The Inflamed Mind

  Praise for The Inflamed Mind

  “Psychiatrists are re-thinking depression. Is depression due to trauma, a chemical imbalance, brain circuits misfiring? In this beautifully written book, Professor Edward Bullmore shows us why we need to look at the immune system if we want to understand depression. This approach not only bridges the mind and body, it suggests new approaches to treatment. The Inflamed Mind is an important book, a hopeful book, for anyone who wants to think about depression in a new way.”

  Tom Insel MD, Co-founder and President, Mindstrong Health

  * * *

  “The Inflamed Mind confronts the reader with the converging revolutions in neuroscience and immunology that give rise to a new perspective about depression and its treatment. It traces the roots of dualism, the tendency to view mind dissociated from body, and then calls for moving beyond dualism in order to understand how inflammation in the body affects brain and mind. In an erudite, enjoyable, and accessible way, Professor Bullmore conveys the profound impact of this new perspective by helping us to appreciate the links between traditional ‘medical’ and ‘psychiatric’ syndromes and it identifies new anti-inflammatory treatments that may cross the boundary from general medicine to psychiatry.”

  John H. Krystal, M.D., Robert L. McNeil, Jr., Professor of Translational Research; Chair, Department of Psychiatry, Yale University School of Medicine

  * * *

  “The Inflamed Mind is not only a dramatic breakthrough in our understanding of depression. It is an extraordinary exploration of what it is to be human.”

  Matthew d’Ancona, author of Post Truth

  “A compelling and highly readable argument that some forms of mental illness, especially depression, are really diseases of the immune system. If Ed Bullmore is right, psychiatry is on the brink of a revolution - the reunion of body and mind.”

  Sir Colin Blakemore, Professor of Neuroscience and Philosophy, School of Advanced Sciences, University of London

  * * *

  “Not so long ago neuro-immunology was regarded with derision within medical circles. Professor Bullmore has been a leading figure in highlighting how wrong that was. As one of the first people to brand themselves as an immunopsychiatrist, he has led us out of the dark ages and shone the light on the crucial link between systemic inflammation and mental illness. This set of insights is creating a paradigm shift in psychiatry which heralds a new field of personalised psychiatry in the same way that we are seeing personalised therapy in cancer.”

  Sir Robert Lechler, President of the Academy of Medical Sciences

  * * *

  “Here is a narrative that tells of exciting new approaches to reducing mental illness while capturing the essence of a powerful strand in fundamental brain science. Even better: it is easy to read without overly simplifying its subject.”

  Sir Philip Campbell, Editor-in-Chief, Nature

  * * *

  “Suddenly an expert who wants to stop and question everything we thought we knew. This is a lesson in the workings of the brain far too important to ignore.”

  Jeremy Vine, BBC

  CONTENTS

  Preface

  Chapter 1: Daring to think differently

  Root canal blues

  Neuro-immunology and immuno-psychiatry

  What does an inflamed mind look like?

  The revolution will not be televised

  Chapter 2: The workings of the immune system

  Inflammation and infection

  Fig 1. Immune cells

  Fig 2. Inflammation

  Location, location, location

  Communication: the medium is the message

  Fig 3. The immune system

  Rapid rebuttal and learning

  Auto-immunity: the flip side

  Chapter 3: Hiding in plain sight

  It’s depressing being ill

  The cogito, God, and the machine

  Fig 4. A lady trying to explain the pineal theory of the human mind and body

  A long shadow

  Mrs P is not alone

  A bona fide blockbuster

  The Cartesian blind spot

  Chapter 4: Melancholia after Descartes

  From black bile to MDD

  A cross to bear

  Super-shrink

  Fig 5. Freud’s first draft of the ego

  Dancing in the sanatorium

  Fig 6. First prophet of pharmaceuticals

  The golden age

  Fig 7. Scenes of joy at the dawn of anti-depressants

  Fig 8. The seer and the synapse

  Farcical serotonin

  Bereft of biomarkers

  Chapter 5: How?

  Extraordinary claims demand extraordinary evidence

  A stubborn fact

  Causes must come first

  The Berlin Wall in the brain

  Fig 9. What I was taught at medical school — and what we now know

  Fig 10. Nervous reflex control of inflammation

  Inflamed brains

  Chapter 6: Why?

  What could make you inflamed (and depressed)?

  Flaming stressed

  Causal chains and cycles

  Ultimately, the answer must always be Darwin

  Fig 11. Emotional faces and emotional brains

  A savannah survival story

  Chapter 7: So what?

  Medical apartheid

  Fig 12. The vicious cycle of stress, inflammation and depression — and ways to break it — an artist’s impression

  Could it be different already?

  Market failure

  Beyond blockbusters: better but not bigger than Prozac

  Alzheimer’s disease and the yin and yang of microglia

  Schizophrenia and auto-intoxication

  Acknowledgements

  Disclaimers

  About the Author

  References

  Index

  To my family

  List of Figures in Order of Appearance

  Figure 1: Immune cells. 2018. Original illustration by Helena Maxwell.

  Figure 2: Inflammation. 2018. Original illustration by Helena Maxwell.

  Figure 3: The immune system. 2018. Original illustration by Helena Maxwell.

  Figure 4: A lady trying to explain the pineal theory of the human mind and body. Engraving from Descartes, René, Treatise of Man, Harvard University Press, 1637.

  Figure 5: Freud’s first draft of the ego. Drawing from Freud, Sigmund, Project for a Scientific Psychology, In: Strachey J, ed. Standard Edition of the Complete Works of Sigmund Freud. Vol 1. London: Hogarth Press; 1895, 1950.

  Figure 6: First prophet of pharmaceuticals. Woodcut from Paracelsus, Astronomica et estrologia opuscula, Cologne, 1567.

  Figure 7: Scenes of joy at the dawn of anti-depressants. Photograph from Life (Magazine), March 3rd 1952.

  Figure 8: The seer and the synapse. Photograph of Santiago Ramón y Cajal and neuron drawing courtesy of the Cajal Institute, Spanish National Research Council (CSIC), Madrid, Spain.

  Figure 9: What I was taught at medical school. 2018.

  Original illustration by Helena Maxwell.

  Figure 10: Nervous reflex control of inflammation. 2018.

  Original illustration by Helena Maxwell.

  Figure 11: Emotional faces and emotional brains. First series from Fu CH, Williams SC, Cleare AJ, et al, ‘Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study.’ Archives of General Psychiatry. 2004;61:877-889. Second series from Darwin, Charles, The Expressions of the Emotions in Man and Animals, London, 1872.

  Figure 12: The vicious cycle of stress, inflammation and depression — and ways
to break it — an artist’s impression. 2018. Original illustration by Helena Maxwell.

  Preface

  One of the things that first attracted me to psychiatry, many years ago, was that it tries to deal with the most personal human afflictions: clinical disturbances of our selves, our emotional balances and imbalances, our states of mind and memories, our ideas about the world and its relationship to us. As a young doctor, the richly individual content of mental health symptoms seemed much more interesting to me than physical health symptoms, like ankle swelling or skin itching. It was also attractive to me, from a scientific perspective, that all these mental symptoms must originate from the brain; but it was not yet known how. It seemed likely to me then, and it still does today, that if we could understand more about how mental health disorders are generated by brain mechanisms we would be in a much stronger position to do something about treatment and prevention. We would probably also feel less ashamed or afraid to talk about mental health issues if we knew more certainly where they came from, or what caused them.

  So, when I was about 30, finding out more about how mental symptoms originated from the brain became a professional research mission for me. At this time, about 1990, many psychiatrists were focused on how brain chemicals like dopamine and serotonin could cause disorders like psychosis and depression. But it was clear there was an enormous amount more still to understand. I realised that I would need to become a scientist as well as a clinical psychiatrist.

  For several years in the 1990s, I was supported by the Wellcome Trust to do a PhD, supervised by Professor Michael Brammer, at the Institute of Psychiatry in London. The first functional magnetic resonance imaging (fMRI) scanners were just starting up, in a few places around the world, and I got involved in mathematical analysis of these newfangled fMRI data, to make maps of human brain function in healthy people and patients with mental health disorders. I started writing and co-writing many scientific papers on neuroimaging, neuroscience and mental health. This was a very exciting transition for me. I was lucky enough to be in the right place at the right time to catch the first wave of fMRI research, which has since expanded massively into a global science ecosystem. I thought it could only be a matter of time, perhaps a few years, certainly by the time I was 50, before the irresistible flood of new discoveries from brain scanning, and brain science generally, must force radical improvements in how we think about and treat mental health disorders.

  It was in that spirit that I started as a Professor of Psychiatry in the University of Cambridge in 1999. At first, I carried on with my brain imaging research, trying to find new ways of measuring and analysing the complex network organisation of the human brain. I am probably most well-known as an academic scientist for my work on network neuroscience or “the connectome”. But that is not the topic of this book.

  As I approached my mid-40s, I couldn’t help noticing that, despite what seemed like a tremendous amount of progress in neuroscience internationally, there was no sign yet of any great change in what was happening day-to-day in local NHS clinics and hospitals. I became restless about the prospect of making any difference to psychiatric practice simply by writing more papers about brain scans. I recognised that the most powerful lever of change in the history of medicine was always the advent of a new treatment. I found myself wanting to know more about how new drug treatments were being discovered for depression, psychosis and other disorders.

  That’s why, in 2005, I took an unusual chance to start working part-time for GlaxoSmithKline, also known as GSK, one of the UK’s biggest pharmaceutical companies. Half the week I spent working in my University lab on the fascinating esoterica of network analysis and the other half I spent working as the director of GSK’s clinical research unit, conveniently located about 200 yards down the hall in Addenbrooke’s Hospital. In the GSK unit, we did a lot of studies to test the effects of new drugs that were in clinical development for psychiatry, neurology and other areas of medicine. It felt exhilarating at times to be inching closer to the promise of new treatments; but then, in 2010, GSK abruptly closed down all its research and development programs in mental health. I realised I was a 50-year-old psychiatrist working for a company that didn’t want to do psychiatry any more. And if a company as big and strong as GSK didn’t see an opportunity to make therapeutic progress in psychiatry, what did that mean for the prospects of those radical improvements in treatment that I had been confidently expecting to witness for the last 20 years? That is the moment I began to start thinking seriously about the ideas that this book is about.

  I became increasingly interested in the work of other scientists who had been pioneering a new field of research that linked the brain and the mind to the workings of the immune system. They called it immuno-psychiatry or neuro-immunology. The first time I heard of it, to be honest, it sounded bonkers to me, for all sorts of good reasons. But as I delved into it deeper, it seemed increasingly plausible that this might be a scientific strategy that was different enough to offer a fresh chance of making therapeutic progress in psychiatry. I talked to lots of people and once again I was lucky. My GSK boss agreed it could be worth looking into and from about 2013 we were supported by the Medical Research Council and the Wellcome Trust to set up research partnerships with other companies and academic experts to find out more about the links between inflammation and depression.

  Hopefully that explains how I came to be involved in the immuno-psychiatry research program that I am still working on scientifically; but it doesn’t explain why I wrote a book about it. Scientists are highly incentivised to write papers for a technically specialised readership of their professional colleagues, rather than books that almost anyone might read. But as I have spent the last five years or so learning more about how the immune system and the nervous system interact, how inflammation of the body can cause mental symptoms like depression, it has increasingly seemed to me that these questions resonate widely. They touch on some very basic ideas about the relationship between the body and the mind, as well as the traditional difference between psychiatry and the rest of medicine. And they point towards not just a few new anti-depressant drugs but a radically reconfigured-dare I say, radically better - way of dealing with mental and physical health disorders together, rather than apart, as we currently do.

  This book does contain some technical language, especially in relation to the immune system, because if I tried to tell the story without any technical details I would not be telling it like it really is. And it is, I think, a really exciting story of how we could begin to see new science make a surprising difference to mental health. I hope you enjoy it.

  Ed Bullmore

  Cambridge, UK

  Chapter 1

  DARING TO THINK DIFFERENTLY

  We all know depression. It touches every family on the planet. Yet we understand surprisingly little about it.

  This dawned on me in an acutely embarrassing way one day in my first few years of training as a psychiatrist, when I was interviewing a man in the outpatient clinic at the Maudsley Hospital in London. In response to my textbook-drilled questioning, he told me that his mood was low, he wasn’t finding any pleasure in life, he was waking up in the small hours and unable to get back to sleep, he wasn’t eating well and had lost a bit of weight, he was guilty about the past and pessimistic about the future. “I think you’re depressed,” I told him. “I already know that,” the patient told me, patiently. “That’s why I asked my GP to refer me to this clinic. What I want to know is why am I depressed and what can you do about it?”

  I tried to explain about anti-depressant drugs, like selective serotonin reuptake inhibitors, or SSRIs, and how they worked. I found myself burbling about serotonin and the idea that depression was caused by a lack of it. Imbalance was the word I had heard more experienced psychiatrists deploy with aplomb on these occasions. “Your symptoms are probably caused by an imbalance of serotonin in your brain and the SSRIs will restore the balance to normal,” I said, waving my hands ar
ound to show how an imbalanced thing could be rebalanced, how his wonky mood would be restored to equilibrium. “How do you know that?” he asked. I started to repeat all the stuff I had just learnt from the textbooks about the serotonin theory of depression, before he interrupted: “No, I mean how do you know that about me? How do you know that the level of serotonin is imbalanced in my brain?” The truth is that I didn’t.

  That was about 25 years ago, and we still don’t have confident or consistent answers to these and many other questions about where depression comes from or what to do about it. Is depression all in the mind? Is my depression “just” the way I am thinking about things? But then why is it so often treated with drugs that work on nerve cells? Is it “really” all in the brain? To our friends and family who are depressed, we may not know what to say. If we are depressed ourselves, we may feel ashamed to say so.

  The silence around depression and other mental health disorders is less deafening now than it was. We are getting better at talking about it, which is good, even if we don’t always agree with each other. We can see that depression is very common, it can be really disabling in many ways and it can reduce both the quality of life - depressed people have less experience of pleasure - and the quantity of life - depressed people have reduced life expectancy. We’re not surprised to read that the economic costs of depression and related disorders are so vast1, 2 that if we could completely cure depression in the UK from the start of the next financial year it would be roughly equivalent to adding 4% to GDP, or tripling the projected annual growth rate of the whole economy from 2% to 6%. If the country somehow became totally un-depressed, we’d boost our national wealth massively.

  But despite our growing awareness of how commonly depressive episodes and disorders crop up among people we know, and the massive scale of the public health challenge that depression represents globally, we still have only limited ways of dealing with it. There are some widely available and moderately effective treatments out there; but there have been no breakthrough advances in the last 30 years. What we had for depression in 1990 - serotonin-tweaking drugs, like Prozac, and psychotherapy - is pretty much still all that we’ve got therapeutically. And that’s evidently not good enough: otherwise depression wouldn’t be on track to become the biggest single cause of disability in the world by 2030.