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JAMA Psychiatry recently published the results of a small randomized clinical trial evaluating the use of probiotics as an adjunctive treatment for inadequately controlled depression. Set in London, 50 outpatients with a primary diagnosis of major depressive disorder (MDD) and a Hamilton Depression Rating Scale (HAMD-17) score greater than 13 (indicating at least mild depression) were randomized to either a probiotic or matching placebo, with all study participants on a stable antidepressant dose, and a primary outcome of a change in depressive scores after 8 weeks. The probiotic contained 14 species, primarily Lactobacillus and Bifidobacterium, as well as Streptococcus thermophilus.
In the two groups baseline depression was moderate, with a HAMD-17 score of 16.5 and 17.3 in the probiotic and placebo group, respectively. The vast majority (92%) of participants were taking a selective serotonin-reuptake inhibitor (SSRI), 6% were taking a serotonin–norepinephrine reuptake inhibitor (SNRI), and 2% had an unspecified medication. Adherence was high, with over 97% of participants taking all required doses.
By week 4, both groups had improvements in their HAMD-17 scores, with a significantly greater reduction in the group receiving the probiotic (a standardized effect size of 0.7). This is considered a moderate effect of probiotics, roughly equivalent to a reduction of one severity grade on depression rating scales. Additionally, scales assessing anxiety (including a 9-item Anxiety/Arousal Inventory of Depressive Symptomatology subscale) showed significant improvement with probiotic supplementation.
This supports the findings of two meta-analyses recently published, one in the Journal of Clinical Medicine and the second in Therapeutic Advances in Psychopharmacology, both by the same authors. These two analyses come to the same conclusion, which is that probiotic supplementation appears to significantly improve symptoms of depression, but only in studies in which it is given as an add-on to existing medication therapy.
It should be noted that only 7 studies are included in these meta-analyses, with just over 400 total participants and a range of dosages, types of probiotics, methodology, etc., and none lasted longer than 8 weeks. Only two of these studies directly assessed stand-alone probiotic therapy (including a total of 150 participants), and these two studies have specific limitations. For instance, in one of the two stand-alone studies, the placebo group was observed to have a significant improvement in depressive symptoms. This raises the possibility that the study was underpowered to detect a difference given such a large placebo response. Additionally, though no differences were observed in overall symptom reduction between groups, there was a significant difference between groups; the probiotic group was found to have a reduction in a measure of vulnerability to depression (cognitive reactivity towards sad mood) in those with mild/moderate depression, suggesting a longer or larger trial might provide more insight (a very small triple-blinded study also found this same effect on cognitive reactivity). In the only other stand-alone trial, a high percentage of participants in the probiotic group (70%) reported prior antidepressant usage, versus only 46% in the placebo group, potentially including more people with treatment-resistant depression, and possibly biasing this study against probiotic efficacy.
Thus, while there is a growing evidence base supporting the use of probiotics as an adjunctive therapy for depression, there is a paucity of studies evaluating stand-alone use, with larger and longer studies called for, as well as a range of probiotic strains and dosages.
Many mechanisms have been suggested to explain the potential benefit of probiotics on mood, with and without adjunctive medication. For example, most antidepressants have antimicrobial activity, and while it is not clear if this is related to a possible mechanism of action or simply an unintended consequence, it’s plausible that probiotics may augment the resultant microbial changes or compensate for the loss of beneficial species. It has also been suggested that specific classes of antidepressant medications have limited efficacy for specific subtypes of depression, such as SSRIs and SNRIs for anxious depression, and that probiotics may provide an additive therapeutic effect for these subtypes.
There is now a considerable body of evidence in both experimental models and humans that the gut microbiome, via the microbiota-gut-brain axis (MGB), modulates mood and contributes to depression. In one of the most detailed reviews published to date in Frontiers in Neuroscience, many of the mechanisms are well-detailed, including communication via the vagus nerve and modulation of the host immune system, as well as microbial production of the many small molecules which have neuroactive effects, such as short-chain fatty acids. The MGB may be modulated by an overabundance of species that produce inflammatory compounds, or a reduced abundance of microbial synthetic capacity may have its own consequences. For instance, in a large Flemish cohort of over 1000 participants, the abundance of butyrate-producing bacteria was associated with greater quality of life, as was the production of a dopamine metabolite (3,4-dihydroxyphenylacetic acid) and a short-chain fatty acid (isovaleric acid). Many neurotransmitters have been found to be synthesized by specific probiotic species, including dopamine, gamma-aminobutyric acid (GABA), serotonin, acetylcholine, etc., with many connections between intestinal barrier permeability, microbiota composition, as well as exposure to stressors. While much complexity remains, this review concludes that “probiotics have shown clinical efficacy in the treatment of depression by modulating the MGB axis” and suggests they may have particular efficacy for certain depression subtypes.
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