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
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
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
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,
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
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
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