StemCell Therapy

At the British Neuroscience Association (BNA)s Festival of Neuroscience in April 2019, we were lucky enough to sit down with some influential neuroscientists to discuss their work. Weve assembled these transcripts into our BNA Interview Series. Here, in our final interview of the series, we talk to Professor Ed Bullmore, who splits his time between academic research at the University of Cambridge and industry research with GSK. Professor Bullmore was at the conference outlining some of the evidence that connects inflammation and depression, and the possibility that the immune system could be targeted as part of future antidepressant treatments.Ruairi Mackenzie (RM): Could you outline the link between inflammation and depression?

Ed Bullmore (EB):Well I think the first thing to say is that inflammation and depression go together, so they co-occur; theyre correlated with each other. That, I would say, is beyond reasonable doubt. You can look at two kinds of evidence for that association. You can look at people who have an inflamed body, who have a major medical inflammatory disorder like arthritis or psoriasis or inflammatory bowel disease and ask the question, is that associated with an increased risk of depression? And it is, very robustly. You can also go to people who have depression but dont have an obvious medical inflammatory disease, you can take a blood test and you can measure the inflammatory state of the immune system in a more sensitive way and you can show a very consistent trend and people have shown this over multiple years and multiple studies that on average, people with depression have slightly but significantly increased levels of inflammatory proteins in circulation compared to healthy controls. So, those two bits of evidence I think put it beyond reasonable doubt that there is an association. The question then is about causation. What drives that association and what is the evidence that inflammation and depression are not just kind of going together but one is driving the other, particularly inflammation driving depression.RM: Whatisthe evidence that inflammation is the driving factor behind depression?

EB:There is a lot of evidence from animal studies. If you make an animal inflamed, you will change its behavior so that it looks as if it might be depressed. You can change their social behavior, their interaction with other animals, they are less likely to drink sweetened water, more likely to drink plain water as if they have lost the capacity for pleasure. There are various other sleep and behavioral changes that you can see in animals that look depressed but perhaps the most convincing evidence comes from studies in humans and one thing that you would predict, if inflammation caused depression, then you might expect to find examples of inflammation preceding or anticipating depression because cause precedes effect. If you look, there is evidence for that too.So if you look at long term follow up studies, epidemiological studies, it has been shown that if you are inflamed but not depressed at one point in time then over follow up you are more likely to be depressed than the people that were not inflamed originally. So theres that kind of evidence. You can see in patients, for example, that have got hepatitis, a viral infection of the liver, if you give them an inflammatory treatment to cure their hepatitis, about a third of them will become depressed.RM: Really? Thats really fascinating, that last piece of evidence. Do you see that over time that if their inflammation goes away for whatever reason, they are less likely to become depressed?

EB:Im not sure that thats been so certainly studied, but what I think is pretty clear is that inflammation can precede depression and that, I would say, is a necessary condition for inflammation to be causal.RM: Depression is an immensely complex condition so different risk factors will have different contributions. Are there any firm numbers on what is the significance of this contribution to depression versus other factors?

EB:Well I think its very important, as your questions is suggesting, were not talking about inflammation explaining every case or experience of depression, but based on blood test measurements, it looks like about a third of people with major depressive disorder might also be inflamed and then you think about all the people with so-called comorbid depression, people with arthritis, inflammatory bowel disease. In rheumatoid arthritis, for example, about 25% of those patients are significantly depressed. So, its quite a big chunk of people. Its not everybody, but its a lot of people, I think.RM: Rheumatoid arthritis and some other conditions which involve chronic inflammation, they dont just impact our bodies but also our social lives. It might make it harder for people to leave the house and socialize with friends and obviously social isolation is also a risk factor of depression. Are there studies or have there been observations made that isolate the two?

EB:No, is the short answer. I mean, I think particularly depression, fatigue and other psychological symptoms have been woefully under investigated, in my opinion, in arthritis and other medical conditions. We need to do much more. The traditional explanation is more what you might call a sociological explanation. Youre depressed because youre thinking about arthritis, because of the impact that it has on your life. It might make it more difficult for you to interact with friends, you may feel gloomy about what the future holds. Are you going to end up in a wheelchair? How is it going to impact on your mobility in the long term? Thats the traditional explanation, and I wouldnt claim that those psychological mechanisms are not at all relevant to the link between depression, arthritis or other inflammatory diseases but I think its important that we allow the possibility that there could be other explanations. There could be a more direct mechanistic link between the autoimmune disease, the inflammatory disease and the body in these patients and their altered mental state.RM: Have there been studies into immunocompromised populations; are they less likely to become depressed?

EB:Its an interesting idea. No, Im not aware that there have been studies looking at immunodeficiencies. I would say there is an opportunity for a lot more work to be done at the interface between mind and body, particularly in what you might traditionally regard as non-psychiatric disorders, and that could include immunodeficiency syndromes as well as autoimmune disorders like arthritis.RM: Are these inflammatory effects isolated to just depression or are there other conditions that are associated?

EB:I think the existing evidence is strongest for depression but if you delve into the literature there is quite a strong story about psychosis in some cases, psychosis being associated with a different kind of abnormality of the immune system. There is a small percentage of patients with a first episode of psychosis who have high levels of autoantibodies. Antibodies that are directed against the bodys own proteins, particularly the glutamate receptor. The anti-NMDA antibody is associated with psychosis and thats an interesting story that people are exploring. I think the other area where there is a lot of interest is neurodegeneration, Alzheimers disease, for example. People are increasingly interested in the idea that when the plaques and tangles of amyloid and tau protein form in the brain, maybe the immune system sees those abnormal proteins as if they were germs, as if they were antigens, and that stimulates an immune response, an inflammatory reaction in the brain which could be damaging to nerve cells and could contribute to neuronal loss and psychological deterioration. So, a lot of companies are interested, I think, in developing new anti-inflammatory treatments to arrest the rate of progression in neurodegenerative disorders.RM: Do these studies look at immune populations specifically within the brain or in the rest of the body as well?

EB:Well its much, much easier to look at the immune system in the rest of the body than the brain. You can get a pretty good read on the immune system from a blood sample but that doesnt tell you anything about the microglial (immune cells resident within the brain) status, for example. I think its one of the key challenges for the field is to develop better biomarkers of brain inflammation. We have very limited options now. You can take a cerebrospinal fluid (CSF) sample and you can measure inflammatory proteins and a few immune cells in a CSF sample but a lot of patients with depression arent going to go along with that. What else have we got? Well you can use various imaging techniques, structural MRI, functional MRI. There are changes in those markers associated with altered levels of peripheral inflammation but the signal itself is not very specific to the immune system. The most promising approach I think, is going to be developments using positron emotional tomography (PET) where you can get a tracer into the blood that will bind to a specific target in the brain and there has been quite a lot of work looking at PET markers that allegedly are specific to microglial activation which have shown increases in Alzheimers disease and also in depression. If you talk to people in the field, I think everybody agrees that the existing PET traces of brain inflammation are better than nothing, but theyre not as specific or sensitive as we want them to be. So I think thats an area where I will hope to see progress over the next few years, is development of better neuroimaging tools for central inflammation.RM: Thinking about the next few years, as a final question, what do you think the future of depression treatment looks like?

EB:Well, what I really hope is that we get away from this idea that depression is just one thing, that everybody is depressed for the same reason and that one day there will be a panacea. That there will be a drug or a psychological intervention thats going to make everybody happy, cure depression for everybody. I think thats been the mindset for a lot of drug development in the past and I think we need to move on from that. Psychiatry, I hope, will catch up with the rest of medicine. The rest of medicine doesnt treat symptoms as if they are all the same, the rest of medicine looks for the causes of symptoms and it tries to treat those causes. So my hope for the future of depression is that we will get to a place where we are beginning to identify causes, we are beginning to get cleverer about identifying which patients are depressed for which particular reason and more precisely targeting treatments to the individuals most likely to respond because their depression is caused by some factor that is responsive to the treatment in question. That kind of more personalized, precise approach is, I hope, where we will get to.RM: Will this strategy involve just pharmacological interventions or also other therapies?

EB: Absolutely, I think thats a very important point. You know, as you have mentioned I work also at GSK and come at this really from the point of view of wondering whether, by focusing on the immune system, could we find the next generation of antidepressant drugs, but the science of neuroimmunology, the interaction between the brain and the immune system, I dont think means that the treatments have to be pharmacological. I think there is a lot of interest in vagal nerve stimulation as a treatment for depression. We know that vagal nerve stimulation often has anti-inflammatory effects. There is a little bit of work in the literature there could be more showing that, for example, meditation has anti-inflammatory effects and so there are a lot of ways in which the immune system could be dampened down or controlled. Diet is another obvious example a lot of inflammation might have its origin in the microbiome could you be effective with a dietary regime change that might alter the microbiome, make it less provocative to the immune system? I think these are all hopes for the future.

Professor Ed Bullmore was speaking to Ruairi J Mackenzie, Science Writer for Technology Networks. Interviews have been edited for length and clarity.

Excerpt from:
BNA Interview Series: Exploring the Inflamed Mind With Professor Ed Bullmore - Technology Networks

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