The first anti-TNF antibodies were available on the NHS as a new medicine for rheumatoid arthritis from 1999, about 10 years after my meeting with Mrs P. I don’t know if she tried anti-TNF treatment years later, or whether it made any difference to her depression, or any other aspect of her rheumatoid disease, if she did. I never saw her again after that one meeting. That was my last job in medicine. My next job was my first one as a psychiatrist. I was about to cross the Cartesian line that organisationally divides the medical profession and the NHS. I was about to specialise as a doctor of mind stuff rather than a doctor of physical mechanism. So I never had hands-on experience as a doctor treating patients with anti-TNF antibodies. I never had the chance to see for myself what happens when a patient like Mrs P has her first anti-TNF treatment. But I have spoken to other doctors and nurses who have had that experience and many of them have told me versions of the same story. The patients cheered up, often rapidly. It was so predictable, I was told, that the nurses on the rheumatology ward at University College Hospital in London all wanted to be the one to set up the intravenous drip for an anti-TNF infusion, because they knew the patient would feel better and be full of gratitude almost immediately. It was so predictable, I learnt, that it had a nickname. They called it the Remicade high.
It’s exactly what you’d expect if cytokines caused depression: that anti-cytokines should be anti-depressant, that a shot of anti-TNF should make people with inflamed minds feel high. However, despite the fact that it has become part of common parlance in day-to-day clinical practice, the Remicade high has not yet been taken too seriously. It has usually been written off as a placebo response - meaning that if patients were given an innocuous infusion of glucose, but told it was Remicade, they’d still have a Remicade high. Their highness was supposed to be a mental reflection on their prospects of improved physical health following a fancy new treatment. “High? Well you would be, wouldn’t you, if you thought that you’d just been treated with a new blockbuster that was going to cure your joint disease?” There have been only a few scientific studies designed to challenge this familiar rigmarole, to test the post-Cartesian hypothesis that patients rapidly feel better after anti-TNF treatment, not because they think positively about the implications of the drug, but because the drug has directly beneficial anti-inflammatory effects on their brain.23 The Remicade high could be giving us a big clue about a new way of treating depression, fatigue and other symptoms of the inflamed mind, a clue we will investigate later. But so far medicine has mostly discounted it as a trick of the mind. It’s another thing hiding in plain sight, camouflaged by our Cartesian blind spot.
• • •
In the next chapter, we turn to the world of psychiatry. Traditionally, that changes everything. In a dualist universe, the body and the mind are as different as any two things can be. But as we now pass from one side to the other, as we cross the great divide between those that are sometimes called “proper doctors” and those that are sometimes called “trick cyclists”, we will try to keep hold of the inflammatory threads that may in fact tie body and mind together.
Chapter 4
MELANCHOLIA AFTER DESCARTES
From black bile to MDD
Depression is even more medically ancient than inflammation. We didn’t know the cardinal signs of inflammation until the Romans, but melancholia has been a thing since the Greeks. The physicians trained in the school of Hippocrates, about 400 years BC, recognised two facets of melancholia, which we now call emotional and cognitive. They saw an agony of the soul, or angor animi, which was expressed by fear, despondency, sadness and gloom. And they described a tendency to form pessimistic and unrealistic beliefs, cogitatione defixus, like the patients of Galen “who think they have become a sort of snail so that they must escape everyone in order to avoid having their shell crushed, while others fear that Atlas, who supports the world, may grow weary and vanish”.24
These emotional and cognitive symptoms were explained physiologically, in terms of abnormal bodily function, by an excessive accumulation in the spleen of black bile. According to Hippocratic physiology, this was one of four humours that were supposed between them to control many aspects of the patient’s temperament, susceptibility to disease and response to treatment. Black bile, yellow bile, phlegm and blood were the cardinal humours that circulated throughout the body, their relative balance of influence with respect to each other providing a diagnostic explanation for the clinical appearance of disease. Too much phlegm made a man apathetic and caused rheumatic and chest disease; too much yellow bile made a man angry and more prone to liver disease; too much blood made a man positively sanguine but prone to heart disease; and too much black bile made a man melancholic. The anti-depressant treatments of the time were intended to rebalance the humours, to attenuate the mournful influence of black bile in the body, by diet, exercise, purgatives and bleeding.
Such ancient ideas might seem somewhat ridiculous to us, now that we know there is no such thing as black bile in the body, but they survived for a remarkably long time as the dominant theory of European medicine. English physicians commonly continued to practise in the Hippocratic tradition until the 1850s. And for a melancholic patient a dose of Hippocratic medicine, based on quaintly flawed physiology but physiology nonetheless, would often have been preferable to the alternative treatments based on theology. For example, Celsus, although ancient, was not Hippocratic in his thinking about the root causes of melancholia. Like many people before and since, he regarded it as evidence of demonic possession, a sign that evil spirits had captured the soul of the patient, perhaps as a punishment for wrong-doing or moral laxity. He recommended treatments that were correspondingly severe: exorcism, beating, burning, solitary confinement, restraint by chains and manacles. From the earliest times, throughout the Middle Ages and into the witch-hunting era of the 18th century, countless melancholics must have been treated with extreme cruelty, sanctioned by the zealous certainty that they suffered not from their bodies but from the devil that was in their souls.
It was only after 1850 that the mechanistic revolution in medicine, penetratingly prophesied by Descartes about 200 years earlier, began to get the upper hand over the Hippocratic tradition. (Change always comes slowly to medicine.) But by the 1950s, the pre-Cartesian, pre-dualist medical theory of the ancients - which explained both mental and physical symptoms by the same underlying humours - the same causative factors or agents - had been almost completely dismantled and replaced by the medicine of the body machine. These days there is only one vestigial fragment of the Hippocratic corpus remaining in the modern medical lexicon. The word melancholia is still in use by psychiatrists, not to denote black bile, but as an alternative diagnostic label for what is now more formally called major depressive disorder (MDD).
Just as the ancient signs of inflammation are still taught to every medical student, the modern syndrome of depression is recognisably the same now as when it was first diagnosed as melancholia 2,000 years ago. But the cardinal features of inflammation have since been deeply explained by the new science of immunology, whereas the clinical symptoms of depression are not yet so well understood at the same level of mechanistic detail. The diagnosis of MDD, as officially defined by the American Psychiatric Association’s Diagnostic and Statistical Manual, 5th edition (DSM-5),25 involves ticking boxes on a checklist of depressive symptoms that Galen would have recognised, including anhedonia (loss of pleasure) and anorexia (loss of appetite). If a patient has experienced sadness or lack of pleasure, plus at least four of the five other symptoms on the list, almost every day for at least two weeks but not for more than two years, then that patient has MDD, as defined by the committee of eminent psychiatrists who compiled DSM. There is no need for any blood tests, physical examinations, X-rays or fMRI scans. According to the DSM-5 diagnostic algorithm, there is nothing we can learn from the body that would help us make the diagnosis of MDD. Indeed, if blood tests or X-rays indicated that the patient might have a bodily diseas
e that would unmake the diagnosis of MDD. By decree of DSM-5, a diagnosis of MDD is explicitly excluded if the symptoms could be “attributable to the physiological effects . . . of another medical condition”. So, bizarrely, Mrs P could not have MDD. She could tick all the boxes on the DSM-5 symptom checklist but her rheumatoid arthritis would rule out the diagnosis of MDD. Depression has officially become isolated on the mental side of the dualist divide, just as inflammation has traditionally been restricted to the physical side.
Who cares? Who cares that depression has been mentally segregated by dualism? What does this rather academic philosophising mean in real life for patients who have depression, and for the psychiatrists and psychologists who treat them?
A cross to bear
For a lot of patients, I believe, it means that depression is likely to be seen as a sign of personal failure. If depression is purely mental, if it’s all in the mind, if it’s just a different way of feeling, or thinking about things, or behaving, then shouldn’t I be as responsible for my depression as I am responsible for other purely mental phenomena, like my ideas and my decisions? Feeling personally culpable, feeling as if it is their fault, is a common experience for depressed people. Clinical psychologists regard this as a cognitive bias, a tendency to think negative rather than positive thoughts about oneself, which is a characteristic feature of depression that can be treated by cognitive behavioural therapy (CBT). But in more severe cases, self-critical or obsessively self-blaming thoughts can drive self-punishing or self-harming behaviours, and ideas of personal failure can morph into nihilistic delusions - the patient’s false belief that he has already died. It almost goes without saying that all these self-critically biased states of mind are risk factors for the ultimate auto-destructive act of suicide.
Some degree of psychological assault on one’s sense of self, or even one’s bodily self in a case of suicide, is thus a central and serious part of the experience of depression for many people. And this has been true for several thousand years, so we can’t blame it entirely on Descartes. But I believe that the exclusive segregation of depression to the mental domain - the assumption that it is all in the mind - can exacerbate the sense of guilt that a depressive disorder brings with it, and it can feed the culture of shame and silence that still surrounds depression and other mental health disorders.
It has been said many times, but it is worth repeating, that if my arm is broken I can at least count on the cheerful support of people around me. There will probably be an entertaining story to tell about how it happened, perhaps some thrillingly gory details to share, and other people will generally be happy to listen, to sympathise, to tell in return their own war stories, and to pass on their nuggets of medical advice. But if my mind is broken I can count on none of this. If I am depressed - joyless, hopeless, sleepless and plagued by an incessant sense of worthlessness - I am also much more likely to find myself on my own. I will not be dining out on my unvarnished monologue of despair; people will not be entertained by my story about the funny thing that happened to me in the psychiatric outpatient clinic; they will not be eager to share comparable experiences of their own; the subject will be changed, even my friends may “not know what to say”. If I am working, I will probably not want my employer to write the word depression into my HR file. If I am looking for work, I will probably find some alternative facts to explain the several months of sick leave I was forced to take from my previous job. If I am running for public office the disclosure of depression may be enough to derail my campaign. In some countries, if I was hoping to get married, common knowledge of my depression could be enough to trash my eligibility and to blight the marriage prospects of my brothers and sisters, too.
It’s called stigma. Jesus of Nazareth was stigmatised by the wounding of his hands and feet when he was crucified; he was physically marked as a common criminal subject to the most degrading and humiliating punishment. The modern stigmatisation of depression and other mental health disorders is not so explicitly brutal. We’d like to think that we have become more civilised and, yes, there has been real progress. We no longer do many of the barbaric things we have done in the past to people with mental illness. But we still prefer not to talk about it. We still don’t really know what to say - because if it’s all in his or her mind - aren’t they personally, poor souls, to blame? In the 21st century, depression is stigmatised not so much by what is done to the patient, by physical wounds or barbaric treatments, as by what is not done or said. We exercise a kind of virtual quarantine, separating the depressed person’s experience from ordinary conversation, leaving him or her alone to get over it, to work through it, to pull himself together, to get back to us when she’s sorted herself out.
If the dualist isolation of depression in the mind implies a degree of personal blame for causing the problem, it also implies a degree of personal responsibility for finding the solution. Although it may be too shameful to talk about at home or chat about at work, we expect that a certain kind of talking may be exactly what’s needed for the patient to understand where their feelings are coming from, to build a narrative, to explain to themselves how they became depressed, what their depression means to them. In the weird world of dualism, we might not know what to say to our friends with depression, we might not want to talk about it with them ourselves, but we are also often adamant that they just need to talk about it with someone, someone who’s trained to breach the stigmatised circle of silence.
Super-shrink
For most of the last 100 years or so, it has been common currency that since depression is a disorder of the mind it can and should be cured by the mind. Psychological symptoms need psychological treatment and physical symptoms need physical treatment. It makes perfect sense to a good Cartesian doctor.
The inventor of the world’s first psychological treatment was of course Sigmund Freud. I say “of course” because Freud’s fame is so extraordinary and the influence of his ideas so extraordinarily enduring.
If often he was wrong and, at times, absurd,
To us he is no more a person
Now but a whole climate of opinion
Under whom we conduct our different lives.
We are all Freudians now, as Auden said,26 at least to some degree, whether we like it or not. We all say and do things that issue, however osmotically or obscurely, from the astonishing scope and impact of his analysis. Peak Freud is behind us, no doubt, but he is still the most cited author on Google Scholar, ahead of bibliometric lightweights like Marx and Einstein by a country mile. I remember being awed simply by the sight of the pale-blue spines of the 24 volumes of the Standard Edition of his collected works, lined up on a long shelf in the library of the Institute of Psychiatry in London. The collection of papers and books written by other people about those 24 books by Freud would have filled the entire library.
What has always intrigued me about him was how he got started, and it was not as a psychologist, on the mental side of the Cartesian line. Until his late twenties, Freud aspired to be a brain scientist, a neuroscientist, as we’d now say, working on the physical side of the dualist divide. He was a student of some of the founding fathers of neuroscience and published one of his first papers on the microscopic anatomy, the layout of individual nerve cells, in the spinal cord of “one of the lowest of the fishes”. He wrote a paper on aphasia, the loss of language caused by strokes or other pathological lesions of the brain. He conducted many studies on cocaine, often involving self-administration of a supply he had sourced from the drug company Merck in 1884. Freud became one of the first scientists to discover that cocaine rapidly and reversibly numbed the absorbent membranes of the nose and the eye. He could see this was a discovery with medical impact: perhaps cocaine could be used as a local anaesthetic for nose or eye surgery? It was a discovery that could have made him a star. But, at a crucial moment, he was lured away from his studies to spend a holiday with his fiancée. By the time he returned from this happy hiatus, another (now forgotten) scient
ist had demonstrated that cocaine could be used as a surgical anaesthetic for eye operations on animals, depriving Freud of the public glory of his discovery. As he later remarked, I think ironically, “it was the fault of my fiancée that I was not already famous . . . but I bore [her] no grudge for the interruption”.27 They married and settled down in 1886.
Over the next 10 years, his life switched tracks. Freud knew that the career path of a serious neuroscientist to a professorial chair in the University of Vienna was not open to him, because he was Jewish, although he would have been a strong candidate on merit. He had to spend more time away from the laboratory doing private medical practice to support his wife and family. And his professional relationships became concentrated on intense intellectual “congress” with just a few key peers or comrades, like Josef Breuer and Wilhelm Fliess.
Breuer was an older man, who had already won the high medical accolade of having a bit of the human body named after him (and his colleague, Ewald Hering). Together they had discovered the Hering-Breuer reflex, which slows down your heart rate when you take a deep breath. You can try this at home. Sitting quietly, feel the pulse at your wrist, and count the number of heartbeats in a 30-second period (which should be about 35). Then inhale deeply and hold your breath for 30 seconds, with your chest fully expanded, while you take your pulse again. Then breathe out while still feeling your pulse. You should have found that while your lungs were fully inflated your heart rate slowed down; and then it speeded up when you started breathing normally again. That is the Hering-Breuer reflex in action. Inflation of the lungs quickly, automatically, reflexively slows down the heart rate by sending a signal through the vagus nerve. It is one example of the many ways in which the vagus nerve mediates connections between the brain and the body. But Breuer’s later work with Freud focused instead on hypnosis for the treatment of hysterical symptoms in young women and resulted in their joint publication of a series of case histories in 1895.
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