Personally, I suspect that the most likely root cause for the lack of progress in Alzheimer’s is the same as for the lack of progress in depression: the curse of the blockbuster. Although it was originally described as a single case, and then regarded as exceedingly rare for about 80 years, it has turned out to be unfortunately common. Alzheimer’s disease is now recognised as a major public health and economic challenge, especially in the more rapidly ageing rich countries. As life expectancy improves in poor countries, and more people live into their sixties and beyond, it is predictable that the incidence and impact of Alzheimer’s disease will escalate in developing economies. It is a global disorder. And most global disorders, like depression, obesity, high blood pressure, diabetes, atherosclerosis, etc, have multiple causes. Alzheimer’s disease is no exception. There isn’t one gene for Alzheimer’s; there never was and there never will be. There are many genes that can increase risk of Alzheimer’s, most of them having only modest effects, but collectively acting across a range of biochemical pathways in the brain. And the long process of cognitive decline over decades, the clinical syndrome of progressive dementia, isn’t necessarily driven by the same biological mechanisms all the way.
Once again, we shouldn’t be thinking about it as if it were one thing. We shouldn’t be trying to find a panacea. We should be targeting treatments more precisely at those patients most likely to respond. In that sense, the strategy for developing immune treatments for Alzheimer’s is exactly the same as the high-level strategy for inflamed depression. Use biomarkers to identify the subgroups of patients that are most (and least) likely to respond to treatment in clinical trials. The genetic profile of patients with Alzheimer’s disease is one possible biomarker that could be developed to predict response to anti-inflammatory drugs. For example, one of the genes that has recently been discovered to increase risk for Alzheimer’s disease, called TREM2, is important for controlling the activity of the microglia in the brain.97 It may be that dementia in patients with a risky TREM2 mutation is caused or accelerated by an abnormal state of microglial inflammation. And it is conceivable that this TREM2-positive group of patients, or other Alzheimer’s patients with clear inflammatory risk factors, would be most likely to benefit from anti-inflammatory treatment.
Alzheimer’s isn’t one thing and the brain’s innate immune system is at least two things, yin and yang, protective and self-destructive. This is not classic blockbuster territory. It’s never going to be one size fits all, therapeutically, but you sense there could be some good opportunities to develop personalised immune treatments for Alzheimer’s disease in the next 5-10 years.
Schizophrenia and auto-intoxication
As a new consultant psychiatrist in Cambridge, in 1999, I was one of a team of doctors, nurses and psychologists that set up a clinical service for patients who were experiencing their first symptoms of psychosis. They had heard voices or seen things that weren’t really there: hallucinations. And/ or they believed things that weren’t really true: delusions. Hallucinations and delusions are the diagnostic hallmarks of psychosis - or madness - and have been since the ancients.
We used to see young people, mostly in their late teens or early twenties, who had just become psychotic, and try to work out why that might have happened and what we could do about it. No two patients were the same. No two families were the same. We saw straight-arrow undergraduates from Cambridge colleges as well as the alumni of children’s homes and juvenile detention centres. Their psychotic symptoms were mixed in with variable amounts of anxiety and depression, sometimes with manic euphoria. Sometimes the timing of psychotic symptoms was related to a possibly causal event, like smoking a lot of cannabis at a party, or getting evicted from housing to sleep on the street. Sometimes the psychosis came out of the blue, abruptly, or emerged so gradually that it was difficult to say when it had begun. Sometimes the standard treatments worked well, sometimes they didn’t. Overall, I would say that most patients benefited at least as much from their supportive human contacts with the team as they did from the drugs. But there was one dark question that was always in the back of everyone’s mind. “Am I going mad?” “Is my daughter going mad?” “Is this just the start, the first episode, of a relentless march to down-and-out madness that will blight the rest of our lives?” The diagnosis that everyone dreaded, the word that nobody wanted to say, was schizophrenia.
It’s a word that’s been badly abused and widely misunderstood. It is yet another Greek neologism, meaning split mind, that was coined in the early 20th century by one of Freud’s early followers, who thought that psychosis was all in the mind. Schizophrenia and schizophrenic are now often bandied about in conversation to mean things like split personality, or conflicted, or indecisive, or dangerous, or even politically rivalrous. But what schizophrenia means in psychiatry is much closer to the vision of Emil Kraepelin, who described for the first time the trajectory that our patients and their parents most feared. Kraepelin was not a solitary genius like Freud, Ramón y Cajal, Paracelsus or Descartes. He was an organiser, a systematiser, a manager and an encyclopaedist. He raised funds from Jewish families to build a psychiatric hospital and research institute in Munich - one of the very first buildings to bring neuroscience close to treatment for serious mental illness. He worked with or trained many of the leading figures of German-speaking psychiatry and brain science in the first half of the 20th century, which was in many ways a golden era. Most influentially, he produced 11 editions of his compendious textbook,98 between 1883 and 1925, the year before his death.
Kraepelin marshalled an enormous quantity of clinical observations in support of a simple scheme: psychosis represented one of two possible underlying disease processes - manic-depressive insanity or dementia praecox. One of the key differences between them was their evolution over time, their natural history. Patients with manic depression were expected to swing up and down, perhaps extremely enough to lose touch with reason, but to return to equilibrium between excursions. The trajectory was bumpy in the short term but flat in the long term. Whereas patients with dementia praecox, or precocious dementia in English, suffered a more relentless and progressive course in Kraepelin’s book. He called it “subacute development of a peculiar simple condition of mental weakness occurring at a youthful age”. Young people were becoming demented by madness, progressively less capable and independent, doomed to years on the back wards of large asylums.
Although no one, not even Kraepelin, has ever been entirely convinced that psychosis can be so simply and cleanly divided in two, this formulation is still embedded in the current DSM diagnostic system for psychiatry. The words have changed. Manic-depressive insanity is now bipolar disorder. And dementia praecox has turned into the word that the families of our patients never wanted to talk about.
Kraepelin was highly critical of Freud and the thriving psychoanalytic movement he had inspired. In Kraepelin’s view, the cause of psychosis, especially the type of psychosis we now call schizophrenia, must be physical, not psychological. He stayed on the same side of the Cartesian divide all his life. He didn’t switch tracks like Freud, from the neuroscience lab to the couch. His institute conducted many post mortem examinations of brains from schizophrenic patients but there was no equivalent of Auguste Deter among them. Unlike Alzheimer, working down the hall on Frau D’s brain, Kraepelin never found anything as distinctively peculiar as plaques or tangles in the schizophrenic brains. He recognised that schizophrenia tended to run in families, suggesting that it was genetically heritable, but he had no way of knowing which genes were involved. He proposed that society might wish to rid itself of the inherited risk for schizophrenia, idiocy and other brain disorders by a eugenic programme of controlled breeding. He died before the Nazi party came to power, but some of his ideas fatally outlived him, staining his reputation to this day.
At the end of his life he still didn’t know what caused schizophrenia. He knew it had to come from the body, not the mind, but where in the body? As he stru
ggled with later revisions of his textbook, he was increasingly preoccupied by an idea that somehow never made it into the DSM’s diagnostic criteria for schizophrenia 60 years later: the idea that schizophrenia is a whole-body disease, caused by an auto-intoxication or self-poisoning of the brain by the body. Kraepelin’s auto-intoxication theory sounds superficially auto-immune - the body mistakenly attacking the self - but in the early 20th century much less was known about the immune system than about the body’s hormonal system. Kraepelin’s suspicions were focused on the sex glands, not the lymph glands, as the most likely culprit, the most likely source of a bodily poison that attacked the brain and mind. For many years, he tried “organotherapy”, injecting testicular or other glandular tissue into patients for treatment of schizophrenia, without any benefit.99
It has taken a long time but we now know that Kraepelin was right about at least one big thing: there are genetic causes for schizophrenia. When the human genome was sequenced, in 2000, there was a massive surge of optimism that we would soon be able to find the genes for schizophrenia, as well as for everything else. But only in the last few years have enough DNA data been collected from 37,000 patients to provide a definitive result.100 We now know that there are approximately 320 genes that increase risk of schizophrenia. The single most strongly associated gene is located in a part of the human genome that is known to be important for the immune system and auto-immunity. This gene, called complement component 4 (C4), produces an inflammatory protein. Different people can have different versions of the C4 gene, and produce slightly different versions of the complement protein. Risk for schizophrenia is significantly increased in people who have the genetic variant associated with increased inflammatory signalling and the same genetic mutation causes damage to the synaptic connections between nerve cells in mice.101 It is a stunning series of discoveries to go from no genes, to 320 genes, to understanding that the single biggest genetic risk for schizophrenia is mediated by the immune system. But C4 is still only one of hundreds of risk genes, and the cumulative effect of all known genes is modest. There must be other factors at work.
One of the stubborn facts we have known about schizophrenia for many years is that your risk is increased if you were born in the winter months.102 I remember hearing epidemiologists earnestly discuss this result in the mid-1990s and thinking they must be nuts. It must be some kind of blip in the data. How could season of birth have anything to do with someone developing schizophrenia 19 or 25 years later? Unless it was under the baleful influence of Sagittarius? Fortunately, I didn’t raise my hand to make these penetrating remarks in public at the time. There is strong evidence that winter births are riskier because there is a higher risk of infection in winter. The mother, the fetus in the last months of pregnancy and the new-born baby, are all at increased risk of infection in the winter months. And it has been found that maternal, fetal and neonatal infections are all associated with greater risk for schizophrenia. In experiments with rats and mice, the infection of the mother or the fetus with viruses can cause long-term changes in the development of the nervous system. And the extent to which a virus impacts on development of an animal’s brain is conditioned by the way its immune system reacts to the viral infection. So it is possible that something similar happens in humans. Genes controlling the immune system may predispose babies to react to a common viral infection in a way that somehow derails or diverts the future development of the brain and increases the risk for schizophrenia.103
It would be an extraordinary step forward to understand these exciting new ideas in more detail, to penetrate the awful murk that still envelops the provenance of schizophrenia. But can neuro-immunology do more than that, more than help us to understand schizophrenia in a new way? Can it help us deliver any new treatments that could make a real difference? Here the situation is less advanced than for either depression or Alzheimer’s disease. Fewer trials have been done and fewer drugs have been studied. But there are already some interesting leads to follow. For example, we know that psychotic symptoms that look like schizophrenia can occur in patients who have high levels of an auto-antibody that binds to one of the brain’s key neurotransmitter receptors, called NMDA. Like all auto-antibodies, this one is mistakenly produced by the patient’s immune system to target one of the patient’s own proteins. It is friendly fire, in this case directed against a synaptic receptor that was already known to play a crucial role in psychosis. About eight years ago, some of my old colleagues on the psychosis team at Cambridgeshire & Peterborough NHS Trust decided to measure the levels of this anti-NMDA antibody in the patients they were seeing. In the first 43 patients they tested, four had high levels of autoantibody.104 And when they treated a few of the test-positive patients immunologically, to reduce the levels of auto-antibodies in circulation, they found that it made an immediate and lasting difference to their psychotic symptoms. It’s not a cure; or even a controlled trial (that’s now ongoing); and of course it will not be a panacea (only about 5% of psychosis patients have anti-NMDA auto-antibodies). But it is another reason to be cheerful about how new immunological treatments could be developed in another area of psychiatry where therapeutic progress has stalled in the last 30 years.
• • •
So what? So, maybe, in the next five, 10, 20 years we’ll see accelerated progress in the development of a radical new approach to treatment of depression and other psychiatric disorders.
Maybe we’ll see new drugs that, unlike the old drugs, are not vaguely supposed to work equally well for everyone with depression but are scientifically predicted to work particularly well for some people.
New blood tests to measure the genetic and inflammatory biomarkers that can predict which kind of treatments are likely to work best for which patients.
New clinics that can offer depressed people a more integrated, holistic assessment of their mental and physical health, as if each of them was being individually treated as one patient, not two.
A new breed of doctors more confident about working on both sides of the traditional line between medicine and psychiatry.
A gradual shift away from the culture of apartheid and stigmatisation that compounds the pain of an illness when it is regarded as all in the mind.
So maybe we’ll start winning a few more battles in the fight against the biggest health challenges of the 21st century.
We could be on the cusp of a revolution. It won’t be televised. And I might be wrong. But I think it has already begun.
Acknowledgements
I would like to thank many colleagues, too many to name, in academia, industry and the NHS, for all their help in teaching me to think differently about depression and about how we might develop new treatments in future.
I would particularly like to thank several people who were kind enough to read an early version of this book: Matthew d’Ancona, Simon Baron-Cohen, Claire Brough, Amelia Bullmore, Jeremy Bullmore, Paul Higgins, Peter Jones, Golam Khandaker, Trevor Robbins, Lorinda Turner, Petra Vértes and Jeremy Vine.
I am very grateful to Rebecca Nicolson, Aurea Carpenter and Catherine Gibbs at Short Books for making it into a book; Emma Craigie for copy editing; and Helena Maxwell for her illustrations.
But it would not have been done without my wife, Mary Pitt, who got me started and helped me see it through in many ways.
Disclaimers
The views and opinions expressed in this book are those of the author solely. Likewise any unintended factual errors are my responsibility alone.
I regret that I am not in a position to offer professional advice to readers of this book concerning their personal experiences of mental or physical health disorders.
About the author
Professor Edward Bullmore MB PhD FRCP FRCPsych FMedSci trained in medicine at the University of Oxford and then at St Bartholomew’s Hospital in London. After working as a physician in London and in the University of Hong Kong, he trained as a psychiatrist at St George’s Hospital and the Bethlem Royal and Maud
sley Hospitals in London, and as a clinical scientist at the Institute of Psychiatry, King’s College London. He has been a Professor of Psychiatry in the University of Cambridge since 1999 and is currently Head of the Department of Psychiatry and Director of the Wolfson Brain Imaging Centre in the Department of Clinical Neurosciences. Since 2005, he has also worked part-time for GlaxoSmithKline and is currently leading an academic-industrial partnership for the development of new anti-inflammatory drugs for depression. He is a world expert in neuroscience and mental health.
SIMON & SCHUSTER
simonandschuster.com.au
Authors.SimonandSchuster.com/Edward-Bullmore
References
Chapter 1
1. Mental Health Foundation. Fundamental Facts About Mental Health. 2015.
2. Farmer P, Stevenson D. Thriving at Work. UK Government; 2017.
3. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience. 2008;9:46-56.
4. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in Immunology. 2006;27:24-31.
5. Smith RS. The macrophage theory of depression. Medical Hypotheses. 1991;35:298-306.
6. Maes M. Evidence for an immune response in major depression: A review and hypothesis. Progress in Neuropsychopharmacology and Biological Psychiatry. 1995;19:11-38.
The Inflamed Mind Page 19