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Researchers identify characteristic chemical signature for CFS

Posted on 08/30/2016 by wames

UC San Diego Press release, by Scott LaFee, 29 August 2016: Researchers Identify Characteristic Chemical Signature for Chronic Fatigue Syndrome

Discovery, along with revealed underlying biology, could lead to faster, more accurate diagnoses and more effective, personalized therapies

Chronic fatigue syndrome (CFS) is a mysterious and maddening condition, with no cure or known cause. But researchers at the University of California San Diego School of Medicine, using a variety of techniques to identify and assess targeted metabolites in blood plasma, have identified a characteristic chemical signature for the debilitating ailment and an unexpected underlying biology: It is similar to the state of dauer, and other hypometabolic syndromes like caloric restriction, diapause and hibernation.

Dauer is the German word for persistence or long-lived. It is a type of stasis in the development in some invertebrates that is prompted by harsh environmental conditions. The findings are published online in the August 29 issue of PNAS.

“CFS is a very challenging disease,”

said first author Robert K. Naviaux, MD, PhD, professor of medicine, pediatrics and pathology and director of the Mitochondrial and Metabolic Disease Center at UC San Diego School of Medicine.

“It affects multiple systems of the body. Symptoms vary and are common to many other diseases. There is no diagnostic laboratory test. Patients may spend tens of thousands of dollars and years trying to get a correct diagnosis.”

As many as 2.5 million Americans are believed to have CFS. It most often afflicts women in their 30s to 50s, though both genders and all ages can be affected. The primary symptom is severe fatigue lasting at least six months, with corollary symptoms ranging from muscle pain and headaches to sleep and memory problems.

Naviaux and colleagues studied 84 subjects: 45 men and women who met the diagnostic criteria for CFS and 39 matched controls. The researchers targeted 612 metabolites (substances produced by the processes of metabolism) from 63 biochemical pathways in blood plasma. They found that individuals with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites measured were decreased, consistent with hypometabolic syndrome or reduced metabolism. The diagnostic accuracy rate exceeded 90 percent.

“Despite the heterogeneity of CFS, the diversity of factors that lead to this condition, our findings show that the cellular metabolic response is the same in patients,” said Naviaux. “And interestingly, it’s chemically similar to the dauer state you see in some organisms, which kicks in when environmental stresses trigger a slow-down in metabolism to permit survival under conditions that might otherwise cause cell death. In CFS, this slow-down comes at the cost of long-term pain and disability.”

Naviaux said the findings show that CFS possesses an objectively identifiable chemical signature in both men and women and that targeted metabolomics, which provide direct small molecule information, can provide actionable treatment information. Only 25 percent of the metabolite disturbances found in each person were needed for the diagnosis of CFS. Roughly 75 percent of abnormalities were unique to each individual, which Naviaux said is useful in guiding personalized treatment.

“This work opens a fresh path to both understanding the biology of CFS and, more importantly to patients, a robust, rational way to develop new therapeutics for a disease sorely in need of them.”

The study authors noted additional research using larger groups of participants from diverse geographical areas is needed to validate both the universality and specificity of the findings.

Co-authors include: Jane C. Naviaux, Kefeng Li, A. Taylor Bright, William A. Alaynick, and Lin Wang, all at UC San Diego; and Asha Baxter, Neil Nathan, Wayne Anderson, and Eric Gordon, Gordon Medical Associates.

Funding for this research came, in part, from the UC San Diego Christini Fund, The Wright Family Foundation, The Lennox Foundation, the It Takes Guts Foundation, the UC San Diego Mitochondrial Disease Research Fund and gifts from Tom Eames and Tonye Marie Castenada.

Metabolic features of chronic fatigue syndrome, by Robert K. Naviaux, Jane C. Naviaux, Kefeng Lia, A. Taylor Bright, William A. Alaynick, Lin Wang, Asha Baxter, Neil Nathan, Wayne Anderson, and Eric Gordon in PNAS [Published online before print August 29, 2016]

For more information about CFS and mitochondrial research, visit naviauxlab.ucsd.edu

Protein kinase gene dysfunction in severe CFS/ME

Posted on 08/30/2016 by wames

Research abstract:

Background:

The etiology and pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are unknown. However, natural killer (NK) cell dysfunction, in particular reduced NK cytotoxic activity, is a consistent finding in CFS/ME patients. Previous research has reported significant changes in intracellular mitogen-activated protein kinase pathways from isolated NK cells. The purpose of this present investigation was to examine whether protein kinase genes have a role in abnormal NK cell intracellular signaling in CFS/ME.

Method:

Messenger RNA (mRNA) expression of 528 protein kinase genes in isolated NK cells was analyzed (nCounter GX Human Kinase Kit v2 (XT); NanoString Technologies) from moderate (n = 11; age, 54.9 ± 10.3 years) and severe (n = 12; age, 47.5 ± 8.0 years) CFS/ME patients (classified by the 2011 International Consensus Criteria) and nonfatigued controls (n = 11; age, 50.0 ± 12.3 years).

Results:

The expression of 92 protein kinase genes was significantly different in the severe CFS/ME group compared with nonfatigued controls. Among these, 37 genes were significantly upregulated and 55 genes were significantly downregulated in severe CFS/ME patients compared with nonfatigued controls.

Conclusions:

In severe CFS/ME patients, dysfunction in protein kinase genes may contribute to impairments in NK cell intracellular signaling and effector function. Similar changes in protein kinase genes may be present in other cells, potentially contributing to the pathomechanism of this illness.

Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients, by Anu Chacko, Donald R. Staines, Samantha C. Johnston and Sonya M Marshall-Gradisnik in Gene Regulation and Systems Biology 2016:10 85-93, 28 Aug 2016

Posted in News | Tagged Anu Chacko, Dr Samantha Johnston, gene expression, Prof Donald Staines, protein kinase genes, Sonya Marshall-Gradisnik | Comments Off

MRI of hearts of women with CFS found lower left ventricular function

Posted on 08/30/2016 by wames

Research abstract:

Objective:
In chronic fatigue syndrome (CFS), only a few imaging and histopathological studies have previously assessed either cardiac dimensions/function or myocardial tissue, suggesting smaller left ventricular (LV) dimensions, LV wall motion abnormalities and occasionally viral persistence that may lead to cardiomyopathy. The present study with cardiac magnetic resonance (CMR) imaging is the first to use a contrast-enhanced approach to assess cardiac involvement, including tissue characterisation of the LV wall.

Methods:
CMR measurements of 12 female CFS patients were compared with data of 36 age-matched, healthy female controls. With cine imaging, LV volumes, ejection fraction (EF), mass, and wall motion abnormalities were assessed. T2-weighted images were analysed for increased signal intensity, reflecting oedema (i. e. inflammation). In addition, the presence of contrast enhancement, reflecting fibrosis (i. e. myocardial damage), was analysed.

Results:
When comparing CFS patients and healthy controls, LVEF (57.9 p/m 4.3 % vs. 63.7 p/m 3.7 %; p<0.01), end-diastolic diameter (44 p/m 3.7 mm vs. 49 p/m 3.7 mm; p<0.01), as well as body surface area corrected LV end-diastolic volume (77.5 p/m 6.2 ml/m^2 vs. 86.0 p/m 9.3 ml/m^2; p<0.01), stroke volume (44.9 p/m 4.5 ml/m^2 vs. 54.9 p/m 6.3 ml/m^2; p<0.001), and mass (39.8 p/m 6.5 g/m^2 vs. 49.6 p/m 7.1 g/m^2; p=0.02) were significantly lower in patients. Wall motion abnormalities were observed in four patients and contrast enhancement (fibrosis) in three; none of the controls showed wall motion abnormalities or contrast enhancement. None of the patients or controls showed increased signal intensity on the T2-weighted images.

Conclusion:
In patients with CFS, CMR demonstrated lower LV dimensions and a mildly reduced LV function. The presence of myocardial fibrosis in some CFS patients suggests that CMR assessment of cardiac involvement is warranted as part of the scientific exploration, which may imply serial non-invasive examinations.

Chronic fatigue syndrome in women assessed with combined cardiac magnetic resonance imaging, by M.A.G.M. Olimulder, M.A. Galjee, L.J. Wagenaar, J. van Es, J. van der Palen, F.C. Visser, R.C.W. Vermeulen, C. von Birgelen in Netherlands Heart Journal [Preprint]
August 25, 2016

Posted in News | Tagged Cardiovascular magnetic resonance, Left ventricular function, MRI, myocardial damage, RCW Vermeulen | Comments Off

Post-exertional malaise: an exploratory factor analysis

Posted on 08/29/2016 by wames

Research abstract:

Post-exertional malaise is a cardinal symptom of myalgic encephalomyelitis and chronic fatigue syndrome. There are two differing focuses when defining post-exertional malaise: a generalized, full-body fatigue and a muscle-specific fatigue.

This study aimed to discern whether post-exertional malaise is a unified construct or whether it is composed of two smaller constructs, muscle fatigue and generalized fatigue. An exploratory factor analysis was conducted on several symptoms that assess post-exertional malaise. The results suggest that post-exertional malaise is composed of two empirically different experiences, one for generalized fatigue and one for muscle-specific fatigue.

Deconstructing post-exertional malaise: An exploratory factor analysis, by Stephanie L McManimen, Madison L Sunnquist, Leonard A Jason in J Health Psychol August 24, 2016

Posted in News | Tagged chronic fatigue, exploratory factor analysis, Madison L Sunnquist, muscle fatigue, PEM, Post-exertional malaise, Prof Leonard Jason, Stephanie L McManimen | Comments Off

Ampligen – the first drug approved in the world for ME/CFS

Posted on 08/26/2016 by wames

Health rising blog post, by Cort Johnson, 25 August, 2016: Ampligen Takes Big Step Forward – Becomes First Drug Approved Anywhere For Chronic Fatigue Syndrome

Ampligen became the first drug approved for chronic fatigue syndrome (ME/CFS) anywhere in the world this week when ANMAT, the Argentine FDA, approved the drug for use in people with severe ME/CFS.

Why should we get excited about Ampligen’s approval in Argentina? Because Argentina has a modern medical system which includes having a rigorous drug approval process. Hopefully this will be a harbinger of things to come for Ampligen.

Argentina was the first Latin American country Hemispherx Biopharma (HB) – the maker of the drug – tried to get Ampligen approval in. The process, which took four years, began when HB teamed up with GP Pharm, an Argentine pharmaceutical company. GP Pharm used the same studies to shepherd the approval through ANMAT, the Argentine form of the FDA, that HB used in its FDA application for Ampligen two years ago.

Ampligen was approved for use in people with “severe ME/CFS” – a designation that was based on the type of ME/CFS patients that took part in the company’s original U.S. studies. A person with severe ME/CFS in Argentina needs to meet the new IOM and the (old) Holmes criteria, and have a Karnovsky score between 40 and 60 in order to get access to the drug.

40: Disabled; requires special care and assistance.
50: Requires considerable assistance and frequent medical care.
60: Requires occasional assistance, but is able to care for most of his personal needs.

Hemispherx believes that at least 100,000 and perhaps as many as 500,000 patients in the 42 million person country will meet the criteria.

Equel’s has been making the rounds of media outlets to discuss Ampligen. A financial analyst with Crystal Research agreed in an interview at Small Cap Nation – a financial media outlet focused on small companies – that the potential for Ampligen in the ME/CFS market alone was huge. With Ampligen the sole drug even being considered at this point for ME/CFS it would have the market to itself. He called the Argentine approval “very significant” and put the potential valuation of the drug in the multi-billion dollar range.

Watch interview

He also agreed the Argentine approval will make getting approval elsewhere easier.

The FDA Question

I talked with Nancy McGrory at Hemispherx about the recent approval. She believes the approval could help HB in other countries with similar regulatory drug processes. The fact that Ampligen passed muster in a country with a modern medical system with a rigorous drug approval process will likely, McGrory thought, prompt other countries to take a much closer look at the drug.

Ten years ago, she noted, most pharmaceutical drug companies concentrated on getting drug approval at the FDA first in the belief that making it through the FDA’s notoriously tough regulatory process would give other countries confidence that the drug was safe and effective. The FDA – which is focused first on protecting the public health – has proved so risk averse lately, though, that some drug companies are choosing to get drug approval outside the U.S. first.

That brought up the question, though, what’s going with FDA approval for Ampligen? When I asked McGrory about the reception Ampligen was getting at the FDA these days, she sounded hopeful. She said she believed that the work of patients, advocates and ME/CFS experts to educate the FDA about ME/CFS had paid off. The FDA Workshop and other meetings, she believed, really got the message across about how serious disease is, and that produced a sea-change in the agencies attitude towards ME/CFS. The FDA she thought, would like very much to approve a drug for this illness.

Thomas Equels, HB’s new President has made Ampligen approval the companies top priority and has stated that he will to do whatever is necessary to get it done. McGrory said HB officials have meet with the FDA and the NIH several times, and will soon meet to finalize the protocol for what will hopefully be the final phase III study on ME/CFS.

The FDA wants, and is going to get a several hundred person trial. Equel’s job now is to find partners to fund it. The companies new stance – that it’s committed to reach out and either license its technology or find a major pharmaceutical company or investor to assist it – is a distinct change of pace at HB.

In another hopeful note, Hemispherx reported it’s at long last identified a subset of high responders to Ampligen and will present a paper to that effect at the IACFS/ME conference in October. Finding high responders to Ampligen would, of course, greatly help HB be successful in a phase III trial.

Read what Equels said about what a potential investor should know about Ampligen

Posted in News | Tagged ampligen, ANMAT, Argentina, Cort Johnson, Health rising, Hemispherx Biopharma | Comments Off

Milk protein intolerance in ME/CFS

Posted on 08/26/2016 by wames

ME Research UK article, 23 Aug 2016: Milk protein intolerance

Around 20% of people in developed societies have adverse reactions to particular foods, and some have outright food intolerances, defined as undesirable non-allergic reactions that do not involve a direct immune response. The most common food ‘sensitivities’ in the modern world are to gluten, lactose, fructose, milk and eggs, but there are a plethora of other candidates (see Figure).

Food intolerances also have a significant role in ME/CFS. Sensitivity to foodstuffs is one of the possible “immune, gastro-intestinal & genitourinary impairments” used for diagnosis (see the 2011 ICC definition), and many individual patients say that they benefit from avoiding certain foods.

Gluten is a good example, and we know from emails and phone calls to ME Research UK that excluding gluten from the diet improves some patients’ symptoms. These symptoms not only include gut discomfort (abdominal pain, bloating etc.) as might be expected but more systemic manifestations such as brain fog, headache, joint and muscle pain. Now, a new report in the August 2016 issue of Acta Pediatrica (read more) suggests that milk protein may also be contributing to symptoms, at least in some ME/CFS patients.

The very active group led by Prof Peter Rowe at Johns Hopkins University School of Medicine in Baltimore has been conducting a two-year cohort study of physical findings and outcomes in young people with ME/CFS. One of the beauties of a programme of research is that unexpected observations can be followed up, and the group had noticed that a number of their patients had symptoms and signs consistent with a delayed reaction to milk protein.

To test whether milk intolerance might be a factor in the maintenance of illness, they designed a sub-study to examine overall quality of life (including fatigue, sleep and activity limitations caused by physical health problems) before and after a 6-month period of dietary milk protein restriction. Intolerance to milk protein is diagnosed on clinical grounds alone because no validated laboratory tests exist as yet, so the team performed an initial dietary trial.

Of 55 young ME/CFS patients, 17 (31%) were found to be milk-protein intolerant. In the testing phase of the study, a clinically important improvement in the frequency and severity of symptoms was reported by some participants once milk protein was eliminated from their diet. These patients were then put on a milk-free diet for 6 months, and their quality of life was compared at the start and end of the study with that of patients who could tolerate milk protein.

At the start of the study, health-related quality of life was significantly worse in patients who were milk protein intolerant than in those who were not. However, six months after the milk-free diet, quality of life had improved to a greater degree in the patients with milk protein intolerance, and there was no longer a difference in quality of life between the two groups.

Also, milk-intolerant patients on the milk-free diet had improvements in upper gastrointestinal and systemic symptoms, and these improvements occurred within two weeks of starting the diet. Of course, as this was not a randomised trial, it’s not possible to say that these effects were due to the milk-free diet alone. The evidence is certainly suggestive, however, and it may be that a milk-free diet could have a significant positive effect in some ME/CFS patients.

For the authors, the importance of the results is that almost a third of adolescents and young adults with ME/CFS “had evidence of treatable milk protein intolerance”, a higher proportion than expected given the evidence that the prevalence of ‘true’ reactions to food may be quite small in the general population (read more). Crucially, most of the study patients who benefitted from a milk-free diet had previously been unaware of the contribution of milk to their symptoms, probably because of the time delay between consumption and symptoms (unlike in true food allergy where symptoms develop far more rapidly).

The authors point out that for patients with ME/CFS the situation can be clarified by a two-week trial of a milk-free diet. While stopping or reducing milk consumption is not the ‘answer’ to ME/CFS, it’s worth being aware that the symptoms of ME/CFS may be exacerbated in some people by milk, a common foodstuff. If patients’ experience of avoiding gluten is anything to go by (read more), the effects of a milk-free diet for a short period could be both surprising and welcome.

Posted in News | Tagged cow's milk protein intolerance, food intolerance, ME Research UK | Comments Off

Cannabis spray being tested for pain, anxiety & depression in Cardiff

Posted on 08/25/2016 by wames

Wales online article, by Mark Smith, 23 August 2016: People with depression, anxiety and arthritis could use a cannabis spray being tested in Cardiff

The testing is happening at an NHS facility in Cardiff

A cannabis-based vapouriser is being tested in Wales.

We’ve learned that an NHS facility in Cardiff is testing the vapouriser to determine the cannabinoid concentration of the formula.

Two years ago, Wales became the first UK nation to legalise a cannabis based drug for Multiple Sclerosis sufferers.

The new vapouriser is a MediPen, which is inhaled like an e-cigarette.

The MediPen, which is inhaled like an e-cigarette, has been described as a “completely legal and harm-free way to unleash the miraculous health benefits of cannabis”
It has been described as a “completely legal and harm-free way to unleash the miraculous health benefits of cannabis”.

It uses a substance known as cannabidiol, an oil extracted from the cannabis plant that does not contain any of the psychoactive chemicals which get a person high.

It claims to be able to reduce anxiety, depression and even relieve the pain of arthritis and fibromyalgia.

We understand that the cannabidiol (CBD) vaporiser, which can already be bought online, is undergoing quality control measures in Cardiff and Vale University Health Board.

But the exact location cannot be released by the NHS due to a non-disclosure agreement which prevents them from sharing client information.

All contracts scrutinised
A spokesman for Cardiff and Vale University Health Board said:

“As a University Health Board we undertake a number of commercial activities, such as quality control with private companies, including Medipen.

“Due to commercial in confidence we are not able to provide any further details.

“All Cardiff and Vale University Health Board contracts are scrutinised for ethical, legal and commercial sensitivities and any breach of this will be fully investigated by the Health Board.”

MediPen believes that by testing products with the help of the NHS, the public’s perception of cannabis will change.

It says it wants to “end the criminalisation of over one million medicinal users” and make cannabis-based medication readily available to those who need it.

Managing director Jordan Owen said:

“Our contract is for the purposes of safety, quality control and to ensure the consistency of cannabinoid concentration throughout each batch.

“This is something that is extremely important in an industry subject to so many negative connotations, by testing our proprietary formula through a reputable body such as the NHS we are confident that this will have a very positive impact on the public’s perception of cannabis.

“This is a huge leap forward”

“This is a huge leap forward for the UK’s rapidly growing legal cannabis industry and we are confident that by breaking down the negative connotations surrounding cannabis this will have a positive effect on our countries draconian prohibition laws that are having a detrimental impact on the lives of millions of medicinal cannabis users across the UK.”

The MediPen, which is described as a “sleek and stylish portable handheld device ”, can be bought online for as little as £50 and has 17 flavours.

It says it uses cannabis plants grown in the Netherlands with the sole aim of maximising CBD content whilst eliminating any traces of tetrahydrocannabinol, the primary ingredient in marijuana responsible for the high.

See also: abc.net.au, 13 August 2016 Medicinal cannabis scheme will make ‘life worth living’ for Canberra resident

Fatigued, frequently ill and experiencing ever-changing symptoms, Sue Curry has spent years living with a debilitating illness.

“It’s like having the flu, a concussion, multiple sclerosis,” she said.

Her illness, Chronic Fatigue Syndrome or Myalgic Encephalomyelitis (ME), is poorly understood and has no certain pharmacological treatment.

“When we are hit severe, you don’t see us anymore,” Ms Curry said…

Posted in News | Tagged anxiety, cannabis, depression, medipen, pain, Sue Curry | Comments Off

Catalogue of writings by Prof Hooper & Margaret Williams

Posted on 08/25/2016 by wames

A website containing a catalogue of all the articles on ME written by Margaret Williams and Professor Malcolm Hooper can be found at: www.margaretwilliams.me/

The articles in this catalogue have been available on the internet or elsewhere for many years but now for the first time have been brought together in one place. The intention is to provide a valuable historical resource for researchers, advocates, patients and anyone interested in the illness Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. These articles illustrate how the “Wessely School” have ignored the biomedical science on ME/CFS for almost 30 years.

Margaret Williams is the pen-name used by someone who spent her professional life in the British National Health Service (NHS), latterly in a senior clinical capacity for many years until severe ME put an end to her career. For professional and personal reasons she does not wish her own name to be in the public domain.

Malcolm Hooper is Professor Emeritus of Medicinal Chemistry at the University of Sunderland in the UK, and is an advocate for ME/CFS patients. He chaired the International Invest in ME Conference in 2008, 2010, and 2011. He is also the Chief Scientific Adviser to the British Gulf War Veterans Association.

With contributions from Eileen Marshall (1994-2007) and others.

Posted in News | Tagged Eileen Marshall, Margaret Williams, Prof Malcolm Hooper | Comments Off

The role of inflammation & over active immune system in depression

Posted on 08/24/2016 by wames

BBC news report, by James Gallagher, Rachael Buchanan & Andrew Luck-Baker, 24 August 2016: Depression: A revolution in treatment? The Inflamed Mind, BBC Radio 4

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.

Find out more
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.

Joint pain
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.

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.”

Progress
Raiding the cupboards is already showing signs of success. Those early clues in arthritis mean the anti-inflammatory drug sirukomab 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.”

Posted in News | Tagged anti-inflammatory drugs, BBC news, BBC Radio 4, depression, immune activation, inflammation, sirukomab, The inflamed mind | Comments Off

BMJ reports tribunal orders PACE trial release of data

Posted on 08/24/2016 by wames

British Medical Journal news report, by Ingrid Torjesen, 22 August 2016: Tribunal orders university to release data from PACE chronic fatigue study

A tribunal has ruled that Queen Mary University of London must release data from a trial looking at treatment of chronic fatigue syndrome, which found that cognitive behavioural therapy and graded exercise therapy helped to alleviate the symptoms of the condition.1

The findings of the PACE (Pacing, graded Activity, and Cognitive behaviour therapy: a randomised Evaluation) trial, published in the Lancet in 2011,2 were questioned by some academics and patients, who argued that the PACE programme could harm patients.

In March 2014 Alem Matthees, a patient in Australia, submitted a freedom of information request to Queen Mary University of London, where some of the PACE researchers were based, asking for the anonymised patient data to allow analysis of the data according to the study’s original published protocol. The university refused the request, so Matthees filed a complaint with the information commissioner for England. The commissioner ruled in October 2015 that the data had to be released, but the university appealed that decision.

The university’s main arguments for not releasing the data were that they were not sufficiently anonymised and that it did not have permission from participants to publish the data. To require disclosure would damage trust and jeopardise future studies, the university said.

The tribunal dismissed the appeal, saying that it was satisfied that the data had “been anonymised to the extent that the risk of identification is remote.” It added, “There is a strong public interest in releasing the data given the continued academic interest so long after the research was published and the seeming reluctance for Queen Mary University to engage with other academics they thought were seeking to challenge their findings.

“There is insufficient evidence to persuade us that disclosure of the disputed information would cause sufficient prejudice to QMUL’s [Queen Mary University of London’s] research programme, reputation, and funding streams.”

A spokesperson for the university said,

“This has been a complex case and the tribunal’s decision is lengthy. We are studying the decision carefully and considering our response, taking into account the interests of trial participants and the research community.”

Keith Geraghty, honorary research fellow at the University of Manchester, said that he had contacted the PACE researchers to request access to the data to run an independent analysis, but his request “was first ignored, then later refused.”

He added, “I now understand that the authors shared the data with a select few academics who they picked to co-write papers, but they have failed to share the data with the broader scientific community.

Selectively sharing this publicly funded data with collaborators, but refusing to share data with anyone else, is not in the best interests of patients or science, and it creates a perception that the PACE team do not want independent critical analysis of this trial.”

He added that it was “regrettable” that the UK Medical Research Council, which partly funded the £5m (€5.8m; $6.5m) study, “did not specify that the trial data be made available to other researchers.”

Jonathan Edwards, emeritus professor of connective tissue medicine at University College London, said that the tribunal had made the right decision. He noted,

“The reasons given for not providing the information requested are essentially groundless. It is also clearly appreciated that critics of the PACE trial are not young sociopaths—they include senior medical scientists like myself, concerned about poor science.”

References

General Regulatory Chamber. First-tier tribunal. Appeal number EA/2015/0269. 2016. www.informationtribunal.gov.uk/DBFiles/Decision/i1854/Queen%20Mary%20University%20of%20London%20EA-2015-0269%20(12-8-16).PDF

White PD, Goldsmith KA, Johnson AL, et al. PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011;377:823-36. doi:10.1016/S0140-6736(11)60096-2 pmid:21334061

Posted in News | Tagged British medical Journal, Ingrid Torjesen, PACE trial | Comments Off

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