目的
流行病學和遺傳學研究表明炎症和免疫作用在思覺失調症的致病機轉中。動物實驗的研究曾經提到懷孕時期的免疫反應（MIA）會影響子代免疫系統，而思覺失調症的形成是由於免疫的長時間且持續性調控導致腦部發育異常造成的結果，免疫系統與大腦之間的相互作用可能導致思覺失調症患者的情緒、認知和行為改變。然而，較早的發病年齡與遺傳因素和神經發展有關，本研究想探討不同發病年齡的思覺失調症患者及其一等親家屬的神經發展標記和免疫異常是否有關聯。

方法
所有患者均符合DSM-IV診斷思覺失調症的診斷標準。我們收集了思覺失調症患者、及其非精神病一等親家屬和健康對照組的血液樣本。首先，我們會檢測早發型思覺失調症、成人型思覺失調症和健康對照的免疫標記表現。其次，研究將會探討患者和家屬的神經發展缺損與免疫標記的相關性。接下來利用羅吉斯迴歸分析（Logistic regression model）和ROC曲線分析比較思覺失調症患者與其對照組的免疫標記的敏感度、特異度和曲線下面積（AUC）。並且使用部分最小平方判別分析（PLS-LDA）探討思覺失調症患者和健康對照組的免疫標記重要性。最後，我們將建構蛋白交互作用網絡來揭示思覺失調症神經發展基因參與炎症途徑的致病機轉。
 
結果
本研究共收案210位思覺失調症患者，及其83位非精神病一等親家屬和122位健康對照。結果顯示思覺失調症患者和健康對照有顯著差異，早發型思覺失調症和成人型思覺失調症在IL-4有顯著差異，IL-4也在早發型思覺失調症及成人型思覺失調症的親屬之間有顯著差異。而且發現神經發展缺損的思覺失調症患者免疫表現與早發型思覺失調症有相似的結果。進一步，細胞激素的濃度與思覺失調症患者神經發展標記有相關。ROC曲線分析的結果顯示，以IL-4、IL-6和IL-12區分早發型思覺失調症患者和健康對照組的AUC值為0.83、準確度為0.78。另外PLS-LDA判別分析結果顯示，以IL-4、IL-6和IL-12判別早發型思覺失調症患者和健康對照組有83%的個案能被正確分類，交叉驗證判別分析正確率為82%，結果表明細胞激素（IL-4, IL-6和IL-12）在早發型思覺失調症患者有好的鑑別能力。最後，利用訊息路徑富集分析發現免疫基因參與在許多神經發展相關功能和生物進程。

結論
根據研究的結果，細胞激素在早發型思覺失調症和神經發展缺損的思覺失調症患者之間有改變。這些發現支持細胞激素可以解釋精思覺失調症的一些臨床病理特徵。

Purpose
Epidemiological and genetic studies have suggested a role of inflammation and immunity in the pathogenesis of symptoms in schizophrenia. Study of maternal immune activation (MIA) models in animal experiments implicated that immune system changes active and continuously contributed to the aberrant brain development in disease process of schizophrenia. The interactions between the immune system and the aberrant brain development can give rise to changes in mood, cognition and behavior in symptoms of schizophrenia. However, an earlier age of onset is associated with a broad range of genetic factors and neurodevelopmental progress. This study aimed to identify immune abnormality associated with neurodevelopmental deficits in early- and adult- onset schizophrenia patients and their nonpsychotic first-degree relatives.

Methods
All patients fulfilled the diagnostic DSM-IV criteria for schizophrenia. We collected the blood samples from schizophrenia patients, nonpsychotic first-degree relatives of schizophrenia and healthy controls for analysis of immune signals. First, we estimated the immune and metabolic levels among EOS, AOS and healthy control. Second, we investigated the association of immune abnormality with neurodevelopmental deficits and non-deficits patients. Next, logistic regression analysis and receiver operating characteristics (ROC) curve were used to determine the sensitivity, specificity, and the

area under the curve (AUC) of immune markers between schizophrenia patients and controls. Partial least squares-linear discriminant analysis (PLS-LDA) showed that complete separation between schizophrenia patients and controls was achieved based on these cytokines. Finally, we would construct protein-protein interaction networks to reveal the mechanisms of neurodevelopmental genes involved in inflammation pathway in schizophrenia.

Results
There were 210 patients with schizophrenia, 83 nonpsychotic first-degree relatives and 122 healthy controls have been analyzed. Results showed the schizophrenia patients were significantly different to healthy controls. EOS was significantly different to AOS in IL-4 level. IL-4 level was also significantly different between Relatives of EOS and Relatives of AOS. In addition, we found similar results of the immune levels in schizophrenia patients with the neurodevelopmental deficits and non-deficits. ROC curve analysis showed that the AUC of IL-4, IL-6 and IL-12 was 0.83 and accuracy was 0.78 for EOS patients and healthy controls. Moreover, PLS-LDA analysis conducted of IL-4, IL-6 and IL-12 correctly classified 83% cases into EOS patients and healthy controls and cross-validation rate was 82%. Results showed that IL-4, IL-6 and IL-12 had a good classification ability. Finally, we found that many neurodevelopment related functions and biological processes were significantly enriched in immune genes by pathway enrichment analysis.
area under the curve (AUC) of immune markers between schizophrenia patients and controls. Partial least squares-linear discriminant analysis (PLS-LDA) showed that

complete separation between schizophrenia patients and controls was achieved based on these cytokines. Finally, we would construct protein-protein interaction networks to reveal the mechanisms of neurodevelopmental genes involved in inflammation pathway in schizophrenia.

Conclusion
According to our results, cytokine production is altered in EOS and schizophrenia patients with neurodevelopmental deficits. These findings support the hypothesis that cytokines may contribute to some of the clinical and pathophysiological features of schizophrenia.

Akagbosu, C. O., Evans, G. C., Gulick, D., Suckow, R. F., & Bucci, D. J. (2012). Exposure to kynurenic acid during adolescence produces memory deficits in adulthood. Schizophrenia bulletin, 38(4), 769-778.
Akhabir, L., & Sandford, A. J. (2011). Genome‐wide association studies for discovery of genes involved in asthma. Respirology, 16(3), 396-406.
Akiyama, M., Kirihara, T., Takahashi, S., Minami, Y., Yoshinobu, Y., Moriya, T., & Shibata, S. (1999). Modulation of mPer1 gene expression by anxiolytic drugs in mouse cerebellum. British journal of pharmacology, 128(7), 1616-1622.
Aksoy-Poyraz, C., Poyraz, B. Ç., Turan, Ş., & Arıkan, M. K. (2011). Minor physical anomalies and neurological soft signs in patients with schizophrenia and their siblings. Psychiatry research, 190(1), 85-90.
Andreassen, O. A., Harbo, H. F., Wang, Y., Thompson, W. K., Schork, A. J., Mattingsdal, M. et al. (2015). Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci. Molecular psychiatry, 20(2), 207-214.
Arolt, V., Weitzsch, C., Wilke, I., Nolte, A., Pinnow, M., Rothermundt, M., & Kirchner, H. (1997). Production of interferon-gamma in families with multiple occurrence of schizophrenia. Psychiatry research, 66(2), 145-152.
Bachmann, S., Bottmer, C., & Schröder, J. (2005). Neurological soft signs in first-episode schizophrenia: a follow-up study. American Journal of Psychiatry, 162(12), 2337-2343.
Barker, M., & Rayens, W. (2003). Partial least squares for discrimination. Journal of chemometrics, 17(3), 166-173.
Bergink, V., Gibney, S. M., & Drexhage, H. A. (2014). Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biological psychiatry, 75(4), 324-331.
Bilbo, S. D., & Schwarz, J. M. (2012). The immune system and developmental programming of brain and behavior. Frontiers in neuroendocrinology, 33(3), 267-286.
Boche, D., Perry, V. H., & Nicoll, J. A. R. (2013). Review: activation patterns of microglia and their identification in the human brain. Neuropathology and applied neurobiology, 39(1), 3-18.
Boks, M. P., Russo, S., Knegtering, R., & van den Bosch, R. J. (2000). The specificity of neurological signs in schizophrenia: a review. Schizophrenia research, 43(2), 109-116.
Boksa, P. (2010). Effects of prenatal infection on brain development and behavior: a review of findings from animal models. Brain, behavior, and immunity, 24(6), 881-897.
Bombin, I., Arango, C., & Buchanan, R. W. (2005). Significance and meaning of neurological signs in schizophrenia: two decades later. Schizophrenia Bulletin, 31(4), 962-977.
Brown, A. S. (2012). Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Developmental neurobiology, 72(10), 1272-1276.
Brown, A. S., & Derkits, E. J. (2009). Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. American Journal of Psychiatry, 167(3), 261-280.
Brown, A. S. (2006). Prenatal infection as a risk factor for schizophrenia. Schizophrenia bulletin, 32(2), 200-202.
Buchanan, R. W., & Heinrichs, D. W. (1989). The Neurological Evaluation Scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry research, 27(3), 335-350.
Buckley, P. F., Dean, D., Bookstein, F. L., Han, S., Yerukhimovich, M., Min, K. J., & Singer, B. (2005). A three-dimensional morphometric study of craniofacial shape in schizophrenia. American Journal of Psychiatry, 162(3), 606-608.
Cannon, M., Jones, P. B., & Murray, R. M. (2002). Obstetric complications and schizophrenia: historical and meta-analytic review. American Journal of Psychiatry, 159(7), 1080-1092.
Cannon, T. D., Rosso, I. M., Hollister, J. M., Bearden, C. E., Sanchez, L. E., & Hadley, T. (2000). A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia. Schizophrenia Bulletin, 26(2), 351-366.
Carson, M. J., Doose, J. M., Melchior, B., Schmid, C. D., & Ploix, C. C. (2006). CNS immune privilege: hiding in plain sight. Immunological reviews, 213(1), 48-65.
Chaudhry, I. B., Hallak, J., Husain, N., Minhas, F., Stirling, J., Richardson, P. et al. (2012). Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. Journal of psychopharmacology, 26(9), 1185-1193.
Chen, Y. H., Lee, H. C., & Lin, H. C. (2009). Prevalence and risk of atopic disorders among schizophrenia patients: a nationwide population based study. Schizophrenia research, 108(1), 191-196.
Compton, M. T., & Walker, E. F. (2009). Physical manifestations of neurodevelopmental disruption: are minor physical anomalies part of the syndrome of schizophrenia? Schizophrenia Bulletin, 35(2), 425-436.
Compton, M. T., Brudno, J., Kryda, A. D., Bollini, A. M., & Walker, E. F. (2007). Facial measurement differences between patients with schizophrenia and non-psychiatric controls. Schizophrenia research, 93(1), 245-252.
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nature reviews neuroscience, 9(1), 46-56.
Deverman, B. E., & Patterson, P. H. (2009). Cytokines and CNS development. Neuron, 64(1), 61-78.
Ding, M., Song, X., Zhao, J., Gao, J., Li, X., Yang, G. et al. (2014). Activation of Th17 cells in drug naïve, first episode schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 51, 78-82.
Faraggi, D., & Reiser, B. (2002). Estimation of the area under the ROC curve. Statistics in medicine, 21(20), 3093-3106.
Farkas, L. G., & Cheung, G. (1981). Facial asymmetry in healthy North American Caucasians: an anthropometrical study. The Angle orthodontist, 51(1), 70-77.
Fillman, S. G., Cloonan, N., Catts, V. S., Miller, L. C., Wong, J., McCrossin, T. et al. (2013). Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Molecular psychiatry, 18(2), 206-214.
Gaughran, F., O'Neill, E., Sham, P., Daly, R. J., & Shanahan, F. (2002). Soluble interleukin 2 receptor levels in families of people with schizophrenia. Schizophrenia research, 56(3), 235-239.
Gilmore, J. H., Jarskog, L. F., Vadlamudi, S., & Lauder, J. M. (2004). Prenatal Infection and Risk for Schizophrenia: IL-1 [beta], IL-6, and TNF [alpha] Inhibit Cortical Neuron Dendrite Development. Neuropsychopharmacology, 29(7), 1221.
Goldsmith, D. R., Rapaport, M. H., & Miller, B. J. (2016). A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Molecular psychiatry, 21(12), 1696-1709.
Hall, J. G., Froster-Iskenius, U. G., & Allanson, J. E. (1989). Handbook of normal physical measurements (Vol. 177). Oxford University Press.
Harrison, P. J., & Law, A. J. (2006). Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biological psychiatry, 60(2), 132-140.
Heckers, S., Barch, D. M., Bustillo, J., Gaebel, W., Gur, R., Malaspina, D. et al. (2013). Structure of the psychotic disorders classification in DSM‐5. Schizophrenia Research, 150(1), 11-14.
Horn, J. F., Habert, M. O., Kas, A., Malek, Z., Maksud, P., Lacomblez, L. et al. (2009). Differential automatic diagnosis between Alzheimer's disease and frontotemporal dementia based on perfusion SPECT images. Artificial Intelligence in Medicine, 47(2), 147-158.
Ismail, B., Cantor-Graae, E., & McNeil, T. F. (1998). Minor physical anomalies in schizophrenic patients and their siblings. American Journal of Psychiatry, 155(12), 1695-1702.
Jia, P., Wang, L., Meltzer, H. Y., & Zhao, Z. (2010). Common variants conferring risk of schizophrenia: a pathway analysis of GWAS data. Schizophrenia research, 122(1), 38-42.
John, J. P., Arunachalam, V., Ratnam, B., & Isaac, M. K. (2008). Expanding the schizophrenia phenotype: a composite evaluation of neurodevelopmental markers. Comprehensive psychiatry, 49(1), 78-86.
Jones, C. A., Brown, A. M., Auer, D. P., & Fone, K. C. (2011). The mGluR2/3 agonist LY379268 reverses post-weaning social isolation-induced recognition memory deficits in the rat. Psychopharmacology, 214(1), 269-283.
Khandaker, G. M., & Dantzer, R. (2016). Is there a role for immune-to-brain communication in schizophrenia? Psychopharmacology, 233(9), 1559-1573.
Khandaker, G. M., Pearson, R. M., Zammit, S., Lewis, G., & Jones, P. B. (2014). Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA psychiatry, 71(10), 1121-1128.
Khandaker, G. M., Zimbron, J., Lewis, G., & Jones, P. B. (2012). Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychological medicine, 43(02), 239-257.
Kim, Y. K., Myint, A. M., Verkerk, R., Scharpe, S., Steinbusch, H., & Leonard, B. (2009). Cytokine changes and tryptophan metabolites in medication-naive and medication-free schizophrenic patients. Neuropsychobiology, 59(2), 123-129.
Kim, Y. K., Myint, A. M., Lee, B. H., Han, C. S., Lee, H. J., Kim, D. J., & Leonard, B. E. (2004). Th1, Th2 and Th3 cytokine alteration in schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 28(7), 1129-1134.
Kim, Y. K., Suh, I. B., Kim, H., Han, C. S., Lim, C. S., Choi, S. H., & Licinio, J. (2002). The plasma levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs. Molecular Psychiatry, 7(10), 1107.
Kim, D. J., Kim, W., Yoon, S. J., Go, H. J., Choi, B. M., Jun, T. Y., & Kim, Y. K. (2001). Effect of risperidone on serum cytokines. International Journal of Neuroscience, 111(1-2), 11-19.
Knuesel, I., Chicha, L., Britschgi, M., Schobel, S. A., Bodmer, M., Hellings, J. A. et al. (2014). Maternal immune activation and abnormal brain development across CNS disorders. Nature Reviews Neurology, 10(11), 643-660.
Kuzman, M. R., Medved, V., Terzic, J., & Krainc, D. (2009). Genome-wide expression analysis of peripheral blood identifies candidate biomarkers for schizophrenia. Journal of psychiatric research, 43(13), 1073-1077.
Laan, W., Smeets, H., de Wit, N. J., Kahn, R. S., Grobbee, D. E., & Burger, H. (2009). Glucocorticosteroids associated with a decreased risk of psychosis. Journal of clinical psychopharmacology, 29(3), 288-290.
Laruelle, M. (2014). Schizophrenia: from dopaminergic to glutamatergic interventions. Current opinion in pharmacology, 14, 97-102.
Leonard, B. E., Schwarz, M., & Myint, A. M. (2012). The metabolic syndrome in schizophrenia: is inflammation a contributing cause? Journal of Psychopharmacology, 26(5 suppl), 33-41.
Levkovitz, Y., Mendlovich, S., Riwkes, S., Braw, Y., Levkovitch-Verbin, H., Gal, G. et al. (2010). A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. Journal of Clinical Psychiatry, 71(2), 138.
Maes, M., Meltzer, H. Y., Buckley, P., & Bosmans, E. (1995). Plasma-soluble interleukin-2 and transferrin receptor in schizoprenia and major depression. European archives of psychiatry and clinical neuroscience, 244(6), 325-329.
Maj, M. (1998). Critique of the DSM-IV operational diagnostic criteria for schizophrenia. The British Journal of Psychiatry.
Martínez-Gras, I., García-Sánchez, F., Guaza, C., Rodríguez-Jiménez, R., Andrés-Esteban, E., Palomo, T. et al. (2012). Altered immune function in unaffected first-degree biological relatives of schizophrenia patients. Psychiatry research, 200(2), 1022-1025.
McAllister, A. K. (2014). Major histocompatibility complex I in brain development and schizophrenia. Biological psychiatry, 75(4), 262-268.
McFarland, H. F., & Martin, R. (2007). Multiple sclerosis: a complicated picture of autoimmunity. Nature immunology, 8(9), 913-919.
Meyer, U., & Feldon, J. (2010). Epidemiology-driven neurodevelopmental animal models of schizophrenia. Progress in neurobiology, 90(3), 285-326.
Meyer, U., Feldon, J., & Fatemi, S. H. (2009). In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neuroscience & Biobehavioral Reviews, 33(7), 1061-1079.
Middleton, F. A., Pato, C. N., Gentile, K. L., McGann, L., Brown, A. M., Trauzzi, M. et al. (2005). Gene expression analysis of peripheral blood leukocytes from discordant sib‐pairs with schizophrenia and bipolar disorder reveals points of convergence between genetic and functional genomic approaches. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 136(1), 12-25.
Miller, B. J., Buckley, P., Seabolt, W., Mellor, A., & Kirkpatrick, B. (2011). Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biological psychiatry, 70(7), 663-671.
Mittleman, B. B., Castellanos, F. X., Jacobsen, L. K., Rapoport, J. L., Swedo, S. E., & Shearer, G. M. (1997). Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. The Journal of Immunology, 159(6), 2994-2999.
Moffatt, M. F., Kabesch, M., Liang, L., Dixon, A. L., Strachan, D., Heath, S and Heinzmann, A., et al (2007). Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature, 448(7152), 470.
Morar, B., Dragović, M., Waters, F. A. V., Chandler, D., Kalaydjieva, L., & Jablensky, A. (2011). Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition. Molecular psychiatry, 16(8), 860-866.
Müller, N., Riedel, M., Schwarz, M. J., & Engel, R. R. (2005). Clinical effects of COX–2 inhibitors on cognition in schizophrenia. European archives of psychiatry and clinical neuroscience, 255(2), 149-151.
Müller, N., Riedel, M., Scheppach, C., Brandstätter, B., Sokullu, S., Krampe, K. et al. (2002). Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. American Journal of Psychiatry, 159(6), 1029-1034.
Network, T., & Pathway Analysis Subgroup of the Psychiatric Genomics Consortium. (2015). Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nature neuroscience, 18(2), 199-209.
Niemi, L. T., Suvisaari, J. M., Haukka, J. K., & Lönnqvist, J. K. (2005). Childhood predictors of future psychiatric morbidity in offspring of mothers with psychotic disorder. The British Journal of Psychiatry, 186(2), 108-114.
Noto, C., Maes, M., Ota, V. K., Teixeira, A. L., Bressan, R. A., Gadelha, A., & Brietzke, E. (2015). High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance. The World Journal of Biological Psychiatry, 16(6), 422-429.
Noto, C., Ota, V. K., Gouvea, E. S., Rizzo, L. B., Spindola, L., Honda, P. H., ... & Maes, M. (2015). Effects of risperidone on cytokine profile in drug-naive first-episode psychosis. International Journal of Neuropsychopharmacology, 18(4).
Nunes, S. O., Matsuo, T., Kaminami, M. S., Watanabe, M. A. E., Reiche, E. M. V., & Itano, E. N. (2006). An autoimmune or an inflammatory process in patients with schizophrenia, schizoaffective disorder, and in their biological relatives. Schizophrenia research, 84(1), 180-182.
O'Brien, S. M., Scully, P., & Dinan, T. G. (2008). Increased tumor necrosis factor-alpha concentrations with interleukin-4 concentrations in exacerbations of schizophrenia. Psychiatry research, 160(3), 256-262.
Pae, C. U., Yoon, C. H., Kim, T. S., Kim, J. J., Park, S. H., Lee, C. U., ... & Paik, I. H. (2006). Antipsychotic treatment may alter T-helper (TH) 2 arm cytokines. International immunopharmacology, 6(4), 666-671.
Park, K. W., Baik, H. H., & Jin, B. K. (2008). Interleukin-4-induced oxidative stress via microglial NADPH oxidase contributes to the death of hippocampal neurons in vivo. Current aging science, 1(3), 192-201.
Patterson, P. H. (2009). Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behavioural brain research, 204(2), 313-321.
Paul-Samojedny, M., Owczarek, A., Kowalczyk, M., Suchanek, R., Palacz, M., Kucia, K. et al. (2013). Association of interleukin 2 (IL-2), interleukin 6 (IL-6), and TNF-alpha (TNFα) gene polymorphisms with paranoid schizophrenia in a Polish population. The Journal of neuropsychiatry and clinical neurosciences, 25(1), 72-82.
Petryshen, T. L., Middleton, F. A., Kirby, A., Aldinger, K. A., Purcell, S., Tahl, A. R. et al. (2005). Support for involvement of neuregulin 1 in schizophrenia pathophysiology. Molecular psychiatry, 10(4), 366-374.
Pocivavsek, A., Thomas, M. A., Elmer, G. I., Bruno, J. P., & Schwarcz, R. (2014). Continuous kynurenine administration during the prenatal period, but not during adolescence, causes learning and memory deficits in adult rats. Psychopharmacology, 231(14), 2799-2809.
Pollmächer, T., Haack, M., Schuld, A., Kraus, T., & Hinze-Selch, D. (2000). Effects of antipsychotic drugs on cytokine networks. Journal of psychiatric research, 34(6), 369-382.
Preti, A., Pisano, A., Cascio, M. T., Monzani, E., Meneghelli, A., & Cocchi, A. (2012). Obstetric complications in early psychosis: Relation with family history of psychosis. Psychiatry research, 200(2), 708-714.
Rao, J. S., Kim, H. W., Harry, G. J., Rapoport, S. I., & Reese, E. A. (2013). Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophrenia research, 147(1), 24-31.
Rapoport, J. L., Giedd, J. N., & Gogtay, N. (2012). Neurodevelopmental model of schizophrenia: update 2012. Molecular psychiatry, 17(12), 1228-1238.
Rapoport, J. L., Addington, A. M., Frangou, S., & Psych, M. R. C. (2005). The neurodevelopmental model of schizophrenia: update 2005.
Rosso, I. M., Bearden, C. E., Hollister, J. M., Gasperoni, T. L., Sanchez, L. E., Hadley, T., & Cannon, T. D. (2000). Childhood neuromotor dysfunction in schizophrenia patients and their unaffected siblings: a prospective cohort study. Schizophrenia Bulletin, 26(2), 367.
Rubio-Abadal, E., Ochoa, S., Barajas, A., Banos, I., Dolz, M., Sanchez, B. et al. (2015). Birth weight and obstetric complications determine age at onset in first episode of psychosis. Journal of psychiatric research, 65, 108-114.
Sanders, R. D., Keshavan, M. S., Forman, S. D., Pieri, J. N., McLaughlin, N., Allen, D. N., ... & Goldstein, G. (2000). Factor structure of neurologic examination abnormalities in unmedicated schizophrenia. Psychiatry research, 95(3), 237-243.
Schizophrenia Working Group of the Psychiatric Genomics Consortium. (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature, 511(7510), 421-427.
Schmitt, J., Buske‐Kirschbaum, A., & Roessner, V. (2010). Is atopic disease a risk factor for attention‐deficit/hyperactivity disorder? A systematic review. Allergy, 65(12), 1506-1524.
Schwarz, E., van Beveren, N. J., Ramsey, J., Leweke, F. M., Rothermundt, M., Bogerts, B. et al. (2013). Identification of subgroups of schizophrenia patients with changes in either immune or growth factor and hormonal pathways. Schizophrenia bulletin, 40(4), 787-795.
Schwarz, M. J., Krönig, H., Riedel, M., Dehning, S., Douhet, A., Spellmann, I., Müller, N. et al. (2006). IL-2 and IL-4 polymorphisms as candidate genes in schizophrenia. European archives of psychiatry and clinical neuroscience, 256(2), 72-76.
Schwieler, L., Larsson, M. K., Skogh, E., Kegel, M. E., Orhan, F., Abdelmoaty, S. et al. (2015). Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia—significance for activation of the kynurenine pathway. Journal of psychiatry & neuroscience: JPN, 40(2), 126.
Selmeczy, Z., Szelényi, J., & Vizi, E. S. (2003). Intact noradrenaline transporter is needed for the sympathetic fine-tuning of cytokine balance. European journal of pharmacology, 469(1), 175-181.
Shaked, I., Meerson, A., Wolf, Y., Avni, R., Greenberg, D., Gilboa-Geffen, A., & Soreq, H. (2009). MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase. Immunity, 31(6), 965-973.
Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D. et al. (2003). Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome research, 13(11), 2498-2504.
Şimşek, Ş., Yıldırım, V., Çim, A., & Kaya, S. (2016). Serum IL-4 and IL-10 levels correlate with the symptoms of the drug-naive adolescents with first episode, early onset schizophrenia. Journal of child and adolescent psychopharmacology, 26(8), 721-726.
Sirota, P., Meiman, M., Herschko, R., & Bessler, H. (2005). Effect of neuroleptic administration on serum levels of soluble IL-2 receptor-alpha and IL-1 receptor antagonist in schizophrenic patients. Psychiatry research, 134(2), 151-159.
Sivkov, S. T., & Akabaliev, V. H. (2004). Discriminating value of total minor physical anomaly score on the Waldrop physical anomaly scale between schizophrenia patients and normal control subjects. Schizophrenia bulletin, 30(2), 361-366.
Slattery, M. J. (2005). Psychiatric comorbidity associated with atopic disorders in children and adolescents. Immunology and allergy clinics of North America, 25(2), 407-420.
Spanakos, G., Baxevanis, C. N., Economou, M., Gritzapis, A. D., Papamichail, M. P., & Stefanis, C. N. (2001). Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophrenia research, 47(1), 13-25.
Szymona, K., Zdzisińska, B., Karakuła-Juchnowicz, H., Kocki, T., Kandefer-Szerszeń, M., Flis, M., Urbańska, E. M. et al. (2017). Correlations of kynurenic acid, 3-hydroxykynurenine, sIL-2R, IFN-α, and IL-4 with clinical symptoms during acute relapse of schizophrenia. Neurotoxicity Research, 1-10.
Tomasik, J., Rahmoune, H., Guest, P. C., & Bahn, S. (2016). Neuroimmune biomarkers in schizophrenia. Schizophrenia research, 176(1), 3-13.
Tsai, I. N., Lin, J. J., Lu, M. K., Tan, H. P., Jang, F. L., Gan, S. T., & Lin, S. H. (2016). Improving risk assessment and familial aggregation of age at onset in schizophrenia using minor physical anomalies and craniofacial measures. Medicine, 95(30).
Upthegrove, R., Manzanares-Teson, N., & Barnes, N. M. (2014). Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophrenia research, 155(1), 101-108.
Vawter, M. P., Ferran, E., Galke, B., Cooper, K., Bunney, W. E., & Byerley, W. (2004). Microarray screening of lymphocyte gene expression differences in a multiplex schizophrenia pedigree. Schizophrenia research, 67(1), 41-52.
Voisey, J., Mehta, D., McLeay, R., Morris, C. P., Wockner, L. F., Noble, E. P. et al. (2017). Clinically proven drug targets differentially expressed in the prefrontal cortex of schizophrenia patients. Brain, behavior, and immunity, 61, 259-265.
Vuillermot, S., Weber, L., Feldon, J., & Meyer, U. (2010). A longitudinal examination of the neurodevelopmental impact of prenatal immune activation in mice reveals primary defects in dopaminergic development relevant to schizophrenia. Journal of Neuroscience, 30(4), 1270-1287.
Wamboldt, M. Z., Weintraub, P., Krafchick, D., & Wamboldt, F. S. (1996). Psychiatric family history in adolescents with severe asthma. Journal of the American Academy of Child & Adolescent Psychiatry, 35(8), 1042-1049.
Wang, A. K., & Miller, B. J. (2017). Meta-analysis of cerebrospinal fluid cytokine and tryptophan catabolite alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder, and depression. Schizophrenia Bulletin.
Weber, N. S., Cowan, D. N., Millikan, A. M., & Niebuhr, D. W. (2009). Psychiatric and general medical conditions comorbid with schizophrenia in the National Hospital Discharge Survey. Psychiatric Services, 60(8), 1059-1067.
Weinberg, S.M., Jenkins, E.A., Marazita, M.L., Maher, B.S. (2007).Minor physical anomalies in schizophrenia: a meta-analysis.Schizophr. Res, 89, 72–85.
Xu, N., Li, X., & Zhong, Y. (2015). Inflammatory cytokines: potential biomarkers of immunologic dysfunction in autism spectrum disorders. Mediators of inflammation, 2015.
Xu, B., Ionita-Laza, I., Roos, J. L., Boone, B., Woodrick, S., Sun, Y. et al. (2012). De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nature genetics, 44(12), 1365-1369.
Zhu, S., Chan-Yeung, M., Becker, A. B., Dimich-Ward, H., Ferguson, A. C., Manfreda, J., Sandford, A. J. et al. (2000). Polymorphisms of the IL-4, TNF-α, and Fc α RI β genes and the risk of allergic disorders in at-risk infants. American journal of respiratory and critical care medicine, 161(5), 1655-1659.
Zvara, Á., Szekeres, G., Janka, Z., Kelemen, J. Z., Cimmer, C., Sántha, M., & Puskás, L. G. (2005). Over-expression of dopamine D_2 receptor and inwardly rectifying potassium channel genes in drug-naive schizophrenic peripheral blood lymphocytes as potential diagnostic markers. Disease markers, 21(2), 61-69.