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Biomarker May Be Useful In Diagnosing Schizophrenia

Spectroscopic analysis of cerebrospinal fluid reveals possible new biomarkers that could assist in schizophrenia evaluations.

Biochemical analysis of cerebrospinal fluid (CSF) can differentiate schizophrenia patients from healthy controls and show early effects of drug treatment, according to a British study.

Besides its specific results, the study indicates the potential of studying metabolism in the same way that the study of the genome has transformed medicine. The study appeared in the august issue of the online journal PLoS Medicine.

Elaine Holmes, Ph.D., a reader in biological chemistry in the Faculty of Medicine at Imperial College, London, and 10 colleagues, used ¹H nuclear magnetic resonance (¹H NMR) spectroscopy to establish the characteristic patterns in the study. At present, no biomarkers exist to diagnose schizophrenia.

Among the 152 study subjects were 70 healthy volunteers, two groups of drug-naïve patients diagnosed with first-onset schizophrenia (one group with 37 patients, another with 17, used for validation), six patients taking first-generation antipsychotics, and 22 patients taking second-generation antipsychotics. The researchers analyzed CSF samples using ¹H NMR.

Plotting the results revealed a clear difference between the untreated patients with schizophrenia and the healthy volunteers.

A few of the CSF samples did not produce this clear differentiation, however.

The study was too small to make assumptions about patient subgroups, but the four schizophrenia patients who clustered with the control group had an exceptionally good outcome or recovered fully from a first episode of psychosis, said the authors.

"This may indicate the existence of schizophrenia subgroups, and it will be of interest to explore whether clinical parameters, such as disease progression, severity, and/or drug response, relate to distinct metabolic signatures."

Glucose, acetate, alanine, and glutamine resonances accounted for most of the separation between the two groups. Lower acetate, for instance, may reflect "compromised synthesis of myelin-related fatty acids and lipids in the schizophrenia brain." Glucose levels in the patients with schizophrenia were higher than those in controls, although serum glucose levels for both groups were the same. This suggests that some factor in the brain or CSF causes those elevations.

Elevated serum glucose levels and higher rates of type 2 diabetes have been blamed on antipsychotic drug treatment. The current study at least hints that impaired glucose or acetate may be connected to schizophrenia through problems of energy synthesis or lipid biosynthesis.

"It is possible that drug treatment precipitates the onset of diabetes in patients with schizophrenia in the context of a co-predisposition, and that both schizophrenia and diabetes type 2 share common disease mechanisms," wrote Holmes and colleagues.

The researchers also tested the effects of drug treatments on CSF biochemistry. An atypical antipsychotic given for nine days normalized CSF levels in about half the schizophrenia patients. Typical antipsychotics showed no such effect in the six patients using those drugs.

However, patients who had experienced several psychotic episodes before treatment did not see their CSF profiles normalize, boosting the case for early intervention.

The normalizing changes in the CSF occurred within days, well before a clinical response to treatment, which might take weeks or months. If confirmed, this effect might open useful avenues of diagnosis, treatment, and drug development in schizophrenia, said the authors. For instance, this study did not identify the medications used beyond "typical" or "atypical," but a larger trial might test if individual patients varied in their response to specific drugs.

While the results must be replicated and validated, editorialized Rima kaddurah-Daouk, Ph.D., an adjunct associate professor of psychiatry at Duke University, "the study nevertheless exemplifies the potential for metabolomics in the study of human disease."

Metabolomics is the study of the metabolome, the biochemicals in body cells, fluids, or tissues.

"Metabolomics has the potential to map early biochemical changes in disease and hence provide an opportunity to develop predictive biomarkers that can trigger earlier interventions," said kaddurah-Daouk.

The study was supported by the Stanley Medical Research Institute and the Henry Smith Charity.

"Metabolic Profiling of CSF: Evidence That Early Intervention May Impact on Disease Progression and Outcome in Schizophrenia" is posted at <http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0030327>.

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