Biofluid Metabonomics Study On Schizophrenia

Schizophrenia is one of the most common psychiatric disorders, which affects nearly 1 percent of the population worldwide across different cultures and regions. Schizophrenia is a multi-factor disease, resulted from interactions of genetics and environmental risks, the former accounted for 80 percent. Many hypothesis have been proposed for the mechanisms of schizophrenia, however it is yet to be fully elucidated.Clinically, the diagnosis of schizophrenia depends on the subjective impression of positive and negative syndroms of patients to doctors. DSM-IV and ICD-10, established respectively by American Psychological Association and World Health Orgnization, are basic diagnostic tools for schizophrenia., where scales are utilized to qualify and quantify syndromes. However, schizophrenia has heterogeneous presentations, with positive and negative symptoms at different levels of prominence across time and across individuals. Till now, there is not exact definition for schizophrenia syndromes, which makes diagnosis difficult.Systems biology is the effective approach for complex diseases, with genetics, transcriptomics, proteomics and metabonomics studying respective level of life. Metabonomics is the global assessment of endogenous metabolites within a biologic system and represents a "snapshot" reading of gene function, enzyme activity and the physiological landscape. Since loss of metabolic homeostasis is common in critical illness, the metabonomics could have many applications, including providing biomarkers for disease, subtype, efficacy evaluation and toxicology study, as well as insights for metabolism disorders underlying these biomarkers.Based on the platform of gas chromatography time-of-flight mass spectrometry (GC-TOFMS), we investigated the global metabolome in sera and urine of schizophrenia patients and normal controls. A panel of serum markers consisting of glycerate, eicosenoic acid, beta-hydroxybutyrate, pyruvate and cystine was identified as an effective diagnostic tool, achieving an area under the receiver operating characteristic curve (AUC) of 0.945 in the training samples (62 patients and 62 controls) and 0.895 in the test samples (50 patients and 48 controls). Furthermore, a composite panel by the addition of urine beta-hydroxybutyrate to the serum panel, achieved a more satisfactory accuracy, which reached an AUC of 1 in both the training set and the test set. Middle-to-lang and short-to-middle chain fatty acids were found increased respectively in sera and urines of schizophrenia patients compared to normal controls, indicating an upregulated fatty acids metabolism in disease. It is proposed to result from a deficiency of energy from blood glucose in the circulation, which is further evidenced by the accumation of 3-hydroxybutyrate in sera and urines, since it is an alternative energy source for glucose. These results provided metabolic evidences for the hypothesis of energy metabolism disorder from genetics and proteomics studies. Cystine is the preferred form of cysteine for the synthesis of glutathione in astrocytes. The depletion of serum cystine observed in the present study may be indicative of an increased oxidative stress in neurological diseases, which is proposed to recuite cystine in the circulation to synthese glutathione to neutralize reactive oxidative species. Glutamate is the predominant excitatory neurotransmitter of the vertebrate central nervous system. Generally, brain glutamate is compartalized by the brain-blood-barrier aginst from influence of the fluctuation of glutamate concentration in circulation brought by food and/or drink. The elevated concentration of glutamate in serum is proposed to provide energy for the brain or influence the glutamate-GABA homeostatic balance.We also investigated the serum metabolome shift of schizophrenia patients after 4-week medication. Spaces of all metabolome from patients with chlopramazine, clozapine, risperidone were normalized to those of healthy controls. The data suggested metabonomics potential to be used for drug efficacy evaluation and dose instruction.