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!


  1. Just out of interest Emily - do you mention any of this nutrition malarky to your students... or better still, get them to read your blog? It should be part of their curriculum! :)

  2. I will likely mention my blog. There won't be any quizzes, though.

  3. Emily,

    Vitamin D, gluten, celiac disease, intestinal permeability and schizophrenia, does they are not all interconnected? Gluten is correlated with schizophrenia. Low vitamin D is correlated with intestinal permeability, schizophrenia and celiac disease.


  4. I wouldn't call it celiac disease, though. You don't have to have the pathophysiology of celiac disease to have the issues with intestinal permeability, and the wheat antibodies prominent in the urine and serum of schizophrenics are different than the celiac antibodies. The picture of wheat decreasing vitamin d and low vitamin d also being correlated with schizophrenia and low birthrate does make wheat seem more problematic than ever.


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