Last year, Brian Miller and colleagues at the Georgia Health Sciences University reported a meta-analysis of cytokine alterations in the serum of schizophrenia (Sz) subjects. This type of study synthesizes findings from many papers in the literature, in this case 40 papers were analyzed. The overall conclusions were that some cytokines (IL-1beta, IL-6, TGFbeta) may be state markers for Sz (meaning they are altered during the active, acute state of psychosis). The evidence for this is that these cytokine levels can be normalized by anti-psychotic medications. A number of other cytokines (IL-12, IFNgamma, TNFalpha, sIL-2R) may be trait markers for Sz – meaning that their abnormal levels are not altered by anti-psychotic medications and thus may constantly dysregulated in the disease. Readers of my book will be familiar with the idea that cytokines, the small proteins whose levels reflect immune status, are abnormally regulated in Sz (as well as autism and depression). This is part of the evidence that there is immune involvement in Sz, and this meta-analysis provides strong support for this hypothesis.
Another link between the cytokine IL-6 and Sz is reported in a new paper from Zakharyan and colleagues in Armenia. They assessed the association between the presence of various variants of the IL-6 gene and Sz and found that one variant in particular is more frequent in their patient group than in controls. This variant is also associated with higher levels of IL-6 in the serum. Thus, there may be a genetic predisposition towards elevated IL-6, which is linked to Sz.
A key receptor for excitatory synaptic transmission in the brain is the NMDA receptor, and there is evidence that there is a deficit in such transmission in Sz. Mortensen and colleagues in Denmark studied the association of a number of genetic variants of the NMDA receptor with Sz. They also looked for an association between these variants and the presence of anti-herpes simplex virus (HSV-2) in the serum of women who gave birth to offspring with Sz. A link between maternal viral infection and Sz in the offspring had been well established. The rationale for looking for a connection between possible genetic and environmental risk factors was that maternal infection and fever have been associated with altered synaptic transmission in the brains of the offspring. The first result of the Mortensen study was that one variant of he NMDA gene is indeed associated with Sz. The second finding was that two variants are associated with anti-herpes simplex virus (HSV-2) in the serum of women who gave birth to offspring with Sz. The hypothesis for these findings is that activating the maternal immune system dysregulates the NMDA receptor system, and certain genetic variants of that receptor make this event more likely or more susceptible to dysregulation. Studies in rodents have shown that maternal immune activation can cause NMDA dysregulation. The effects of maternal immune activation on fetal brain development and offspring behavior are discussed extensively in my book.
Mortensen’s group also recently published a paper providing evidence that prio autoimmune disease increases the risk for Sz by 29%. This is not surprising since many prior papers have also found this connection (also found in autism). More novel perhaps is their additional finding that any history of infection increases the risk for Sz by 60%. When the two risk factors are combined, The risk for Sz is increased even further. Moreover, the risk increased with the number of hospitalizations for infections. In addition, hospital contact with infection occurred in nearly 24% of individuals prior to a Sz diagnosis – so infection is not just following psychosis. The authors suggest that these results can be explained by this hypothesis: autoimmune disease can lead in some cases to antibodies that cross-react with the brain. While these antibodies are not ordinarily able to cross the blood-brain barrier, an infection causes a loosening of the barrier, allowing the antibodies in, where they can alter the function of brain circuits and influence behavior, perhaps permanently.
Comment from Beth Maloney:
|This last sentence summary is the exact same hypothesis as for PANDAS|