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.