Psychology and Neuroscience of Affective Disorders - Week 3 Lecture PDF

Module: Psychology and Neuroscience of Affective Disorders Week 3: Biological alterations of affective disorders Topic 1: The role of the gut microbiota in affective disorders (Part 4 of 4) Lecture transcript Viktoriya Nikolova, PhD student Department: Centre for Affective Disorders, Academic Psy...

Module: Psychology and Neuroscience of Affective Disorders Week 3: Biological alterations of affective disorders Topic 1: The role of the gut microbiota in affective disorders (Part 4 of 4) Lecture transcript Viktoriya Nikolova, PhD student Department: Centre for Affective Disorders, Academic Psychiatry Slide 4 In this last part, we will discuss some of the main types of microbiota targeted interventions for mental health. One of the most obvious ways to intervene is to just improve our overall diet or add in some more foods containing beneficial bacteria such as fermented foods, for example, as diet is one of the most significant factors that have had the human gut microbiota structure and function. Slide 5 According to the latest dietary recommendations for the prevention of depression as well as some other psychiatric disorders, a healthier and more varied diet, which means one that is reach in fruit, vegetables, and grains with a reduced intake of sugar, salt, and saturated fats and also rich in omega-3 fatty acids is the most beneficial to health. However, to get all of these nutrients, people would need one well rounded diet on an ongoing basis. So this would mean that there's no super foods or magic supplements that are going to guarantee positive mental health by themselves. And similarly, many studies have found that diets rich in ultra processed foods increase the risk of depression. However, there is one problem with dietary © King’s College London 2022 1 interventions outside the context of clinical trials and programmes, and that's just that people don't really stick to them. And not just in psychiatry, even people with life threatening conditions such as multiple heart attacks, people are still resistant to permanently changing their diet and lifestyle, despite there being a very clear rationale and direction for this. And in psychiatry, of course, other than the building of the evidence base for this, there are also additional challenges such as lack of motivation or interest, which are inherent features of depression. As I mentioned earlier, depression is a feature of multiple psychiatric conditions and is frequently comorbid with others, which can make sticking to a particular long-term dietary plan very difficult. Slide 6 So instead, we could also try to promote good health with the use of supplements. There's many different kinds, there's probiotics, prebiotics, synbiotics, etc. And what is the difference exactly between these supplements? Slide 7 The formal definition of probiotics is food supplements that contain only good, beneficial bacteria that when ingested in sufficient quantities, can infer a beneficial effect on our bodies. This can be done either by improving intestinal microbial balance, so gut microbial balance or by further downstream functions of gut bacteria that we previously discussed. As part of the definition, it's also mentioned that these are generally considered to be safe, so issues like intolerance, toxicity or side effects are generally not applicable. And these are usually, the probiotics I mean, are usually composed of bacteria that are already resident in our digestive systems. And here are some examples of probiotic rich food. So for example, cheeses, sauerkraut, generally pickled foods, ginger, and so on. Slide 8 And what is the difference with prebiotics? Prebiotics are also ingredients we can find in food. However, prebiotic is actually another name for fibre, particularly non-digestible fibre that induces the production or activity of beneficial bacteria, so of probiotics. They provide essentially the food that is needed for probiotics to thrive on. And this is fibre that our bodies without this bacteria cannot digest, and therefore we can't get the further downstream beneficial benefits from them. So prebiotics can be found in cocoa, onion, garlic, cabbage, and bananas, but specifically the green phase of bananas. However, there are very few clinical trials using prebiotics to date, and the results from these have not been very convincing in mood disorders. So we won't be focusing on them much today. Slide 9 A few more useful definitions. There's also synbiotics, which are a mixture of probiotic and prebiotic in the same supplement, really. And there are also psychobiotics, which is a term that was coined in recent years and essentially means supplements, so probiotics, synbiotics, and so on, that when taken in sufficient quantity, can yield positive psychiatric effects. And this term was coined by John Cryan and Ted Dinan, who wrote a very interesting similar book © King’s College London 2022 2 called The Psychobiotic Revolution, which I highly recommend for you to read if you want really an easy, fascinating, and more in-depth read into this topic. Slide 10 And before we proceed onto discussing the existing clinical trial evidence of probiotic in mood disorders, there's one thing I wanted to mention. And this is that, even though this whole topic has become a hot topic in psychiatry in recent years, the concept of modulating gut bacteria with probiotics to impact mood is by no means new. In fact, probiotics existed in more or less the same form that we know them today since the early 20th century. Some of the first scientific evidence for their use in psychiatry came from the Bethlehem Royal Hospital in London, which has always had a strong link with the Institute of Psychiatry, Psychology in Neuroscience at King's. What was found then in a series of inpatient case studies was that probiotics and specifically different types of lactobacillus improved clinical outcomes in patients with psychiatric conditions. Slide 11 This wasn't just limited case studies. This actually grew quite a bit into a large scale commercial marketing campaign of probiotic supplements throughout the '20s and '30s. If you look in the reference list, you'll find a link to actual newspaper adverts from The New York Times from the 1930s offering probiotic enriched milk to feel brighter and to improve your mood and health as well. The reason this approach was abandoned in the 1930s was that there wasn't sufficient understanding of the underlying mechanisms behind this approach, and doubt crept in. Basically, people started questioning whether it's worth spending their money for this. And this was the case until recently. So what is different now that we didn't have before are the advanced microbiology sequencing technologies which have allowed us to look inside the human microbiota and fill this gap in understanding. Slide 12 Several studies have examined the potential of probiotics to alleviate mood, anxiety, and stress in healthy people. There is people without mental health diagnosis giving rise to the term psychobiotics. So for example, a research group headed by Messaoudi et al, demonstrated in a double-blind, placebo controlled study that a combination of lactobacillus and bifidobacterium supplements reduced depressive and anxiety symptoms. Two other studies, one in healthy volunteers and one in patients with chronic fatigue syndrome, demonstrated a consumption of different kinds of lactobacillus also lead to improvements in self-rated mood as well as in clinical measures of depression and anxiety. And there's other studies that have used multispecies probiotics, so that is probiotics with more than two or three different bacteria types, have reported a significant reduction in cognitive activity to depressive thoughts or to sad mood and significant improvement in people suffering from stress and exhaustion. And finally, there are also neuroimaging studies showing that there are brain related changes following probiotic consumption, particularly in brain regions where we process emotions. © King’s College London 2022 3 Slide 13 And one last thing before we turn to the clinical trials of probiotics for effective disorders. I just wanted to remind you of the clinical trial pipeline that you may already be aware of, typical medication development process. What we have is a number of years where we're doing laboratory studies until we identify a compound with therapeutic potential and tested in cell culture or animal studies. And only then can we proceed to the human phase of trials. In Phase I studies, this is where you determine the safety of a drug just on a few people, generally healthy volunteers. After that, you have Phase II, where we study the drug, especially its efficacy and safety, into a larger number of people. Generally, this is in the hundreds. And then in Phase III, we include thousands of people and look more thoroughly for effectiveness in more representative groups of people. And these phases can take anywhere up to 10 years. And then there's also the bus marketing phase, where we can continue setting the drug after it's already widely available and approved. So probiotics and similar foods or supplements or vitamins often skip this entire regulatory procedure because they are considered to be harmless. And while this can sound good as it brings beneficial things to patients faster, it is also a pitfall because if you don't go through this thorough process, you cannot gather the high quality data that is necessary to back up your health claims that probiotics, for example, work in depression. This can increase this doubt that, again, we had in the 1920s and '30s, that they don't really work. They can follow the faith of the numerous supplements you can find in any supermarket where you're making the choice every time of, is this really worth my money? Does it do anything? Slide 14 Now to the clinical studies, this slide shows a systematic review and meta-analysis of 34 controlled clinical trials of probiotics or probiotics in depression and anxiety. And what was found was that probiotics, as I mentioned earlier, didn't really differ from placebo on their effects on anxiety and depression symptoms. However, probiotics on the other hand, yielded small but significant effects on depression and anxiety. And when we looked further, deeper into this, what we see is that probiotic effects grow larger when they are given to clinical communities rather than healthy people who are experiencing just some symptoms of depression. Slide 15 We performed the similar meta-analysis in 2021. But what we wanted to do is look more specifically in these clinical populations, where the effects of probiotics are more pronounced and see what there's any differences there or anything more than we can learn. So this slide is showing you the studies that were available in 2021, and these were seven studies in people with clinical depression. You can generally see that these are very small studies under 100 people in each, and they're otherwise quite similar in terms of methodology. So the probiotics were administered for generally eight weeks, with the exception of one study, they gave it just for six weeks. They generally contain Lactobacillus, Bifidobacterium, and a couple of studies had multi strain probiotics. Importantly, five of these studies were administering the probiotics in addition to the patient's ongoing antidepressant, and only two studies administered to medication free participants. © King’s College London 2022 4 Slide 16 What we found in our meta analysis was that all the studies they use probiotics, in addition to an antidepressant, showed a positive effect of probiotics on depressive symptoms with a very good effect size, whereas the two studies so these are lower down in the graph, they used probiotics as a standalone treatment, showed a non significant effect on symptoms. As you can see, the diamond there is crossing the line of no effect. And again, even though this can only be considered as preliminary evidence due to the small number of studies and sample sizes, this top panel where antidepressants and probiotics are used together is quite promising in showing us the probiotics can be really beneficial in this population. However, what we don't know is why do they only work as auto medication? You might want to have a think about that a bit further and consider what the possible explanations might be. And if you're interested, you can have a look at this publication of ours from suggested reading list. Slide 17 And again to put all of this evidence in context, what do we know about the effects of probiotics in other disorders outside of affective disorders, or even further into the effective disorder spectrum? This is another systematic review, which is also recent since 2019, which examined a number of psychiatric conditions, and what they found was that much like we did, probiotics seemed to offer some benefit in major depressive disorder and also interestingly, in Alzheimer's disease. However, they only found one study in bipolar disorder, which showed that particularly in the manic state, probiotics can reduce hospitalisation and rehospitalisation rates. However, it seems that in autism spectrum disorders and schizophrenia, the evidence is quite controversial and limited. So far we can't say the probiotics offer any benefits there at all. Slide 18 And now let's talk about one last type of intervention, which often sparks much interest the faecal microbiota transplants that I mentioned earlier. So this microbiota transplant approach is generally designed to restore healthy microorganisms via donors tools to people that may need it. So in terms of clinical practice, it's most often used for the treatment of Clostridium difficile or C difficile infection, or in some bowel diseases. However, of course, for mood disorders, the first studies to test this approach were done in animals. So one of these studies is very nicely called "Transferring the blues." What this research group did is they transplanted microbiota through a faecal microbiota transplant from patients with major depressive disorder to germ free mice. And surprisingly, what they found was that this transplant induced both the behavioural and physiological profile resembling depression in these animals, whereas transplant from healthy controls did not. That is, the mice exhibited depression like behaviours, as measured according to the most commonly used tasks in this area of research that is animal models of depression, such as the four swim test, open field test, elevated plus maze tests and so on, which you can see more about in this paper, which will be in the reference list. But I also found elevations of certain biomarkers of depression, meaning that the physiological profile of depression was also reflected in these animals. © King’s College London 2022 5 Slide 19 And this study has since been replicated independently by another research group elsewhere, as well as in conditions like schizophrenia, autism spectrum disorder and eating disorders as well. So what all these fascinating studies show us is that this balanced microbiota is not just a symptom or consequence of psychiatric conditions, but it can also be a cause. And it also suggests that we need to apply caution when transplanting healthy microbiota, or what we consider to be healthy microbiota in patients with, for example, bowel diseases because the microbiota can carry a footprint of our mental illness as well. Slide 20 And even though the evidence from faecal microbiota transplant studies in animals are quite promising, its applications in people with affective disorders are still limited. There are three examples of such case studies on the slide. One is by Hinton from 2020 which was a case report looking at the effects of faecal microbiota transplantation in bipolar disorder patient. Another is by Parker et al who also looked at bipolar disorder in 2022, so a very recent paper. And finally the third paper is by Doll et al who looked at faecal microbiota transplantation as an add on therapy for depression. As you can imagine, this intervention is typically done through an invasive procedure which can be quite unpleasant for patients who may prefer any other treatment alternative instead. Therefore, we need to build a serious, scientific, rational and evidence based, and this needs to be strong enough for patients to want to take this treatment. Nevertheless, this is actually turning into quite the business. There are multiple clinics, especially across the US, who offer this treatment and this type of transplant privately for many things other than what is commonly used for, including for depression. Slide 21 Having said that, this area is starting to grow and shift from case studies into clinical trials. The slide show the results of a recent search in a clinical trial register for faecal microbiota transplant trials for effective disorders. At the moment, it seems that there are three studies that are recruiting for a larger trial. A couple to have an unknown such as and a few that have been terminated, most likely due to lack of uptake from patients. So basically what this means is watch this space, as a result from these trials should come in in the near future. Slide 22 And just to give you a brief summary of this lecture and a few take home messages, I think that what you've seen in this lecture is how important systems beyond the brain are for mental health. So what we really need to do in the treatment of psychiatric illness is have a more integrated approach to prevention, management and treatment, and that I hope that you have seen that the good microbiota is a promising therapeutic target and among the interventions that we covered, the one that shows most promise so far are probiotics, and this is the case for several psychiatric symptoms and disorders, but so far, most so for depression. © King’s College London 2022 6 Slide 23 Thank you for listening, I hope you enjoy this lecture and if you have any questions or would like to discuss anything further, please contact me on my email, that's [email protected]. © King’s College London 2022 7