Friday, November 1, 2013

Gluten and Schizophrenia Again (with an added splash of Toxo!)

Researchers have been chasing the elusive links between gluten and major mental illness for decades. Despite some hyperbolic coverage in Wheat Belly and slightly more convincing coverage in Grain Brain, there is, so far, quite a bit of smoke, but no fire outside a few case studies. Curt Dohan had quite a few papers back in the day (including this one), and much more recently Faith Dickerson, now armed with antibody titres, could be more precise (including in this paper).

In the last couple years the rather stunning data from the CATIE trial (a very large multi-center study of schizophrenia treatment run by NIMH in the last decade) that schizophrenics were 5X as likely to have anti-tTG antibodies as healthy controls and over 7X the likelihood of having high AGA (antibodies to gliadin) compared to normal controls has made more researchers take notice. Yet on face, all we could really say is, wow, a certain subset of people with schizophrenia sure do have some suspicious antibodies to different wheat proteins, and it is pretty clear that devastating neurological illness can be caused by gluten (dystonias in some people, for example) without the classic celiac gut findings, but is the issue in schizophrenia a leaky gut (thus higher antibody titres to certain food moieties) or the wheat itself, or both? I covered these questions in a bit more detail here.

One major issue with the theory that wheat causes schizophrenia is that schizophrenia seems to have a similar prevalence in gluten and non-gluten eating areas, but since "schizophrenia"is pretty clearly recognized as a final common pathway for a number of different genetic and environmental pathologies, it wouldn't necessarily torpedo the gluten theory. Now, finally, we can test whether gluten-free diets help symptoms in the subset of schizophrenics who have suspicious wheat antibodies. The newest round of researchers, led by Jessica Jackson (along with Alessio Fasano) at the University of Maryland and Emily Severance at Johns Hopkins, are following these leads.

Come A Little Closer: Cage the Elephant

First off, we have "A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies." This paper starts off with discussing the mixed results of previous trials (7 in all) of gluten-free diets in schizophrenia, showing a subset with real improvement (and some with remission, which is an astonishing finding), but many without improvement whatsoever. None of these studies tried to differentiate schizophrenics with or without anti-tTG and AGA, mostly because they were done before these titres were available. The paper makes the distinction that anti-tTG antibodies are more likely to signify celiac disease, whereas AGA is more likely to signify non-celiac gluten sensitivity. In the current paper, exactly two patients with schizophrenia (one woman symptomatic since 1976 and a man symptomatic for the past 8 years) and positive antibody titres (one for anti-tTG and one for AGA) who were stable on medicines but still symptomatic (pretty common) were put in an inpatient unit and observed on a gluten-free diet for two weeks.

The woman had improved concentration and attention (critical, because psychotic symptoms often respond relatively well to medication, but poor executive functioning, attention and concentration are not so responsive, and those deficits keep many people with schizophrenia from being able to function independently). The man had some reduction in psychotic symptoms and increased insight into his condition. Since schizophrenia is a progressive neurodegenerative disease, seeing improvement, particularly in the woman who had been sick since 1976 from a non-medicine intervention in two weeks' time is at the least interesting.

The limitations of this study are profound. Open label, about as tiny as you can get, and obviously taking someone and sticking him or her in an inpatient unit with structure and observation is an intervention all on its own. But the level of improvement was enough that Schizophrenia Research (not the topmost tier of psychiatry journals, but certainly no Medical Hypothesis) published the paper, and it is available free full text on pubmed if you care to click the link above.

The second paper was sent to me by the amazing Victoria Prince (who just finished her last rotations in medical school. Woo hoo!) I love this paper, and I want to give Emily Severance a hug just for the ideas it brings together. She already deserves a hug for the previous paper I discussed in this article: Schizophrenia and the Gut. We know schizophrenia is multitudes, it's complex, it's genetic and environmental and immune-mediated. Ergo: Anti-Gluten Immune Response following Toxoplasma gondii Infection in Mice. (I know, mice.) It's also available free full text over at PLOSone.

Anyway, we already know that folks with schizophrenia have higher levels of gut inflammation (measured by checking antibodies to known infections that get into the system when there is gut inflammation or infections that actively cause gut inflammation, such as our old friend Toxoplasma gondii), and the newer the onset of illness, the more likely you are to find gut inflammation, AND the more antibodies to gluten and casein you have, the more likely you are to have these signs of gut inflammation. So Dr. Severance sought to answer some of the questions raised by this finding. Did the infection cause a gut pathology that allowed neurotoxic food fragments to attack the brain of the genetically susceptible? Were the infections themselves the problem in the brain, and the food antibodies just secondary to the infections? Well, it is difficult (not to say unethical) to do the sorts of experiments you need to answer these questions in humans, but mice can be housed and infected and their little immune systems examined in greater numbers over several generations more readily.

So the researchers took mice and gave them delicious T gondii infected rodent chow (via infected ground up mouse brains!!). They infected some adult mice and a subset of female mice who were then knocked up so they could check the pups for gut inflammation as well…there are a lot of mini-experiments in this paper and I won't explain them all to death here, as the paper is freely available. Anyway, after infection with T gondii, serum antibodies to wheat proteins and complement activation (not a sign of well-bred mice but rather a measure of inflammation) increased in the infected groups but not in the mock-infected or uninfected groups. The anti-wheat antibodies in mouse pups born to the infected moms were also significantly higher than in those born to uninfected mouse moms.

So here we have proof, in mice, that infection with Toxoplasma, a known risk factor for schizophrenia in humans, leads to the generation of anti-gluten antibodies, presumably via a gut inflammatory mechanism. Most importantly, in the mouse pups, the anti-gluten antibodies and infection happen at a time of critical neurodevelopment. Thus the combination of infection and, perhaps, a dietary enhancer (such as, possibly, gluten) could be working in concert to make someone vulnerable to developing schizophrenia later on. The "gut inflammatory" mechanism is vague at this point. In celiac disease in humans (more associated with the anti-tTG antibodies), there is definitely gut damage and permeability. In non-celiac gluten sensitivity (more associated with AGA), there doesn't seem to be frank leakage, but apparently large gluten peptides can cross the border via transcytosis and this may happen more readily if the gut is infected and the immune system is on the case and things…frankly the exact details of gluten and the gut continue to elude us. Check out the last paragraph of this paper (BIG HUGS):

In summary, the models described in this paper provide appropriate experimental tools to examine the impacts of gluten peptides, T. gondii and associated immune activation on brain physiology. As we accumulate more information from analyses of clinical biomarkers, we can adapt these animal models to test the effects of dietary modifications and other types of infections on behavioral endpoints, the pharmacological outcomes of specific antipsychotics on immune system parameters, and the autoimmune response responses triggered by T. gondii infection. Ultimately, we envision a translational system by which we can fully evaluate the interface of environmental perturbation and genetic predisposition as it relates to serious neurodevelopmental disorders such as schizophrenia, bipolar disorder, and autism.

I've never been a very linear person; I tend to absorb and think about things all at once. That's part of what I like about my so-called Evolutionary Psychiatry. We can think about lots of things at once as they impact physiology, immune activation, and genetics. The researchers who also seem to think this way, but can also break down these questions and not leave gaping holes (Severance's previous experiment where she took the trouble to go across the ocean to study gut and immune activation in medication naiive and medicated schizophrenics, taking out a major confounder in most schizophrenia research in the US) are the kinds of thinkers we need who can do good science to work out these big complex tangles. I can't wait for the next papers to come out. In the mean time, there is no clinical guidance. Is it worth checking your schizophrenics for anti-tTG and AGA? What are the risks of recommending a gluten-free diet and what is the likelihood it will be strictly followed in an outpatient setting?

Always, more questions than answers.

22 comments:

  1. I'm not a doctor, neither I'm a patient, but I have had a huge interest in mental disorders in the last few years (that's why I follow your blog). In my opinion, in regards to the question in your last paragraph, I believe that it doesn't hurt if you prescribe a gluten-free diet to your patients. If you don't prescribe it and you don't keep your own notes of their progress, you'll never know in your practice if gluten is to blame or not. I don't think it will hurt your patients in any way, if anything, they should see much better overall health regardless if it treats their mental problems or not.

    I'd say that these few things could be prescribed to patients without a risk:
    - Going completely gluten free, no exceptions on this. No restriction on the other grains.
    - Limiting seed oils, sugars, processed carbs (although not necessarily eliminating them completely, let them have the occasional GF pasta/cereal etc). Soak beans for 24 hours if possible before cooking.
    - Cook with coconut oil, olive oil on salads, eat WILD fish/shellfish/sea-veggies almost daily, pastured eggs and good quality meat when possible, lots of veggies, fruits, some nuts & seeds. As important: eat fermented foods, bone broth, offal, and home-made goat or water kefir (super important IMHO).
    - Wouldn't hurt: D3, Mg, CoQ10 Ubiquinol (not Ubiquinone), and maybe K2-Mk4 & Acetyl L-carnitine in the first stages. No need to replenish after their boxes empty (except maybe for Mg, since modern food is deficient on it).
    - Sleep a lot. See the sun daily. Exercise 2-3 times a week, or at least walk daily. Meditate for 20-30 mins daily.

    That's it. I think it's a simpler diet/lifestyle than going full Paleo-ketogenic (which is of course more effective, but way more difficult to follow). These are the main points of Paleo that are known to make asymptomatic so many diseases, without going fanatic about its every detail and remove too many foods from the diet. In fact, what I suggested above adds more foods than removing foods! I've seen people getting better when following this "lite-Paleo" version without going full Paleo, so it might help some mental patients too. It leaves wiggling room for the patient to enjoy some foods that are not that bad when eaten seldom (e.g. a GF pizza), so it makes the diet easier to follow.

    So why not try it with your patients and see if it works 6 months down the line? I'd love to come back to your blog 6 months later, and read the results of this "test". Sure, these findings would still be considered anecdotal, but coming from a doctor, they would have a bigger impact than random people on random forums saying that GF helped them. There are many such forum posts now, in the last 2 years, but they're scattered, and no one is listening to these people who have found their health through GF. But it can be a different deal if the results are multiple, and they come from a doctor. Food for thought. :-)

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    1. On a one on one basis, it is a very low risk intervention. As a general recommendation, we would need more data. Is it worth the cost to check for the antibodies, is it just worthwhile to have everyone with schizophrenia do a strict GF trial? I have a few folks with serious mental illness doing very very well GF, but many have a lot of battles to fight, and GF is not one of the challenges they want to face at the moment.

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    2. I like your suggestions, Eugenia. But I would like to add that with someone with schizophrenia (I don't like to use "schizophrenic" because I think it defines the person by their illness), it is incredibly challenging for that person to be on a regular schedule. So things like meditation a few times a week, and exercise a few times a week are very very hard. I usually don't comment on blogs/forums but I thought this was important to note, and I've grown up around people with this illness so I'm very familiar with it. The tendencies they exhibit toward patterns can sometimes be consistent...but because the rationality is not there, it's often interrupted cyclically and choices people make are usually not the healthiest. I do think thought that any way to steer away from social isolation is incredibly important.

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  2. One clarification to my diet suggestion above, where I said that "allow all other GF grains", I'd still stay away from oats. Too close genetically to wheat, and often contaminated with it.

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    1. Oats can be perfectly fine as part of a gluten-free diet: http://www.sciencedirect.com/science/article/pii/S0002822302000809

      From this study: http://www.ncbi.nlm.nih.gov/pubmed/18301937
      It states that "However, the potential toxicity of avenin, the corresponding protein in oats has been evaluated and the results showed that the immunogenic sequences present in gliadin are missing in avenin [68]." and that "At the end, in coeliac children in remission, oats had no detrimental effect on intestinal histology or serology. In contrast, the gluten challenge group relapsed after 3–12 months"... so you SHOULD be prescribing oats to people on a gluten-free diet, because it helps keep them gluten-free.

      Also, oats are simply healthy: http://www.ncbi.nlm.nih.gov/pubmed/23072529

      Just an FYI.

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    2. I would not eat oats even if you pay me to. A lot of Paleo dieters tried oats and got almost as sick as with eating gluten, many reports about it. The biggest problem is possibly the wheat contamination with it though.

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    3. [Dr Deans, I hope you allow this comment.]

      Whitefox: this is a newer study than the ones you mentioned: http://www.ncbi.nlm.nih.gov/pubmed/24240659 In it, it says that oats are not always safe. It depends on the cultivar. This also new study also says that it depends on the cultivar of oats or their contamination: http://www.ncbi.nlm.nih.gov/pubmed/24264227 Since very few oats are certified gluten-free (from contamination), and absolutely *none* of them mentions their cultivar, I don't personally consider oats to be safe. I'm sure there are some types of oats that are safe, but they don't give us the whole information we need to make an informed decisions if we should consume them or not.

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    4. I was excited to read your post on inositol, and sad I couldn't get your dopamine topics to show. However, I can't reconcile how someone so open minded leaves out that there are a plethora of components to the GM wheat we have to which individuals react. Sadly, Cyrex is the only lab I know of that tests for these, and since eliminating wheat doesn't make anyone billions in pharm dollars and would hurt the processed food industry are you REALLY surprised there aren't more studies published? There aren't many studies on GMOs because money and connections keep it that way. Few journals have maintained any integrity, so please don't dismiss the surmounting case study evidence for lack of heavily-funded "studies"

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  3. Cats cause schizophrenia!

    http://en.wikipedia.org/wiki/Toxoplasmosis

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  4. Interesting post.
    You might also be interested in the below study showing errors of metabolism in some with "schizophrenia" spectrum disorder.....

    http://www.nature.com/mp/journal/v18/n1/fig_tab/mp2011131t3.html
    http://www.nature.com/mp/journal/v18/n1/full/mp2011131a.html

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  5. I don't know about gluten/wheat and the problems they cause, except for weight. I am overweight only because I love bread. How do i know? From my mother's example.

    Once past fifty my mother stopped eating bread (but had oatmeal every morning) except for half a role a week, her big "treat" with tea (no milk, no sugar). She remained trim and fit into advanced old age, and her mind worked just fine (no dementia in either side of the family). In fact on her death bed (no drugs, no pain) she like to do algebra word problems for amusement. Those of us in the family who eat bread are overweight. those who don't it are not.

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  6. Dr. Deans, Great post and how nice to read your declaration, "I've never been a very linear person; I tend to absorb and think about things all at once." Very much like the mind-body works with its environnment, interdependently and holistically. I appreciate your piecing these parts of a larger puzzle together as we all continue to evolve.

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  7. I had a question about IF...I take a couple prescription medications that if I don't take around the same time I get nauseous. Is it alright to take a prescription medication during an intermittent fast (I didn't see this mentioned on your articles about IF)?

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    1. It really depends on the meds. Some upset the stomach if they are not taken with food, but after you get used to the med not so much. Others have entirely different absorptions with or without food (for example, synthroid without food and geodon with a 500 calorie meal).

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  8. Hi Emily Deans,
    A new study has apparently found more links between Schizophrenia spectrum disorders and Lactic Acid/ATP.............

    http://m.medwirenews.com/61/105073/Psychotic_disorders/Novel_approach_confirms_dysfunctional_energy_production_in_schizophrenia

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  9. According to one study, a history of any autoimmune disease is associated with a 45% increase in risk for schizophrenia. Given that many of these diseases appear to be caused by gut dysbiosis [which itself has numerous causes], perhaps schizophrenia is also caused by it?
    Susceptibility to or protections from various autoimmune diseases is conferred by HLA (human leukocyte antigen) alleles. A genome-wide association study implicated the HLA-C*01:02 allele as a risk factor at the major histocompatibility complex locus in schizophrenia, and DRB1*03:01 and also B*08:01 as being protective [replicating an earlier study]. For frequencies of these alleles in populations worldwide, see: www.allelefrequencies.net

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  10. Perhaps you're looking at schizophrenia in the wrong way, as a disease rather than as a constellation of symptoms. (To this end your "final common pathway" idea is relevant.)

    The analogy would be pruritus -- itching -- which can be due to an extraordinary variety of things like eczema, dry skin, lymphoma, poison ivy, and -- dermatitis herpetiformis (DH), which is related to gluten sensitivity. Now, DH is interesting. For one thing it is almost always misdiagnosed by primary care providers. Second, although it responds well to a gluten free diet, gluten free diets are so difficult to follow that we dermatologists most often rely on dapsone, which works very quickly. It's even used it as a therapeutic test for DH while waiting for the biopsy results, since if you don’t get an early lesion the pathology can be confusing. Maybe a trial of dapsone in schizophrenia would be worthwhile. I googled the combination and can't find that it's been done yet.

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  11. Very interesting post Dr.Deans, I'll have to dive into those papers later on :D

    "it is a very low risk intervention" - How can eating a diet described by Eugenia be considered risky for a human…at ANY level? If a gorilla was being fed bad 'zoo food' & was sick, no one would ever dream of saying 'switching him to his wild diet & mimicking his natural environment is low risk'…maintaining bad habits IS a major risk. That doesn't mean it is the be-all end-all approach to medicine, but returning to baseline healthy habits should not have the work risky associated with it (IMHO)...

    "we would need more data" - By that standard, what 'data' did we ever have justifying (most) neolithic dietary & lifestyle habits? [or even suggesting they could plausibly be healthy?]

    Your blog is careful to distinguish between speculation and established fact (the latter being quite rare of course)….but in between there is a mountain of reason to move one way or another.
    For the sake of argument, what hypothetical situation would have to arise for your to tell a someone 'hey, I wouldn't worry about consuming gluten-containing grains?"…I haven't come up with one where I'd feel justified. Can you?

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  12. I'm a person who has been gluten free since the mid 80's & diagnosed by biopsy in 1990. I had psych issues. Heard auditory hallucinations which I think may be linked to B-12 deficiency. What made me go on a gf diet was horrible, terrible migraines that wouldn't let up. Migraines and bloating. I have a copy of an article by Dr. Dohan. It's a commencement address in which he describes how he made the connection between gluten sensitivity and schizophrenia. You might want to consider that the inflammation might be significant in itself. I was a long time member of the celiac on - line support group and there were a few autism researchers who were curious about the link also because of the gf /cf autism diet. So there has to be something more. My first clue when I was sick was a positive response to niacin. (which scared the sh*! out of me, as my psych dx back in the '70s was depression. But there were those voices). But niacin worked. Excluding grains worked also, very well, until I reached meno in the 1990s. Then I had to go looking again.

    I have a small, healed over bifida at the base of my spine. So when I got reading about the folate/autism connection, I decided to do a little more investigation. My older brother has already had 2 blood clots, so I convinced my doctor to test me genetically. I have the A1298C variant courtesy of both my mother and father. And I'm pretty sure that niacin is necessary for the proper functioning of the BH4 cycle. I'm not shilling for anybody, I'm just thinking that I'm part of a particular subset that is more vulnerable. Incidentally, that inflammation...I didn't get a handle on it till I revisited my father's gout...he loved beans, but they didn't love him back. I'm not intolerant of just soy and soybeans, and soybean oil, but all legumes. Even guar gum. Because in the 1990s I was thinking I was probably in the autistic spectrum, another symptomatic label, I had come something called purine autism, or purine metabolic defect. In England, there's an organization called PUMPA. There's not much info on this side of the ocean. It kind of pulls everything together for me. Too much nitrogen in my blood, not enough niacin to clear it out. Intestinal damage (biopsy proven) that could cause malabsorption of nutrients including B -12.

    Interested to hear your thoughts.

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  13. Love your posts. Mental illness runs in my husband's family and I watched as bipolar disorder took hold of my husband - suffering panic attacks, extreme highs and lows and receiving little help from the various professionals he sought help from. Then my child was diagnosed with celiac disease - our family went gluten free to support our child -and after a week of sever and scary withdrawal symptoms, my husband's mental health issues started to fade while his aawareness became heightened. A year later, now gluten and (mostly) casein free - he has "control" of his disorder, it is not gone but it is in check as long as he strictly gluten free and better yet when dairy/casein free. If he accidentally gets glutened (or intentional cheats) - The symptoms return.

    My point....yes - test, test, test! The cost of the blood work is minimal in comparison to lifelong meds. But if gluten is a factor, long term dietary support and nutritional counseling services are crucial for the patient who may suffer when gluten free is done wrong and who doesn't always have the ability to chose responsibly.

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    1. Glad to hear your husband is doing well! Unfortunately, gluten intolerance or celiac disease don't show up on blood tests a lot of the times. Such a false-negative test is what kept me sick for over 10 years, thinking that I wasn't celiac (only a genetic test revealed it, recently). The surest way is to cut down offending foods for at least 30 days and see how it goes, IMHO.

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