Note: today’s blog is very much a group effort. It’s been written by a dozen people from the Centre for Affective Disorders (CfAD) at King’s College London where I led a workshop yesterday introducing them to blogging and social media. We critically appraised this study together and look forward to hearing your feedback. Thanks to everyone from CfAD who joined in yesterday and especially to Becci Strawbridge and Caroline Loveland for making it happen.
Do let me know if you want me to come and run an introduction to blogging and social media at your University. You’ll learn a lot and it’s great fun!
There has been a surge of interest linking diet and mental health recently and some of this research has been covered on the Mental Elf. The blog last month from Murtada Alsaif on diet and depression is the most recent example, and today we’re highlighting a new systematic review on probiotics for depression.
It’s well known that major depressive disorder is a mental health problem that will affect up to 20% of the population at some point in their lifetime. It’s characterised by low mood, loss of interest, feelings of guilt, hopelessness, and changes in appetite and sleep.
The gut-brain axis is much less commonly discussed outside of the scientific community. In simple terms it can be described as a two-way street between the brain and the gut (Foster et al, 2013). A considerable amount of high quality basic science research has been carried out that supports the existence of the gut-brain axis, but to date scientists have struggled to translate this lab-based work into interventions that can be applied in real-world settings.
Probiotics are live microorganisms that are administered as dietary supplements or as food products, such as yoghurt. Experimentally, several probiotic bacteria have been tested for health benefits (Foster et al, 2013).
So, we were excited to read about a new systematic review of probiotics for depression that looks to bring together all of the high quality randomised controlled trials in the field and provide a definitive summary of the best current evidence (Wallace & Milev, 2017).
It’s worth noting that both reviewers have received research funding from Lallemand Health Solutions (who specialise in the production and marketing of probiotic for human use) although they state that the funder did not contribute to any part of the research or writing of this article.
Fact or folklore? Scientists first discovered the anxiety-reducing effect of probiotics on ostriches.
Methods
The authors set out to systematically review the literature on depressive symptoms and probiotics. They used the standard PRISMA method for selecting studies and the quality of included clinical trials was assessed using the Jadad Scale.
They searched Medline, PsycINFO, Embase, CINAHL and Web of Science. They report the keywords used for their search included depression, mood disorder, emotions, probiotics, lactobacillus, bifidobacterium and gut-brain axis, but we could not find a full description of their actual search strategy either in the article or in an online data supplement.
Their search found 566 unique studies, which were screened by one of the authors down to 136 trials (excluding those that were irrelevant or not in the English language). Two authors then independently screened the remaining full-text articles and resolved any disagreements between themselves as to which were eligible.
The final review included 10 randomised controlled trials (7 of which were double-blind), but we found it hard to piece together the included studies and their characteristics because only 6 of them seem to have been included in the table of studies (table 1 in the open access paper). We didn’t have time to download and read the 10 RCTs!
No meta-analysis was conducted in this review, which makes sense because the included studies are very different and could not be pooled reliably.
Results
So, do probiotics improve depressed mood? The short answer is, we can’t tell from this evidence.
The studies reviewed were small, and examined a wide variety of different people (those with clinical depression, those with self-reported depressive symptoms and others):
- One study included patients with clinical depression (confirmed by using the Beck Depression Inventory) and this trial did find a clear effect of probiotic use on depressed mood (Akkasheh et al, 2016)
- 4 studies looked at depressive symptoms (not clinically diagnosed depression)
- 2 of these found no change in depressive symptoms
- 1 found that depression scores were reduced in only those with the highest initial scores
- 1 found a clear effect of probiotic use on depressive symptoms
Seven out of the 10 included studies also looked at symptoms of anxiety, which weren’t the focus of this review:
- 5 reported some positive effects of probiotics, but again most of these participants did not have a confirmed anxiety disorder, just self-reported symptoms.
The longest probiotic trial (6 months – Gruenwald et al, 2002) investigated participants who were suffering from stress and exhaustion, using a multi-vitamin probiotic compound, and reported generalised improvements particularly surrounding stress levels and gastrointestinal difficulties that were one of the strongest findings within this review.
Additionally, three studies looked at some isolated tests of thinking skills or responses; one found no effect at all and the others observed improvements in some measures of cognition.
Some studies have shown that taking probiotics could help in improving symptoms of depression or anxiety, but others have shown no difference.
Conclusion
Despite this range of findings, the authors’ discussion and conclusion of their research is targeted primarily at depression. They describe the trials included in their review as “robust” and conclude that:
The evidence for probiotics alleviating depressive symptoms is compelling but additional double-blind randomized control trials in clinical populations are warranted to further assess efficacy.
Further research is certainly warranted before any firm conclusions can be drawn. We strongly disagree that these findings are robust and compelling. Here’s why…
Limitations
- The findings reported in this paper are (at best) mixed, with only 10 heterogeneous studies included, we cannot be sure of probiotics’ precise effects on mood when the included research has such a diverse population of patients and interventions.
- The tests of mood are mainly self-reported by study participants rather than objectively measured by researchers or doctors blinded to the treatment that was received. This makes any improvements measured by the trials much more open to bias.
- There are many different dietary compounds (in and outside the category of probiotics) and we really can’t tell which work better than others, how these microbiota interact with other dietary compounds and (importantly) antidepressant medication. There is reasonably robust basic science showing a link between probiotics and mood, but we are not aware of any compelling evidence in humans in a clinical setting. If it does exist, it’s certainly not been included in this review.
- A lack of detail on the literature search means that it’s hard to tell from the paper how systematic and reliable the search actually was. Clearly it’s vital that any systematic review finds all of the primary research in the field. It looks like no checking of reference lists was done and no contacting of authors to find other studies (published or unpublished). The fairly insensitive search strategy, unclear date limit of search and English language limit also make us nervous that not all of the trials of probiotics for depression were included in this review. We conducted a very quick PubMed search ((systematic [sb]) AND (probiotics and depression)) and found two other recent systematic reviews on this topic:
- Pirbaglou et al, 2016: which found 10 RCTs (4 in clinically diagnosed and 6 in non-clinical samples), 7 of which were not included in the Wallace & Milev study
- Huang et al, 2016: which found 5 RCTs (all on clinical cohorts), 4 of which were not included in the Wallace & Milev study
- There are a number of errors in the Wallace & Milev paper, which make it difficult to appraise. Not all of the studies included in the review (n=10) appear in the table of included studies (n=6). Some of the citation numbers are incorrect, so following up the reference lists is quite tricky.
Summary
Our feeling is that this review has made unfounded claims relating to the evidence about probiotics for depression, suggesting that the primary research is “robust” and the results of this review are “compelling”. Sure, the reviewers acknowledge that further research is needed, but they start their conclusion with this statement: “The evidence for probiotics alleviating depressive symptoms is compelling”. In this world of soundbites and tweets, it’s dangerous to publish misleading and unfounded headlines, because many people just read the headline and then head off to the yoghurt aisle in their local supermarket!
There is definitely promise for these bacteria in treating mood disorders, but the translation of basic science into a real-world setting is likely to take some time, and may not result in safe and effective treatments. At present, we just don’t know if probiotics can help reduce depression, so don’t go putting all of your ostrich eggs in one yoghurt pot quite yet.
There are lots of effective therapies for depression. It’s not yet time to add probiotics to the list.
Links
Primary paper
Wallace CJ, Milev R. (2017) The effects of probiotics on depressive symptoms in humans: a systematic review. Ann Gen Psychiatry. 2017 Feb 20;16:14. doi: 10.1186/s12991-017-0138-2. eCollection 2017
Other references
Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M, et al. (2016) Clinical and metabolic response to probiotic administration in patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial. Nutrition. 2016;32(3):315–20. [PubMed abstract]
Foster JA, Neufeld KAM. (2013) Gut–brain axis: how the microbiome influences anxiety and depression (PDF). Trends Neurosci. 2013;36(5):305–12.
Gruenwald J, Graubaum HJ, Harde A. (2002) Effect of a probiotic multivitamin compound on stress and exhaustion. Adv Ther. 2002;19(3):141–50. [PubMed abstract]
Huang R, Wang K, Hu J. (2016) Effect of Probiotics on Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. 2016 Aug 6;8(8). pii: E483. doi: 10.3390/nu8080483.
Pirbaglou M, Katz J, de Souza RJ, Stearns JC, Motamed M, Ritvo P. (2016) Probiotic supplementation can positively affect anxiety and depressive symptoms: a systematic review of randomized controlled trials. Nutr Res. 2016 Sep;36(9):889-98. doi: 10.1016/j.nutres.2016.06.009. Epub 2016 Jun 21. Review. [PubMed abstract]
Hello all,
Thank you for this detailed and well thought-out critical appraisal of our paper. I’d like to start out by taking the time to address some of the issues raised:
First, the issue of the incomplete table: this was an error of the production team during publication, and NOT of the authors. An erratum was published shortly after, publishing the full table of 10 articles. This can be found if you simply search the title of the article with ‘erratum’.
Second, Huang and Pirbaglou’s systematic reviews, which are of high quality, were published just weeks before we submitted our final manuscript and while ideally all studies up until publication date would be included, due to the peer review process, this is sometimes unfortunately impossible. I do appreciate the concern with the shortfall of detail on the literature search itself. Several articles included in those systematic reviews were not included in ours due to publication dates (our literature search was up until June 2016) or differing criteria. Our review was aimed at looking at the effect of a probiotic supplement or diet supplemented in probiotic-containing food/drink on symptoms of depression in samples generalizable to the general population or clinical samples of depression or related mental health issues (i.e. not petrochemical workers exclusively). My apologies if this was unclear.
Finally, we describe these findings as robust and compelling, because over half of of the studies assessed did indeed find improvements in the symptoms of depression we were assessing. I disagree that we have made unfounded claims and published misleading information and “unfounded headlines”.
I do agree with you however – and as we stated clearly in the article – that there is still a distinct dearth of evidence in clinical populations that needs to be filled in order to make evidence-based claim that probiotics could help alleviate symptoms associated with depression. Our conclusions in this review were based on results that we find very promising in a field where the research is relatively new and sparing.
I hope this has helped clarify some of the issues your critical appraisal has brought forward and perhaps provoke some more thought and discussion with your members and readers.
Hi Caroline,
Thanks so much for your reply, we really appreciate the dialogue.
It must have been frustrating for the journal not to publish all of the tables in the original paper; I’ll be interested to look at the erratum.
I am interested in the differential effects on depression and anxiety – it seems as though the clinical evidence is slightly stronger for anxiety symptoms than depression. Did you focus more on depression because of a greater theoretical basis in the animal literature (I have to admit I’m not too familiar with the preclinical evidence base)?
We agree that the lack of evidence so far is quite surprising. It seems like much more investigation is now starting to be done so hopefully we’ll know more soon. We noticed that your team have received research funding from Lallemand Health Solutions and were wondering whether you are running studies yourself in this area?
Superb, useful critique of this paper. Just what you need. Thanks.
[…] Probiotics for depression: robust and compelling evidence? […]
very helpful work, thanks