利培酮治疗精神分裂症患者血浆和尿液的代谢组学研究
|
摘要
关于精神分裂症发生的确切机制至今仍不清楚,但多数研究认为和中枢神经递质代谢的紊乱失衡有关,同时最近研究表明,精神分裂症患者糖、脂代谢异常率、代谢综合征发生率显著高于普通人群,提示精神分裂症并非单纯只是中枢神经系统的疾病,而更可能是全身性的系统疾病。
为从系统代谢物的角度,更加全面地探讨精神分裂症的发病和治疗机制,本课题采用基于超高效液相-串联质谱(UPLC-MS/MS)和氢核磁共振(1H NMR)的代谢组学技术进行了以下研究：(1)服用利培酮的精神分裂症病人血浆、尿液中单胺类与氨基酸类神经递质代谢状况与正常人之间的差异,治疗前后的变化,以及与临床精神症状的相关性研究；(2)利用代谢组学多元统计方法对精神分裂症病人血浆、尿液中神经递质的代谢轮廓进行分析并构建数学模型；(3)使用UPLC-MS/MS对入组的病人血浆、尿液中的代谢物进行全扫描分析,考察机体在利培酮治疗期间代谢谱的动态变化,以及首发与复发病人的代谢轮廓差异；(4)采用UPLC-MS/MS和1H NMR对首发精神分裂症患者样品进行系统全面的代谢组学扫描分析,筛选反映疾病与利培酮治疗的生物标示物,并考察其变化趋势。
研究结果表明：(1)精神分裂症病人与正常人血浆、尿液中神经递质的代谢均存在显著差异,有些差异只存在于精神分裂症的亚组之中,血浆中神经递质的代谢与临床症状的相关性更好,尿液中神经递质代谢的差异更显著；(2)利培酮治疗后使血浆、尿液中神经递质的代谢轮廓逐渐向正常恢复,并且构建的相关数学模型可用于精神分裂症的诊断和亚型辨别；(3)UPLC-MS/MS对精神分裂症病人血浆和尿液的扫描数据表明,精神分裂病人与正常人机体的整体代谢状况在未服药之前便已存在着差异,并且在利培酮治疗的过程中这种差异非但没有减小,反而有逐渐扩大的趋势。首发与复发精神分裂症患者在整个治疗过程中代谢轮廓均存在显著性差异,但它们的差异随着药物治疗的进行在逐渐缩小；(4)通过对首发精神分裂症病人血浆和尿液的UPLC-MS/MS和1H NMR代谢组学研究,鉴定出的生物标示物有丙氨酸、缬氨酸、甘氨酸、葡萄糖、乳酸、脂蛋白、不饱和脂肪酸、脂质、乙酰乙酸、3-羟基丁酸、磷脂酰胆碱、溶血磷脂酰胆碱、柠檬酸、α-酮戊二酸、肌酸、肌酐、尿酸、牛磺酸、马尿酸、氧化三甲胺、3-吲哚丁酸和孕二醇,提示可能精神分症病人机体的氨基酸代谢、糖代谢、脂质代谢和能量代谢均有异常,并且存在着氧化应激、肠道微菌群紊乱和内分泌失调的状况。
通过本课题对利培酮治疗精神分裂症患者的代谢组学研究,从另一角度描绘了现在临床抗精神病治疗所面临的窘境：抗精神病药物在改善精神分裂症患者精神症状的同时,可能却使他们的整体健康状况逐渐恶化。
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.
为从系统代谢物的角度,更加全面地探讨精神分裂症的发病和治疗机制,本课题采用基于超高效液相-串联质谱(UPLC-MS/MS)和氢核磁共振(1H NMR)的代谢组学技术进行了以下研究：(1)服用利培酮的精神分裂症病人血浆、尿液中单胺类与氨基酸类神经递质代谢状况与正常人之间的差异,治疗前后的变化,以及与临床精神症状的相关性研究；(2)利用代谢组学多元统计方法对精神分裂症病人血浆、尿液中神经递质的代谢轮廓进行分析并构建数学模型；(3)使用UPLC-MS/MS对入组的病人血浆、尿液中的代谢物进行全扫描分析,考察机体在利培酮治疗期间代谢谱的动态变化,以及首发与复发病人的代谢轮廓差异；(4)采用UPLC-MS/MS和1H NMR对首发精神分裂症患者样品进行系统全面的代谢组学扫描分析,筛选反映疾病与利培酮治疗的生物标示物,并考察其变化趋势。
研究结果表明：(1)精神分裂症病人与正常人血浆、尿液中神经递质的代谢均存在显著差异,有些差异只存在于精神分裂症的亚组之中,血浆中神经递质的代谢与临床症状的相关性更好,尿液中神经递质代谢的差异更显著；(2)利培酮治疗后使血浆、尿液中神经递质的代谢轮廓逐渐向正常恢复,并且构建的相关数学模型可用于精神分裂症的诊断和亚型辨别；(3)UPLC-MS/MS对精神分裂症病人血浆和尿液的扫描数据表明,精神分裂病人与正常人机体的整体代谢状况在未服药之前便已存在着差异,并且在利培酮治疗的过程中这种差异非但没有减小,反而有逐渐扩大的趋势。首发与复发精神分裂症患者在整个治疗过程中代谢轮廓均存在显著性差异,但它们的差异随着药物治疗的进行在逐渐缩小；(4)通过对首发精神分裂症病人血浆和尿液的UPLC-MS/MS和1H NMR代谢组学研究,鉴定出的生物标示物有丙氨酸、缬氨酸、甘氨酸、葡萄糖、乳酸、脂蛋白、不饱和脂肪酸、脂质、乙酰乙酸、3-羟基丁酸、磷脂酰胆碱、溶血磷脂酰胆碱、柠檬酸、α-酮戊二酸、肌酸、肌酐、尿酸、牛磺酸、马尿酸、氧化三甲胺、3-吲哚丁酸和孕二醇,提示可能精神分症病人机体的氨基酸代谢、糖代谢、脂质代谢和能量代谢均有异常,并且存在着氧化应激、肠道微菌群紊乱和内分泌失调的状况。
通过本课题对利培酮治疗精神分裂症患者的代谢组学研究,从另一角度描绘了现在临床抗精神病治疗所面临的窘境：抗精神病药物在改善精神分裂症患者精神症状的同时,可能却使他们的整体健康状况逐渐恶化。
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.
引文
[1]Pederson AM, Tefft BM, Babigian HM, Risks of mortality of suicide attempters compared with psychiatric and general population. Suicide 1975; 5:145-157.
[2]Shinfuku, N. ed. Mental health care in the Western Pacific Region. International Journal of Mental Health,1993,22; Shinfuku, N. A study of the public health approach to mental health in the Western Pacific Region with specific reference to developing countries. Manila, WHO,1993.
[3]American Psychiatry Association,2000. Diagonostic and statistical manual of mental disorder, fourth ed., text revision (DSM-IV-TR). American Psychiatric Association, Washington, DC.
[4]First MB, Spitzer RL, Gibbon M, Williams JBW.2002. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). Biometrics Research. New York State Psychiatric Institute, New York.
[5]Thaker GK, Carpenter JR. Advances in schizophrenia. Nat Med,2001; 7: 667-671.
[6]Badner J, Gershon E. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatr 2002; 7:405-411.
[7]Lewis C, Levinson D, Wise L, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II:Schizophrenia. Am J Hum Genet 2003; 73:34-48.
[8]Moore, H., West, A.R., Grace, A.A., The regulation of forebrain dopamine transmission:relevance to the pathophysiology and psychopathology of schizophrenia. Biological Psychiatry 1999; 46,40-55.
[9]Crow T.J. Molecular pathology of schizophrenia:more than one disease process? Br Med J.1980; 280:66-68.
[10]Prosser E.S. Csernansky J.G., Kaplan J, Thiemann S., Becker T.J., Hollister, L.E., Depression, parkinsonia symptoms and negative symptoms in schizophrenics treated with neuroleptics. J Nerv Ment Dis 1987; 175:100-105.
[11]Andreasen, N.C., Positive vs. negative schizophrenia:a critical evaluation. Schizophr Bull 1985; 11:380-389.
[12]Davidson M, Keefe RS, Mohs RC, Siever LJ, Losonczy MF, Horvath TB, Davis KL, L-dopa challenge and relapse in schizophrenia. Am J Psychiatry 1987; 144:934-938.
[13]Moncrieff, J. A critique of the dopamine hypothesis of schizophrenia and psychosis. Harvard Review of Psychiatry 2009; 17:215-225.
[14]Bernberg DE, van Kammen DP, Lake CR, Ballenger JC, Marder SR, Bunney Jr WE. The effects of pimozide on CSF norepinephrine in schizophrenia Am J Psychiatry 1981; 138:1045-1050.
[15]See, R.E., Fido, A. A., Maurice, M., Ibrahim, M.M., Salama, G., Risperidone-induced increase of plasma norepinephrine is not correlated with symptom improvement in chronic schizophrenia. Biological Psychiatry 1999; 45,1653-1656.
[16]Carpenter W T, Heinrichs DW, Alphs LD. Treatment of negative symptoms, schizophr Bull 1985; 11:440-452.
[17]Meltzer HY. Biological studies in schizophrenia, Schizophr Bull 1987;13: 77-113.
[18]Kemali D, Maj M, Iorio G, Marciano F, Nolfe G, Galderisi S, Salvati A. Relationship between CSF noradrenaline level, C-EEG indicators of activation and psychoses ratting in drug-free schizophrenic patients, Acta Psychiatry Scand 1985; 71:19-24.
[19]Yamamoto K, Hornykiewicz O., Proposal for a noradrenaline hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 913-922.
[20]Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 1996; 153:466-476.
[21]Geyer, M.A., Vollenweider, F.X.,. Serotonin research:contributions to understanding psychoses. Trends in pharmacological sciences 2008; 29: 445-453.
[22]Luby ED, Cohen BD, Rosenbaum G, et al. Study of a new sehizophrenomimetic drug:seruyl. Arch Neurology and Psychiatry,1959, 81:363-369.
[23]Lodge D, Aram JA, Church J, et al. Excitatory amino acids and phencyclidine-like drugs. In:Hicks TP, Lodge D, McLennan H, editors. Excitatory amino acid transmission. Now York:Alan R. Liss lnc, 1987; 83-90.
[24]Roberts E. Prospects for research on schizophrenia. An hypotheses suggesting that there is a defect in the GABA system in schizophrenia. Neurosci Res Program Bull.1972; 10:468-482.
[25]Benes FM. Development of the glutamate, GABA, and dopamine systems in relation to NRH-induced neurotoxicity. Biol Psychiatry.1995; 38:783-787.
[26]Crow TJ. Molecular pathology of schizophrenia:more than one disease process? Bri Med J 1980; 280:66-68.
[27]Ford ES. Prevalence of metabolic syndrome defined by the international diabetes federation among adults in the US. Diabetes Care,2005,28: 2745-2749.
[28]Henderson DC, Cagliero E, Gray C et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities:A five-year naturalistic study. Am Psychiatry 2000; 157:975-978.
[29]Meyer J, Koro CE, Litalien GJ, The metabolic syndrome and schizophrenia. Int Rev Psychiatry 2005; 17:173-180.
[30]Becker KG. The common variants/multiple disease hypothesis of common complex genetic disorders. Med Hypotheses 2004; 62:309-317.
[31]Mukherjee S, Decina P, Bocola V, et al. Diabetes mellitus in schizophrenic patients. Compr Psychiat 1996; 37:68-73.
[32]许国旺,杨军.代谢组学及其研究进展.色谱,2003；21：316-320.
[33]许彬,王海龙,魏开华,张学敏,杨松成.代谢组学分析技术及其在几类 重大疾病研究中的应用.分析测试学报,2006；25：128-132.
[34]夏建飞,梁琼麟,胡坪,王义明,罗国安.代谢组学研究策略与方法的新进展.分析化学,2009；37：136-143.
[35]Yao, J.K., Reddy, R.D., Metabolic investigation in psychiatric disorders. Molecular Neurobiology 2005; 31:193-203.
[36]Holmes, E., Tsang, T.M., Huang, J.T., Leweke, F.M., Koethe, D., Gerth, C.W., Nolden, B.M., Gross, S., Schreiber, D., Nicholson, J.K., Bahn, S., Metabolic profiling of CSF:evidence that early intervention may impact on disease progression and outcome in schizophrenia. PLoS Medicine 2006; 3: 1420-1428.
[37]Huang, J.T., Leweke, F.M., Tsang, T.M., Koethe, D., Kranaster, L., Gerth, C.W., Gross, S., Schreiber, D., Ruhrmann, S., Schultze-Lutter, F., Klosterkotter, J., Holmes, E., Bahn, S., CSF metabolic and proteomic profiles in patients prodromal for psychosis. PLoS One 2007; 22:1-7.
[38]Tsang, T.M., Huang, J.T., Holmes, E., Bahn, S., Metabolic profiling of plasma from discordant schizophrenia twins:correlation between lipid signals and global functioning in female schizophrenia patiens. Journal of proteome research.2006; 5:756-760.
[39]Kaddurah-Daouk, R., McEvoy, J., Baillie, R.A., Lee, D., Yao, J.K., Doraiswamy, P.M., Krishnan, K.R.R., Metabolomic mapping of atypical antipsychotic effects in schizophrenia. Molecular psychiatry; 2007; 12: 934-945.
[40]Davidson, M., Losonczy, M.F., Mohs, R.C., Lesser, J.C., Powchik, P., Freed, L.B., Davis, B.M., Mykytyn, V.V., Davis, K.L., Effects of debrisoquin and haloperidol on plasma homovanillic acid concentration in schizophrenic patients. Neuropsychopharmacology 1987; 1:17-23.
[41]Konicki, P. E., Owen, R. R., Litman, R. E., Pickar, D., The acute effects of central-and peripheral-acting dopamine antagonists on plasma HVA in schizophrenic patients. Life sciences 1991; 48:1411-1416.
[42]Kaminski, R., Powchick, P., Warne, P.A., Goldstein, M., McQueeney, R.T., Davidson, M., Measurement of plasma homovanillic acid concentrations in schizophrenic patients. Progress in Neuro-Psychopharmacology and Biological Psychiatry 1990; 14:271-287.
[43]Liu G.S., Chen J.N., Ma Y.F., Simultaneous determination of catecholamines and polyamines in PC-12 cell extracts by micellar electrokinetic capillary chromatography with ultraviolet absorbance detection, J Chromatogr B 2004; 805:281-288.
[44]Siren H., Karjalainen U., Study of catecholamines in patient urine samples by capillary electrophoresis, J Chromatogr A.1999; 853:527-533.
[45]Yoshitake T., Fujino K., Kehr J., Ishida J., Nohta H., Yamaguchi M., Simultaneous determination of norepinephrine, serotonin, and 5-hydroxyindole-3-acetic acid in microdialysis samples from rat brain by microbore column liquid chromatography with fluorescence detection following derivatization with benzylamine, Anal. Biochem.2003; 312:125-133.
[46]Fotopoulou M.A., Ioannou P.C., Post-column terbium complexation and sensitized fluorescence detection for the determination of norepinephrine, epinephrine and dopamine using high-performance liquid chromatography, Anal.Chim.Acta.2002; 462:179-185.
[47]Jin W., Jin L.T., Shi G.Y., Ye J.N., Determination of monoamine transmitters and their metabolites by capillary electrophoresis with electrochemical detection, Anal. Chim. Acta.1999; 382:33-37.
[48]Zhang S., Xu Q., Zhang W., Jin L.T., Jin J.Y., In vivo monitoring of the monoamine neurotransmitters in rat brain using microdialysis sampling with liquid chromatography electrochemical detection, Anal. Chim. Acta.2001; 427: 45-53.
[49]Parrot S., Bert L., Badina L.M., Sauvinet V., Mas J.C., Senas L.L., Robert F., Bouilloux J.P., Chagny M.F.S., Denoroy L., Renaud B., Microdialysis Monitoring of Catecholamines and Excitatory Amino Acids in the Rat and Mouse Brain:Recent Developments Based on Capillary Electrophoresis with Laser-Induced Fluorescence Detection-A Mini-Review, Cell.Mol.Neurobiol. 2003; 23:793-804.
[50]Xiong S.X., Han H.W., Zhao R., Chen Y., Liu G.Q., Capillary electrophoresis of catecholamines with laser-induced fluorescence intensified charge-coupled device detection, Biomed.Chromatogr.2001; 15:83-88.
[51]Carrera V., Sabater E., Vilanova E., Sogorb M.A., A simple and rapid HPLC-MS method for the simultaneous determination of epinephrine, norepinephrine, dopamine and 5-hydroxytryptamine:Application to the secretion of bovine chromaffin cell cultures, J. Chromatogr. B.2007; 847: 88-94.
[52]Ozcan S., Senyuva H.Z., Improved and simplified liquid chromatography/ atmospheric pressurechemical ionization mass spectrometry method for the analysis of underivatized free amino acids in various foods, J. Chromatogr. A. 2006;1135:179-185.
[53]Vlckova M., Schwarz M.A., Determination of cationic neurotransmitters and metabolites in brain homogenates by microchip electrophoresis and carbon nanotube-modified amperometry, J. Chromatogr. A.2007; 1142:214-221.
[54]Jemal M., High-throughput quantitative bioanalysis by LC/MS/MS, Biomed. Chromatogr.2000; 14:422-429.
[55]Gu Q., Shi X.Z., Yin P. Y., Gao P., Lu X., Xu G.W, Analysis of catecholamines and their metabolites in adrenal gland by liquid chromatography tandem mass spectrometry, Anal. Chim. Acta.2008; 609:192-200.
[56]Su F.L., Wang F., Zhu R.H., Li H.D., Determination of 5-Hydroxytryptamine, Norepinephrine, Dopamine and Their Metabolites in Rat Brain Tissue by LC-ESI-MS-MS, Chromatographia.2009; 34:207-213.
[57]Beaudry F., Guenette S. A., Winterborn A., Marier J.F, Vachon P., Development of a rapid and sensitive LC-ESI/MS/MS assay for the quantification of propofol using a simple off-line dansyl chloride derivatization reaction to enhance signal intensity, J. Pharm. Biomed. Anal 2005; 39: 411-417.
[58]Peaston R.T., Weinkove C., Measurement of catecholamines and their metabolites, Ann. Clin. Biochem.2004; 41:17-38.
[59]Blin O. A comparative review of new antipsychotics, Can. J. Psychiatry.1999; 44:235-244.
[60]Mannens G. Huang M.L, Meuldermans W, Hendrickx J, Woestenborghs R, Heykants J. Absorption. metabolism and excretion of risperidone in humans. Drug. Metab. Dispos. Biol. Fate. Chem 1993; 21:1134-1141.
[61]Nagasaki T, Ohkubo T, Sugawara K, Yasui N., Furukori H., Kaneko S., Determinadon of risperidone and 9-hydroxyrisperidone in human plasma by high-performance liquid chromatography:application to therapeutic drug monitoring in Japanese patients with schizophrenia J. Pharm. Biomed. Anal 1999; 19:595-601
[62]Huang ML, Van Peer A. Woestenborgh R, De Coster R, Heykants J, Jansen AA, Zylicz Z, Visscher H.W., Jonkman J.H. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 1993; 54:257-268.
[63]Flarakos J, Luo W, Aman M, Svinarov D., Gerber N., Vouros P., Quantification of risperidone and 9-hydroxyrispefidone in plasma and saliva from adult and pediatric patients by liquid chromatography-Mass spectrometry. J ChromatogrA,2004; 1026,175-183.
[64]Balant-Gorgia A.E, Gex-Fabry M, Genet C., Balant L.P., Therapeutic drug monitoring of risperidone using a new, rapid HPLC method Reappraisal of inter individual variability factors. Ther Drug Monit 1999; 21:105-115.
[65]Titiet K, Deridet E, Cardone E, Abouelfath A, Moore N, Simplified high-performance liquid chromatographic method for determination of risperidone and 9-hydroxyrisperidone in plasma after overdose. J Chromatogr B.2002; 772:373-378.
[66]Remmerie B.M.M, Sips L.L. A, de Vries R., de Jong J., Validated method for the determination of risperidone and 9-hydroxyriperidone in human plasma by liquid chromatography-tandem mass spectrometry. J. Chromatogr. B,2003, 783:461-472.
[67]Aravagiri M, Marder S.R., Simultaneous determination of risperidone and 9-hydroxyrisperidone in plasma by liquid chromatography/electrospray tandem mass spectrometry. J Mass Spectrom,2000; 35:718-724
[68]Bergstrom and Oberg, MultiSimplex 98, Karlskrona, Sweden,1998.
[69]Shakerian F., Dadfarnia S., Shabani A.M.H., Rohani M., MultiSimplex optimization of on-line sorbent proconcentration and determination of iron by FI-AAS and microcolumn of immobilized ferron, Talanta.2008; 77:551-555.
[70]Delgado A., Usobiaga A., Prieto A., Zuloaga O., De Diego A., Madariaga J.M., Optimisation of the headspace-solid phase microextraction for organomercury and organotin compound determination in sediment and biota J. Sep. Sci.2008; 31:768-774.
[71]Ferreiros N., Iriarte G., Alonso R.M., Jimenez R.M., MultiSimplex and experimental design as chemometric tools to optimize a SPE-HPLC-UV method for the determination of eprosartan in human plasma samples, Talanta. 2006; 69:747-756.
[72]Tan I.K., Gajra B., Plasma and urine amino acid profiles in a healthy adult Singapore Ann. Acad. Med. Singapore.2006; 35:468-475.
[73]Mao H.M., Chen B.G., Qian X.M., Liu Z.M., Simultaneous determination of twelve biogenic amines in serum by high performance liquid chromatography, Microchem. J.2009; 91:176-180.
[74]Kang X.J., Xiao J., Huang X., Gu Z.Z, Optimization of dansyl derivatization and chromatographic conditions in the determination of neuroactive amino acids of biological samples, Clin. Chim. Acta.2006; 366:352-356.
[75]Salvador A., Moretton C., Piram A., Faure R., On-line solid-phase extraction with on-support derivatization for high-sensitivity liquid chromatography tandem mass spectrometry of estrogens in influent/effluent of wastewater treatment plants J. Chromatogr. A.2007; 1145:102-109.
[76]Gros C., Labouesse B., Study of the dansylation reaction of amino acids, peptides and proteins, Eur. J. Biochem.1969; 7:463-470.
[77]Moncrieff, J., A critique of the dopamine hypothesis of schizophrenia and psychosis. Harvard Review of Psychiatry 2009; 17:215-225.
[78]Oades, R.D., Klimke, A., Henning, U., Rao, M.L., Relations of clinical features, subgroups and medication to serum monoamines in schizophrenia. Human Psychopharmacology 2002; 17:15-27.
[79]Oades, R.D., Ropcke, B., Henning, U., Klimke, A., Neuropsychological measures of attention and memory function in schizophrenia:relationships with symptom dimensions and serummonoamine activity. Behavioral and Brain Functions 2005; 1:14-30.
[80]Oades, R.D., Ropcke, B., Eggers, C., Monoamine activity reflected in urine of young patients with obsessive compulsive disorder, psychosis with and without reality distortion and healthy subjects:an explorative analysis. J Neural Transm 1994; 96:143-159.
[81]van der Heijden FMMA, Tuinier S, Fekkes D, Sijben AES, Kahn RS, Verhoeven WMA. Atypical antipsychotics and the relevance of glutamate and serotonin. Eur Neuropsychopharmacol 2004;14:259-265.
[82]Maeshima H, Ohnuma T, Sakai Y, Shibata N, Baba H, Ihara H, et al. Increased plasma glutamate by antipsychotic medication and its relationship to glutaminase 1 and 2 genotypes in schizophrenia-Juntendo University Schizophrenia Projects (JUSP). Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:1410-1418.
[83]Carpenter W.T., Kirkpatrick B., Buchanan R.W., Schizophrenia:syndromes and diseases. J Psychiat Res 1999; 33,473-475.
[84]Marc D.T., Ailts J.W., Ailts Campeau D.C., Bull M.J., Olson B.K.L. Neurotransmitters excreted in the urine as biomarkers of nervous system activity:validity and clinical applicability. Neurosci Biobehav Rev 2011; 35: 635-644.
[85]Kopp, U., Bradley, T., Hjemdahl, P. Renal venous outflow and urinary excretion of norepinephrine, epinephrine, and dopamine during graded renal nerve stimulation. Am.J.Physiol.1983; 244:E52-E60.
[86]Wise, C., Stein, L., Dopamine-β-hydroxylase deficiency in the brains of schizophrenia patients. Science 1973; 181:344-347.
[87]Wyatt, R.J., Potkin, S.G., Bridge, T.P., Phelps, B.H., Wise, C.D., Monoamine oxidase in schizophrenia:an overview. Schizophrenia Bull 1980; 6:199-206.
[88]Dao-Castellana, M.H., Paillere-Martinot, M.L., Hantraye, P., Attar-Levy, D., Remy, P., Crouzel, C., et al., Presynaptic dopaminergic function in the striatum of schizophrenic patients. Schizophr Res 1997; 23:167-174.
[89]Hietala, J., Syvalahti, E., Vilkman, H., Vuorio, K., Rakkolainen, V., Bergman, J., et al., Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia. Schizophr Res 1999; 35:41-50.
[90]Eldrup, E., Significance and origin of DOPA, DOPAC, and dopamine-sulphate in plasma, tissues and cerebrospinal fluid. Dan Med Bull 2004; 51:34-62.
[91]Carpenter Jr., W.T., Murphy, D.L., Wyatt, R.J., Platelet monoamine oxidase activity in acute schizophrenia. The American Journal of Psychiatry 1975; 132: 438-441.
[92]Chen, M.-L., Chen, C.-H., Chronic antipsychotics treatment regulates MAOA, MAOB and COMT gene expression in rat frontal cortex. J Psychiat Res 2007; 41:57-62.
[93]Brown, A.S., Gewirtz, G., Harkavy-Friedman, J., Cooper, T., Brebion, G., Amador, X.F., et al., Effects of clozapine on plasma catecholamines and relation to treatment response in schizophrenia:a within-subject comparison with haloperidol. Neuropsychopharmacology 1997; 17:317-325.
[94]See, R.E., Fido, A.A., Maurice, M., Ibrahim, M.M., Salama, G., Risperidone-induced increase of plasma norepinephrine is not correlated with symptom improvement in chronic schizophrenia. Biol Psychiat 1999; 45: 1653-1656
[95]Elman, I., Goldstein, D.S., Green, A.I., Eisenhofer, G., Folio, C.J., Holmes, C.S., et al., Effects of risperidone on the periphreal noradrenegic system in patients with schizophrenia:a comparison with clozapine and placebo. Neuropsychopharmacology 2002; 27:293-300.
[96]Oades, R.D., Ropcke, B., Henning, U., Klimke, A., Neuropsychological measures of attention and memory function in schizophrenia:relationships with symptom dimensions and serum monoamine activity. Behavioral and Brain Functions 2005; 1:14-30.
[97]Breier, A., Serotonin, schizophrenia and antipsychotic drug action. Schizophr Res 1995; 14:187-202.
[98]Moncrieff, J., A critique of the dopamine hypothesis of schizophrenia and psychosis. Harvard Rev Psychiatr 2009; 17:215-225.
[99]Ichikawa, J., Ishii, H., Bonaccorso, S., Fowler, W.L., O'Laughlin, I.A., Meltzer, H.Y.,5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation:a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 2001; 76: 1521-1531.
[100]Issa, F., Gerhardt, G.A., Bartko, J.J., Suddath, R.L., Lynch, M, Gamache, P.H., et al., A multidimensional approach to analysis of cerebrospinal fluid biogenic amines in schizophrenia:Ⅰ. Comparisons with healthy control subjects and neuroleptictreated/unmedicated pairs analyses. Psychiat Res 1994; 52:237-249.
[101]Oades, R.D., Klimke, A., Henning, U., Rao, M.L., Relations of clinical features, subgroups and medication to serum monoamines in schizophrenia. Hum Psychopharmacol Clin Exp 2002; 17:15-27.
[102]Grimm J, See R. Unique activation of extracellular striato-pallidal neurotransmitters in rats following acute risperidone. Brain Res 1998; 801: 182-189.
[103]Kikumoto O, Okamoto Y, Hayakawa H, Yokota N, Kawai K, Motohashi N, et al. Effects of risperidone on catalepsy and cerebral dopamine, serotonin and GABA metabolism in the rat:Comparison with haloperidol. Jpn J Psychopharmacol 1993;13:39-42.
[104]Roy-Byrne P, Cowley D, Hommer D, Greenblatt D, Kramer G, Petty F. Effect of acute and chronic benzodiazepines on plasma GABA in anxious patients and controls. Psychopharmacology 1992;109:153-156.
[105]Palomino A, Vallejo-Illarramendi A, Gonzalez-Pinto A, Aldama A, Gonzalez-Gomez C,Mosquera F, et al. Decreased levels of plasma BDNF in first-episode schizophrenia and bipolar disorder patients. Schizophr Res 2006; 86:321-322.
[106]Matute C, Melone M, Vallejo-Illarramendi A, Conti F. Increased expression of the astrocytic glutamate transporter GLT-1 in the prefrontal cortex of schizophrenics. Glia 2005; 49:451-455.
[107]Chen M.K, Tsang T.M, Harris L.W, Guest P.C, Holmes E, Bahn S., Evidence for diease and antipsychotic medication effects in post-mortem brain from schizophrenia patients. Mol Psychiatr 2010; 1-14.
[108]Nicholson J.K, Foxall P.J., Spraul M., Farrant R.D., Lindon J.C.,750 MHz 1H and 1H-13C NMR spectroscopy of human blood plasma. Anal Chem 1995; 67: 793-811.
[109]Zuppi C, Messana I, Forni F, Rossi C, Pennacchietti L, Ferrari F, Giardina B, 1H NMR spectra of normal urines:Reference ranges of the major metabolites. Clin Chim Acta 1997; 265:85-97.
[110]Smeraldi E., Lucca A., Macciardi F., Bellodi L. Increased concentrations of various amino acids in schizophrenic patients-Evidence for heterozygosity effects? Hum Genet 1987; 76:138-140
[111]Herberth M., Koethe D., Chen TMK., Krzyszton ND., Schoeffmann S., Guest PC., Rahmoune H., Harris LW., Kranaster L., Leweke FM., Bahn S. Impaired glycolytic response in peripheral blood mononuclear cells of first-onset antipsychotic-naive schizophrenia patients. Mol Psychiatr 2011; 16:848-859.
[112]Xie GX., Chen TL., Qiu YP., Shi P., Zheng XJ., Su MM., Zhao AH., Zhou ZT. Jia W. Urine metabolite profiling offers potential early diagnosis of oral cancer. Metabolomics.2011, DOI 10.1007/s11306-011-0302-7
[113]Yang YX., Li CL., Nie X, Feng XS, Chen WX, Yue Y., Tang HR, Deng F. Metabonomic studies of human hepatocellular carcinoma using High-Resolution Magic-Angle Spinning 1H NMR Spectroscopy in conjunction with multivariate data analysis. J Proteome Res 2007; 6:2605-2614.
[114]Wu GY, Amino acids:metabolism, functions, and nutrition. Amino Acids 2009; 37:1-17.
[115]Javitt DC, Zylberman I, Zukin SR, Heresco-Levy U, Lindenmayer JP. Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry 1994; 151:1234-1236.
[116]Kohen D., Diabetes mellitus and schizophrenia:historical perspective Brit J Psychiat.2004; 184:s64-s66.
[117]Ryan M.C., Collins P., Thakore J.H., Impaired fasting glucose tolerance in first-episode, drug naive patients with schizophrenia. Am J Psychiatry 2003; 160:284-289.
[118]Martin BC., Warram JH., Krolewski AS., Bergman RN., Soeldner JS., Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus:results of a 25-year follow-up study. Lancet 1992; 340:925-929.
[119]Marklova E, Albahri Z, Nozickova M. HPLC profiling of Trp-related metabolites in humans. Adv Exp Med Biol.2003;527:739-744.
[120]Silverstein MN, Wakim KG, Bahn RC. The influence of tryptophan metabolites on tissue uptake of glucose. Metabolism.1967;16:410-412.
[121]Boston, P.F., Dursun, S.M., Reveley, M.A., Cholesterol and mental disorder. Brit J Psychiat 1996a; 169:682-689.
[122]Levin Y., Wang L., Schwarz E., Koethe D., Leweke FM., Bahn S. Global proteomic profiling reveals altered proteomic signature in schizophrenia serum. Mol Psychiatr 2010; 15:1088-1100.
[123]Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S, Kaplan DB, Tretta MG, Allen M. Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry 1991; 48:563-568.
[124]Yao JK, Stanley JA., Reddy RD., Keshavan MS., Pettegrew JW. Correlations between peripheral polyunsaturated fatty acid content and in vivo membrane phospholipid metabolites. Biol Psychiatry 2002; 52:823-830.
[125]Huang T.L., Ghen J.F., Serum lipid profiles and schizophrenia:Effects of conventional or atypical antipsychotic drugs in Taiwan. Schizophr Res.2005; 80:55-59.
[126]Gattaz WF, Sehinitt A, Maras A. Increased platelet phospholipase A2 activity in schizophrenia. Schizophr Res,1995;16:1-6.
[127]Khan MM, Evans DR, Gunna V, Scheffer RE, Parikh VV, Mahadik SP. Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics. Schizophr Res.2002;58:1-10.
[128]Arakawa T., Goto T., Okada Y., Effect of ketone body (D-3-hydroxybutyrate) on neural activity and energy metabolism in hippocampal slices of the adult guinea pig. Neurosci Lett.1991; 130:53-56.
[129]王靖雯,汪海乳酸在脑能量代谢中作用的研究进展。解放军预防医学杂志[J],2007；25：69-72.
[130]Pellerin L. Lactate as a pivotal element in neuron-glia metabolic cooperation. Neurochem Int 2003; 43:331-338.
[131]Schurr A., Payne RS., Tseng MT., Gozal E, Gozal D. Excitotoxic preconditioning elicited by both glutamate and hypoxia and abolished by lactate transport inhibition in rat hippocampal slices. Neurosci Lett 2001; 307: 151-154.
[132]Ros J., Pecinska N., Alessandri B., Landolt H., Fillenz M. Lactate reduces glutamate-induced neurotoxicity in rat cortex. J Neurosci Res 2001; 66: 790-794.
[133]Prabakaran S., Swatton JE., Ryan MM., Huffaker SJ., Huang JT-J., Griffin JL., Wayland M., Freeman T., Dudbridge F., Lilley KS., Krap NA., Hester S., Tkachev D., Mimmack ML., Yolken RH., Webster MJ., Torrey EF., Bahn S. Mitochondrial dysfunction in schizophrenia:evidence for compromised brain metabolism and oxidative stress. Mol Psychiatr 2004; 9:684-697.
[134]Lan MJ., McLoughlin GA., Griffin JL., Tsang TM., Huang JTJ., Yuan P., Manji H., Holmes E., Bahn S. Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder. Mol Psychiatr 2009; 14:269-279.
[135]Wolkin A., Sanfilipo M., Wolf AP., Angrist B., Brodie JD., Rotrosen J. Negative symptoms and hypofrontality in chronic schizophrenia. Arch Gen Psychiatry 1992; 49:959-965.
[136]Khaitovich P., Lockstone HE., Wayland MT., Tsang TM., Jayatilaka SD., Guo AJ., Zhou J., Somel M., Harris LW., Holmes E., Paabo S., Bahn S. Metabolic changes in schizophrenia and human brain evolution. Genome Biol 2008; 9: R124.
[137]Schaffer S.W., Azuma J., Mozaffari M. Role of antioxidant activity of taurine in diabetes. Can J Physiol Pharmacol 2009; 87:91-99.
[138]Reddy R., Keshavan M., Yao J.K., Reduced plasma antioxidants in first-episode patients with schizophrenia. Schizophr Res 2003; 62:205-212.
[139]Colles S.M., Chisolm G.M., Lysophosphatidylcholine-induced cellular injury in cultured fibroblasts involves oxidative events. J Lipid Res 2000; 41: 1188-1198.
[140]Quinn MT, Parthasarathy S, Steinberg D. Lysophosphatidylcholine:a chemotactic factor for human monocytes and its potential role in atherogenesis. Proc Natl Acad Sci U S A.1988; 85:2805-2809.
[141]McMurray, H. F., Parthasarathy, S., Steinberg, D. Oxidatively modified low density lipoprotein is a chemoattractant for human T lymphocytes. J Clin Invest, 1993; 92:1004-1008.
[142]]Kugiyama, K., Kerns, S. A., Morrisett, J. D., Roberts, R., Henry, P. D. Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins. Nature,1990; 344:160-162.
[143]Sakai, M., Miyazaki, A., Hakamata, H., Sakaki, T., Yui, S., Yamazaki, M., Shichiri, M., Horiuchi, S. Lysophosphatidylcholine plays an essential role in the mitogenic effect of oxidized low density lipoprotein on murine macrophages. J Biol Chem,1994; 269:31430-31435
[144]Locher, R., Weisser, B., Mengden, T., Brunner, C., Vetter, W. Lysolecithin actions on vascular smooth muscle cells. Biochem Biophys Res Commun,1992; 183:156-162.
[145]Kohno M, Yokokawa K, Yasunari K, Minami M, Kano H, Hanehira T, Yoshikawa J. Induction by lysophosphatidylcholine, a major phospholipid component of atherogenic lipoproteins, of human coronary artery smooth muscle cell migration. Circulation.1998; 98:353-359.
[146]Murugesan G, Fox PL. Role of lysophosphatidylcholine in the inhibition of endothelial cell motility by oxidized low density lipoprotein. J Clin Invest. 1996; 97:2736-2744.
[147]Iwase M, Sonoki K, Sasaki N, Ohdo S, Higuchi S, Hattori H, Iida M. Lysophosphatidylcholine contents in plasma LDL in patients with type 2 diabetes mellitus:Relation with lipoprotein-associated phospholipase A2 and effects of simvastatin treatment. Atherosclerosis.2008; 196:931-936.
[148]Sonoki K, Iwase M, Sasaki N, Ohdo S, Higuchi S, Matsuyama N, Iida M. Relations of lysophosphatidylcholine in low-density lipoprotein with serum lipoprotein-associated phospholipase A2, paraoxonase and homocysteine thiolactonase activities in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract.2009;86:117-123.
[149]Huo T, Cai S, Lu X, Sha Y, Yu M, Li F. Metabonomic study of biochemical changes in the serum of type 2 diabetes mellitus patients after the treatment of metformin hydrochloride J Pharm Biomed Anal.2009; 49:976-982.
[150]Noto H, Chitkara P, Raskin P. The role of lipoprotein-associated phospholipase A2 in the metabolic syndrome and diabetes. J Diab Complications 2006;20: 343-348.
[151]Amir G., Terrance W., Subhdeep V., Sanjay G., David K., Prakash S., Comorbidity of irritable bowel syndrome in psychiatric patients:A review, American journal of therapeutics.2003;10:61-67.
[152]Gupta S, Masand PS, Kaplan D, Bhandary A, Hendricks S. The relationship between schizophrenia and irritable bowel syndrome (IBS). Schizophr Res. 1997;23:265-268.
[153]O'Mahony S.M., Marchesi J.R., Scully P et al. Early life stress alters behavior, immunity, and microbiota in rats:implications for irritable bowel syndrome and psychiatric illness. Biol Psychiatry 2009; 65:263-267.
[154]Metcalf MG, Evans JJ., Mackenzie JA. Indices of ovulation:comparison of plasma and salivary levels of progesterone with urinary pregnanediol. J. Endocr. 1984; 100:75-80.
[155]Judge SM, Quade JP, Arrata WSM, Chatterton Jr RT. Time-course relationships between serum LH, serum progesterone and urinary pregnanediol concentrations in normal women. Steriods 1978; 31:175-187.
[156]Breier A., Buchanan RW., The effects of metabolic stress on plasma progesterone in healthy volunteers and schizophrenic patients. Life Sci,1992; 51:1527-1534.
[157]Elman I, Breier A. Effects of acute metabolic stress on plasma progesterone and testosterone in male subjects:relationship to pituitary-adrenocortical axis activation. Life Sci.1997; 61:1705-1712.
[158]Costrini NV., Kalkhoff RK. Relative effects of pregnancy, estradiol, and progesterone on plasma insulin and pancreatic islet insulin secretion. J Clin Invest.1971; 50:992-999.
[159]Battista P.J., Condon W.A., Serotonin-induced stimulation of progesterone production by cow luteal cells in vitro. J Reprod Fert 1986; 76:231-238.
[160]Ohnuma T, Sakai Y, Maeshima H, Hatano T, Hanzawa R, Abe S, Kida S, Shibata N, Suzuki T, Arai H. Changes in plasma glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical symptoms improve:Results from the Juntendo University Schizophrenia Projects (JUSP) Prog Neuropsychopharmacol Biol Psychiatry.2008;32:1905-1912.
[161]Neeman G, Blanaru M, Bloch B, Kremer I, Ermilov M, Javitt DC, Heresco-Levy U. Relation of plasma glycine, serine, and homocysteine levels to schizophrenia symptoms and medication type. Am J Psychiatry. 2005;162:1738-1740.
[162]Williams JB, Mallorga PJ, Jeffrey Conn P, Pettibone DJ, Sur C Effects of typical and atypical antipsychotics on human glycine transporters. Schizophr Res.2004;71:103-112.
[163]Scheen AJ, De Hert MA. Abnormal glucose metabolism in patients treated with antipsychotics. Diabetes Metab.2007; 33:169-175.
[164]Chiu CC, Chen KP, Liu HC, Lu MLThe early effect of olanzapine and risperidone on insulin secretion in atypical-naive schizophrenic patients. J Clin Psychopharmacol.2006; 26:504-507.
[165]Dwyer DS, Donohoe D. Induction of hyperglycemia in mice with atypical antipsychotic drugs that inhibit glucose uptake. Pharmacol Biochem Behav. 2003;75:255-260.
[166]Murashita M, Inoue T, Kusumi I, Nakagawa S, Itoh K, Tanaka T, Izumi T, Hosoda H, Kangawa K, Koyama T. Glucose and lipid metabolism of long-term risperidone monotherapy in patients with schizophrenia. Psychiatry Clin Neurosci.2007;61:54-58.
[167]Smith RC, Lindenmayer JP, Hu Q, Kelly E, Viviano TF, Cornwell J, Vaidhyanathaswamy S, Marcovina S, Davis JM. Effects of olanzapine and risperidone on lipid metabolism in chronic schizophrenic patients with long-term antipsychotic treatment:a randomized five month study Schizophr Res.2010; 120:204-209.
[168]Shafrir E, Raz I. Diabetes:mellitus or lipidus? Diabetologia.2003;46:433-440.
[169]Vidarsdottir S, de Leeuw van Weenen JE, Frolich M, Roelfsema F, Romijn JA, Pijl H. Effects of olanzapine and haloperidol on the metabolic status of healthy men. J Clin Endocrinol Metab.2009; 95:118-125.
[170]Albaugh VL, Vary TC, Ilkayeva O, Wenner BR, Maresca KP, Joyal JL, Breazeale S, Elich TD, Lang CH, Lynch CJ. Atypical Antipsychotics Rapidly and Inappropriately Switch Peripheral Fuel Utilization to Lipids, Impairing Metabolic Flexibility in Rodents. Schizophr Bull doi:10.1093/schbul/sbq053
[171]Gattaz WF, Kollisch M, Thuren T, Virtanen JA, Kinnunen PKJ. Increased plasma phospholipase A2 activity in schizophrenic patients:reduction after neuroleptic therapy. Biol Psychiatry 1987; 22:421-426.
[172]Tavares H, Yacubian J, Talib LL, Barbosa NR, Gattaz WF. Increased phospholipase A2 activity in schizophrenia with absent response to niacin. Schizophr Res.2003;61:1-6.
[173]Schmitt A, Maras A, Petroianu G, Braus DF, Scheuer L, Gattaz WF. Effects of antipsychotic treatment on membrane phospholipid metabolism in schizophrenia J Neural Transm.2001;108:1081-1091.
[174]Trzeciak HI, Kalacinski W, Malecki A, Kokot D. Effect of neuroleptics on phospholipase A2 activity in the brain of rats. Eur Arch Psychiatry Clin Neurosci 1995; 245:179-182.
[175]Kropp S, Kern V, Lange K, Degner D, Hajak G, Kornhuber J, Ruther E, Emrich HM, Schneider U, Bleich S. Oxidative stress during treatment with first- and second-generation antipsychotics. J Neuropsychiatry Clin Neurosci. 2005;17:227-231.
[176]O'Brien E, Dedova I, Duffy L, Cordwell S, Karl T, Matsumoto I. Effects of chronic risperidone treatment on the striatal protein profiles in rats. Brain Res. 2006; 1113:24-32.
[177]Modica-Napolitano JS, Lagace CJ, Brennan WA, Aprille JR. Differential effects of typical and atypical neuroleptics on mitochondrial function in vitro. Arch Pharm Res 2003;26:951-959.
[178]Melkersson K. Serum creatine kinase levels in chronic psychosis patients--a comparison between atypical and conventional antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry.2006; 30:1277-1282.
[179]Shirayama Y, Hashimoto K, Suzuki Y, Higuchi T. Correlation of plasma neurosteroid levels to the severity of negative symptoms in male patients with schizophrenia. Schizophr Res.2002; 58:69-74.
[180]Barbaccia ML, Affricano D, Purdy RH, Maciocco E, Spiga F, Biggio G. Clozapine, but not haloperidol, increases brain concentrations of neuroactive steroids in the rat. Neuropsychopharmacology.2001;25:489-497.
[181]Marx CE, Duncan GE, Gilmore JH, Lieberman JA, Morrow AL. Olanzapine increases allopregnanolone in the rat cerebral cortex Biol Psychiatry. 2000;47:1000-1004.
[182]Bitran D, Purdy RH, Kellogg CK. Anxiolytic effect of progesterone is associated with increases in cortical allopregnanolone and GABAA receptor function. Pharmacol Biochem Behav 1993; 45:423-428.
[183]Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J Neuroendocrinol 1995; 7:171-177.
[184]Friess E, Tagaya H, Trachsel L, Holsboer F, Rupprecht R. Progesterone-induced changes in sleep in male subjects. Am J Physiol 1997; 272:E885-E891.
[185]Backstrom T, Zetterlund B, Blom S, Romano M. Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy. Acta Neurol Scand 1984; 69:240-248.
[186]Wetzel CHR, Hermann B, Behl C, Pestel E, Rammes G, Zieglgansberger W, Holsboer F, Rupprecht R. Functional antagonistic properties of gondadal steroids at the 5-HT3 receptor. Mol Endocrinol 1998;12:1441-1451.
[187]Pariante CM, Dazzan P, Danese A, Morgan KD, Brudaglio F, Morgan C, Fearon P, Orr K, Hutchinson G, Pantelis C, Velakoulis D, Jones PB, Leff J, Murray RM. Increased pituitary volume in antipsychotic-free and antipsychotic-treated patients of the AEsop first-onset psychosis study. Neuropsychopharmacology.2005;30:1923-1931.
[188]Wieck A. Haddad p. Hyperprolactinaemia caused by antipsychotic drugs:This common side effect needs more attention. BMJ,2002; 324:250-252.
[1]Benes FM, Berretta S. GABAergic interneurons:implications for understanding schizophrenia and bipolar disorder[J]. Neuropsychopharmacology,2001; 25:1-27.
[2]Lewis DA, Volk DW, Hashimoto T. Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia:a novel target for the treatment of working memory dysfunction[J]. Psychopharmacology,2003; 174:143-150.
[3]Volk DW, Austin MC, Pierri JN, et al. Decreased glutamic acid decarboxylase 67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia[J]. Arch Gen Psychiatr,2000; 57:237-245.
[4]Vawter MP, Crook JM, Hyde TM, et al. Microarray analysis of gene expression in the prefrontal cortex in schizophrenia:a preliminary study [J]. Schizophr Res, 2002; 58:11-20.
[5]DrachevaS, ElhakemSL, McGurkSR, et al. GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions for elderly patients with schizophrenia[J], JNeurosci Res,2004; 76:581-592.
[6]Hashimoto T, Volk DW, Eggan SM, et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia[J]. J Neurosci,2003; 16:6315-6326.
[7]Tsutomu S, Akihiko O, Yusuke N, et al. Changes in density of calcium-binding-protein-immunoreactive GABAergic neurons in prefrontal cortex in schizophrenia and bipolar disorder[J]. Neuropathology,2007,28: 143-150.
[8]Gavin PR, Zuhal AM, Joanna CN, et al. Calcium binding protein markers of GABA deficits in schizophrenia -Post mortem studies and animal models[J]. Neurotoxicity Research,2004,6:57-62.
[9]Rodrigo Paz H. Pathophysiological models of schizophrenia; from dopamine to glutamate, and glutamate to GABA[J]. Rev Chil Neuro-Psiquiat,2005; 43: 314-328.
[10]David AL, Bita M. Cognitive dysfunction in schizophrenia-Convergence of y-aminobutyric acid and glutamate alterations[J]. Ach Neurol,2006; 63: 1372-1376.
[11]Reynolds GP, Czudek C, Andrews HB. Deficit and hemispheric asymmetry of GAB A uptake sites in the hippocampus in schizophrenia[J]. Biol Psychiatr, 1990; 27:1038-1044.
[12]Simpson MD, Slater P, Deakin JF, et al. Reduced GAB A uptake sites in the temporal lobe in schizophrenia[J]. Neurosci Lett,1989; 107:211-215.
[13]Simpson MD, Slater P, Deakin JF. Comparison of glutamate and gamma-aminobutyric acid uptake binding sites in frontal and temporal lobes in schizophrenia[J]. Biol Psychiatr,1998; 44:423-427.
[14]Volk DW, Austin MC, Pierri JN, et al. GABA transporter-1 mRNA in prefrontal cortex in schizophrenia:decreased expression in a subset of neurons[J]. Am J Psychiatr,2001;158:256-265.
[15]Volk DW, Pierri JN, Fritschy JM, et al. Reciprocal alterations in pre-and postsynaptic inhibitory markers at chandelier cells inputs to pyramidal neurons in schizophrenia[J]. Cereb Cortex,2002; 12:1063-1070.
[16]Schleimer S B, HintonT, DixonG, et al. GABA transporters GAT-1 and GAT-3 in the human dorsolateral prefrontal cortex in schizophrenia[J]. Neuropsychobiology,2004; 50:226-230.
[17]Hanada S, Mita T, Nishino N, Tanaka C. [3H]Muscimol binding sites increased in autopsied brains of chronic schizophrenics [J]. Life Sci,1987; 40:259-266.
[18]Benes FM, Vincent SL, Marie A, Khan Y. Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subject[J]. Neuroscience,1996; 75:1021-1031.
[19]Benes FM, Khan Y, Vincent SL, et al. Differences in the sub regional and cellular distribution of GABAA receptor binding in the hippocampal formation of schizophrenic brain[J]. Synapse,1996; 22:338-349.
[20]Dean B, Hussain T, Hayes W, et al. Changes in serotonin2A and GABA(A) receptors in schizophrenia:studies on the human dorsolateral prefrontal cortex [J]. JNeurochem,1999; 72:1593-1599.
[21]Benes FM, Wickramasinghe R, Vincent SL, et al. Uncoupling of GABA(A) and benzodiazepine receptor binding activity in the hippocampal formation of schizophrenic brain[J]. Brain Res,1997; 755:121-129.
[22]Volk DW, Pierri JN, Fritschy JM, Auh S, Sampson AR, Lewis DA. Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cells inputs to pyramidal neurons in schizophrenia[J]. Cereb Cortex,2002; 12:1063-1070.
[23]Impagnatiello F, Guidotti AR, Pesold C, et al. A decrease of reeling expression as a putative vulnerability factor in schizophrenia[J]. Proc Natl Acad Sci,1998; 95:15718-15723.
[24]Chao D, XF Huang. Increased density of GABAA receptors in the superior temporal gyrus in schizophrenia[J]. Exp Brain Res,2006; 168:587-590.
[25]Zink M, Schmitt A, May B, et al. Differential effects of long-term treatment with cloazapine or haloperidol on GABA receptor building and GAD67 expression[J]. Schizophr Res,2004; 66:151-157.
[26]Mizukami K, Ishikawa M, Hidaka S, et al Immunohistochemical localization of GABAB receptor in the entorhinal cortex and inferior temporal cortex of schizophrenia brain[J].Prog Neuropsychopharmacol Biol Psychiatry,2002; 26: 393-396.
[27]Ishikawa M, Mizukami K, Iwakiri M, et al. Immunohistochemical and immunoblot analysis of-aminobutyric acid B receptor in the prefrontal cortex of subjects with schizophrenia and bipolar disorder[J].Neurosci Lett,2005; 383: 272-277.
[28]Schahram Akbarian. Restoring GABAergic signaling and neuronal synchrony in schizophrenia[J].Am J Psychiatry,2008; 165:1507-1509
[29]Hanns M, Uwe R, Detlev B, et al. Regulation of cognition and symptoms of psychosis:focus on GABAA receptors and glycine transporter 1[J]. Pharmacol Biochem Behavior,2008; 90:58-64.
[30]David AL, Raymond YC, Cameron SC, et al. Subunit-selective modulation of GAB A type A receptor neurotransmission and cognition in schizophrenia [J]. Am JPsychiatry,2008; 165:1585-1593.
[31]Sawako A, Kazuhiro T, Hiroyuki M, et al Involvement of pallidotegmental neurons in methamphetamine-and MK-801-induced impairment of prepulse inhibition of the acoustic startle reflex in mice:reversal by GABAB receptor agonist bacolfen[J]. Neuropsychopharmacolog,2008; 33:3164-3175.
[32]Yona G, Abraham N, Irit GA, et al. BL-1020:A novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia[J]. Eur Neuropsychopharmacol,2009; 19:1-13.
[33]Richard FS, Else S. Clozapine and several other antipsychotic/antidepressant drugs preferentially blocks the same "core" fraction of GABAA receptors [J]. Neurochem Res,1998; 23:1283-1290.
[34]J. MA, N. YE, N. LANGE, et al. Dynorphinergic GABA neurons are a target of both typical and atypical antipsychotic drugs in the nucleus accumbens shell, central amygdaloid nucleus and thalamic central medial nucleus[J]. Neuroscience,2003; 121:991-998.
[35]Scott AH, Amanda G, Kerry JR. Prepulse inhibition deficits in GAD65 knockout mice and the effect of antipsychotic treatment[J]. Neuropsychopharmacology, 2004; 29:1610-1619.
[2]Shinfuku, N. ed. Mental health care in the Western Pacific Region. International Journal of Mental Health,1993,22; Shinfuku, N. A study of the public health approach to mental health in the Western Pacific Region with specific reference to developing countries. Manila, WHO,1993.
[3]American Psychiatry Association,2000. Diagonostic and statistical manual of mental disorder, fourth ed., text revision (DSM-IV-TR). American Psychiatric Association, Washington, DC.
[4]First MB, Spitzer RL, Gibbon M, Williams JBW.2002. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). Biometrics Research. New York State Psychiatric Institute, New York.
[5]Thaker GK, Carpenter JR. Advances in schizophrenia. Nat Med,2001; 7: 667-671.
[6]Badner J, Gershon E. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatr 2002; 7:405-411.
[7]Lewis C, Levinson D, Wise L, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II:Schizophrenia. Am J Hum Genet 2003; 73:34-48.
[8]Moore, H., West, A.R., Grace, A.A., The regulation of forebrain dopamine transmission:relevance to the pathophysiology and psychopathology of schizophrenia. Biological Psychiatry 1999; 46,40-55.
[9]Crow T.J. Molecular pathology of schizophrenia:more than one disease process? Br Med J.1980; 280:66-68.
[10]Prosser E.S. Csernansky J.G., Kaplan J, Thiemann S., Becker T.J., Hollister, L.E., Depression, parkinsonia symptoms and negative symptoms in schizophrenics treated with neuroleptics. J Nerv Ment Dis 1987; 175:100-105.
[11]Andreasen, N.C., Positive vs. negative schizophrenia:a critical evaluation. Schizophr Bull 1985; 11:380-389.
[12]Davidson M, Keefe RS, Mohs RC, Siever LJ, Losonczy MF, Horvath TB, Davis KL, L-dopa challenge and relapse in schizophrenia. Am J Psychiatry 1987; 144:934-938.
[13]Moncrieff, J. A critique of the dopamine hypothesis of schizophrenia and psychosis. Harvard Review of Psychiatry 2009; 17:215-225.
[14]Bernberg DE, van Kammen DP, Lake CR, Ballenger JC, Marder SR, Bunney Jr WE. The effects of pimozide on CSF norepinephrine in schizophrenia Am J Psychiatry 1981; 138:1045-1050.
[15]See, R.E., Fido, A. A., Maurice, M., Ibrahim, M.M., Salama, G., Risperidone-induced increase of plasma norepinephrine is not correlated with symptom improvement in chronic schizophrenia. Biological Psychiatry 1999; 45,1653-1656.
[16]Carpenter W T, Heinrichs DW, Alphs LD. Treatment of negative symptoms, schizophr Bull 1985; 11:440-452.
[17]Meltzer HY. Biological studies in schizophrenia, Schizophr Bull 1987;13: 77-113.
[18]Kemali D, Maj M, Iorio G, Marciano F, Nolfe G, Galderisi S, Salvati A. Relationship between CSF noradrenaline level, C-EEG indicators of activation and psychoses ratting in drug-free schizophrenic patients, Acta Psychiatry Scand 1985; 71:19-24.
[19]Yamamoto K, Hornykiewicz O., Proposal for a noradrenaline hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 913-922.
[20]Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 1996; 153:466-476.
[21]Geyer, M.A., Vollenweider, F.X.,. Serotonin research:contributions to understanding psychoses. Trends in pharmacological sciences 2008; 29: 445-453.
[22]Luby ED, Cohen BD, Rosenbaum G, et al. Study of a new sehizophrenomimetic drug:seruyl. Arch Neurology and Psychiatry,1959, 81:363-369.
[23]Lodge D, Aram JA, Church J, et al. Excitatory amino acids and phencyclidine-like drugs. In:Hicks TP, Lodge D, McLennan H, editors. Excitatory amino acid transmission. Now York:Alan R. Liss lnc, 1987; 83-90.
[24]Roberts E. Prospects for research on schizophrenia. An hypotheses suggesting that there is a defect in the GABA system in schizophrenia. Neurosci Res Program Bull.1972; 10:468-482.
[25]Benes FM. Development of the glutamate, GABA, and dopamine systems in relation to NRH-induced neurotoxicity. Biol Psychiatry.1995; 38:783-787.
[26]Crow TJ. Molecular pathology of schizophrenia:more than one disease process? Bri Med J 1980; 280:66-68.
[27]Ford ES. Prevalence of metabolic syndrome defined by the international diabetes federation among adults in the US. Diabetes Care,2005,28: 2745-2749.
[28]Henderson DC, Cagliero E, Gray C et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities:A five-year naturalistic study. Am Psychiatry 2000; 157:975-978.
[29]Meyer J, Koro CE, Litalien GJ, The metabolic syndrome and schizophrenia. Int Rev Psychiatry 2005; 17:173-180.
[30]Becker KG. The common variants/multiple disease hypothesis of common complex genetic disorders. Med Hypotheses 2004; 62:309-317.
[31]Mukherjee S, Decina P, Bocola V, et al. Diabetes mellitus in schizophrenic patients. Compr Psychiat 1996; 37:68-73.
[32]许国旺,杨军.代谢组学及其研究进展.色谱,2003；21：316-320.
[33]许彬,王海龙,魏开华,张学敏,杨松成.代谢组学分析技术及其在几类 重大疾病研究中的应用.分析测试学报,2006；25：128-132.
[34]夏建飞,梁琼麟,胡坪,王义明,罗国安.代谢组学研究策略与方法的新进展.分析化学,2009；37：136-143.
[35]Yao, J.K., Reddy, R.D., Metabolic investigation in psychiatric disorders. Molecular Neurobiology 2005; 31:193-203.
[36]Holmes, E., Tsang, T.M., Huang, J.T., Leweke, F.M., Koethe, D., Gerth, C.W., Nolden, B.M., Gross, S., Schreiber, D., Nicholson, J.K., Bahn, S., Metabolic profiling of CSF:evidence that early intervention may impact on disease progression and outcome in schizophrenia. PLoS Medicine 2006; 3: 1420-1428.
[37]Huang, J.T., Leweke, F.M., Tsang, T.M., Koethe, D., Kranaster, L., Gerth, C.W., Gross, S., Schreiber, D., Ruhrmann, S., Schultze-Lutter, F., Klosterkotter, J., Holmes, E., Bahn, S., CSF metabolic and proteomic profiles in patients prodromal for psychosis. PLoS One 2007; 22:1-7.
[38]Tsang, T.M., Huang, J.T., Holmes, E., Bahn, S., Metabolic profiling of plasma from discordant schizophrenia twins:correlation between lipid signals and global functioning in female schizophrenia patiens. Journal of proteome research.2006; 5:756-760.
[39]Kaddurah-Daouk, R., McEvoy, J., Baillie, R.A., Lee, D., Yao, J.K., Doraiswamy, P.M., Krishnan, K.R.R., Metabolomic mapping of atypical antipsychotic effects in schizophrenia. Molecular psychiatry; 2007; 12: 934-945.
[40]Davidson, M., Losonczy, M.F., Mohs, R.C., Lesser, J.C., Powchik, P., Freed, L.B., Davis, B.M., Mykytyn, V.V., Davis, K.L., Effects of debrisoquin and haloperidol on plasma homovanillic acid concentration in schizophrenic patients. Neuropsychopharmacology 1987; 1:17-23.
[41]Konicki, P. E., Owen, R. R., Litman, R. E., Pickar, D., The acute effects of central-and peripheral-acting dopamine antagonists on plasma HVA in schizophrenic patients. Life sciences 1991; 48:1411-1416.
[42]Kaminski, R., Powchick, P., Warne, P.A., Goldstein, M., McQueeney, R.T., Davidson, M., Measurement of plasma homovanillic acid concentrations in schizophrenic patients. Progress in Neuro-Psychopharmacology and Biological Psychiatry 1990; 14:271-287.
[43]Liu G.S., Chen J.N., Ma Y.F., Simultaneous determination of catecholamines and polyamines in PC-12 cell extracts by micellar electrokinetic capillary chromatography with ultraviolet absorbance detection, J Chromatogr B 2004; 805:281-288.
[44]Siren H., Karjalainen U., Study of catecholamines in patient urine samples by capillary electrophoresis, J Chromatogr A.1999; 853:527-533.
[45]Yoshitake T., Fujino K., Kehr J., Ishida J., Nohta H., Yamaguchi M., Simultaneous determination of norepinephrine, serotonin, and 5-hydroxyindole-3-acetic acid in microdialysis samples from rat brain by microbore column liquid chromatography with fluorescence detection following derivatization with benzylamine, Anal. Biochem.2003; 312:125-133.
[46]Fotopoulou M.A., Ioannou P.C., Post-column terbium complexation and sensitized fluorescence detection for the determination of norepinephrine, epinephrine and dopamine using high-performance liquid chromatography, Anal.Chim.Acta.2002; 462:179-185.
[47]Jin W., Jin L.T., Shi G.Y., Ye J.N., Determination of monoamine transmitters and their metabolites by capillary electrophoresis with electrochemical detection, Anal. Chim. Acta.1999; 382:33-37.
[48]Zhang S., Xu Q., Zhang W., Jin L.T., Jin J.Y., In vivo monitoring of the monoamine neurotransmitters in rat brain using microdialysis sampling with liquid chromatography electrochemical detection, Anal. Chim. Acta.2001; 427: 45-53.
[49]Parrot S., Bert L., Badina L.M., Sauvinet V., Mas J.C., Senas L.L., Robert F., Bouilloux J.P., Chagny M.F.S., Denoroy L., Renaud B., Microdialysis Monitoring of Catecholamines and Excitatory Amino Acids in the Rat and Mouse Brain:Recent Developments Based on Capillary Electrophoresis with Laser-Induced Fluorescence Detection-A Mini-Review, Cell.Mol.Neurobiol. 2003; 23:793-804.
[50]Xiong S.X., Han H.W., Zhao R., Chen Y., Liu G.Q., Capillary electrophoresis of catecholamines with laser-induced fluorescence intensified charge-coupled device detection, Biomed.Chromatogr.2001; 15:83-88.
[51]Carrera V., Sabater E., Vilanova E., Sogorb M.A., A simple and rapid HPLC-MS method for the simultaneous determination of epinephrine, norepinephrine, dopamine and 5-hydroxytryptamine:Application to the secretion of bovine chromaffin cell cultures, J. Chromatogr. B.2007; 847: 88-94.
[52]Ozcan S., Senyuva H.Z., Improved and simplified liquid chromatography/ atmospheric pressurechemical ionization mass spectrometry method for the analysis of underivatized free amino acids in various foods, J. Chromatogr. A. 2006;1135:179-185.
[53]Vlckova M., Schwarz M.A., Determination of cationic neurotransmitters and metabolites in brain homogenates by microchip electrophoresis and carbon nanotube-modified amperometry, J. Chromatogr. A.2007; 1142:214-221.
[54]Jemal M., High-throughput quantitative bioanalysis by LC/MS/MS, Biomed. Chromatogr.2000; 14:422-429.
[55]Gu Q., Shi X.Z., Yin P. Y., Gao P., Lu X., Xu G.W, Analysis of catecholamines and their metabolites in adrenal gland by liquid chromatography tandem mass spectrometry, Anal. Chim. Acta.2008; 609:192-200.
[56]Su F.L., Wang F., Zhu R.H., Li H.D., Determination of 5-Hydroxytryptamine, Norepinephrine, Dopamine and Their Metabolites in Rat Brain Tissue by LC-ESI-MS-MS, Chromatographia.2009; 34:207-213.
[57]Beaudry F., Guenette S. A., Winterborn A., Marier J.F, Vachon P., Development of a rapid and sensitive LC-ESI/MS/MS assay for the quantification of propofol using a simple off-line dansyl chloride derivatization reaction to enhance signal intensity, J. Pharm. Biomed. Anal 2005; 39: 411-417.
[58]Peaston R.T., Weinkove C., Measurement of catecholamines and their metabolites, Ann. Clin. Biochem.2004; 41:17-38.
[59]Blin O. A comparative review of new antipsychotics, Can. J. Psychiatry.1999; 44:235-244.
[60]Mannens G. Huang M.L, Meuldermans W, Hendrickx J, Woestenborghs R, Heykants J. Absorption. metabolism and excretion of risperidone in humans. Drug. Metab. Dispos. Biol. Fate. Chem 1993; 21:1134-1141.
[61]Nagasaki T, Ohkubo T, Sugawara K, Yasui N., Furukori H., Kaneko S., Determinadon of risperidone and 9-hydroxyrisperidone in human plasma by high-performance liquid chromatography:application to therapeutic drug monitoring in Japanese patients with schizophrenia J. Pharm. Biomed. Anal 1999; 19:595-601
[62]Huang ML, Van Peer A. Woestenborgh R, De Coster R, Heykants J, Jansen AA, Zylicz Z, Visscher H.W., Jonkman J.H. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 1993; 54:257-268.
[63]Flarakos J, Luo W, Aman M, Svinarov D., Gerber N., Vouros P., Quantification of risperidone and 9-hydroxyrispefidone in plasma and saliva from adult and pediatric patients by liquid chromatography-Mass spectrometry. J ChromatogrA,2004; 1026,175-183.
[64]Balant-Gorgia A.E, Gex-Fabry M, Genet C., Balant L.P., Therapeutic drug monitoring of risperidone using a new, rapid HPLC method Reappraisal of inter individual variability factors. Ther Drug Monit 1999; 21:105-115.
[65]Titiet K, Deridet E, Cardone E, Abouelfath A, Moore N, Simplified high-performance liquid chromatographic method for determination of risperidone and 9-hydroxyrisperidone in plasma after overdose. J Chromatogr B.2002; 772:373-378.
[66]Remmerie B.M.M, Sips L.L. A, de Vries R., de Jong J., Validated method for the determination of risperidone and 9-hydroxyriperidone in human plasma by liquid chromatography-tandem mass spectrometry. J. Chromatogr. B,2003, 783:461-472.
[67]Aravagiri M, Marder S.R., Simultaneous determination of risperidone and 9-hydroxyrisperidone in plasma by liquid chromatography/electrospray tandem mass spectrometry. J Mass Spectrom,2000; 35:718-724
[68]Bergstrom and Oberg, MultiSimplex 98, Karlskrona, Sweden,1998.
[69]Shakerian F., Dadfarnia S., Shabani A.M.H., Rohani M., MultiSimplex optimization of on-line sorbent proconcentration and determination of iron by FI-AAS and microcolumn of immobilized ferron, Talanta.2008; 77:551-555.
[70]Delgado A., Usobiaga A., Prieto A., Zuloaga O., De Diego A., Madariaga J.M., Optimisation of the headspace-solid phase microextraction for organomercury and organotin compound determination in sediment and biota J. Sep. Sci.2008; 31:768-774.
[71]Ferreiros N., Iriarte G., Alonso R.M., Jimenez R.M., MultiSimplex and experimental design as chemometric tools to optimize a SPE-HPLC-UV method for the determination of eprosartan in human plasma samples, Talanta. 2006; 69:747-756.
[72]Tan I.K., Gajra B., Plasma and urine amino acid profiles in a healthy adult Singapore Ann. Acad. Med. Singapore.2006; 35:468-475.
[73]Mao H.M., Chen B.G., Qian X.M., Liu Z.M., Simultaneous determination of twelve biogenic amines in serum by high performance liquid chromatography, Microchem. J.2009; 91:176-180.
[74]Kang X.J., Xiao J., Huang X., Gu Z.Z, Optimization of dansyl derivatization and chromatographic conditions in the determination of neuroactive amino acids of biological samples, Clin. Chim. Acta.2006; 366:352-356.
[75]Salvador A., Moretton C., Piram A., Faure R., On-line solid-phase extraction with on-support derivatization for high-sensitivity liquid chromatography tandem mass spectrometry of estrogens in influent/effluent of wastewater treatment plants J. Chromatogr. A.2007; 1145:102-109.
[76]Gros C., Labouesse B., Study of the dansylation reaction of amino acids, peptides and proteins, Eur. J. Biochem.1969; 7:463-470.
[77]Moncrieff, J., A critique of the dopamine hypothesis of schizophrenia and psychosis. Harvard Review of Psychiatry 2009; 17:215-225.
[78]Oades, R.D., Klimke, A., Henning, U., Rao, M.L., Relations of clinical features, subgroups and medication to serum monoamines in schizophrenia. Human Psychopharmacology 2002; 17:15-27.
[79]Oades, R.D., Ropcke, B., Henning, U., Klimke, A., Neuropsychological measures of attention and memory function in schizophrenia:relationships with symptom dimensions and serummonoamine activity. Behavioral and Brain Functions 2005; 1:14-30.
[80]Oades, R.D., Ropcke, B., Eggers, C., Monoamine activity reflected in urine of young patients with obsessive compulsive disorder, psychosis with and without reality distortion and healthy subjects:an explorative analysis. J Neural Transm 1994; 96:143-159.
[81]van der Heijden FMMA, Tuinier S, Fekkes D, Sijben AES, Kahn RS, Verhoeven WMA. Atypical antipsychotics and the relevance of glutamate and serotonin. Eur Neuropsychopharmacol 2004;14:259-265.
[82]Maeshima H, Ohnuma T, Sakai Y, Shibata N, Baba H, Ihara H, et al. Increased plasma glutamate by antipsychotic medication and its relationship to glutaminase 1 and 2 genotypes in schizophrenia-Juntendo University Schizophrenia Projects (JUSP). Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:1410-1418.
[83]Carpenter W.T., Kirkpatrick B., Buchanan R.W., Schizophrenia:syndromes and diseases. J Psychiat Res 1999; 33,473-475.
[84]Marc D.T., Ailts J.W., Ailts Campeau D.C., Bull M.J., Olson B.K.L. Neurotransmitters excreted in the urine as biomarkers of nervous system activity:validity and clinical applicability. Neurosci Biobehav Rev 2011; 35: 635-644.
[85]Kopp, U., Bradley, T., Hjemdahl, P. Renal venous outflow and urinary excretion of norepinephrine, epinephrine, and dopamine during graded renal nerve stimulation. Am.J.Physiol.1983; 244:E52-E60.
[86]Wise, C., Stein, L., Dopamine-β-hydroxylase deficiency in the brains of schizophrenia patients. Science 1973; 181:344-347.
[87]Wyatt, R.J., Potkin, S.G., Bridge, T.P., Phelps, B.H., Wise, C.D., Monoamine oxidase in schizophrenia:an overview. Schizophrenia Bull 1980; 6:199-206.
[88]Dao-Castellana, M.H., Paillere-Martinot, M.L., Hantraye, P., Attar-Levy, D., Remy, P., Crouzel, C., et al., Presynaptic dopaminergic function in the striatum of schizophrenic patients. Schizophr Res 1997; 23:167-174.
[89]Hietala, J., Syvalahti, E., Vilkman, H., Vuorio, K., Rakkolainen, V., Bergman, J., et al., Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia. Schizophr Res 1999; 35:41-50.
[90]Eldrup, E., Significance and origin of DOPA, DOPAC, and dopamine-sulphate in plasma, tissues and cerebrospinal fluid. Dan Med Bull 2004; 51:34-62.
[91]Carpenter Jr., W.T., Murphy, D.L., Wyatt, R.J., Platelet monoamine oxidase activity in acute schizophrenia. The American Journal of Psychiatry 1975; 132: 438-441.
[92]Chen, M.-L., Chen, C.-H., Chronic antipsychotics treatment regulates MAOA, MAOB and COMT gene expression in rat frontal cortex. J Psychiat Res 2007; 41:57-62.
[93]Brown, A.S., Gewirtz, G., Harkavy-Friedman, J., Cooper, T., Brebion, G., Amador, X.F., et al., Effects of clozapine on plasma catecholamines and relation to treatment response in schizophrenia:a within-subject comparison with haloperidol. Neuropsychopharmacology 1997; 17:317-325.
[94]See, R.E., Fido, A.A., Maurice, M., Ibrahim, M.M., Salama, G., Risperidone-induced increase of plasma norepinephrine is not correlated with symptom improvement in chronic schizophrenia. Biol Psychiat 1999; 45: 1653-1656
[95]Elman, I., Goldstein, D.S., Green, A.I., Eisenhofer, G., Folio, C.J., Holmes, C.S., et al., Effects of risperidone on the periphreal noradrenegic system in patients with schizophrenia:a comparison with clozapine and placebo. Neuropsychopharmacology 2002; 27:293-300.
[96]Oades, R.D., Ropcke, B., Henning, U., Klimke, A., Neuropsychological measures of attention and memory function in schizophrenia:relationships with symptom dimensions and serum monoamine activity. Behavioral and Brain Functions 2005; 1:14-30.
[97]Breier, A., Serotonin, schizophrenia and antipsychotic drug action. Schizophr Res 1995; 14:187-202.
[98]Moncrieff, J., A critique of the dopamine hypothesis of schizophrenia and psychosis. Harvard Rev Psychiatr 2009; 17:215-225.
[99]Ichikawa, J., Ishii, H., Bonaccorso, S., Fowler, W.L., O'Laughlin, I.A., Meltzer, H.Y.,5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation:a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 2001; 76: 1521-1531.
[100]Issa, F., Gerhardt, G.A., Bartko, J.J., Suddath, R.L., Lynch, M, Gamache, P.H., et al., A multidimensional approach to analysis of cerebrospinal fluid biogenic amines in schizophrenia:Ⅰ. Comparisons with healthy control subjects and neuroleptictreated/unmedicated pairs analyses. Psychiat Res 1994; 52:237-249.
[101]Oades, R.D., Klimke, A., Henning, U., Rao, M.L., Relations of clinical features, subgroups and medication to serum monoamines in schizophrenia. Hum Psychopharmacol Clin Exp 2002; 17:15-27.
[102]Grimm J, See R. Unique activation of extracellular striato-pallidal neurotransmitters in rats following acute risperidone. Brain Res 1998; 801: 182-189.
[103]Kikumoto O, Okamoto Y, Hayakawa H, Yokota N, Kawai K, Motohashi N, et al. Effects of risperidone on catalepsy and cerebral dopamine, serotonin and GABA metabolism in the rat:Comparison with haloperidol. Jpn J Psychopharmacol 1993;13:39-42.
[104]Roy-Byrne P, Cowley D, Hommer D, Greenblatt D, Kramer G, Petty F. Effect of acute and chronic benzodiazepines on plasma GABA in anxious patients and controls. Psychopharmacology 1992;109:153-156.
[105]Palomino A, Vallejo-Illarramendi A, Gonzalez-Pinto A, Aldama A, Gonzalez-Gomez C,Mosquera F, et al. Decreased levels of plasma BDNF in first-episode schizophrenia and bipolar disorder patients. Schizophr Res 2006; 86:321-322.
[106]Matute C, Melone M, Vallejo-Illarramendi A, Conti F. Increased expression of the astrocytic glutamate transporter GLT-1 in the prefrontal cortex of schizophrenics. Glia 2005; 49:451-455.
[107]Chen M.K, Tsang T.M, Harris L.W, Guest P.C, Holmes E, Bahn S., Evidence for diease and antipsychotic medication effects in post-mortem brain from schizophrenia patients. Mol Psychiatr 2010; 1-14.
[108]Nicholson J.K, Foxall P.J., Spraul M., Farrant R.D., Lindon J.C.,750 MHz 1H and 1H-13C NMR spectroscopy of human blood plasma. Anal Chem 1995; 67: 793-811.
[109]Zuppi C, Messana I, Forni F, Rossi C, Pennacchietti L, Ferrari F, Giardina B, 1H NMR spectra of normal urines:Reference ranges of the major metabolites. Clin Chim Acta 1997; 265:85-97.
[110]Smeraldi E., Lucca A., Macciardi F., Bellodi L. Increased concentrations of various amino acids in schizophrenic patients-Evidence for heterozygosity effects? Hum Genet 1987; 76:138-140
[111]Herberth M., Koethe D., Chen TMK., Krzyszton ND., Schoeffmann S., Guest PC., Rahmoune H., Harris LW., Kranaster L., Leweke FM., Bahn S. Impaired glycolytic response in peripheral blood mononuclear cells of first-onset antipsychotic-naive schizophrenia patients. Mol Psychiatr 2011; 16:848-859.
[112]Xie GX., Chen TL., Qiu YP., Shi P., Zheng XJ., Su MM., Zhao AH., Zhou ZT. Jia W. Urine metabolite profiling offers potential early diagnosis of oral cancer. Metabolomics.2011, DOI 10.1007/s11306-011-0302-7
[113]Yang YX., Li CL., Nie X, Feng XS, Chen WX, Yue Y., Tang HR, Deng F. Metabonomic studies of human hepatocellular carcinoma using High-Resolution Magic-Angle Spinning 1H NMR Spectroscopy in conjunction with multivariate data analysis. J Proteome Res 2007; 6:2605-2614.
[114]Wu GY, Amino acids:metabolism, functions, and nutrition. Amino Acids 2009; 37:1-17.
[115]Javitt DC, Zylberman I, Zukin SR, Heresco-Levy U, Lindenmayer JP. Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry 1994; 151:1234-1236.
[116]Kohen D., Diabetes mellitus and schizophrenia:historical perspective Brit J Psychiat.2004; 184:s64-s66.
[117]Ryan M.C., Collins P., Thakore J.H., Impaired fasting glucose tolerance in first-episode, drug naive patients with schizophrenia. Am J Psychiatry 2003; 160:284-289.
[118]Martin BC., Warram JH., Krolewski AS., Bergman RN., Soeldner JS., Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus:results of a 25-year follow-up study. Lancet 1992; 340:925-929.
[119]Marklova E, Albahri Z, Nozickova M. HPLC profiling of Trp-related metabolites in humans. Adv Exp Med Biol.2003;527:739-744.
[120]Silverstein MN, Wakim KG, Bahn RC. The influence of tryptophan metabolites on tissue uptake of glucose. Metabolism.1967;16:410-412.
[121]Boston, P.F., Dursun, S.M., Reveley, M.A., Cholesterol and mental disorder. Brit J Psychiat 1996a; 169:682-689.
[122]Levin Y., Wang L., Schwarz E., Koethe D., Leweke FM., Bahn S. Global proteomic profiling reveals altered proteomic signature in schizophrenia serum. Mol Psychiatr 2010; 15:1088-1100.
[123]Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S, Kaplan DB, Tretta MG, Allen M. Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry 1991; 48:563-568.
[124]Yao JK, Stanley JA., Reddy RD., Keshavan MS., Pettegrew JW. Correlations between peripheral polyunsaturated fatty acid content and in vivo membrane phospholipid metabolites. Biol Psychiatry 2002; 52:823-830.
[125]Huang T.L., Ghen J.F., Serum lipid profiles and schizophrenia:Effects of conventional or atypical antipsychotic drugs in Taiwan. Schizophr Res.2005; 80:55-59.
[126]Gattaz WF, Sehinitt A, Maras A. Increased platelet phospholipase A2 activity in schizophrenia. Schizophr Res,1995;16:1-6.
[127]Khan MM, Evans DR, Gunna V, Scheffer RE, Parikh VV, Mahadik SP. Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics. Schizophr Res.2002;58:1-10.
[128]Arakawa T., Goto T., Okada Y., Effect of ketone body (D-3-hydroxybutyrate) on neural activity and energy metabolism in hippocampal slices of the adult guinea pig. Neurosci Lett.1991; 130:53-56.
[129]王靖雯,汪海乳酸在脑能量代谢中作用的研究进展。解放军预防医学杂志[J],2007；25：69-72.
[130]Pellerin L. Lactate as a pivotal element in neuron-glia metabolic cooperation. Neurochem Int 2003; 43:331-338.
[131]Schurr A., Payne RS., Tseng MT., Gozal E, Gozal D. Excitotoxic preconditioning elicited by both glutamate and hypoxia and abolished by lactate transport inhibition in rat hippocampal slices. Neurosci Lett 2001; 307: 151-154.
[132]Ros J., Pecinska N., Alessandri B., Landolt H., Fillenz M. Lactate reduces glutamate-induced neurotoxicity in rat cortex. J Neurosci Res 2001; 66: 790-794.
[133]Prabakaran S., Swatton JE., Ryan MM., Huffaker SJ., Huang JT-J., Griffin JL., Wayland M., Freeman T., Dudbridge F., Lilley KS., Krap NA., Hester S., Tkachev D., Mimmack ML., Yolken RH., Webster MJ., Torrey EF., Bahn S. Mitochondrial dysfunction in schizophrenia:evidence for compromised brain metabolism and oxidative stress. Mol Psychiatr 2004; 9:684-697.
[134]Lan MJ., McLoughlin GA., Griffin JL., Tsang TM., Huang JTJ., Yuan P., Manji H., Holmes E., Bahn S. Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder. Mol Psychiatr 2009; 14:269-279.
[135]Wolkin A., Sanfilipo M., Wolf AP., Angrist B., Brodie JD., Rotrosen J. Negative symptoms and hypofrontality in chronic schizophrenia. Arch Gen Psychiatry 1992; 49:959-965.
[136]Khaitovich P., Lockstone HE., Wayland MT., Tsang TM., Jayatilaka SD., Guo AJ., Zhou J., Somel M., Harris LW., Holmes E., Paabo S., Bahn S. Metabolic changes in schizophrenia and human brain evolution. Genome Biol 2008; 9: R124.
[137]Schaffer S.W., Azuma J., Mozaffari M. Role of antioxidant activity of taurine in diabetes. Can J Physiol Pharmacol 2009; 87:91-99.
[138]Reddy R., Keshavan M., Yao J.K., Reduced plasma antioxidants in first-episode patients with schizophrenia. Schizophr Res 2003; 62:205-212.
[139]Colles S.M., Chisolm G.M., Lysophosphatidylcholine-induced cellular injury in cultured fibroblasts involves oxidative events. J Lipid Res 2000; 41: 1188-1198.
[140]Quinn MT, Parthasarathy S, Steinberg D. Lysophosphatidylcholine:a chemotactic factor for human monocytes and its potential role in atherogenesis. Proc Natl Acad Sci U S A.1988; 85:2805-2809.
[141]McMurray, H. F., Parthasarathy, S., Steinberg, D. Oxidatively modified low density lipoprotein is a chemoattractant for human T lymphocytes. J Clin Invest, 1993; 92:1004-1008.
[142]]Kugiyama, K., Kerns, S. A., Morrisett, J. D., Roberts, R., Henry, P. D. Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins. Nature,1990; 344:160-162.
[143]Sakai, M., Miyazaki, A., Hakamata, H., Sakaki, T., Yui, S., Yamazaki, M., Shichiri, M., Horiuchi, S. Lysophosphatidylcholine plays an essential role in the mitogenic effect of oxidized low density lipoprotein on murine macrophages. J Biol Chem,1994; 269:31430-31435
[144]Locher, R., Weisser, B., Mengden, T., Brunner, C., Vetter, W. Lysolecithin actions on vascular smooth muscle cells. Biochem Biophys Res Commun,1992; 183:156-162.
[145]Kohno M, Yokokawa K, Yasunari K, Minami M, Kano H, Hanehira T, Yoshikawa J. Induction by lysophosphatidylcholine, a major phospholipid component of atherogenic lipoproteins, of human coronary artery smooth muscle cell migration. Circulation.1998; 98:353-359.
[146]Murugesan G, Fox PL. Role of lysophosphatidylcholine in the inhibition of endothelial cell motility by oxidized low density lipoprotein. J Clin Invest. 1996; 97:2736-2744.
[147]Iwase M, Sonoki K, Sasaki N, Ohdo S, Higuchi S, Hattori H, Iida M. Lysophosphatidylcholine contents in plasma LDL in patients with type 2 diabetes mellitus:Relation with lipoprotein-associated phospholipase A2 and effects of simvastatin treatment. Atherosclerosis.2008; 196:931-936.
[148]Sonoki K, Iwase M, Sasaki N, Ohdo S, Higuchi S, Matsuyama N, Iida M. Relations of lysophosphatidylcholine in low-density lipoprotein with serum lipoprotein-associated phospholipase A2, paraoxonase and homocysteine thiolactonase activities in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract.2009;86:117-123.
[149]Huo T, Cai S, Lu X, Sha Y, Yu M, Li F. Metabonomic study of biochemical changes in the serum of type 2 diabetes mellitus patients after the treatment of metformin hydrochloride J Pharm Biomed Anal.2009; 49:976-982.
[150]Noto H, Chitkara P, Raskin P. The role of lipoprotein-associated phospholipase A2 in the metabolic syndrome and diabetes. J Diab Complications 2006;20: 343-348.
[151]Amir G., Terrance W., Subhdeep V., Sanjay G., David K., Prakash S., Comorbidity of irritable bowel syndrome in psychiatric patients:A review, American journal of therapeutics.2003;10:61-67.
[152]Gupta S, Masand PS, Kaplan D, Bhandary A, Hendricks S. The relationship between schizophrenia and irritable bowel syndrome (IBS). Schizophr Res. 1997;23:265-268.
[153]O'Mahony S.M., Marchesi J.R., Scully P et al. Early life stress alters behavior, immunity, and microbiota in rats:implications for irritable bowel syndrome and psychiatric illness. Biol Psychiatry 2009; 65:263-267.
[154]Metcalf MG, Evans JJ., Mackenzie JA. Indices of ovulation:comparison of plasma and salivary levels of progesterone with urinary pregnanediol. J. Endocr. 1984; 100:75-80.
[155]Judge SM, Quade JP, Arrata WSM, Chatterton Jr RT. Time-course relationships between serum LH, serum progesterone and urinary pregnanediol concentrations in normal women. Steriods 1978; 31:175-187.
[156]Breier A., Buchanan RW., The effects of metabolic stress on plasma progesterone in healthy volunteers and schizophrenic patients. Life Sci,1992; 51:1527-1534.
[157]Elman I, Breier A. Effects of acute metabolic stress on plasma progesterone and testosterone in male subjects:relationship to pituitary-adrenocortical axis activation. Life Sci.1997; 61:1705-1712.
[158]Costrini NV., Kalkhoff RK. Relative effects of pregnancy, estradiol, and progesterone on plasma insulin and pancreatic islet insulin secretion. J Clin Invest.1971; 50:992-999.
[159]Battista P.J., Condon W.A., Serotonin-induced stimulation of progesterone production by cow luteal cells in vitro. J Reprod Fert 1986; 76:231-238.
[160]Ohnuma T, Sakai Y, Maeshima H, Hatano T, Hanzawa R, Abe S, Kida S, Shibata N, Suzuki T, Arai H. Changes in plasma glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical symptoms improve:Results from the Juntendo University Schizophrenia Projects (JUSP) Prog Neuropsychopharmacol Biol Psychiatry.2008;32:1905-1912.
[161]Neeman G, Blanaru M, Bloch B, Kremer I, Ermilov M, Javitt DC, Heresco-Levy U. Relation of plasma glycine, serine, and homocysteine levels to schizophrenia symptoms and medication type. Am J Psychiatry. 2005;162:1738-1740.
[162]Williams JB, Mallorga PJ, Jeffrey Conn P, Pettibone DJ, Sur C Effects of typical and atypical antipsychotics on human glycine transporters. Schizophr Res.2004;71:103-112.
[163]Scheen AJ, De Hert MA. Abnormal glucose metabolism in patients treated with antipsychotics. Diabetes Metab.2007; 33:169-175.
[164]Chiu CC, Chen KP, Liu HC, Lu MLThe early effect of olanzapine and risperidone on insulin secretion in atypical-naive schizophrenic patients. J Clin Psychopharmacol.2006; 26:504-507.
[165]Dwyer DS, Donohoe D. Induction of hyperglycemia in mice with atypical antipsychotic drugs that inhibit glucose uptake. Pharmacol Biochem Behav. 2003;75:255-260.
[166]Murashita M, Inoue T, Kusumi I, Nakagawa S, Itoh K, Tanaka T, Izumi T, Hosoda H, Kangawa K, Koyama T. Glucose and lipid metabolism of long-term risperidone monotherapy in patients with schizophrenia. Psychiatry Clin Neurosci.2007;61:54-58.
[167]Smith RC, Lindenmayer JP, Hu Q, Kelly E, Viviano TF, Cornwell J, Vaidhyanathaswamy S, Marcovina S, Davis JM. Effects of olanzapine and risperidone on lipid metabolism in chronic schizophrenic patients with long-term antipsychotic treatment:a randomized five month study Schizophr Res.2010; 120:204-209.
[168]Shafrir E, Raz I. Diabetes:mellitus or lipidus? Diabetologia.2003;46:433-440.
[169]Vidarsdottir S, de Leeuw van Weenen JE, Frolich M, Roelfsema F, Romijn JA, Pijl H. Effects of olanzapine and haloperidol on the metabolic status of healthy men. J Clin Endocrinol Metab.2009; 95:118-125.
[170]Albaugh VL, Vary TC, Ilkayeva O, Wenner BR, Maresca KP, Joyal JL, Breazeale S, Elich TD, Lang CH, Lynch CJ. Atypical Antipsychotics Rapidly and Inappropriately Switch Peripheral Fuel Utilization to Lipids, Impairing Metabolic Flexibility in Rodents. Schizophr Bull doi:10.1093/schbul/sbq053
[171]Gattaz WF, Kollisch M, Thuren T, Virtanen JA, Kinnunen PKJ. Increased plasma phospholipase A2 activity in schizophrenic patients:reduction after neuroleptic therapy. Biol Psychiatry 1987; 22:421-426.
[172]Tavares H, Yacubian J, Talib LL, Barbosa NR, Gattaz WF. Increased phospholipase A2 activity in schizophrenia with absent response to niacin. Schizophr Res.2003;61:1-6.
[173]Schmitt A, Maras A, Petroianu G, Braus DF, Scheuer L, Gattaz WF. Effects of antipsychotic treatment on membrane phospholipid metabolism in schizophrenia J Neural Transm.2001;108:1081-1091.
[174]Trzeciak HI, Kalacinski W, Malecki A, Kokot D. Effect of neuroleptics on phospholipase A2 activity in the brain of rats. Eur Arch Psychiatry Clin Neurosci 1995; 245:179-182.
[175]Kropp S, Kern V, Lange K, Degner D, Hajak G, Kornhuber J, Ruther E, Emrich HM, Schneider U, Bleich S. Oxidative stress during treatment with first- and second-generation antipsychotics. J Neuropsychiatry Clin Neurosci. 2005;17:227-231.
[176]O'Brien E, Dedova I, Duffy L, Cordwell S, Karl T, Matsumoto I. Effects of chronic risperidone treatment on the striatal protein profiles in rats. Brain Res. 2006; 1113:24-32.
[177]Modica-Napolitano JS, Lagace CJ, Brennan WA, Aprille JR. Differential effects of typical and atypical neuroleptics on mitochondrial function in vitro. Arch Pharm Res 2003;26:951-959.
[178]Melkersson K. Serum creatine kinase levels in chronic psychosis patients--a comparison between atypical and conventional antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry.2006; 30:1277-1282.
[179]Shirayama Y, Hashimoto K, Suzuki Y, Higuchi T. Correlation of plasma neurosteroid levels to the severity of negative symptoms in male patients with schizophrenia. Schizophr Res.2002; 58:69-74.
[180]Barbaccia ML, Affricano D, Purdy RH, Maciocco E, Spiga F, Biggio G. Clozapine, but not haloperidol, increases brain concentrations of neuroactive steroids in the rat. Neuropsychopharmacology.2001;25:489-497.
[181]Marx CE, Duncan GE, Gilmore JH, Lieberman JA, Morrow AL. Olanzapine increases allopregnanolone in the rat cerebral cortex Biol Psychiatry. 2000;47:1000-1004.
[182]Bitran D, Purdy RH, Kellogg CK. Anxiolytic effect of progesterone is associated with increases in cortical allopregnanolone and GABAA receptor function. Pharmacol Biochem Behav 1993; 45:423-428.
[183]Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J Neuroendocrinol 1995; 7:171-177.
[184]Friess E, Tagaya H, Trachsel L, Holsboer F, Rupprecht R. Progesterone-induced changes in sleep in male subjects. Am J Physiol 1997; 272:E885-E891.
[185]Backstrom T, Zetterlund B, Blom S, Romano M. Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy. Acta Neurol Scand 1984; 69:240-248.
[186]Wetzel CHR, Hermann B, Behl C, Pestel E, Rammes G, Zieglgansberger W, Holsboer F, Rupprecht R. Functional antagonistic properties of gondadal steroids at the 5-HT3 receptor. Mol Endocrinol 1998;12:1441-1451.
[187]Pariante CM, Dazzan P, Danese A, Morgan KD, Brudaglio F, Morgan C, Fearon P, Orr K, Hutchinson G, Pantelis C, Velakoulis D, Jones PB, Leff J, Murray RM. Increased pituitary volume in antipsychotic-free and antipsychotic-treated patients of the AEsop first-onset psychosis study. Neuropsychopharmacology.2005;30:1923-1931.
[188]Wieck A. Haddad p. Hyperprolactinaemia caused by antipsychotic drugs:This common side effect needs more attention. BMJ,2002; 324:250-252.
[1]Benes FM, Berretta S. GABAergic interneurons:implications for understanding schizophrenia and bipolar disorder[J]. Neuropsychopharmacology,2001; 25:1-27.
[2]Lewis DA, Volk DW, Hashimoto T. Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia:a novel target for the treatment of working memory dysfunction[J]. Psychopharmacology,2003; 174:143-150.
[3]Volk DW, Austin MC, Pierri JN, et al. Decreased glutamic acid decarboxylase 67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia[J]. Arch Gen Psychiatr,2000; 57:237-245.
[4]Vawter MP, Crook JM, Hyde TM, et al. Microarray analysis of gene expression in the prefrontal cortex in schizophrenia:a preliminary study [J]. Schizophr Res, 2002; 58:11-20.
[5]DrachevaS, ElhakemSL, McGurkSR, et al. GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions for elderly patients with schizophrenia[J], JNeurosci Res,2004; 76:581-592.
[6]Hashimoto T, Volk DW, Eggan SM, et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia[J]. J Neurosci,2003; 16:6315-6326.
[7]Tsutomu S, Akihiko O, Yusuke N, et al. Changes in density of calcium-binding-protein-immunoreactive GABAergic neurons in prefrontal cortex in schizophrenia and bipolar disorder[J]. Neuropathology,2007,28: 143-150.
[8]Gavin PR, Zuhal AM, Joanna CN, et al. Calcium binding protein markers of GABA deficits in schizophrenia -Post mortem studies and animal models[J]. Neurotoxicity Research,2004,6:57-62.
[9]Rodrigo Paz H. Pathophysiological models of schizophrenia; from dopamine to glutamate, and glutamate to GABA[J]. Rev Chil Neuro-Psiquiat,2005; 43: 314-328.
[10]David AL, Bita M. Cognitive dysfunction in schizophrenia-Convergence of y-aminobutyric acid and glutamate alterations[J]. Ach Neurol,2006; 63: 1372-1376.
[11]Reynolds GP, Czudek C, Andrews HB. Deficit and hemispheric asymmetry of GAB A uptake sites in the hippocampus in schizophrenia[J]. Biol Psychiatr, 1990; 27:1038-1044.
[12]Simpson MD, Slater P, Deakin JF, et al. Reduced GAB A uptake sites in the temporal lobe in schizophrenia[J]. Neurosci Lett,1989; 107:211-215.
[13]Simpson MD, Slater P, Deakin JF. Comparison of glutamate and gamma-aminobutyric acid uptake binding sites in frontal and temporal lobes in schizophrenia[J]. Biol Psychiatr,1998; 44:423-427.
[14]Volk DW, Austin MC, Pierri JN, et al. GABA transporter-1 mRNA in prefrontal cortex in schizophrenia:decreased expression in a subset of neurons[J]. Am J Psychiatr,2001;158:256-265.
[15]Volk DW, Pierri JN, Fritschy JM, et al. Reciprocal alterations in pre-and postsynaptic inhibitory markers at chandelier cells inputs to pyramidal neurons in schizophrenia[J]. Cereb Cortex,2002; 12:1063-1070.
[16]Schleimer S B, HintonT, DixonG, et al. GABA transporters GAT-1 and GAT-3 in the human dorsolateral prefrontal cortex in schizophrenia[J]. Neuropsychobiology,2004; 50:226-230.
[17]Hanada S, Mita T, Nishino N, Tanaka C. [3H]Muscimol binding sites increased in autopsied brains of chronic schizophrenics [J]. Life Sci,1987; 40:259-266.
[18]Benes FM, Vincent SL, Marie A, Khan Y. Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subject[J]. Neuroscience,1996; 75:1021-1031.
[19]Benes FM, Khan Y, Vincent SL, et al. Differences in the sub regional and cellular distribution of GABAA receptor binding in the hippocampal formation of schizophrenic brain[J]. Synapse,1996; 22:338-349.
[20]Dean B, Hussain T, Hayes W, et al. Changes in serotonin2A and GABA(A) receptors in schizophrenia:studies on the human dorsolateral prefrontal cortex [J]. JNeurochem,1999; 72:1593-1599.
[21]Benes FM, Wickramasinghe R, Vincent SL, et al. Uncoupling of GABA(A) and benzodiazepine receptor binding activity in the hippocampal formation of schizophrenic brain[J]. Brain Res,1997; 755:121-129.
[22]Volk DW, Pierri JN, Fritschy JM, Auh S, Sampson AR, Lewis DA. Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cells inputs to pyramidal neurons in schizophrenia[J]. Cereb Cortex,2002; 12:1063-1070.
[23]Impagnatiello F, Guidotti AR, Pesold C, et al. A decrease of reeling expression as a putative vulnerability factor in schizophrenia[J]. Proc Natl Acad Sci,1998; 95:15718-15723.
[24]Chao D, XF Huang. Increased density of GABAA receptors in the superior temporal gyrus in schizophrenia[J]. Exp Brain Res,2006; 168:587-590.
[25]Zink M, Schmitt A, May B, et al. Differential effects of long-term treatment with cloazapine or haloperidol on GABA receptor building and GAD67 expression[J]. Schizophr Res,2004; 66:151-157.
[26]Mizukami K, Ishikawa M, Hidaka S, et al Immunohistochemical localization of GABAB receptor in the entorhinal cortex and inferior temporal cortex of schizophrenia brain[J].Prog Neuropsychopharmacol Biol Psychiatry,2002; 26: 393-396.
[27]Ishikawa M, Mizukami K, Iwakiri M, et al. Immunohistochemical and immunoblot analysis of-aminobutyric acid B receptor in the prefrontal cortex of subjects with schizophrenia and bipolar disorder[J].Neurosci Lett,2005; 383: 272-277.
[28]Schahram Akbarian. Restoring GABAergic signaling and neuronal synchrony in schizophrenia[J].Am J Psychiatry,2008; 165:1507-1509
[29]Hanns M, Uwe R, Detlev B, et al. Regulation of cognition and symptoms of psychosis:focus on GABAA receptors and glycine transporter 1[J]. Pharmacol Biochem Behavior,2008; 90:58-64.
[30]David AL, Raymond YC, Cameron SC, et al. Subunit-selective modulation of GAB A type A receptor neurotransmission and cognition in schizophrenia [J]. Am JPsychiatry,2008; 165:1585-1593.
[31]Sawako A, Kazuhiro T, Hiroyuki M, et al Involvement of pallidotegmental neurons in methamphetamine-and MK-801-induced impairment of prepulse inhibition of the acoustic startle reflex in mice:reversal by GABAB receptor agonist bacolfen[J]. Neuropsychopharmacolog,2008; 33:3164-3175.
[32]Yona G, Abraham N, Irit GA, et al. BL-1020:A novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia[J]. Eur Neuropsychopharmacol,2009; 19:1-13.
[33]Richard FS, Else S. Clozapine and several other antipsychotic/antidepressant drugs preferentially blocks the same "core" fraction of GABAA receptors [J]. Neurochem Res,1998; 23:1283-1290.
[34]J. MA, N. YE, N. LANGE, et al. Dynorphinergic GABA neurons are a target of both typical and atypical antipsychotic drugs in the nucleus accumbens shell, central amygdaloid nucleus and thalamic central medial nucleus[J]. Neuroscience,2003; 121:991-998.
[35]Scott AH, Amanda G, Kerry JR. Prepulse inhibition deficits in GAD65 knockout mice and the effect of antipsychotic treatment[J]. Neuropsychopharmacology, 2004; 29:1610-1619.