Wheat and Schizophrenia

I'm in the middle of an introduction to vegetable oils post, but in the midst of tweaking that one, my youngest woke up from her nap, and I moved to the family room to observe her toddling about while I glanced at this seriously interesting paper, Genetic Hypothesis of Idiopathic Schizophrenia: It's Exorphin Connection. Free full text! Click the gray box on the upper right.

Schizophrenia is an unfortunate brain disease. Inherited often, progressive, presents usually with social withdrawal, paranoia, hearing voices, that sort of thing. After a while you get a kind of "burnout" effect where the voices and whatnot lessen, but the afflicted is left with all the negative symptoms of social withdrawal, thought blocking, and an inexpressiveness known as "flat affect." MRI of the brain will show "large ventricles" at this point, meaning cell death (brain damage) has caused the active, lively part of the brain to shrink. Dementia, basically. You'll see schizophrenia in any large public park in any major city. Go ask the guy on the bench with holey shoes if he wants a sandwich, and see what he says. If it's paranoid meaningless word salad, that's schizophrenia, most likely. He had parents, brothers, sisters, maybe even a college degree. There aren't enough group homes, even if he were willing to stay.

Anyway, most of the research is focused on dopamine and genetic polymorphisms of the receptor (yawn), some on acetylcholine, histamine, serotonin. The usual questions about ineffective brain chemistry. The usual treatment is neuroleptic medication (hopefully decreases excess dopamine in the right place and leaves it well enough alone in other corners of the brain). Read a popular press book called "The Food-Mood Connection" which sounds like my sort of book, really, until the the author (who has a PhD of some sort!) explained that schizophrenia in a certain case was caused by childhood teasing. Poor man was treated with horrible prescription medicine and his genetics were examined, but I suppose some serious teasing psychoanalysis would have cured that schizophrenia eventually...it must have been his mother, come to think of it.

Anyway, there's a funny thing about schizophrenia, turns out that quite a few of the adult schizophrenics on Handford's inpatient unit in 1967 happened to have a major history of celiac disease (gluten/wheat intolerance) as children. As in 50-100 times the amount of celiac disease that one would expect by chance. Celiac doctors also noticed their patients were schizophrenic about 10X as often as the general population. That's a lot!

Allow me to paraphrase and expand on Table 1 of this paper, "Major Evidence that Peptides from Grain Glutens Evoke Idiopathic Schizophrenia in Those with Its Genotype"

1) In the 1960s, many observations suggested celiac disease and schizophrenia shared some genes. The role of gluten in schizophrenia was examined.
2) Epidemiologic studies showed a strong, dose-dependent relationship between grain intake and schizophrenia (Pacific islanders who ate no wheat had extremely rare occurence of schizophrenia - 2 in 65,000 rather than about 1 in 100 as we have in the grain-eating West. Then the same islanders changed their diet and began eating wheat - and schizophrenia became common).
3) Clinical trials and showed that gluten made new-onset acutely ill schizophrenics worse. Only occasional long-term patients responded to gluten restriction (remember, the affected brain cells of the long-term schizophrenics are already dead, so getting rid of the possible poison that killed the cells won't make much difference).
4) NIH investigators looked for poisonous protein fragments derived from gluten, gliadin, and casein. They found them - potent opiate (yes, opiate as in morphine. Or heroin) analogs they called "exorphins." They did these studies in rats, and I've read several of them. Very creepy. Turns out, you take wheat gluten, add stomach enzymes, and you end up with fragments of proteins that are potent opiates (1). The cute thing is these fragments aren't digested by the small intestine and definitely end up in the body and brain of rats that are fed gluten orally. Inject these same proteins directly into the brains of poor unfortunate rats, and you get rat seizures.
5) People with schizophrenia have a lot of these opioid-like small gluten-derived peptides in their urine. Way more than people without schizophrenia.


Let me review what is perhaps the most important part of the paper - a gluten-free diet definitely improved some of the new-onset schizophrenics on the inpatient unit. Not all of them. But 2 out of 17 or so. Putting back the wheat made the affected a lot worse. 115 patients on a locked ward were all given a gluten free milk free diet (remember the casein issue). They were released into the community (got better?) on average twice as fast as the similar patients on another, diet as usual ward (p=.009). It is of note that repeat studies didn't show the same thing, but instead of 17 or 115 patients, these studies had 4 or 8 patients, and they used chronic schizophrenics (end stage, when the brain cells are already gone).

Historically, prior to WWII, when grain consumption was super-high and neuroleptics (those medications, as you recall, which affect brain dopamine levels and are used to treat schizophrenia) did not yet exist, there are reports of schizophrenics having marked, unexplained fluctuations in weight and gut symptoms, poor iron absorption just like celiac sufferers, and "post-mortem abnormalities like those subsequently discovered in celiac patients." Why aren't these found now? Well, it turns out that a side effect of neuroleptics is that they decrease the permeability of the gut. Meaning gluten may not be able to weasel through quite so easily.

Which begs the question, is that the side effect? Or perhaps the principle effect?
Who knows?

Not psychiatrists in 2010. The paper (from 1988) finishes by suggesting a number of methods to investigate this connection further. One of the suggestions was morally bankrupt (feed the identical twins of schizophrenics a high gluten diet to see what happens!), but intriguing. That study wasn't done (fortunately). Nor, looking at pubmed (via eCommons), were any others (that I could find. I'm not the wiliest research paper discoverer so I might have missed one). The article is mentioned in a few review articles, and schizophrenics were left to eat wheat in peace.

Edit: I shouldn't be such a cynic, and I should search harder before I post - Here are more recent studies, including one from last month (Thanks to the commenter for the link - why I love blogging. Interactive! Editable! We can all stand on eachother's shoulders and the shoulders of past giants). All told, they throw out some more "biochemical smoke" about the link between schizophrenia and gluten:

Markers of Gluten Sensitivity and Celiac Disease in Recent-Onset Psychosis and Multi-Episode Schizophrenia: Conclusions - Individuals with recent-onset psychosis and with multi-episode schizophrenia who have increased antibodies to gliadin may share some immunologic features of celiac disease, but their immune response to gliadin differs from that of celiac disease.

Novel immune response to gluten in individuals with schizophrenia: The researchers here looked at all sorts of different anti-gliadin antibodies and celiac disease associated biomarkers (meaning some different antibodies and also specific celiac MHC genes - basically genetic predispositions to have autoimmune response to wheat). They also did some fancy chromatography to find if the schizophrenic's blood reacted to other wheat proteins, and then it sounds like they used "peptide mass mapping" to figure out what the wheat proteins were that the schizophrenics were reacting to - and the results were... schizophrenics of the wheat-reactive subtype had lots of anti-wheat protein immune response, and a lot of them were completely different than those found in celiac disease.

A Case Report of the Resolution of Schizophrenic Symptoms on a Ketogenic Diet That link is to the full text. It doesn't need much translating to make it more understandable - the title says it all.

This article from 2006 is also cited often, and I did look at it before I posted the first time, but it doesn't add that much: The gluten connection: the association between schizophrenia and celiac disease. Basically it says there are case reviews in the literature that show dramatic improvements in schizophrenia on a gluten-free diet (these studies were the same ones commented on in the original paper that I reviewed in detail at the top of the post) and that only a subset of schizophrenics are affected. (The researchers in residency would always refer to them as "the schizophrenias" rather than "schizophrenia." It is several different diseases, lumped into a similar symptom cluster because we don't fully understand the pathology, and in psychiatry, lumping is done by symptoms, as that made the most sense for research purposes.)

I would love to take a look at this one, but my institutional access won't get me there for the moment - A PILOT STUDY OF THE KETOGENIC DIET IN SCHIZOPHRENIA
PACHECO et al. Am J Psychiatry.1965; 121: 1110-1111. We'll track it down eventually.


The bottom line? Schizophrenia is a progressive and destructive psychotic mental illness that, at the moment, can sometimes be managed with medications and community therapeutic support, but does not have a cure. Some people with schizophrenia are bound to have the gluten-sensitive variety, and a few lucky souls apparently have been cured among the case reports. A gluten-free diet is safe and doesn't have side effects - I don't see a good argument against giving it a try for anyone with schizophrenia who is willing to give it a go, at least for a few months (how long? 3? 5? I'll look more into that one), while more data is being gathered. (You *might* get even better results with stabilizing your GABA receptors and whatnot via a ketogenic (very low carbohydrate) diet. More on this later! Very little research in psychiatry...) The worst thing that happens is you find you are not one of the gluten-sensitive schizophrenics, and you've gone without bread for a little while. The best thing that happens is that your symptoms get better, possibly quite a lot better.