The Inflamed Mind Read online

  Social stresses less singular and extreme than a bereavement can also cause inflammatory activation of macrophages.14 Biomarkers of inflammation, like cytokines and CRP, are increased in many stressful situations, including poverty, debt and social isolation. Carers of patients with Alzheimer’s disease, people with day-to-day responsibility for a spouse or relative with dementia, have increased inflammatory biomarkers.74 So do adults who suffered poverty, neglect or maltreatment as children.

  An important epidemiological study from New Zealand followed a cohort of 1,037 children born in 1972-73 in the city of Dunedin.15 The children were carefully assessed for their socio-economic status (roughly speaking, the wealth of their parents), their social isolation and their experience of maltreatment. When they were reassessed as adults 30 years later, it was found that the incidence of inflammation, depression and obesity was approximately twice as high in the adults who had been impoverished, isolated or abused as children. We have known for decades that the immune system has a long-term memory for childhood infections or vaccinations. Now we are beginning to understand that the immune system could also be able to remember childhood episodes of assault or famine or any other severe threat to the self’s early survival. Child abuse survivors may enter adult life with their immune system set on a hair-trigger, poised to react to minor infections and social setbacks with a disproportionate inflammatory response that causes depressive symptoms. There could perhaps be a novel, immune-related explanation for the adverse effects of childhood abuse on adult mental health, effects that were first courageously recognised by Freud (and Breuer) more than 100 years ago.

  But you don’t have to be depressed, bereaved or abused to know what social stress is like. There are some things that almost everyone finds stressful to some degree, and public speaking is one of them. Standing up in front of a lot of people to talk to them all at once, even for a few minutes, almost always causes a subjective sense of apprehension or anxiety, accompanied by an objective bodily state of arousal with increased blood pressure, heart rate and sweating. The body’s response to public speaking is a muted form of its fight-or-flight response to many different challenges: to pump up adrenaline and noradrenaline, to activate the sympathetic nervous system. And, at the same time, to ramp down the calming, anti-adrenaline effects of the vagus nerve. For some people, this adrenalised, anxious state is so aversive they just won’t put themselves through it. Being asked questions in public, as we medical students were interrogated on the wards at Bart’s, is also stressful. Even people who now seem to be very comfortable with public speaking, very quick on their feet with questions, will often have worked hard in the past to master their automatic, reflexive anxieties about doing it. That much we have known about the stress of public speaking for a long time. What has only become known more recently is that even relatively minor stresses like public speaking cause rapid inflammatory activation of the body.

  The Trier social stress test is designed to simulate the challenge of public speaking in an experimentally controlled way. The experimental subject or participant is asked to address an audience of four people for 12 minutes and is then tested by members of the audience on mental arithmetic questions for four minutes. Often the experiment is set up so that the participant speaks from a standing position in front of a table, on the other side of which is seated the audience, each of them wearing a white lab coat and a dissatisfied expression. We can probably all imagine how stressful this experience will be for the participants - even though they know consciously that it is not for real, it is an ethically approved experiment, and nothing can go seriously wrong for them as a result of their performance.

  A group of happy and healthy schoolteachers, who felt professionally satisfied by their work in German schools in the 1990s, participated in a recent study which required them to provide two blood samples for testing, once before and once after they had done the Trier social stress test.75 The macrophages circulating in their blood were significantly more activated, were pumping out more cytokines, immediately after public speaking than they had been before. And then the experiment was repeated with a second group of schoolteachers, who were professionally frustrated by their work. Teaching is a notoriously stressful job, with high levels of early retirement and absence due to sickness, and this second group of teachers felt that the effort they were putting into their work was not adequately rewarded; the burden of their responsibilities was not compensated by money, promotion, or the respect of their students and colleagues. They were still managing to come in to work but they were burning out. The macrophages of the burnt-out teachers were angrier than the macrophages of the happy teachers before the test; and they became even angrier as a result of the added stress of public speaking.

  We don’t yet know for sure exactly how a stressful event, like public speaking, could activate the immune system but there are a couple of plausible ideas under investigation. For example, we know that the adrenaline rush in response to stress sends a danger signal to macrophages, triggering the same kind of angry response as a signal of dangerous infection like LPS. We also know that stress can interfere with the hormonal system in the body, making macrophages less responsive to the calming effects of steroids.10 There are many details still to resolve, as always, but that’s one of the fascinating things about science: every step forward generates more questions.

  Causal chains and circles

  Stringing it all together, we can now claim to understand how inflammation causes depression, and where that inflammation could come from in the first place. We can construct a simple linear narrative, tell a story with a beginning, a middle and an end. Once upon a time, there was stress, which caused inflammation, and then depression, in the end. That could be how stress causes depression. That’s now a plausible and testable mechanistic hypothesis that deserves further investigation, especially in relation to the development of new treatments for depression.

  But it could also be possible for the causal relationships between stress, inflammation and depression to be circular rather than linear.76 It is not unusual for patients to find that their depression puts them under greater social stress - being depressed they are more likely to be socially withdrawn and lacking energy. They will almost certainly suffer some degree of stigmatisation, their most supportive relationships may deteriorate, they may lose income or economic status, they may become more reliant on state benefits. In other words, there are many social ways in which depression can cause stress, to add to the neuro-immunological ways we now know by which stress can cause depression.

  It could be a vicious cycle. Greater exposure to early severe stress - like child abuse - could increase the body’s natural tendency to become inflamed in response to social stresses later in life. Increased inflammation in response to stress could drive greater changes in the brain, causing more severe depression. Then the depression itself - the diagnosis and treatment of MDD - could act to increase the risk of more stress arising in the future, and so on, and on.

  I can recall seeing a patient, a young woman, who had been sexually abused by her stepfather between the ages of 11 and 13. She had some minor depressive symptoms in adolescence, as many young women do, but she seemed to be OK. Then he died, when she was in her twenties, which brought it all back to the surface, and out into the open with her family, and triggered a major depressive disorder. For a while she was very unwell - she hated and seriously harmed herself, believing that her stepfather was Satan and she must follow him into hell. She was admitted to a psychiatric hospital for treatment against her will. When she came out, four months later, she was better, at first, less depressed when I asked her the usual questions in the outpatient clinic. But she’d lost her place in the world. She’d lost the flat she was renting with friends. She’d missed deadlines for job applications. Her family was still torn apart by the impact of her stepfather’s death. Many professionals and other people tried to help. But she was adrift, socially stressed by her isolation, and it wasn’t
long before she was back in hospital, this time with greater suicidal determination. She tried all the usual anti-depressant drugs, without much obvious benefit. In the end, I am sure it was her family coming back together, and supporting her, that did the most to help her recovery.

  Now when I think back on her story - which is not an unusual kind of story in mental health services - I wonder how much of it could have an inflammatory angle. Were her blood and brain macrophages activated by the abuse, primed to kick off throughout her adolescence, and then explosively reactivated by the stress of her abuser’s death? Is that why she became depressed the first time? And were her macrophages still on high alert, like those of burnt-out schoolteachers, when she encountered new social stresses, coming out of hospital? Like schoolteachers doing the Trier social stress test, did she have an inflammatory over-reaction to the additional stress, of social demotion and disorientation, caused by her first depression? Is that why she became depressed the second time? In her case, we’ll never know for sure if such a positive feedback loop was cycling viciously from stress to inflammation to depression and back to stress. It didn’t cross our minds at the time. We never thought about inflammation, or did blood tests for immune biomarkers, in psychiatric outpatient clinics back then.

  In future, I think we will know more about the circular logic of stress, inflammation and depression, and we should be able to use this knowledge to make a difference to treatment of depression (Fig. 12). But this still won’t address the ultimate question: why does inflammation cause depression?

  Ultimately, the answer must always be Darwin

  When it comes to biological systems - or life as we know it, scientifically - the answer to the question “why?” is always the same: natural selection. Why do finches have differently shaped beaks on the different islands of the Galapagos archipelago? Why do some orchids produce flowers that look like bees? Why does an elephant have tusks or a tiger have stripes? The ultimate reason for any biological phenomenon or phenotype to appear in life, or to disappear into the fossil record, is that it is more or less adaptive, more or less likely to make an organism fit to survive. Random genetic mutations constantly generate minor variations on the theme of existing species. If some genetic mutations happen, by chance, to make the organism more adaptive, more resilient, or in any other way more reproductively successful, then the mutated form of the gene will be naturally selected for onward transmission to future generations, and the species will slowly evolve along the trajectory coded by expression of the selected gene. The standard answer to the why question for tiger stripes is that the first tiger with a mutant pigment gene that randomly produced camouflage stripes turned out to be less vulnerable to predators or rival tigers, more likely to survive and reproduce, so that the stripy mutation was naturally selected in generation after generation as the species evolved to the point that all tigers were striped.

  That is the modern evolutionary synthesis, the biggest idea in biology, the bringing-together of genetics and the Darwinian principle of natural selection, which can explain why almost everything in life is as it is. Can it help us answer the general question: why are so many of us depressed? Or the more mechanistic question: why does the immune system cause people to become depressed?

  If you ask Google about Darwin and depression, the top-ranked hits will not lead you to his evolutionary theory of depression but to other people’s theories about his depression. Charles Darwin suffered all sorts of symptoms throughout his adult life, both bodily symptoms like vomiting and flatulence, and mental symptoms like panic and fatigue. He couldn’t cope with the stress of public speaking in defence of his controversial ideas and he never had what you might call a proper job. He secluded himself from the world, living quietly on his private income in an old rectory outside London, writing his books about earthworms, barnacles and the origin of species. While he was alive, he baffled the many physicians he consulted but found some relief from spa treatments, homeopathy and a diet without dairy products.

  Even after his death, the origin of Darwin’s illness has remained a surprisingly lively topic. At least 30 different diagnoses have been proposed, ranging from postural hypotension to lactose intolerance and melancholia. One of the more exotic ideas is that he picked up a nasty infection, called Chagas disease, when he was bitten by the “great black bug of the Pampas” while exploring Argentina on his voyage on HMS Beagle. It’s a story that might seem to suit my story well: one can imagine a chronic bacterial infection like Chagas disease causing inflammation which in turn caused Darwin’s social withdrawal and other depressive behaviours when he returned to England. But one moral of my story is that we need biomarkers to make a diagnosis of inflamed depression. Despite some recent, misguided attempts to exhume Darwin’s body from his grave in Westminster Abbey for DNA testing, we don’t have any biomarkers on him. And personally I think we should let his bones rest in peace.

  There is less confusion about Darwin’s interest in insanity than there is about his own state of mind. As a young man, he discussed cases of madness with his father, a physician, and in later life he corresponded extensively with Henry Maudsley, the 19th-century English psychiatrist who founded the hospital named after him in London. What Darwin wanted to know from Maudsley, and the other asylum superintendents he corresponded with, was what their patients looked like, what facial expressions were characteristic of melancholia or mania.

  Darwin held the view that human emotions were expressed by, or might even be caused by, contraction of facial muscles, and that these muscular mechanisms for emotional expression were inherited by descent from animals. This is an idea that might seem easy to endorse these days. Yes, of course, we can tell if people are happy or sad by whether they’re smiling or frowning. And many people believe that they can tell by a dog’s or a horse’s facial expression if it is feeling bored or anxious or surprised. Darwin’s idea of “grief muscles”, which cause emotion by expressing it in the face, is even compatible with the recent discovery that Botox injections, used cosmetically to iron out the wrinkles of ageing by paralysing facial muscles, have strong anti-depressant effects.77

  However, this idea of emotional expression has some troubling implications from a Cartesian perspective. If human emotions are expressed or generated by bodily mechanisms, inherited by descent from lower animals, then they cannot be the province of the mind or soul. Darwin’s ideas about the facial expression of emotions pushed his evolutionary theory close to the heart of human nature and provided a material explanation for fine feelings that many of his contemporaries would have preferred to believe had a spiritual meaning. Darwin managed the prospect of ideological conflict, which he did not enjoy, by amassing copious quantities of data. Reasoning that “the insane ought to be studied as they are liable to the strongest passions and give vent to them”, he included second-hand descriptions, and pioneered the use of photographs, provided by Maudsley and others, to convey the facial expressions of the inmates of their asylums in his book The Expression of the Emotions in Man and Animals.78 (Fig 11).

  Darwin used clinical data on “the insane” to inform his thinking about evolution. But what he did not do was turn things around and try using evolutionary theory to inform our thinking about the origins of insanity. Darwin and Maudsley were both well aware that psychiatric disorders tended to run in families and were therefore heritable. Darwin was worried about the risk of insanity arising in his own large family because of his consanguineous marriage to his cousin Emma. Maudsley, like Kraepelin and other psychiatrists of the time, could see patterns of familial clustering and generational transmission in large asylum populations of schizophrenia, manic-depressive insanity, psychopathy and a myriad other diagnostically labelled cases.

  According to Darwinian theory, a melancholic or depressive disposition, like any other trait that passed from one generation to another, must be subject to natural selection and must somehow make depressed people fitter and more likely to survive. But that is counter-intuiti
ve and counter-factual: we know that serious mental [sic] illness is a mortal blow to fitness, as witnessed by the 15-year cut to life expectancy of patients with schizophrenia and bipolar disorder in the UK in 2018. On the face of it, there is no survival advantage, no competitive edge, no reproductive reward for serious mental illness. So how has it come to be? How has depression evolved, if not to make us fitter?

  Figure 11: Emotional faces and emotional brains. Darwin collected observations on patients with melancholia and other species of insanity from the well-stocked asylums of eminent European neurologists and psychiatrists. He paid particular attention to the orientation of the eyebrows, and the pattern of muscular ridges and furrows between them, the omega sign, so called because it was supposed to look like O. More than 100 years later, the standard test faces chosen to express a normal range of sadness for fMRI research studies are still Darwinian in their focus on eyebrow angle as a signal of mood. As Darwin might have predicted, but never knew, the saddest faces cause the strongest activation of an emotional brain network that we have inherited by descent from other animals.

  The heritability of mental disorders posed a question for natural selection that Darwin didn’t get to before he died. Maudsley, on the other hand, had time to answer the question more explicitly, but in a non-Darwinian way that took us in totally the wrong direction for about 50 disastrous years. He was one of many fin de siècle psychiatrists who thought that the progression of mental disorders and criminal types from one generation to another was not dictated by Darwinian natural selection but by an earlier theory of evolution, proposed by Jean-Baptiste Lamarck, who died a few years before the young Darwin set out on his voyage on HMS Beagle in 1831. Lamarck can be credited with writing the first biological theory of evolution, the first step away from the Old Testament’s assertion that all the plant and animal species of life were divinely created and therefore eternally unchanging. Lamarck’s theory expected life forms to change, to become increasingly complex, to evolve; but to do so by the inheritance of acquired characteristics, rather than by the selection of randomly mutated genes.