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Molecular Neurobiology

, Volume 53, Issue 8, pp 5701–5709 | Cite as

Depression, Cytokine, and Cytokine by Treatment Interactions Modulate Gene Expression in Antipsychotic Naïve First Episode Psychosis

  • Cristiano Noto
  • Vanessa Kiyomi Ota
  • Marcos Leite Santoro
  • Eduardo Sauerbronn Gouvea
  • Patricia Natalia Silva
  • Leticia Maria Spindola
  • Quirino Cordeiro
  • Rodrigo Affonseca Bressan
  • Ary Gadelha
  • Elisa Brietzke
  • Sintia Iole Belangero
  • Michael Maes
Article

Abstract

In schizophrenia, genetic and environmental factors affect neurodevelopment and neuroprogressive trajectory. Altered expression of neuro-immune genes and increased levels of cytokines are observed, especially in patients with comorbid depression. However, it remains unclear whether circulating levels of cytokines and expression of these genes are associated, and how antipsychotic treatments impact this association. Relationships between messenger RNA (mRNA) expression of 11 schizophrenia-related genes and circulating levels of cytokines (interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α) were analyzed in 174 antipsychotic naïve first episode psychosis (FEP) and in 77 healthy controls. A subgroup of 72 patients was reassessed after treatment with risperidone. FEP patients were divided into those with and without depression. FEP patients with depression showed increased COMT expression and decreased NDEL1 expression. Increased IL-6 was associated with lowered AKT1 and DROSHA expression, while increased IL-10 was associated with increased NDEL1, DISC1, and MBP expression. IL-6 levels significantly increased the risperidone-induced expression of AKT1, DICER1, DROSHA, and COMT mRNA. The differential mRNA gene expression in FEP is largely associated with increased cytokine levels. While increased IL-6 may downregulate AKT-mediated cellular functions and dysregulate genes involved in microRNA (miRNA) machinery, increased IL-10 has neuroprotective properties. Increased IL-6 levels may prime the expression of genes (AKT1, DICER1, DROSHA, and COMT) in response to risperidone, suggesting that cytokine × treatment × gene interactions may improve cell function profiles. FEP patients with depression show a different gene expression profile reinforcing the theory that depression in FEP is a different phenotype.

Keywords

Schizophrenia First-episode psychosis Antipsychotic naïve Neuroprogression Gene expression Depression Inflammation Immune 

Notes

Compliance with Ethical Standards

All participants provided written informed consent prior to enrollment in this study. The study was approved by the Research Ethics Committee of UNIFESP (Sao Paulo, Brazil) and carried out in accordance with the Declaration of Helsinki.

Conflict of Interest

Dr. Noto has received a scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Dr. Gadelha was on the speakers’ bureau and/or has acted as a consultant for Janssen-Cilag in the last 12 months and has also received research support from Brazilian government institutions (CNPq). Dr. Bressan has received research funding from FAPESP, CNPq, CAPES, Fundação Safra, Fundação ABADS, Janssen, Eli Lilly, Lundbeck, Novartis and Roche, has served as a speaker for Astra Zeneca, Bristol, Janssen, Lundbeck and Revista Brasileira de Psiquiatria, and is a shareholder of Radiopharmacus Ltda and Biomolecular Technology Ltda. Dr. Maes is supported by CNPq (Conselho Nacional de Desenvolvimento Cientifico e Technologia) PVE fellowship at the Health Sciences Graduate Program, Londrina State University (UEL). The other authors have no conflicts of interest to disclose.

Role of Funding Source

Funding for this study was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2010/08968-6, 2010/19176-3, 2011/50740-5 and 2013/10498-6), Brazil.x

Supplementary material

12035_2015_9489_MOESM1_ESM.docx (69 kb)
ESM 1 (DOCX 68 kb)

References

  1. 1.
    Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE et al (2013) Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 382(9904):1575–1586. doi: 10.1016/S0140-6736(13)61611-6 CrossRefPubMedGoogle Scholar
  2. 2.
    Arnedo J, Svrakic DM, Del Val C, Romero-Zaliz R, Hernandez-Cuervo H, Molecular Genetics of Schizophrenia C, Fanous AH, Pato MT et al (2014) Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies. Am J Psychiatry. doi: 10.1176/appi.ajp.2014.14040435 PubMedGoogle Scholar
  3. 3.
    Davis J, Moylan S, Harvey BH, Maes M, Berk M (2014) Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Austral N Z J Psychiatr 48(6):512–529. doi: 10.1177/0004867414533012 CrossRefGoogle Scholar
  4. 4.
    Sullivan PF, Kendler KS, Neale MC (2003) Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 60(12):1187–1192. doi: 10.1001/archpsyc.60.12.1187 CrossRefPubMedGoogle Scholar
  5. 5.
    Bodmer W, Bonilla C (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 40(6):695–701. doi: 10.1038/ng.f.136 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Schizophrenia Working Group of the Psychiatric Genomics C (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511(7510):421–427. doi: 10.1038/nature13595 CrossRefGoogle Scholar
  7. 7.
    Anderson G, Berk M, Dodd S, Bechter K, Altamura AC, Dell’osso B, Kanba S, Monji A et al (2013) Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 42:1–4. doi: 10.1016/j.pnpbp.2012.10.008 CrossRefGoogle Scholar
  8. 8.
    Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S, Bergen SE, Collins AL et al (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45(10):1150–1159. doi: 10.1038/ng.2742 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Meyer U (2013) Developmental neuroinflammation and schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 42:20–34. doi: 10.1016/j.pnpbp.2011.11.003 CrossRefGoogle Scholar
  10. 10.
    Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B (2011) Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 70(7):663–671. doi: 10.1016/j.biopsych.2011.04.013 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Park KM, Bowers WJ (2010) Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal 22(7):977–983. doi: 10.1016/j.cellsig.2010.01.010 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Pan W, Zadina JE, Harlan RE, Weber JT, Banks WA, Kastin AJ (1997) Tumor necrosis factor-alpha: a neuromodulator in the CNS. Neurosci Biobehav Rev 21(5):603–613CrossRefPubMedGoogle Scholar
  13. 13.
    Dunn AJ, Wang J, Ando T (1999) Effects of cytokines on cerebral neurotransmission. Comparison with the effects of stress. Adv Exp Med Biol 461:117–127. doi: 10.1007/978-0-585-37970-8_8 CrossRefPubMedGoogle Scholar
  14. 14.
    Thompson CD, Zurko JC, Hanna BF, Hellenbrand DJ, Hanna A (2013) The therapeutic role of interleukin-10 after spinal cord injury. J Neurotrauma 30(15):1311–1324. doi: 10.1089/neu.2012.2651 CrossRefPubMedGoogle Scholar
  15. 15.
    Calabrese F, Rossetti AC, Racagni G, Gass P, Riva MA, Molteni R (2014) Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity. Front Cell Neurosci 8:430. doi: 10.3389/fncel.2014.00430 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Song XQ, Lv LX, Li WQ, Hao YH, Zhao JP (2009) The interaction of nuclear factor-kappa B and cytokines is associated with schizophrenia. Biol Psychiatry 65(6):481–488. doi: 10.1016/j.biopsych.2008.10.018 CrossRefPubMedGoogle Scholar
  17. 17.
    Mattson MP, Culmsee C, Yu Z, Camandola S (2000) Roles of nuclear factor kappaB in neuronal survival and plasticity. J Neurochem 74(2):443–456CrossRefPubMedGoogle Scholar
  18. 18.
    Hodge DR, Xiao W, Clausen PA, Heidecker G, Szyf M, Farrar WL (2001) Interleukin-6 regulation of the human DNA methyltransferase (HDNMT) gene in human erythroleukemia cells. J Biol Chem 276(43):39508–39511. doi: 10.1074/jbc.C100343200 CrossRefPubMedGoogle Scholar
  19. 19.
    Saradalekshmi KR, Neetha NV, Sathyan S, Nair IV, Nair CM, Banerjee M (2014) DNA methyl transferase (DNMT) gene polymorphisms could be a primary event in epigenetic susceptibility to schizophrenia. PLoS One 9(5):e98182. doi: 10.1371/journal.pone.0098182 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wockner LF, Noble EP, Lawford BR, Young RM, Morris CP, Whitehall VL, Voisey J (2014) Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients. Translat Psychiatr 4:e339. doi: 10.1038/tp.2013.111 CrossRefGoogle Scholar
  21. 21.
    Noto C, Ota VK, Gouvea ES, Rizzo LB, Spindola LM, Honda PH, Cordeiro Q, Belangero SI et al (2014) Effects of risperidone on cytokine profile in drug-naive first-episode psychosis. Int J Neuropsychopharmacol / Off Sci J Coll Int Neuropsychopharmacol 18 (4). doi: 10.1093/ijnp/pyu042
  22. 22.
    Noto C, Ota VK, Gadelha A, Noto MN, Barbosa DS, Bonifacio KL, Nunes SO, Cordeiro Q et al (2015) Oxidative stress in drug naive first episode psychosis and antioxidant effects of risperidone. J Psychiatr Res 68:210–216. doi: 10.1016/j.jpsychires.2015.07.003 CrossRefPubMedGoogle Scholar
  23. 23.
    Ota VK, Noto C, Gadelha A, Santoro ML, Ortiz BB, Andrade EH, Tasso BC, Spindola LM et al (2014) Evaluation of neurotransmitter receptor gene expression identifies GABA receptor changes: a follow-up study in antipsychotic-naive patients with first-episode psychosis. J Psychiatr Res 56:130–136. doi: 10.1016/j.jpsychires.2014.05.012 CrossRefPubMedGoogle Scholar
  24. 24.
    Ota VK, Noto C, Gadelha A, Santoro ML, Spindola LM, Gouvea ES, Stilhano RS, Ortiz BB et al (2014) Changes in gene expression and methylation in the blood of patients with first-episode psychosis. Schizophr Res. doi: 10.1016/j.schres.2014.09.008 Google Scholar
  25. 25.
    Ota VK, Noto C, Gadelha A, Santoro ML, Silva PN, Melaragno MI, Smith Mde A, Cordeiro Q et al (2013) Neurotransmitter receptor and regulatory gene expression in peripheral blood of Brazilian drug-naive first-episode psychosis patients before and after antipsychotic treatment. Psychiatry Res 210(3):1290–1292. doi: 10.1016/j.psychres.2013.09.016 CrossRefPubMedGoogle Scholar
  26. 26.
    Gozdzik-Zelazny A, Borecki L, Pokorski M (2011) Depressive symptoms in schizophrenic patients. Europ J Med Res 16(12):549–552CrossRefGoogle Scholar
  27. 27.
    Upthegrove R, Birchwood M, Ross K, Brunett K, McCollum R, Jones L (2010) The evolution of depression and suicidality in first episode psychosis. Acta Psychiatr Scand 122(3):211–218. doi: 10.1111/j.1600-0447.2009.01506.x CrossRefPubMedGoogle Scholar
  28. 28.
    Noto C, Gadelha A, Belangero SI, Spindola LM, Rocha NP, de Miranda AS, Teixeira AL, Cardoso Smith MA et al (2013) Circulating levels of sTNFR1 as a marker of severe clinical course in schizophrenia. J Psychiatr Res 47(4):467–471. doi: 10.1016/j.jpsychires.2012.12.010 CrossRefPubMedGoogle Scholar
  29. 29.
    Vessoni AL (1993) Adaptação e estudo de confiabilidade da escala de avaliação das síndromes positiva e negativa para a esquizofrenia no Brasil. Escola Paulista de Medicina, São PauloGoogle Scholar
  30. 30.
    Addington D, Addington J, Maticka-Tyndale E (1993) Assessing depression in schizophrenia: the Calgary Depression Scale. British J Psychiatr Suppl 22:39–44Google Scholar
  31. 31.
    Hayashi MA, Portaro FC, Tambourgi DV, Sucupira M, Yamane T, Fernandes BL, Ferro ES, Reboucas NA et al (2000) Molecular and immunochemical evidences demonstrate that endooligopeptidase A is the predominant cytosolic oligopeptidase of rabbit brain. Biochem Biophys Res Commun 269(1):7–13. doi: 10.1006/bbrc.2000.2243 CrossRefPubMedGoogle Scholar
  32. 32.
    Rampino A, Walker RM, Torrance HS, Anderson SM, Fazio L, Di Giorgio A, Taurisano P, Gelao B et al (2014) Expression of DISC1-interactome members correlates with cognitive phenotypes related to schizophrenia. PLoS One 9(6):e99892. doi: 10.1371/journal.pone.0099892 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Gadelha A, Machado MF, Yonamine CM, Sato JR, Juliano MA, Oliveira V, Bressan RA, Hayashi MA (2013) Plasma Ndel1 enzyme activity is reduced in patients with schizophrenia—a potential biomarker? J Psychiatr Res 47(5):657–663. doi: 10.1016/j.jpsychires.2013.01.009 CrossRefPubMedGoogle Scholar
  34. 34.
    Kumarasinghe N, Beveridge NJ, Gardiner E, Scott RJ, Yasawardene S, Perera A, Mendis J, Suriyakumara K et al (2013) Gene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving AKT1 that are corrected by antipsychotic medication. Int J Neuropsychopharmacol 16(7):1483–1503. doi: 10.1017/S1461145713000035 CrossRefPubMedGoogle Scholar
  35. 35.
    Kamiya A, Tomoda T, Chang J, Takaki M, Zhan C, Morita M, Cascio MB, Elashvili S et al (2006) DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1. Hum Mol Genet 15(22):3313–3323. doi: 10.1093/hmg/ddl407 CrossRefPubMedGoogle Scholar
  36. 36.
    Hayashi MA, Portaro FC, Bastos MF, Guerreiro JR, Oliveira V, Gorrao SS, Tambourgi DV, Sant’Anna OA et al (2005) Inhibition of NUDEL (nuclear distribution element-like)-oligopeptidase activity by disrupted-in-schizophrenia 1. Proc Natl Acad Sci U S A 102(10):3828–3833. doi: 10.1073/pnas.0500330102 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Hayashi MA, Guerreiro JR, Charych E, Kamiya A, Barbosa RL, Machado MF, Campeiro JD, Oliveira V et al (2010) Assessing the role of endooligopeptidase activity of Ndel1 (nuclear-distribution gene E homolog like-1) in neurite outgrowth. Mol Cell Neurosci 44(4):353–361. doi: 10.1016/j.mcn.2010.04.006 CrossRefPubMedGoogle Scholar
  38. 38.
    Ira E, Zanoni M, Ruggeri M, Dazzan P, Tosato S (2013) COMT, neuropsychological function and brain structure in schizophrenia: a systematic review and neurobiological interpretation. J Psychiatr Neurosci : JPN 38(6):366–380. doi: 10.1503/jpn.120178 CrossRefGoogle Scholar
  39. 39.
    Sonmez N, Rossberg JI, Evensen J, Barder HE, Haahr U, Ten Velden HW, Joa I, Johannessen JO et al (2014) Depressive symptoms in first-episode psychosis: a 10-year follow-up study. Early Interven Psychiatr. doi: 10.1111/eip.12163 Google Scholar
  40. 40.
    Talarowska M, Szemraj J, Berk M, Maes M, Galecki P (2015) Oxidant/antioxidant imbalance is an inherent feature of depression. BMC Psychiatr 15:71. doi: 10.1186/s12888-015-0454-5 CrossRefGoogle Scholar
  41. 41.
    Al-Hakeim HK, Al-Rammahi DA, Al-Dujaili AH (2015) IL-6, IL-18, sIL-2R, and TNFalpha proinflammatory markers in depression and schizophrenia patients who are free of overt inflammation. J Affect Disord 182:106–114. doi: 10.1016/j.jad.2015.04.044 CrossRefPubMedGoogle Scholar
  42. 42.
    Noto C, Ota VK, Santoro ML, Ortiz BB, Rizzo LB, Higuchi CH, Cordeiro Q, Belangero SI et al (2015) Effects of depression on the cytokine profile in drug naive first-episode psychosis. Schizophr Res. doi: 10.1016/j.schres.2015.01.026 Google Scholar
  43. 43.
    Kim S, Hwang Y, Webster MJ, Lee D (2015) Differential activation of immune/inflammatory response-related co-expression modules in the hippocampus across the major psychiatric disorders. Mol Psychiatry. doi: 10.1038/mp.2015.79 Google Scholar
  44. 44.
    Beveridge NJ, Cairns MJ (2012) MicroRNA dysregulation in schizophrenia. Neurobiol Dis 46(2):263–271. doi: 10.1016/j.nbd.2011.12.029 CrossRefPubMedGoogle Scholar
  45. 45.
    Sun E, Shi Y (2014) MicroRNAs: small molecules with big roles in neurodevelopment and diseases. Exp Neurol. doi: 10.1016/j.expneurol.2014.08.005 PubMedCentralGoogle Scholar
  46. 46.
    Balu DT, Coyle JT (2011) Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. Neurosci Biobehav Rev 35(3):848–870. doi: 10.1016/j.neubiorev.2010.10.005 CrossRefPubMedGoogle Scholar
  47. 47.
    Chalecka-Franaszek E, Chuang DM (1999) Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci U S A 96(15):8745–8750CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    De Sarno P, Li X, Jope RS (2002) Regulation of Akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium. Neuropharmacology 43(7):1158–1164CrossRefPubMedGoogle Scholar
  49. 49.
    Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA (2004) Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 36(2):131–137. doi: 10.1038/ng1296 CrossRefPubMedGoogle Scholar
  50. 50.
    Kim JY, Duan X, Liu CY, Jang MH, Guo JU, Pow-anpongkul N, Kang E, Song H et al (2009) DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron 63(6):761–773. doi: 10.1016/j.neuron.2009.08.008 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P et al (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425(6956):415–419. doi: 10.1038/nature01957 CrossRefPubMedGoogle Scholar
  52. 52.
    Aggarwal S, Yurlova L, Simons M (2011) Central nervous system myelin: structure, synthesis and assembly. Trends Cell Biol 21(10):585–593. doi: 10.1016/j.tcb.2011.06.004 CrossRefPubMedGoogle Scholar
  53. 53.
    Matthews PR, Eastwood SL, Harrison PJ (2012) Reduced myelin basic protein and actin-related gene expression in visual cortex in schizophrenia. PLoS One 7(6):e38211. doi: 10.1371/journal.pone.0038211 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB, Starkey M, Webster MJ et al (2003) Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362(9386):798–805. doi: 10.1016/S0140-6736(03)14289-4 CrossRefPubMedGoogle Scholar
  55. 55.
    Santoro ML, Gadelha A, Ota VK, Cunha GR, Asevedo E, Noto CS, Spindola LM, Pan PM et al (2015) Gene expression analysis in blood of ultra-high risk subjects compared to first-episode of psychosis patients and controls. World J Biol Psychiatr:1–6. doi: 10.3109/15622975.2015.1048724
  56. 56.
    Santarelli DM, Beveridge NJ, Tooney PA, Cairns MJ (2011) Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia. Biol Psychiatry 69(2):180–187. doi: 10.1016/j.biopsych.2010.09.030 CrossRefPubMedGoogle Scholar
  57. 57.
    Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ (2010) Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry 15(12):1176–1189. doi: 10.1038/mp.2009.84 CrossRefPubMedGoogle Scholar
  58. 58.
    Sanders AR, Goring HH, Duan J, Drigalenko EI, Moy W, Freda J, He D, Shi J et al (2013) Transcriptome study of differential expression in schizophrenia. Hum Mol Genet 22(24):5001–5014. doi: 10.1093/hmg/ddt350 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Giraldez AJ, Cinalli RM, Glasner ME, Enright AJ, Thomson JM, Baskerville S, Hammond SM, Bartel DP et al (2005) MicroRNAs regulate brain morphogenesis in zebrafish. Science 308(5723):833–838. doi: 10.1126/science.1109020 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Cristiano Noto
    • 1
    • 2
  • Vanessa Kiyomi Ota
    • 1
    • 3
  • Marcos Leite Santoro
    • 3
  • Eduardo Sauerbronn Gouvea
    • 2
    • 3
  • Patricia Natalia Silva
    • 3
  • Leticia Maria Spindola
    • 3
  • Quirino Cordeiro
    • 1
    • 2
  • Rodrigo Affonseca Bressan
    • 1
  • Ary Gadelha
    • 1
  • Elisa Brietzke
    • 1
  • Sintia Iole Belangero
    • 3
  • Michael Maes
    • 4
    • 5
  1. 1.Department of PsychiatryUniversidade Federal de São Paulo (UNIFESP)Sao PauloBrazil
  2. 2.First Episode Psychosis ProgramFaculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP)Sao PauloBrazil
  3. 3.Genetics Division, Department of Morphology and GeneticsUniversidade Federal de Sao Paulo (UNIFESP)Sao PauloBrazil
  4. 4.Health Sciences Graduate Program, Health Sciences CenterState University of Londrina (UEL)LondrinaBrazil
  5. 5.Department of PsychiatryChulalongkorn UniversityBangkokThailand

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