Monday, February 24, 2014

Schizophrenia- Ever thought of Microbial involvement?


    A few posts earlier I had talked about Immunology inside the central nervous system (Link). My idea was to highlight how Neuroimmunology is different from what happens in other part of the body. I made a note that immune cells inside CNS has a role to play in cognition and a variety of Neurobehavioral functions. One of my common argument is that microbes are more involved in our biology that is actually thought to be (this one argument that keeps appearing in posts). In a yet another post earlier, I had talked about influence of "Transposable elements" and its influence on conditions such as Alzheimer's, Parkinson's and Schizophrenia. In this post, I explore how infections play a role (if not a major), in some of the neurobehavioral disorders. 

Table 1: Common organisms in context
with Neurobehavioral disorders.
       Many different pathogens have been studied in context with Neurobehavioral and Psychiatric disorders. The list of organisms that has been studied in this regard is shown in Table 1. In theory it is possible, many more organism are involved.

       I believe almost everyone has heard of schizophrenia. It is a mental disorder characterized by a breakdown in thinking and poor emotional responses. In the simplest molecular terminology, it is misfiring and miscommunication of neurons. Patients suffer from Hallucinations, feels like they are possessed, and other qualities of insanity. The actual cause of this horrific problem has not been fully solved.

    Genome wide studies have shown that there is a genetic cause in a small subgroup of peoples. The genes that are linked include- Neuroregulin 1, Dysbindin, Proline dehydrogenase, G72 etc, but most interestingly HLA phenotypes (a major proportion). Schizophrenia is classified into- Catatonic, Paranoid, Disorganised, Residual and undifferentiated. For details please go here. The bottom line is that the patient has had a neural damage during brain development which has lead to false wiring and firing od neurons. That explains the onset age usually around the teenage. However, in a subgroup of patients, there appears to be no risk factors and dont respond to classical therapy. Why?

     In coming, Pathological Neuroimmunology. It has been convincingly shown that increased levels of IL-8 in the mother during pregnancy (especially in second trimester), uncontrolled IL 6 in CSF, blocking NMDA (N methyl D aspartate) and its receptor, other autoimmune disorder etc have all been implicated in schizophrenia. It has been shown that cytokines can directly influence important brain region development (As shown by some MRI studies). For example, IL 6 is activated in case of infection and IL 6 can effect the hippocampus, grey matter etc. This data convincingly shows that immunology has some role. Of all these, NMDA antagonism is a very attractive candidate and has received lot of attention. Studies have speculated that NR1a and NR2b epitopes are important. An important question remains unanswered in this case. What triggers antibody production, or dysregulation of chemokines in the first place? It would be very tempting for people to speculate genes and environmental risk factors as most important important factors. Partly true. But it has now become increasingly clear that infection by itself has an active role. To draw conclusions from studies is very hard in this case, as both sides of the argument exists.

     That maynot be impressive. Especially since i have put in a lot of speculative data there. A landmark paper in JAMA showed that atleast 1/3rd of the people who developed mood disorder and significant association with infection and to a small extent had autoimmunity.

   There are a lot of studies that I could cite. For example, Antibodies in GI tract and contents of normal flora in GIT has a significant effectin bipolar disorder. A condition called as PANDAS (Paediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections) that shows up as Obsessive compulsive disorder is very much related to Strepto infection and cross reacting antibody. These are just some of the examples that show that Neuro is not an isolated system.

    It is important to note that infection and inflammation are not the sole cause. But they do form a subtype, which if recognised well enough, should help us develop better treatment options. A word of caution here. Many chronic diseases have been associated with infection and inflammation such as as Obesity, Diabetes, Atherosclerosis, Autoimmune disorders etc (The list keeps growing). We don't have sufficient evidence yet to fully prove the theroy. But remember, Lack of evidence is not evidence of absence. Research is actively on.
Müller N (2014). Immunology of schizophrenia. Neuroimmunomodulation, 21 (2-3), 109-16 PMID: 24557043

Marsland AL, Gianaros PJ, Abramowitch SM, Manuck SB, & Hariri AR (2008). Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults. Biological psychiatry, 64 (6), 484-90 PMID: 18514163

Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J, & Mortensen PB (2013). Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA psychiatry, 70 (8), 812-20 PMID: 23760347

Murphy, Tanya K. (2012-02--1) Clinical Factors Associated with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections. , 160(2), 314-319. DOI: 10.1016/j.jpeds.2011.07.012 

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