Sunday, January 27, 2013

Is Schizophrenia an Autoimmune Disease?

Psychopathology and particularly psychosis has had a bit of a research dance with immunology over the past several years. For example, women with post-partum psychosis are more likely than controls to have anti-thyroid antibodies. And folks with schizophrenia and bipolar disorder are more likely to have strange anti-wheat protein antibodies than controls. In the recent, very large CATIE trial, 23.% of those with schizophrenia had IgA anti-AGA antibiodies (anti-gliadin) compared to 3.1% of a comparison group, and 5.4% had high levels of tTG antibodies compared to 0.8% of the comparison group.

Brahms Violin Concerto (very long, really famous bit begins at around minute 35)

No one is sure what these immune reactions mean. But it would be interesting to see how immune modulators might affect psychosis in a clinical trial. In evolutionary medicine, immune and inflammatory modulators could include a dietary intervention, probiotics, or even helminth therapies. To my knowledge, none of these have been applied to schizophrenia or post-partum psychosis in a clinical trial of any kind.

This week, a paper came out in the renamed Archives of General Psychiatry (Now JAMA Psychiatry) linking schizophrenia to a set of autoantibodies. The findings in this paper lend more credence to the idea that a subset of schizophrenia may be caused by an immune attack on the brain.  Blood from a group of unmedicated, hospitalized schizophrenics was compared to blood from people admitted with major depressive disorder, borderline personality disorder, and healthy controls.

9.9% of the actuely ill schizophrenics were found to have anti-NMDA receptor antibodies, compared with 2.8% of those with major depressive disorder, 0.4% of controls, and 0 of those with borderline personality disorder. The NMDA receptor (glutamate is the key neurotransmitter at this receptor) is known to be associated with psychotic symptoms. PCP and ketamine are NMDA receptor antagonists that rather famously cause agitation and psychosis.

Now there is already an illness of anti-NMDA receptors called "NMDA-R encephalitis." It affects  young women with a rare type of ovarian tumor called a teratoma, and presents with psychosis, agitation, memory problems, and seizures. It tends to progress to problems with the autonomic nervous system (which can control breathing, temperature and blood pressure regulation) and cause a catatonic state. It is treated, like many life-threatening autoimmune conditions, with high dose steroids and plasmaphoresis (or plasma exchange, which can clear the blood of the offending autoantibodies). The autoantibodies in the cases of NMDA-R encephalitis are to a different specific protein subunit of the receptor and tend to be in much higher concentrations than the folks with autoantibodies who had acute schizophrenia, so it is not exactly the same disease.  In this trial, however, two of the patients originally diagnosed with schizophrenia were re-diagnosed as NMDA-R encephalitis due to the type of antibodies they had. They also had some intriguing physical symptoms and CNS and blood  inflammatory markers that aren't typically found in schizophrenia.

But it is fascinating and needs to be studied in more populations at greater length. Is there a time coming when 10% of our first break psychosis patients might be getting plasma exchange and steroids? Would they be maintained on autoimmune dietary protocols (if effective for blood titres of antibodies) and relatively benign chronic immune modulators (again, just hypothesizing in an exciting sort of way) such as pig whipworm or killed M vaccae?

As always, more questions than answers, but getting one step closer to the bottom of the pathology of mental illness and brain diseases is always interesting, and always gives me hope. And what about the healthy control and the patients with major depressive disorder who had anti-NMDA-R antibodies? Are they more likely to have problems with psychosis or psychopathology? I suppose we will have to wait and see.

19 comments:

  1. Another area for comparison is neuropsychiatric lupus and its various manifestations. There are at least 3 chapters in Lahita's classic "Systemic Lupus Eryhtematosus" that describe syndromes and correlates with immunological testing. There is probably room for a review that pulls together the work in Lupus with recent cytokine studies on schizophrenia and the antibody studies that you cite.

    One of the issues with immunology is the lack of specificity and low prevalence of positive studies. I worked at a hospital consulting on medical and surgical patients and we had an antibody panel for "limbic encephalitis". That panel was rarely positive for this rare entity and as I thought about it- I asked myself why it would be? In a lot of these situations I think we are dealing with highly idiosyncratic reactions and the need to identify a unique rather than population based process.

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    1. Yes, there are a number of studies with various autoantibodies and psychosis, but anti-NMDA were the most common (this is not the first study to find them, but the largest I believe), and they tested for antibodies to several subunits of the receptors and combinations of subunits as well to find the 10%. There's a long way to go before any sort of laboratory panel… as I think of all my rhematoid factor negative rheumatoid arthritis patients, Anti-ss negative sjogrens, etc. Psychiatry ain't got nothing on rheumatology ;-)

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  2. I wonder if the manifestation of psychosis/schizophrenia could be seen / would be seen as an evolutionary adaptation in response to brain autoimmunity - that is, is there something "special" about the onset of schizophrenic symptoms that could be helping reduce or "deal" with the inflammatory response in a similar way insulin resistance might be an adaptation. obviously, in both the case of schizophrenia and IR, the adaptation, while saving life, is ultimately detrimental to the organism, but is a best attempt of our biology to "deal"
    this is a great blog! Thanks

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  3. Like your blog. Dieting for Sanity. Been there, done that.
    Like this post too. Thanks for bringing it up. My guess is schizophrenia is probably a combination of really common infections/allergies. The fact that y'all are looking for one trigger is the reason nobody ever finds it...

    I believe that most psychiatric disorders fit that description though. I personally have narcolepsy and my research indicates the sleep attacks are caused by a non-celiac allergy to gluten. After forty years of sleep disturbances, obesity and depression I went on a gluten-free diet and recovered in a couple weeks. I have reports from dozens of narcoleptics who experienced the same result.
    But there are also indications that narcolepsy is triggered by strep infection. The gluten intolerance may actually be a long term consequence of a streptococcal autoimmune reaction such as PANDAS or Sydenham's.

    I have been researching those ideas for about five years. If you would like to read more, please see my website- www.zombieinstitute.net It also covers the glucose/insulin problems narcoleptics experience
    I think you might find a fresh outlook on the problem.

    I do have unpublished ideas about the evolutionary benefits of all this, but I'm pretty sure that psychosis is not one of them. It's merely a predictable manifestation of acute pathology.
    Hope you stop by- my research indicates much of Psychiatry actually is misdiagnosed Rheumatology.

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  4. Hello. I am the author of "It's Not Mental" and one of my contacts just showed this to me. THANK YOU! Like Heidi, I found my family's "Schizophrenia" to be a physical issue, and it was, indeed, linked to autoimmune and narcoleptic-type issues! In spite of various close family relatives with "schizophrenia" we did beat that family curse with the younger daughter (the older one had had "bipolar disorder" for 13 years and is now FINE).

    My younger girl had CHILDHOOD-Onset Schizoaffective.

    With the younger daughter, I had been sick throughout my pregnancy with both Chickenpox and one sinus infection after another due to allergies. I was on antibiotics for months, which wipe out normal, necessary, gut bacteria. Then, to top it off, she was a C-section. Her sleep was *extremely* disturbed. She had allergies. She had pains.

    She is now doing well with healing the gut, (dietary changes including no gluten or dairy), some hormones (including thyroid medications for Hypothalamic hypothyroidism), food supplements, and narcolepsy medications.

    All the older daughter had needed was thyroid medication, gut healing & diet change, and vitamins.

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    1. Dear Jeanie,

      I am a science writer for the Atlantic Magazine and I am very interested in your family's story for an upcoming article that I am writing about the division between the mind and the brain in modern medicine. I would love it if we could talk a bit further by email or phone. Please feel free to contact me at your convenience: langjpl@gmail.com

      Sincerely,

      Joshua Lang

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  5. my daughter was diagnosed with PANDAS after a strep infection. PANDAS is i believe related to tourette's. but her father has tourette's, so the infection might have just triggered what she was already genetically primed for. before the PANDAS at 10 yo, she did not have eye tics or throat clearing tics. after the pandas she did. those cleared up pretty quickly, but she has some other behavior at 15 yo which is co-morbid with tourettes, like mild OCD and ADHD. she also has a lot of sensitivities to sudden temp change that will make her break out in a rash, just like her father. she also has a dust allergy and produces a lot of phlegm in the morning like her father.

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  6. The anwer to this specific question me is clear: No No, because there is no such unitary disease/diagnosis/experience as schizophrenia. Two people can have the same diagnosis of schizophrenia but share no symptoms (to cut a long story short). Until we seriously start to take a nore nuanced view of of psychotic experiences, we continue to complicate the struggle to understand the aetiology of psychotic experiences. Such blunt questions also severely obscure the environmental factors involved in the pathogenesis of psychotic experiences, and reduce 'schizophrenia' to a purely 'biological' level of explanation, and do our patients a disservice.

    Of course, the answer to the question, 'may altered immune responses increase the probability of certain psychotic experiences?' is different. I need to read the paper (when I can access it), because it probably covers such possibilities, but I guess it is highly probable that the experience of psychosis (including trauma/stress) may also affect the immune system, and that altered immune markers may be a result (as well as a causal factor) of the psychotic experience. Antipsychotic treatment may also affect immune markers?

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  7. From Lahita (actually Ch 28 (p 494-495) by Mackay, Ulug, and Volpe):

    "There are some limited data to suggest that brain endothelial cells express N-methyl-D-aspartate receptors (NMDAR) and that glutamate binding results in increased BBB permeability, suggesting that anti-NMDAR antibodies may have direct effects on BBB integrity"

    and:

    "Autoantibodies, the hallmark of SLE, have been shown to traverse the BBB in murine and human studies. For example, antibodies to NMDAR (anti-NMDAR) are present in the sera of 50% of lupus patients and these autoantibodies have been shown to bind NMDAR on neurons resulting in temporary neuronal dysfunction and apoptotic cell death".

    and:

    "The murine model demonstrates that, once inside the CNS the NMDAR antibodies cause regional neuronal dysfunction associated with specific behavioral changes. In human SLE, CSF titers of anti-NMDAR antibodies correlate with diffuse NPSLE symptoms whereas serum levels do not.."

    Working on a diagram right now.

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  8. Thank you for posting this, I found it very interesting.

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  9. In some cases,particularly Disorganised Type Schizophrenia I think it is.The problem is that most Psychiatrists are not aware that NMDA receptor encephalitis even exists let alone that anti NMDA antibodies are also found in some people termed with "pure" Schizophrenia-ie:people with only psych type symptoms & not seizures etc.This test isn't even available here in Australia and most psyche don't do anything beyond perhaps testing for thyroid.There's no awareness here regarding things like psychosis in Hashimotos encephalopathy etc & patients doctors here are lazy & prefer to diagnose people with things like somatisation etc. It's a crying shame to think of how many treatment resistant SZ patients could be here left lingering in institutions when they could possibly have an autoimmune process but it wasn't found in time due to lack of awareness/disbelief from docs in this country & they now could have permanent cognitive damage because antibody mediated processes need to be aborted before permanent damage is done sometimes.Also I wonder if some called somatisers/those with symptoms that don't quite fit could also have an autoimmune process.Perhaps extreme stress creates a brain vulnerability for this?............

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  10. Hello - I have a son who is on his 5th hospital admission with psychosis in 2 years. Diagnosis has shifted from schizophrenia to schizoaffective disorder. He won't comply with medication when being treated in the community, so they put him on depot injection (flupenthixoldecanoate) and he calls it his poison. A year on this found him stable but miserable. Four months without it and now a relapse.
    I have auto immune diseases, as did my mother.
    Who can I direct him to, to find better treatment? We're in Melbourne, Australia
    Thanks very much - Robyn

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    1. You could try one of the two GAPS diet practitioners in Melbourne. Look on gaps.me, and than 'find a GAPS practitioner' in the menu on the right.

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    2. Dear RobynB,
      I am outside Australia not quite far. I have been reading almost all cases on this site and just pick on you and would be pleased to help your son. We are honest and we are not taking a single cent for this help. We have been treating bipolar and schizo cases with good success in our alternative approach. We have different reasons to the cause especially if modern medicine (drug) wont work. No need of seeing the patient, only to contact by phone and email for instruction to be given that need to be done on your side. We need to explain more through emails. If you have faith in what we are saying please contact us at cexorint@gmail.com
      Sincerely
      Bari Jal

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  11. These articles regarding Psychiatric symptoms in Paraneoplastic disorders, and Immunotherapy in Schizophrenia might interest you.

    http://ajp.psychiatryonline.org/Mobile/article.aspx?articleID=102429
    http://www.nature.com/mp/journal/v12/n5/abs/4001959a.html

    Perhaps it's time to do large scale Immune markers testing and Brain Antibodies testing in not only patients with first episode psychosis,but also in patients with chronic treatment resistant Schizophrenia,Disorganised Schizophrenia,Schizoaffective Disorder,and patients with cognitive loss of unknown origin.
    The outcome might be some Schizophrenia subtypes being reclassified as "organic" cause,a similar disorder as Cns Lupus.

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  12. The below articles regarding Psychiatric symptoms in Paraneoplastic disorders, and Immunotherapy for Schizophrenia might interest you.

    http://ajp.psychiatryonline.org/Mobile/article.aspx?articleID=102429
    http://www.nature.com/mp/journal/v12/n5/abs/4001959a.html

    Perhaps it's time for large scale Immune markers testing and Brain Antibodies testing in not just patients with first episode psychosis but also in patients with schizoaffective,disorganised type schizophrenia,chronic treatment resistant,cognitive loss of unknown cause,psychiatric patients in prisons etc...
    The end result might be some Schizophrenia subtypes being reclassified as being an "organic" illness,similar to Cns Lupus.

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  13. These articles regarding Psychiatric symptoms in Paraneoplastic disorders and Immunotherapy for Schizophrenia might interest you.
    Large scale testing of Brain Antibodies in patients with Schizoaffective disorder,Disorganised Schizophrenia,treatment resistant etc would be interesting.

    http://ajp.psychiatryonline.org/Mobile/article.aspx?articleID=102429
    http://www.ncbi.nlm.nih.gov/m/pubmed/23538571/
    http://www.nature.com/mp/journal/v12/n5/abs/4001959a.html

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  14. Hi great blog, I'm a final year socual work student in the UK currently on placement in an esrly intervention in psychosis team. I have a case of female in her twenties with sudden first episode psychosis shortly after removsl of an ovarian cyst. When examined revealed teratoma. Father has schizophrenia and sister also since age 14 and is treatment redistant. My client has also been treatment resistant over last 7 weeks. The medical an team assumptions are schizophrenia but it just didn't add up today I decided to do some research and have found lits on anti Nmdar if I have to fight for a differential diagnosis on Monday is a lumber puncher the route most reluable. Any advice would be great thanks in advance

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    1. I really don't know about the full work-up and diagnosis for encephalitis on the floor. In this particular study they checked blood antibodies, and as I recall from some poster sessions/case studies at the last APA they did LPs and blood...there is almost always some sort of neurological finding that would be unusual for straight-up schizophrenia. Given her strong family hx and her age it is also possible it is a first break. It could happen with a severe stressor such as surgery.

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