Depression: A revolution in treatment?
It's not very often we get to talk about a revolution in understanding and treating depression and yet now doctors are talking about "one of the strongest discoveries in psychiatry for the last 20 years".
It is based around the idea that some people are being betrayed by their fiercest protector. That their immune system is altering their brain.
The illness exacts a heavy toll on 350 million people around the world, among them Hayley Mason, from Cambridgeshire:
"My depression gets so bad that I can't leave the bed, I can't leave the bedroom, I can't go downstairs and be with my partner and his kids.
The 30-year-old added: "I can't have the TV on, I can't have noise and light, I have suicidal thoughts, I have self-harmed, I can't leave the house, I can't drive.
"And just generally I am completely confined to my own home and everything else just feels too much."
Anti-depressant drugs and psychological treatments, like cognitive behavioural therapy, help the majority of people.
But many don't respond to existing therapies and so some scientists are now exploring a new frontier - whether the immune system could be causing depression.
"I think we have to be quite radical," says Prof Ed Bullmore, the head of psychiatry at the University of Cambridge.
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.
"Their behaviour changes, they may become less sociable, more sleepy, more withdrawn.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.
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You can listen to The Inflamed Mind documentary on BBC Radio 4 at 21:00 BST and then here on iPlayer.
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.
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.
Prof Iain McInnes, a consultant rheumatologist, said: "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.
Prof McInnes added: "We scanned the brains of people with rheumatoid arthritis, we then gave them a very specific immune targeted therapy and then we imaged them again afterwards.
"What we are starting to see when we give anti-inflammatory medicines is quite remarkable changes in the neuro-chemical circuitry in the brain.
"The brain pathways involved in mediating depression were favourably 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.
Could I be depressed?
If you are having trouble understanding any of these questions, or at any point you start to feel distressed, please stop and seek the advice of a medical professional. See the links below for organisations that may be able to help you.
About the self assessment: The first eight questions are taken from a measure known as the Patient Health Questionnaire 9 or PHQ-9, used by doctors to assess and monitor depression severity. The PHQ-9 was developed by Dr Robert L Spitzer, Dr Janet B W Williams, Dr Kurt Kroenke and colleagues, with an educational grant from Pfizer Inc.
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.
"We know from studies that if you have high levels of inflammation today you're at higher risk of becoming depressed over the next weeks or months even if you are perfectly well."
He's shown that not only are depressed patients more likely to have high levels of inflammation, but 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 drug treatments.
But there's something confusing here. The immune system responds to infection and that doesn't seem to fit the usual story of depression.
Take Jennifer Streeting, a trainee midwife in London, who traces her mental health problems back to when she was 14.
"My nana passed away and my mum had breast cancer and if you ask my therapist now she puts it down to grief and not really dealing with that at the time, I think there was just a lot going on."
Prof Pariante argues it is actually these awful moments in our lives that change our immune system, priming it to increase the risk of depression years later.
He said: "We think the immune system is the key mechanism by which early life events produce this long-term effect.
"We have some data showing adult individuals who have a history of early life trauma, even if they have never been depressed, have an activated immune system so they are in a state of risk."
The hope is that drugs targeting the immune system will provide much needed treatments for patients, particularly for those like Jennifer who seem to have tried them all.
"I had sertraline, I had Prozac, there was another one, I got started on citalopram, I was put on duloxetine, mirtazapine as well. I was on three at one point."
She is now on a combination of drugs that seem to be working for her, but it has been a long journey.
"It is totally trial and error," said Prof Pariante.
He added: "We are not able to predict right from the beginning whether someone will respond.
"We think by measuring inflammation in the blood we'll actually be able to identify individuals that do require more complex, intensive antidepressant treatment, maybe a combination of an antidepressant and and anti-inflammatory."
Most of us have common anti-inflammatories like ibuprofen at home, but doctors warn against experimenting at home, while clinical trials are taking place to prove whether this will work in patients.
The world's largest medical research charity, the Wellcome Trust, has brought together universities and the pharmaceutical industry.
The aim is to consolidate the evidence to accelerate the field; ultimately they want to find a new treatment for depression and develop a test to identify those who will benefit.
Cambridge University's Prof Bullmore is leading the consortium. But we interviewed him at his other employer, GlaxoSmithKline.
The company's immuno-inflammation laboratory is where scientists are developing new molecules which they hope will become effective medicines for inflammatory disorders.
That process will take more than a decade, but Prof Bullmore says there may already be a drug out there.
"One of the exciting things about immunopsychiatry 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.
"They 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."
Raiding the cupboards is already showing signs of success. Those early clues in arthritis mean the anti-inflammatory drug sirukumab is now being trialled in depressed patients.
So are drugs targeting the immune system about to transform the treatment of depression?
Prof Bullmore argues: "I don't think they are going to be a panacea, I don't think we're talking about a scenario in future where every patient with symptoms of depression is going to be offered an anti-inflammatory drug.
"I don't think that makes sense and frankly that sort of blockbuster one-size-fits-all approach to development of drugs for psychiatry has not been helpful to us in the past.
"We have to take a more personalised or stratified approach, 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.
Depression is a disease that affects hundreds of millions of people. Even if anti-inflammatories help just a small proportion of them - that would still be a huge number of patients. But if immunotherapy becomes a success, its biggest impact may be on the way we think about the disease, making people less likely to believe sufferers should just "pull themselves together".
"I hate that phrase, if I could I would," says Jennifer.
She adds: "Just as if someone had diabetes and their insulin levels weren't working correctly, you wouldn't say, 'Oh snap out of it, stop having a hypo.'"
Hayley feels the same: "If there was a way to say depression was a physical problem I think it would make a massive difference, I think people would treat depression as something that is not made up and going on in the head.
"It would be seen as a genuine condition, it would validate a lot of people's feelings."
Prof Pariante concludes: "It is groundbreaking because, for the first time, we are demonstrating that depression is not only a disorder of the mind, in fact it is not even only a disorder of the brain, it is a disorder of the whole body."