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Neuroimaging and the Longitudinal Course of Schizophrenia

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Neuroimaging of Schizophrenia and Other Primary Psychotic Disorders

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Abstract

For many decades, neuroimaging studies have consistently demonstrated the presence of brain pathological changes associated with the diagnosis of schizophrenia, more recently using magnetic resonance imaging (MRI). With several thousands of patients examined in different disease stages, MRI studies have allowed investigations of the possible patterns of progression of such brain changes over the longitudinal course of schizophrenia after the initial onset of symptoms. Overall, the available MRI data indicate that structural brain abnormalities associated with the diagnosis of schizophrenia may progress from the first psychotic episode (or even in the prodromal stage) to chronic disease states, particularly during the initial few years after illness onset. Such progressive brain changes are probably restricted to subgroups of patients with an unremitting disease course and poorer outcome. Conversely, there is some evidence from longitudinal MRI studies suggesting that brain abnormalities in cases of schizophrenia with better prognosis may be even reversible. In addition, longitudinal MRI studies also suggest that the degree of progression of brain structural abnormalities over the course of schizophrenia is likely (at least partially) to be under the influence of chronic antipsychotic usage.

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References

  1. DeLisi LE. The concept of progressive brain change in schizophrenia: implications for understanding schizophrenia. Schizophr Bull. 2008;34(2):312–21. https://doi.org/10.1093/schbul/sbm164.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Johnstone EC, Crow TJ, Frith CD, et al. Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancet. 1976;2(7992):924–6.

    Article  CAS  PubMed  Google Scholar 

  3. Weinberger DR, Torrey EF, Wyatt RJ. Cerebellar atrophy in chronic schizophrenia. Lancet. 1979;1(8118):718–9.

    Article  CAS  PubMed  Google Scholar 

  4. Weinberger DR, Torrey EF, Neophytides AN, et al. Lateral cerebral ventricular enlargement in chronic schizophrenia. Arch Gen Psychiatry. 1979;36(7):735–9.

    Article  CAS  PubMed  Google Scholar 

  5. Weinberger DR, Torrey EF, Neophytides AN, et al. Structural abnormalities in the cerebral cortex of chronic schizophrenic patients. Arch Gen Psychiatry. 1979;36(9):935–9.

    Article  CAS  PubMed  Google Scholar 

  6. Zipursky RB, Reilly TJ, Murray RM. The myth of schizophrenia as a progressive brain disease. Schizophr Bull. 2013;39(6):1363–72. https://doi.org/10.1093/schbul/sbs135.

    Article  PubMed  Google Scholar 

  7. Eickhoff SB, Bzdok D, Laird AR, et al. Activation likelihood estimation meta-analysis revisited. NeuroImage. 2012;59(3):2349–61. https://doi.org/10.1016/j.neuroimage.2011.09.017.

    Article  PubMed  Google Scholar 

  8. Ellison-Wright I, Glahn DC, Laird AR, et al. The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. Am J Psychiatry. 2008;165(8):1015–23. https://doi.org/10.1176/appi.ajp.2008.07101562.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chan RC, Di X, McAlonan GM, et al. Brain anatomical abnormalities in high-risk individuals, first-episode, and chronic schizophrenia: an activation likelihood estimation meta-analysis of illness progression. Schizophr Bull. 2011;37(1):177–88. https://doi.org/10.1093/schbul/sbp073.

    Article  PubMed  Google Scholar 

  10. Hajima SV, Van Haren N, Cahn W, et al. Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophr Bull. 2013;39(5):1129–38. https://doi.org/10.1093/schbul/sbs118.

    Article  Google Scholar 

  11. Meisenzahl EM, Koutsouleris N, Bottlender R, et al. Structural brain alterations at different stages of schizophrenia: a voxel-based morphometric study. Schizophr Res. 2008;104(1–3):44–60. https://doi.org/10.1016/j.schres.2008.06.023.

    Article  CAS  PubMed  Google Scholar 

  12. Torres US, Duran FL, Schaufelberger MS, et al. Patterns of regional gray matter loss at different stages of schizophrenia: a multisite, cross-sectional VBM study in first-episode and chronic illness. Neuroimage Clin. 2016;12:1–15. https://doi.org/10.1016/j.nicl.2016.06.002.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Schaufelberger MS, Duran FL, Lappin JM, et al. Grey matter abnormalities in Brazilians with first-episode psychosis. Br J Psychiatry Suppl. 2007;51:s117–s22. https://doi.org/10.1192/bjp.191.51.s117.

    Article  PubMed  Google Scholar 

  14. Häfner H, Nowotny B. Epidemiology of early-onset schizophrenia. Eur Arch Psychiatry Clin Neurosci. 1995;245(2):80–92.

    Article  PubMed  Google Scholar 

  15. Clemmensen L, Vernal DL, Steinhausen HC. A systematic review of the long-term outcome of early onset schizophrenia. BMC Psychiatry. 2012;12:150. https://doi.org/10.1186/1471-244X-12-150.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Olabi B, Ellison-Wright I, McIntosh AM, et al. Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol Psychiatry. 2011;70(1):88–96. https://doi.org/10.1016/j.biopsych.2011.01.032.

    Article  PubMed  Google Scholar 

  17. Chakos MH, Lieberman JA, Bilder RM, et al. Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. Am J Psychiatry. 1994;151(10):1430–6.

    Article  CAS  PubMed  Google Scholar 

  18. Prasad KM, Eack SM, Goradia D, et al. Progressive gray matter loss and changes in cognitive functioning associated with exposure to herpes simplex virus 1 in schizophrenia: a longitudinal study. Am J Psychiatry. 2011;168(8):822–30. https://doi.org/10.1176/appi.ajp.2011.10101423.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Gur RE, Cowell P, Turetsky BI, et al. A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry. 1998;55(2):145–52.

    Article  CAS  PubMed  Google Scholar 

  20. Puri BK, Hutton SB, Saeed N, et al. A serial longitudinal quantitative MRI study of cerebral changes in first-episode schizophrenia using image segmentation and subvoxel registration. Psychiatry Res. 2001;106(2):141–50.

    Article  CAS  PubMed  Google Scholar 

  21. Boonstra G, Cahn W, Schnack HG, et al. Duration of untreated illness in schizophrenia is not associated with 5-year brain volume change. Schizophr Res. 2011;132(1):84–90. https://doi.org/10.1016/j.schres.2011.07.018.

    Article  PubMed  Google Scholar 

  22. Clark GM, Mackay CE, Davidson ME, et al. Paracingulate sulcus asymmetry; sex difference, correlation with semantic fluency and change over time in adolescent onset psychosis. Psychiatry Res. 2010;184(1):10–5. https://doi.org/10.1016/j.pscychresns.2010.06.012.

    Article  PubMed  Google Scholar 

  23. Palaniyappan L, Crow TJ, Hough M, et al. Gyrification of Broca’s region is anomalously lateralized at onset of schizophrenia in adolescence and regresses at 2 year follow-up. Schizophr Res. 2013;147(1):39–45. https://doi.org/10.1016/j.schres.2013.03.028.

    Article  CAS  PubMed  Google Scholar 

  24. Tauscher-Wisniewski S, Tauscher J, Logan J, et al. Caudate volume changes in first episode psychosis parallel the effects of normal aging: a 5-year follow-up study. Schizophr Res. 2002;58(2–3):185–818.

    Article  PubMed  Google Scholar 

  25. Andreasen NC, Nopoulos P, Magnotta V, et al. Progressive brain change in schizophrenia: a prospective longitudinal study of first-episode schizophrenia. Biol Psychiatry. 2011;70(7):672–9. https://doi.org/10.1016/j.biopsych.2011.05.017.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lee SH, Niznikiewicz M, Asami T, et al. Initial and progressive gray matter abnormalities in insular gyrus and temporal pole in first-episode schizophrenia contrasted with first-episode affective psychosis. Schizophr Bull. 2016;42(3):790–801. https://doi.org/10.1093/schbul/sbv177.

    Article  PubMed  Google Scholar 

  27. Whitworth AB, Kemmler G, Honeder M, et al. Longitudinal volumetric MRI study in first- and multiple-episode male schizophrenia patients. Psychiatry Res. 2005;140(3):225–37.

    Article  PubMed  Google Scholar 

  28. Lieberman JA, Tollefson GD, Charles C, et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry. 2005;62(4):361–70.

    Article  CAS  PubMed  Google Scholar 

  29. Mamah D, Harms MP, Barch D, et al. Hippocampal shape and volume changes with antipsychotics in early stage psychotic illness. Front Psychiatry. 2012;3:96. https://doi.org/10.3389/fpsyt.2012.00096.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Whitford TJ, Grieve SM, Farrow TF, et al. Volumetric white matter abnormalities in first-episode schizophrenia: a longitudinal, tensor-based morphometry study. Am J Psychiatry. 2007;164(7):1082–9.

    Article  PubMed  Google Scholar 

  31. Glenthoj A, Glenthoj BY, Mackeprang T, et al. Basal ganglia volumes in drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug. Psychiatry Res. 2007;154(3):199–208.

    Article  CAS  PubMed  Google Scholar 

  32. Roiz-Santiáñez R, Ortiz-García de la Foz V, Ayesa-Arriola R, et al. No progression of the alterations in the cortical thickness of individuals with schizophrenia-spectrum disorder: a three-year longitudinal magnetic resonance imaging study of first-episode patients. Psychol Med. 2015;45(13):2861–71. https://doi.org/10.1017/S0033291715000811.

    Article  PubMed  Google Scholar 

  33. Arango C, Rapado-Castro M, Reig S, et al. Progressive brain changes in children and adolescents with first-episode psychosis. Arch Gen Psychiatry. 2012;69(1):16–26. https://doi.org/10.1001/archgenpsychiatry.2011.150.

    Article  PubMed  Google Scholar 

  34. Kasparek T, Prikryl R, Schwarz D, et al. Gray matter morphology and the level of functioning in one-year follow-up of first-episode schizophrenia patients. Prog Neuro-Psychopharmacol Biol Psychiatry. 2009;33(8):1438–46. https://doi.org/10.1016/j.pnpbp.2009.07.025.

    Article  Google Scholar 

  35. Mané A, Falcon C, Mateos JJ, et al. Progressive gray matter changes in first episode schizophrenia: a 4-year longitudinal magnetic resonance study using VBM. Schizophr Res. 2009;114(1–3):136–43. https://doi.org/10.1016/j.schres.2009.07.014.

    Article  PubMed  Google Scholar 

  36. Takahashi T, Wood SJ, Yung AR, et al. Progressive gray matter reduction of the superior temporal gyrus during transition to psychosis. Arch Gen Psychiatry. 2009;66(4):366–76. https://doi.org/10.1001/archgenpsychiatry.2009.12.

    Article  PubMed  Google Scholar 

  37. Takahashi T, Nakamura K, Ikeda E, et al. Longitudinal MRI study of the midline brain regions in first-episode schizophrenia. Psychiatry Res. 2013;212(2):150–3. https://doi.org/10.1016/j.pscychresns.2012.12.001.

    Article  PubMed  Google Scholar 

  38. Schaufelberger MS, Lappin JM, Duran FL, et al. Lack of progression of brain abnormalities in first-episode psychosis: a longitudinal magnetic resonance imaging study. Psychol Med. 2011;41(8):1677–89. https://doi.org/10.1017/S0033291710002163.

    Article  CAS  PubMed  Google Scholar 

  39. Rosa PG, Zanetti MV, Duran FL, et al. What determines continuing grey matter changes in first-episode schizophrenia and affective psychosis? Psychol Med. 2015;45(4):817–28. https://doi.org/10.1017/S0033291714001895.

    Article  CAS  PubMed  Google Scholar 

  40. de Castro-Manglano P, Mechelli A, Soutullo C, et al. Longitudinal changes in brain structure following the first episode of psychosis. Psychiatry Res. 2011;191(3):166–3. https://doi.org/10.1016/j.pscychresns.2010.10.010.

    Article  PubMed  Google Scholar 

  41. Li M, Chen Z, Deng W, et al. Volume increases in putamen associated with positive symptom reduction in previously drug-naive schizophrenia after 6 weeks antipsychotic treatment. Psychol Med. 2012;42(7):1475–83. https://doi.org/10.1017/S0033291711002157.

    Article  CAS  PubMed  Google Scholar 

  42. Wang Q, Cheung C, Deng W, et al. White-matter microstructure in previously drug-naive patients with schizophrenia after 6 weeks of treatment. Psychol Med. 2013;43(11):2301–9. https://doi.org/10.1017/S0033291713000238.

    Article  CAS  PubMed  Google Scholar 

  43. Lappin JM, Morgan C, Chalavi S, et al. Bilateral hippocampal increase following first-episode psychosis is associated with good clinical, functional and cognitive outcomes. Psychol Med. 2014;44(6):1279–91. https://doi.org/10.1017/S0033291713001712.

    Article  CAS  PubMed  Google Scholar 

  44. Gutiérrez-Galve L, Chu EM, Leeson VC, et al. A longitudinal study of cortical changes and their cognitive correlates in patients followed up after first-episode psychosis. Psychol Med. 2015;45(1):205–16. https://doi.org/10.1017/S0033291714001433.

    Article  PubMed  Google Scholar 

  45. Kawano M, Sawada K, Shimodera S, et al. Hippocampal subfield volumes in first episode and chronic schizophrenia. PLoS One. 2015;10(2):e0117785. https://doi.org/10.1371/journal.pone.0117785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Haukvik UK, Hartberg CB, Nerland S, et al. No progressive brain changes during a 1-year follow-up of patients with first-episode psychosis. Psychol Med. 2016;46(3):589–98. https://doi.org/10.1017/S003329171500210X.

    Article  CAS  PubMed  Google Scholar 

  47. Jørgensen KN, Nesvåg R, Nerland S, et al. Brain volume change in first-episode psychosis: an effect of antipsychotic medication independent of BMI change. Acta Psychiatr Scand. 2017;135(2):117–26. https://doi.org/10.1111/acps.12677.

    Article  CAS  PubMed  Google Scholar 

  48. DeLisi LE, Stritzke P, Riordan H, et al. The timing of brain morphological changes in schizophrenia and their relationship to clinical outcome. Biol Psychiatry. 1992;31(3):241–54.

    Article  CAS  PubMed  Google Scholar 

  49. DeLisi LE, Tew W, Xie S, et al. A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: preliminary findings. Biol Psychiatry. 1995;38(6):349–60.

    Article  CAS  PubMed  Google Scholar 

  50. DeLisi LE, Sakuma M, Tew W, et al. Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Res. 1997;74(3):129–40.

    Article  CAS  PubMed  Google Scholar 

  51. DeLisi LE, Sakuma M, Maurizio AM, et al. Cerebral ventricular change over the first 10 years after the onset of schizophrenia. Psychiatry Res. 2004;130(1):57–70.

    Article  PubMed  Google Scholar 

  52. Trzesniak C, Schaufelberger MS, Duran FL, et al. Longitudinal follow-up of cavum septum pellucidum and adhesio interthalamica alterations in first-episode psychosis: a population-based MRI study. Psychol Med. 2012;42(12):2523–34.

    Article  CAS  PubMed  Google Scholar 

  53. Ho BC, Andreasen NC, Nopoulos P, et al. Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Arch Gen Psychiatry. 2003;60(6):585–94.

    Article  PubMed  Google Scholar 

  54. Whitford TJ, Grieve SM, Farrow TF, et al. Progressive grey matter atrophy over the first 2–3 years of illness in first-episode schizophrenia: a tensor-based morphometry study. NeuroImage. 2006;32(2):511–9.

    Article  PubMed  Google Scholar 

  55. James AC, Javaloyes A, James S, et al. Evidence for non-progressive changes in adolescent-onset schizophrenia: follow-up magnetic resonance imaging study. Br J Psychiatry. 2002;180:339–44.

    Article  CAS  PubMed  Google Scholar 

  56. James AC, James S, Smith DM, et al. Cerebellar, prefrontal cortex, and thalamic volumes over two time points in adolescent-onset schizophrenia. Am J Psychiatry. 2004;161(6):1023–9.

    Article  PubMed  Google Scholar 

  57. Nakamura M, Salisbury DF, Hirayasu Y, et al. Neocortical gray matter volume in first-episode schizophrenia and first-episode affective psychosis: a cross-sectional and longitudinal MRI study. Biol Psychiatry. 2007;62(7):773–83.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Cahn W, Hulshoff Pol HE, Lems EB, et al. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry. 2002;59(11):1002–10.

    Article  PubMed  Google Scholar 

  59. Rais M, Cahn W, Van Haren N, et al. Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients. Am J Psychiatry. 2008;165(4):490–6. https://doi.org/10.1176/appi.ajp.2007.07071110.

    Article  PubMed  Google Scholar 

  60. Reig S, Moreno C, Moreno D, et al. Progression of brain volume changes in adolescent-onset psychosis. Schizophr Bull. 2009;35(1):233–43. https://doi.org/10.1093/schbul/sbm160.

    Article  PubMed  Google Scholar 

  61. Suárez-Pinilla P, Roiz-Santiáñez R, de la Foz VO, et al. BDNF Val66Met variants and brain volume changes in non-affective psychosis patients and healthy controls: a 3 year follow-up study. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;45:201–6. https://doi.org/10.1016/j.pnpbp.2013.05.014.

    Article  PubMed  CAS  Google Scholar 

  62. Ota M, Obu S, Sato N, et al. Progressive brain changes in schizophrenia: a 1-year follow-up study of diffusion tensor imaging. Acta Neuropsychiatr. 2009;21(6):301–7. https://doi.org/10.1111/j.1601-5215.2009.00422.x.

    Article  PubMed  Google Scholar 

  63. Mitelman SA, Nikiforova YK, Canfield EL, et al. A longitudinal study of the corpus callosum in chronic schizophrenia. Schizophr Res. 2009;114(1–3):144–53. https://doi.org/10.1016/j.schres.2009.07.021.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Sun Y, Chen Y, Lee R, et al. Disruption of brain anatomical networks in schizophrenia: a longitudinal, diffusion tensor imaging based study. Schizophr Res. 2016;171(1–3):149–57. https://doi.org/10.1016/j.schres.2016.01.025.

    Article  PubMed  Google Scholar 

  65. Vita A, De Peri L, Deste G, et al. Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies. Transl Psychiatry. 2012;2:e190. https://doi.org/10.1038/tp.2012.116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Fusar-Poli P, Smieskova R, Kempton MJ, et al. Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neurosci Biobehav Rev. 2013;37(8):1680–91. https://doi.org/10.1016/j.neubiorev.2013.06.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fraguas D, Merchán-Naranjo J, del Rey-Mejías Á, et al. A longitudinal study on the relationship between duration of untreated psychosis and executive function in early-onset first-episode psychosis. Schizophr Res. 2014;158(1–3):126–33. https://doi.org/10.1016/j.schres.2014.06.038.

    Article  PubMed  Google Scholar 

  68. van Haren NE, Cahn W, Hulshoff Pol HE, et al. Schizophrenia as a progressive brain disease. Eur Psychiatry. 2008;23(4):245–54. https://doi.org/10.1016/j.eurpsy.2007.10.013.

    Article  PubMed  Google Scholar 

  69. van Haren NE, Kahn RS. Progressive brain tissue loss in schizophrenia. Schizophr Res. 2016;173(3):121–3. https://doi.org/10.1016/j.schres.2016.03.023.

    Article  PubMed  Google Scholar 

  70. Tanskanen P, Ridler K, Murray GK, et al. Morphometric brain abnormalities in schizophrenia in a population-based sample: relationship to duration of illness. Schizophr Bull. 2010;36(4):766–77. https://doi.org/10.1093/schbul/sbn141.

    Article  PubMed  Google Scholar 

  71. Kasai K, Shenton ME, Salisbury DF, et al. Progressive decrease of left superior temporal gyrus gray matter volume in patients with first-episode schizophrenia. Am J Psychiatry. 2003;160(1):156–64.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Kasai K, Shenton ME, Salisbury DF, et al. Progressive decrease of left Heschl gyrus and planum temporale gray matter volume in first-episode schizophrenia: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry. 2003;60(8):766–75.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Lieberman J, Chakos M, Wu H, et al. Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry. 2001;49(6):487–99.

    Article  CAS  PubMed  Google Scholar 

  74. Hulshoff Pol HE, Schnack HG, Mandl RC, et al. Focal gray matter density changes in schizophrenia. Arch Gen Psychiatry. 2001;58(12):1118–25.

    Article  CAS  PubMed  Google Scholar 

  75. Cahn W, Rais M, Stigter FP, et al. Psychosis and brain volume changes during the first five years of schizophrenia. Eur Neuropsychopharmacol. 2009;19(2):147–51. https://doi.org/10.1016/j.euroneuro.2008.10.006.

    Article  CAS  PubMed  Google Scholar 

  76. Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 2015;1:15067. https://doi.org/10.1038/nrdp.2015.67.

    Article  PubMed  Google Scholar 

  77. Fusar-Poli P, Meyer-Lindenberg A. Forty years of structural imaging in psychosis: promises and truth. Acta Psychiatr Scand. 2016;134(3):207–24. https://doi.org/10.1111/acps.12619.

    Article  CAS  PubMed  Google Scholar 

  78. Keshavan MS, Haas GL, Kahn CE, et al. Superior temporal gyrus and the course of early schizophrenia: progressive, static, or reversible? J Psychiatr Res. 1998;32(3–4):161–7.

    Article  CAS  PubMed  Google Scholar 

  79. Jääskeläinen E, Juola P, Kurtti J, et al. Associations between brain morphology and outcome in schizophrenia in a general population sample. Eur Psychiatry. 2014;29(7):456–62. https://doi.org/10.1016/j.eurpsy.2013.10.006.

    Article  PubMed  Google Scholar 

  80. Wassink TH, Andreasen NC, Nopoulos P, et al. Cerebellar morphology as a predictor of symptom and psychosocial outcome in schizophrenia. Biol Psychiatry. 1999;45(1):41–8.

    Article  CAS  PubMed  Google Scholar 

  81. Staal WG, Hulshoff Pol HE, Schnack HG, et al. Structural brain abnormalities in chronic schizophrenia at the extremes of the outcome spectrum. Am J Psychiatry. 2001;158(7):1140–2.

    Article  CAS  PubMed  Google Scholar 

  82. Brickman AM, Buchsbaum MS, Ivanov Z, et al. Internal capsule size in good-outcome and poor-outcome schizophrenia. J Neuropsychiatr Clin Neurosci. 2006;18(3):364–76.

    Article  Google Scholar 

  83. Mitelman SA, Brickman AM, Shihabuddin L, et al. A comprehensive assessment of gray and white matter volumes and their relationship to outcome and severity in schizophrenia. NeuroImage. 2007;37(2):449–62.

    Article  PubMed  Google Scholar 

  84. Molina V, Hernández JA, Sanz J, et al. Subcortical and cortical gray matter differences between Kraepelinian and non-Kraepelinian schizophrenia patients identified using voxel-based morphometry. Psychiatry Res. 2010;184(1):16–22. https://doi.org/10.1016/j.pscychresns.2010.06.006.

    Article  PubMed  Google Scholar 

  85. Goldman M, Tandon R, DeQuardo JR, et al. Biological predictors of 1-year outcome in schizophrenia in males and females. Schizophr Res. 1996;21(2):65–73.

    Article  CAS  PubMed  Google Scholar 

  86. DeLisi LE, Sakuma M, Ge S, et al. Association of brain structural change with the heterogeneous course of schizophrenia from early childhood through five years subsequent to a first hospitalization. Psychiatry Res. 1998;84(2–3):75–88.

    Article  CAS  PubMed  Google Scholar 

  87. van Haren NE, Cahn W, Hulshoff Pol HE, et al. Brain volumes as predictor of outcome in recent-onset schizophrenia: a multi-center MRI study. Schizophr Res. 2003;64(1):41–52.

    Article  PubMed  Google Scholar 

  88. Robinson DG, Woerner MG, McMeniman M, et al. Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry. 2004;161(3):473–9.

    Article  PubMed  Google Scholar 

  89. Bachmann S, Bottmer C, Schröder J, et al. Compliance with medication but not structural MRI measures predict functional outcome in first-episode schizophrenia patients. Schizophr Res. 2007;90(1–3):355–6.

    Article  PubMed  Google Scholar 

  90. Koo MS, Levitt JJ, Salisbury DF, et al. A cross-sectional and longitudinal magnetic resonance imaging study of cingulate gyrus gray matter volume abnormalities in first-episode schizophrenia and first-episode affective psychosis. Arch Gen Psychiatry. 2008;65(7):746–60. https://doi.org/10.1001/archpsyc.65.7.746.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Cahn W, van Haren NE, Hulshoff Pol HE, et al. Brain volume changes in the first year of illness and 5-year outcome of schizophrenia. Br J Psychiatry. 2006;189:381–2.

    Article  CAS  PubMed  Google Scholar 

  92. van Haren NE, Schnack HG, Cahn W, et al. Changes in cortical thickness during the course of illness in schizophrenia. Arch Gen Psychiatry. 2011;68(9):871–80. https://doi.org/10.1001/archgenpsychiatry.2011.88.

    Article  PubMed  Google Scholar 

  93. Dusi N, Bellani M, Perlini C, et al. Progressive disability and prefrontal shrinkage in schizophrenia patients with poor outcome: a 3-year longitudinal study. Schizophr Res. 2017;179:104–11. https://doi.org/10.1016/j.schres.2016.09.013.

    Article  CAS  PubMed  Google Scholar 

  94. Quarantelli M, Palladino O, Prinster A, et al. Patients with poor response to antipsychotics have a more severe pattern of frontal atrophy: a voxel-based morphometry study of treatment resistance in schizophrenia. Biomed Res Int. 2014;2014:325052. https://doi.org/10.1155/2014/325052.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Veijola J, Guo JY, Moilanen JS, et al. Longitudinal changes in total brain volume in schizophrenia: relation to symptom severity, cognition and antipsychotic medication. PLoS One. 2014;9(7):e101689. https://doi.org/10.1371/journal.pone.0101689.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Dorph-Petersen KA, Pierri JN, Perel JM, et al. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology. 2005;30(9):1649–61.

    Article  CAS  PubMed  Google Scholar 

  97. Konopaske GT, Dorph-Petersen KA, Pierri JN, et al. Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology. 2007;32(6):1216–23.

    Article  CAS  PubMed  Google Scholar 

  98. Shah C, Zhang W, Xiao Y, et al. Common pattern of gray-matter abnormalities in drug-naïve and medicated first-episode schizophrenia: a multimodal meta-analysis. Psychol Med. 2017;47(3):401–13. https://doi.org/10.1017/S0033291716002683.

    Article  CAS  PubMed  Google Scholar 

  99. Ho BC, Andreasen NC, Ziebell S, et al. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 2011;68(2):128–37. https://doi.org/10.1001/archgenpsychiatry.2010.199.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Théberge J, Williamson KE, Aoyama N, et al. Longitudinal grey-matter and glutamatergic losses first-episode schizophrenia. Br J Psychiatry. 2007;191:325–34.

    Article  PubMed  Google Scholar 

  101. Wood SJ, Velakoulis D, Smith DJ, et al. A longitudinal study of hippocampal volume in first episode psychosis and chronic schizophrenia. Schizophr Res. 2001;52(1–2):37–46.

    Article  CAS  PubMed  Google Scholar 

  102. Moncrieff J, Leo J. A systematic review of the effects of antipsychotic drugs on brain volume. Psychol Med. 2010;40(9):1409–22. https://doi.org/10.1017/S0033291709992297.

    Article  CAS  PubMed  Google Scholar 

  103. Roiz-Santiañez R, Suarez-Pinilla P, Crespo-Facorro B. Brain structural effects of antipsychotic treatment in schizophrenia: a systematic review. Curr Neuropharmacol. 2015;13(4):422–34.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Vita A, De Peri L, Deste G, et al. The effect of antipsychotic treatment on cortical gray matter changes in schizophrenia: does the class matter? A meta-analysis and meta-regression of longitudinal magnetic resonance imaging studies. Biol Psychiatry. 2015;78(6):403–12. https://doi.org/10.1016/j.biopsych.2015.02.008.

    Article  CAS  PubMed  Google Scholar 

  105. Pantelis C, Velakoulis D, McGorry PD, et al. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet. 2003;361(9354):281–8.

    Article  PubMed  Google Scholar 

  106. Suvisaari J, Keinänen J, Eskelinen S, et al. Diabetes and schizophrenia. Curr Diab Rep. 2016;16(2):16. https://doi.org/10.1007/s11892-015-0704-4.

    Article  PubMed  Google Scholar 

  107. Willette AA, Kapogiannis D. Does the brain shrink as the waist expands? Ageing Res Rev. 2015;20:86–97. https://doi.org/10.1016/j.arr.2014.03.007.

    Article  PubMed  Google Scholar 

  108. McIntyre RS, Kenna HA, Nguyen HT, et al. Brain volume abnormalities and neurocognitive deficits in diabetes mellitus: points of pathophysiological commonality with mood disorders? Adv Ther. 2010;27(2):63–80. https://doi.org/10.1007/s12325-010-0011-z.

    Article  PubMed  Google Scholar 

  109. Poirier MF, Canceil O, Baylé F, et al. Prevalence of smoking in psychiatric patients. Prog Neuro-Psychopharmacol Biol Psychiatry. 2002;26(3):529–37.

    Article  Google Scholar 

  110. Gage SH, Hickman M, Zammit S. Association between cannabis and psychosis: epidemiologic evidence. Biol Psychiatry. 2016;79(7):549–56. https://doi.org/10.1016/j.biopsych.2015.08.001.

    Article  PubMed  Google Scholar 

  111. Murray RM, Englund A, Abi-Dargham A, et al. Cannabis-associated psychosis: neural substrate and clinical impact. Neuropharmacology. 2017;124:89–104.

    Article  CAS  PubMed  Google Scholar 

  112. Van Haren NE, Cahn W, Hulshoff Pol H, et al. Confounders of excessive brain volume loss in schizophrenia. Neurosci Biobehav Rev. 2012;37(10 Pt 1):2418–23. https://doi.org/10.1016/j.neubiorev.2012.09.006.

    Article  PubMed  Google Scholar 

  113. French L, Gray C, Leonard G, et al. Early cannabis use, polygenic risk score for schizophrenia and brain maturation in adolescence. JAMA Psychiatry. 2015;72(10):1002–11. https://doi.org/10.1001/jamapsychiatry.2015.1131.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Gurillo P, Jauhar S, Murray RM, et al. Does tobacco use cause psychosis? Systematic review and meta-analysis. Lancet Psychiatry. 2015;2(8):718–25. https://doi.org/10.1016/S2215-0366(15)00152-2.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Van Haren NE, Koolschijn PC, Cahn W, et al. Cigarette smoking and progressive brain volume loss in schizophrenia. Eur Neuropsychopharmacol. 2010;20(7):454–8. https://doi.org/10.1016/j.euroneuro.2010.02.009.

    Article  CAS  PubMed  Google Scholar 

  116. Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology. 2004;174(1):151–62.

    Article  CAS  PubMed  Google Scholar 

  117. Glantz LA, Gilmore JH, Lieberman JA, et al. Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr Res. 2006;81(1):47–63.

    Article  PubMed  Google Scholar 

  118. Garey L. When cortical development goes wrong: schizophrenia as a neurodevelopmental disease of microcircuits. J Anat. 2010;217(4):324–33. https://doi.org/10.1111/j.1469-7580.2010.01231.x.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Adriano F, Caltagirone C, Spalletta G. Hippocampal volume reduction in first-episode and chronic schizophrenia: a review and meta-analysis. Neuroscientist. 2012;18(2):180–200. https://doi.org/10.1177/1073858410395147.

    Article  PubMed  Google Scholar 

  120. Falkai P, Malchow B, Schmitt A. Aerobic exercise and its effects on cognition in schizophrenia. Curr Opin Psychiatry. 2017;30(3):171–5. https://doi.org/10.1097/YCO.0000000000000326.

    Article  PubMed  Google Scholar 

  121. Muraki K, Tanigaki K. Neuronal migration abnormalities and its possible implications for schizophrenia. Front Neurosci. 2015;9:74. https://doi.org/10.3389/fnins.2015.00074.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Giedd JN, Raznahan A, Alexander-Bloch A, et al. Child psychiatry branch of the National Institute of Mental Health longitudinal structural magnetic resonance imaging study of human brain development. Neuropsychopharmacology. 2015;40(1):43–9. https://doi.org/10.1038/npp.2014.236.

    Article  PubMed  Google Scholar 

  123. Selemon LD, Goldman-Rakic PS. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry. 1999;45(1):17–25.

    Article  CAS  PubMed  Google Scholar 

  124. Cannon TD, van Erp TG, Bearden CE, et al. Early and late neurodevelopmental influences in the prodrome to schizophrenia: contributions of genes, environment, and their interactions. Schizophr Bull. 2003;29(4):653–69.

    Article  PubMed  Google Scholar 

  125. Selemon LD, Zecevic N. Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry. 2015;5:e623. https://doi.org/10.1038/tp.2015.115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Dorph-Petersen KA, Delevich KM, Marcsisin MJ, et al. Pyramidal neuron number in layer 3 of primary auditory cortex of subjects with schizophrenia. Brain Res. 2009;1285:42–57. https://doi.org/10.1016/j.brainres.2009.06.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Prasad KM, Burgess AM, Keshavan MS, et al. Neuropil pruning in early-course schizophrenia: immunological, clinical, and neurocognitive correlates. Biol Psychiatry Cogn Neurosci Neuroimaging. 2016;6:528–38. https://doi.org/10.1016/j.bpsc.2016.08.007.

    Article  Google Scholar 

  128. Harrison PJ. Postmortem studies in schizophrenia. Dialogues Clin Neurosci. 2000;2(4):349–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Falkai P, Mike O, Inez MG, et al. A roadmap to disentangle the molecular etiology of schizophrenia. Eur Psychiatry. 2008;23(4):224–32. https://doi.org/10.1016/j.eurpsy.2008.02.006.

    Article  PubMed  Google Scholar 

  130. Addington AM, Gornick M, Duckworth J, et al. GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss. Mol Psychiatry. 2005;10(6):581–8.

    Article  CAS  PubMed  Google Scholar 

  131. Poels EM, Kegeles LS, Kantrowitz JT, et al. Imaging glutamate in schizophrenia: review of findings and implications for drug discovery. Mol Psychiatry. 2014;19(1):20–9. https://doi.org/10.1038/mp.2013.136.

    Article  CAS  PubMed  Google Scholar 

  132. DeLisi LE. Is schizophrenia a lifetime disorder of brain plasticity, growth and aging? Schizophr Res. 1997;23(2):119–29.

    Article  CAS  PubMed  Google Scholar 

  133. Schnack HG, van Haren NE, Nieuwenhuis M, et al. Accelerated brain aging in schizophrenia: a longitudinal pattern recognition study. Am J Psychiatry. 2016;173(6):607–16. https://doi.org/10.1176/appi.ajp.2015.15070922.

    Article  PubMed  Google Scholar 

  134. Cropley VL, Klauser P, Lenroot RK, et al. Accelerated gray and white matter deterioration with age in schizophrenia. Am J Psychiatry. 2017;174(3):286–95. https://doi.org/10.1176/appi.ajp.2016.16050610.

    Article  PubMed  Google Scholar 

  135. Kao HT, Cawthon RM, Delisi LE, et al. Rapid telomere erosion in schizophrenia. Mol Psychiatry. 2008;13(2):118–9.

    Article  CAS  PubMed  Google Scholar 

  136. Laskaris LE, Di Biase MA, Everall I, et al. Microglial activation and progressive brain changes in schizophrenia. Br J Pharmacol. 2016;173(4):666–80. https://doi.org/10.1111/bph.13364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Miller BJ, Buckley P, Seabolt W, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663–71. https://doi.org/10.1016/j.biopsych.2011.04.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Misiak B, Stańczykiewicz B, Kotowicz K, et al. Cytokines and C-reactive protein alterations with respect to cognitive impairment in schizophrenia and bipolar disorder: a systematic review. Schizophr Res. 2017;192:16–29. https://doi.org/10.1016/j.schres.2017.04.015.

    Article  PubMed  Google Scholar 

  139. Dieset I, Haukvik UK, Melle I, et al. Association between altered brain morphology and elevated peripheral endothelial markers--implications for psychotic disorders. Schizophr Res. 2015;61(2–3):222–8. https://doi.org/10.1016/j.schres.2014.11.006.

    Article  Google Scholar 

  140. Pillai A, Howell KR, Ahmed AO, et al. Association of serum VEGF levels with prefrontal cortex volume in schizophrenia. Mol Psychiatry. 2016;1(5):686–92. https://doi.org/10.1038/mp.2015.96.

    Article  CAS  Google Scholar 

  141. Drakesmith M, Dutt A, Fonville L, et al. Mediation of developmental risk factors for psychosis by white matter microstructure in young adults with psychotic experiences. JAMA Psychiatry. 2016;73(4):396–406. https://doi.org/10.1001/jamapsychiatry.2015.3375.

    Article  PubMed  Google Scholar 

  142. Camchong J, MacDonald AW 3rd, Bell C, et al. Altered functional and anatomical connectivity in schizophrenia. Schizophr Bull. 2011;37(3):640–50.

    Article  PubMed  Google Scholar 

  143. Suárez-Pinilla P, Roíz-Santiañez R, Mata I, et al. Progressive structural brain changes and NRG1 gene variants in first-episode nonaffective psychosis. Neuropsychobiology. 2015;71(2):103–11.

    Article  PubMed  CAS  Google Scholar 

  144. Suárez-Pinilla P, Roiz-Santiañez R, Ortiz-García de la Foz V, et al. Brain structural and clinical changes after first episode psychosis: focus on cannabinoid receptor 1 polymorphisms. Psychiatry Res. 2015;233(2):112–9. https://doi.org/10.1016/j.pscychresns.2015.05.005.

    Article  PubMed  Google Scholar 

  145. Brans RG, van Haren NE, van Baal GC, et al. Longitudinal MRI study in schizophrenia patients and their healthy siblings. Br J Psychiatry. 2008;193(5):422–3. https://doi.org/10.1192/bjp.bp.107.041467.

    Article  PubMed  Google Scholar 

  146. Hedman AM, van Haren NE, van Baal GC, et al. Heritability of cortical thickness changes over time in twin pairs discordant for schizophrenia. Schizophr Res. 2016;173(3):192–9. https://doi.org/10.1016/j.schres.2015.06.021.

    Article  PubMed  Google Scholar 

  147. Haddad L, Schäfer A, Streit F, et al. Brain structure correlates of urban upbringing, an environmental risk factor for schizophrenia. Schizophr Bull. 2015;41(1):115–22. https://doi.org/10.1093/schbul/sbu072.

    Article  PubMed  Google Scholar 

  148. Akdeniz C, Tost H, Streit F, et al. Neuroimaging evidence for a role of neural social stress processing in ethnic minority-associated environmental risk. JAMA Psychiatry. 2014;71(6):672–80. https://doi.org/10.1001/jamapsychiatry.2014.35. Erratum in: JAMA Psychiatry. 2014;71(8):888.

    Article  PubMed  Google Scholar 

  149. Frissen A, van Os J, Habets P, Genetic Risk and Outcome in Psychosis (G.R.O.U.P.), et al. No evidence of association between childhood urban environment and cortical thinning in psychotic disorder. PLoS One. 2017;12(1):e0166651. https://doi.org/10.1371/journal.pone.0166651. Erratum in: PLoS One 2017;12(5):e0178312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Hallak JE, de Paula AL, Chaves C, et al. An overview on the search for schizophrenia biomarkers. CNS Neurol Disord Drug Targets. 2015;14(8):996–1000.

    Article  CAS  PubMed  Google Scholar 

  151. Kapur S, Phillips AG, Insel TR. Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Mol Psychiatry. 2012;17(12):1174–9. https://doi.org/10.1038/mp.2012.105.

    Article  CAS  PubMed  Google Scholar 

  152. Thompson PM, Stein JL, Medland SE, et al. The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data. Brain Imaging Behav. 2014;8(2):153–82. https://doi.org/10.1007/s11682-013-9269-5.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Schmaal L, Hibar DP, Sämann PG, et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry. 2017;22(6):900–9. https://doi.org/10.1038/mp.2016.60.

    Article  CAS  PubMed  Google Scholar 

  154. Okada N, Fukunaga M, Yamashita F, et al. Abnormal asymmetries in subcortical brain volume in schizophrenia. Mol Psychiatry. 2016;21(10):1460–6. https://doi.org/10.1038/mp.2015.209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. van Erp TG, Hibar DP, Rasmussen JM, et al. Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. Mol Psychiatry. 2016;21(4):585. https://doi.org/10.1038/mp.2015.118.

    Article  PubMed  Google Scholar 

  156. Rathore S, Habes M, Iftikhar MA, et al. A review on neuroimaging-based classification studies and associated feature extraction methods for Alzheimer’s disease and its prodromal stages. NeuroImage. 2017;155:530–48. https://doi.org/10.1016/j.neuroimage.2017.03.057.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil

    Geraldo F. Busatto & Pedro G. P. Rosa

  2. Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil

    Geraldo F. Busatto & Pedro G. P. Rosa

  3. Early Psychosis Interventions and Clinical Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry Psychology and Neuroscience (IoPPN), King’s College London, London, UK

    Paolo Fusar-Poli

  4. Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy

    Paolo Fusar-Poli

  5. VA Boston Healthcare System, Harvard Medical School, Brockton, MA, USA

    Lynn E. DeLisi

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  1. Geraldo F. Busatto
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  2. Pedro G. P. Rosa
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  3. Paolo Fusar-Poli
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  4. Lynn E. DeLisi
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Editors and Affiliations

  1. Department of Psychiatry, University of Campania “Luigi Vanvitelli”, Naples, Italy

    Silvana Galderisi

  2. Harvard Medical School, The VA Boston Healthcare System, Brockton, MA, USA

    Lynn E. DeLisi

  3. Department of Psychiatry (UPK), University of Basel, Basel, Switzerland

    Stefan Borgwardt

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Busatto, G.F., Rosa, P.G.P., Fusar-Poli, P., DeLisi, L.E. (2019). Neuroimaging and the Longitudinal Course of Schizophrenia. In: Galderisi, S., DeLisi, L., Borgwardt, S. (eds) Neuroimaging of Schizophrenia and Other Primary Psychotic Disorders . Springer, Cham. https://doi.org/10.1007/978-3-319-97307-4_5

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