A Systemic Look At Schizophrenia

Because schizophrenia is a psychiatric disorder, its physical manifestations must all be in the brain, right? Maybe not. Proteomic studies using cells from other parts of the body are showing that there might be a systemic aspect of the disorder. The ability to use nonbrain cells to study schizophrenia could make it easier to find biomarkers of the disease and to develop diagnostic tools.

To date, most studies of the disorder have been done with brain tissue taken from schizophrenia patients after death. A major drawback of such studies is that the tissue might no longer reflect the circumstances that existed while the patient was still alive.

“The problem with psychiatric disorders is that you can’t take biopsies at different disease stages,” says Sabine Bahn, director of the Cambridge Institute for Psychiatric Research at the University of Cambridge. “Patients would not be too happy to have pieces of brain taken at different time points.”

Bahn and her colleagues are investigating disease markers in tissues such as skin, immune cells, and blood serum to find samples that give a real-time picture of the disease. Their studies of protein expression in fibroblasts (skin cells) on schizophrenia patients’ arms have identified systemic problems such as cell-cycle abnormalities (J. Proteome Res. 2010, 9, 521).

“It’s clear that schizophrenia has a very strong genetic component,” Bahn says. “Most genes are not used only in the brain. If there is an underlying abnormality at the genetic level that leads to pathology in the brain, the assumption can be made that there should also be dysregulation in the peripheral system. It may not lead to pathology, but it may reflect the pathology in the brain.”

Bahn and her coworkers have seen that 40% of the changes observed in the brains of schizophrenia patients also occur in the peripheral systems. The affected pathways include cell replication, immune function, and glucose metabolism.

“We were pleased that some of our previous findings could be reproduced in the fibroblast system,” Bahn says. “It was reassuring that we can trace central nervous system abnormalities in the peripheral system.”

Bahn started out working with fibroblasts, but she is now using immune cells in her schizophrenia studies. Skin cells are easier to culture than immune cells, but the latter have the advantage that they are involved in more signaling pathways. Immune cells are “much more similar to neurons in the way they have to communicate with other cells,” Bahn says.

Other researchers see both advantages and disadvantages in using peripheral cells to study schizophrenia. “Differentially expressed proteins in blood and cerebrospinal fluid might be used as good biomarkers, but they are not always as informative as brain proteins regarding an understanding of the disease,” says Daniel Martins-de-Souza, a schizophrenia researcher at Max Planck Institute of Psychiatry, in Munich.

Earlier studies from other labs suggest that the link between neural cells and peripheral cells might not be so clear cut. In a gene expression study using white blood cells and skin cells from schizophrenia patients and control individuals, Nicholas A. Matigian and coworkers of Queensland Institute of Medical Research, in Australia, found no convergent set of differentially expressed genes in the different cell types (PLoS One 2008, 3, e2412). The lack of a common set of changes in white blood cells and fibroblasts “weakens the case that these nonneuronal tissue sources are informative for detecting the underlying causative genetic and epigenetic changes responsible for” schizophrenia, the researchers wrote.

Bahn nevertheless believes peripheral-cell-based diagnostics will be useful. She and her coworkers have identified schizophrenia biomarkers in serum, and working with the company Rules-Based Medicine, located in Austin, Texas, and Lake Placid, N.Y., she expects that a serum-based test to aid in the diagnosis of schizophrenia will be launched sometime this year.

“We’ve identified a signature of numerous protein biomarkers, which give a very high sensitivity and specificity,” Bahn says. “We’ve looked at hundreds of samples from patients and controls and other disorders that are related to schizophrenia.”

The test would help confirm diagnoses made on the basis of conventional methods. “The customary window is often a delay of several years until someone is confirmed and diagnosed,” Bahn says. “We know very well that if patients are treated early in the disease process, we improve outcome.”

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