Biomarkers that can be used for the early diagnosis of schizophrenia are urgently required because there are currently no objective diagnostic tests available. New research recently published in PLoS Medicine could be a step towards such biomarkers. The authors show that metabolite profiles from cerebrospinal fluid (CSF) reveal patterns that could identify high-risk individuals and enable more appropriate and timely therapeutic intervention.
The use of NMR spectroscopy and principal components analysis (PCA) to identify profiles of metabolites from bodily fluid is well established. However, there have been few studies of this type looking at the metabolite profile of CSF for diagnostic purposes. Bahn and colleagues therefore set out to identify differences in CSF metabolites between patients with schizophrenia and healthy volunteers. They analysed CSF metabolites from drug-naive patients diagnosed with a single episode of paranoid schizophrenia; schizophrenic patients undergoing treatment with either typical or atypical antipsychotic medication (including both first-episode onset and patients who have suffered several psychotic episodes); and demographically matched healthy volunteers.
The authors observed several trends in the CSF metabolite signatures that merit further investigation. A significant increase in glucose, and a decrease in lactate and acetate, was observed in the CSF but not the serum of drug-naive schizophrenic patients, suggesting a brain-specific change in the levels of these metabolites. These metabolite levels were normalized in 50% of patients with first-episode onset schizophrenia by treatment with atypical, but not typical, antipsychotic drugs. Additionally, it was noted that this normalization did not occur in patients who had suffered several psychotic episodes before treatment was initiated.
These findings provide some illuminating insights into schizophrenia pathology and the efficacy of treatment. Studies have previously shown that first-episode onset schizophrenic patients often have an abnormally high fasting glucose tolerance and there is also a prevalence of type 2 diabetes among sufferers. The authors propose that antipsychotic drug treatment might exacerbate an existing 'co-predisposition' to these two diseases, and that they might actually share a common disease mechanism. The observed decrease in acetate and lactate also suggests a different preference for energy source in cells of the schizophrenic brain, which might provide a clue to understanding the pathogenesis of the disease.
However, until more is understood about schizophrenia disease mechanisms that can be used in the discovery of novel drugs, this preliminary metabolite signature could at least direct the best use of current treatment options. For example, the fact that only first-episode onset schizophrenic patients had a normalized metabolite profile after drug treatment provides the first molecular evidence that early intervention is crucial to treatment outcome. Moreover, although most of the drug-naive first-episode onset samples clustered tightly, the presence of some outliers suggests that disease subgroups might exist for schizophrenia that might require different treatment regimens for maximum success. Further investigation is needed to translate these early molecular indicators into robust biomarkers for schizophrenia, but this study provides an initial proof-of-concept for CSF profiling of biomarkers for psychiatric diseases.