Metabolic Profiling of CSF: Evidence That Early Intervention May Impact on Disease Progression and Outcome in Schizophrenia
Elaine Holmes1, Tsz M. Tsang1, Jeffrey T.-J. Huang2, F. Markus Leweke3, Dagmar Koethe3, Christoph W. Gerth3, Brit M. Nolden3, Sonja Gross3, Daniela Schreiber3, Jeremy K. Nicholson1, Sabine Bahn2*
1 Biological Chemistry, Biomedical Sciences Division, Faculty of Medicine, Imperial College, London, United Kingdom, 2 Institute of Biotechnology, University of Cambridge, Cambridge, United Kingdom, 3 Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
Background
The 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.
Conclusions
Our 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.
Funding: The study was funded through grants from the Stanley Medical Research Institute (USA) and the Henry Smith Charity (UK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Academic Editor: John McGrath, University of Queensland, Australia
Received: January 12, 2006; Accepted: May 26, 2006; Published: August 22, 2006
DOI: 10.1371/journal.pmed.0030327
Copyright: © 2006 Holmes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited....
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