Could an inflamed brain be a hidden cause of depression?

11 Jul

NS 3027:
* 29 June 2015 by Dara Mohammadi

The body’s immune system is designed to make us hide away when we
get sick. But modern life could be sending this recovery response
off track

MIKE had struggled with depression his whole life, but one day in
1995 it all got too much. “I completely fell apart,” he says. “I
backed out of life.”

Mike tried to kill himself with an overdose of prescription
painkillers. Medics saved him, but the next 15 years of treatment
brought little respite. He cycled through dozens of types of
antidepressants, with side effects including sickness, insomnia and
anxiety. Nothing worked.

Then, in 2010, Mike received a call from his doctor, offering him
the chance to take part in a clinical trial. Rather than targeting
brain chemistry, as most standard antidepressants do, this was a
trial of a drug normally reserved for Crohn’s disease, an
inflammatory bowel condition where the body’s immune system attacks
the gut. Desperate for a break, he signed up. And it worked. About a
week after the first treatment, the fog of depression cleared. “I
just sort of woke up,” Mike says.

This trial is one of a growing number of studies probing the idea
that the inflammatory response, which normally helps us when we get
sick, might occasionally wreak havoc in the brain. It has been
implicated in a number of disorders – from depression to
schizophrenia and Alzheimer’s disease.

That such a well-understood physical process might lie behind these
brain disorders is a cause for optimism – turn off the inflammatory
signals in the body, and you might be able to modify or even banish
the symptoms in the brain. Even better, there may be readily
available drugs that could help. “There is growing awareness that
neuro-inflammation seems to play a role in a variety of psychiatric
and also neurodegenerative disorders,” says Claudia Buss at the
Charite-University of Medicine in Berlin, Germany.
“Anti-inflammatory treatments may have a great potential in treating

We’re all too familiar with the lethargy and low mood that sweep
over us when sickness strikes, driving us to curl up under a duvet.
These are the effects of inflammation, the first line of defence in
the body’s two-pronged response to infection or injury.

On detection of a harmful stimulus, macrophages, a type of white
blood cell, release signalling molecules called cytokines. These
signals of inflammation rally other immune cells to the scene to
help fight infection or repair damage. They also make their way to
the brain, which has a separate immune system to the rest of the
body, divided by the blood-brain barrier.

The signals trigger neuro-inflammation, which is where microglial
cells come into play. These are macrophage-like cells in the brain
that secrete further cytokines to bring about “sickness behaviours”:
low mood, loss of appetite and lethargy.

This all makes sense from an evolutionary perspective – if our early
ancestors felt tired and miserable when they were poorly they’d be
less likely to leave their caves, and therefore to spread germs or
pick up another infection while the immune system was compromised.

But there is reason to think that this protective system is not
coping so well with modern life. Diseases like diabetes cause
constantly elevated levels of inflammation. Obesity and stress also
trigger it. All of this bombards our brains with low-level signals
that we should be feeling under the weather. “The brain is still
operating with this ancient instruction manual,” says Charles
Raison, at the University of Arizona. “It receives the signals and
perceives them as an immediate threat to survival. So if the signals
keep coming the brain keeps us feeling miserable.”

The link between depression and inflammation is not in itself new.
People who have diabetes, which Mike has, or rheumatoid arthritis,
are known to have elevated baseline levels of inflammation and to
also be at higher risk of depression. In the US, people with
diabetes are twice as likely to have depression as the average

About a third of people with depression also have higher than normal
levels of inflammatory cytokines in the blood, and most of these
people don’t respond to standard drugs.

Further evidence for the link between inflammation in the body and
disease in the brain came last year with the first study to measure
inflammation in children and see what happened when they grew up. By
the time they were 18, those who had high levels of inflammatory
markers in the blood when they were 9 years old were significantly
more likely to have had bouts of depression, or a psychotic disorder
like schizophrenia.

The obvious question, then, is whether drugs that work to dampen the
inflammatory response could also help to treat depression.

The trial that Mike enrolled in, led by Raison, is one of a handful
of studies testing that idea. The drug being trialled was
infliximab, a powerful anti-inflammatory already used to treat
Crohn’s disease. It works by blocking the action of an inflammatory
cytokine called TNF-alpha.

Mike was one of the 60 participants, who all had treatment-resistant
depression. Each received three intravenous infusions of either
infliximab or a placebo over 12 weeks.

At first, the results seemed disappointing; there was no difference
between groups. But then Raison’s team homed in on just the
participants who’d started off with high levels of inflammation. In
these people, infliximab did significantly better than placebo in
terms of improving symptoms such as low mood, fatigue, anxiety and
thoughts of suicide.

Mike was one of them, and since his treatment with infliximab, he
says his depression has been much more manageable. “The idea that I
was thinking about killing myself seems so alien that it could have
been another person,” he says.

By Raison’s own admission, the study was small and his findings need
to be substantiated by others. And an important complication casts a
shadow on what might otherwise be a cause for celebration: patients
with normal levels of inflammation seemed to do worse after
infliximab treatment.

This shows that increased inflammation is not a contributor in all
people with depression, says Raison, and that blocking it in
patients with normal levels can be harmful: “People rush to put all
inflammation in one pot, but at low levels it might be doing
something good.”

Mike had a clear suspect for his elevated levels of inflammatory
cytokines – his diabetes. But there is another aspect of modern-day
life that increases inflammation and that is psychosocial stress.

Over millions of years of evolution, stress has been a good
indicator that the body might be wounded. So in response to stress
hormones such as adrenaline and cortisol, macrophages secrete
cytokines to pre-emptively ramp up inflammation and prepare the body
for a possible infection.

“Before, you’d only get stressed if you had a lion chasing you or if
you were starving and had to hunt,” says Carmine Pariante, a
psychiatrist at King’s College London, who studies the link between
the immune system and depression. “Now we get stressed because of
traffic or because our boss shouts at us. None of these wounds us
physically, so we don’t need inflammation. But it’s still there,
working away on our brain.”

Since most people are exposed to these kinds of everyday stressors,
why should they cause depression in only some of us?

Pariante thinks that, although stress, diabetes and so on can cause
inflammation to spike in anyone, it’s only the people with high
baseline levels of inflammation who tip over into depression. People
can have high baseline levels for several reasons: their genes might
predispose them to mount an over-sensitive inflammatory response. Or
perhaps something happened during their early development to ramp up
the dial.

We know that trauma during childhood such as physical or mental
abuse can increase the risk of both physical and mental illness
later in life, including depression, anxiety and post-traumatic
stress disorder. The mechanism at play is still poorly understood,
but Pariante is one of a group of psychiatrists who think that
trauma when a child’s mind and body are still developing can
hard-wire the immune system to run high for a lifetime, presumably
as an adaptation for living in dangerous environments where there’s
a high risk of injury.

Childhood trauma

Strong evidence for this comes from the Dunedin cohort study, which
continues to follow more than 1000 people born in 1973. Pariante
analysed the data, and found that those who were abused or neglected
as children tended to have much higher levels of inflammation than
those who’d had a stress-free childhood. Pariante has also just
published a review of 25 studies that found childhood trauma had a
significant impact on markers of inflammation in adulthood.

Again, Mike’s story fits the script – he was physically and sexually
abused as a child, and spent much of his youth bouncing between
different foster families.

Inflammation might play a role even earlier still, during
development in the womb. Last year, Buss presented a study at the
Society for Neuroscience meeting in Washington DC, in which she
found that babies born to women who had high levels of inflammation
during pregnancy tended to have weaker connections in the
brain,which might predispose these children to mental illness later
on. The brain area affected was the default mode network, where weak
connections are implicated in a number of psychiatric conditions in
adulthood, including ADHD, autism, schizophrenia and depression.

Inflammation is also now thought to play an important role in
Alzheimer’s disease (see “Inflamed in the brain”), but its precise
contribution to these complex conditions, which seem to have
multiple causes, remains poorly understood. Attempts to treat
schizophrenia with anti-inflammatory drugs have had mixed results,
for instance, and as Raison found with depression, there may be
pockets of people who respond better to these drugs than others.
There are also other complications, including the risks of prolonged
treatment with powerful anti-inflammatories that suppress the immune

Even so, for Pariante, the ramifications of the idea that depression
might be caused, and treated, in much the same way as allergies and
asthma, are seismic. “Suddenly it brings depression into the context
of just another medical disorder,” he says. That might help overcome
the stigma and discrimination that is thought to deter half of
people with depression from seeking treatment.

Knowing that inflammation plays a role in mental health also means
we can all take steps to buffer ourselves from its effects. Obesity,
smoking, inactivity, and a poor diet can all increase inflammation.
Conversely, regular exercise and a diet rich in omega-3 oils and
wholegrains have all been shown to reduce it. Many studies have
reinforced the link between unhealthy lifestyles, chronic
inflammatory conditions such as obesity, and depression. And the
link between obesity and Alzheimer’s has led some to call it a kind
of “brain diabetes”.

“It’s not just about hoping that pharmaceutical companies are going
to pop up with a drug that’s going to fix things,” says Hugh Perry,
a neuroimmunologist at Southampton University, UK. ” We’ve known it
for some time: healthy body, healthy mind.” One person paying
attention is Mike. “I’m still a little overweight but I’m changing
my lifestyle and am trying to eat better,” he says.

As well as adopting a healthy lifestyle, more than ever it might be
wise to monitor inflammation and treat it when it’s too high,
including during pregnancy and childhood when the brain is
developing fast. Blood tests for elevated cytokines might flag that
it’s time to unwind, or be used to identify people at high risk of
suicide. Pariante’s vision is that in 10 years’ time, you might go
to the doctor, have a blood test for inflammation, and walk out with
an effective treatment. “This would be a huge leap for psychiatry,”
he says.

The inflammatory response, which is designed to keep us safe when we
get sick, might lie behind some cases of depression (see main
story). But it is also thought to play a role in the death of cells
associated with neurodegenerative conditions such as Alzheimer’s

The brain is protected from the body’s aggressive immune system by
the blood-brain barrier, but has its own immune cells that can be
activated by signals from the body’s inflammatory response.

Hugh Perry, a neuroimmunologist at Southampton University, UK,
suspects that immune cells in the brain called microglia could be
killing off neurons.

One of the many roles of microglia is to scavenge debris from the
brain. Perry’s theory is that microglia are activated by
characteristic deposits of amyloid protein in the brains of people
with Alzheimer’s, but they struggle to remove it and so are kept in
a chronically excited state.

Then, when signals of inflammation come in from the body – whether
from infections, stress, or chronic disease – microglia secrete
cytokines to induce sickness behaviour as they normally would. But
because they are already in their activated form, they secrete them
at such high concentrations that they kill surrounding neurons (see
“In sickness and in health”, below).

Microglia in their activated form were first spotted in the brains
of people with Alzheimer’s disease in the early 1980s, but many
dismissed the notion that this brain inflammation was damaging.
Instead, they said, the amyloid deposits were the main cause of
neuron death and the inflammation was the brain’s way of trying to

In the last five years, the tide has turned in favour of Perry’s
inflammation model. This is mainly thanks to genetic studies that
have found people with the disease are more likely to have mutations
in genes that keep the activity of microglia in check.

“It’s almost universally accepted now that inflammation is part of
the main driver of Alzheimer’s,” says geneticist John Hardy of
University College London, who carried out some of this research.

Hardy was a sceptic who has now reconsidered his views. He still
believes that the protein deposits are an important target for
potential treatment, but says that inflammation could be too.

Perry along with Clive Holmes, also at Southampton, and their
colleagues are now conducting trials of a drug called etanercept in
people with Alzheimer’s – an anti-inflammatory that is normally used
to treat rheumatoid arthritis. Their preliminary research has shown
that the drug was safe, and did not increase the risk of infection –
an important consideration when giving elderly individuals a drug
that suppresses their immune system. There were also hints that the
treatment helped with some symptoms, including poor memory.

In the next few months, Holmes plans to run a follow-on study in
which his team will measure the direct effect of this treatment on
inflammation in the brain. The ultimate aim is a bigger trial with a
sufficient number of participants to specifically test clinical
outcomes such as cognitive decline.

Dara Mohammadi is a freelance writer based in London


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