depression: add-on probiotics helps

 Another article just came out suggesting a significant clinical role for the gut microbiota/brain interaction, this time for depression and anxiety. This small study found benefit in adding probiotics as adjunctive treatment for patients with insufficient response to antidepressant meds (see depression probiotics jamapsych2023 in dropbox, or doi:10.1001/jamapsychiatry.2023.1817) 

 

Details:

-- 49 patients with moderate major depressive disorder (MDD) on antidepressants but having incomplete response to the meds were randomized to probiotics versus placebo in this UK study, between 2019-2022.

-- Patients were 18 to 55 years old, were taking an approved antidepressant at a stable dose for at least six weeks, and did not have bipolar disorder, psychosis, eating disorders, personality disorders, substance dependence, suicidal ideation, serious medical illnesses, were taking gastrointestinal medications, smoked, were pregnant or breast-feeding, or were on a vegan diet

-- Median age 32, 80% female, BMI 24, 92% were on SSRIs/only 3 people were on SNRIs (all 3 were in the probiotic group)

    -- as a small study, the distribution of those randomized to probiotics versus placebo did not match perfectly: all seven Asian patients were in the probiotic group, 20 versus 13 white people were in the placebo group; BMI was 26 in the placebo group and 23 in the probiotic group; the duration of probiotics was 59 weeks in the probiotic group and 34 in the placebo group

    -- baseline clinical scores:

        -- Hamilton Depression Rating Scale (HAMD-17): 17 (moderate depression)

        -- Inventory of Depressive Symptomatology (IDS): 37 (moderate depression)

        -- Hamilton Anxiety Reading Scale (HAMA): 16 (mild anxiety)

        -- General Anxiety Disorder (GAD-7):11 (moderate anxiety)

-- Probiotics included 8 billion colony forming units per day, consisting of four variants of Bifidobacteria, eight of Lactobacillus, as well as Bacillus subtilis, and Streptococcus thermophilus

-- main outcomes: retention, acceptability, and tolerability of probiotics and placebo; effect of probiotics added to antidepressant medications on clinical symptoms:

    -- assessed for depression: HAMD-17 and IDS

    -- assessed for anxiety: HAMA) and GAD-7

-- of note, this was considered a small pilot study , and these scores which are used as indicators for a definitive trial

 

Results:

-- three people in the placebo group versus one on probiotics dropped out of the study

-- adherence rates were 97%

-- psychological testing scores:

 

 

 

-- they also assessed the patients'Clinical Global Impression Improvement subscale (CGI-I), finding:

 

 

adverse effects: no serious adverse reactions and no dropouts owing to adverse effects. Nausea and indigestion were experienced only in the probiotic group but were transient and did not require medications. No difference in gastrointestinal symptoms scores

 

Commentary:

-- roughly 60% of people with major depressive disorder have some degree of nonresponse to first-line treatments, and one third continue to experience symptoms despite further treatment

-- in a 2021 meta-analysis of seven randomized controlled trials with 404 patients, these same authors found that probiotics seemed to be effective in reducing depressive symptoms when added to antidepressants. they did not find that probiotics by themselves were beneficial (https://www.mdpi.com/2077-0383/10/4/647 )

-- a small 2022 study also found that probiotics added on to meds decreased depressive symptoms. These patients also underwent functional brain MRIs, had a 6-minute task evaluating emotional face processing including neutral and fearful faces, and found that putamen activation in response to neutral faces was significantly decreased after the probiotics (https://www.nature.com/articles/s41398-022-01977-z )

    -- “the putamen is involved in learning and motor control, including speech articulation, language functions, reward, cognitive functioning, and addiction”, per https://www.ncbi.nlm.nih.gov/books/NBK542170/#:~:text=The%20putamen%20is%20involved%20in,%2C%20cognitive%20functioning%2C%20and%20addiction.

    -- so, this study found that depressed patients on probiotics had more appropriate neural responses to people with "neutral" faces (ie no activation of the putamen) vs people with fearful faces.

 

-- In this current pilot study they found that those patients in the probiotic arm experienced on average a reduction of one severity grade on both of the depression rating scales, and that anxiety-somatic symptoms may have been particularly improved by the probiotics

-- the probiotics were well tolerated with a low attrition rate, high adherence rate, and no serious adverse reactions

 

-- these trials do support in concept that changes in the gut microbiota are associated with neurologic/psych effects, reflecting the importance of the gut-brain axis.

    -- There used to be arguments in the medical community about the frequently held mind/body dichotomy, that if we could not explain a clinical problem by assessing the body, then perhaps the issue was with the mind. Our evolving understanding of the gut/brain axis adds physiologic as well as clinical evidence that the mind/body dichotomy really does not make any sense (and, in reality, never did…..): medical conditions do not neatly fit into the mind or the body as binary categories, but typically reflect a bidirectional interaction

 

Limitations:

-- this was a small, pilot study, and results cannot be generalized without a larger confirmatory study

-- almost all the patients were on SSRIs, limiting generalizability of these results to other medical treatments

-- there was no evaluation of nonmedical therapies found to be effective (eg psychotherapy), or the combination with medical therapy, limiting generalizability to patients on these proven interventions

-- medication adherence was documented by medication capsule counts and may not be completely accurate

-- there were many exclusions in the people accepted into this study, which might limit the overall generalizability of the results to the broader population (ie, the patients we see....)

 

So, these trials do support in concept that changes in the gut microbiota are associated with neurologic/psych effects, reflecting the importance of the gut-brain axis, as elaborated in the prior blog (http://gmodestmedblogs.blogspot.com/2023/07/gastroparesis-high-placebonocebo.html ).

 

A few other comments:

-- Of course, further studies are necessary before we should include probiotics as a major part of our treatment of depression or anxiety

-- There are many unanswered questions about the probiotics. For example, which specific microbial species should be involved in the probiotics, including both the combinations that work best as well as the dosages? Does the effect on depression/anxiety last (there did seem to be decreased improvement by probiotics at the 8-week vs 4-week assessment in this pilot study)?  We clearly need more long-term data on clinical efficacy of these probiotics

-- what about other interventions that improve the microbiota? For example, we know that exercise improves mood. And exercise does improve the health of the microbiome. same with a healthy diet. It would be useful to have studies on diet and exercise to assess changes in both the microbiome composition and clinical outcomes in those with depression/anxiety

 

geoff

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