the follow-up after eight weeks, indicating a remission rate of 55% in the probiotics group compared to a 40% remission rate in the placebo group. The importance of compliance during probiotic supplementation should be highlighted and is as important as in general antidepressant therapy.”
In other words, patients need to take the probiotic very regularly, and they will not see immediate benefit. Even then, this intervention only increases the chance of remission by 15%. Perhaps the regularity of exposure is the key to benefit more than dose intensity?
In recent years the explanation for probiotic action has shifted. A growing body of literature reveals that probiotics need not be viable to provide benefit, so our long-held image that live endogenous bacteria take up habitation in the human gut and then provide benefit may be inaccurate.22 According to Piqué et al, “Heat-treated probiotic cells, cell-free supernatants, and purified key components are able to confer beneficial effects, mainly immunomodulatory effects, protection against enteropathogens, and maintenance of intestinal barrier integrity.”23 Actual colony-forming units ingested may not be the determinant of effectiveness. Instead, the concentration of specific chemical messengers that are delivered may be what is important, along with regularity of exposure.