“Sometimes I think I’m so overwhelmed that the little, simple things that other people do or say really set me off emotionally, which we know only makes the pain worse.“ Person with Fibromyalgia


Why is every day such a roller coaster?

One of the most puzzling aspects of my Chronic Fatigue Syndrome/Fibromyaglia has been my body’s unusual sensitivity to stress. Oddly, it’s not the big stressful events, it’s the smaller, day to day stuff that’s been so confronting. Every day, it seems, is a roller coaster ride of symptoms that often flares up with the slightest stressor.

A review article suggests that with regards to the body; infection, physical or psychological stress – it’s all the same.

Depression, ME/CFS and FM

We know that while depression is at times found in Chronic Fatigue Syndrome and Fibromyalgia the disorders are very different. The search for answers, the tendency to overdo in ME/CFS and FM, the different type of HPA axis activity, and, perhaps most strikingly, the inability of depression or anxiety to influence ME/CFS and FM study results, indicate the diseases have large differences.

Woman Saying Stop

ME/CFS and Fibromyalgia are NOT depression; but that doesn’t mean an inflammatory milieu doesn’t underlie all three.

A recent study finding that neither stress nor mood disorders increased an adolescent’s chances of coming down with ME/CFS after an infection indicates chronic fatigue syndrome is not a behavioral disorder. Studies assessing how much mood disorders contribute to study findings in ME/CFS rarely find that they affect them at all.

This doesn’t mean that some aspects of depression may not be relevant. Rates of depression appear to be fairly high in both disorders, stressful events can trigger any of the three disorders, and stress exacerbates each. Maes has suggested that depression and ME/CFS as well as other disorders share a common inflammatory basis.

It’s that inflammatory basis of these disorders that drives the discussion in this review article.

From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression. Slavich GMIrwin MRPsychol Bull. 2014 Jan 13. [Epub ahead of print]

Inflammation, Depression, Sickness Behavior and Micheal Maes

The close similarity between the  symptoms of ‘sickness behavior’ and those found in  depression has suggested  to researchers that depression could be immune mediated; i.e. is caused by cytokines, and, indeed, hundreds of animal studies show cytokines cause  hypersomnia, fatigue, anorexia, cognitive problems, reduced motor responses, and reduced social and exploratory behavior.

Essentially these studies indicate that increased inflammation produces results in animals that are very similar to what major depressive disorder looks like in humans. In the early 1990’s  Michael Maes – now doing a great deal of  research on ME/CFS – was one of the first to put forth this theory.  (Several Maes papers propose similar inflammatory processes underlie ME/CFS and FM and depression. )

Stress – A Major Inflammation Trigger

A early clue in the inflammation/stress connection is the fact that inflammatory disorders such as rheumatoid arthritis, chronic pain, cardiovascular diseases, diabetes, and obesity appear to be particularly associated with depression. This suggests that inflammation may both set the stage for a variety of disorders and increase the risk of mood changes at the same time.

Infection and physical injury have long been known to trigger inflammation, but recent work suggests that ‘stress’, including psychological stress, can invoke inflammation in the body as well.

A Turned-on Anticipatory Immune Response Spells Trouble

“We have proposed that the primary innate immune system response to contemporary social stressors involves up-regulation of proinflammatory immune response genes, which combat bacteria and other extracellular pathogens, and a reciprocal down-regulation of antiviral immune response genes, which target intracellular pathogens such as viruses” (Irwin & Cole, 2011).

on/off switch

Could your anticipatory immune response be on overdrive?

Intriguingly, the inflammation is initiated by the  immune system arm that has been most implicated in ME/CFS: the innate immune system that immediately reacts to pathogens.

These researchers assert, though, that the immune system doesn’t need a pathogen to get into gear, it simply needs the possibility of a pathogen or an injury or simply a dangerous situation. In the cave man times the anticipatory immune system might get triggered by a dangerous animal; in modern times it can get triggered by any situation that’s perceived as a potential threat. (Such as simply the thought of a walk around the block for a person with ME/CFS or FM?)

When triggered, the anticipatory immune response mobilizes cells of the innate immune response to start moving to sites of potential injury or infection (i.e., to the mucosal areas such as the gut, mouth and nose where pathogens first contact the body).

Continual triggering of the anticipatory immune response via infection or other stressors up-regulates immune factors that fight bacteria and extracellular pathogens (Th2 response), and down-regulates immune factors that fight viruses (Th1); i.e., it reduces our ability to fight viruses.

(This ‘increased Th2/decreased Th1 response has been proposed many times in Chronic Fatigue Syndrome.)

But how did that response get locked in?

Out of Whack Stress Response = Out of Whack Immune System

The key to this chronic immune imbalance, the authors believe, is a stress response that causes an inflammatory response to get triggered quickly and easily. 

HPA Axis and Autonomic Nervous Systems

Stress response

Do the stress response systems in ME/CFS and FM set up for an ongoing activation of their ‘anticipatory immune response’?

Activation of the HPA axis usually reduces inflammation, but under conditions of constant stress, a phenomenon called ‘glucocorticoid resistance’ may occur. Glucocortoid resistance may or may not be associated with ME/CFS or FM, but low cortisol, which has similar effects, is.

Either way, the HPA axis becomes a contributor, not a hindrance, to inflammation, and in fact, HPA axis associated inflammation is believed to contribute to a variety of disorders including cardiovascular diseases, rheumatoid arthritis and other autoimmune disorders, asthma, PTSD, and generalized anxiety.

The sustained sympathetic nervous system response  seen in the heart rate variability results in both ME/CFS and Fibromyalgia, also results in a Th2 dominant immune response.

The immune findings in Chronic Fatigue Syndrome then, may reflect a stress response that gets turned on quickly and easily.

A Locked in Stress – Inflammatory Response

Greater Risk in ME/CFS and FM?

Given the issues many ME/CFS and  FM patients face getting locked into a hair-trigger inflammatory response might not be too surprising.

It turns out that stressful major life events (such as chronic illness, death of family member, divorce, or loss of one’s job) are the single greatest predictor for depression, and major life events that result in ‘interpersonal loss’ or ‘social rejection‘ are particularly powerful. People who experience a major life event that results in the severing of ties with a person are particularly at risk.

Many people with chronic fatigue syndrome and fibromyalgia, of course, experience losing friends, spouses, and even other family members post-ME/CFS. Rejection by the medical profession is another sort of ‘interpersonal loss’ that often occurs.

bombs in path

The big emotional stressors that modify health – rejection and isolation – are there in spades in FM and ME/CFS

With regards to psychological stressors, conflict, threat, isolation and rejection, all of which are greatly increased in ME/CFS, appear to be particularly effective at producing inflammation.

The weakened social ties may be particularly disturbing given that having stronger social ties can reduce the risk of mortality by up to 50%, a result that is only matched by quitting smoking. Socially isolated individuals are 2 to 5 times more likely to have increased levels of the inflammatory factor, CRP,  than people who are not socially isolated.

(If this scenario is correct then many people with Fibromyalgia and Chronic Fatigue Syndrome are not only battling an inflammatory response that’s on a hair trigger, but the lack of acceptance and understanding both in the medical and public arenas (“But you look so healthy!”) means they also face personal issues that may increase the inflammatory component of their illness. Several studies have suggested that emotional distress triggers physical symptoms in ME/CFS.)

Inflammatory Disorders Show Up Again

It’s not surprising that each of these losses increases the patient’s risk of depression. What is surprising is how these types of losses affect some illnesses. Studies indicate that these types of stressors markedly exacerbate disorders such as asthma, cardiovascular disease, rheumatoid arthritis, and some cancers. What do these disorders have in common? They all have a strong inflammatory component.

This suggests that stress, whether it’s from an infection or is psychological enhances inflammation.

Inflammation Itself Causes Stress

IL-6 may play a key role in producing symptoms in ME/CFS and other inflammatory disorders

IL-6 may play a key role in producing symptoms in ME/CFS and other inflammatory disorders

It’s a bit worse than that.  Studies indicating inflammatory states  are associated with increased stress suggest that just being in an inflammatory state is emotionally stressful. Increased levels of IL-1B, for instance, are associated with increased feelings of stress and more difficulty maintaining a positive outlook, while Il-6 is associated with increased anxiety, depression, and anger,

Studies indicate that both early and later life stress is associated with increased levels of inflammatory cytokines (Il-6) and inflammatory markers (c-reactive protein aka CRP). Negative social interactions in daily life are also associated with increased IL-6 levels.

The same brain regions (insula and anterior cingulate cortex) appear to be engaged whether one is fighting off a bacterial infection or is exposed to stress.  Importantly, these regions of the brain play a large role in determining how much pain we experience.

ME/CFS and FM Interlude  (Not From Review Article)

All of these cytokines have been associated with ME/CFS.  Il-6 appeared to help set the stage for entry into ME/CFS after infectious mononucleosis. Emotional distress in ME/CFS was most strongly associated with IL-6  levels in another. IL-6 was most associated with symptoms in another.

“Neural systems involved in processing physical pain (e.g., resulting from intense cold or heat) also play a role in processing social pain (e.g., resulting from social evaluation or rejection).”

It also appears that the parts of the brain that process physical pain also play a role in processing ‘social pain’. This, of course, brings up the question whether the over-active pain circuits in FM  that increase pain in response to physical stressors such as exercise and even the touch of clothing also translate into greater physical pain in response to difficult social situations/negative thoughts?

Neuro-inflammatory  Sensitization

The authors believe this integrated neuro-immune system primes an individual  for further inflammation and further stress in a process called ‘neuro-inflammatory sensitization’, .

In the short term chronic stress activates the inflammatory response and  parts of the brain that causes increased pain, social  anxiety,  hypervigilance and the anticipation of adversity.  In the medium term this evolves into disrupted sleep,  chronic pain, social withdrawal and a depressed mood, and finally, if it goes on for several years, to increased  susceptibility to infections and inflammatory diseases, accelerated aging and increased mortality.

Reducing Inflammation – Reducing Stress / Reducing Stress – Reducing Inflammation


The anti-inflammatory Celecoxib proved surprisingly effective in treating some people with depression

If the authors are right then anti-inflammatories should be able to reduce stress, fatigue, pain and mood problems, and, in fact, it’s become clear that some antidepressants reduce pro-inflammatory cytokine levels.  Celexicob’s strong performance in an antidepressant trial suggested how large a role the immune system may play in producing depression. (Celexicob plus an antidepressant had 50% greater results than the antidepressant alone. Pridgen’s use of Celexicob as an antiviral in his Fibromyalgia trial suggests another use for this anti-inflammatory.)

About 50% of depressed patients were classified as responders in an Etanercept (TNF-a suppressor) trial. Finally, in the much same way as we’ll see in the Antoni study below,  a subset of patients (depressed patients with high levels of an inflammatory marker (CRP)) responded well  to another TNF-a inhibitor, inflammable Infliximab. Infliximab improved anxiety, depression, rates of suicidal thoughts, fatigue, etc., in this heretofore treatment resistant group.

(The Gut Approach – Levels of C-reactive protein (CRP), tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) in ME/CFS patients dropped significantly with six weeks of  bifidobacterium infantis 35624  supplementation.  The study did not, unfortunately track symptoms changes, but it did suggest the inflammatory milieu and hence the depression, etc. in ME/CFS could be driven by the gut.)

Targeting Subgroups That Benefit From Stress Management

 “It appears that IL-6 may be a plausible cytokine “biomarker” for designating a neuroimmune dysfunction subgroup of CFS patients who are especially sensitive to emotional distress responses as they relate to symptom exacerbation. ” Antoni et. al

Like any other ‘treatment modality’ stress management techniques are only effective for some. Antoni et. al propose immune factors can determine which ME/CFS patients benefit most from stress management techniques such as relaxation, reappraising stressful situations, and having good interpersonal skills.  They found these techniques were most effective in patients at the “tipping point” of neuroimmune dysfunction (those with high IL-6 levels) and did not make a difference in those  with normal IL-6 levels.

Antoni et. al. point out some studies suggest that whatever gains  occur from CBT do not derive from modifying one’s illness perceptions but from portions of the program that reduce emotional distress. CBT’s effectiveness may be limited, in fact, by it’s core focus on modifying ‘illness beliefs’.

A better approach might be to modify, at least in some patients, the emotional distress and the inflammation it promotes.


Physical and emotional stress may very well trigger the same physiological reaction in the body.  With ME/CFS and FM patients displaying a kind of stress response that promotes inflammation and it’s symptoms (fatigue, pain, mood, cognitive problems), and  dealing with inflammation both from a physiological and an emotional standpoint might  be a good idea.  Eventually immune tests may be able to target people most likely to benefit from mind/body therapies.


Like the blog you're reading? Don't miss another one.

Get the most in-depth information available on the latest ME/CFS and FM treatment and research findings by registering for Health Rising's free  ME/CFS and Fibromyalgia blog here.

Stay on Top of the News!

Subscribe To Health Rising’s Free Information on Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia (FM), Long COVID and Related Diseases.

Thank you for signing up!

Pin It on Pinterest

Share This