From depression to dementia, inflammation is medicine’s new frontier
Unlikely as it may seem, #inflammation has become a hashtag. It seems to be everywhere suddenly, up to all sorts of tricks. Rather than simply being on our side, fighting infections and healing wounds, it turns out to have a dark side as well: the role it plays in causing us harm.
It’s now clear that inflammation is part of the problem in many, if not all, diseases of the body. And targeting immune or inflammatory causes of disease has led to a series of breakthroughs, from new treatments for rheumatoid arthritis and other autoimmune diseases in the 1990s, through to the advent of immunotherapy for some cancers in the 2010s. Even more pervasively, low-grade inflammation, detectable only by blood tests, is increasingly considered to be part of the reason why common life experiences such as poverty, stress, obesity or ageing are bad for public health.
The brain is rapidly emerging as one of the new frontiers for inflammation. Doctors like myself, who went to medical school in the 20th century, were taught to think that there was an impermeable barrier between the brain and the immune system. In the 21st century, however, it has become clear that they are deeply interconnected and talk to each other all the time. Medical minds are now opening up to the idea that inflammation could be as widely and deeply implicated in brain and mind disorders as it is in bodily disorders.
Advances in treatment of multiple sclerosis have shown the way. Many of the new medicines for MS were designed and proven to protect patients from brain damage caused by their own immune systems. The reasonably well-informed hope – and I emphasise those words at this stage – is that targeting brain inflammation could lead to breakthroughs in prevention and treatment of depression, dementia and psychosis on a par with the proven impact of immunological medicines for arthritis, cancer and MS. Indeed, a drug originally licensed for multiple sclerosis is already being tried as a possible immune treatment for schizophrenia.
Is that hope realistic for depression? It is beyond reasonable doubt that inflammation and depression are correlated with each other – or comorbid, to use some unlovable but important medical jargon. The key scientific questions are about causation, not correlation. Does inflammation cause depression? And, if so, how? One experiment that scientists have designed to tackle these questions is to do two functional MRI brain scans, one before and one after an inflammatory response has been deliberately provoked by the injection of typhoid vaccine. If there’s a difference in the two scans, that shows that bodily inflammation can cause changes in the way the brain works; if not, that would be a problem for the theory that inflammation can cause depression.
A recent meta-analysis reviewed data from 14 independent versions of this experiment. On average, the data showed a robust effect of inflammation on brain activity. These results confirmed that bodily inflammation can cause changes in how the brain works. Encouragingly, they also localised the effect of inflammation to particular parts of the brain that were already known to be involved in depression and many other psychiatric disorders.
If inflammation can cause depression then anti-inflammatory drugs should work as antidepressants. Several
studies have reviewed clinical trial data on thousands of patients treated with anti-inflammatory drugs for arthritis and other bodily disorders that are commonly associated with depressive symptoms. Overall, patients treated with anti-inflammatory drugs, rather than a placebo, had significantly improved mental health scores. However, there is a caveat. The largest and most rigorous of these studies were designed to test drug effects on physical health and that makes it difficult to interpret the results too strongly as proof of beneficial effects on mental health.
The next step is to run studies designed from the outset to test new antiinflammatory drugs as antidepressants, or to test existing antidepressants for anti-inflammatory effects. In doing so, we must avoid repeating one of our most habitual mistakes about depression, which is thinking that it’s all one thing, always with the same root cause. So we shouldn’t be looking for the next “blockbuster” that can be automatically prescribed to make the whole world happier. We should be looking for ways to match the choice of treatment to the cause of psychiatric symptoms on a more personalised basis. And using blood tests to measure inflammation could help us to make those choices.
For example, a consortium funded by the Wellcome Trust has just started a trial of a new anti-inflammatory drug for depression. It is one of the first antidepressant trials ever to use blood tests to screen for inflammation in potential participants. If the blood tests show no evidence of inflammation then patients will not be recruited into the trial, because if they are not inflamed, there is no reason to think they will benefit from antiinflammatory treatment.
An alternative example might be ketamine, which has just been licensed in the UK for treatment of depression. It works by blocking a receptor for glutamate in the brain but it doesn’t work equally well for everyone. We know that inflammation can increase the amount of glutamate in the brain, so it’s predictable that more inflamed patients might be more responsive to the glutamate-blocking effects of ketamine. In future, we might use blood tests or biomarkers of inflammation to predict which depressed people are most likely to benefit from ketamine.
The therapeutic scope of these new insights is potentially bigger than depression or drugs. The pharmaceutical and biotech industry is invested in testing anti-inflammatory drugs for Alzheimer’s and Parkinson’s disease. There is also interest in the role of diet, obesity, stress, gum disease, the gut microbiome and other risk factors in low-grade inflammation that could be controlled without drugs.
There are now dozens of studies measuring the anti-inflammatory effects of psychological interventions, such as meditation or mindfulness, or lifestyle management programmes, diets or exercise regimes.
My personal favourite is an American trial to test the idea that lowgrade inflammation can accelerate cognitive impairment with ageing, and that cleaning our teeth more carefully can control low-grade gum inflammation (periodontitis) and thus protect us from senility as we grow older. This trial is still ongoing so the results are not yet known. But I like the thinking behind it. Who would have thought that a brighter smile and a better shortterm memory could be so directly connected? And, ideally, attainable by an intervention as simple and scalable as a toothbrush?
All of this gives us an interesting new perspective on how body, brain and mind are related to each other. And that could be important in thinking about how we scientifically design and deliver the most effective physical and mental healthcare systems for the future. This is vital at a time when mental health disorders and dementia account for a growing proportion of global disability, and health and social care costs.
Currently, physical and mental health services are sharply segregated, reflecting a philosophical prejudice against viewing the mind and body as deeply intertwined. The links that many patients recognise in their own experience of illness tend to be somewhat discounted by the standard NHS provision of mental or physical healthcare services. In contrast, the new science of inflammation and the brain is clearly aligned with arguments for breaking down these barriers in clinical practice. More than that, though, it has the potential to transform our thinking about illness more broadly. The barrier between mind and body, for so long a dogmatic conviction, appears to be crumbling.
• Professor Edward Bullmore heads the department of psychiatry at Cambridge University. He is the author of The Inflamed Mind