A Combined UPLC-MS/MS And~1H NMR-based Metabonomic Study Of Plasma And Urine From Schizophrenics Treated With Risperidone

The exact mechanism underlying schizophrenia remains unclear. However, among all the hypotheses proposed to explain its pathophysiology, the disturbance and imbalance in the metabolism of central neurotransmission involved in schizophrenia are mostly studied and acquainted with. At the mean time, recent researches showed that the prevalence of metabolic syndrome, disturbances of glucose and lipid metabolism were substantially increased in schizophrenia, leading to the new recognition that the schizophrenia syndrome may be systematic instead of solely central.With the aim to investigate the mechanism of the pathophysiology and treatment of schizophrenia from a more systematic view, we conducted a combined ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and1H Nuclear magnetic resonance (1H NMR)-based metabonomic study of plasma and urine from schizophrenics treated with risperidone, focusing on:(1) the differences in monoamine and amino acid neurotransmitter metabolisms between schizophrenics and paired controls, their alterations during risperidone treatment, and the clinical correlation of biochemical indices with symptomatology;(2) neurotransmitter metabolic profiling of plasma and urine samples of schizophrenic patients and controls;(3) metabonomic study based on the UPLC-MS full scan data, investigating the dynamic trajectory of metabolic profiles of schizophrenics and comparing the difference between first-episode and relapsed subgroup;(4) metabolic alterations in the first-episode schizophrenic patients, to identify the biomarkers affecting classification and reveal their change trends during treatment.The results were as follows:(1) There are multiple significant differences in the neurotransmitter metabolism between schizophrenics and paired controls. Some of the reported differences relate only to a subgroup of patients. The biochemical indices in plasma better correlate to the symptom domains, whereas the difference in neurotransmitter metabolism of urine turn out to be more prominent;(2) The neurotransmitter profiles of plasma and urine from schizophrenics are restoring under the antipsychotic treatment with risperidone. Moreover, the metabonomic models based on the neurotransmitter indices tested could be used as a potential tool for schizophrenia diagnosis and subgroup classifying.(3) Bodyfluid metabolic profiling employing UPLC-MS full scan data have shown the discrepancy between schizophrenics and controls, and further demonstrated that risperidone treatment would strikingly widen the existing gap in the situation. The metabolic profile difference in the first-episode versus relapsed subgroup stands throughout the observation, but it has become gradually smaller during treatment.(4) The biomarkers identified by a combined UPLC-MS/MS and1H NMR-based metabonomic study on the first-episode schizophrenics were alanine, valine, glycine, glucose, lactate, lipoproteins, unsaturated fatty acids, lipid, acetoacetate,3-hydroxybutyrate, phosphatidylcholine, lysophosphatidylcholines, citrate, a-ketoglutarate, creatine, creatinine, uric acid, taurine,3-indolebutyrate, hippurate, trimethylamine-N-oxide and pregnanediol, illustrating the perturbations of amino acid metabolism, sugar metabolism, lipid metabolism and energy metabolism, as well as systemic oxidative stress, gut microflora variation and endocrine dyscrasia they are possibly suffering from.The stated metabonomic study of risperidone treated schizophrenic patients vividly describes a dilemma of current antipsychotic medication from another angle, that is, antipsychotic drugs may aggravate the already existing disruptions in their system health condition when alleviating clinical mental symptom dimensions.