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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