CSF Biomarkers Studied as Factors to Predict Schizophrenia Onset

Could certain molecules in the cerebrospinal fluid eventually help predict the onset of psychosis?

Lindsay Hayes, Ph.D.

That is a possibility, a study led by Lindsay Hayes, Ph.D., a postdoctoral fellow at the Johns Hopkins Schizophrenia Center, and Akira Sawa, M.D., Ph.D., director of the center, found. The results were published online April 17 in Schizophrenia Bulletin.

Since recent evidence suggests that the immune system in conjunction with infection might play a role in the pathology of schizophrenia, Hayes, Sawa, and colleagues conducted a study to determine whether various immune system molecules in the cerebrospinal fluid might correlate with the presence of schizophrenia or with its prodromal phase.

The study included 46 subjects with DSM-IV-diagnosed schizophrenia; 15 subjects at risk of schizophrenia according to one of three criteria—attenuated positive symptoms, brief limited intermittent psychotic symptoms, or a recent decline in function combined with having a first- or second-degree relative with a history of a DSM-IV psychotic disorder—and 35 control subjects. None of the subjects with schizophrenia or at risk for the disorder were taking antipsychotic medications, although a few at-risk subjects were taking low-dose benzodiazepines.

Cerebrospinal fluid from each of the subjects was evaluated for levels of 90 different molecules. Most of these molecules had primarily immune-system functions; some, such as testosterone and adiponectin, did not. “However, there is some evidence that testosterone may also have some immune modulatory roles,” Hayes told Psychiatric News.

The researchers found significant differences between the schizophrenia group and the control group, as well as between the schizophrenia-risk group and the control group, on levels of 15 of the 90 molecules assessed. This led them to the belief that these molecules may play a role in the origins of schizophrenia.

They discovered as well that the levels of six of these molecules—alpha-2-macroglobulin, fibrinogen, interleukin-6 receptor, stem cell factor, transforming growth factor alpha, and tumor necrosis factor receptor two—were even more decreased in the schizophrenia-risk group than in the group that already had schizophrenia, while the levels of three of these molecules—interleukin-8, monocyte chemotactic protein 2, and testosterone (in males only)—were more elevated in the schizophrenia-risk group than in the group that already had a schizophrenia diagnosis.

It is thus possible that such excessively decreased or increased levels might serve as predictive biomarkers for the onset of schizophrenia, the researchers hypothesized.

“However, this data is very preliminary and needs to be validated with additional large cohorts and in longitudinal studies to confirm their predictive impact,” Hayes cautioned.

“This is an interesting study,” Alan Brown, M.D., a professor of psychiatry and epidemiology at Columbia University, said in an interview with Psychiatric News. Brown has conducted research on infectious agents that might be linked to development of schizophrenia. “The study’s strengths include the fact that the cerebrospinal fluid is being measured, which is directly indicative of neuroinflammation, and the inclusion of subjects with at-risk mental states, which decreases, at least to some degree, the possibility of the influence of confounding factors, such as those associated with lifestyle differences.”

However, “Since many analytes were measured, one needs to be somewhat cautious in interpretation given the multiple comparisons,” Brown pointed out. Yet the finding that “the abnormalities appeared to be greater in those with at-risk mental states than with schizophrenia suggests that a longitudinal study with cerebrospinal fluid immunologic biomarkers in the same individuals tested at different time points could be very promising.”

The study was funded by the National Institutes of Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute. ■