Chapter 7
SO WHAT?
Change can come slowly to medicine. It is a highly regulated and professionally conservative business, and there are overwhelmingly good reasons for that. Nonetheless, it can be frustrating. Countless people have noticed a link between inflammation and depression in their own lives. It is not uncommon to become seriously depressed after breaking a bone, or to experience mood swings that oscillate in sync with the exacerbations and remissions of inflammatory bowel disease. Chronic fatigue syndrome, which has some features in common with depression, can follow glandular fever, a viral infection of lymphocytes in adolescence. The menopausal transition, which is associated with a high rate of depression and anti-depressant drug use among mid-life women, is also associated with an increase in peripheral inflammation.81 And it is not only biological factors that can affect both mood states and the immune system. Social factors, like adversity or conflict, can also cause inflammation, which might help to explain the very frequent experience of depression being triggered by adult or childhood stress.
But what practical advice can contemporary scientific medicine offer on this theoretical basis? What kind of advanced services might be available for treatment of the inflamed mind? To manage expectations up front, we should think positive in the medium term, but know that the treatment options for inflamed depression are limited at the time of writing (2018).
Many patients struggle to access healthcare that is joined up, between body and mind, across the old Cartesian fault-line. Physicians often prefer looking at X-rays to making eye contact; psychiatrists have been trained to leave their stethoscopes at home. It is very difficult, at least in the British NHS in 2018, for a patient with inflamed depression (or dementia or psychosis) to find a clinical service that will deal in an even-handed way with both the physical and mental aspects of their condition. There is talk, at a high level in governments and other important bodies, about “parity of esteem” between physical health and mental health. People working in NHS mental health services would love to believe that this is more than just an inspiring phrase. But there is not yet much sign of integrated and equitable delivery of specialist physical and mental health services to patients.
Arguably, the medical profession has been slow to acknowledge the importance of such an integrated approach to physical and mental health, not at all because individual doctors or scientists are incompetent or negligent or heartless, but because the well-trained eye has a Cartesian blind spot. Like all blind spots, this both blinds us to something (that’s hiding in plain sight) and blinds us to our blindness. We can’t see something and we can’t see that we can’t see it.
Neuro-immunology has begun to give us new insight into how and why the immune system can link body and mind. But so what? What can we do with this new knowledge that could really make a difference to the experiences of people with depression?
The immune perspective on depression could open up several possible new lines of treatment. Development of anti-inflammatory drugs and antibodies, as next generation anti-depressants, is one obvious way to go. It is also likely that immunological thinking will increasingly influence the development of new drug treatments for other brain and mental health disorders, like Alzheimer’s disease and schizophrenia. But recognising the causal links between body, brain and mind that are mediated by the immune system does not lead only to new drug treatments, and is not relevant only to biotech and pharmaceutical companies. Neuro-immunology could inform the development and optimisation in practice of other treatments that are more attractive to the many depressed patients who don’t like taking drugs and the many mental health practitioners who don’t like prescribing them. Bearing in mind what we now know about how the vagus nerve controls inflammation, maybe we could use nerve-stimulating devices to treat inflamed depression? And recalling the crucial importance of stress for both inflammation and depression, maybe we can monitor the effectiveness of psychological and social interventions by inflammatory biofeedback?
I am uncharacteristically bullish about the chances of progress (Fig. 12). But none of this has yet happened; and we can’t be sure it ever will happen until it has actually begun to make a real difference to the experience of being clinically depressed.
Medical apartheid
These days, specialist medical services are routinely split down the middle, following the Cartesian divide between body and mind. Patients see a physician, who attends to the physical aspects of their disorder, or they see a psychiatrist or psychologist, who attends to the mental aspects. Physicians and psychiatrists are separately trained as specialists in one or other of the dualist domains. Cross-talk is not encouraged. Physicians are expected to acquire deep expertise in the biological mechanisms of physical health disorders but have a licence to ignore mental health. Psychiatrists are expected to have esoteric knowledge about the psychological causes of mental health disorders but not to be competent in matters of physical health. I am caricaturing, but slightly. I saw both sides of the divide in the space of about six months in 1989 as I transitioned from the end of my training as a physician, when I learnt that it was professionally OK to do nothing about mental health symptoms, in a case like Mrs P, to the start of my training as a psychiatrist, when I learnt that it was professionally suspect to do anything about physical health symptoms.
For the first few months of my new life as a psychiatrist, I brought my stethoscope to work with me, which was immediately regarded as eccentric, and I couldn’t help noticing that many of the so-called mental patients on the wards had undiagnosed or untreated physical disorders. I remember seeing a man who had been diagnosed as having panic attacks and alcohol dependence. Reading through his notes, I could see that my new colleagues had reasoned that his panicky symptoms of a racing pulse and over-breathing were caused by his mental state of anxiety, and that he was self-medicating with alcohol in a misguided effort to subdue his anxiety and control his panic attacks. It was all in the mind. I listened to his heart and lungs with my stethoscope and it seemed that the story could be told the other way round. His heavy drinking was causing his heart muscle to fail - it was a case of alcoholic cardiomyopathy, to use the physicianly jargon - and the heart failure was causing his body to pump adrenaline, which was driving his panic and anxiety. It was not all in the mind. These were mental symptoms of a physical disorder.
Figure 12: The vicious cycle of stress, inflammation and depression — and ways to break it — an artist’s impression. Inflammation can change how the brain works, which causes mood changes and depressive disorders, which increase the risk of social stresses, which cause bodily inflammation, and so on. There could be be several ways to break this vicious cycle. In a dualist world, depression is all in the mind and treatment is psychological. Since the 1950s, we have in practice also often treated depression with drugs that act on the brain. Stress relief or control is an expected benefit of meditation or mindfulness training; but major causes of social stress, like poverty
or abuse, are not easily soluble. The new therapeutic idea is that we could also try breaking this vicious cycle, as it passes through the body, by targeting the inflammatory links between depression and social stress as well as between depression and bodily disorders like arthritis and obesity. This could mean re-purposing drugs, like anti-cytokine antibody infusions, that are already used for treating the bodily signs and symptoms of inflammation but have not yet been used as treatments for the inflamed mind.
After a couple of such cases, the consultant psychiatrist I was working for at the time had a quiet word with me. Of course it was a good thing, she said, that I was helping this man and others to find medical treatment. But what did it signify about my attitude to becoming a psychiatrist? Had I fully accepted - or was I in denial - that I was now on a very different career path, which would take me ever further away from the world of the body and ever deeper into the world of the mind? She saw my stethoscope as a kind of comfort blanket, a symptom of my anxiety about leavin
g behind the more prestigious, white-coated company of physicians and becoming a lowly psychiatrist instead. “I think you need to cut the umbilical cord,” she said, smiling at me bravely, meaning I had to abandon medical practice if I was to be reborn as a psychiatrist. I didn’t think I was in denial; but then, you wouldn’t, would you? I quickly realised that if I assertively denied that I was in denial this would be interpreted, from her Freudian perspective, as libidinal reinforcement of my unconscious defence mechanisms, as proof that she was right. I still have my stethoscope, on a shelf in my office, but I haven’t used it for about 25 years.
It is just another anecdote, I know, but I don’t think my experiences as a medical student, a young physician, or a young psychiatrist, were or are particularly unusual. I see them all as trivial but typical consequences of the Cartesian partition of the human condition into two qualitatively distinct domains, reflected in the rigid demarcation of physical from mental health. The more serious consequence of this medical apartheid, in my opinion, is that it is a bad deal for patients.
We have seen already that apartheid was not a good deal for medical patients, like Mrs P. She was left stranded in no-man’s land with her “co-morbid depression”. Her physicians didn’t see it as their problem. A psychiatrist couldn’t call it a bona fide case of MDD. Her fatigue, pessimism and sense of brain fog were not well recognised or treated on either side of the line. Mrs P was effectively left alone to “get over” or “work through” or “worry less about” significant psychological symptoms of her rheumatoid disease. The culture of stigmatisation and shame would have discouraged her from complaining that the medicine wasn’t working - she still felt like shit. If she was a good patient, and Mrs P was, she would get on with it, readjust, move on, admirably, somehow. Since then, 1989, there has been some improvement in psychological awareness in medical outpatient clinics, but depression, fatigue and cognitive function are not routinely assessed in patients with major inflammatory disorders in the UK. It seems very likely that there are many people with serious inflammatory disorders who have unrecognised and under-treated psychological symptoms. I would be extremely surprised if there aren’t other Mrs Ps out there even today, invisible to their Cartesian physicians.
And I think medical apartheid is also a bad deal for psychiatric patients. One of the most shocking healthcare statistics I know is that the average life expectancy of patients with serious mental illness is at least 10 years less than expected.82 If you’ve got a long-term disabling mental illness, like MDD or bipolar disorder or schizophrenia, you’re likely to die at a much younger age, even if you live in a rich city like London in 2018. To put it another way, the impact of chronic schizophrenia on life expectancy, the lethality of schizophrenia, is about the same as the lethality of cancer: both cause the loss of 10-15 years of life.
Often when I’ve shared these statistics with people, they’ve said, yes/but, it must be because of the suicides. It must be that the life of a patient with serious mental illness is reduced, on average, because disorders of the mind can so derange reason that some patients kill themselves, often while they’re still young. But that Cartesian reflex is not the right answer. Even if you take out all deaths by suicide, the life expectancy of people with serious mental illness is still cut by a decade.83 So-called mental patients are dying younger from physical disorders - like diabetes, heart and lung disease. This could be because, in apartheid healthcare systems, schizophrenia and bipolar disorder are treated solely as diseases of the mind, and many patients have unrecognised and under-treated diseases of the body. People with severe mental illness often have difficulties with self-care and with accessing appropriate medical, educational and social services. Some of the commonly used drugs for psychotic symptoms cause weight gain and diabetes. There are many factors in play but the base fact that serious mental illness is as lethal as cancer cannot be written off as a statistical quirk, attributable to the biasing of the data by a few young deaths by suicide among patients with severe depression, bipolar disorder or schizophrenia. Many patients of all ages with serious mental illness also have serious physical illness. Their prospects are critically disadvantaged by having to negotiate health services that are split between mind and body.
Could it be different already?
Let’s imagine that you know someone who is depressed, a friend or a family member, and as you’ve been reading this book you’ve been wondering how much of this new science of immuno-psychiatry might be relevant to him. Is there anything that could be done differently now, as a result of thinking about his immune system, that could help him to recover from depression?
What would happen to him if he went to his GP in 2018 and asked her if his depression was anything to do with inflammation? What would the doctor be able to do to assess whether his depression really was related to inflammation? And if it was, what then could she do about it? I’m afraid the most likely outcome would be underwhelming, even if his doctor is terrific, open-minded, well-informed, and has plenty of time on her hands.
What could she actually do with him sitting there in front of her? She could ask him a lot of questions to work out if he had a medical disorder, like Mrs P’s rheumatoid disease, that is known to cause severe inflammation. But if the answer to all those questions was negative - he had no known inflammatory disease - that wouldn’t mean he wasn’t inflamed enough to cause depression. It could be that he’s got an inflammatory disease that he doesn’t know about because it hasn’t yet been diagnosed. Or it could be that he’s moderately inflamed because he’s overweight, or because he’s stressed by looking after his wife with Alzheimer’s disease, or because he was badly treated as a child, or because he is elderly, or some combination of these and other common factors that are known to cause inflammation.
His doctor might sigh. The only way to know more is to do a blood test. But what tests for inflammation are realistically affordable and available in general practice? In 2018 in the UK, the choice is limited. His doctor could probably be persuaded to check his full blood count - measuring the number of macrophages, lymphocytes and other white blood cells in circulation - and the blood level of C-reactive protein, or CRP.
Let’s say the doctor does a blood test for CRP and the result is 4.8 mg/L. What does it mean? It’s not stratospherically high - so it doesn’t suggest he’s got a major undiagnosed disorder, which is good news. But it’s outside the normal range. Most doctors reckon that CRP should be less than 3 mg/L to count as normal, so 4.8 is enough to count as low-grade or moderate inflammation. Your friend or family member would then have more reason to believe that his depression could be related to his bodily inflammation; but what could he or his doctor do differently as a result?
An obvious idea would be to try taking one of the many anti-inflammatory drugs that are already in widespread use, like aspirin. If his depression is caused by inflammation then trying an anti-inflammatory drug makes sense, in principle; but would probably not be recommended by his doctor, in practice. There are two good reasons for current medical reluctance to prescribe anti-inflammatory drugs for patients with inflamed depression. First, there is no solid evidence that aspirin or any other anti-inflammatory drug already in medical use has anti-depressant effects. The clinical trials that would be needed to provide such evidence have simply not been done. There is strong but circumstantial evidence that some anti-inflammatory drugs (minocycline and diclofenac, in particular) have anti-depressant effects when they are prescribed for pain or other inflammatory symptoms.77 But no anti-inflammatory drugs are officially licensed for treatment of depression. Second, even if your friend’s doctor was prepared to prescribe an anti-inflammatory drug “off label” or speculatively, without clear evidence that it was likely to work, she would be deterred by the certain safety risks. Aspirin, for example, commonly causes stomach irritation, ulceration and bleeding. A doctor obedient to the Hippocratic oath to abstain from doing harm to her patients will not prescribe a risky drug in the absence of evidence
that the risk is likely to be outweighed by the benefit.
So a careful doctor in 2018 is likely to steer your friend away from existing anti-inflammatory drugs and towards treatment of the underlying cause of his inflammation. And there is a long list of possible reasons for low-grade inflammation to consider, including obesity, age, social stress and seasonal cycles, which I’ve already mentioned, as well as some that I haven’t.
Periodontitis, literally inflammation around the teeth, would be top of my list of culprits if I was inflamed and depressed. This is a low-grade chronic infection that can easily get forgotten because most doctors don’t think about it, seeing it as a dentist’s business, and most dentists aren’t paid to think about the links between gum disease and depression. Does your friend have bad breath? It could be relevant.
Various gastrointestinal disturbances, like irritable bowel syndrome or intermittent colitis, are also likely suspects. The gut is full of bacterial antigens, some of them toxic, and the walls of the gut are eight metres long, about four to five times longer than our average height. All along the watchtowers of this long frontier, between the self and hordes of possibly hostile non-self bacteria, macrophages are concentrated. There are constant skirmishes between invasive gut bacteria and defensive macrophages that pump cytokines into the circulation, and could push up CRP. The inflammatory intensity of so-called leaky gut syndrome is a product of the toxicity of the bacterial flora of the bowel - the microbiome - and the strength of immune response. So someone with a deprived or abused childhood, one can imagine, whose macrophage army is already on yellow alert after exposure to such early and severe social stress, might have a more inflamed and depressed reaction to hostile gut bacteria in the microbiome many years later. It’s complicated. Not only are there many individual factors that can each cause lowgrade inflammation, they can also interact with each other to compound their inflammatory effects.
The Inflamed Mind Page 16