24 June 2015

An inflamed brain may be a hidden cause of depression

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

Raven perched on a red brain
Brain under siege

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.

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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 them.”

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.”

“If the immune 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 person.

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.

“Childhood trauma can hard-wire the immune system to run high for a lifetime”

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 brain-related conditions later on. The brain area affected was the default mode network, where weak connections are implicated in a number of 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 system.

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.

“Suddenly it brings depression into the context of just another medical disorder”

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.

Inflamed in the brain

Target the immune system to treat Alzheimer’s

Could an inflamed brain be a hidden cause of depression?

Hitting the target (Image: Robert Carter)

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 disease.

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 respond.

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.