Inflamed Bodies, Depressed Minds

The mysterious connection between the immune system and the brain

Images: Jutta Kuss/Getty

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.