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.
Showing posts sorted by relevance for query schizophrenia. Sort by date Show all posts
Showing posts sorted by relevance for query schizophrenia. Sort by date Show all posts
Saturday, June 19, 2010
Thursday, May 5, 2011
Nature and Nurture - The Basis of Mental Illness
"So what's more important, doc? Genes or how you were raised?"
I'm asked that question or a variation thereof quite frequently. Some people wonder how much they can do to truly change, and others are concerned about the risk of mental illness their children might have. It's an important question, and while the simple answer is, "both are important," the complicated answer describes the very essence of the biology of psychopathology. And in that biology you also see the clues for cures.
So, yes, a molecular biology-heavy post. That calls for some music. Hmmm. The Airborne Toxic Event - Changing (right click to open in new tab).
Mental illness, as it turns out, has some of the highest genetic loading of any common illness*. Of course there are some rather famous single-gene disorders (like Huntington's or cystic fibrosis) whose risk seems to be almost entirely genetic, but right up there is schizophrenia, where 80% of the risk is genetic. That means if you have no relatives with schizophrenia, it is unlikely you will develop it. Genetic loading counts for a large portion of the risk for bipolar disorder and major depressive disorder as well.
Schizophrenia is the most studied of many of these disorders at a basic science level, I would say. And it is pretty clear that patients with schizophrenia and their close relatives have decreased prefrontal cortical efficiency. Since the prefrontal cortex is responsible for planning, elements of memory, controlling impulsivity, predicting outcomes, and many other important parts of thinking, having an inefficient cortex is very problematic, to say the least. Here's a slide showing the prefrontal network in schizophrenia:
You can click for a bigger version, of course, but the details aren't important for this blog post - the slide is really just a demonstration of the complexity and some of the neurons involved.
So, if schizophrenia is genetic, and we know the location in the brain where the first problems arise, can't we nail down the gene? In the last 5 years we've developed the capability to sequence genomes and check out genetic polymorphisms (differences in genes between one person and another) both rapidly and cheaply. This has enabled us to do a brute force hack of the genome, looking at the genes of many families and finding those genes that are common to families with schizophrenia and are absent in families without schizophrenia. I wrote about a similar study done for migraines a while back.
These types of genetic studies are fantastic - but you end up with tens of thousands of data points, so you can't possibly use the typical p value cut-off of 95% probability that the results are not due to chance (that's a decent enough definition for our purposes today - here's the real definition of p value). With that many data points and a p<0.05 cut-off, you are definitely going to end up with hundreds or even thousands of "statistically significant" correlations due to random chance. Therefore for studies like these, the cut-off is much, much smaller -- often <10 to the -8, for example.
Well, these studies have been done for schizophrenia, and two genes popped up, and they are not particularly exciting. Certain variants of the genes for NRGN and TGF4 were found to have an odds ratio of 1.21 and 1.33 for developing schizophrenia. That means if you have those genetic variants, instead of having a 0.5-1% of developing schizophrenia like the general population, you have a 0.6-1.2% chance of developing it (or thereabouts). So not a particularly risky genetic lot to draw!
What did we find out from these studies? Individual genes don't matter that much in the development of schizophrenia. But wait - didn't we just say that the risk for schizophrenia is 80% genetic? Well, let me throw out one more intimidating slide - a picture of the ErbB4 signaling pathway (this is just one bit of nerve signaling in certain areas, just one path by which signals get transmitted in a certain set of neurons - click for a better resolution, but again the big picture is far, far more important here than the details).
The Strokes - Under Cover of Darkness
The great thing about the brute force hack genetic studies is that if you have a computer, thousands of data points, and some grad students, you can just as easily look for correlations of not only 1, but 2 or 3 or 4 genetic polymorphisms. And when the schizophrenia researchers did that with the various genes associated with the ErbB4 signaling pathway, they hit the jackpot. All these genes interact with each other, like links in a chain. Break one link, and the brain can compensate. But break two links (so have two unfortunate genetic polymorphisms in this pathway), and your signaling becomes more inefficient. Your risk of schizophrenia goes up 8-fold. Break three links in the chain, and the risk for schizophrenia goes up 27-fold.
I'm using schizophrenia as an example - and many of the same genes and a severe inefficiency of the prefrontal cortical network are implicated in autism, by the way. Autism is likely to be, in a sense, a variant of schizophrenia that strikes much earlier in life. A similar story (but in different areas of the brain and with different specific signaling pathways) can be told for anxiety, depression, ADHD…
For heaven's sake I don't care how many rock songs you link, who cares and what does this have to do with nutrition and environment and blah blah blah…
All these pathways and all these signals have been running along using the nutrients and lifestyle we have evolved for thousands and thousands of generations. The signaling depends upon having magnesium, zinc, cholesterol, omega 3s and arachidonic acid, vitamin D, creatine, CoQ10, restorative sleep, appropriate lighting, proper energy efficiency and neuronal recovery and repair. Some of us are nearly bullet-proof. We have lickety-split efficient neural networks that seem to be able to run on garbage. Others of us have some sort of problem somewhere, and we need all our compensatory mechanisms working, and we need to give our neural networks all the raw materials in the right amounts.
My next post will focus more on depression, trauma, and the nitty-gritty of epigenetics. In the mean time let me reiterate:
What we do matters. What we eat matters. To be the optimal human being from the genetic hand we were given, we'd best live in a way that compliments our biochemical programming.
* Much of the information I'm presenting today is from lectures I attended last week by Carl Salzman, MD (of Harvard), Jeffrey Lieberman MD (of Columbia), and Daniel Weinberger MD (of NIMH and NIH) - all are world famous researchers in psychosis and psychiatry. I had the pleasure of attending many lectures by Dr. Salzman during my residency. These lectures were not sponsored in any fashion by the pharmaceutical industry.
I'm asked that question or a variation thereof quite frequently. Some people wonder how much they can do to truly change, and others are concerned about the risk of mental illness their children might have. It's an important question, and while the simple answer is, "both are important," the complicated answer describes the very essence of the biology of psychopathology. And in that biology you also see the clues for cures.
So, yes, a molecular biology-heavy post. That calls for some music. Hmmm. The Airborne Toxic Event - Changing (right click to open in new tab).
Mental illness, as it turns out, has some of the highest genetic loading of any common illness*. Of course there are some rather famous single-gene disorders (like Huntington's or cystic fibrosis) whose risk seems to be almost entirely genetic, but right up there is schizophrenia, where 80% of the risk is genetic. That means if you have no relatives with schizophrenia, it is unlikely you will develop it. Genetic loading counts for a large portion of the risk for bipolar disorder and major depressive disorder as well.
Schizophrenia is the most studied of many of these disorders at a basic science level, I would say. And it is pretty clear that patients with schizophrenia and their close relatives have decreased prefrontal cortical efficiency. Since the prefrontal cortex is responsible for planning, elements of memory, controlling impulsivity, predicting outcomes, and many other important parts of thinking, having an inefficient cortex is very problematic, to say the least. Here's a slide showing the prefrontal network in schizophrenia:
You can click for a bigger version, of course, but the details aren't important for this blog post - the slide is really just a demonstration of the complexity and some of the neurons involved.
So, if schizophrenia is genetic, and we know the location in the brain where the first problems arise, can't we nail down the gene? In the last 5 years we've developed the capability to sequence genomes and check out genetic polymorphisms (differences in genes between one person and another) both rapidly and cheaply. This has enabled us to do a brute force hack of the genome, looking at the genes of many families and finding those genes that are common to families with schizophrenia and are absent in families without schizophrenia. I wrote about a similar study done for migraines a while back.
These types of genetic studies are fantastic - but you end up with tens of thousands of data points, so you can't possibly use the typical p value cut-off of 95% probability that the results are not due to chance (that's a decent enough definition for our purposes today - here's the real definition of p value). With that many data points and a p<0.05 cut-off, you are definitely going to end up with hundreds or even thousands of "statistically significant" correlations due to random chance. Therefore for studies like these, the cut-off is much, much smaller -- often <10 to the -8, for example.
Well, these studies have been done for schizophrenia, and two genes popped up, and they are not particularly exciting. Certain variants of the genes for NRGN and TGF4 were found to have an odds ratio of 1.21 and 1.33 for developing schizophrenia. That means if you have those genetic variants, instead of having a 0.5-1% of developing schizophrenia like the general population, you have a 0.6-1.2% chance of developing it (or thereabouts). So not a particularly risky genetic lot to draw!
What did we find out from these studies? Individual genes don't matter that much in the development of schizophrenia. But wait - didn't we just say that the risk for schizophrenia is 80% genetic? Well, let me throw out one more intimidating slide - a picture of the ErbB4 signaling pathway (this is just one bit of nerve signaling in certain areas, just one path by which signals get transmitted in a certain set of neurons - click for a better resolution, but again the big picture is far, far more important here than the details).
The Strokes - Under Cover of Darkness
The great thing about the brute force hack genetic studies is that if you have a computer, thousands of data points, and some grad students, you can just as easily look for correlations of not only 1, but 2 or 3 or 4 genetic polymorphisms. And when the schizophrenia researchers did that with the various genes associated with the ErbB4 signaling pathway, they hit the jackpot. All these genes interact with each other, like links in a chain. Break one link, and the brain can compensate. But break two links (so have two unfortunate genetic polymorphisms in this pathway), and your signaling becomes more inefficient. Your risk of schizophrenia goes up 8-fold. Break three links in the chain, and the risk for schizophrenia goes up 27-fold.
I'm using schizophrenia as an example - and many of the same genes and a severe inefficiency of the prefrontal cortical network are implicated in autism, by the way. Autism is likely to be, in a sense, a variant of schizophrenia that strikes much earlier in life. A similar story (but in different areas of the brain and with different specific signaling pathways) can be told for anxiety, depression, ADHD…
For heaven's sake I don't care how many rock songs you link, who cares and what does this have to do with nutrition and environment and blah blah blah…
All these pathways and all these signals have been running along using the nutrients and lifestyle we have evolved for thousands and thousands of generations. The signaling depends upon having magnesium, zinc, cholesterol, omega 3s and arachidonic acid, vitamin D, creatine, CoQ10, restorative sleep, appropriate lighting, proper energy efficiency and neuronal recovery and repair. Some of us are nearly bullet-proof. We have lickety-split efficient neural networks that seem to be able to run on garbage. Others of us have some sort of problem somewhere, and we need all our compensatory mechanisms working, and we need to give our neural networks all the raw materials in the right amounts.
My next post will focus more on depression, trauma, and the nitty-gritty of epigenetics. In the mean time let me reiterate:
What we do matters. What we eat matters. To be the optimal human being from the genetic hand we were given, we'd best live in a way that compliments our biochemical programming.
* Much of the information I'm presenting today is from lectures I attended last week by Carl Salzman, MD (of Harvard), Jeffrey Lieberman MD (of Columbia), and Daniel Weinberger MD (of NIMH and NIH) - all are world famous researchers in psychosis and psychiatry. I had the pleasure of attending many lectures by Dr. Salzman during my residency. These lectures were not sponsored in any fashion by the pharmaceutical industry.
Tuesday, September 14, 2010
Schizophrenia Round-up and Back to School
Today I went back to school. Every fall, I help teach the introduction to psychiatry class for the second year medical students at my institution. I work with a small group, teaching basic interviewing and write-up skills. Today was a large lecture, though, so I got to be in the audience, thumbing through this month's stack of journals while the students were Introduced to Psychiatry.
There are a few interesting papers in the Archives of General Psychiatry this month, which isn't always the case. The Archives tends to have really tedious genetic polymorphism and functional MRI studies out the wazoo. You get paper headings like "Reduced brain white matter integrity in trichotillomania." Which, believe me, is not even as interesting as it sounds. Still, the Archives is an excellent journal and they don't accept horrible studies, just boring ones.
The first interesting one is "Modification of Cognitive Performance in Schizophrenia by Complexin 2 Gene Polymorphisms." (I know, it sounds really boring! But give it a chance.) Turns out this group in Germany put together a database of genetic data for schizophrenia research. 23 different research centers compiled the genetic data of 1071 patients with schizophrenia and 1079 controls. Then they threw the DNA into their big machines, and out pops loads of data. Over 3000 phenotypic data points for each patient! There's a specific gene, complexin 2, which codes for a type of protein that regulates how synaptic signaling happens in the brain. Specifically, complexin 1 and 2 control the release of the soluble-N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE). Differences in the complexin 2 proteins and mRNA have been noted in previous autopsy studies of schizophrenics, so the genes were an obvious place to look. In those autopsy studies, a significant decrease in complexin 2 was found in regions of the brain that are specifically damaged in schizophrenia (like the dorsolateral prefrontal cortex and the hippocampus). This same protein/gene expression was found to be decreased in studies of bipolar disorder, Alzheimer's, and Huntington's disease, but in different parts of the brain more affected by those other disorders. All of the disorders, though , have symptoms of cognitive impairment, meaning in the advanced stages of each disease, you just can't think as clearly as you once did. And, sure enough, when they traced the schizophrenia patients who had certain types of poorly expressed complexin 2 gene, they tended to have more cognitive impairment than the other schizophrenia patients
Okay, that's not particularly interesting, at least from an evolutionary medicine standpoint. Except I couldn't help but notice all those disorders up there (except bipolar disorder) are ones I've discussed in the blog who have some evidence to link them to wheat or to metabolic syndrome. Mice with knocked out complexin 2 genes have a few issues, but apparently not cognitive ones. Until you take those mice and deprive them of their mothers. Then the complexin 2 knockout mice get mouse dementia, of sorts. It's the genetic difference plus the stress that seems to cause the disease. Good old two-hit hypothesis.
Next up is one that will warm the cockles of your sun-worshiping hearts. "Neonatal Vitamin D Status and Risk of Schizophrenia: A Population-Based Case Control Study." Thank you, Netherlands, who apparently keeps dried blood samples from all the babies born there. The researchers took 424 individuals with schizophrenia and 424 sex and age matched controls, and pulled their blood samples from the big bank 'o blood, and figured out each neonate's vitamin D levels.
Vitamin D is a big suspect in schizophrenia for the following reasons - Vitamin D undoubtedly plays a role in the development of the brain. People born in winter and spring have higher risk for developing schizophrenia, and the farther you are born from the equator, the more likely your birth month will be a factor. Immigrants with dark skin who move to northern countries also have children with higher rates of schizophrenia. In addition, city kids are more likely to develop schizophrenia compared to country kids. This study is the first time someone was able to go back and directly check the vitamin D levels from neonatal blood of people who later get schizophrenia.
The average level of vitamin D (measured as 25 (OH) vitamin D3) varied widely from winter to summer, with babies born in March (cases and controls) having the lowest levels, around 26 (deficient), and babies born in August having an average level of nearly 50 (which is good). One caveat - the actual level may be misleading. The level might degrade over time, and these samples were up to 27 years old when tested. However, since there were matched controls of the same age for each patient, it was presumed that the degradation would be the same for both sets of data.
But now the key results - babies born with a vitamin D level of 46.5 had the lowest risk for schizophrenia (again, that might not be the actual level, measured so many years later). The babies within the lowest two quintiles (the lowest 40%) of vitamin D levels had significantly increased risk. Surprisingly, babies in the highest quintile, with the highest vitamin D levels, had higher risk too. The researchers were able to go back and check for all sorts of variables which might confound things - UV light therapy at birth for high bilirubin might affect vitamin D levels, for example, admission to the NICU, age, sex, etc. etc. and nothing seemed to change the overall U-shaped data curve, with the "sweet spot" between the 3rd and 4th quintiles of vitamin D levels. Now the researchers wisely emphasized caution when considering these results - it's an observational study, and there can be plenty of confounders nobody thought of. However, if the cause-effect relationship holds true, the researchers suggest that mere vitamin D supplementation in dark-skinned immigrants in northern countries could reduce the incidence of schizophrenia in those populations by "a staggering 87%."
A third study in this same issue is called "Birth Weight, Schizophrenia, and Adult Mental Disorder," where the researchers did pretty much what you might think, but on a very large scale. They followed 1.49 million single babies born in Sweden and Denmark between 1973 and 1986. Both countries have "comprehensive national registers of psychiatric treatment." In 2002 (Sweden) and 2005 (Denmark), these countries had 5,445 registered cases of schizophrenia and 57,455 cases of "any adult psychiatric disorder." (My first thought - 5445 cases of schizophrenia seems low out of 1.49 million, and it is only 0.37 %. There should be around 14,900 cases as the worldwide prevalence is right around 1%. Just something to keep in mind!)
The results - birth weight of less than 2500 grams (5 pounds, 8 ounces) in these babies translated into a higher risk for schizophrenia, and the risk actually decreases (for schizophrenia) as the birth weights go up. The heavier the kiddos were, the lower the risk, all the way up to >4500g (that's 9 pounds, 15 ounces). Low birth weight also translated into a higher risk for all mental disorders, including an aggregate "all diagnoses" group and for each subgroup of substance abuse, mood disorders (like major depression and bipolar disorder), and anxiety disorders. And, indeed, in the subgroups, the higher the birth weight (all the way up to the megababy 10 pounder and above group), the lower the risk.
Interesting! Obviously, very low birth weight is associated with all sorts of issues - premature delivery, infection, brain hemorrhages - any or all of these could have stress on the baby's forming brain. It is interesting that the heavy babies had lower risk than the so-called normal weight babies. I actually would have expected another "U-shaped" curve here. But no! Still, there could be huge confounders. High birth weights are associated with gestational diabetes, but I'm not sure how common that was in Sweden and Denmark back in the 70s and 80s, so maybe it wouldn't be as much of a factor as I would have thought.
One of those confounding factors could actually be vitamin D! This study showed maternal vitamin D intake associated with birth weight (low vitamin D = lower average birth weight), and it was postulated that adequate vitamin D intake protects moms from infections. This study is a little more interesting - white women with a vitamin D level from 60-80 had the lowest risk of having small for gestational age babies, but there was no relationship between vitamin D levels and birth weight in black women. And, of course Don Matesz blogged today about this study, showing that pregnant women who took 4000 IU vitamin D daily had a lower risk of preterm birth.
All told, several interesting findings this month. Don't get vitamin D deficient! But try not to go nuts with the supplementation either. Levels are best! Ask your doctor, or go to Grassroots Health to order a home test. I tend to aim for a level of 50, but perhaps pregnant women would want to go just a bit higher (Caucasian women may want to aim for that 60-80 range). Be sure you are getting your K2 also! I always use pastured butter, but I also have a vitamin D supplement that comes with K2 in it.
Believe it or not, there is another blog-worthy study in this month's Archives, but I will save it for later in the week. See you then!
There are a few interesting papers in the Archives of General Psychiatry this month, which isn't always the case. The Archives tends to have really tedious genetic polymorphism and functional MRI studies out the wazoo. You get paper headings like "Reduced brain white matter integrity in trichotillomania." Which, believe me, is not even as interesting as it sounds. Still, the Archives is an excellent journal and they don't accept horrible studies, just boring ones.
The first interesting one is "Modification of Cognitive Performance in Schizophrenia by Complexin 2 Gene Polymorphisms." (I know, it sounds really boring! But give it a chance.) Turns out this group in Germany put together a database of genetic data for schizophrenia research. 23 different research centers compiled the genetic data of 1071 patients with schizophrenia and 1079 controls. Then they threw the DNA into their big machines, and out pops loads of data. Over 3000 phenotypic data points for each patient! There's a specific gene, complexin 2, which codes for a type of protein that regulates how synaptic signaling happens in the brain. Specifically, complexin 1 and 2 control the release of the soluble-N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE). Differences in the complexin 2 proteins and mRNA have been noted in previous autopsy studies of schizophrenics, so the genes were an obvious place to look. In those autopsy studies, a significant decrease in complexin 2 was found in regions of the brain that are specifically damaged in schizophrenia (like the dorsolateral prefrontal cortex and the hippocampus). This same protein/gene expression was found to be decreased in studies of bipolar disorder, Alzheimer's, and Huntington's disease, but in different parts of the brain more affected by those other disorders. All of the disorders, though , have symptoms of cognitive impairment, meaning in the advanced stages of each disease, you just can't think as clearly as you once did. And, sure enough, when they traced the schizophrenia patients who had certain types of poorly expressed complexin 2 gene, they tended to have more cognitive impairment than the other schizophrenia patients
Okay, that's not particularly interesting, at least from an evolutionary medicine standpoint. Except I couldn't help but notice all those disorders up there (except bipolar disorder) are ones I've discussed in the blog who have some evidence to link them to wheat or to metabolic syndrome. Mice with knocked out complexin 2 genes have a few issues, but apparently not cognitive ones. Until you take those mice and deprive them of their mothers. Then the complexin 2 knockout mice get mouse dementia, of sorts. It's the genetic difference plus the stress that seems to cause the disease. Good old two-hit hypothesis.
Next up is one that will warm the cockles of your sun-worshiping hearts. "Neonatal Vitamin D Status and Risk of Schizophrenia: A Population-Based Case Control Study." Thank you, Netherlands, who apparently keeps dried blood samples from all the babies born there. The researchers took 424 individuals with schizophrenia and 424 sex and age matched controls, and pulled their blood samples from the big bank 'o blood, and figured out each neonate's vitamin D levels.
Vitamin D is a big suspect in schizophrenia for the following reasons - Vitamin D undoubtedly plays a role in the development of the brain. People born in winter and spring have higher risk for developing schizophrenia, and the farther you are born from the equator, the more likely your birth month will be a factor. Immigrants with dark skin who move to northern countries also have children with higher rates of schizophrenia. In addition, city kids are more likely to develop schizophrenia compared to country kids. This study is the first time someone was able to go back and directly check the vitamin D levels from neonatal blood of people who later get schizophrenia.
The average level of vitamin D (measured as 25 (OH) vitamin D3) varied widely from winter to summer, with babies born in March (cases and controls) having the lowest levels, around 26 (deficient), and babies born in August having an average level of nearly 50 (which is good). One caveat - the actual level may be misleading. The level might degrade over time, and these samples were up to 27 years old when tested. However, since there were matched controls of the same age for each patient, it was presumed that the degradation would be the same for both sets of data.
But now the key results - babies born with a vitamin D level of 46.5 had the lowest risk for schizophrenia (again, that might not be the actual level, measured so many years later). The babies within the lowest two quintiles (the lowest 40%) of vitamin D levels had significantly increased risk. Surprisingly, babies in the highest quintile, with the highest vitamin D levels, had higher risk too. The researchers were able to go back and check for all sorts of variables which might confound things - UV light therapy at birth for high bilirubin might affect vitamin D levels, for example, admission to the NICU, age, sex, etc. etc. and nothing seemed to change the overall U-shaped data curve, with the "sweet spot" between the 3rd and 4th quintiles of vitamin D levels. Now the researchers wisely emphasized caution when considering these results - it's an observational study, and there can be plenty of confounders nobody thought of. However, if the cause-effect relationship holds true, the researchers suggest that mere vitamin D supplementation in dark-skinned immigrants in northern countries could reduce the incidence of schizophrenia in those populations by "a staggering 87%."
A third study in this same issue is called "Birth Weight, Schizophrenia, and Adult Mental Disorder," where the researchers did pretty much what you might think, but on a very large scale. They followed 1.49 million single babies born in Sweden and Denmark between 1973 and 1986. Both countries have "comprehensive national registers of psychiatric treatment." In 2002 (Sweden) and 2005 (Denmark), these countries had 5,445 registered cases of schizophrenia and 57,455 cases of "any adult psychiatric disorder." (My first thought - 5445 cases of schizophrenia seems low out of 1.49 million, and it is only 0.37 %. There should be around 14,900 cases as the worldwide prevalence is right around 1%. Just something to keep in mind!)
The results - birth weight of less than 2500 grams (5 pounds, 8 ounces) in these babies translated into a higher risk for schizophrenia, and the risk actually decreases (for schizophrenia) as the birth weights go up. The heavier the kiddos were, the lower the risk, all the way up to >4500g (that's 9 pounds, 15 ounces). Low birth weight also translated into a higher risk for all mental disorders, including an aggregate "all diagnoses" group and for each subgroup of substance abuse, mood disorders (like major depression and bipolar disorder), and anxiety disorders. And, indeed, in the subgroups, the higher the birth weight (all the way up to the megababy 10 pounder and above group), the lower the risk.
Interesting! Obviously, very low birth weight is associated with all sorts of issues - premature delivery, infection, brain hemorrhages - any or all of these could have stress on the baby's forming brain. It is interesting that the heavy babies had lower risk than the so-called normal weight babies. I actually would have expected another "U-shaped" curve here. But no! Still, there could be huge confounders. High birth weights are associated with gestational diabetes, but I'm not sure how common that was in Sweden and Denmark back in the 70s and 80s, so maybe it wouldn't be as much of a factor as I would have thought.
One of those confounding factors could actually be vitamin D! This study showed maternal vitamin D intake associated with birth weight (low vitamin D = lower average birth weight), and it was postulated that adequate vitamin D intake protects moms from infections. This study is a little more interesting - white women with a vitamin D level from 60-80 had the lowest risk of having small for gestational age babies, but there was no relationship between vitamin D levels and birth weight in black women. And, of course Don Matesz blogged today about this study, showing that pregnant women who took 4000 IU vitamin D daily had a lower risk of preterm birth.
All told, several interesting findings this month. Don't get vitamin D deficient! But try not to go nuts with the supplementation either. Levels are best! Ask your doctor, or go to Grassroots Health to order a home test. I tend to aim for a level of 50, but perhaps pregnant women would want to go just a bit higher (Caucasian women may want to aim for that 60-80 range). Be sure you are getting your K2 also! I always use pastured butter, but I also have a vitamin D supplement that comes with K2 in it.
Believe it or not, there is another blog-worthy study in this month's Archives, but I will save it for later in the week. See you then!
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):
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.
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.
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.
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.
Thursday, October 6, 2011
Slam-dunked and Wheat Belly
All right. Work has been really, well, working me lately, so I've barely had time to sleep, much less to review papers, keep up with the blogosphere, and write.
I do like this song, though (right click to open in new tab): Days are Forgotten (and it is getting very difficult to find songs on youtube that will play without ads upfront - sorry if there is an ad on this one! It had a glitch and skipped the ad but might not work for everyone :()
Despite the time crunch, I did manage to squeeze in Wheat Belly over the weekend (most of it), and read the rest last night.
No, I don't like it.
No, I don't eat wheat as a rule, and I am not a grain industry shill.
But I don't feel I have to put my name out in support of a shoddy, sloppy book just because the overall message "wheat sux" agrees with my thoughts that wheat gluten and other wheat proteins likely are inflammatory in many people and cause problems for more than just those with celiac disease. I think most physicians and researchers with critical thinking skills will find this book useless and full of hyperbole. For those not taken in by the confident tone, it may do more harm than good.
Why don't I like Wheat Belly? In short, it is the carelessness and simplicity of the message. Hyperbole and poorly supported, confident claims. Obesity and chronic illness is a complicated subject. It doesn't come down to wheat. Wheat isn't responsible (entirely) for "moobs" or the other too-cute phrases Dr. Davis churns out ad nauseum throughout the book.
An example? In chapter 4, Dr. Davis spends a bit of time discussing the evidence linking wheat to schizophrenia and addiction. I've discussed this issue at some length and noted the obvious circumstantiality of the evidence and the need for more research. (see Wheat and Schizophrenia and Wheat and Serious Mental Illness). And while Dr. Dohan (who was the major researcher who championed the wheat causes schizophrenia meme) felt he had evidence that schizophrenia has increased incidence in wheat-eating populations, most modern schizophrenia researchers make note that schizophrenia is pretty consistent in incidence across many populations - around 1%-1.3% incidence, in the developing world and in the Western world, in rice eating Chinese areas and the wheat-eating American Midwest.
Dr. Davis says: "while it seems unlikely that wheat exposure caused schizophrenia in the first place, the observations of Dr. Dohan and others suggest that wheat is associated with measurable worsening of symptoms." I don't get that quote at all. Is the incidence of schizophrenia higher in non-wheat eating countries or not? Do exorphins cause psychotic symptoms or not? Schizophrenia, after all, is defined by the symptoms. Something that "worsens" schizophrenia will cause schizophrenia, a symptomatically defined illness, as I've discussed earlier in my posts on cannabis.
But where I find the book to be critically annoying is in the discussion of addiction and opiates. Wheat, as we know, has break-down components that are exorphins, which activate the opiate receptors in the brain and nervous system (the same receptors that are activated by our natural endorphins, opium, morphine, heroin, percocet, and other opiate painkillers). The opiate pathway is part of the reward pathway in the brain, and is actually activated by anything "rewarding" - such as sex, exercise, drugs, gambling, and rock and roll.
Where I agree with Dr. Davis is that I have seen clinical evidence that some people seem to be "addicted" to wheat. Particularly night bread binge-eaters. They talk about bread much like one of my opiate addict patients would talk about oxycontin. They can't stop eating it even after they are full, and even when they desperately want to lose weight. They will leave their cozy house and pick up crackers, pretzels, fast food with fluffy bread, or a fresh loaf to eat at night. Critically, in certain cases (where more evidence-based methods have been tried), I've managed to stop these cravings and binge behaviors with naltrexone, which blocks the opiate receptors and short-circuits reward. The problem is, ALL reward is mediated through opiate and dopamine, so using naltrexone doesn't tell you that you've blocked specific wheat exorphins - maybe the person has a real jones for fresh steaming lovely bread for simple reward sake - like some people love chocolate, Pringles, or cocaine.
It's a good message, though, and something that should be researched. But then Dr. Davis comes up with this sentence (and also states he has seen the withdrawal and "brain fog" from wheat in "thousands of people"then later "I've personally witnessed hundreds of people…"), which is incredibly jarring and ruins the credibility of the message: "Let's pretend you're an inner-city heroin addict. You get knifed during a drug deal gone sour and get carted to the nearest trauma emergency room. Because you're high on heroin, you kick and scream at the ER staff trying to help you. So these nice people strap you down and inject you with a drug called naloxone, and you are instantly not high."
Naloxone (and it's orally administered cousin, naltrexone), is an opiate blocker, or "opiate antagonist." It will immediately knock opiates off the opiate receptor and put someone high on opiates into instant withdrawal. This is not only extremely unpleasant, it tends to make people very agitated, unhappy, and even violent. If you have to do it to save someone's life, you do it. If someone is overdosing on opiates and loses the chemical signal to breathe, it will be lifesaving. If someone is alert and active and still high on heroin, injecting someone with naloxone would be a galactically stupid thing to do, particularly if you were just injured in a knife fight and needed some painkilling. Injecting someone with naloxone will mean that the strong painkillers will not work in someone who will have a high tolerance to hospital painkillers.
Any emergency room physician, nurse, or doctor with a shred of ER experiecne will read that sentence in "Wheat Belly" and go, "huh? What is this guy talking about, and is he galactically stupid?"
Honestly, I think it is a throwaway line that was carelessly written and carelessly published. And other "paleo" books like "The Vegetarian Myth" are full of lines like that. But you know what, I have a much higher standard for a cardiologist than I do for a non-scientist like Lierre Keith. I want real science, real risks, real data. Not hyperbole and nonsense.
So no, I don't recommend Wheat Belly. And I don't recommend eating wheat either.
(Nor am I saying that Dr. Davis is stupid - far from it - just careless in his phrasing. If you are going to take on Conventional Wisdom of Healthy Whole Wheat, you really have to "bring it." It was not brought.)
I do like this song, though (right click to open in new tab): Days are Forgotten (and it is getting very difficult to find songs on youtube that will play without ads upfront - sorry if there is an ad on this one! It had a glitch and skipped the ad but might not work for everyone :()
Despite the time crunch, I did manage to squeeze in Wheat Belly over the weekend (most of it), and read the rest last night.
No, I don't like it.
No, I don't eat wheat as a rule, and I am not a grain industry shill.
But I don't feel I have to put my name out in support of a shoddy, sloppy book just because the overall message "wheat sux" agrees with my thoughts that wheat gluten and other wheat proteins likely are inflammatory in many people and cause problems for more than just those with celiac disease. I think most physicians and researchers with critical thinking skills will find this book useless and full of hyperbole. For those not taken in by the confident tone, it may do more harm than good.
Why don't I like Wheat Belly? In short, it is the carelessness and simplicity of the message. Hyperbole and poorly supported, confident claims. Obesity and chronic illness is a complicated subject. It doesn't come down to wheat. Wheat isn't responsible (entirely) for "moobs" or the other too-cute phrases Dr. Davis churns out ad nauseum throughout the book.
An example? In chapter 4, Dr. Davis spends a bit of time discussing the evidence linking wheat to schizophrenia and addiction. I've discussed this issue at some length and noted the obvious circumstantiality of the evidence and the need for more research. (see Wheat and Schizophrenia and Wheat and Serious Mental Illness). And while Dr. Dohan (who was the major researcher who championed the wheat causes schizophrenia meme) felt he had evidence that schizophrenia has increased incidence in wheat-eating populations, most modern schizophrenia researchers make note that schizophrenia is pretty consistent in incidence across many populations - around 1%-1.3% incidence, in the developing world and in the Western world, in rice eating Chinese areas and the wheat-eating American Midwest.
Dr. Davis says: "while it seems unlikely that wheat exposure caused schizophrenia in the first place, the observations of Dr. Dohan and others suggest that wheat is associated with measurable worsening of symptoms." I don't get that quote at all. Is the incidence of schizophrenia higher in non-wheat eating countries or not? Do exorphins cause psychotic symptoms or not? Schizophrenia, after all, is defined by the symptoms. Something that "worsens" schizophrenia will cause schizophrenia, a symptomatically defined illness, as I've discussed earlier in my posts on cannabis.
But where I find the book to be critically annoying is in the discussion of addiction and opiates. Wheat, as we know, has break-down components that are exorphins, which activate the opiate receptors in the brain and nervous system (the same receptors that are activated by our natural endorphins, opium, morphine, heroin, percocet, and other opiate painkillers). The opiate pathway is part of the reward pathway in the brain, and is actually activated by anything "rewarding" - such as sex, exercise, drugs, gambling, and rock and roll.
Where I agree with Dr. Davis is that I have seen clinical evidence that some people seem to be "addicted" to wheat. Particularly night bread binge-eaters. They talk about bread much like one of my opiate addict patients would talk about oxycontin. They can't stop eating it even after they are full, and even when they desperately want to lose weight. They will leave their cozy house and pick up crackers, pretzels, fast food with fluffy bread, or a fresh loaf to eat at night. Critically, in certain cases (where more evidence-based methods have been tried), I've managed to stop these cravings and binge behaviors with naltrexone, which blocks the opiate receptors and short-circuits reward. The problem is, ALL reward is mediated through opiate and dopamine, so using naltrexone doesn't tell you that you've blocked specific wheat exorphins - maybe the person has a real jones for fresh steaming lovely bread for simple reward sake - like some people love chocolate, Pringles, or cocaine.
It's a good message, though, and something that should be researched. But then Dr. Davis comes up with this sentence (and also states he has seen the withdrawal and "brain fog" from wheat in "thousands of people"then later "I've personally witnessed hundreds of people…"), which is incredibly jarring and ruins the credibility of the message: "Let's pretend you're an inner-city heroin addict. You get knifed during a drug deal gone sour and get carted to the nearest trauma emergency room. Because you're high on heroin, you kick and scream at the ER staff trying to help you. So these nice people strap you down and inject you with a drug called naloxone, and you are instantly not high."
Naloxone (and it's orally administered cousin, naltrexone), is an opiate blocker, or "opiate antagonist." It will immediately knock opiates off the opiate receptor and put someone high on opiates into instant withdrawal. This is not only extremely unpleasant, it tends to make people very agitated, unhappy, and even violent. If you have to do it to save someone's life, you do it. If someone is overdosing on opiates and loses the chemical signal to breathe, it will be lifesaving. If someone is alert and active and still high on heroin, injecting someone with naloxone would be a galactically stupid thing to do, particularly if you were just injured in a knife fight and needed some painkilling. Injecting someone with naloxone will mean that the strong painkillers will not work in someone who will have a high tolerance to hospital painkillers.
Any emergency room physician, nurse, or doctor with a shred of ER experiecne will read that sentence in "Wheat Belly" and go, "huh? What is this guy talking about, and is he galactically stupid?"
Honestly, I think it is a throwaway line that was carelessly written and carelessly published. And other "paleo" books like "The Vegetarian Myth" are full of lines like that. But you know what, I have a much higher standard for a cardiologist than I do for a non-scientist like Lierre Keith. I want real science, real risks, real data. Not hyperbole and nonsense.
So no, I don't recommend Wheat Belly. And I don't recommend eating wheat either.
(Nor am I saying that Dr. Davis is stupid - far from it - just careless in his phrasing. If you are going to take on Conventional Wisdom of Healthy Whole Wheat, you really have to "bring it." It was not brought.)
Wednesday, June 22, 2011
The Creative Advantage
One thing I hardly ever do is discuss what most people would consider real "Evolutionary Psychiatry." That is, how do diseases such as schizophrenia or autism, which in their worst forms are obviously so detrimental to evolutionary fitness that they would seem to represent a genetic dead end, continue in the gene pool. It doesn't make much sense at first glance. However, one could postulate that, just as the heterozygote carriers of sickle cell anemia are relatively protected against malaria, having some schizophrenia-risk genes could convey some sort of benefit for close relatives. And one must also consider the possibility that the schizophrenia phenotype is worse now than it may have been for much of human history - with plenty of vitamin D, no wheat (speculatively :-) ) or common modern pathogens, it is possible the schizophrenia may not have developed as fully or been as debilitating.
Given dopamine's role in creativity, motivation, and drive, the suspected genetic advantage of being a relative of a schizophrenic is that you may have a bit of extra dopamine, but not so much it will make you psychotic. Psychotic thought is disjointed and disorganized - creative thought is taking seemingly unrelated or unexpected ideas and bringing them together in a novel way.
Sounds reasonable. But what about the data proving it? Well, there has been a lot of speculation looking back at known geniuses and their psychopathologies. It is felt it is no coincidence that many geniuses were not particularly psychologically healthy. A more recent study selected 30 creative writers at a workshop and compared them to controls - writers had higher rates of affective disorders (several variations of this study have been done with the same results). Studies of bipolar individuals showed they scored higher on scales measuring creativity than folks with unipolar depression or non-creative controls - the bipolar folks scored the same as creative healthy controls.
In Iceland, the histories of 486 male relatives of schizophrenics were investigated - these men were more likely to be prominent historically than the general population, and there was a significant increase in those who were specifically successful in creative endeavors.
But all those studies are small, and many rely on historical records. However, a brand new paper from the British Journal of Psychiatry documents a large, population based study of 300,000 individuals with severe forms of affective disorders or schizophrenia from a large population registry in Sweden, where there is data on hospital admissions, diagnoses, IQ, occupation, and detailed family records as well. The were able to find several tens of thousands of folks with bipolar disorder and schizophrenia, and over two hundred thousand diagnosed with unipolar depression.
The results? People with schizophrenia and bipolar disorder (with the effect stronger in schizophrenia) were more likely to have parents and siblings who were in creative professions. Bipolar patients also were more likely to have creative offspring. The ORs aren't huge - ranging from around 1.2 to 1.6, but the bars don't cross the 1.0 line suggesting a real correlation. There were no strong statistically significant correlations between having a relative with unipolar depression and engaging in creative professions (described as "including scientific and artistic occupations.") As one would expect for a genetic link, as relationships got further away (half-siblings, cousins, etc.) the correlations weakened accordingly.
The reverse sort of "non-creative" correlation was also true - folks with schizophrenia were significantly less likely to have relatives who were accountants and auditors.
And the IQ connection (only measured in men in this Swedish registry) - those in creative professions had a higher IQ on average, however, the IQs of people with schizophrenia, unipolar depression, bipolar depression and their relatives were lower on average than people without any of the three diagnoses. IQ was accounted for in the correlations we talked about in the previous paragraphs and did not weaken the genetic association between creativity and severe psychiatric illness (specifically bipolar disorder and schizophrenia).
Well. That is all very interesting! I might go on to be a real Evolutionary Psychiatrist after all.
Given dopamine's role in creativity, motivation, and drive, the suspected genetic advantage of being a relative of a schizophrenic is that you may have a bit of extra dopamine, but not so much it will make you psychotic. Psychotic thought is disjointed and disorganized - creative thought is taking seemingly unrelated or unexpected ideas and bringing them together in a novel way.
Sounds reasonable. But what about the data proving it? Well, there has been a lot of speculation looking back at known geniuses and their psychopathologies. It is felt it is no coincidence that many geniuses were not particularly psychologically healthy. A more recent study selected 30 creative writers at a workshop and compared them to controls - writers had higher rates of affective disorders (several variations of this study have been done with the same results). Studies of bipolar individuals showed they scored higher on scales measuring creativity than folks with unipolar depression or non-creative controls - the bipolar folks scored the same as creative healthy controls.
In Iceland, the histories of 486 male relatives of schizophrenics were investigated - these men were more likely to be prominent historically than the general population, and there was a significant increase in those who were specifically successful in creative endeavors.
But all those studies are small, and many rely on historical records. However, a brand new paper from the British Journal of Psychiatry documents a large, population based study of 300,000 individuals with severe forms of affective disorders or schizophrenia from a large population registry in Sweden, where there is data on hospital admissions, diagnoses, IQ, occupation, and detailed family records as well. The were able to find several tens of thousands of folks with bipolar disorder and schizophrenia, and over two hundred thousand diagnosed with unipolar depression.
The results? People with schizophrenia and bipolar disorder (with the effect stronger in schizophrenia) were more likely to have parents and siblings who were in creative professions. Bipolar patients also were more likely to have creative offspring. The ORs aren't huge - ranging from around 1.2 to 1.6, but the bars don't cross the 1.0 line suggesting a real correlation. There were no strong statistically significant correlations between having a relative with unipolar depression and engaging in creative professions (described as "including scientific and artistic occupations.") As one would expect for a genetic link, as relationships got further away (half-siblings, cousins, etc.) the correlations weakened accordingly.
The reverse sort of "non-creative" correlation was also true - folks with schizophrenia were significantly less likely to have relatives who were accountants and auditors.
And the IQ connection (only measured in men in this Swedish registry) - those in creative professions had a higher IQ on average, however, the IQs of people with schizophrenia, unipolar depression, bipolar depression and their relatives were lower on average than people without any of the three diagnoses. IQ was accounted for in the correlations we talked about in the previous paragraphs and did not weaken the genetic association between creativity and severe psychiatric illness (specifically bipolar disorder and schizophrenia).
Well. That is all very interesting! I might go on to be a real Evolutionary Psychiatrist after all.
Saturday, May 12, 2012
Mom's Wheat Sensitivity and Offspring's Schizophrenia Risk
In the midst of all the chaos this week came a very interesting diet/mental illness risk paper. Particularly good because it comes from the premier psychiatry journal (that we in the biz call the "Green Journal" because the cover is… well…anyway): The American Journal of Psychiatry (and looks like the full text is available for free) --- Maternal antibodies to dietary antigens and risk of nonaffective psychosis in offspring.
"Nonaffective psychosis" are psychotic disorders not related to major depressive disorder or bipolar disorder (both of which can cause psychotic symptoms during severe episodes). The most common primary nonaffective psychosis will be schizophrenia, though there are a few other rarer disorders, such as delusional disorder.
Lest we forget who the enemy is, it is inflammation. Yes, our immune system, in the context of our modern lifestyle is often like an group of soldiers armed to the teeth with too much to do on one hand (all these modern epidemics of infections) and too little on the other (wherefore art thou, old friends?). Lest we forget, without inflammation, we will die. Our immune system is necessary, just like an army from time to time.
To put the screws on schizophrenia risk, let's say now, with relative surety, that there is no single cause. Schizophrenia isn't even a single disorder, but rather a variety of disorders with similar enough symptoms to be lumped together by that most imperfect of documents, the DSMIV. But, a few things come up over and over when we look at the suspicious characters, and these things all go back to the immune system (inflammation), genetic risk, and those contributions to the pathology of schizophrenia (ultimately brain damage of a particular kind, a neurodegenerative disease).
Risk factors for developing schizophrenia that I've heard over the years:
Family history
Urban
Advanced paternal age (and to a lesser extent, advanced maternal age)
Infections (particularly toxo and herpes)
Birth in the winter months (could be associated with infections or…)
...Low vitamin D at birth
Complications during pregnancy or birth
Cannabis use, particularly at a young age
(before I forget, it's a beautiful day… Punching in a dream by Naked and Famous)
So we get the usual hodgepodge of genetic risk (family history) plus environmental stress (particularly severe stressors that occur when the brain is forming) = increased risk of developing the disease(es). Ultimately at a certain stage of development (typically late adolescence for men and about 10 years later for women), brain cells begin to die, signals misfire, and we end up with the typical symptoms.
It makes perfect sense that if we have a sensitivity to something in our diet, inflammation will increase, and that risk for all sorts of autoimmune conditions and other chronic diseases will increase. And, as we already know, there is an association between schizophrenia and celiac disease, and schizophrenia and weird wheat antibodies.
So now, the new paper in the Green Journal. It's one of those cool studies that are only possible in Scandanavian countries where you pay 70% of your income in taxes and the government keeps tab on all your health information from birth to death. In this case, the neonatal blood samples of a whole population of folks were collected (everyone in born Sweden since 1975) and a sample of folks later diagnosed with schizophrenia and matched healthy controls were analyzed. IgG antibodies (immune response) to gliadin (from wheat) and casein (from milk) were measured. Newborns have immature immune systems and do not make IgG antibodies. These antibodies must have been made by the mother and passed through the placenta in the late stages of pregnancy to the baby.
Don't all run out and get expensive IgG tests to see if you are "sensitive" to foods. I've never seen anything compelling to show me these tests were a reliable indicator of allergies. Wheat is so commonly eaten that almost anyone with an inflamed or "leaky" gut will have IgG antibodies floating around… however, in this study, it was the 10% of folks who had the highest IgG signal to gliadin whose offspring had increased risk of schizophrenia. IgG antibodies to casein were not linked to any increased risk. If only the 5% of babies with the very highest levels of IgG antibodies to gliadin were consider, the odds ratio of developing schizophrenia later in life jumps to 2.5. Don't get me wrong, the absolute risk will still be pretty low, but any time an odds ratio jumps to >2 one should prick up one's ears as it is an interesting finding. These findings were not attenuated by adjusting for confounders.
In general, a highly positive IgG test to gliadin means you have a risk of having celiac disease (though it is not one of the standard tests, which are typically measures of types of HLA genes, anti tissue transglutaminiase, and IgA to gliadin). Did the moms with the highest IgG in this study have untreated celiac disease, and thus a fully flowered autoimmune disease with all the inflammation on board, affecting mom as well as fetus? Sure, except full blown untreated maternal celiac disease is typically associated with malnutrition and small birth weight, whereas in this study there was no correlation between high anti-gliadin IgG and low birth weight. In addition, while 90% of folks with celiac will have the HLA-DQA*0501 and DQB*0201 alleles, these alelles are not increased among folks with schziphrenia.
All told, once again we have a link between wheat and schizophrenia, one not explained by celiac disease alone. More unveiling of the connection needs to be done.
"Nonaffective psychosis" are psychotic disorders not related to major depressive disorder or bipolar disorder (both of which can cause psychotic symptoms during severe episodes). The most common primary nonaffective psychosis will be schizophrenia, though there are a few other rarer disorders, such as delusional disorder.
Lest we forget who the enemy is, it is inflammation. Yes, our immune system, in the context of our modern lifestyle is often like an group of soldiers armed to the teeth with too much to do on one hand (all these modern epidemics of infections) and too little on the other (wherefore art thou, old friends?). Lest we forget, without inflammation, we will die. Our immune system is necessary, just like an army from time to time.
To put the screws on schizophrenia risk, let's say now, with relative surety, that there is no single cause. Schizophrenia isn't even a single disorder, but rather a variety of disorders with similar enough symptoms to be lumped together by that most imperfect of documents, the DSMIV. But, a few things come up over and over when we look at the suspicious characters, and these things all go back to the immune system (inflammation), genetic risk, and those contributions to the pathology of schizophrenia (ultimately brain damage of a particular kind, a neurodegenerative disease).
Risk factors for developing schizophrenia that I've heard over the years:
Family history
Urban
Advanced paternal age (and to a lesser extent, advanced maternal age)
Infections (particularly toxo and herpes)
Birth in the winter months (could be associated with infections or…)
...Low vitamin D at birth
Complications during pregnancy or birth
Cannabis use, particularly at a young age
(before I forget, it's a beautiful day… Punching in a dream by Naked and Famous)
So we get the usual hodgepodge of genetic risk (family history) plus environmental stress (particularly severe stressors that occur when the brain is forming) = increased risk of developing the disease(es). Ultimately at a certain stage of development (typically late adolescence for men and about 10 years later for women), brain cells begin to die, signals misfire, and we end up with the typical symptoms.
It makes perfect sense that if we have a sensitivity to something in our diet, inflammation will increase, and that risk for all sorts of autoimmune conditions and other chronic diseases will increase. And, as we already know, there is an association between schizophrenia and celiac disease, and schizophrenia and weird wheat antibodies.
So now, the new paper in the Green Journal. It's one of those cool studies that are only possible in Scandanavian countries where you pay 70% of your income in taxes and the government keeps tab on all your health information from birth to death. In this case, the neonatal blood samples of a whole population of folks were collected (everyone in born Sweden since 1975) and a sample of folks later diagnosed with schizophrenia and matched healthy controls were analyzed. IgG antibodies (immune response) to gliadin (from wheat) and casein (from milk) were measured. Newborns have immature immune systems and do not make IgG antibodies. These antibodies must have been made by the mother and passed through the placenta in the late stages of pregnancy to the baby.
Don't all run out and get expensive IgG tests to see if you are "sensitive" to foods. I've never seen anything compelling to show me these tests were a reliable indicator of allergies. Wheat is so commonly eaten that almost anyone with an inflamed or "leaky" gut will have IgG antibodies floating around… however, in this study, it was the 10% of folks who had the highest IgG signal to gliadin whose offspring had increased risk of schizophrenia. IgG antibodies to casein were not linked to any increased risk. If only the 5% of babies with the very highest levels of IgG antibodies to gliadin were consider, the odds ratio of developing schizophrenia later in life jumps to 2.5. Don't get me wrong, the absolute risk will still be pretty low, but any time an odds ratio jumps to >2 one should prick up one's ears as it is an interesting finding. These findings were not attenuated by adjusting for confounders.
In general, a highly positive IgG test to gliadin means you have a risk of having celiac disease (though it is not one of the standard tests, which are typically measures of types of HLA genes, anti tissue transglutaminiase, and IgA to gliadin). Did the moms with the highest IgG in this study have untreated celiac disease, and thus a fully flowered autoimmune disease with all the inflammation on board, affecting mom as well as fetus? Sure, except full blown untreated maternal celiac disease is typically associated with malnutrition and small birth weight, whereas in this study there was no correlation between high anti-gliadin IgG and low birth weight. In addition, while 90% of folks with celiac will have the HLA-DQA*0501 and DQB*0201 alleles, these alelles are not increased among folks with schziphrenia.
All told, once again we have a link between wheat and schizophrenia, one not explained by celiac disease alone. More unveiling of the connection needs to be done.
Sunday, October 9, 2011
Infections and Schizophrenia Risk
Whew. Quite a response over my disappointment in Wheat Belly. And Melissa gives us an informed and reasoned review (mine was more of a visceral reaction). It's hard for me to see the merit in a book just because the idea of wheat not being ideal for human consumption agrees with my own views.
On the interesting papers front, a couple of new articles shine more light on the relationship between infections and mental disorders. I consider this type of thing "evolutionary psychiatry" as it brings us closer to finding the true pathology of illness, inflammation, and disease. In addition, the typical evolutionary prescription of nutrient-rich and anti-inflammatory diets and appropriate amounts of vitamin D ought to increase resistance to infection and resilience to the inflammation and autoimmune issues that may be spurred on by such infections.
The first paper is from Denmark, Toxoplasma Infection and Later Development of Schizophrenia in Mothers, from August's American Journal of Psychiatry. There is also an enlightening editorial in the same issue.
Toxoplasma gondii is a parasite that one can pick up from contaminated cat feces, from eating undercooked meat containing the infectious cysts or contaminated vegetables, and from being a fetus whose mother is infected. Infection in pregnant women can cause major birth defects in offspring, and this fact is the origin of the common advice for pregnant women not to clean litter boxes. Studies have linked infection with toxoplasma with schizophrenia since the 1950s. More recently the association was confirmed in a 2008 study of the US military. All these early studies were retrospective and observational, which is the weakest sort of experimental data this side of the anecdote. Meaning folks with schizophrenia were compared with normal controls, and it turned out that people with schizophrenia have a higher rate of previous exposure to toxoplasma.
A step up from the retrospective, after the fact sort of study is the observational cohort study. In this type of study, a group of people are followed for many years to see what develops. This type of experiment presumably takes away what sorts of bias can be introduced by finding cases after the fact. (For example, do people with prodromal symptoms of schizophrenia engage in behavior that makes it more likely for them to be infected with toxoplasma - washing hands less, or not cooking meat as thoroughly?) Scandinavian countries are hotbeds of these studies, as they've collected all sorts of medical data on pretty much all of their citizens for a generation now.
In Denmark, 45,609 women were followed from childbirth, when antibodies indicating prior prenatal exposure (or not) to toxoplasma in their babies were measured by heel-stick 5-10 days after being born. All these antibodies circulating in the baby's bloodstream were made by the mother, not the baby, as a baby won't make too much in the way of these sorts of antibodies (IgG) until the immune system is a bit more mature, by 3-6 months. Therefore mothers with babies who were positive for T gondii exposure were presumed infected themselves. Some, but not all, of the mothers had been tested for IgG levels in the first trimester of pregnancy - these levels correlated with the newborn levels that were available for all the mothers.
Over the following years (the women were followed from 1992-2008), 80 of the mothers developed schizophrenia. The ones whose babies had the highest IgG levels had a higher risk of developing schizophrenia than those who had babies with the lowest levels (the risk was increased by 1.73-fold, which was statistically significant - though with a population risk of approximately 1%, toxoplasma seems to increase the risk to about 1.7%). Other meta-analysis have shown odds ratios of around 2.54-2.73 (odds ratios above two are considered a significant finding). In the Danish study, adjustments were made for confounders (such as age, urban or rural, and other known risk factors), and women already diagnosed with schizophrenia at the beginning of the study were obviously excluded.
Why would infection with T gondii increase the risk of schizophrenia? Active infection in the central nervous system can certainly cause huge problems (such as seizures) and inflammation. In addition, our immune reactions to these infections can cause problems, especially if something on the infectious particle looks a bit like something in our own cells. The classic example of this type of problem is rheumatic heart disease, most likely caused by our own antibodies attacking heart tissue after a strep infection. It is also thought that neurological symptoms of lupus are caused by these neuro-specific auto-antibodies. In the case of toxoplasma, it is a possibility that the anti-toxo IgG antibodies react with neural tissue and might help the immune system attack the NMDA receptors in particular.
The paper appeared in the same August, 2011 issue of the American Journal of Psychiatry. In this study, there were four groups of folks - schizophrenic patients (none of whom were on antipsychotic medication) who were seropositive for HSV1 infection or not positive, and normal healthy controls who were also positive for HSV1 infection or not. All these folks were followed with some cognitive testing and neuroimaging at the beginning of the study and at one year. It was found that the schizophrenic folks with HSV1 infection had significant worsening of certain measures of cognitive functioning and shrinking of gray matter in certain regions (meaning the brain cells are dying off). The other three groups of people didn't have these changes.
Here is what the researchers had to say about the possibilities:
Monitoring, modulating, and avoiding these infections seem like different ways to decrease the risk of central nervous system symptoms.
On the interesting papers front, a couple of new articles shine more light on the relationship between infections and mental disorders. I consider this type of thing "evolutionary psychiatry" as it brings us closer to finding the true pathology of illness, inflammation, and disease. In addition, the typical evolutionary prescription of nutrient-rich and anti-inflammatory diets and appropriate amounts of vitamin D ought to increase resistance to infection and resilience to the inflammation and autoimmune issues that may be spurred on by such infections.
The first paper is from Denmark, Toxoplasma Infection and Later Development of Schizophrenia in Mothers, from August's American Journal of Psychiatry. There is also an enlightening editorial in the same issue.
Toxoplasma gondii is a parasite that one can pick up from contaminated cat feces, from eating undercooked meat containing the infectious cysts or contaminated vegetables, and from being a fetus whose mother is infected. Infection in pregnant women can cause major birth defects in offspring, and this fact is the origin of the common advice for pregnant women not to clean litter boxes. Studies have linked infection with toxoplasma with schizophrenia since the 1950s. More recently the association was confirmed in a 2008 study of the US military. All these early studies were retrospective and observational, which is the weakest sort of experimental data this side of the anecdote. Meaning folks with schizophrenia were compared with normal controls, and it turned out that people with schizophrenia have a higher rate of previous exposure to toxoplasma.
A step up from the retrospective, after the fact sort of study is the observational cohort study. In this type of study, a group of people are followed for many years to see what develops. This type of experiment presumably takes away what sorts of bias can be introduced by finding cases after the fact. (For example, do people with prodromal symptoms of schizophrenia engage in behavior that makes it more likely for them to be infected with toxoplasma - washing hands less, or not cooking meat as thoroughly?) Scandinavian countries are hotbeds of these studies, as they've collected all sorts of medical data on pretty much all of their citizens for a generation now.
In Denmark, 45,609 women were followed from childbirth, when antibodies indicating prior prenatal exposure (or not) to toxoplasma in their babies were measured by heel-stick 5-10 days after being born. All these antibodies circulating in the baby's bloodstream were made by the mother, not the baby, as a baby won't make too much in the way of these sorts of antibodies (IgG) until the immune system is a bit more mature, by 3-6 months. Therefore mothers with babies who were positive for T gondii exposure were presumed infected themselves. Some, but not all, of the mothers had been tested for IgG levels in the first trimester of pregnancy - these levels correlated with the newborn levels that were available for all the mothers.
Over the following years (the women were followed from 1992-2008), 80 of the mothers developed schizophrenia. The ones whose babies had the highest IgG levels had a higher risk of developing schizophrenia than those who had babies with the lowest levels (the risk was increased by 1.73-fold, which was statistically significant - though with a population risk of approximately 1%, toxoplasma seems to increase the risk to about 1.7%). Other meta-analysis have shown odds ratios of around 2.54-2.73 (odds ratios above two are considered a significant finding). In the Danish study, adjustments were made for confounders (such as age, urban or rural, and other known risk factors), and women already diagnosed with schizophrenia at the beginning of the study were obviously excluded.
Why would infection with T gondii increase the risk of schizophrenia? Active infection in the central nervous system can certainly cause huge problems (such as seizures) and inflammation. In addition, our immune reactions to these infections can cause problems, especially if something on the infectious particle looks a bit like something in our own cells. The classic example of this type of problem is rheumatic heart disease, most likely caused by our own antibodies attacking heart tissue after a strep infection. It is also thought that neurological symptoms of lupus are caused by these neuro-specific auto-antibodies. In the case of toxoplasma, it is a possibility that the anti-toxo IgG antibodies react with neural tissue and might help the immune system attack the NMDA receptors in particular.
The paper appeared in the same August, 2011 issue of the American Journal of Psychiatry. In this study, there were four groups of folks - schizophrenic patients (none of whom were on antipsychotic medication) who were seropositive for HSV1 infection or not positive, and normal healthy controls who were also positive for HSV1 infection or not. All these folks were followed with some cognitive testing and neuroimaging at the beginning of the study and at one year. It was found that the schizophrenic folks with HSV1 infection had significant worsening of certain measures of cognitive functioning and shrinking of gray matter in certain regions (meaning the brain cells are dying off). The other three groups of people didn't have these changes.
Here is what the researchers had to say about the possibilities:
There are several plausible explanations for the observed changes. In the rodent and rabbit models of CNS HSV1 exposure, latent infection and reactivation directly affected functioning through neuronal death or dysfunction. Neuronal death resulted from apoptosis. Neuronal dysfunction during reactivation and latency resulted from modulation of apoptosis and autophagy, host cell translational shutoff, oxidative damage, and/ or neurotransmitter alterations. Even with peripheral infections, HSV1 could alter neurotransmission through release of cytokines, especially chemokines, which may be elevated in HSV1-exposed individuals. Human studies support some of these observations. These processes occur throughout the life of an infected person.In short, infection (even a smoldering latent infection without obvious active signs) in the brain or periphery can lead to all sorts of changes in the way the cell handles energy and self-destruction and general inflammatory badness.
Monitoring, modulating, and avoiding these infections seem like different ways to decrease the risk of central nervous system symptoms.
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.
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.
Tuesday, June 18, 2013
Infection and Psychosis in Schizophrenia
Last year the daughter of one of my patients called me. "Mom is acting really strange. She's being aggressive, and she thinks my Dad is still alive. I don't think she slept last night. Do you think she needs an increase in her medication?"
My patient was a sweet 70 year old woman with a psychosis-heavy bipolar disorder who could get paranoid from time to time, but was never violent, and had been stable on a low dose of medicine for many years. I told her daughter, "If she didn't fall down and hit her head somehow, I think she has a urinary tract infection (UTI). You should take her in to see her primary care doctor if she'll let you. Otherwise, you might need to take her to the ER."
A few hours later, the daughter called me back, quite amazed. "You were right! Her doctor says she has a bad UTI. How did you diagnose that over the phone?"
I'm sure all my psychiatrist/doctor readers were guessing the outcome right away. UTIs rather famously turn into strange behavior in the elderly, particularly in those with dementia. One time when I was on call in the emergency room, we got a consult for new-onset obsessive compulsive disorder in 77 year old. My fellow resident and I exchanged looks and told the emergency room intern to wait for the results of the urinalysis before we were consulted. 77 year olds don't develop OCD out of the blue without something else medical going on. We were correct…she had a urinary tract infection. The "OCD" resolved with antibiotics. The tricky part for doctors is that these UTIs can occur without any of the usual symptoms we are used to hearing about. No incontinence, fever, or urinary urgency. Or sometimes the patient can't tell us about these symptoms.
So we already know that urinary tract infections can cause pretty weird behavior in vulnerable people. Recently Brian Miller, MD from Georgia Health Sciences University wrote an article in Psychiatric Times about his recent study in the Journal of Clinical Psychiatry: "A Prevalence Study of Urinary Tract Infections in Acute Relapse of Schizophrenia." Not only do I have a subscription to JCP, but my academic access should grant me full access, but on a Sunday morning I was unable to get a copy of the full text because JCP's website is HORRIBLE. In desperation I emailed Dr. Miller, and on Monday morning he very kindly sent me not only a copy of the full text article, but also his letter to the editor in Schizophrenia Research. Thank you!
Schizophrenia is associated with hugely increased mortality, and those afflicted die in increased numbers and earlier from almost every major leading cause of death. Heart disease is most famous (blamed on the increased schizophrenic tendency to smoke and to the effects of the medications), but schizophrenics have an 8-fold increased risk of death by pneumonia. Is it from lack of self-care and not being organized enough to go to the doctor for serious medical symptoms? Maybe. That has been the assumption. But recent studies have shown what is no surprise to followers of Evolutionary Psychiatry. Schizophrenia is not just a brain disease, it is a disease of immune function. Schizophrenics have major abnormalities in levels of inflammatory cytokines, C-reactive protein, and reduced neutrophil activity. Neutrophils are a first-line response to inflammation and are vital to keeping us safe from bacterial infection.
Despite all these abnormalities, Dr. Miller notes in his paper that there are NO studies of the prevalence of infection at the time of infection of hospitalization for acute illness relapse in patient with schizophrenia. As all clinical psychiatrists will know, schizophrenics can remain relatively stable for many years, then have terrible relapses of psychotic behavior. Often going off medication or substance abuse is blamed (and may well be responsible). But sometimes something else is going on… and it may well be a bacterial infection. Dr. Miller studied healthy controls and some long-term schizophrenics admitted with acute psychotic relapse. He found that those hospitalized with schizophrenia, men and women, were 29 times as likely as controls to have a urinary tract infection. 35% of subjects in the acute relapse group had serologic/urinalysis evidence of a UTI as opposed to 5% of stable outpatient and 3% of controls.
There are reports of certain antibiotic treatment associate with increased risk of psychosis (cipro and gatifloaxin are known)… is it the antibiotics, or the UTI they were treating? It is well-known that elderly and particularly demented patients are vulnerable to odd behavior caused by urinary tract infections. It is not beyond the realm of possibility that people with schizophrenia are vulnerable to the same pathology.
The time is coming that schizophrenia is recognized as a full-body immune dysregulation disorder, from the gut to the brain to the neutrophils. At that point are the psychiatrists going to be removed from the picture and the allergists and rheumatologists to step forward? We'll see.
Monday, March 11, 2013
Folate and Negative Symptoms in Schizophrenia
The psychiatric symptoms of schizophrenia are defined in two major categories, "positive" and "negative." So-called positve symptoms are called so because they are an addition that people without psychosis don't experience, such as hallucinations and delusions and disorganized behavior. The negative symptoms represent functions being taken away from the brain and can be apathy, social withdrawal, and loss of motivation and emotional expressiveness.
Earlier today, a paper (free full text) was released from JAMA Psychiatry detailing a multi-center trial of placebo vs 2 mg folate and 400 micrograms of B12 for folks diagnosed with schizophrenia. All the patients (140, aged 18-68) had residual symptoms but were stabilized on antipsychotic medications for at least 6 months and on a stable dose for at least 6 weeks.
All the patients had genetic evaluations of their folate systems and measurements of red blood cell levels of folate. Red blood cell levels of folate don't necessarily correlate with levels in the central nervous system, which is just something to keep in mind. However, in other studies, folate metabolite measurements in the central nervous system seem to flatten and be maintained at a relatively moderate level of red blood cell folate, and levels correlate more closely at lower levels of folate.
The folate cycle is complicated. Please see this article… and several articles linked from that one for more detail. However, in short, folate is an important nutrient necessary to make neurotransmitters, DNA, and also to help with the activation or deactivation of DNA via a process called methylation (which is basically just adding groups of -CH3 molecules).
Folate deficiency has long been linked to schizophrenia. Certain groups of people with hereditary deficits in their folate cycle metabolism are more likely to be schizophrenic than the general population, and cohorts of babies born during famines are more likely to develop schizophrenia a few decades later. A few of the particular genes include the C77T variant of the MTHFR gene (the young man in the case study of B12 deficiency and psychosis had this variation of this gene). MTHFR is needed to make folate from food into the kinds of folate we use in the body, and many of us have a less efficient version of this enzyme. Each copy (we have two) of the C77T version (rather than C77C, the more typical version) reduces MTHFR activity by 35%. Other missense variants in genes coding for FOLH1 (a peptide that sits on the intestinal brush border and helps dietary folate be absorbed into the body), COMT, and methionine synthase also confer a higher risk of schizophrenia. More interestingly, problems with these genes will predict a greater negative symptom burden in schizophrenia but seem to have no relationship to the positive symptoms.
Back to the current study. Folate (in rather large doses, 2mg) and B12 were used together as the B12 would facilitate the action of the folate in helping the folate cycle… cycle through. In more biochemical terms, B12 is a cofactor for methionine synthase (MTR), which remethylates homocysteine into methionine, which is then converted into the universal methyl donor S-adenosylmethionine (SAMe).
The long and the short of it…supplementation failed to separate from placebo for the general study group. HOWEVER, among those with the (more efficient) version of the FOLH1 gene and to a lesser degree among other folate cycle genetic variants, folate and B12 supplementation did seem to significantly help negative symptoms in schizophrenia, but not the positive ones.
An important point to make is that negative symptoms are extremely difficult to treat. It is, relatively speaking, fairly straightforward to decrease positive symptoms of hallucinations and disorganized behavior with medications in most people with psychosis. Apathy, social withdrawal, and flattened emotions tend to remain and be very debilitating. (In addition, the medicine can also cause a flattened affect). Therefore finding any intervention, particularly one with presumably far fewer side effects than antipsychotic medication that might help the negative symptoms is an exciting finding.
An important point to make is that negative symptoms are extremely difficult to treat. It is, relatively speaking, fairly straightforward to decrease positive symptoms of hallucinations and disorganized behavior with medications in most people with psychosis. Apathy, social withdrawal, and flattened emotions tend to remain and be very debilitating. (In addition, the medicine can also cause a flattened affect). Therefore finding any intervention, particularly one with presumably far fewer side effects than antipsychotic medication that might help the negative symptoms is an exciting finding.
Genetic testing in psychiatry is still in its infancy. In many cases (such as finding if someone is a rapid metabolizer of certain antidepressants) the tests have modest usefulness in the Real World where such tests are generally paid for out of pocket. But with this study we are really starting to unlock some real clinical utility, and as genetic testing becomes cheaper and more readily available, it might help us design personalized treatments.
Friday, June 22, 2012
Anti-inflammatories and Schizophrenia
Short little post on a paper from a few weeks ago from the Journal of Clinical Psychiatry: Nonsteroidal Anti-Inflammatory Drugs in Schizophrenia: Ready for Practice or a Good Start? A Meta-Analysis.
Nothing spectacular here, just some interesting arguments and correlations to add to the literature that major mental illness has an inflammatory pathology, and that searching for anti-inflammatory solutions (and I consider an anti-inflammatory (nutrient-rich, low toxin) diet, proper sleep, proper coping, appropriate exercise and stress reduction as some of these non-prescription solutions to be examined further) is a reasonable course of action, and not woo-ville.
My usual radio haunts have been disappointing recently for brand new music. But The Heavy came out with a new single this week, and I'm liking it: What Makes A Good Man. It sounds really good in the car, but I hope you're not driving right now.
All right, some suspicious correlations suggesting the immune system and inflammation may be involved:
1) People with schizophrenia and their close family members have higher risk of autoimmune disorders.
2) Men who have used steroids and NSAIDS (such as naproxen or ibuprofen) have a decreased prevalence of schizophrenia.
3) PET scans of folks with schizophrenia show increased numbers of active microglia in the brains (microglia are immune cells in the central nervous system, activated to fight infection or in autoimmune conditions or inflammation).
4) With brute force hacks of genomes of folks with schizophrenia, one of the gene areas that keeps popping up are markers in the major histocompatibility complex (MHC) region on chromosome 6. MHC genes code for the markers we put up on our cells to label them as ME so our own immune army doesn't take us out.
5) There are abnormal levels of inflammatory cytokines, immune markers, and autoimmune antibodies in the serum and spinal fluid of folks with schizophrenia.
So something in the immune system is amiss. Maybe gut-punching inflammation could help the symptoms. Enter the NSAIDS (non-steroidal anti-inflammatory drugs). They work by inhibiting the conversion of our old frenemy arachidonic acid (AA, made from the omega 6 linoleic acid, but also available as is from various animal foods) into the class of molecules called prostaglandins. Prostaglandins help mediate pain, inflammation, and thermal regulation, which is why you might pop an Advil when you have a fever or a muscle ache (or both).
Now, NSAIDS are known to trash the gut and the kidneys if you aren't careful, and various versions may kill you dead with a heart attack (Vioxx) in the long term, and pregnant women and those with ulcers and ulcerative colitis and some others should avoid them…but as I am not currently afflicted with any of the previous conditions I would still take it in lieu of acetaminophen, personally, when I am not toughing it out. Like last Monday, when my children gave me a little virus that toasted me all the way up to 103.3. Personally I'm cool with 102s but the 103s start to make me worry about brain fry-age, particularly in adults.
(An oldie but a goodie: Neil Finn: She Will Have Her Way Definitely worth the ad…)
More specifically: AA + the enzymes COX1 and COX2 make prostaglandins, which mediate pieces of the inflammatory response. NSAIDS like ibuprofen, naproxen, diclofenac and acetylsalicylic acid (otherwise known as aspirin) will block COX1 and COX2, reducing the ability of the body to make prostaglandins.
So will doing that not only help a fever or an aching muscle, but also the symptoms of schizophrenia? What does the literature say?
All the randomized controlled trials of antipsychotic medication augmentation with an NSAID were analyzed in this meta-analysis. (No one official is just using Advil for psychosis.) In the literature there were 5 (small) RCTs, for a total of 264 patients. The trials all used celecoxib (a selective COX2 inhibitor) or aspirin, and lasted from 5 weeks to 3 months. 4 of the 5 studies all had similar results, modestly but significantly helpful in both "positive" symptoms such as hearing voices and "negative" symptoms such as social withdrawal. One study showed the NSAIDs not to be helpful, compared to placebo. Apparently two other unpublished studies also showed celecoxib to be unhelpful, so we have to be cautious about these findings.
More specifically, with a few of the celecoxib studies, the NSAID didn't appear to be particularly active in the central nervous system, as expression of COX2 wasn't altered in the hippocampus and there were no changes in the cytokine profiles in immune cells called mononuclear cells. In the aspirin study, however, they were able to detect a treatment effect with differences in cytokine profiles due to the drug. Since COX1 prostaglandins cause platelet aggregation, inhibiting COX1 leads to the supposed cardioprotective effects (but also the increased risk of ulcers) of the nonselective NSAIDS. It's a bit irritating that all these studies were done with the selective COX2 inhibitor, celecoxib, but since it was the one on patent, I'm guessing that's why the money was spent there. It would be interesting to see larger studies done with ibuprofen or aspirin, frankly.
Well! More wait and see.
Nothing spectacular here, just some interesting arguments and correlations to add to the literature that major mental illness has an inflammatory pathology, and that searching for anti-inflammatory solutions (and I consider an anti-inflammatory (nutrient-rich, low toxin) diet, proper sleep, proper coping, appropriate exercise and stress reduction as some of these non-prescription solutions to be examined further) is a reasonable course of action, and not woo-ville.
My usual radio haunts have been disappointing recently for brand new music. But The Heavy came out with a new single this week, and I'm liking it: What Makes A Good Man. It sounds really good in the car, but I hope you're not driving right now.
All right, some suspicious correlations suggesting the immune system and inflammation may be involved:
1) People with schizophrenia and their close family members have higher risk of autoimmune disorders.
2) Men who have used steroids and NSAIDS (such as naproxen or ibuprofen) have a decreased prevalence of schizophrenia.
3) PET scans of folks with schizophrenia show increased numbers of active microglia in the brains (microglia are immune cells in the central nervous system, activated to fight infection or in autoimmune conditions or inflammation).
4) With brute force hacks of genomes of folks with schizophrenia, one of the gene areas that keeps popping up are markers in the major histocompatibility complex (MHC) region on chromosome 6. MHC genes code for the markers we put up on our cells to label them as ME so our own immune army doesn't take us out.
5) There are abnormal levels of inflammatory cytokines, immune markers, and autoimmune antibodies in the serum and spinal fluid of folks with schizophrenia.
So something in the immune system is amiss. Maybe gut-punching inflammation could help the symptoms. Enter the NSAIDS (non-steroidal anti-inflammatory drugs). They work by inhibiting the conversion of our old frenemy arachidonic acid (AA, made from the omega 6 linoleic acid, but also available as is from various animal foods) into the class of molecules called prostaglandins. Prostaglandins help mediate pain, inflammation, and thermal regulation, which is why you might pop an Advil when you have a fever or a muscle ache (or both).
Now, NSAIDS are known to trash the gut and the kidneys if you aren't careful, and various versions may kill you dead with a heart attack (Vioxx) in the long term, and pregnant women and those with ulcers and ulcerative colitis and some others should avoid them…but as I am not currently afflicted with any of the previous conditions I would still take it in lieu of acetaminophen, personally, when I am not toughing it out. Like last Monday, when my children gave me a little virus that toasted me all the way up to 103.3. Personally I'm cool with 102s but the 103s start to make me worry about brain fry-age, particularly in adults.
(An oldie but a goodie: Neil Finn: She Will Have Her Way Definitely worth the ad…)
More specifically: AA + the enzymes COX1 and COX2 make prostaglandins, which mediate pieces of the inflammatory response. NSAIDS like ibuprofen, naproxen, diclofenac and acetylsalicylic acid (otherwise known as aspirin) will block COX1 and COX2, reducing the ability of the body to make prostaglandins.
So will doing that not only help a fever or an aching muscle, but also the symptoms of schizophrenia? What does the literature say?
All the randomized controlled trials of antipsychotic medication augmentation with an NSAID were analyzed in this meta-analysis. (No one official is just using Advil for psychosis.) In the literature there were 5 (small) RCTs, for a total of 264 patients. The trials all used celecoxib (a selective COX2 inhibitor) or aspirin, and lasted from 5 weeks to 3 months. 4 of the 5 studies all had similar results, modestly but significantly helpful in both "positive" symptoms such as hearing voices and "negative" symptoms such as social withdrawal. One study showed the NSAIDs not to be helpful, compared to placebo. Apparently two other unpublished studies also showed celecoxib to be unhelpful, so we have to be cautious about these findings.
More specifically, with a few of the celecoxib studies, the NSAID didn't appear to be particularly active in the central nervous system, as expression of COX2 wasn't altered in the hippocampus and there were no changes in the cytokine profiles in immune cells called mononuclear cells. In the aspirin study, however, they were able to detect a treatment effect with differences in cytokine profiles due to the drug. Since COX1 prostaglandins cause platelet aggregation, inhibiting COX1 leads to the supposed cardioprotective effects (but also the increased risk of ulcers) of the nonselective NSAIDS. It's a bit irritating that all these studies were done with the selective COX2 inhibitor, celecoxib, but since it was the one on patent, I'm guessing that's why the money was spent there. It would be interesting to see larger studies done with ibuprofen or aspirin, frankly.
Well! More wait and see.
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