̽��ֱ�� of Cambridge - Golam Khandaker

Inflammation links heart disease and depression, study finds

cjb250 — Tue, 19 Mar 2019 00:01:32 +0000

While inflammation is a natural response necessary to fight off infection, chronic inflammation – which may result from psychological stress as well as lifestyle factors such as smoking, excessive alcohol intake, physical inactivity and obesity – is harmful.

̽��ֱ��link between heart disease and depression is well documented. People who have a heart attack are at a significantly higher risk of experiencing depression. Yet scientists have been unable to determine whether this is due to the two conditions sharing common genetic factors or whether shared environmental factors provide the link.

“It is possible that heart disease and depression share common underlying biological mechanisms, which manifest as two different conditions in two different organs – the cardiovascular system and the brain,” says Dr Golam Khandaker, a Wellcome Trust Intermediate Clinical Fellow at the ̽��ֱ�� of Cambridge. “Our work suggests that inflammation could be a shared mechanism for these conditions.”

In a study published today in the journal Molecular Psychiatry, Dr Khandaker and colleague Dr Stephen Burgess led a team of researchers from Cambridge who examined this link by studying data relating to almost 370,000 middle-aged participants of UK Biobank.

First, the team looked at whether family history of coronary heart disease was associated with risk of major depression. They found that people who reported at least one parent having died of heart disease were 20% more likely to develop depression at some point in their life.

Next, the researchers calculated a genetic risk score for coronary heart disease – a measure of the contribution made by the various genes known to increase the risk of heart disease. Heart disease is a so-called ‘polygenic’ disease – in other words, it is caused not by a single genetic variant, but rather by a large number of genes, each increasing an individual’s chances of developing heart disease by a small amount. Unlike for family history, however, the researchers found no strong association between the genetic predisposition for heart disease and the likelihood of experiencing depression.

Together, these results suggest that the link between heart disease and depression cannot be explained by a common genetic predisposition to the two diseases. Instead, it implies that something about an individual’s environment – such as the risk factors they are exposed to – not only increases their risk of heart disease, but at the same time increases their risk of depression.

This finding was given further support by the next stage of the team’s research. They used a technique known as Mendelian randomisation to investigate 15 biomarkers – biological ‘red flags’ – associated with increased risk of coronary heart disease. Mendelian randomisation is a statistical technique that allows researchers to rule out the influence of factors that otherwise confuse, or confound, a study, such as social status.

Of these common biomarkers, they found that triglycerides (a type of fat found in the blood) and the inflammation-related proteins IL-6 and CRP were also risk factors for depression.

Both IL-6 and CRP are inflammatory markers that are produced in response to damaging stimuli, such as infection, stress or smoking. Studies by Dr Khandaker and others have previously shown that people with elevated levels of IL-6 and CRP in the blood are more prone to develop depression, and that levels of these biomarkers are high in some patients during acute depressive episode. Elevated markers of inflammation are also seen in people with treatment resistant depression. This has raised the prospect that anti-inflammatory drugs might be used to treat some patients with depression. Dr Khandaker is currently involved in a clinical trial to test tocilizumab, an anti-inflammatory drug used for the treatment of rheumatoid arthritis that inhibits IL-6, to see if reducing inflammation leads to improvement in mood and cognitive function in patients with depression.

While the link between triglycerides and coronary heart disease is well documented, it is not clear why they, too, should contribute to depression. ̽��ֱ��link is unlikely to be related by obesity, for example, as this study has found no evidence for a causal link between body mass index (BMI) and depression.

“Although we don’t know what the shared mechanisms between these diseases are, we now have clues to work with that point towards the involvement of the immune system,” says Dr Burgess. “Identifying genetic variants that regulate modifiable risk factors helps to find what is actually driving disease risk.”

̽��ֱ��research was funded by Wellcome and MQ: Transforming Mental Health.

Dr Sophie Dix, Director of Research at MQ, says: “This study adds important new insight into the emergence and risk of depression, a significantly under researched area.

“Taking a holistic view of a person’s health – such as looking at heart disease and depression together – enables us to understand how factors like traumatic experiences and the environment impact on both our physical and mental health.

“This research shows clearly the shared biological changes that are involved. This not only opens opportunities for earlier diagnosis, but also create a solid foundation for exploring new treatments or using existing treatments differently. We need to stop thinking about mental and physical health in isolation and continue this example of bringing sciences together to create real change.”

Reference
Khandaker, GM et al. Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort. Molecular Psychiatry; 19 March 2019; DOI: 10.1038/s41380-019-0395-3

People with heart disease are more likely to suffer from depression, and the opposite is also true. Now, scientists at the ̽��ֱ�� of Cambridge believe they have identified a link between these two conditions: inflammation – the body’s response to negative environmental factors, such as stress.

It is possible that heart disease and depression share common underlying biological mechanisms, which manifest as two different conditions in two different organs – the cardiovascular system and the brain

Golam Khandaker

Mitchell Hollander

Man

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Anti-inflammatory drugs could help treat symptoms of depression, study suggests

cjb250 — Tue, 18 Oct 2016 07:57:48 +0000

Researchers from the Department of Psychiatry at Cambridge led a team that analysed data from 20 clinical trials involving the use of anti-cytokine drugs to treat a range of autoimmune inflammatory diseases. By looking at additional beneficial side-effects of the treatments, the researchers were able to show that there was a significant antidepressant effect from the drugs compared to a placebo based on a meta-analysis of seven randomised controlled trials. Meta-analyses of the other types of clinical trials showed similar results.

When we are exposed to an infection, for example influenza or a stomach bug, our immune system fights back to control and remove the infection. During this process, immune cells flood the blood stream with proteins known as cytokines. This process is known as systemic inflammation.

Even when we are healthy, our bodies carry trace levels of these proteins – known as ‘inflammatory markers’ – which rise exponentially in response to infection. Previous work from the team found that children with high everyday levels of one of these markers are at greater risk of developing depression and psychosis in adulthood, suggesting a role for the immune system, particularly chronic low-grade systemic inflammation, in mental illness.

Inflammation can also occur as a result of the immune system mistaking healthy cells for infected cells and attacking the body, leading to autoimmune inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn’s disease. New types of anti-inflammatory drugs called anti-cytokine monoclonal antibodies and cytokine inhibitors have been developed recently, some of which are now routinely used for patients who respond poorly to conventional treatments. Many more are currently undergoing clinical trials to test their efficacy and safety.

̽��ֱ��team of researchers carried out a meta-analysis of these clinical trials and found that the drugs led to an improvement in the severity of depressive symptoms independently of improvements in physical illness. In other words, regardless of whether a drug successfully treated rheumatoid arthritis, for example, it would still help improve a patient’s depressive symptoms. Their results are published today in the journal Molecular Psychiatry.

Dr Golam Khandaker, who led the study, says: “It’s becoming increasingly clear to us that inflammation plays a role in depression, at least for some individuals, and now our review suggests that it may be possible to treat these individuals using some anti-inflammatory drugs. These are not your everyday anti-inflammatory drugs such as ibuprofen, however, but a particular new class of drugs.”

“It’s too early to say whether these anti-cytokine drugs can be used in clinical practice for depression, however,” adds Professor Peter Jones, co-author of the study. “We will need clinical trials to test how effective they are in patients who do not have the chronic conditions for which the drugs have been developed, such as rheumatoid arthritis or Crohn’s disease. On top of this, some existing drugs can have potentially serious side effects, which would need to be addressed.”

Dr Khandaker and colleagues believe that anti-inflammatory drugs may offer hope for patients for whom current antidepressants are ineffective. Although the trials reviewed by the team involve physical illnesses that trigger inflammation – and hence potentially contribute to depression – their previous work found a connection between depression and baseline levels of inflammation in healthy people (when someone does not have an acute infection), which can be caused by a number of factors such as genes and psychological stress.

“About a third of patients who are resistant to antidepressants show evidence of inflammation,” adds Dr Khandaker. “So, anti-inflammatory treatments could be relevant for a large number of people who suffer from depression.

“ ̽��ֱ��current approach of a ‘one-size-fits-all’ medicine to treat depression is problematic. All currently available antidepressants target a particular type of neurotransmitter, but a third of patients do not respond to these drugs. We are now entering the era of ‘personalised medicine’ where we can tailor treatments to individual patients. This approach is starting to show success in treating cancers, and it’s possible that in future we would use anti-inflammatory drugs in psychiatry for certain patients with depression.”

̽��ֱ��research was mainly funded by the Wellcome Trust, with further support from the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.

Reference
Kappelmann, N et al. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Molecular Psychiatry; 18 Oct 2016; DOI: 10.1038/mp.2016.167

Anti-inflammatory drugs similar to those used to treat conditions such as rheumatoid arthritis and psoriasis could in future be used to treat some cases of depression, concludes a review led by the ̽��ֱ�� of Cambridge, which further implicates our immune system in mental health disorders.

It’s becoming increasingly clear to us that inflammation plays a role in depression, at least for some individuals, and now our review suggests that it may be possible to treat these individuals using some anti-inflammatory drugs

Golam Khandaker

Boudewijn Berends

Depressing fog

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Mind and body: Scientists identify immune system link to mental illness

cjb250 — Wed, 13 Aug 2014 20:00:00 +0000

̽��ֱ��study, published today in JAMA Psychiatry, indicates that mental illness and chronic physical illness such as coronary heart disease and type 2 diabetes may share common biological mechanisms.

When we are exposed to an infection, for example influenza or a stomach bug, our immune system fights back to control and remove the infection. During this process, immune cells flood the blood stream with proteins such as interleukin-6 (IL-6), a tell-tale marker of infection. However, even when we are healthy, our bodies carry trace levels of these proteins – known as ‘inflammatory markers’ – which rise exponentially in response to infection.

Now, researchers have carried out the first ever longitudinal study – a study that follows the same cohort of people over a long period of time – to examine the link between these markers in childhood and subsequent mental illness.

A team of scientists led by the ̽��ֱ�� of Cambridge studied a sample of 4,500 individuals from the Avon Longitudinal Study of Parents and Children – also known as Children of the 90s – taking blood samples at age 9 and following up at age 18 to see if they had experienced episodes of depression or psychosis. ̽��ֱ��team divided the individuals into three groups, depending on whether their everyday levels of IL-6 were low, medium or high. They found that those children in the ‘high’ group were nearly two times more likely to have experienced depression or psychosis than those in the ‘low’ group.

Dr Golam Khandaker from the Department of Psychiatry at the ̽��ֱ�� of Cambridge, who led the study, says: “Our immune system acts like a thermostat, turned down low most of the time, but cranked up when we have an infection. In some people, the thermostat is always set slightly higher, behaving as if they have a persistent low level infection – these people appear to be at a higher risk of developing depression and psychosis. It’s too early to say whether this association is causal, and we are carrying out additional studies to examine this association further.”

̽��ֱ��research indicates that chronic physical illness such as coronary heart disease and type 2 diabetes may share a common mechanism with mental illness. People with depression and schizophrenia are known to have a much higher risk of developing heart disease and diabetes, and elevated levels of IL-6 have previously been shown to increase the risk of heart disease and type 2 diabetes.

Professor Peter Jones, Head of the Department of Psychiatry and senior author of the study, says: “Inflammation may be a common mechanism that influences both our physical and mental health. It is possible that early life adversity and stress lead to persistent increase in levels of IL-6 and other inflammatory markers in our body, which, in turn, increase the risk of a number of chronic physical and mental illness.”

Indeed, low birth weight, a marker of impaired foetal development, is associated with increased everyday levels of inflammatory markers as well as greater risks of heart disease, diabetes, depression and schizophrenia in adults.

This potential common mechanism could help explain why physical exercise and diet, classic ways of reducing risk of heart disease, for example, are also thought to improve mood and help depression. ̽��ֱ��group is now planning additional studies to confirm whether inflammation is a common link between chronic physical and mental illness.

̽��ֱ��research also hints at interesting ways of potentially treating illnesses such as depression: anti-inflammatory drugs. Treatment with anti-inflammatory agents leads to levels of inflammatory markers falling to normal. Previous research has suggested that anti-inflammatory drugs such as aspirin used in conjunction with antipsychotic treatments may be more effective than just the antipsychotics themselves. A multicentre trial is currently underway, into whether the antibiotic minocycline, used for the treatment of acne, can be used to treat lack of enjoyment, social withdrawal, apathy and other so called negative symptoms in schizophrenia. Minocycline is able to penetrate the ‘blood-brain barrier’, a highly selective permeability barrier which protects the central nervous system from potentially harmful substances circulating in our blood.

̽��ֱ��‘blood-brain barrier’ is also at the centre of a potential puzzle raised by research such as today’s research: how can the immune system have an effect in the brain when many inflammatory markers and antibodies cannot penetrate this barrier? Studies in mice suggest that the answer may lie in the vagus nerve, which connects the brain to the abdomen. When activated by inflammatory markers in the gut, it sends a signal to the brain, where immune cells produce proteins such as IL-6, leading to increased metabolism (and hence decreased levels) of the ‘happiness hormone’ serotonin in the brain. Similarly, the signals trigger an increase in toxic chemicals such as nitric oxide, quinolonic acid, and kynurenic acid, which are bad for the functioning of nerve cells.

̽��ֱ��research was mainly funded by the Wellcome Trust, with further support from the National Institute for Health Research Cambridge Biomedical Research Centre and the Medical Research Council.

Children with high everyday levels of a protein released into the blood in response to infection are at greater risk of developing depression and psychosis in adulthood, according to new research which suggests a role for the immune system in mental illness.

Inflammation may be a common mechanism that influences both our physical and mental health

Peter Jones

Stu

Burnt out

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