Mental Health: Emotions & immunity Converge

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Mental ill health will be the single biggest cause of disability in the next 20 years

“About 80% of all cases of depression are preceded by a stressful life event. The most depressing stressors are events that involve both loss of an important relationship and social rejection”  — Professor Edward Bullmore (British Professor of Psychiatry, University of Cambridge, Author of The Inflamed Mind, A radical new approach to depression).

Mental health is an umbrella term for many conditions.  Our mental health affects how we think, feel and act.  But it also impacts our physical health, how our body deals with infection, how we recover and repair.  Worldwide, ill mental health will be the single biggest cause of disability in the next 20 years. Although the stigma is fading, and society is slowly being kinder and more open, time has stood still with regard to treatments with little developments in the last three decades.  We may not question whether depression is really an illness, as many once did, but we still don’t know what causes it — or how to treat it.  Treatment of mental health disorders is at an important juncture.  The current pill-popping prescription focused model has achieved only modest benefits in addressing the burden of poor mental health worldwide.  New breakthrough science linking the brain and the immune system, bridges the mind and body, opening a whole new way of thinking about mental health and outlining a possible future revolution for prevention and treatment of mental ill health.

A surprising finding.

It may sound surprising that the immune system should be involved in mental health.  Twenty years ago, no one imagined that the immune system had anything to do with the brain. But in fact, the links between mental health and immunity are very strong.  For example, just think about how you felt last time you had flu - the overlap of your immune system dealing with the virus with depressive symptoms - social withdrawal, changes in appetitive, malaise, failure to concentrate and fatigue.  These so-called ‘sickness behaviours’ are adaptive changes in our behaviour triggered by our infection fighting immunological chemical messengers as they whizz around our body.  They instruct us to reorganise our priorities towards rest and recovery.  Further evidence of the involvement of the immune system in brain health comes from recent findings that patients who survive sepsis – an overwhelming and life-threatening immune response to infection - present later with long-term cognitive impairment, depression and anxiety as a result of the strong immune response they experienced.  It’s now more common to find the immune system, more specifically its inflammatory capabilities, frequently named in the medical literature as the root cause of mental ill health and a host of psychiatric conditions.  Inflammation is emerging as the sine qua non of all mental illness.  Not only that, it was previously thought that people suffering from chronic inflammatory diseases such as rheumatoid arthritis were depressed because of reasons unrelated to their physical disease.  They know it’s a long-term disease and can foresee that it will no doubt get inexorably worse until a very dismal end.  But recent dramatic breakthroughs suggest that these co-morbid depressive symptoms are actually a psychological result of having raised inflammatory markers due to their diagnosis.  This link between immunity and psychology is a two-way street.  We know, for example, that people who have had heart attacks as a result of inflammation in the arteries have a 50% increase in depression.  And depression is a risk factor for heart disease and poor recovery from a heart attack.  Ultimately inflammation is important to the body, it’s our main defence from infection and not something we need to completely extinguish.  But inflammation by design is only ever meant to be a short-term assault.  The importance of inflammation and the likelihood that there is a “sweet spot” or optimal level of inflammatory activity as regards to mood state.

More than the genes we are born with

Depression runs in families. If your parents have been depressed, the chances that you have been or will be depressed are significantly increased.  But the answer to the question of nature versus nurture has remained obscure.  A study published in 2018 was able to pinpoint for the first time a selection of genes associated with an increased risk of depression - a significant milestone but one that also raises as many questions as answers.  There were 44 genes in total, so quite a few, but each contributing a moderately small risk – so not a single binary genetic switch.  With more research it’s likely that this number of mental health related genes will rise further still.  So, firstly what are these genes?  Many of them are, not surprisingly important to the function of the nervous system.  More surprisingly, many of these depression genes play a key role in the working of the immune system, in particular its inflammatory response.  And secondly, why have these particular genetic variants that promote depression hung around through evolution?  Well, until fairly recently in history (say less than 100 years), infection was the major cause of death.  These genetic variations that promote depression are thought to have arisen during evolution because they helped our ancestors fight infection.  Realistically, all of us will have inherited some of the genes for depression which places us on a continuous spectrum of risk.  Our chances of becoming depressed will therefore depend in part on how many genes and their cumulative impact. 

But what about if you haven’t got an overt chronic inflammatory disease like rheumatoid arthritis or heart disease? Or if you are not one of the unlucky ones with the perfect storm of mental ill health susceptibility genes. What is causing the immune system to go awry and result in an inappropriate, depression inducing inflammation?  The immune system is not fully matured at birth. The cells are there, but how they will develop and how well they are regulated is very much nurtured by our encounters and adventures, shaped by our changing emotions and surroundings.  Ultimately influenced by our upbringing.  This impact on our immune system is more than the genes you are both with.  But that only makes sense.  No other system in the body places such a premium on adaptability – except maybe the brain.  If our immune system didn’t respond to emotional adversity in our ever-changing environment, then we are dead ducks.  For decades we’ve known that social stress is a major risk factor for depression.  Now it seems that inflammation could be one of the missing links because its known that social stress can cause increased inflammation of the body, causing changes in how the brain works which in turn could contribute to the mental symptoms of depression.  Studies now show that childhood stress can damage immune system and have long lasting effects on health.  Scientists found that long after difficult events had passed, stress was still having a negative impact on the immune system well into adulthood even if they had never felt depressed.

The drugs don’t work

There have been no major advances in treatment for depression since the 1990’s, despite it being the major single cause of medical disability in the world.  Recent history is telling us if we want to make therapeutic breakthroughs in an area which remains incredibly important in terms of disability and suffering then we've got to think differently.  Based on this new way of thinking about the role of the immune system in mental health, there is now evolving work on anti-inflammatory agents as novel antidepressants.  Anti-inflammatory agents may not have broad application as antidepressants compared to, for example, drugs that treat depression by manipulating the neurotransmitter serotonin (SSRI’S - selective serotonin reuptake inhibitors), but rather help a subset of depressed patients who exhibit clinical signs of inflammation.  We know that about one-third of depressed patients have consistently high levels of inflammation and those with an overactive immune system are also less likely to respond to anti-depressants.  This is a big deal because a third of patients don't get any benefit from the standard anti-depressant medications like SSRIs.  The hope is that by measuring inflammation in the blood, drugs targeting the immune system will provide much needed treatments for those patients who are non-responders to conventional treatments.  There are already early clues in clinical trials that this approach is starting to work.  Depression is a disease that affects hundreds of millions of people. Even if anti-inflammatory approaches help just a small proportion of them - that would still be a huge number of patients.  But if anything, the biggest impact may be on the way we think about the disease, making people less likely to believe sufferers should just "pull themselves together".  But don’t throw the commonly used anti-depressants out just yet – there is now evidence that commonly used SSRI’s which affect our brain chemistry may also affect the user's immune system. That's because serotonin appears to be passed between key cells in the immune system, and that serotonin is specifically used to activate an immune response.

What else?

Although it may not be accessible to everyone, are things many other things that can be done to try and avoid or improve a mental health disorder.  Conveniently much of these overlap with avoiding triggering unruly inflammatory responses by the immune system.  Like a sensible lifestyle - not drinking too much, avoiding drugs.  Cultivating a strong social network of family or friends can be very helpful to people. Physical exercise and staying physically fit can also be advantageous to your mental health.  It’s now well accepted that brain health and mental illness are impacted by nutrition via several mechanisms.  Nutritional medicine is now a mainstream concept in psychological health and is also a known determinant of inflammation and immune health. A recent evidence-based profiling of foods clinically proven to play a role in depressive disorders paves a new framework to prescribing a dietary pattern for prevention or to promote recovery.  Finally, the emerging role of gut flora (i.e., the microbiome) as a possible key player in the regulation of mood, cognition, and anxiety suggests that we are only beginning to discover the potential of food as medicine.  These little gut bugs work hard in our digestive tract to earn their keep, breaking down our food & providing a pharmucopia of ‘post-biotic’ metabolites important for our metabolism but also immune health.  The idea of taking supplemental gut bugs in the form of probiotics could benefit mental health has been met with much excitement but until recently clinical studies were largely lacking.  Until recently - a remarkable new study has found that probiotics to be effective in preventing psychiatric re-hospitalisations.  There is certainly no magic bullet but a deeper awareness of diet and lifestyle as modifiable factors influencing both risk and progression is certainly a step in the right direction. 

The future is bright

Overall, the future of mental health research in is bright.  Although the determinants of mental health are complex, this emerging and compelling evidence for the role of the immune system as a crucial factor is compelling.  Both the immune system and neuronal system are sensing systems, intimately entwined with each other.  They are the only two body systems that put a premium on adaptability.  This new scientific knowledge that the immune system can affect our minds warrants a need to look at physical and mental diseases in a different way.  To explore the links between the immune system and mental health much more deeply and consider the “whole” of the patient, from immune type to personality.  There is now a burgeoning field of research in the fields of neuroscience and psychology paralleled by just as remarkable advances in immunology. Looking at mental ill health through this immunological lens, coupled with increased awareness, it won’t, hopefully, be long before the connections between these two highly evolved complex communication systems will be sought, recognized, and explored as an additional tool to prevent and treat these conditions of the mind.