Mad Girl


When the journalist Bryony Gordon wrote about her struggle with depression she was taken aback by her readers’ reaction. In her memoir Mad Girl she recalls:
‘Of all the subjects I had written about in my career, not one of them had elicited a response like this… I received hundreds and hundreds of messages from people sharing their own stories of mental illness. Strangers sent me cards. Friends I had always seen as upbeat and jolly, who had probably always seen me as upbeat and jolly, pulled me to one side and told me about the diseases in their own minds.’

Gordon has intermittently suffered from the condition since her teenage years but only decided to write about it recently, partly to counter the stigma surrounding it.
Now, with the launch of her podcast, Mad World, in which Prince Harry talks with extraordinary frankness about his own mental health problems, she has taken another well-aimed swing at that stigma. (Along with the Duke and Duchess of Cambridge, Prince Harry is promoting the Heads Together campaign which aims to remove the negative associations surrounding mental illness.)
‘One of the things about depression is that it lies to you,’ says Gordon.
‘It tells you you’re a freak, that no one will understand, that you’re the only person in the world thinking what you’re thinking. So not only are you lying paralysed in bed, incapable of getting up and unable to see a way out, but you also feel a deep sense of shame.’
Depression is said to be the second biggest cause of disability in the world, affecting 350 million people worldwide.
Typical symptoms include anhedonia — an inability to feel pleasure — and an unassailable sense of despair, sometimes leading to self-harm and suicide.
It is a poorly understood illness, often wrongly associated with some sort of moral weakness or mental frailty.
However, research suggests that for tens of millions of people, depression might be caused by a malfunction of the immune system. In other words, it is not ‘all in the mind’.
The Wellcome Trust has brought together a team of UK scientists with researchers from pharmaceutical companies to investigate whether depression can be treated by targeting the immune system.
The consortium is being led by Professor Ed Bullmore, head of the Department of Psychiatry at Cambridge University, who also works for GlaxoSmithKline.
‘In the treatment of depression, we haven’t been making as much progress as we’d like to see over the last 20 years or so,’ he says.
‘If you go to see a doctor with the symptoms of depression, they will almost certainly give you a referral for cognitive behavioural therapy or prescribe you an anti-depressant that is similar to anti-depressants that have been on the market since the early 1960s.
‘Most existing anti-depressants work by increasing the amount of serotonin in the brain — an important neurotransmitter that affects mood — but they don’t work for everybody. About a third of patients with depression respond quite well to that sort of treatment, about a third have persistent symptoms, and the remainder have a partial response.’
The consortium’s initial findings, which are consistent with other studies, suggest that the third of patients for whom antidepressant drugs don’t work may have higher-than-normal levels of inflammation, a function of the immune system.
That means there is an association between inflammation and depression. But the consortium is exploring the idea that, in these patients, the inflammation is actually causing the depression.
How do we know that it is not the depression causing the inflammation?
‘There are a variety of strands of evidence,’ explains Jonathan Cavanagh, professor of psychiatry at Glasgow University, one of the institutions participating in the Wellcome Trust project.
‘For example, we’ve studied the behaviour of animals such as mice before and after introducing inflammation. Behaviour is normal prior to the introduction of inflammatory proteins but afterwards they display anhedonia, which we can measure using different, controlled experiments.
‘Human patients treated with inflammatory drugs — some conditions such as hepatitis C would be treated with interferon, which is essentially an inflammatory protein — have a substantial chance of developing depression, even if they’ve never had it before.
‘Conversely, people suffering from inflammatory conditions such as rheumatoid arthritis have a tendency to suffer from depression and anti-inflammatory treatments appear to have some anti-depressant benefit – apparently separate from the improvement in physical symptoms.’
So if the inflammation is causing the depression — possibly by producing chemicals that interfere with the production of serotonin — what is causing the inflammation? There are a number of possibilities.
Inflammation is the body’s response to infection but it can be triggered by stress and exacerbated by an unhealthy lifestyle.
There is also some research suggesting that children exposed to high levels of infection or to severe stressors such as traumatic life events are more likely to suffer from depression as adults.
Carmine Pariante, professor of biological psychiatry at King’s College, London, says: ‘With these individuals, the exposure to stress early in life modifies the functioning of the inflammatory system — it sets it to a higher sensitivity if you like. When these people encounter stressful life events later in life, the inflammatory system over-reacts and precipitates the depressive episode.’
And people who have never experienced depression probably do know something of what it feels like. Flu or a bad cold often begins with a period of appetite loss, listlessness, an ability to focus and a lack of interest in anything other than hugging the sofa. This is because the body reacts to the infection with inflammation, which in turn causes these mood changes.
The Wellcome Trust project, once it has investigated the immune system of patients with depression, will carry out medicine trials, using re-purposed anti-inflammatory drugs. If it can show that drugs that have already been developed or are in development, albeit for another purpose, are effective, the normally very lengthy process of creating new treatments will be considerably shortened.
It will also revive the interest of big pharmaceutical companies who have in recent years pulled back from psychiatric drugs research and development, a notoriously challenging area.
Pariante says: ‘I think within five to ten years we will be at the stage where we are able to change clinical practice.
‘For the first time we are beginning to understand depression from a larger biological perspective which moves away from the mechanisms that we have studied for the last 40 years and introduces a prominent role for the inflammatory system. That is a major step forward in terms of developing a completely new therapeutic mechanism and in understanding depression is not “all in the mind” — it is not even all in the brain. It is a disorder of the whole body. It sends a message in terms of the stigma that has been attached to depression. It invites us to view it in terms of simply being unwell, akin to any other medical condition, rather than as something that patients need to be ashamed of.’
Bullmore says: ‘There will be people out there who say that mental health is not really a medical problem, that it’s a psychological problem and finding new drugs isn’t necessarily the answer. But I’d argue that it’s extremely unlikely that 350 million people have all become depressed for the same reason and if we can work out more clearly how inflammation causes depression in some cases, that could open the door to new medicines for at least a percentage of patients who might have tried and failed to derive much benefit from existing treatment.’
He is at pains to point out that the Wellcome Trust research is currently at an early stage and that nothing has yet been proven. However, if the case is made for anti-inflammatory treatments for depression, it will be a major breakthrough.
‘We’re not claiming that they will be a panacea or that they will work for every patient,’ he says. ‘But for some people, used alongside other treatments, we hope that this could be a big step forward.’

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