Lost in Translation: Latest Revolution of Depression

Many report that the depression becomes so overwhelming that they are unable to leave the bed or leave the house. Sensitivity to light and noise have also been reported as well as thoughts of self-harm and/or suicide. Individuals who experience these symptoms have immune systems that alter their brain into depression. Depression effects 350 million people worldwide and this recent discovery on depression is the strongest one made in the last 20 years. [C]

 

The Depression Revolution-Neurobiological reveals new and exciting possibilities for successful treatments for depression. Regions of the brain those mainly connected to the body's stress system shows that depression is physiological as well as emotional. Neurotransmitters like serotonin function abnormally in depression—but so do lots of other things. It challenges the perception that depression is a disorder solely from the neck up. Depression affects the heart, bones, and stress system. [B]

The evidence that the adult brain is much more plastic than expected and that experiences as well as environment(s) change brain circuits which underlies emotion is a great revelation for scientists everywhere. This revolution in depression will force a revised view of all human behavior and its capacity for change. [B]

 

The idea that there is a global derangement of the serotonin or nor-epinephrine system has shown that this information is no longer sustainable from recent brain imaging findings. The data reveals that what distinguishes depressed individuals from non-depressed individuals are patterns of regional brain function (aka: differences in specific circuits). [B]

 

Anti-depressant drugs and psychological treatments, like cognitive behavioral therapy, have helped most people struggling with depression but many do not respond to any of the existing therapies. Consequently, scientists have been exploring new approaches such as the possibility of the immune system causing the depression. [C]

INTRODUCTION: 

The Psychiatric Genomics Consortium in "Nature Genetics"  reported that depression is typically genetic and we are just now starting to understand how and why this is the case. If your parents have been depressed, the chances that you have been or will be depressed are significantly increased. The background risk of depression in the general population is about one in four – each of us has a 25% chance of becoming depressed at some point in our lives. And if your parents have been depressed, your risk jumps by a factor of three. [A]

Controversy has also swirled around the question of which has greater influence- nature or nurture. For example, is the depressed son of a depressed mother the victim of her inadequate parenting and the emotionally chilly, unloving environment she provided during the early years of his life? Or is he depressed because he inherited her depressive genes that biologically determined his emotional fate, regardless of her parenting skills? Is it nature or nurture, genetics or environment, which explain why depression runs in families? [A]

The psychological operations we've always thought of as mental are now traceable biologically to circuits—the brain's wiring and firing patterns—and to molecular mechanics inside brain cells. It's fairly obvious that this knowledge should lead to whole platoons of antidepressant drugs that take new and improved biological tacks to the disorder. [B]

 

Less obvious may be that the new biology of depression also makes a strong case for non-drug therapies. "Non-pharmacological treatments may exert quite specific biological effects in being able to affect certain select brain regions," Davidson points out. "The deficit in activation of the prefrontal cortex that we and others have identified in depression may be something that can be changed with cognitive therapy." Or a stripped-down and tightly focused component of cognitive therapy called behavioral activation, pioneered by psychologist Neil Jacobson at the University of Washington. [B]

 

He's at the forefront of this new approach: "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." The focus is on an errant immune system causing inflammation in the body and altering mood.And Prof Bullmore argues that's something we can all relate to, if we just think back to the last time we had a cold or flu. He said: "Depression and inflammation often go hand in hand, if you have flu, the immune system reacts to that, you become inflamed and very often people find that their mood changes too. [C]

 

To explore this revolutionary new idea in depression, we visited an arthritis clinic at Glasgow Royal Infirmary. It is perhaps an unexpected location, but it was in clinics like this that doctors noticed something unusual. Rheumatoid arthritis is caused by the immune system attacking the joints. And when patients were given precise anti-inflammatory drugs that calmed down specific parts of the immune response, their mood improved. [C]

When we give these therapies we see a fairly rapid increase in a sense of well-being, mood state improving quite remarkably often disproportionately given the amount of inflammation we can see in their joints and their skin. It suggests the patients were not simply feeling happier as they were in less pain, but that something more profound was going on. [C]

 

"Their behavior changes, they may become less sociable, more sleepy, more withdrawn.

"They may begin to have some of the negative ways of thinking that are characteristic of depression and all of that follows an infection."It is a subtle and yet significant shift in thinking. The argument is we don't just feel sorry for ourselves when we are sick, but that the chemicals involved in inflammation are directly affecting our mood.[C]

 

Inflammation is part of the immune system's response to danger. It is a hugely complicated process to prepare our body to fight off hostile forces. If inflammation is too low then an infection can get out of hand. If it is too high, it causes damage. And for some reason, about one-third of depressed patients have consistently high levels of inflammation. Hayley is one of them: "I do have raised inflammation markers, I think normal is under 0.7 and mine is 40, it's coming up regularly in blood tests." There is now a patchwork quilt of evidence suggesting inflammation is more than something you simply find in some depressed patients, but is actually the cause of their disease. That the immune system can alter the workings of the brain. [C]

 

The brains of people with rheumatoid arthritis were scanned and observed, they were then given a very specific immune targeted therapy, and then scanned their brain after. When anti-inflammatory medicines are given remarkable changes in the neuro-chemical circuitry in the brain can be seen. The brain pathways involved in mediating depression were favorably changed in people who were given immune interventions. One possible explanation is that inflammatory chemicals enter the brain. There they interrupt the production of serotonin - a key neurotransmitter that's linked to mood. [C]

To hear more we visited Carmine Pariante's laboratory at King's College London. The professor of biological psychiatry has been piecing together the evidence on inflammation and depression for 20 years. He told the BBC: "Nearly 30% to 40% of depressed patients have high levels of inflammation and in these people we think it is part of the causal process. "The evidence supporting this idea is that high levels of inflammation are present even if someone is not depressed, but is at risk of becoming depressed. [C] 

Previously conducted studies have proven that high levels of inflammation means a higher risk of becoming depressed over the upcoming weeks or months even if you feel perfectly fine. Not only are depressed patients more likely to have high levels of inflammation but have an overactive immune system makes their body less likely to respond to anti-depressents. This is groundbreaking because many patients, about 1/3 of patients, do not feel the benefits from medications. [C]

But there's something confusing here. The immune system responds to infection, but this does not make sense when talking about depression. The horrid moments in our lives have the power to alter our immune system and prime it to increase the risk of depression years later.  A possible thought is that the immune system is the key mechanism where early life events produce this long term effect. Data observed from adult volunteers with history of early life trauma-even if never expressing periods of depression in their lives- had an activated immune system which makes them at risk. [C]

The hope is that drugs targeting the immune system will provide much needed treatments for patients, particularly for those who have tried them all. The process of the right medications is a long and tricky process of 'trial and error'. Also, its difficult to predict if someone will be effected in the beginning but by measuring inflammation in blood, they will be able to identify the people who need more complex, intensive anti-depressant treatment, or even possibly a combination of antidepressant and anti-inflammatory. [C]

Clinical trials are taking place to prove whether home remedies of anti-inflammatories like ibuprofen will work on patients, but until the results come in do not try it at home. The world's largest medical research charity, 'Wellcome Trust', has brought together universities and the pharmaceutical industry. The goal is to consolidate the evidence to accelerate the field. More specifically the hope is to find a new treatment for depression and develop a test to identify who will benefit from it. [C]

They hope will become effective medicines for inflammatory disorders, but the process will take over a decade and the medication might already be available to the public. Whats so exciting about immuno-psychiatry is that because of the success of immunology in other areas of medicine there are already many drugs that are far beyond this stage of development. These drugs may already be licensed or in late-stage clinical trials so the timeline from start of work on that project to delivering a medicine that might make a difference to patients could be much shorter. [C]

Raiding the cupboards is already showing signs of success. Those early clues in arthritis mean the anti-inflammatory drug sirukumab is now being trialed in depressed patients. So are drugs targeting the immune system about to transform the treatment of depression? Not every patient with symptoms of depression is going to be offered an anti-inflammatory drug. The goal is to create more personalized treatments or stratified approach, because not everyone that is depressed is depressed for the same reason. That will require a blood test to identify which patients will benefit from immune-based therapies. [C]

Depression is a disease that affects hundreds of millions of people and even if anti-inflammatories help just a small proportion of them, this means a large number of patients will benefit. Most importantly, if immuno-therapy becomes a success, its biggest impact may be on the way we think about the disease. For the first time, researchers have been able to demonstrate that depression is not only a disorder of the mind or brain, but a disorder of the entire body. If a diabetic's insulin levels did not function properly society does not tell them to :snap out of it!" If these studies prove to the public that depression is a physical problem it will have a large impact on its negative perception. Depression would then be treated as a genuine condition and validate a lot of peoples feelings and what they are going through. [C]

BACKGROUND INFORMATION:

In the 20th century, psychiatrists ingeniously teased out some answers to these questions. For example, it was found that pairs of identical twins, with 100% identical DNA, were more likely to have similar experiences of depression than were pairs of non-identical twins, with 50% identical DNA. This indicated clearly that depression is genetically heritable. But well into the 21st century, the precise identity of the “genes for depression” remained obscure. Since 2000, there has been a sustained international research effort to discover these genes, but the field has been bedeviled by false dawns and inconsistent results. [A]

 

That is why the study published last week is such a significant milestone. For the first time, scientists around the world, with leading contributions from the UK’s world-class centers of psychiatric genetics research largely funded by the Medical Research Council at the University of Cardiff University, 

University of Edinburgh University and King’s College London, have been able to combine DNA data on a large enough sample to pinpoint which locations on the genome are associated with an increased risk of depression. So we now know, with a high degree of confidence, something important about depression that we didn’t know this time last year. We know that there are at least 44 genes, out of the 20,000 genes comprising the human genome, which contribute to the transmission of risk for depression from one generation to the next. [A]

 

RESEARCH:

However, this raises at least as many issues as it resolves. Let’s first dwell on the fact that there are many risk genes, each of which contributes a small quantum of risk. In other words, there is not a single smoking gun, a solitary rogue gene that works like a binary switch, inevitably causing depression in those unfortunate enough to inherit it. More realistically, all of us will have inherited some of the genes for depression and our chances of becoming depressed will depend in part on how many and their cumulative impact. As research continues and even larger samples of DNA become available for analysis, it is likely that the number of genes associated with depression will increase further still. [A]

This is telling us that we shouldn’t be thinking about a black-and-white distinction between us and them, between depressed patients and healthy people: it is much more likely that our complex genetic inheritance puts all of us on a continuous spectrum of risk. What are these genes and what do they tell us about the root causes of depression? It turns out that many of them are known to play important roles in the biology of the nervous system. This fits with the basic idea that disturbances of the mind must reflect some underlying disturbance of the brain. [A]

More surprisingly, many of the risk genes for depression also play a part in the workings of the immune system. There is growing evidence that inflammation, the defensive response of the immune system to threats such as infection, can cause depression. We are also becoming more aware that social stress can cause increased inflammation of the body. 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: stress provokes an inflammatory response by the body, which causes changes in how the brain works, which in turn cause the mental symptoms of depression. [A]

CONCLUSION: 

It may also be changed with medication. Davidson was encouraged enough to begin his own study of meditation. He is specifically testing how it affects patterns of activation of the prefrontal cortex, whether it activates the left side and stimulates positive emotions, or deactivates the right side, decreasing the volume of negative messages so that they don't disrupt everything else. The answers are yet to come. [B] 

Knowing the risk genes for depression also has important implications for practical treatment. There have been no major advances in treatment for depression since about 1990, despite it being the major single cause of medical disability in the world. We need to find new ways forward therapeutically and new genetics is a great place to start the search for treatments that can cut through more precisely to the cause or mechanism of depression. It is easy to imagine how new antidepressant drugs could in future be designed to target inflammatory proteins coded by depression risk genes. It is exciting to think that the new genetics of depression could unlock therapeutic progress in psychiatry as well. [A]

Finally, although I think these genetic discoveries are fundamental, I don’t see them as ideologically divisive. They don’t prove that depression is “all in the brain” or that psychological treatment is pointless. The genetics will be biologically pre-eminent but, as we understand more about what all these “genes for depression” do, we may discover that many of them control the response of the brain or the body to environmental stress. In which case, the treatment that works best for an individual patient could be a drug targeting a gene or intervention targeting an environmental factor such as stress. In short, I believe that a deeper understanding of the genetics of depression will lead us beyond the question we started from: is it nature or nurture, gene or environment? The answer will turn out to be both. [A]

Links:
[A] https://www.theguardian.com/commentisfree/2018/apr/29/revolution-in-our-understaning-of-depression-will-be-life-transforming
[for more visit: Edward Bullmore is head of the department of psychiatry, Cambridge University and author of The Inflamed Mind (Short Books)]
[B] https://www.psychologytoday.com/us/articles/199903/the-depression-revolution
[C] http://www.bbc.com/news/health-37166293

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