Abstract
BackgroundThe identification of schizophrenia biomarkers is a crucial step towards improving current diagnosis, developing new presymptomatic treatments, identifying high-risk individuals and disease subgroups, and assessing the efficacy of preventative interventions at a rate that is not currently possible.Methods and Findings 1H nuclear magnetic resonance spectroscopy in conjunction with computerized pattern recognition analysis were employed to investigate metabolic profiles of a total of 152 cerebrospinal fluid (CSF) samples from drug-naïve or minimally treated patients with first-onset paranoid schizophrenia (referred to as “schizophrenia” in the following text) and healthy controls. Partial least square discriminant analysis showed a highly significant separation of patients with first-onset schizophrenia away from healthy controls. Short-term treatment with antipsychotic medication resulted in a normalization of the disease signature in over half the patients, well before overt clinical improvement. No normalization was observed in patients in which treatment had not been initiated at first presentation, providing the first molecular evidence for the importance of early intervention for psychotic disorders. Furthermore, the alterations identified in drug-naïve patients could be validated in a test sample set achieving a sensitivity and specificity of 82% and 85%, respectively.ConclusionsOur findings suggest brain-specific alterations in glucoregulatory processes in the CSF of drug-naïve patients with first-onset schizophrenia, implying that these abnormalities are intrinsic to the disease, rather than a side effect of antipsychotic medication. Short-term treatment with atypical antipsychotic medication resulted in a normalization of the CSF disease signature in half the patients well before a clinical improvement would be expected. Furthermore, our results suggest that the initiation of antipsychotic treatment during a first psychotic episode may influence treatment response and/or outcome.
Highlights
The current diagnosis of schizophrenia remains subjective, because of the complex spectrum of symptoms and their similarities to other mental disorders, and due to the lack of empirical disease markers
Plots of partial least square discriminant analysis (PLS-DA) scores based on 1H nuclear magnetic resonance (NMR) spectra of cerebrospinal fluid (CSF) samples showed a clear differentiation between healthy volunteers and drug-naıve patients with first-onset schizophrenia (Figure 1)
Results from 1H NMR spectroscopy showed significantly elevated glucose concentrations in CSF samples from drug-naıve patients with first-onset schizophrenia, as compared to the demographically matched control group, with a relative increase in concentration of 6.5% (p 1⁄4 0.04; calculated from a distinct resonance signal at 3.68–3.72 ppm)
Summary
The current diagnosis of schizophrenia remains subjective, because of the complex spectrum of symptoms and their similarities to other mental disorders, and due to the lack of empirical disease markers. Biomarkers derived from global expression profiling techniques performed on readily accessible body fluids, such as cerebrospinal fluid (CSF), serum, urine, or saliva, can help identify disease subtypes, aid in predicting and monitoring treatment response and compliance, and identify novel drug targets. These biomarkers could open up the possibility of developing new early or presymptomatic treatments to improve outcomes or even prevent pathology. The researchers studied the metabolic state of patients and healthy volunteers (controls) In other words, they focused on the small molecules present in cells, tissues, or body fluids. Focusing on the metabolic state makes sense for a disease like schizophrenia, since many different genetic and environmental factors are thought to be responsible for causing it
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