Friday, March 30, 2012

Schizophrenia and the Gut

If you are going to do something, go ahead and do it right.  Honestly, that's why I write the blog (in part). I wanted to know more about the interface between diet, lifestyle, inflammation, and the pathology of mental illness, and I couldn't find a trustworthy source.  It requires a lot of work and combing the literature, but at least it is interesting, and I learn a lot.

However, I have to say, much of the literature is pretty sad.  There are a bunch of quick & "easy" research projects requiring people, in general, to fill out some forms.  Occasionally medical records are chased down, and sometimes some physical markers are followed.  Then someone brings in the statistical wizard to generate the results, and the authors try to tie it all together with some references.  Occasionally there is a randomized trial, but the whole experiment has holes one could drive a truck through, so to speak, so one hardly knows what the information means. I'll take what I can get, and it's easy for me to be critical as I am not a researcher and I don't have to generate grants to keep my office real estate in the academic medical center.  But it is always nice to see a paper where they went that extra step.  They closed the loop, and with actual testing, not just extra math.

Black Keys--Gold on the Ceiling (right click to open in new tab)

The paper of the day is impressive for a variety of reasons:  Gastrointestinal inflammation and associated immune activation in schizophrenia (via the twitter feed of that zen dude Chris Kresser.)

And let's step back and think about the history of schizophrenia for a bit.  Nowadays in the era of specialized medicine, psychiatrists think BRAIN when it comes to "organic" issues and CHILDHOOD/LIFESTYLE/PERSONALITY when it comes to coping problems.  The pendulum has swung back and forth between the two (coping vs. brain pathology) in a crazy psychiatry war, more or less.  A better understanding of the functional metabolism of the brain is finally bridging the gap, but let me tell you, in a post 1960s academic medicine setting, no one except the radicals were tying the gut to schizophrenia.  It just wasn't on the radar.

And if you really think about it, once thorazine and the other dopamine blockers began marching out the doorways of Big Pharma, we had a nice and pretty brain-centered theory wherein the neurons began going haywire, producing psychosis.  Since drugs like cocaine and meth that increase dopamine can produce psychosis, and dopamine blockers reduce psychosis, everyone was happy.  And while a bunch of other neurotransmitters like glutamate and serotonin and acetylcholine and histamine appear to be tied in, it was still all the same variation of the same theory, and you know if we could just get the right combination of drugs to block the right neurotransmitters, maybe we could beat this thing.  The conception of a special, protected space beyond the "blood brain barrier" led to this lack of holistic thinking as well.

What we forgot is that schizophrenia has always been a whole-body disease, particularly involving the gut.  Celiac has a special link with schizophrenia, and adults with schizophrenia at autopsy often have extensive inflammatory changes in the GI tract.  These associations have gone back to the literature from the 1920s, prior to the development of the antipsychotics.  In the present day, it is nearly impossible to separate the effects of the illness itself from possible effects of antipsychotic medication.  Antipsychotics are known for slowing motility and probably affect the gut immune system by reducing the inflammatory response there, perhaps even reducing gut leakiness.  Curtis Dohan thought this last bit might actually be the primary therapeutic action of antipsychotics, rather than all that fancy dopamine blocking stuff in the brain.

(Do you know the doctors most likely to use the old fashioned antipsychotics and antidepressants, all of which have pretty impressive GI effects?  Psychiatrists, neurologists, and gastroenterologists.  Reglan and phernergan are dopamine blockers, chemically not all that different from antipsychotics like Haldol or Thorazine).

Think how radical that idea is.  Dopamine blockers ameliorate psychotic symptoms by reducing inflammation in the gut??  Okay, it's a cute theory, but except for Dohan and Dickerson, not a whole lot of good folks were doing work on it for many decades.

So this "Gastrointestinal inflammation and associated immune activation in schizophrenia" paper from Schizophrenia Research is rather like a bolt of lightning.  It was done at Sherppard Pratt/Johns Hopkins, for heaven's sake.

Here's the design.  Take a group of folks who developed schizophrenia within the past 24 months.  Then take a group of folks who have had schizophrenia for many years (average > 20 yrs).  Then compare to some normal controls recruited from the community.  These normal controls from the community were determined to be relatively free of psychiatric disease via a structured clinical interview (SCID), which is the gold standard.  (These little gold standard touches take some extra work and make me happy.  It can take an hour or more to administer a SCID.  I remember a Maes paper where he recruited the controls from employees in his lab.  Often folks who work in psych have an interest due to personal issues or close family members who have psychiatric problems, so the research field employees might make for biased controls.  I don't always comment on these issues with papers because there simply isn't time…)  The researchers then checked the subjects for serum antibodies to gluten, casein, T gondii, Saccharomyces cerevisiae, and some other bugs associated with schizophrenia or gut issues, and crunched the numbers.  (So we have an observational study, but with some nice data collection and a further twist I will get into later)  Antibodies to S. cerevisiae in the system (called ASCA) are used as a marker of intestinal inflammation (and can be used to help diagnose Crohn's disease, for example).

There are some gender-related twists and turns, but for the most part, they found that folks with new onset and longstanding schizophrenia had significantly elevated ASCA levels compared to controls.  High levels of ASCA correlated (for the most part) with anti-casein and anti-gluten antibodies, which would make sense.  If you have gut inflammation, then casein and gluten proteins could seep into the system, and your immune system starts to attack them.  Since gluten and casein could be neuroactive (and maybe neurotoxic), they could be another part of the pathology of schizophrenia (and autism, etc.).  ASCA levels did not significantly correlate with anti-gluten and anti-casein antibodies in the control group, which is interesting.

All right, but who cares.  All these folks with schizophrenia were recruited from Johns Hopkins, and pretty much all of them will be medicated.  The medication could be a part of some of these immune and inflammatory effects.  The researchers thought of this tangle, and they designed a second experiment with a second cohort comparing unmedicated recent onset schizophrenia patients in Germany with medicated recent onset schizophrenics from the same area.  Those recent onset unmedicated schizophrenics had about 1.5X the ASCA measures of the recent onset medicated schizophrenics from the same German cohort.

And, tying it all together with other associations between infections and schizophrenia, the new onset patients had significantly higher positive antibodies for T. gondii than the non-recent onset folks or the controls.

SO, we have found that folks with schizophrenia have a higher level of gut inflammation and antibodies to glutein and casein than conrols.  Could these vulnerabilities somehow begin in the brain?  Or does the issue start with the gut, immune activation, and systemic poisons (neuroactive food fragments and infections) hastening an inflammatory decline in the brain in the genetically vulnerable?  Do antipsychotics work by being anti-inflammatory in the gut, by decreasing dopamine activation in the brain, or both? (or neither?).

All pretty interesting questions.

18 comments:

  1. pretty awesome paper. Thanks for the review. Have you seen or heard about anyone improving on a non gluten/casein diet? I suppose most patients would be on antipsychotics, confounding the results?

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  2. Aron, one of my links is to my psychology today article on Wheat and Schizophrenia. Dohan reports about a gluten-free inpatient psychiatric unit where folks supposedly got better much faster than on a second, gluten-saturated unit. But there isn't much solid stuff to hang our hats on at this point.

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  3. I would assume dopamine (and serotonin) blockade would be at least palliative in psychosis / hallucinations of any origin as these drugs are effective in any kind of psychosis, whether it is drug induced or schizophrenic or manic ... so if a GI disease is causative of some schizophrenias I don't necessarily think APs are targeting the GI disease, just masking the symptoms of psychosis in general.

    It is known some APs can reduce the immune system, like clozaril (noted s/e agranulocytosis). I believe it's stated that many other APs have a depressant effect on the immune system although clozapine is the most well known as it can be fatal. Perhaps those schizophrenics who are refractory and end up on clozapine are the ones with progressive immune disease.

    I also wonder if the metabolic destruction induced by dopamine blockade (insulin resistance and diabetes) leads to even greater immune suppression, so in a round about way the diabetic-like state from APs helps break the immune system, thus suppress the progression of autoimmunity induced mental illness.

    Wonder what your opinion is of tardive psychosis? I rarely hear this discussed, but it stands to logic that if movement disorders are a consequence dopamine receptor upregulation so would be worsened thought disorder. Considering how noted TD is (because it is physically obvious and cannot be ignored), we never hear of tardive psychosis.

    The problem with schizophrenia is that patients are often mentally impaired, cannot advocate for themselves, are very vulnerable to mental health care workers (thus, the antipsychiatry movement). Any adverse effects or outcomes are often confused with the progression of the disease. I wonder how many supposed noted long term complications of schizophrenia / deterioration / progression is actually the result of exposure to antipsychotic drugs.

    My grandmother was schizophrenic. She was hauled off to the state bin about 1952 and never released, and died there in her early 50s of unknown cause although it was rumored to be cancer (there you go, evidence of drug induced immune system dysregulation heh).. Treatment for schizophrenia is pretty much non-existent, even today. The APs seem to work by inhibiting thought in general.

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  4. Hmm, they used to use fasting as a treatment for schizophrenia in Russia. Maybe they still do. It was claimed to be effective. Google fasting schizophrenia and the first hit is an old paper about it. Could it work through similar (gut related) mechanisms?

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  5. Enjoyed the article.

    Off topic: The other night I was reading "Hyperactivity and Diet" and when I read this paragraph I paused.
    "The results of the study, however, were impressive enough that the UK and several other European countries banned the use of the studied food additives, so Skittles sold in the UK have no sunset yellow or tartrazine, though as far as I know, Skittles in the US have the same old recipe of hyperactive family fun. Sodium benzoate was not banned."
    The reason for the pause was because Skittles was in the news this week with Trayvon Williams. Then tonight I see in the newspaper that Skittles is being swamped as Skittles are becoming as much a cultural icon as hoodies.

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  6. There's a Norwegian doctor who's been looking into the link between gluten/kasein and autism (ASD). Isn't there a lot of similarities in the pathology of autism and schizophrenia?

    http://www.ncbi.nlm.nih.gov/pubmed?term=%22Reichelt%20KL%22%5BAuthor%5D

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  7. dont forget icu doctors, we use bucket loads of anti-psychotics :) although fewer as people learn to not cause delirium in the first place.

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    1. You are bringing back fond memories of a psych consult in the ICU. Them: "He's acting crazy!" Patient: Speaking in tongues, trying to climb up the walls. Me (holding med sheet): "Maybe it's the 27 doses of morphine he's had in the last 24 hours, combined with 8mg of ativan, 400mg of benadryl, and those three nicotine patches he's wearing for some reason."

      Are they really learning how not to cause delirium?

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    2. Speaking as a nurse, usually that configuration of tons of drugs is a result of med staff trying to control insanity / cater to the lunatic's outrageous agitated demands and keep them under control and docile.
      However, psychiatrists always end up assuming that the patient is crazy BECAUSE of the opiates/benzos/nicotine/benadryl and refuse to believe there was preexisting nuttery. It's very annoying. Sure no doubt ineffective drugs make crazy worse but invariably the psych consult comes in and says "THEY ARE CRAZY AND NOT SLEEPING AND AGITATED BECAUSE YOU ARE GIVING THEM TOO MUCH ATIVAN AND XANAX AND ALL THESE DRUGS ARE MAKING THEM DELIROUS".

      Actually, crazy patients who are agitated and hostile and not sleeping typically end up requesting a million mgs of opiates and a billion of benzos and staff doesn't know what to do so they comply to keep him under control.

      PS the three nicotine patches are because the nurses are too scared to come near him and take them off because he might flip and swing.

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    3. In my experience, the patients with delirium rarely have any psych history, and the typical symptoms are qualitatively different than a straight-up psychosis. It masks as a psych problem (typically psychosis or depression) so I have been called in to address it.

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  8. @Woo there are extensive records of schizophrenia prior to the use of antipsychotic medication showing a neurologic decline and even autopsy studies with shrunken brains, so we know the disease itself is basically a progressive, devastating dementing process. But muscle stiffness and even malignant catatonia occured in the years before medication (malignant catatonia is very very similar to NMS). The antipsychotics can cause rebound psychosis upon discontinuation and may also cause an element of brain shrinkage (most alarming paper was in Feb 2011 in the Archives of General Psychiatry). I have patients living in the community and doing well on medication, working at high-level jobs who become flagrantly psychotic off meds. It would basically be considered malpractice not to start someone/recommend meds at first break in the US. Does that mean the meds are perfect and everything will be rosy? Absolutely not. The meds can have terrible, even deadly side effects.

    rps: there is a case study of a ketogenic diet eliminating psychotic symptoms in the literature. It could be a similar mechanism and could also affect the gut.

    Pal - yes, there are quite a few similarities except for the stage of development when it occurs. Also families where both illnesses cluster.

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  9. "What we forgot is that schizophrenia has always been a whole-body disease, particularly involving the gut." I have a close family member who suffers what I label "episodes" - they seem to be total breaks with reality, hearing voices, seeing things that aren't there, etc. And I noticed just anecdotally that when these episodes would kick in, he seemed to spend inordinate amounts of time in the bathroom. Constantly. All night.

    At the time I had no idea of the gut/brain axis connection or that acting nuts was related in any way to the GI tract, but just thought the constant trips to the bathroom odd, to say the least.

    And he was telling me he recently listened to a BBC podcast where a guy when in for some kind of surgery that "went bad" and the poor guy ended up in a psychotic state for a number of days. What freaked my relative out was that what they English guy described to a "t" was one of his own episodes. Which got us talking about the madness of King George which was related to his GI tract & turned his excrement a strange shade?

    I keep wondering if I should start encouraging my relative to eat raw sauerkraut every day as a way of helping him maintain & heal his GI tract.

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  10. Why not to check all schizophrenics for at least gluten and casein antibodies? May be it is not a bad (but not realistic) idea to check whole population. I understand it could be some false positives or negatives, insurance coverage may be a problem, but some people could be helped.

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  11. When I read this ScienceDaily article, I cringed and snickered simultaneously, www.sciencedaily.com/releases/2007/11/071115082317.htm

    "The findings suggest that, even though the NHI program reduces financial barriers to care for people with [mental*] illness, schizophrenics are still at a disadvantage in obtaining timely treatment for physical problems."

    *the word "mentally" mistakenly printed. I was expecting them to mention and make a closing comment to include correlation with inflammatory GI issues, but instead they go for the socioeconomic, political angle. It frustrated me that they ignored the immunological, physiological events that could predispose a person with preexisting schizophrenia or schizoaffective disorder to develop appendicitis.

    I have my own anecdotes of what I've dealt with, never on psychiatric meds, but no one values anecdote- so, one day, objective science will win the war I've been forced to wage since my childhood. I'll find a scientific way to give my anecdotes some value, then.

    I do think, though, that my [no psych meds] history might interest someone if it were to turn out that my t. gondii antibody levels are unusually high, and if that correlated unmistakeably with my (since age 7): depression, fructose malabsorption, histamine intolerance, dysmenorrhea, yeast overgrowth, high sensitivity to sugar of any kind, skin issues (peeling, rash, chapped lips), auditory hallucinations /panic attacks, anger /mania, hypomania, anxiety, appendicitis followed by appendectomy, (and on and on and on).

    I'm under no illusions. I've found solutions to alleviate my symptoms -in combination with amateur study of research papers- to be able to theorize why they've worked. It's not 1 thing, it's a personalized cascade of food exclusion, inclusion and supplements. I'd just like the rest of the world to understand how I figured it all out, so that other people going through what I went through can recover -sooner- without the detrimental side effects of a cocktail of medications.

    In closing, if you Google /read about magnesium deficiency (B-6 deficiency also noteworthy) in relation to a particular trio of SNP trouble in the gene that regulates the COMT pathway (val-158-met) you might find it interesting. Its relation to symptoms of anxiety and paranoia (elevation of catecholamines which the COMT pathway isn't breaking down efficiently enough) should especially be worth reading about, definitely in connection with norepinephrine levels affecting glutamate.

    There may also be a connection to a deficiency of the building blocks the body needs /uses to biochemically generate /replenish tissue levels of diamine oxidase (a.k.a. histaminase) in order to break down elevated histamine levels. The connection is to IBS and inflammation. If you haven't read the article on Histamine Intolerance published in The American Journal of Clinical Nutrition (comes up first thing on Google) it's very easy to follow.

    Happy paper trails!

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  12. Hi Emily

    Thanks for this article, I am going to link it to my blog.

    I had three psychotic episodes over a period of twelve years, and have a diagnosis of schizophrenia. I have been off medication now for a long time (more than eleven years) and have four children and a happy and busy life - in other words, I am completely well.

    I think now that the root of my problems was anxiety, which had developed into a general anxiety order or social phobia (I am guessing, from what I have learned recently on the Net and from books!) Although I have been happy with my life for a long time, I accepted until very recently that this anxiety would always be a part of my personality.

    However, about four months ago I stopped eating gluten. Within weeks the anxiety lessened, and now it is no longer an issue at all - to the point that I travelled alone to London two weeks ago to speak to the Schizophrenia Commission, and did not feel even a twinge of nerves. In fact I really enjoyed the day - and this would have been impossible until very recently.

    I have also been having CBT, and this has helped too - I suppose I had such a bunch of neuroses built up over such a long time, and had very low self-esteem as a result of it all. The therapist was very good and in just ten sessions has helped me to sort out the tangle of my thinking.

    I do not now beleive that schizophrenia really exists. I am not denying that I was extremely ill, but I do not think my problems fitted a pattern which could fairly be given a particular label. The label itself stopped me from even attempting to recover for many years.

    I also do not believe that 'schizophrenia' is hereditory - partly perhaps I choose not to because of my children. I think anyone can break down, given enough stress, and I make sure that our family environment is as constant and as loving as can be, and I hope that this way I can protect my children from any extreme emotional distress.

    However, I do not see any harm in hedging my bets. Obviously I always try to feed my children well, but I have made up my mind now (in the half hour since I read your article) to try even harder, and to monitor them closely for signs of gut trouble, to try to pre-empt any problems occurring. So thank you very much for prompting me to look more closely at this angle!

    Incidentally, you mentioned in an earlier comment here that you have several patients who function very well on their medication, but break down as soon as they try to stop it. I read Richard Bentall's book, 'Doctoring the Mind' recently, and he writes of the fact that psychiatric medication dampens down the dopamine receptors in the brain, which then react by regenerating to about fifty per cent of their pre-med level. Then, he says, when the patient stops the medication, the original dopamine receptors fire up again, so the patient has one hundred and fifty per cent. The consequent breakdown is understandable in this context, not as a result of simply stopping the drugs, but as a more complicated issue, which deserves further research.

    There is so much information available now, I feel that new light is constantly being shed on the subject of mental health. The issue is how to spread this information to all concerned - I would like direct you to the Mad In America website, which comes up with new insights almost daily.

    As you say in this article, there is no need for a battle just because there are lots of different perspectives on treatment. Everyone wants to help the mentally ill, and if both sides can inform each other of developments in a measured and polite way, progress will surely be quicker.

    All the best, Louise

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  13. Interesting topic, I hope I can follow. On schizophrenic patients before the drug era I still think it's premature to assume it's a degenerative neurological illness and the generation cannot be not due to other factors. But I'd like to see the research and criticism of it. And then there's the issue cause and effect even if other biological factors are ruled out.

    Unfortunately the degenerative and fatalistic model is deep rooted now and often for other disorders, and seems to ignore cases where people recover without lifelong drug treatment (outside the standard mental health system treatment from what I've seen). However critics like to focus simply on the drugs as an alternative explanation for degneration instead of a holistic view from what I've seen.

    I don't see the need to *immediately* medicate someone the first time they become psychotic if they can come out of the state anyway. The antipsychotics given to me didn't help me come out of psychosis, and twice I stopped the drugs (because of weight gain) while delusional with paranoia and came out of the psychosis a few weeks later anyway.

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  14. Emily Deans, you are a blessing. I just can't read enough of your stuff. Thank you.

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  15. Emily,
    Are you familiar with the work of Dr Natasha Campbell-McBride? She is a neurologist who cured her son of autism by healing his gut with diet. She has written books on "Gut and Psychology Syndrome" GAPS which explain how mental illness develops by poor diet, stress, bacteria passed from mother to child during the birth process. One of my children has schizophrenia and has been on clozaril for close to 12 years and has been able to have that medication reduced from 500 mg to 50 mg a day by following the gaps protocol at first, then seeing a naturopath to check for food allergies and for recommendations for supplements. He was doing very well until he started drinking for a short period of time, which caused him to be delusional, but only in regards to me (which I can't explain, we've always been real close). I think that shows that if the gut is healed, or healing, a great deal of recovery can be achieved, but that it is very important to stay away from all food and drink that is nutritionally harmful.

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