1. Patients launch a $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
ME/CFS and Beating the Clock
For Jody Smith, the ticking of a clock was enough at one time to chase her back to her bed. But with the passage of time, she has been able to reclaim her living room ...
Discuss the article on the Forums.

Depression Tied to Infections, Autoimmune Disease

Discussion in 'Other Health News and Research' started by natasa778, Jun 15, 2013.

  1. natasa778

    natasa778 Senior Member

    Messages:
    1,330
    Likes:
    1,045
    London UK
    http://www.medpagetoday.com/Psychiatry/Depression/39794


    Depression Tied to Infections, Autoimmune Disease

    By Crystal Phend, Senior Staff Writer, MedPage Today
    Autoimmune disease and severe infections may increase risk of developing depression and other mood disorders, a population-based study suggested.

    Any contact with a hospital for autoimmune disease was associated with an independent and significant 45% higher risk of a subsequent mood disorder diagnosis, Michael Eriksen Benros, MD, of Denmark's Aarhus University, and colleagues reported online in JAMA Psychiatry.

    Hospitalization for any infection was associated with a significant 62% elevated risk of later mood disorders.

    If that association was causal and could be eliminated, 12% of all mood disorders could be avoided, the researchers estimated.

    A history of both severe infection and autoimmune disease synergistically boosted the risk 2.35-fold (95% confidence interval 2.25-2.46).

    "These associations are compatible with the hypothesis of a general immunologic response affecting the brain in subgroups of patients with mood disorders," the researchers concluded.

    However, "it remains unclear precisely how the immunologic process affects the brain and whether it is a causal relationship or an epiphenomenon of underlying genetic, psychological, or non-immune-related mechanisms," they acknowledged.

    There is some suggestive evidence for a causal link in that proinflammatory cytokines and other immune components can alter neurotransmitter and neuroendocrine function. Animal and human experiments have shown activation of inflammatory reactions can induce mood disorder symptoms.

    Also, systemic inflammation can produce symptoms of fatigue, reduced appetite, sleep disturbance, and others that are similar to the symptoms of depression. Some studies have suggested progression to depression in vulnerable individuals after prolonged periods, Benros' group pointed out.

    While the results could spur research into preventive treatments, Linda Carpenter, MD, a psychiatrist at Brown University in Providence, R.I., predicted that the immediate impact will be to call attention to comorbidities in psychiatry.

    "For a long time psychiatrists have been asking people 'Tell me about your life, what's stressful, what was your early life like,'" she told MedPage Today. "We know those things create risk. We ask people about family members. But we haven't really been paying attention to the health of the immune system and inflammatory conditions in our patients."

    At this point, though, it would be premature to treat patients differently based on infectious and immune history, she cautioned.

    Their study included all 3.56 million people born from 1945 through 1996 in Denmark, followed through 2010 in national longitudinal registries.

    Among them, 91,637 were diagnosed with a mood disorder by a psychiatrist in a hospital, outpatient clinic, or emergency department setting at some point in their lifetime.

    About a third of those diagnosed with a mood disorder had a prior infection diagnosis recorded in the hospital contact databases and 5% had at least one autoimmune disease diagnosis.

    Both the severe infections and autoimmune disease had a dose-response relationship with the risk of hospital contact for a subsequent mood disorder.

    "The risk of mood disorders increased with the temporal proximity of the last infection, especially in persons with autoimmune diseases for whom an infection within the last year increased the risk of mood disorders more than four times, suggesting that the results might be due to a contemporary inflammatory process," the researchers noted.

    The relationships were seen across sites of infection and type of autoimmune disease, although highest for hepatitis and sepsis among infections and for autoimmune diseases with "suspected presence of brain-reactive antibodies, particularly when combined with an infection."

    Sensitivity analyses didn't indicate difference by substance abuse or psychiatric family history, though the effect was greater among those over age 30.

    Limitations included lack of data on less severe cases of infection, autoimmune disorders, and mood disorders that didn't lead to a hospital contact as well as inability to draw causal conclusions from observational data.

    "It remains unclear whether the results can be generalized to the more frequently occurring less severe infections and mood disorders treated by the general practitioner or to those going untreated," Benros' group noted.
  2. Mark

    Mark Acting CEO

    Messages:
    4,460
    Likes:
    1,838
    Sofa, UK
    This puts an interesting slant on Jason's findings about CCC and ICC increasing diagnosis of patients with mood disorders. I've been wondering about this in recent days; my thought has been that, contrary to Cort's interpretation that we should avoid CCC and ICC, if it is true that our desire to avoid association with mood disorders has been colouring our interpretation and depression is increased by autoimmunity and infections, then we may have been thinking about this issue the wrong way round.

    Conventional wisdom among the ME/CFS world has denied depression and anxiety and psych disorders as correlates of 'true ME', and suggested instead that these are confounding issues, that patients with those issues are mixed into the wastebasket. It may sound heretical, but with the way things have been mixed in terms of case definitions, is it really heretical to ask whether the putative infection-induced autoimmune condition we are looking at when we think about Rituximab, B cells, etc, might be a risk factor for producing major depressive disorder?

    I'm nervously expecting to be pointed at papers showing that there isn't an association between ME/CFS and mood disorders, but I think the research here has been contradictory and obfuscated by definitions, and I wonder if it's time to have another look at those past findings through a new lens, looking even more carefully at the case definitions used. I'm just wondering now whether the polarised political scene may have further obfuscated our interpretation of these results and re-thinking this issue of associations with mood disorders might point to a way out of the political tangle.

    Just thinking aloud a bit really, and trying in particular to make sense of the issue about CCC/ICC including lots of mood disorders - perhaps if we turn a bit of conventional wisdom on its head there may be something emerging here. After all, how many times have we heard forum members say (in angry opposition to suggestions that ME/CFS is psychosomatic) that any depression or anxiety they experience is a consequence of living with ME and not a cause of the ME? And others say they have no depression or anxiety. If we think of depression and anxiety as a potential physical consequence of autoimmunity, perhaps that might suggest a way out of the maze? A can of worms for sure, but how otherwise do CCC/ICC proponents respond to Jason et al's challenging findings and Cort's critique of the request for CCC to be adopted?
  3. Lotus97

    Lotus97 Senior Member

    Messages:
    2,012
    Likes:
    405
    United States
    I think part of it might be due to the activation of the microglia. Also, it seems infection can cause apoptosis of astrocytes.(Except for the second and third one, there's more information in the articles than just what I'm posting here. Also, the first article talks about other infections besides just Lyme disease. Click the links for more information)
    ===========================
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847353/
    Microglia in Infectious Diseases of the Central Nervous System
    Abstract
    Microglia are the resident macrophage population in the central nervous system (CNS) parenchyma and, as such, are poised to provide a first line of defense against invading pathogens. Microglia are endowed with a vast repertoire of pattern recognition receptors that include such family members as Toll-like receptors and phagocytic receptors, which collectively function to sense and eliminate microbes invading the CNS parenchyma. In addition, microglial activation elicits a broad range of pro-inflammatory cytokines and chemokines that are involved in the recruitment and subsequent activation of peripheral immune cells infiltrating the infected CNS. Studies from several laboratories have demonstrated the ability of microglia to sense and respond to a wide variety of pathogens capable of colonizing the CNS including bacterial, viral, and fungal species. This review will highlight the role of microglia in microbial recognition and the resultant antipathogen response that ensues in an attempt to clear these infections. Implications as to whether microglial activation is uniformly beneficial to the CNS or in some circumstances may exacerbate pathology will also be discussed.
    Keywords: microglia, bacterial meningitis, brain abscess, Lyme neuroborreliosis, Toxoplasmaencephalitis, cerebral malaria, fungal infections, review
    Microglial recognition of Borrelia burgdorferi and Lyme neuroborreliosis
    The spirochete B. burgdorferi (sensu lato) is the etiologic agent of Lyme disease, the most frequently occurring vector-borne infection in the USA (Hengge et al. 2003; Rupprecht et al. 2008). B. burgdorferitransmission occurs through Ixodes ticks and is also endemic in Europe and parts of Asia. Lyme disease initially propagates in the skin before it disseminates through the blood stream to other organ systems. In addition, B. burgdorferi displays tissue tropism for the nervous system, where neurologic involvement occurs in up to 20% of patients who present with cranial neuritis, meningoradiculitis, or encephalitis (Pfister et al. 1994; Rupprecht et al. 2008). Colonization of the CNS with B. burgdorferifrom the blood is associated with inflammation of the meninges, nerve roots, brain, and spinal cord resulting in the clinical manifestations of neuroborreliosis (Pfister and Rupprecht 2006; Rupprecht et al. 2008). Furthermore, marked levels of pro-inflammatory molecules such as IL-6 and TNF-α are associated with Lyme disease, as well as the induction of an important inflammatory enzyme, cyclooxygenase-2 (COX-2; Ramesh et al. 2008; Rasley et al. 2002). However, the inflammatory mechanisms that are involved in the CNS immune responses to B. burgdorferi are not currently well understood based on the limited availability of an adequate animal model. To date, the only animal model where evidence of Lyme neuroborreliosis has been demonstrated is in rhesus macaques (Pachner et al. 2001).
    ===========================
    http://www.ncbi.nlm.nih.gov/pubmed/12466036
    The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans.

    Wichers M, Maes M.
    Source

    Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands.


    Abstract

    Administration of the cytokines interferon-alpha and interleukin-2 is used for the treatment of various disorders, such as hepatitis C and various forms of cancer. The most serious side-effects are symptoms associated with depression, including fatigue, increased sleepiness, irritability, loss of appetite as well as cognitive changes. However, great differences exist in the prevalence of the development of depressive symptoms across studies. Differences in doses and duration of therapy may be sources of variation as well as individual differences of patients, such as a history of psychiatric illness. In addition, sensitization effects may contribute to differential responses of patients to the administration of cytokines. In animals administration of pro-inflammatory cytokines induces a pattern of behavioural alterations called 'sickness behaviour' which resembles the vegetative symptoms of depression in humans. Changes in serotonin (5-HT) receptors and in levels of 5-HT and its precursor tryptophan in depressed people support a role for 5-HT in the development of depression. In addition, evidence exists for a dysregulation of the noradrenergic system and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis in depression. Some mechanisms exist which make it possible for cytokines to cross the blood-brain barrier. Pro-inflammatory cytokines such as IL-1beta, IFN-alpha, IFN-gamma and TNF-alpha affect the 5-HT metabolism directly and/or indirectly by stimulating the enzyme indoleamine 2,3-dioxygenase which leads to a peripheral depletion of tryptophan. IL-1, IL-2 and TNF-alpha influence noradrenergic activity and IL-1, IL-6 and TNF-alpha are found to be potent stimulators of the HPA axis. Altogether, administration of cytokines may induce alterations in the brain resembling those found in depressed patients, which leads to the hypothesis that cytokines induce depression by their influence on the 5-HT, noradrenergic and HPA system.

    ===========================
    http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000659
    Microglia Are Mediators of Borrelia burgdorferi–Induced Apoptosis in SH-SY5Y Neuronal Cells
    Abstract
    Inflammation has long been implicated as a contributor to pathogenesis in many CNS illnesses, including Lyme neuroborreliosis. Borrelia burgdorferi is the spirochete that causes Lyme disease and it is known to potently induce the production of inflammatory mediators in a variety of cells. In experiments where B. burgdorferi was co-cultured in vitro with primary microglia, we observed robust expression and release of IL-6 and IL-8, CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES), but we detected no induction of microglial apoptosis. In contrast, SH-SY5Y (SY) neuroblastoma cells co-cultured with B. burgdorferiexpressed negligible amounts of inflammatory mediators and also remained resistant to apoptosis. When SY cells were co-cultured with microglia and B. burgdorferi, significant neuronal apoptosis consistently occurred. Confocal microscopy imaging of these cell cultures stained for apoptosis and with cell type-specific markers confirmed that it was predominantly the SY cells that were dying. Microarray analysis demonstrated an intense microglia-mediated inflammatory response to B. burgdorferi including up-regulation in gene transcripts for TLR-2 and NFκβ. Surprisingly, a pathway that exhibited profound changes in regard to inflammatory signaling was triggering receptor expressed on myeloid cells-1 (TREM1). Significant transcript alterations in essential p53 pathway genes also occurred in SY cells cultured in the presence of microglia and B. burgdorferi, which indicated a shift from cell survival to preparation for apoptosis when compared to SY cells cultured in the presence of B. burgdorferi alone. Taken together, these findings indicate that B. burgdorferi is not directly toxic to SY cells; rather, these cells become distressed and die in the inflammatory surroundings generated by microglia through a bystander effect. If, as we hypothesized, neuronal apoptosis is the key pathogenic event in Lyme neuroborreliosis, then targeting microglial responses may be a significant therapeutic approach for the treatment of this form of Lyme disease.

    ===========================
    http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=1590
    Inflammation, Glutamate, and Glia in Depression: A Literature Review
    Abstract
    Multiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. In this review we provide an overview of how these two systems may interact. Excess levels of inflammatory mediators occur in a subgroup of depressed patients. Studies of acute experimental activation of the immune system with endotoxin and of chronic activation during interferon-α treatment show that inflammation can cause depression. Peripheral inflammation leads to microglial activation which could interfere with excitatory amino acid metabolism leading to inappropriate glutamate receptor activation. Loss of astroglia, a feature of depression, upsets the balance of anti- and pro-inflammatory mediators and further impairs the removal of excitatory amino acids. Microglia activated by excess inflammation, astroglial loss, and inappropriate glutamate receptor activation ultimately disrupt the delicate balance of neuroprotective versus neurotoxic effects in the brain, potentially leading to depression.
    Introduction
    Depression is a common and debilitating disorder for which current treatments are inadequate. The pathogenesis of depression is not well understood. The annual prevalence of depression is 7% and the lifetime prevalence is 16%.1,2 In addition to significant disability,3depression is associated with excess mortality,4,5 particularly from cardiovascular disease.6 Current antidepressants, which target monoamines, only produce remission in 30% of patients. Part of the problem lies in the fact that the pathophysiology of depression has not been elucidated, and treatments are based on empirical data, not mechanisms of action. It remains unclear how these drugs actually work, since their ability to increase synaptic concentrations of monoamines is immediate, while their clinical effects take 2–4 weeks to become apparent.7 The aim of this article is to provide an overview of studies implicating inflammation in depression, and propose a model of how excess inflammation may interact with glutamate and glia to cause depression.
    [​IMG]
  4. Bob

    Bob

    Messages:
    7,432
    Likes:
    8,569
    England, UK
    The following extract seems like it could potentially be particularly relevant for CFS/ME...
    And the following extract fits in with some recent discussions (click here) re ME and autoimmunity to 5-HT:
  5. Bob

    Bob

    Messages:
    7,432
    Likes:
    8,569
    England, UK
    This is dangerous territory for our community, for reasons that you have hinted at, but i agree with your post.
    The problem is that ME just hasn't been researched properly or methodically, and when any psychiatric comorbidity has been researched, it's been hijacked as evidence for a primary psychiatric illness.
    Any real biomedical exploration of these issues would be helpful, if it wasn't so easily hijacked, and the results twisted, contorted and perverted.

    I can't really see how Jason's research tells us anything, other than ME patients with severe symptoms are more likely to suffer from comorbid psychiatric issues, but that doesn't really seem surprising, at all. (Note that it was a very small study, and it didn't draw any conclusions.)
    Any severely incapacitating and distressing illness would surely have a higher level of psychiatric comorbidity than healthy controls?
    It's an area that perhaps should be explored methodically, if it can be done properly, without it being hijacked.
  6. Lotus97

    Lotus97 Senior Member

    Messages:
    2,012
    Likes:
    405
    United States
  7. Marco

    Marco Old blackguard

    Messages:
    1,136
    Likes:
    737
    Near Cognac, France
    Thanks Lotus

    This blog sets out my own personal perspective on case definitions which I did expect to be unpopular but I also feel our reluctance (for obvious reasons) to discuss 'mood' and other 'psychiatric co-morbidities' has been counterproductive :

    When definitions obscure

    http://www.cortjohnson.org/blog/201...atory-view-of-chronic-fatigue-syndrome-pt-iv/

    If we insist that ME/CFS is a neurological (or neuroinflammatory as I would suggest) condition, then elevated rates of these symptoms is to be expected. After all they are pretty much the norm in other neurological conditions and the underlying pathology doesn't selectively spare brain regions associated with 'mood'.
  8. Valentijn

    Valentijn Activity Level: 3

    Messages:
    5,585
    Likes:
    7,123
    Amersfoort, Netherlands
    You might be right, but I think the Jason paper (the recent one?) had a fundamental problem in that psychiatric diagnosis was made prior to (and without considering the potential of) ME/CFS diagnosis, and using the DSM. Which basically allows symptoms unexplained by a medical diagnosis to count as evidence of a mood disorder. If those same patients were re-examined for psychiatric disorders with physical, cognitive, and neurological ME/CFS symptoms being excluded from indicating psychiatric disorder, the results might be far less indicative of mood disorder.

    Which brings me to a related question for the current study - how were the patients diagnosed with depression?
    parvofighter likes this.
  9. natasa778

    natasa778 Senior Member

    Messages:
    1,330
    Likes:
    1,045
    London UK
    I wasn't aware it was heretical tbh as makes total sense.


    One other bit from above study to consider:

    What is not to say that this could be relevant to many of those with 'just depression and anxiety and psych disorders' - i.e. it is possible that many of those who suffered milder immune/infectious insults and/or had lower underlying risk factors end up as having 'just depression and psych disorders' rather than fully blown ME. (which is not to say that having them added to ME study cohorts wouldn't confuse results, as clearly pathophysiology would be different or more specific, even when origins/roots of their psych illness are similar to that of ME patients)
  10. Lotus97

    Lotus97 Senior Member

    Messages:
    2,012
    Likes:
    405
    United States
    The link I posted and the link you posted are both from part IV, but they're different articles. There's also a part 3a, but is there a 3b too? I'm sort of confused now. How many articles are there in the series?
  11. Marco

    Marco Old blackguard

    Messages:
    1,136
    Likes:
    737
    Near Cognac, France

    Sorry about that. I'd originally intended a four part series but there were comments that the blogs were too long and Cort and I decided to split them. They do follow a logical order though (or at least they did to me when writing them!)

    Roughly (without rechecking the titles) they break down like this :

    Part I - Not fatigue after all - Sensory Gating

    http://www.cortjohnson.org/blog/201...xplain-chronic-fatigue-syndrome-mecfs-better/

    Part II - Glutamate - another piece in the puzzle

    http://www.cortjohnson.org/blog/201...fs-puzzle-the-neuroinflammatory-series-pt-ii/

    Part III - (a) Stiff person syndrome intro

    http://www.cortjohnson.org/blog/201...romyalgia-the-neuroinflammation-series-pt-3a/

    (b) Stiff person syndrome - 'co-morbid' anxiety etc

    http://www.cortjohnson.org/blog/201...-possible-model-for-chronic-fatigue-syndrome/

    Part IV - (a) A personal perspective on ME/CFS

    http://www.cortjohnson.org/blog/201...atory-view-of-chronic-fatigue-syndrome-pt-iv/

    (b) Can the neuroinflammatory explain ME/CFS symptoms

    http://www.cortjohnson.org/blog/201...akes-on-symptoms-of-chronic-fatigue-syndrome/

    Not on line yet : -

    IV - (c) Can the neuroinflammatory model explain immune findings and onset
    IV - (d) Potential research avenues/treatments

    Phew!!!! :)

    There'll now be a fifth one roughly entitled - Sensory gating in ME/CFS - validation? - due to some findings I came across lately

    I hope that helps - maybe Cort could group the blogs by author?

    PS - Thanks for the interest!
    Lotus97 likes this.
  12. stephano75

    stephano75

    Messages:
    11
    Likes:
    7
    The ME/CFS community has done itself a massive disservice by only/primarily characterising disturbed mood as a 'reactive' phenomenon in the condition- lots of sufferers have disturbed mood as a central symptom- hardly surprising for an illness that involves the brain and central nervous system. Incidentally- it was Jay Goldstein who said CFS could be "..shoehorned into a definition of atypical or treatment-resistant depression." I can understand the extreme sensitivity and need to emphasise this is a physiological condition, rather than psychological. That's fine, but don't throw the baby out with the bathwater as some reflex response to the psychobabblers. As someone who has been suffering for 17 years, I say without fear my version of CFS absolutely involves disturbed mood and it's entirely physiological. It waxes and wanes with the other symptoms- when I have a good patch, mood improves along with all the other 'physical' symptoms. The issue lies with arbitrary mind/body distinctions. Incidentally, I am endlessly frustrated, enraged and crushed by this illness, but the only depression I have is endogenous to the illness. There is nothing 'reactive' about it when it's there - my only 'reaction' is continued, steely determination to make things better.
    natasa778, Marco and Bob like this.

See more popular forum discussions.

Share This Page