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 Progressive Gray Matter Loss and Changes in Cognitive Functioning Associated With Exposure to Herpes Simplex Virus 1 in Schizophrenia: A Longitudinal Study 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.