Ed Bullmore on 'Inflamed Depression' - The Anne Silk Lecture 2019

my name is Colin Blakemore I'm here to welcome you to the seventh and Silke lecture which is going to be given this year by Edie bull more ed is a fellow of the Academy of Medical Sciences of the Royal College of Psychiatrists and a fellow of the Royal College of Physicians the and silk lecture is an annual lecture which is sponsored by the silk charitable trust it's co-organized by the Royal Society of Medicine and the British neuroscience Association and it's given it ultimately at the RSM in London and these festivals of of neuroscience the overarching theme of the and silk lectures is progress in neuroscience across the whole range of effort from fundamental research right through to translational and clinical research we're especially grateful to doctor and silk herself who's the founder of the Charitable Trusts for sponsoring these these public lectures this year's answer lecture will be given by ed bolt ed Bill Moore he's professor of psychiatry at Cambridge and also he's a vice president of experimental medicine at GSK Glaxo Smith SmithKline he studied medicine at Christchurch in Oxford and finished his his clinical training at Bart's in London he taught for a year he he taught for a year in Hong Kong and then trained for his specialization in psychiatry in in in London he then did a PhD at King's College in London working in the then emerging field of magnetic resonance imaging of the brain and his international reputation is is largely built on his his computational approach to the analysis of MRI and the network connectivity which can be revealed through MRI and the time analysis of signals from the brain he's been professor of psychiatry at Cambridge since 1999 join GSK in 2005 his commitment clinically has been to the the understanding of mental health disorders particularly from the from a from a biological perspective I want to know it once you can know how the the the brain is responsible for mental conditions and in his very recent public book which I really recommend you should look at the the inflamed mind it's it's a wonderful read the describes is an interesting personal conversion almost a kind of paulien moment in his career in which his interpretation of the origin of mental disorders has changed really quite radically and that's what he's going to talk to us about tonight I presume since the the title of his lecture is inflamed depression ed boomer well good evening Thank You Colin for that introduction it's a real honor to be invited to give the end silk lecture and thank you all for turning out on this evening to hear me talk about depression as you have heard I work half time for GSK and half time for GlaxoSmithKline which is of course a pharmaceutical company and these are my full disclosures just for transparency but my story really starts when I started training as a psychiatrist and that was around about 1989 1990 and I found myself at this place which is the Maudsley hospital in South London which at that time certainly we were taught and I understood it to be the epicenter of British psychiatry the place where anybody who wanted to be anybody in British psychiatry should go for their for their training and it is a wonderful place in terms of the research and educational culture and there I am you know about 30 years ago looking quite pleased with myself in the slightly grotty surroundings of the Mosley Hospital and one of the things that taught me more than anything else while I was there was an interview I had with a patient who came to see me in the outpatient clinic I'd probably been a psychiatrist or training psychiatrist for not much more than a year and this man late thirties early forties came in and he said you know I'm feeling bad I can't concentrate my work performance has dropped off I looked at the future I can't see anything worth living for I looked into the past and I just found a lot of memories I feel guilty about my appetites not what it was have lost a bit of weight I can't remember when I last had sex and sometimes I'm wondering if life's really worth living and I looked at him and in what I hoped was a wise way I said you know what I think he might be depressed and he was very unimpressed by that remark he said look I know I'm depressed that's the reason I'm here I asked my GP to refer me because I knew I was depressed the question is what are you going to do about it and as it all Elena it's a great time for treatment of depression a lot of excitement whether there's new drugs for example prozac you might have heard of serotonin boosting drugs just been released we're very excited about them and we believe that if you have those drugs it might sort of fix this chemical imbalance in your brain that abnormal levels of serotonin might be causing your symptoms and he looked at me sharpen he said well how do you know that and I began to kind of regurgitate the stuff I'd just been reading about from the textbooks the Sira tonin theory of depression and so on and he said know what how do you know that about me how do you know the levels of serotonin in my brain are unbalanced and we looked at each other and I think for a moment both recognized that I had no answer to that question in fact I had no clue how to find an answer for that question but having peered into the abyss of my ignorance we politely found other things to talk about and after a while he left the clinic with a prescription for Prozac or some other serotonin boosting drug but he left me feeling a bit of a fraud he left me feeling like one of these guys the sort of eighteenth-century physicians so mercilessly satirized by Malia who by their erudite palpation of the pulse were able to diagnose these subtle disturbances of humors circulating in the body the black bar the collar and so on often as a prelude to some rather unpleasant treatment he left me feeling like a bit of a quack if I'm honest now if we jump forward 30 years and look at where we are in terms of the treatment of depression one of the startling things is that nothing much has changed the drug treatment of depression the mainstay is still the kind of drugs that I was talking about in the monsley outpatient clinic back in 1990 these drugs boost levels in the synapse in the communication channel between nerve cells webserie tone in adrenaline and noradrenaline work as neurotransmitters all of these drugs are supposed to increase transmission between nerve cells by boosting the levels of those molecules and I don't mean to be nihilistic it's not like these drugs are utterly useless they do work moderately well on average and you can see that quite clearly in this chart and this is the result of a meta-analysis in other words an accumulated analysis of all the clinical trial data on antidepressant drugs that were available at the time and just to orientate you because you'll be seeing a few of these kind of charts generally speaking those vertical line indicates no difference between a drug the active drug and a placebo and each of these little blue squares indicates the difference in terms of antidepressant efficacy of one of a number of antidepressant drugs shown here on the left now if these drugs didn't work then these little blue boxes and the horizontal lines that run through them would intersect this vertical line indicating that there was no significant difference between antidepressant drug treatment and placebo and as you can see hopefully from the back of the hole actually all of these drugs are by this measure looks significantly different from placebo but we still have a lot of questions we still don't have a very good answer to the question that patient asked me back in 1990 how do we know in any particular patient that there are abnormal levels of these neurotransmitters we don't partly for that reason we're not very good at predicting who's going to respond and who's not going to respond to these treatments and we know that about at least a third of patients will not respond very well to these drugs there's been very little therapeutic progress if there had been therapeutic progress you might expect that this drug right at the top which is farthest away from a vertical line of no effect would be the newest but in fact it's amitriptyline as some of you may know that's the one of the oldest antidepressants it's been out there since the early 1960s so not much progress and yet depression is far from cured it's still very common if you look at the top 20 causes of medical disability around the world the pressure is consistently in the top one or two or three in fact some people think that in coming years depression is on track to become the single biggest medical cause of disability worldwide so very high levels of them that need not very much therapeutic innovation you might think that was a big driver to invest to find new treatments but in fact the industry has retracted withdrawn from the area and this came home to me very sharply in 2010 when I and a number of other GSK colleagues were called to a teleconference with some urgency and I heard my boss at the time announced that with immediate effect we were out of psychiatry we're going to close two big research sites one in Italy one in England dozens of projects were going to be terminated hundreds of jobs were going to be made redundant it was a complete wipe out of psychiatry and a few weeks after that I went back to my boss a little bit plaintively and I said I know it's not all about me but forgive me I'm having a moment of existential crisis I'm a psychiatrist working for a company that doesn't seem to want to do psychiatry anymore can you tell me is there any hope would we ever go back and do drug development for depression again and he said well I you know I'd never say never but if we were going to do drug development the depression again it would have to be completely different to the way we did in the past because we know that that was not working that we were putting in hundred hundreds of millions of pounds into R&D we were not finding any great new treatments so tell me come back and tell me how we could do it differently and that really got me thinking it got me thinking about an area of psychiatry that others have heard about but hadn't paid too much attention to up until that point the idea that the immune system might have something to do with mood and other mental states and the first time I heard that idea I thought it was a bit nuts but as I hope to persuade you over the next 40 minutes or so there is actually some pretty good reasons why that might be a line of enquiry worth pursuing further but before I go there let me just say a little bit about the immune system what is it what does it do well one of the things the immune system does probably it's single biggest purpose is it keeps us alive in a world full of hostile agents out to get us it's a crucial part of our survival package and particularly in the old days and here you can see in the old days a couple of cavemen having a fight in an era way before hospitals and hygiene and antibiotics and one of them has been injured a spear has pierced his hand and a few days later his hand has changed it's become swollen reddened it's tender it's painful it's not as useful to him as it used to be it's lost its normal function those are the classical clinical signs of inflammation and inflammation is one of the things that the immune system does particularly as a first in response to defend us against infection now what is driving those kind of obvious clinical signs of inflammation is actually a very complex pattern of molecular and cellular events that we can see microscopically and I've shown this here very schematically here's the here's the spear coated with these sort of unpleasant looking bacteria so it's a an infectious trauma penetrating the skin and the first line of response is these cells I've drawn them as like kind of pac-man motifs but they're designed to represent macrophages a Greek word meaning big eating cells and that's what they do they're big cells when they eat bacteria they digest them they destroy them and that is one way that they cope with the threat of infection but they also produce these inflammatory proteins or hormones if you will the technical word for the missed cytokines they come out of the metrof ages they get into the blood and they circulate throughout the body stimulating other macrophages elsewhere to come to the site of infection to reinforce the first-line response now there's an awful lot of detail that I'm not including this diagram but the key thing to get out of this slide is that although inflammation might look local the swelling and the tenderness and the pain might be restricted to the hand in fact the inflammatory response is generally systemic it generally involves the whole body to some extent and certainly the whole immune system and the immune system is you know one of the things I think people can find difficult about it is first of all this question its location you know the nervous system is we know at least that 90 something percent of it is in one place in the head in the brain but the immune system is much more distributed it's in the spleen it's in the bone marrow it's in the thymus gland it's in the lymph nodes it's everywhere and it has to be everywhere because threats to our survival can come from anywhere so the macrophages that I talked about sitting in the hand they're also present in but in the in the gums around the teeth everywhere in the in the body which might be exposed to infection the front line of the self if you will is manned by these Centurion like cells sitting quietly for the most part waiting for infection and then mobilizing a response but the macrophages alone signal through command and control centers like the spleen and the lymph nodes they communicate with other immune cells like lymphocytes and encourage the lymphocytes for example to produce antibodies that circulate back through the blood and can help the macrophages deal with the infection or whatever the local threat to the self happens to be so the key thing is it is a system it's a complex system it's highly integrated its adaptive it learns it has a memory it also has an inbuilt or innate capacity to detect threat it's a crucial part of the reason why we're all here that we've all survived is the vigilance of the immune system now what's that got to do with depression well I would dare to say that all of us have had first or second hand experience of an association between depression and inflammation I first really recognized this about a year before I started the Maudsley before I started as a psychiatrist I was still training as a physician and I saw a lady like this a caller mrs. P who came to a medical outpatient clinic because she had problems with her hands swollen tender joints in other hands it's like muscle wasting some disfigurement of her hands and other joints and I spent a bit of time talking to her about these and other symptoms and signs of rheumatoid arthritis and it was all pretty clear-cut diagnostically and then perhaps because I was already thinking I might be a psychiatrist rather than the physician I started asking her about her state of mind and in language very similar to the words that I'd later hear from the man I met at honestly she told me that she was lacking in energy she really struggled to get going in the morning it was very difficult for her to concentrate on things she felt like a brain was in a fog she was pessimistic about what the future might hold in short she was depressed and I thought that I've made a bit of a diagnostic discovery I rushed to tell the consultant in charge I said you know mrs. P she's not got just got rheumatoid arthritis she's also depressed and this man looked at me and said depressed well you would be wouldn't you and with that we changed the subject and talked about something else and mrs. P left the clinic as depressed as she had been when she arrived with no suggestion about how to make her mental state improve now that simple expression well you would be wouldn't you to my mind now speaks to quite a complex set of assumptions about many things in medicine you could for example go back to the days of Descartes oops a bigger puddle before going back to the days of Descartes let me just make the point that this lady or mrs. P her experience is not that unusual it's not that uncommon depressive symptoms are very commonly associated with medical inflammatory disorders these are data from clinical trials done by GSK and Janssen in patients with arthritis inflammatory bowel disease psoriasis and so on and what you see here is that in these patients about 10 to 30 percent of them have significant depressive symptoms particularly patients with rheumatoid arthritis indeed you can show that the incidence of depressive symptoms in these medical inflammatory disorders is positively correlated with levels of an inflammatory protein called CRP or C reactive protein that we can measure in the blood so there's a very strong association when you look in inflammatory disease these patients very often have depression and fatigue anxiety and other psychological symptoms it's not unusual but we don't really look in that direction very acutely in ordinary medical practice we tend to say well you would be wouldn't here and as I mentioned earlier I think that covers quite a complex set of assumptions you could say it goes back to the work of Descartes who in the early 17th century formulated this idea of dualism the split between a body that exists in the physical world Abbes the laws of physics is mathematically tractable experimentally knowable on the one hand and on the other hand the mind or as they can't called it the soul which in every way is as different from the physical world as it's possible to be it's immaterial it's insubstantial it is in some way connected to God rather than the physical materiality of the world we are each a deus ex machina in Descartes famous phrase and that although it might not be explicitly regarded as a part of the medical education is a an assumption that is still very prevalent in medicine still has a lot to do with how medical training is organized how medical services are provided and so on so maybe when the consultant said to me well you would be wouldn't you he was drawing on his deep knowledge of early enlightenment philosophy or maybe like me he thought it must be the case that mrs. P was depressed because you would be because if you knew that your future held in all probability the prospect of increasing disability you would rationally reflect on that and psychologically conclude that the outlook was gloomy that is the conventional explanation the alternative explanation could be that the inflammatory process in her body was more directly driving the changes in her mind but we couldn't really allow ourselves to think that in the late 1980s or early 1990s because as I was taught at medical school the brain was immune privileged it was kept completely apart from the immune system in the body by something called the blood-brain barrier which was conceived to be a bit like the Berlin Wall in the brain it was a impermeable barrier which made it impossible for immune cells and proteins circulating in the blood to get across from the blood into the brain and have any effect either on the kind of transmitters like serotonin that we thought were important for depression or the larger scale organization of the brain the the networks that link areas such as the cingulate and the amygdala to form large scale circuits that are important for mood mood regulation and mood disorders when we saw mrs. P in 1990 the Berlin Wall in the brain was securely in place and the idea that the immune disorder in her body could have propagated through the blood-brain barrier and had any effect on any of this microscopic or macroscopic circuitry that might ultimately explain her mood was inconceivable what if you look not so much at people who have inflammatory disorder and ask are they depressed but turn the question the other way around and look at people who are depressed and ask do they have any evidence of inflammation and if you do that experiment and people began to do this in about 1990 if you just take blood from patients with depression healthy controls you measure inflammatory proteins and compare the difference between them you can see that over time over the last 25 years people have done that experiment over and over again very consistent evidence has emerged and again I'm showing you Metro analytic results so you're looking for the these little horizontal lines should be clearly apart from this vertical line here in the middle if there was no difference between depressed people and healthy controls in these levels of cytokines the horizontal lines would cut the vertical line but you can see that as the evidence is accumulated it's become clear that there are indeed modest but highly significant little increases in inflammatory proteins cytokines and c-reactive protein shown here in patients with depression so we have evidence both from looking at arthritis and depression and from looking at depression and inflammatory markers like CRP and interleukin 6 or cytokine the depression and inflammation are associated with each other and I think that is beyond reasonable doubt I think we have to accept that as a fact that there is an association to be explained the question then becomes how do we explain it and in particular what's the evidence that this association could be causally explained that inflammation might be directly driving a depression now there's a lot of evidence for that argument from animal experiments as people may know if you make an animal inflamed it very immediately changes its behavior in ways that make it look as if it might be depressed its social behavior changes its eating behavior changes sleeping behavior changes if it's less inclined to prefer sweet fluid over plain water as if it had lost its normal pleasure-seeking capacity to prefer sweetened liquid so there is a lot of animal evidence in favor of causality but what about the human evidence now obviously there are many things that we can do with animal experiments that we simply can't in humans but one simple way of beginning to get a causality is to look at events unfolding in time causes precede effects so if inflammation caused depression we'd expect to find examples of inflammation preceding or anticipating depression and this little bar chart here is showing you one I think quite striking example of that temporal precedence these are data from a birth cohort that was set up several years ago in Bristol and southwest England so everybody born in a particular year was recruited into the study and then followed up year after year longitudinally over time at the age of nine a blood sample was taken from these children and tested for levels of aisle six an inflammatory cytokine nine years later when the kids were 18 19 years old they were assessed for depression and what the bar chart is showing is that the level of aisle 6 at the age of nine it was quite a strong predictor of the risk of depression at the age of 18 if you were a child whose levels of cytokines were in the bottom third of the distribution at the age of nine he's got a significantly reduced risk of depression compared to a child whose levels of cytokine were in the top third of the distribution age nine so that is inflammation preceding depression over the span of about nine years and you can see other examples of the same sequence if you have a vaccination I had a vaccination a couple of years ago I went to the clinic the nurse said I'm going to give you the shot you might think about taking tomorrow off work because you're not gonna feel so great I said why she said well it's just the body's way of getting used to things so not a very good explanation but it was quite an accurate prediction I didn't feel so great the next day I'd been inflamed by the vaccination my mood changed subsequently another example hepatitis nasty viral infection of the liver one of the first effective treatments was to give people a shot of the cytokine to make them more inflamed so the immune system would be as it were motivated to hunt down and kill the virus and the liver it worked quite well of hepatitis but one unexpected and unintended consequence was about six weeks later up to a third of those patients were significantly depressed they've not been depressed before that they became depressed after they've been exposed to an inflammatory shock-like interferon so that I would say satisfies a necessary condition for causality that inflammation precedes depression but it's not clearly sufficient we need a more detailed mechanistic step-by-step understanding of how inflammation in the body could cause something to change in the mind and as I mentioned earlier that mechanistic pathway was blocked historically by the impermeability of the blood-brain barrier but just as the Berlin Wall has come down since 1989 so in the same period roughly speaking not the same reason the blood-brain barrier we now understand to be much more permeable than we did 30 years ago we now know that there are many channels of communication in fact between the peripheral immune system in the blood and the brain there are many ways in which inflammatory proteins and indeed inflammatory cells can get across the blood-brain barrier or signal inflammatory states across the blood-brain barrier and once those peripheral inflammatory signals have made it into the brain they can activate the brains own immune cells the macrophages or microglia that sit in the brain can be stimulated by a peripheral inflammatory signal to release their own cytokines and we know again mainly from animal experiments that nerve cells exposed to high levels of these inflammatory proteins often change their function in a disadvantageous way makes nerve cells more likely to die it changes their synaptic plasticity it changes their metabolism of transmitters like serotonin so there is a mechanistic sequence that we can see more clearly in animals than in humans still but there is a sequence of events that is conceivable whereby peripheral inflammation signals across the blood-brain barrier changes central inflammatory cell activity microbial activity which in turn changes neuronal function which could alter large-scale circuits and lead to changes in mood states that is conceivable what's the evidence for that in humans well we've known for a long time in fact this goes back to Darwin that our ways of expressing emotion or rather stereotyped and it's correspondingly quite easy to detect emotion in the faces of other people and if you look at these faces happy sad fearful faces we know that that tends to induce in you are the same kind of emotional state as represented in the face we also know that if you look at those faces while you're lying in an fMRI scanner the simply looking at a sad face for example will tend to increase the amount of activity the functional activation of areas the brain like the cingulate and the amygdala that are important for emotional processing and mood disorders and this basis a colleague of mine Neil Harrison did an interesting experiment he said ok we'll will scan people while they're looking at these emotional faces but we'll do it twice once after they've had a typhoid vaccination and once after they've had a placebo injection and as I've mentioned a typhoid vaccination makes you inflamed that's the point it arouses the immune system and what they showed in this experiment was that the people that had had the time for vaccination they became a bit more depressed the levels of inflammatory protein were increased in their circulation but crucially the people that became more depressed also showed greater changes in this brain region a part of the emotional brain circuitry and indeed the connectivity the functional connectivity between cingulate amygdala and other components of the emotional brain Network was significantly correlated with the increase in inflammatory proteins induced by vaccination in this experiment so it's an example of how we can begin to unpick step by step how a peripheral inflammatory change can cause changes in brain function and in turn changes in mood and if you followed the argument so far I've claimed that it's beyond reasonable doubt that inflammation and depression are associated with each other that we that that relationship satisfies a necessary condition for causality which is that inflammation can precede depression and that there is emerging evidence from animal and human studies for a mechanistic sequence of events that could explain our inflammation might cause depression but you might then ask question and it's a question that you could ask of any causal explanation what causes the cause if inflammation causes depression where does the inflammation come from in the first place and there are in fact a number of bodily factors that many of which are already identified as associated with depression but we are increasingly aware also increase inflammation obesity for example the higher the BMI the higher the body mass index the greater the fat mass all other things being equal the greater the level of inflammatory proteins and circulation gut microbiome big focus of research particularly here in Ireland with people like Ted Don and John crying I'm working on this in our guts we have about one and a half kilograms of a bacteria of germs you could change the diet you change the bacterial population maybe the immune cells and the lining of the gut see that as a friend maybe they mount an inflammatory response maybe that's one way in which diet could change mood chronic periodontitis or gum disease I'll spare you the gory details of it if you're interested there's more about this in the book it's one of my personal experiences of chronic inflammation it's overlooked often psychiatrists don't tend to inspect people's teeth dentists don't tend to ask people about their mental states menopause age all associated with increased risks or increased levels of inflammatory proteins in the literature even even the winter months there's quite a strong seasonal cycle of inflammatory cytokines with higher levels in january/february in the northern hemisphere july-august in the southern hemisphere but what I think is particularly interesting when we're talking about the link between inflammation and depression is to consider some of the emerging evidence about the role of social stress on the immune system you know we're very familiar with the idea that the immune system helps us defend against biological threats by like infection but what about the parallel idea that the immune system might have something to do with our response to social threats again an idea that 10-15 years ago might have seemed a bit bonkers but now you look at the literature and there's evidence that bereavement for example caring for a dependent relative childhood adversity or abuse all of these events in people's lives seem to be associated with increased levels of inflammation I'll give you an example of of how people have begun looking at this experimentally this is again not a study of patients primarily this in fact is a study of teachers of teaching we know is a notoriously stressful business many teachers feel that they put more effort in to their work than they are rewarded by their employment and in this study the investigators found two groups of teachers they found a chronically stressed group will call them burnt out and they found a more resilient buoyant group of teachers they brought them into the lab and they took a blood sample they found in the blood in the circulating blood they extracted the macrophages while the coal monocytes to be precise but they found the circulating macrophages in these patients in these teachers blood they put them in a dish in the lab and they exposed them to a bacterial challenge they made the immune cells think that they were under attack and then they measured the amount of inflammatory protein that the immune cells produced and what they found was that the immune cells harvested from the blood of the burnt-out teachers had higher levels of inflammatory protein production compared to the more resilient teachers at baseline and then the investigators did something a little bit wicked which is they put all of these teachers in a situation not unlike the situation I'm in at the moment public speaking that is a well-known stressful it's not as of course as severe as stress or as bereavement but it causes a lot of people some stress and experimentally you can simulate public speaking by something called the trial social stress test shown here so you have the the teacher the participant standing up in front of this panel of white coated pundits while being asked to do mental arithmetic I'm judged on their performance it's quite a stressful experience I'm sure you can imagine and what they found was that as a result of that acute stress the amount of inflammatory proteins produced by the monocytes or macrophages sampled from the teachers blood was increased somewhat in both cases you can see after the social stress of public speaking even the resilient teachers showed an increase in climate reactivity of these circulating cells but the increase was even greater in the burnt-out teachers suggesting that chronic stress puts the immune system on a higher level of alert if you will and makes or magnifies the inflammatory response to any subsequent more acute stress that I think is a very interesting line of inquiry to follow on in future years how does stress impact on the immune system and could that help us explain why exactly stress is the biggest single known risk factor for depression so you begin to I hope get the idea that we could be thinking about this sort of vicious cycle if you will that inflammation whether it comes from arthritis obesity or social stress crosses the blood-brain barrier changes the way that nerve cells work the way that large-scale emotional brain circuits work that in turn causes changes on our mental stage makes us depressed and being depressed may make us more likely to experience other stressful events a vicious cycle could ensue now this is drawn obviously at a very high level somewhat childishly as a caricature to get the message across but those of you are they more sort of neuroscientific bent maybe sort of encouraged to know that there is under the hood of that schematic quite a well-articulated biological model again this is mostly based on animals but here it is the stress of a social threat is picked up in the brain and part of the brains response involves sending an impulse through the sympathetic nervous system to the immune system causing the release from the bone marrow and the spleen of inflammatory immune cells circulate in the body and there may traffic across the blood-brain barrier squeezing between the cells of the blood vessel walls into the brain and there increase the inflammatory milieu of the concentration of inflammatory proteins triggering change in neuronal function change perhaps ultimately in behavior and mood so there is a growing awareness of how these things are mechanistically related to each other but so far I've really only addressed in terms of causality the question how for a completely satisfactory causal explanation we'd also like to know the answer the question why why might it be that inflammation could cause depression and like most biological why questions that answer has to come back to darling there must be a sense in which depressive behavior is or was invoked by the immune system to help to survive and there is a theory an evolutionary theory it's not mine but it's out there that that is indeed what happened that going back to our cavemen in ancestral times we focus so far on what the immune system is doing to handle the infection in his hand in terms of local inflammation but we've drawn him with a sad looking expression and there is a theory that that part of the way that the immune system evolved to help us survive was essentially to co-opt the brain to induce behavioural changes social withdrawal changes and sleep changes in appetite that somehow or other might have helped people survive infection and trauma in an era before there were effective treatments now like many evolutionary theories and this is not the first and nor will it be I'm sure the last evolutionary theory of depression it's open to criticisms are just so story you know you can make up what you like about what might have happened in the dim and distant past but if this was the case if there is an evolutionary story to be told about the links between inflammation depression one place I think we might look for clues is the genetics of depression and as Michael Meany mentioned just a moment ago in his extraordinary talk the genetics of depression has been a black box until really very recently I mean it's only in the last 12 months that the number of DNA samples on patients with depression has become sufficiently big to be able to identify with certainty specific genes associated with risk of depression and these are genes each of a tiny effect but it is still from the point of view of understanding links between inflammation depression very interesting to understand do any of these risk genes for depression that we've only just identified have anything to do with the immune system as the evolutionary theory might predict and this is very much still work in progress but here's the whole genome laid out on the horizontal axis and you can see these these powers in a so called Manhattan port showing which genes are most significantly associated with depression we need to understand what those genes do and one simple way is to look them up what for example does this gene do but is most significantly associated with depression well it's something called olfactory medium for and if you look it up it turns out to have been important in controlling the gut response to infection in mice now that is not a deep and compelling genomic analysis it's just a first look but it's the kind of result that would be anticipated by the evolutionary theory that the risk genes for depression should have something to do with the immune response but so what you know I can talk about gee was I can talk about Descartes do it all day long but what difference is this going to make to the problem I started with which is depression is the single biggest cause of disability in the world or on track to become so and we haven't had much in the way of therapeutic innovation since Prozac if inflammation causes depression then it's quite reasonable to expect that anti-inflammatory interventions might treat it depression could that be the case I would say maybe yes but not yet and never for everyone my vision of how this might work out therapeutically is not that anti-inflammatory drugs are going to emerge as a new panacea but there in the not-too-distant future we might find ourselves in a situation where people with depression come into the clinic we identify that they have that syndrome of depression but we use some kind of biomarker perhaps a blood test to identify whether that particular patient is both inflamed and depressed and if they are inflamed then maybe there's an anti-inflammatory treatment that might help them with their depression if they're not inflamed well there are other treatments for depression that could be used instead it's a more personalized precise approach to treatment in almost all other parts of Medicine this would be regarded as motherhood and apple pie you don't treat the symptoms you treat the cause in psychiatry it would be quite a big step forward if we could get to that point now is there any evidence already the anti-inflammatory drugs could have that kind of antidepressant potential well yes actually there's quite a lot of circumstantial evidence if you look at clinical trials of anti-inflammatory drugs in patients again with psoriasis inflammatory bowel disease rheumatoid arthritis many of those trials a few questions will have been asked about mood and mental state not a deep examination but enough to allow a sort of secondary or post or analysis and this may be difficult to see from the back of the hall but again this is a meta analytic approach to looking at data from thousands of patients treated with a range of different anti-inflammatory drugs and on average there is a significant effect they are significantly antidepressant these anti-inflammatory treatments in fact the effect size which is about point three is in the same ballpark as the overall effect size of serotonin boosting drugs like prozac the obvious caveat is that these are patients with a physical disease who's been given an anti-inflammatory treatment or maybe their mental state is improved just because their joints are less painful or they're more optimistic about their prognosis because the drug has worked on the physical disease we can to some extent discount that alternative explanation so we can look for example the group of patients with arthritis who did not respond in terms of their arthritis who were physically non-responsive and we can ask the question what happened to their mood state it turns out from this analysis here that even if those you look at those patients who did not physically respond there is evidence for an improvement in their mental state so it's difficult to discount that along the lines of weather would be wouldn't you you would feel less depressed because your physical state was improved because we seem to see improvements in mental state even when the physical condition hasn't improved but when we come to trying to treat psychiatric depression depression without I made a major medical disorder in the background one thing we know already is that this isn't gonna be very effective unless were clever about biomarkers were clever about targeting treatment we know that because there's already been a trial with an anti-inflammatory drug for depression well-designed clever trial and you can see here the scores of the patients treated at depression severity scores decreasing over time to approximately the same extent whether they got the active drug or the placebo in short the trial was a failure if you looked at all patients altogether but if you looked at particularly those patients that had high levels of inflammatory protein high levels of CRP at baseline they showed a significant trend to improved so if the implication from that study is that we shouldn't be thinking about this as a one-size-fits-all it's not going to be the case that everybody with depression is going to feel less depressed as a result of anti-inflammatory treatment but if we could find biomarkers that identified which patients were both inflamed and depressed and target our treatment on those particular individuals that might be more successful what are the biomarkers that were looking for they might not be single proteins they might be changes in gene expression they might be networks of change in gene expression and we've seen some examples of that already of significantly increased expression of a cluster of genes all specialized for innate immune response for the inflammatory response to infection in depression this is work from Mary Ellen Lionel who's just started as an MRC PhD fellowship looking in this area it's a complex story here's a correlation matrix showing the pattern of relationship between multiple immune markers cell counts proteins gene expression transcripts and psychological markers of depression the details are not important the key thing is to understand that out of a single blood sample there are many different peripheral immune markers we could measure many of them seem to be correlated both with each other and with mental states in people with depression and the hunt goes on to find which of those peripheral biomarkers might be most informative I think we also need to think about the brain what can we measure in the brain in humans that might be sensitive to inflammation might give us a guide to which patients are most likely to respond to anti-inflammatory interventions well we can look at functional MRI and as Colin said when he introduced me you know a lot of what I did before getting involved in immunology and inflammation was analysis of functional MRI data you can show that the connectivity patterns in functional MRI data are quite sensitive for the levels of inflammatory proteins like CRP in the blood these are data showing that as you go from healthy controls to onion flame depression to more inflamed depression you progressively lose functional connectivity between components of the emotional brain circuitry in the in the in the in the depressed brain and there are other imaging techniques as a technique called positron emission tomography which involves injecting a radioactive tracer that targets a particular molecule in the brain if you could find a molecule that was specific to microglia or to immune cells in the brain that would give us a more direct read on brain inflammation we people have begun doing those sort of experiments these are data from John O'Brien one of my colleagues in Cambridge showing in elderly people with depression the pet marker that we used that is sensitive to microglial activity is increased in binding particularly in the cingulate cortex in people with depression and we've seen similar results ourselves biomarker discovery whether in the periphery or the brain is going to be absolutely crucial and in some way is the cutting edge of the therapeutic approach for immunology and depression but in finishing I just want to leave you with two final thoughts first although I've come for this from a drug discovery background I want to emphasize that the links between the brain and immune system aren't only relevant for drug treatment there are other interventions like for example vagal nerve stimulation is licensed for treatment of depression in the States and we know or have done done recently to realize that one-way vagal nerve stimulation might work is by reducing inflammation there's a vagal inflammatory reflex a new piece of physiology that's been discovered in the last 15 years that shows how intimately the brain and the immune system homeostatic aliy interact so stimulating the nervous system electrically rather than pharmacologically couldn't trade off the same neurological interactions that I've been talking about so it's not just drugs and the second point is it's not just depression anti-inflammatory invent interventions might be relevant for many other disorders this is the first patient with Alzheimer's disease when Alzheimer looked at our brain he discovered these clumps of peculiar material he called and we now know that abnormally folded or aggregated proteins and people have increasingly become aware that the immune system might see those abnormal proteins as if they were alien proteins they might stimulate an immune response and the inflammatory reaction to protein deposits in the brain might contribute to neuronal loss and to the progressive loss of cognitive faculties that we recognize us as dementia so a lot of interest in the industry about anti-inflammatory approaches to neurodegenerative disorders as well as depression and with that I'll finish this is the book that I wrote to try and sort of explain a bit of more of the background and these are the final sentences we could be on the cusp of a revolution which I recognize as a potentially grandiose claim what I'm talking about is the idea that we might be able to step back from the dualist orthodoxy the split between body and mind that has dominated Western medicine for so long it won't be televised that means it's going to take a long time it's probably a multi-generational project and I might be wrong you know this isn't all cut and dried some of what I've said tonight is quite speculative but I think it has already begun thank you [Applause] thank you very much Eid for a really fascinating lecture I'm sure there'll be questions I had said they'd be happy to take questions could you wait for a microphone there are some roving mics which you could see around the room before I'm asking or otherwise your question won't be heard generally so are there questions please yes has there been any studies for the weather the weather the weather the brain is able to influence the the immunes immune system you have been telling that the the immune system influences the pain and it also in fact you connected it to an evolutionary theory but that was a very acute event of immediate this thing but we have seen I'm a I'm a surgeon so I we have seen in our own own practice people who are depressed are more prone to to develop infections they are more prone to develop malignancies in for one of the things we use to tell the patients with terminal malignancies is to give you know anti anti anti depressants so that so the brain influencing in an opposite manner has there been any studies or you think only in this one way it works you know thank you yeah it's interesting question and you know it's it's well known that shocks bereavement for example that increased depression also increase the risk of mortality associated with rather physical disease so it's an interesting question it has been less of a interesting question if I'm honest for me I've been really rather focused on inflammation causing depression but if you remember what I showed you about the vagal inflammatory reflex rather briefly the vagus nerve which comes out the brain innovates pretty much the whole body has a very pronounced anti-inflammatory effect you can switch on or off in fact levels of inflammation in the body by stimulating or not stimulating the vagus nerve it has been shown quite clearly and a lot of people are interested in using and developing new bioelectronic techniques to stimulate the vagus nerve more precisely to control inflammation in physical diseases like Crohn's disease and arthritis so that's one particular mechanism by which the nervous system ultimately the brain through that parasympathetic outflow through the note through the vagus nerve can damp down inflammation if you ask the more sort of general question how can the state can the State of Mind control inflammation I think that is a much more early days but there are for example some small-scale studies showing that meditation and other mindfulness practices can have some effects on immune markers peripherally I think that needs a lot more work but to my mind it's not inconceivable that one could for example develop biofeedback tools that helped people exert more conscious control or more mental control of peripheral inflammatory status why not it could be a two-way street as your question implied yes sir is it a microphone yeah which okay well there first yeah thanks that was fascinating so you showed how the overall efficacy of antidepressant drugs hasn't improved much in the last 40 years or ever I'm wondering if there's a timing effect like if people obviously have cancer is diagnosed earlier than their treatment is more effective is that the case with depression and if so do you think is to do with the brain connectivity patterns getting more lodged in the longer a person's depressed or something to do with the immune as depression so I think well one aspect of your question is is is depression more treatable early I think there is some evidence that repeated episodes of depression make response to the later episodes less complete than the gnarlier episodes but it's not a you know I don't think that's a particularly I'm not sure that that's related to the immune story I've been talking about I think one thing that we do know is that amongst the large group of patients patients approximately 1/3 who do not respond very well to conventional treatments there is some evidence that those people have increased levels of inflammation so if you ask the question you know who are these people with depression and inflammation it's quite likely that many of them will be I think patients who've had multiple trials of conventional antidepressants not responded very convincingly to any of them and there could be a mechanistic explanation for that I mentioned briefly that inflammation in the brain changes serotonin metabolism it might by that mechanism make people less responsive to serotonin boosting drugs so I think in terms of the treat ability of depression response Civet of depression to conventional drugs there is some suggestion that the less responsive patients may be more inflamed and from a you know a drug development point of view that's quite important you know if you think where would you imagine a new intervention a new antidepressant treatment being most effective or most successful it's probably not going to be as a replacement for first-line treatment with serotonin boosting drugs it would be much more I think imaginable to think of a new anti-inflammatory intervention coming along as an adjunctive treatment or a second-line treatment to help people that had not responded terribly well the more conventional first line options the questions as it as a Berliner I'd like to remark if if I'm allowed to that the Berlin wall is still present and moved to people's heads but two people said only and so leading up to my question do you think methods like for example the wim HOF method which is called shock therapy to the body like taking an ice bath and could actually be heat stimulus that can train the immune response and also cure depression in it well you know I suppose the experience the last several years has made me a lot more open-minded about things that I might in the past have discounted for example the link between diet and mood I was pretty sort of dismissive of that if I'm honest but when you think about it through the micro biome the gastrointestinal immune cells and you begin to think well actually these ideas could be mechanistically feasible and a number of treatments that are not part of mainstream circuitry or mainstream medicine might become more respectable if we understood how they worked so I'm open-minded about many things that you know a while ago I might have discounted but the key thing is that we need to see the science in support of all this you know I have been struck by the number of books for example calling themselves things like anti-inflammatory diet I bought a few I looked through them I couldn't see any evidence that any of the dietary advice was evidence-based in terms of its effects on the immune system and one good thing about drug development is that the standards of proof are very high you know to get an anti-inflammatory drug out there you've really got to show that it works if we can apply the same standards of evidence to normal pharmacological interventions be they water swimming diet meditation if we could show that those interventions had the mechanistically sensible effects on the immune system which could contribute to their therapeutic efficacy that would be a wonderful thing I don't think it's inconceivable but I think we need to do the science and do the science to the same standard as we would for a more traditional pharmacological treatment sorry can I just ask we haven't heard anything about any of the side effects for anti-inflammatory drugs or antidepressant drugs that's just one question I've been a yoga teacher for about 20 years and I've also played around with as you call them anti-inflammatory diets for a very long time and I can say categorically that in the laboratory of my body and my brain cutting out inflammatory foods definitely changes your mood within hours or within 24 hours at least so you know the science is not going to come from you know proving that diet and exercise and all the lifestyle stuff that actually works for depression and inflammation because I also have arthritis it's not going to be proved because there's no money in it and unfortunately you know you're a smart man but you work for a drug company so all the money that's been put into this possibly revolutionary new research is still about drugs giving people drugs when they have depression and they have arthritis and unfortunately no matter how good those drugs are there's always gonna be side effects so what I'm here I'm supposed to say to people is that if you're strong enough and disciplined enough to change your diet and lifestyle and eat really well and look after yourself look after your stress levels change your job if you need to get rid of your partner if you need to and you know move country if you need to but if you want to take care of your mental and physical well-being into your senior years then you need to eat really clean and exercise well and sleep well and do all of those things that make us happy and human and that's just where we're at and you're at the cutting edge of the Orthodox medic approach to depression and that's all very well and it's great to see that things are changing but truly I feel that there's a much simpler answer to anxiety depression and all of the problems that we're facing in this world because of toxicity and environmental environmental damage that we're doing so that's all I would just want to say thank you well you know I definitely would not disagree with a lot of what you just said there certainly are side effects of all drugs you know one of the questions have sometimes been asked is so you know are you saying that basically I should go out to the chemist and buy a lot of they'd be profane or a lot of aspirin isn't that isn't that an anti-inflammatory drug or might that make me less depressed but of course you know they all have side effects the anti-inflammatory drug that was used in the trial of depression that I showed you has quite serious side effects it makes people much more susceptible to infection if you if you damp down the immune system with a drug you are going to to some extent disable the body's defense against infection and you can see that so there are certainly side effects and we have to measure the risk of any treatment against its benefit and that is you know what I hope will emerge as we do more work focused on drug treatments for inflamed depression but you're absolutely right the drugs are not my whole necessarily the whole story a lot of people don't like taking drugs or can't tolerate side effects and there are going to be lifestyle changes that could be effective I absolutely wouldn't disagree with that I think the thing I'm curious about though is how do those lifestyle changes work and you know it can we you might think this is relevant but it to me it matters you know if I'm saying to somebody if I'm you know it goes back suppose it goes back to that anecdote I told about my first patient at the Maudsley if I'm if I'm recommending a treatment to patients I would like to know how it works and I'd really like to be confident that if they take my advice there's a decent chance of of improvement in their symptoms as a result in other words I'd like to be able to predict therapeutic efficacy and I think I can do that more confidently if I understand a bit more about the underlying mechanisms so that's why I'm curious a lot and not restricted in my imagination at least two pharmacological interventions as I said at the end you know there are other ways that we could manipulate the immune system which might turn out to be antidepressant but whether it's diet whether it's lifestyle changes yoga meditation cold water swimming drugs electrical stimulation whatever it might be I would like there to personally I would like to understand and certainly as one does for a successful drug development program how it works and that it really does work in the way that it's advertised um sorry I had a question about you mentioned that Alzheimer's might also be affected by inflammation um but I was just wondering about if you've also looked at other psychiatric disorders so for instance I was thinking about schizophrenia and research that actually pretty similar evidence that you discussed in your talk so for instance certain genes that have been implicated in schizophrenia are also thought to be involved in inflammation and there were those large epidemiological studies from Denmark that found that sort of those individuals who had autumn autoimmune disorders or serious infections were more likely to develop schizophrenia so basically wondering how specific do you think this is to depression our perhaps other psychiatric disorders being similarly affected well I think you're right there's definitely some interesting evidence linking inflammation or the immune system generally to schizophrenia I mean for example the top hit in the schizophrenia G was genetic analysis is a is a complement gene related to the immune system and I think we're beginning to understand that actually the immunes quite important in controlling the development of the nervous system you know there's some quite interesting evidence that the changes in connectivity between nerve cells the so called synaptic pruning process that we see is as part of normal development is managed in large part by the immune cells in the brain so the immune cells are important in shaping how the brain develops and that's important because again as Michael Meany said in his talk when we think about psychiatry I think we're increasingly thinking about childhood adolescence as the critical periods because that's where a lot of these disorders first arise that's when they first arise I should say and we have to understand therefore psychosis depression bipolar disorder anxiety as they emerge in adolescence presumably that has something to do with the development of the nervous system and the immune system seems to have a part to play in that that we don't fully understand yet so is it just depression and psychiatry definitely not I think you know the reason I focus on depression is because at least in my mind that is the bit of psychiatry where the evidence base is currently most secure but there's a decent evidence around psychosis and various aspects of immunology as you mentioned and if you look you'll find that there are immune theories of autism of ADHD of addiction you know in a way it's it's in a little bit worrying that seems that the immune system has something to do with almost every psychiatric syndrome that's been looked at from that perspective and that I think is a conceivable again but we need more evidence I mean some of the disorders where people have looked for links to the immune system if you if you look in detail at the studies the number of patients the way that the stoners have been designed it's suggestive evidence but it's not you compelling so again I'm suppose I'm pleading for more more understanding I'm not trying to close off possible avenues of further exploration I think there are lots of ways are lots of disorders potentially that could be relevant to a sort of more immunological approach but depression currently as the sort of biggest sort of weight of evidence in its favor in future years I'm confident that more evidence will accrue to help us understand the part that the immune system plays particularly in the development of the brain and how that might be relevant to increasing risk for the emergence of many psychiatric disorders that arise for the first time in the transition to adulthood I think this is probably the last question hello and thank you for your lecture I was wondering have you investigated a possible link between inflammation and postpartum blues or even postpartum depression no I haven't I haven't looked that at all but there is again you know there's a there's a small number of studies out there looking at that and of course you know actually postpartum events you know it's quite easy to think about them from an immunological point of view because of course the child the fetus is an alien you know it's a it's a different it's biologically different for the mother and you can imagine how the process of birth could potentially expose the mother to antigens that stimulate an immune response and that might be related to depression again you know as I said already really my mind is opened to or has been open by this the challenge of the really the challenge of the failure of a conventional way of thinking about depression has prompted me and others to think quite differently about the links between body and mind and once you go down that road and you start taking seriously some of the evidence not just sort of clinical medical evidence but some of those sort of physiological results that urged highlighting the very close relationship between the immune system in the nervous system I think it allows one to think that differently about a number of areas and postpartum illness you know I think should be understood more clearly from that in a logical perspective what I generally always say is many of these ideas that you and others in the audience have come up with to me they're interesting they're conceivable I wouldn't discount them or rule them out but I do think in each and every case if this is going to be credible if it's going to stand the test of time we do need to see good quality data we need to see more investment more scientific research until we into these areas to really be sure that we're not just clutching at immunology in the same way as those 18th century physicians we're talking about black bile it needs to be a really worked out mechanistic explanation I think if that's if it's really gonna move us all forward in terms of understanding and treatment not just a depression but of many psychiatric disorders well thank you very much it's been a really a very useful discussion I think and a fantastic lecture this lectures been recorded so if you want to watch it again it should be available online soon thanks to and silk and the silk trust she could not be here unfortunately this evening but she'll be able to watch it herself online so thanks to her for sponsoring this this lecture and finally of course thanks to Ed for such a thought-provoking talk [Applause]

Channel: British Neuroscience Association

Views: 3,915

Keywords: Neuroscience, depression, psychiatry, inflammation, immune system, medicine, brain, nervous system, mental health, science, research, mind

Id: C34EsI4PeKQ

Length: 74min 52sec (4492 seconds)

Published: Thu May 02 2019