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 (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 around 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 learned 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 once 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 vast that if we could completely cure depression in the U.K. from the start of the next financial year, it would be roughly equivalent to adding 4 percent to the GDP or tripling the projected annual growth rate of the whole economy from 2 percent to 6 percent. If the country somehow became totally undepressed, we’d boost our national wealth massively.
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 past 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.
We must dare to think differently.
One day in 1989, when I was training as a physician, just before I started to specialize in psychiatry, I saw a woman in her late fifties with an inflammatory disease called rheumatoid arthritis. I’ll call her Mrs. P. She had been arthritic for many years. The joints in her hands were painfully swollen and disfigured by scarring. The collagen and bone in her knees had been destroyed so that the joints no longer worked smoothly and she found it difficult to walk. Together, we talked through the long list of physical signs and symptoms that are diagnostic of rheumatoid arthritis. She ticked all the boxes. Then I asked her a few questions that weren’t on the standard checklist. I asked about her state of mind, her mood, and over the course of the next 10 minutes or so, she quietly but clearly told me that she had very low levels of energy, nothing gave her pleasure anymore, her sleep was disturbed, and she was preoccupied by pessimistic and guilty thoughts. She was depressed.
The conventional medical wisdom was that the patient was depressed because she knew she had a disease. It did not occur to us that depression might originate in the body.
I was pleased with myself. I thought I had made a minor medical discovery by doubling her diagnoses. She had come to see me with rheumatoid arthritis; I had added depressive disorder. I rushed to tell my senior physician this important news: “Mrs. P is not only arthritic, she’s also depressed.” He was not impressed by my diagnostic acumen. “Depressed? Well, you would be, wouldn’t you?”
We could both recognize that Mrs. P was depressed and she was inflamed. However, the conventional medical wisdom of the time was that she was depressed because she knew she had a chronic inflammatory disease. It was all in the mind. It did not occur to either of us that it might originate in the body. That Mrs. P might be depressed, not because she knew she was inflamed, but simply because she was inflamed. Mrs. P left the clinic no less likely to be depressed or fatigued than she was when she’d arrived. We’d not dared to think differently, and we’d done nothing to make a difference.
About 30 years down the road, we are becoming much more fluent in a new way of thinking scientifically about the links between depression and inflammation, between mind and body, as I recently discovered for myself after a visit to the dentist.
Root Canal Blues
A few years ago, I had an old filling in one of my molars that had gone rotten and the became infected. My dentist needed to drill out the cavity all the way to the tips of the roots of the tooth. Undergoing root canal surgery is not my favorite way to while away an hour or so, but I knew it had to be done. I was cheerful enough when I obediently hopped up on the chair and opened wide. But as soon as it was all done, I wanted to go home, go to bed, and not talk to anyone. And when I was alone at home, I found myself cogitating gloomily on the grave until I went to sleep.
The next morning, I got up, went to work, and forgot about mortality. I had endured some drilling of my tooth and some bruising of my gums, and I had briefly experienced some mental and behavioral symptoms: lethargy, social withdrawal, morbid rumination. You could say I had been a bit depressed, but hey, who likes going to the dentist?
There seems to be nothing out of the ordinary about this sequence of events — and there isn’t — but the ordinary explanation for it turns out to be not the only one.
The brief burst of inflammation in my mouth could directly have caused the changes in my mood that I noticed immediately after the surgery.
The traditional way of thinking about this tiny episode of illness starts with my body’s immune response to infection and injury. My tooth had been infected by some bacteria; my gums had become inflamed in response to that infection; the dentist’s drilling and scraping, although intended to achieve a long-term surgical cure, had the short-term disadvantage of making my gums even more inflamed and increasing the risk of the bacteria spreading from my tooth into my bloodstream. The reason I went to the dentist, and what happened to me when I got there, amounted to a challenge to my body’s integrity, a threat to my survival, and a clarion call to my immune system to step up its inflammatory response.
Working out this mechanistic chain of cause and effect, which leads from a physical attack, like an injury or an infection, to an inflammatory response from the immune system, is one of the truly game-changing triumphs of scientific medicine. This is the triumph of immunology, the science that now permeates our understanding of almost all diseases, and underpins the therapeutic success of vaccination, transplant surgery, and successful new drugs for diseases like rheumatoid arthritis, multiple sclerosis, and increasingly more kinds of cancer. This immensely powerful science can provide a minutely detailed explanation for how infection in my tooth could cause local inflammation of my gums and how surgery could acutely exacerbate the inflammation.
But immunology has not yet had nearly so much to say about what inflammation feels like for the inflamed patient or how inflammation can have effects on thoughts and behavior. Why did I want to be by myself? Why did I want to go to bed and stay there? Why was I so gloomy? The answers to questions like these have traditionally come from psychology, rather than immunology.
Thus I told myself a psychological story, that my close encounter with the dentist must have reminded me that I was literally getting long in the tooth. And this concrete affirmation of a well-worn metaphor for mortality must have triggered a period of rational pessimism as I calculated how much longer I might have to live. To paraphrase my self-diagnosis and put it another way: I became momentarily depressed because I thought about the implications of my root canal surgery. My mental state was a reflection or meditation on my physical state, rather than directly caused by my physical state.
To the extent that you are still unsurprised by this story, you are a dualist. Because the conventional medical explanation for what happened to me is dualist — it exists in two domains, physical and mental, with only a nebulous point of connection between them. Everything that happened up to and including my visit to the dentist is precisely explained in the physical domain by the biological science of infection and immunity. Everything that happened to my mood and behavior after I went to the dentist is explained in the mental domain by the psychologically meaningful story I told myself about getting long in the tooth.
At the time, about 2013, when I explained my own experience of inflammation and depression in this way, I found it somewhat comforting “to know.” Now, looking back, I am finally surprised. I am surprised to realize how incomplete and convoluted the standard dualist explanation seems to be — now that I know there could be a very different kind of explanation for what happened to me. There is another way of thinking about my root canal blues. I could have been momentarily depressed simply because I was inflamed, not because I thought about the consequences of being inflamed. The brief, transient burst of inflammation in my mouth could have directly caused the changes in my mood, behavior, and cognition that I noticed immediately after the surgery.
This new explanation is logically simpler than the familiar dualist reasoning I used when I told myself the story about getting long in the tooth. The stream of explanatory narrative doesn’t run into the sand in the physical domain, when I get out of the dentist’s chair, and then miraculously resurface in the mental domain, when I am back at home despondently in bed. Now the chain of cause and effect can run from start to finish in the physical domain — from the initial cause of an infected tooth to the final effect of a depressed mood.
But causality is tough to nail down scientifically. To be completely confident that inflammation can cause depression, we’d want to know the answers to two big questions:
How, exactly, step by step, can inflammatory changes in the body’s immune system cause changes in the way the brain works so as to make people feel depressed?
Why is a depressed patient inflamed in the first place? And why should the body’s inflammatory response, which is supposed to be on our side, which has evolved to help us win the battle against disease, be causing us to feel depressed?
Back when I met Mrs. P, about 30 years ago, these questions about causality went almost unasked, and there were no good scientific or medical answers to them.
By the time of my root canal surgery, in 2013, the questions were being asked much more often, and more precisely, and the answers were becoming clearer, thanks to the work of a disruptive new science, which has continued to make rapid progress in the past five years.
Why should the body’s inflammatory response, which is supposed to be on our side in the battle against disease, be causing us to feel depressed?
Like a lot of new science, this one has emerged at the interfaces between more established domains of knowledge. It exists at the boundaries between immunology, neuroscience, psychology, and psychiatry. It goes by a variety of ungainly, often hyphenated names — like neuro-immunology or immuno-psychiatry — that speak to its hybrid origins and its transgressive ambitions to link brain, body, and mind by the mechanisms of the immune system. Neuro-immunology investigates how the immune system interacts with the brain or nervous system, whereas immuno-psychiatry is focused more on how the immune system interacts with the mind and mental health.
Neuro-Immunology and Immuno-Psychiatry
The first few people brave enough to call themselves neuro-immunologists were a tiny tribe regarded with some condescension and suspicion by more mainstream scientists. It wasn’t considered professionally respectable to investigate connections between the brain (the province of neuroscience) and the immune system (the province of immunology). Not respectable not least because it was well known in the 20th century that the brain and the immune system had nothing to do with each other. The white blood cells and antibodies of the immune system circulated in the bloodstream and could pass through the spleen and lymph nodes and various other immunologically important organs of the body. But the cells and proteins of the body’s immune system couldn’t percolate so freely through the brain because it was protected by something called the blood-brain barrier. The BBB, as it’s also known, was explained to me at medical school in the 1980s as something like a Berlin Wall that kept the immune system completely apart from the nervous system. The solidity of the BBB exposed the nascent theories of neuro-immunology to the withering scorn of more traditionally minded scientists. How could neuro-immunologists seriously propose, as they began to do from about 1990, that levels of inflammatory proteins measured by a blood test had anything to do with the brain or the mind, when it was well known that proteins couldn’t cross the barrier between blood and brain? It wasn’t just wrong; it was worse than that.
The Berlin Wall concept of the BBB was the physical embodiment of powerful older ideas, the dualist ideas dating back to Descartes, that mind and body, as we now say, or soul and body, as he said, are utterly different. The 17th-century philosophy of Cartesian dualism is the foundational bedrock of Western scientific medicine. And the disembodiment of the brain by the rigid interdiction of the BBB was a concrete realization of this philosophy. So when the pioneer neuro-immunologists proposed that inflammatory proteins in the blood could get across the BBB to have effects on the mind, they weren’t regarded merely as wrong about the biology, but deeply disrespectful of the philosophical underpinnings of scientific medicine.
It is now clear that a lot of what I was taught in medical school is wrong. It has become increasingly obvious that the existence of the BBB does not prohibit all immunological cross talk between the brain and the body. We now know that inflammatory proteins in the blood, called cytokines, can send signals across the BBB, from the body to the brain and the mind. I will say more about cytokines later, but if you’ve never heard of them before, you can think of them as hormones that circulate in the bloodstream, creating powerful inflammatory effects throughout the body, including the brain. So when the dentist started probing my gums and scraping my teeth, she would have caused immune cells in my mouth to produce cytokines, which then circulated throughout my body in my blood and communicated inflammatory signals across the supposedly impermeable BBB to reach the nerve cells in my brain and cause my mind to become inflamed.
What Does an Inflamed Mind Look Like?
Mental inflammation, I used to think, without thinking about it too hard, might be similar to physical inflammation. As we have known since Roman times, the body becomes red and swollen when it is inflamed. So I used to imagine the inflamed mind was metaphorically red and swollen, angry and excessive, passionate, out of control, and potentially dangerous—closest in psychiatric parlance to a state of mania. But the image of an inflamed mind that I conjure up now is almost the opposite: not a choleric and threatening person but a melancholic and withdrawn one. Like Mrs. P, her hands swollen and deformed by inflammatory joint disease, silently wondering why she felt so gloomy and tired. I now think of her as typical of an inflamed mind, not metaphorically speaking, but mechanistically speaking.
The shift from metaphors to mechanisms of the inflamed mind begins by acknowledging the overwhelming evidence for a strong association between inflammation and depression. Simply recognizing this association, which is sometimes hiding in plain sight, is the right place to start. But the crucial questions are about causality. For a new, post-dualist way of thinking to take root, it must be scientifically established that inflammation is not merely associated or linked with depression, but that it can directly cause depression.
One way of teasing apart cause and effect is by looking at the sequence of events in time. Causes must come before effects. So if inflammation is a cause of depressive symptoms, we would expect to find evidence that inflammation can occur before depression, and there is some such evidence from recent research. For example, a 2014 study of 15,000 children in Bristol and southwest England found that children who were not depressed but were slightly inflamed at the age of nine were significantly more likely to be depressed 10 years later as 18-year-olds. This is one of dozens of human studies and hundreds of animal studies that have shown that inflammation can anticipate or precede depression or depressive behaviors.
But precedence alone is not sufficient for inflammation to be taken seriously as a cause of depression. Skeptical scientists and doctors will need to know how, by what exact biological mechanisms, inflammation can cause depression, step by step from cytokines in the blood to changes in the brain that can in turn cause depressive changes in mood. Here, too, there is supportive evidence from recent experiments in animals and humans.
If a rat is experimentally injected with infectious bacteria, it behaves a bit like I did after the dentist. It withdraws from social contact with other animals; it doesn’t move so much; its sleeping and eating cycles are disturbed. In short, infection reliably causes a syndrome in animals — called sickness behavior — that is roughly recognizable as akin to the human experience of depression. In fact, you don’t even need to infect a rat to see this sickness behavior. It is enough to inject the rat with cytokines, proving that it is not the germ itself that causes sickness behavior but the immune response to infection. Inflammation directly causes depression-like behaviors in animals — that is beyond doubt.
We also understand how inflammation can have effects on the brains of rats and mice. We know that nerve cells exposed to cytokines are more likely to die and less likely to be regenerated. We know that when nerve cells are inflamed, the connections or synapses between them are less capable of learning patterns of information and that inflammation reduces the supply of serotonin as a transmitter between nerve cells. For animals, at least, an explanatory chain is taking shape that can directly link inflammation of the body to changes in how nerve cells work in the brain, which in turn causes sickness behavior that looks like depression.
To work out the equivalent chain of connections in humans is not easy. We can’t experimentally infect people with dangerous bacteria, we can’t inject cytokines (or anything else) directly into the brains of healthy people, and it is impossible to see what inflammation does to living human nerve cells, one cell at a time. The vast majority of human nerve cells — about 100 billion of them — are densely packed together in the brain, and the brain is extremely well protected from the outside world by the bony skull. The only way we can “see” what is going on inside the skull of a living human is with brain-scanning techniques like magnetic resonance imaging. Recent fMRI research has begun to produce evidence that inflammation of the body can have a direct causal effect on the human brain and mood. For example, when healthy young people were injected with a vaccine against typhoid, their immune systems reacted like the immune system of a rat injected with bacteria, and cytokine levels spiked in their blood. The vaccinated volunteers also became mildly depressed; their post-vaccination depression was associated with greater activation of regions of the brain that we know are hardwired for emotional expression.
So the science of immuno-psychiatry has matured to the point that it can help me answer the question of how I became depressed after the dentist in a new and logically seamless way. I don’t need a ghost in the machine. I can plausibly argue that the surge of cytokines caused by my root canal surgery sent an inflammatory signal across the BBB to cause a change in the emotion-processing networks of nerve cells in my brain, which in turn caused an episode of depression that led my mind to dwell on the grave. There is credible experimental evidence for every step of this extraordinary, dualism-defying explanation. But still, it is not entirely complete. There are gaps and anomalies in the existing evidence base, to be sure, as there always will be in any rapidly advancing area of science. But even if we had a complete answer to the question of “how,” we would still want to know the answer to the question of “why.”
There is as yet no well-known way by which doctors can leverage this new knowledge to help people with depression.
The only scientifically acceptable answer to that question is in terms of evolution. Why does inflammation cause depression? It can only be because of natural selection. There must be some sense in which a depressive response to infection or any other inflammatory challenge is (or was) advantageous for our survival. And we must have inherited genes that were naturally selected in previous generations to make us more likely to benefit from a depressive response to inflammation. If I want to, I can reasonably speculate that the reason I became momentarily depressed after the dentist is because I have inherited genes that helped my ancestors survive infections in the past. This genetic inheritance might well have helped me recover from the minor trauma of root canal treatment by aggressively killing off any infectious germs and by dictating that I should stay in bed and conserve my energy while that happened.
Of course, the real importance of these linked new sciences of neuro-immunology and immuno-psychiatry is not that they give me a different way of explaining why I don’t like going to the dentist. What matters much more is that once we have begun to map a path to follow from the body, via the immune system, to the brain and the mind — once we have articulated a post-dualist concept of the inflamed mind — we should be able to find entirely new ways of dealing with mental health disorders.
The Revolution Will Not Be Televised
Depression, schizophrenia, autism, addiction, Alzheimer’s disease—there is a long and mournful list of disorders that psychiatrists, clinical psychologists, and neurologists ordinarily treat either as if they were “all in the mind” or as if they were “all in the brain.” Let’s say I had not bounced back to work the day after the dentist. Let’s imagine I had become progressively more withdrawn and melancholic until my wife eventually persuaded me to see a doctor. What would have happened? My GP probably would have asked me a few questions about my state of mind and then offered a course of psychotherapy (to resolve my issues about mortality) or a prescription of antidepressants (to correct some notional imbalance of serotonin or other neurotransmitters in my brain). It is unlikely that my doctor would have attached much diagnostic significance to the root canal story. It is virtually certain that he would not have ordered a blood test to measure cytokine levels or to see if I had genetic risk factors for a depressive response to inflammation. It is inconceivable that he would have recommended an anti-inflammatory drug (like aspirin) instead of an antidepressant (like Prozac). In all probability, I would have been sensibly, competently, traditionally treated as if my mood had nothing to do with my immune system. Just like I had traditionally treated Mrs. P.
Scientifically, there may still be questions to resolve about causality, but the link between inflammation and depression is indisputable. So why am I so confident that the doctor I might have consulted about post-dental depression would pay no attention to my immune system? The answer is partly just that medicine is a conservative, highly regulated profession. It is not unusual for changes in practice to lag several decades behind conceptual advances in biological science. A good example of the sometimes slower-than-hoped-for pace of medical progress is the real-life impact of the double helix.
Watson and Crick published the architectural principles of deoxyribonucleic acid (DNA) in 1953, opening up entirely new fields of genetic science and molecular biology. This was a critical turning point in the formation of what became the central orthodoxy of biology — the theory that genetic information is coded by the sequence of DNA molecules and that different sequences of DNA specify how different proteins are assembled by precisely stringing together hundreds of thousands of amino acids. Since proteins are an enormously large and diverse group of molecules in the human body — including antibodies, cytokines, enzymes, and many hormones — our deeper understanding of how protein synthesis is genetically controlled by DNA has been widely recognized as one of the most important advances in the history of biology.
About 50 years later, at a White House ceremony in January 2000 where President Bill Clinton celebrated the sequencing of the human genome, he spoke with unbounded millennial optimism about the genome: “without a doubt the most important, most wondrous map ever produced by humankind.” He saw this as a scientific advance with the potential to deliver medical breakthroughs on an extraordinary scale and at an extraordinary rate. “It is now conceivable that our children’s children will know the term ‘cancer’ only as a constellation of stars.” Now, almost 20 years after he spoke those words, Bill Clinton is a grandfather, but we are nowhere near consigning the word to common use only in horoscopes. In the British National Health Service (NHS) in 2018, genetics has made a life-or-death difference to some patients with leukemia or breast cancer, who are lucky enough to have a genetic profile that makes them more likely to respond to new anti-cancer medicines. But it will take many more generations for the therapeutic potential of genetics to play out across the whole spectrum of health services.
So it is reasonable to expect a fairly slow burn for immuno-psychiatry in practice. In the NHS in 2018, immunology has made no difference whatsoever to any patients with depression, psychosis, or Alzheimer’s disease. There are no licensed medicines or other treatments for depression that act primarily on the immune system. There are fascinating new insights into how high levels of social stress can increase bodily inflammation. And there is growing evidence that people who have experienced adversity or abuse in childhood are more likely to be inflamed as children and adults. It is also increasingly clear that depressed patients who are also inflamed are less likely to respond well to treatment with conventional antidepressant drugs. But there is as yet no well-known way by which doctors or other mental health practitioners can leverage this new knowledge to help people with depression. And until my GP is in a position to offer an immunological treatment for depression, I wouldn’t expect him to spend too much time entertaining a fancy new immunological way of thinking about where depressive symptoms come from.
Personally, I expect this to change. I can imagine a future in which the old dividing lines between mental and physical illness are redrawn, the 400-year-old habit of dualist diagnosis is kicked, and the immune system becomes much more central to how we think about — and treat — psychological and behavioral symptoms like depression. I can easily imagine that there could be some decisive moves in this direction over the next five years or so. The lesson of history is that medical revolutions do not make good reality TV. But there is a current of scientific change running under the surface of day-to-day medical practice that could transform the way we deal with depression and other mental health disorders. We can move on from the old polarized view of depression as all in the mind or all in the brain to see it as rooted also in the body; to see depression instead as a response of the whole organism or human self to the challenges of survival in a hostile world.