The depression-inflammation link: Is a treatment revolution coming?

by Donna Chisholm / 10 October, 2018
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Kathryn Moake. Photo/John Collie.

As science reveals the depth of the connection between the immune system and depression, are we on the brink of a treatment revolution? Donna Chisholm investigates.

When the black dog turned up again last year, Kathryn Moake didn’t waste any time in taming it. She went straight to her GP.

“I could be one of those middle-aged women who disappears from home and is found hiding behind a bush,” she told the doctor. She was tearful, anxious, and felt her life was out of control.

At 51, the Christchurch primary school teacher knew how bleak things could become if her depression wasn’t controlled. As a young mother, she’d had an almost overwhelming urge to step in front of oncoming cars. “The only reason I didn’t do it was because my five-year-old and 18-month-old daughters were with me and I didn’t want them to see it.”

Following that doctor’s visit in March last year, she began to join the dots between her mental and physical health. After years of low iron levels and extreme fatigue, and more recently rumbling digestive symptoms, she was finally diagnosed with coeliac disease, an autoimmune disorder that causes an inflammatory response in the gut to dietary gluten. She also had symptoms of irritable bowel.

What if her depression, coeliac disease and bowel symptoms were related, linked to a misfiring immune system that was turning her body against itself, in both her gut and her brain?

It’s a question that’s gained renewed momentum with the recent release of The Inflamed Mind, a book by Cambridge University psychiatrist Professor Edward Bullmore, which details evidence of the emerging role of inflammation in depression – and nails down the coffin lid on the notion that body and mind are separate.

He says the idea that the blood-brain barrier is an impermeable “Berlin Wall” is one in which Western medics have been indoctrinated; it continues to inform their thinking that depression is “all in the mind”. Even relatively young doctors still believe it, he told North & South. “People of my vintage who went through medical training had it drummed into them, and medical education changes so slowly,” he says. “If you’re trained in the Western medical tradition, you’re probably the toughest audience – but talking to patients, it’s easy.”

Amid the scientific and medical research in the book, Bullmore relates two personal stories that have informed his work. The first happened when, while training as a physician in 1989, he saw patient “Mrs P”, a woman in her late 50s who had the inflammatory autoimmune disease rheumatoid arthritis. She was so painfully swollen and disfigured, she found it difficult to walk and when Bullmore questioned her about her state of mind, he found she was also depressed. He reported this to his senior physician, who was unimpressed.

“Depressed? Well, you would be, wouldn’t you?” he said.

It didn’t occur to either of them, writes Bullmore, that the woman’s depression might be a physical response to her inflammation, rather than a psychological reaction to her pain and disability.

Bullmore’s second anecdote refers to his recent root canal surgery, which he says caused a temporary bout of lethargy, social withdrawal and morbid thoughts. “My tooth had been infected by some bacteria; my gums had become inflamed in response to that infection; the dentists’ drilling and scraping… had the short-term disadvantage of making my gums even more inflamed and increasing the risk of the bacteria spreading from my tooth into my bloodstream. [It] amounted to a challenge to my body’s integrity, a threat to my survival and a clarion call to my immune system to step up its inflammatory response.”

Typically, those symptoms would have been explained away in psychological, not immunological terms: the close encounter with the dentist was a reminder he was literally getting long in the tooth, triggering a period of “rational pessimism”. It was far more likely, he writes, that he was depressed because he was inflamed.

Inflammation is, of course, part of the immune system’s normal healthy response to help us heal after injury or infection; the same process can be triggered by acute or chronic stress. We can also feed the body’s inflammatory responses with a poor diet, inactivity and disrupted sleep. But sometimes, when the body fires up that response, it can’t always dampen it down again, leading to autoimmune conditions such as Mrs P’s rheumatoid arthritis and Kathryn Moake’s coeliac disease. But what happens when that inflammation affects the brain as well as the body?

Edward Bullmore. Photo/Judith Weik.

Since the book, Bullmore has been inundated by questions from patients with depression, asking whether simple anti-inflammatories such as ibuprofen or aspirin might be the holy grail of treatment.  They’re not, he says: the drugs have side effects that may be harmful, and so far, there’s little clinical evidence they would alleviate depression. But, he points out in the book, there’s no financial incentive for drug companies to conduct expensive clinical trials for depression because the medicines are off-patent anyway.

Bullmore believes about a third of cases of major depression have an inflammatory link, and that’s where he’d be targeting research into new treatments. However, the only routine blood test for inflammatory markers measures C-reactive proteins, which are produced in the liver and rise in response to inflammation. It’s a blunt tool, and increased levels could signal anything from gum disease to heart disease. “This isn’t ready for primetime in terms of people going to their doctor and getting a test that is designed to pick out an inflammatory mechanism that contributes to depression, but I don’t think this is going to be the only test available in future.” 

The biomarkers that are thought to have a much more important role in signalling depression are what’s known as pro-inflammatory cytokines (see 'The inflammatory process explained' below), and they are more difficult and more expensive to measure.

Auckland mental health nurse practitioner Anna Elders, a cognitive behavioural therapist, believes a blood test might be superfluous anyway. “Once you start looking at the holistic picture, you almost don’t need to go down that route. You find out this person has dermatitis, had childhood asthma or eczema and irritable bowel. There’s a host of inflammatory-type symptoms so it would be unlikely there’d be no inflammation, whether it shows up in the blood or not.”

Elders, who’s worked in mental health for 17 years and is a professional teaching fellow at Auckland University, estimates inflammation is a contributor in about half of the patients she sees with depression. “In those who report more lifelong mental health problems, who were first depressed in childhood or adolescence, there is a real clinical picture of inflammatory-driven autoimmune conditions, poor quality of life and current stress.”

Anna Elders. Photo/Rebekah Robinson.

It’s difficult to pull apart the relative weight of the various clinical drivers. “I describe it to patients like the old game of Pick-up Sticks. You hold them and let them go, and then get this messy array of inter-connectedness, knowing that when you shift one, five others move at the same time. It helps us think about the true holistic nature of how we operate as human beings, but it provides a great challenge to how we approach treatment.”

She’s discussed the potential role of inflammation with patients for the past two or three years. “Many have a mixture of amazement at being given a picture that makes a lot of sense, to tie things together to help them understand why life has been such a challenge. They can feel a bit daunted by it and some are very frustrated that no one has talked to them about it in this way before. But it gives them a lot of hope because they see a bunch of different ways they can intervene with their health and shift the way their future might look.”

Antidepressants work well for some, but her patients with inflammation often have a poorer response to the drugs and more side effects. Elders says at this stage, she looks to dietary and lifestyle interventions before recommending patients be tested for inflammation.

As a nurse practitioner, she can prescribe antidepressants, but has also tried micronutrient supplements, which have been the subject of years of research by Julia Rucklidge’s team at Canterbury University. Rucklidge, a professor of clinical psychology, has found the micronutrients improved the wellbeing of people with ADHD and she’s now recruiting participants for a new trial to test their effectiveness in people with anxiety and depression.

An illustration of a tumour necrosis factor (TNF)-alpha, a pro-inflammatory protein that's thought to be linked to depression.

The inflammatory process explained

How can inflammation, the body’s physical response to injury and infection, possibly lead to depression? To understand the inflammatory process, it’s necessary to understand the role of a few key players in our immune system: macrophages, cytokines and lymphocytes.

Macrophages fire up when the body encounters a foreign invader. They break down substances such as bacteria and dish them up to the lymphocytes to target and destroy them. The macrophages also produce proteins called cytokines, which have either pro- or anti-inflammatory effects (and, confusingly, sometimes both). It’s a group of pro-inflammatory cytokines – interleukin 1, tumour necrosis factor (TNF)-alpha and interleukin 6 – that has excited the interest of scientists investigating the links between inflammation and depression.

Typically, these cytokines are used as signals to turn on some later aspects of the immune system, and their production tends to increase when we need them, and reduce when we don’t.

Here’s where some fascinating animal studies come in. Rats injected with infectious bacteria tend to withdraw from social contact, move less, and have disturbed sleep and eating behaviour – symptoms commonly seen in depression. But you don’t need to infect a rat with the actual bacteria to see this sort of sickness behaviour: injecting a rat with cytokines alone will produce the same effect, suggesting it’s not the germ itself that makes the animal sick, but the immune response to it.

Research has also shown that if a bacterial toxin is injected into the rat, the toxin itself won’t get into the brain – the blood–brain barrier will prevent that – but the inflammatory signals from the response to the toxin will.

The brain’s macrophages, known as microglial cells, pick up those signals and start producing cytokines, which in turn damage nerve cells in surrounding tissue. The result, says Edward Bullmore in The Inflamed Mind, is that nerve cells die or shrink, and the supply of neurotransmitters such as serotonin (which are produced in the brain as well as the gut) is disrupted. “Not only can angry microglial cells kill nerve cells in their immediate neighbourhood, they can also block the regenerative process that would form new nerve cells in their place.”

The fact that the cytokines change the way neurons make and release serotonin may also explain why people who are inflamed respond less well to traditional SSRI antidepressants, which prolong the amount of time serotonin stays in the synapse (the communication junction between neurons). “When inflammation reduces the amount of serotonin released into the synapses, it is effectively pulling in the opposite direction to SSRIs.”

Anti-TNF drugs have been used in rheumatoid arthritis since the late 1990s, and Bullmore’s book notes the experiences of doctors and nurses treating patients with the early infusions of one drug, infliximab (Remicade).

“They knew the patient would feel better and be full of gratitude almost immediately. It was so predictable that it had a nickname. They called it the Remicade high. It’s exactly what you’d expect if cytokines caused depression: that anti-cytokines should be anti-depressant; that a shot of anti-TNF should make people with inflamed minds feel high.”

The point was also proved in reverse, when patients with hepatitis B being treated with interferon, an inflammatory cytokine to boost the immune response to the hepatitis virus, became depressive. “This is not a side effect, but a sign that the treatment is having its intended effect of stimulating an inflammatory response. This happens to people who were not depressed immediately before the interferon injection. Their experience provides some of the clearest evidence in humans that an inflammatory stimulus can cause depression.”

C-reactive proteins and pro-inflammatory cytokines are all present at higher levels in people who have depression than in people who don’t. They’re also higher in other disorders such as obesity, diabetes and cardiovascular disease. But while they are markedly higher in conditions such as blood poisoning, they’re only mildly to moderately raised in people with depression.

Of course, it’s not just infection and injury that spark an inflammatory response, but also stress, poverty and adverse childhood experiences.

One of the more contentious suggestions in Bullmore’s book is that we become more inflamed naturally as we age, and accordingly, become more anxious and depressed. Other experts disagree, citing what’s known as the happiness “u-curve”, reflecting the fact we have the highest rates of depression and anxiety in our youth and old age, but a period of relative mood stability and wellbeing in our middle years.

While we may be prone as we age to chronic conditions involving degeneration, those conditions aren’t necessarily inflammation related, says Auckland University Associate Professor Roger Booth, a specialist in psychoneuroimmunology, the study of how the mind and nervous and immune systems interact. Booth believes we are years away from routinely using anti-inflammatories in patients with depression, pointing to the need for research to identify which patients might respond to the treatment, which treatments would work, and also the possible downsides.

“Inflammation is a useful process that anti-inflammatories dampen down. Long-term dampening will have adverse effects, so it’s not going to be a case of, ‘I’ll be okay with my depression if I take this [anti-inflammatory] pill for the rest of my life.’ I don’t think we are anywhere close to that sort of thing.”

Long-term, for example, it could stop the immune system responding effectively to life-threatening infections. “What we don’t know is whether a short course of an anti-inflammatory would reset the circuitry so when you came off it, all was well, or it was manageable with lifestyle changes. Anti-inflammatories are going to change a number of pathways, some of which we know a bit about and some we don’t know enough about, and that’s likely to end up causing a whole lot of other problems.”

Twenty years ago, the influence of the immune system on the nervous system wasn’t thought to be particularly significant, he says. “Now, the two are very much enmeshed and novel pathways of understanding emerge, as well as potentially novel treatments. But then we run the risk of saying, ‘We’ve got this magic bullet that will solve everything.’ It won’t be that simple.”

That, at least, is something all the experts we spoke to agree with. Psychiatrist Richard Porter, professor and head of the department of psychological medicine at the Otago Medical School in Christchurch, says one issue of many associated with the routine use of anti-inflammatories in depression is that no one knows at what level inflammation should be treated.

“There is increasing evidence that inflammation is important as a factor in depression, but it’s too complex a disease to determine one root cause.” He believes inflammation is probably “very important” in more severe depression. “Milder depression is often a psychological response to stress, with fewer biological abnormalities in brain and body.”

But Porter says he’d be likely to recommend the use of cholesterol-lowering statins in people with depression who had, for example, some risk factors for cardiovascular disease. “Statins are quite significantly anti-inflammatory. GPs would have different thresholds for recommending statins and some would be quite conservative, but my advice would be to be less conservative if a patient has a history of depression.”

Some of the biggest studies in the world of drug treatments, including statins, for inflammatory-related depression are being done across the ditch, at Melbourne’s Deakin University, under the leadership of renowned neuroscientist and psychiatrist Professor Michael Berk. He told North & South that Deakin has three or four clinical trials underway. In one just completed involving the old antibiotic minocycline, which also reduces inflammation, the researchers were able to show antidepressant effects. They’ve also shown an amino acid called N-Acetyl cysteine, which has anti-inflammatory and antidepressant properties, is useful for schizophrenia and bipolar disorder, and possibly depression as well.

Deakin did the first epidemiological studies showing statins can reduce the risk of depression, and researchers there are just finishing a clinical trial on the effectiveness of statins and aspirin in youth depression. A further study on the use of aspirin to prevent depression is scheduled for analysis by the end of the year. A number of international studies have also shown promising results with the arthritis drug celecoxib (Celebrex), which can boost the effectiveness of antidepressants.

One of Deakin’s most robust pieces of work has been research showing how improving diet – increasing vegetable, fruit, wholegrain, legumes, fish and nut consumption while reducing sweets and processed foods – can ease depression. Last year, Deakin’s Food and Mood Centre published the results of a 12-week randomised controlled trial showing that a third of those on a dietary regime went into remission for their depression, compared to only 8% who had social support alone.

Berk says that, as a clinician, he’d be far more likely to recommend antidepressants, psychotherapy, exercise, smoking cessation and diet modification because the risks are minimal.

“It’s too early in the piece to recommend anti-inflammatory strategies. I don’t think the evidence, as exciting as it is, is robust enough for clinicians to do routinely, and remember, there is an opportunity cost. Whenever you tell people to do something, most people will adhere to one or two recommendations and not others. If you tell them to do five things, they are not going to do five things.”

The chronic, low-grade inflammation that’s associated with depression is not only linked to stress and poor diet, says Berk, but to many other factors, including inactivity, obesity, smoking, dental caries, sleep disturbance, allergies, vitamin-D deficiency and leaky gut.

Professor Michael Berk says the evidence for anti-inflammatory strategies is “exciting” but not yet robust enough for clinicians to use routinely.

Ahh, at last, that G-word. The Gut. No story exploring the causes of illness these days seems complete without a nod to our microbiome – and depression is no exception, with gut bacteria producing an estimated 90% of the body’s serotonin, a neurotransmitter that has a key role in regulating mood.

The state of the gut microbiota has been associated with schizophrenia, autism, anxiety and major depression. At birth, babies inherit their microbiota from their mothers, but diet in the first three years of life also plays a critical role in determining the microbiome footprint in adulthood. Having that footprint doesn’t mean it’s impossible to alter, though – dietary changes can reduce the level of inflammatory markers in the bowel in just two weeks.

Scientists acknowledge it can be difficult to separate cause and effect – does mental ill health cause a poor diet rather than the other way around? – but most studies that have investigated whether the illness comes first have so far ruled it out. Last year, the Probiotics in Pregnancy Study of more than 400 Auckland and Wellington women, funded by the Health Research Council and Fonterra and run by Auckland University, found that those who took a probiotic daily during pregnancy and for six months after birth halved their risk of clinically significant anxiety.

In 2009, the Dunedin Multidisciplinary Health and Development Study reported that adults at 32 were twice as likely to have inflammation and depression if they’d been maltreated as children – although not all of the study participants who had depression were also inflamed. The study found that even mild increases in inflammation levels appeared to predict increased risk of heart disease in apparently healthy people.

Study director Professor Richie Poulton told North & South that when the team examined the existing science before its analysis, it was a confused picture; depression was associated with inflammation in some studies, but not all. “We then reasoned that what might link the two was a third factor – specifically, a history of child maltreatment – because it’s well known that adversity in childhood can raise the risk of heart disease in later life as well as increase the likelihood of developing depression. That’s exactly what we found: it was only those depressed adults who had a history of childhood maltreatment that had significantly high levels of systemic inflammation in their fourth decade of life.”

Left: The Dunedin Multidisciplinary Health and Development Study led by Professor Richie Poulton has linked childhood maltreatment with later inflammation and depression. Photo/Guy Frederick. Right: Auckland University Associate Professor Roger Booth says the immune and nervous systems are “enmeshed” and research could lead to novel treatments. Photo/Ken Downie.

The Dunedin paper suggested that doctors routinely assess depressed patients for childhood mistreatment to identify those with elevated risk of inflammation and potentially poor health. Poulton says the study will further examine the interactions between physical, social and psychological factors in ill health when its assessment of participants, now aged 45, is finished early next year.

Bullmore says the emerging links between stress and inflammation help to bring together the biological and psychosocial sides of the depression equation. “The key thing is the mechanism. If we say stress causes depression, it’s a bit like saying light causes vision – there’s a whole sequence of events in the middle but we don’t yet understand all the intervening stages.

He says a “careful doctor” in 2018 is likely to steer a patient away from existing anti-inflammatory drugs, towards treatment of the underlying condition. “Periodontitis, literally inflammation around the teeth, would be top of my list of culprits if I was inflamed and depressed. This is a low-grade chronic infection that can easily get forgotten because most doctors don’t think about it, and most dentists aren’t paid to think about the links between gum disease and depression.”

Gastrointestinal disturbances, such as irritable bowel (as in Kathryn Moake’s case) or intermittent colitis, are also likely suspects, he says, with so-called “leaky gut” allowing bacteria through the intestinal wall to cause inflammation in the body. The condition would be exacerbated if the immune system is already on high alert because of a deprived or abusive childhood.

Moake is still battling her irritable bowel symptoms, but after more than a year on antidepressants, says her low mood is under control, even after a marriage breakdown. She’s confident childhood stress isn’t a cause of her depression – “we were very lucky to have a lovely childhood with awesome parents and everything we needed” – but she’s planning to return to her doctor to have her inflammatory markers tested.

“I probably haven’t been as robust as I would have been if I hadn’t had the inflammatory stuff going on,” she says.

In the meantime, she’s exploring natural ways to improve her health. “I’m trying really hard with sleep, and I’ve given up all caffeine and alcohol – not that I drank much before.” She says she’d never “go it alone” by trying over-the-counter anti-inflammatories. “You’ve got to be working alongside someone who knows what they’re doing.”

It might be too early for patients such as Moake, but Bullmore says a “best-case scenario” would result in “decisive moves” in treatment within five or 10 years. “Maybe we’ll see new drugs that, unlike the old ones, are not vaguely supposed to work equally well for everyone, but are scientifically predicted to work particularly well for some.

“We could be on the cusp of a revolution. I might be wrong, but I think it has already begun.”

This article was first published in the September 2018 issue of North & South.

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