The neurobiology and treatment of first-episode schizophrenia

Molecular Psychiatry

Volumn 20, Issue 1, 2015, Pages 84-97

  Kahn, R S ^a   Sommer, I E ^a  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFLAMMATORY AGENT; DOPAMINE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; NEUROLEPTIC AGENT;

COGNITIVE DEFECT; DOPAMINE METABOLISM; HUMAN; META ANALYSIS (TOPIC); NEUROBIOLOGY; PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PSYCHOPHARMACOTHERAPY; PSYCHOSIS; REVIEW; SCHIZOPHRENIA; SOCIAL DISABILITY; BRAIN; COGNITION DISORDERS; COMPLICATION; GENETICS; METABOLISM; ONSET AGE; PATHOLOGY;

AGE OF ONSET; ANTIPSYCHOTIC AGENTS; BRAIN; COGNITION DISORDERS; HUMANS; NEUROBIOLOGY; RECEPTORS, N-METHYL-D-ASPARTATE; SCHIZOPHRENIA;

EID: 84922223423     PISSN: 13594184     EISSN: 14765578     Source Type: Journal    
DOI: 10.1038/mp.2014.66     Document Type: Review

References (225)

1. Kahn RS, Keefe RS. Schizophrenia is a cognitive illness: time for a change in focus. JAMA Psychiatry 2013; 70: 1107-1112.
2. Haijma SV, Van Haren N, Cahn W, Koolschijn PC, Hulshoff Pol HE, Kahn RS. Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophr Bull 2013; 39: 1129-1138.
3. ORahilly, R Müller, F. Human Embryology & Teratology. Wiley-Liss: New York, NY, USA, 1992.
4. Sgouros S, Hockley AD, Goldin JH, Wake MJ, Natarajan K. Intracranial volume change in craniosynostosis. J Neurosurg 1999; 91: 617-625.
5. Blakemore SJ. Imaging brain development: the adolescent brain. Neuroimage 2012; 61: 397-406.
6. Hulshoff Pol HE, Kahn RS. What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr Bull 2008; 34: 354-366.
7. Hulshoff Pol HE, Brans RG, van Haren NE, Schnack HG, Langen M, Baar WF et al. Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia. Biol Psychiatry 2004; 55: 126-130.
8. Cahn W, van Haren NE, Hulshoff Pol HE, Schnack HG, Caspers E, Laponder DA et al. Brain volume changes in the first year of illness and 5-year outcome of schizophrenia. Br J Psychiatry 2006; 189: 381-382.
9. van Haren NE, Cahn W, Hulshoff Pol HE, Kahn RS. Confounders of excessive brain volume loss in schizophrenia. Neurosci Biobehav Rev 2013; 37: 2418-2423.
10. van Haren NE, Schnack HG, Cahn W, van den Heuvel MP, Lepage C, Collins L et al. Changes in cortical thickness during the course of illness in schizophrenia. Arch Gen Psychiatry 2011; 68: 871-880.
11. Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry 2011; 68: 128-137.
12. Andreasen NC, Liu D, Ziebell S, Vora A, Ho BC. Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: a prospective longitudinal MRI study. Am J Psychiatry 2013; 170: 609-615.
13. Mandl RC, Rais M, van Baal GC, van Haren NE, Cahn W, Kahn RS et al. Altered white matter connectivity in never-medicated patients with schizophrenia. Hum Brain Mapp 2013; 34: 2353-2365.
14. Reis Marques T, Taylor H, Chaddock C, Dell'acqua F, Handley R, Reinders AA et al. White matter integrity as a predictor of response to treatment in first episode psychosis. Brain 2014; 137: 172-182.
15. Kuswanto CN, Teh I, Lee TS, Sim K. Diffusion tensor imaging findings of white matter changes in first episode schizophrenia: a systematic review. Clin Psychopharmacol Neurosci 2012; 10: 13-24.
16. Radua J, Borgwardt S, Crescini A, Mataix-Cols D, Meyer-Lindenberg A, McGuire PK et al. Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication. Neurosci Biobehav Rev 2012; 36: 2325-2333.
17. Vita A, De Peri L, Deste G, Sacchetti E. Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies. Transl Psychiatry 2012; 2: e190.
18. van Haren NE, Cahn W, Hulshoff Pol HE, Kahn RS. The course of brain abnormalities in schizophrenia: can we slow the progression? J Psychopharmacol 2012; 26: 8-14.
19. van Haren NE, Cahn W, Hulshoff Pol HE, Kahn RS. Schizophrenia as a progressive brain disease. Eur Psychiatry 2008; 23: 245-254.
20. Hulshoff Pol HE, Kahn RS. What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr Bull. 2008; 34: 354-366.
21. Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA. Brain volume in firstepisode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br J Psychiatry 2006; 188: 510-518.
22. Wang Q, Cheung C, Deng W, Li M, Huang C, Ma X et al. White-matter microstructure in previously drug-naive patients with schizophrenia after 6 weeks of treatment. Psychol Med 2013; 43: 2301-2309.
23. Friedrich VL Jr, Byne W, Buitron C, Perl DP, Davis KL. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry 2003; 53: 1075-1085.
24. Schmitt A, Steyskal C, Bernstein HG, Schneider-Axmann T, Parlapani E, Schaeffer EL et al. Stereologic investigation of the posterior part of the hippocampus in schizophrenia. Acta Neuropathol 2009; 117: 395-407.
25. Fusar-Poli P, Deste G, Smieskova R, Barlati S, Yung AR, Howes O et al. Cognitive functioning in prodromal psychosis: a meta-analysis. Arch Gen Psychiatry 2012; 69: 562-571.
26. Gajwani R, Patterson P, Birchwood M. Attachment: developmental pathways to affective dysregulation in young people at ultra-high risk of developing psychosis. Br J Clin Psychol 2013; 52: 424-437.
27. Fusar-Poli P, Nelson B, Valmaggia L, Yung AR, McGuire PK. Comorbid depressive and anxiety disorders in 509 individuals with an at-risk mental state: impact on psychopathology and transition to psychosis. Schizophr Bull 2014; 40: 120-131.
28. Simon AE, Grdel M, Cattapan-Ludewig K, Gruber K, Ballinari P, Roth B et al. Cognitive functioning in at-risk mental states for psychosis and 2-year clinical outcome. Schizophr Res 2012; 142: 108-115.
29. Simon AE, Borgwardt S, Riecher-Rssler A, Velthorst E, de Haan L, Fusar-Poli P. Moving beyond transition outcomes: Meta-analysis of remission rates in individuals at high clinical risk for psychosis. Psychiatry Res 2013; 209: 266-272.
30. Wood SJ, Reniers RL, Heinze K. Neuroimaging findings in the at-risk mental state: a review of recent literature. Can J Psychiatry 2013; 58: 13-18.
31. Mechelli A, Riecher-Rssler A, Meisenzahl EM, Tognin S, Wood SJ, Borgwardt SJ et al. Neuroanatomical abnormalities that predate the onset of psychosis: a multicenter study. Arch Gen Psychiatry 2011; 68: 489-495.
32. Samartzis L, Dima D, Fusar-Poli P, Kyriakopoulos M. White matter alterations in early stages of schizophrenia: a systematic review of diffusion tensor imaging studies. J Neuroimaging 2014; 24: 101-110.
33. Karlsgodt KH, Niendam TA, Bearden CE, Cannon TD. White matter integrity and prediction of social and role functioning in subjects at ultra-high risk for psychosis. Biol Psychiatry 2009; 66: 562-569.
34. Niendam TA, Bearden CE, Johnson JK, McKinley M, Loewy R, O'Brien M et al. Neurocognitive performance and functional disability in the psychosis prodrome. Schizophr Res 2006; 84: 100-111.
35. Lin A, Wood SJ, Nelson B, Brewer WJ, Spiliotacopoulos D, Bruxner A et al. Neurocognitive predictors of functional outcome two to 13 years after identification as ultra-high risk for psychosis. Schizophr Res 2011; 132: 1-7.
36. van Oel CJ, Sitskoorn MM, Cremer MP, Kahn RS. School performance as a premorbid marker for schizophrenia: a twin study. Schizophr Bull 2002; 28: 401-414.
37. Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry 2009; 66: 13-20.
38. Howes OD, Bose SK, Turkheimer F, Valli I, Egerton A, Valmaggia LR et al. Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study. Am J Psychiatry 2011; 168: 1311-1317.
39. Bonoldi I, Howes OD. The enduring centrality of dopamine in the pathophysiology of schizophrenia: in vivo evidence from the prodrome to the first psychotic episode. Adv Pharmacol 2013; 68: 199-220.
40. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III-the final common pathway. Schizophr Bull 2009; 35: 549-562.
41. Winton-Brown TT, Fusar-Poli P, Ungless MA, Howes OD. Dopaminergic basis of salience dysregulation in psychosis. Trends Neurosci 2014; 37: 85-94.
42. Bach ME, Simpson EH, Kahn L, Marshall JJ, Kandel ER, Kellendonk C. Transient and selective overexpression of D2 receptors in the striatum causes persistent deficits in conditional associative learning. Proc Natl Acad Sci USA 2008; 105: 16027-16032.
43. Anticevic A, Gancsos M, Murray JD, Repovs G, Driesen NR, Ennis DJ et al. NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia. Proc Natl Acad Sci USA 2012; 109: 16720-16725.
44. Schwartz TL, Sachdeva S, Stahl SM. Genetic data supporting the NMDA glutamate receptor hypothesis for schizophrenia. Curr Pharm Des 2012; 18: 1580-1592.
45. Krystal JH, Anand A, Moghaddam B. Effects of NMDA receptor antagonists: implications for the pathophysiology of schizophrenia. Arch Gen Psychiatry 2002; 59: 663-664.
46. Snyder MA, Gao WJ. NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia. Front Cell Neurosci 2013; 7: 31.
47. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10: 40-68, image 5.
48. Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH et al. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 2006; 12: 824-828.
49. Fromer M, Pocklington AJ, Kavanagh DH, William HJ, Dwyer S, Gormley P et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 2014; 506: 179-184.
50. Wang M, Yang Y, Wang CJ, Gamo NJ, Jin LE, Mazer JA et al. NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron 2013; 77: 736-749.
51. Samuelsson AM, Jennische E, Hansson HA, Holmng A. Prenatal exposure to interleukin-6 results in inflammatory neurodegeneration in hippocampus with NMDA/GABA(A) dysregulation and impaired spatial learning. Am J Physiol Regul Integr Comp Physiol 2006; 290: R1345-R1356.
52. El-Khodor BF, Flores G, Srivastava LK, Boksa P. Effects of birth insult and stress at adulthood on excitatory amino acid receptors in adult rat brain. Synapse 2004; 54: 138-146.
53. Kaur C, Sivakumar V, Ang LS, Sundaresan A. Hypoxic damage to the periventricular white matter in neonatal brain: role of vascular endothelial growth factor, nitric oxide and excitotoxicity. J Neurochem 2006; 98: 1200-1216.
54. Owen D, Setiawan E, Li A, McCabe L, Matthews SG. Regulation of N-methyl-Daspartate receptor subunit expression in the fetal guinea pig brain. Biol Reprod 2004; 71: 676-683.
55. Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence. J Psychiatr Res 1982-1983; 17: 319-334.
56. Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312-324.
57. Curley AA, Arion D, Volk DW, Asafu-Adjei JK, Sampson AR, Fish KN et al. Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features. Am J Psychiatry 2011; 168: 921-929.
58. Hyde TM, Lipska BK, Ali T, Mathew SV, Law AJ, Metitiri OE et al. Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia. J Neurosci 2011; 31: 11088-11095.
59. Hoff AL, Svetina C, Shields G, Stewart J, DeLisi LE. Ten year longitudinal study of neuropsychological functioning subsequent to a first episode of schizophrenia. Schizophr Res 2005; 78: 27-34.
60. Floresco SB, Todd CL, Grace AA. Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J Neurosci 2001; 21: 4915-4922.
61. Adell A, Jimnez-Snchez L, Lpez-Gil X, Romn T. Is the acute NMDA receptor hypofunction a valid model of schizophrenia? Schizophr Bull 2012; 38: 9-14.
62. Rowland LM, Kontson K, West J, Edden RA, Zhu H, Wijtenburg SA et al. In vivo measurements of glutamate, GABA, and NAAG in schizophrenia. Schizophr Bull 2013; 39: 1096-1104.
63. Rowland LM, Bustillo JR, Mullins PG, Jung RE, Lenroot R, Landgraf E et al. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatry 2005; 162: 394-396.
64. Tibbo P, Hanstock C, Valiakalayil A, Allen P. 3-T proton MRS investigation of glutamate and glutamine in adolescents at high genetic risk for schizophrenia. Am J Psychiatry 2004; 161: 1116-1118.
65. Keshavan MS, Dick RM, Diwadkar VA, Montrose DM, Prasad KM, Stanley JA. Striatal metabolic alterations in non-psychotic adolescent offspring at risk for schizophrenia: a (1)H spectroscopy study. Schizophr Res 2009; 115: 88-93.
66. de la Fuente-Sandoval C, Len-Ortiz P, Favila R, Stephano S, Mamo D, Ramrez-Bermdez J et al. Higher levels of glutamate in the associative-striatum of subjects with prodromal symptoms of schizophrenia and patients with firstepisode psychosis. Neuropsychopharmacology 2011; 36: 1781-1791.
67. de la Fuente-Sandoval C, Len-Ortiz P, Azcrraga M, Favila R, Stephano S, Graff-Guerrero A. Striatal glutamate and the conversion to psychosis: a prospective 1H-MRS imaging study. Int J Neuropsychopharmacol 2013; 16: 471-475.
68. Tandon N, Bolo NR, Sanghavi K, Mathew IT, Francis AN, Stanley JA et al. Brain metabolite alterations in young adults at familial high risk for schizophrenia using proton magnetic resonance spectroscopy. Schizophr Res 2013; 148: 59-66.
69. Stone JM, Day F, Tsagaraki H, Valli I, McLean MA, Lythgoe DJ et al. OASIS. Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume. Biol Psychiatry 2009; 66: 533-539.
70. Fusar-Poli P, Broome MR, Matthiasson P, Woolley JB, Mechelli A, Johns LC et al. Prefrontal function at presentation directly related to clinical outcome in people at ultrahigh risk of psychosis. Schizophr Bull 2011; 37: 189-198.
71. Yoo SY, Yeon S, Choi CH, Kang DH, Lee JM, Shin NY et al. Proton magnetic resonance spectroscopy in subjects with high genetic risk of schizophrenia: investigation of anterior cingulate, dorsolateral prefrontal cortex and thalamus. Schizophr Res 2009; 111: 86-93.
72. Natsubori T, Inoue H, Abe O, Takano Y, Iwashiro N, Aoki Y et al. Reduced frontal Glutamate + Glutamine and N-Acetylaspartate levels in patients with chronic schizophrenia but not in those at clinical high risk for psychosis or with firstepisode schizophrenia. Schizophr Bull advance online publication, 10 September 2013; PMID: 24023251 (e-pub ahead of print).
73. Bartha R, Williamson PC, Drost DJ, Malla A, Carr TJ, Cortese L et al. Measurement of glutamate and glutamine in the medial prefrontal cortex of never-treated schizophrenic patients and healthy controls by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1997; 54: 959-965.
74. Thberge J, Jensen JE, Rowland LM. Regarding "Increased prefrontal and hippocampal glutamate concentration in schizophrenia: evidence from a magnetic resonance spectroscopy study. Biol Psychiatry 2007; 61: 1218-1219.
75. Bustillo JR, Rowland LM, Mullins P, Jung R, Chen H, Qualls C et al. 1H-MRS at 4 tesla in minimally treated early schizophrenia. Mol Psychiatry. 2010; 15: 629.636.
76. Stanley JA, Williamson PC, Drost DJ, Rylett RJ, Carr TJ, Malla A et al. An in vivo proton magnetic resonance spectroscopy study of schizophrenia patients. Schizophr Bull 1996; 22: 597.609.
77. Wood SJ, Yucel M, Wellard RM, Harrison BJ, Clarke K, Fornito A et al. Evidence for neuronal dysfunction in the anterior cingulate of patients with schizophrenia: a proton magnetic resonance spectroscopy study at 3 T. Schizophr Res 2007; 94: 328.331.
78. Galiska B, Szulc A, Tarasow E, Kubas B, Dzienis W, Czernikiewicz A et al. Duration of untreated psychosis and proton magnetic resonance spectroscopy (1H-MRS) findings in first-episode schizophrenia. Med Sci Monit 2009; 15: CR82.CR88.
79. Bustillo JR, Chen H, Gasparovic C, Mullins P, Caprihan A, Qualls C et al. Glutamate as a marker of cognitive function in schizophrenia: a proton spectroscopic imaging study at 4 Tesla. Biol Psychiatry 2011; 69: 19.27.
80. Marsman A, van den Heuvel MP, Klomp DW, Kahn RS, Luijten PR, Hulshoff Pol HE. Glutamate in schizophrenia: a focused review and meta-analysis of 1H-MRS studies. Schizophr Bull 2013; 39: 120.129.
81. Bustillo JR, Chen H, Jones T, Lemke N, Abbott C, Qualls C et al. Increased glutamine in patients undergoing long-term treatment for schizophrenia: a proton magnetic resonance spectroscopy study at 3 T. JAMA Psychiatry 2014; 71: 265.272.
82. Goto N, Yoshimura R, Moriya J, Kakeda S, Ueda N, Ikenouchi-Sugita A et al. Reduction of brain gamma-aminobutyric acid (GABA) concentrations in earlystage schizophrenia patients: 3T Proton MRS study. Schizophr Res 2009; 112: 192.193.
83. Yoon JH, Maddock RJ, Rokem A, Silver MA, Minzenberg MJ, Ragland JD et al. GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression. J Neurosci 2010; 30: 3777.3781.
84. Tayoshi S, Nakataki M, Sumitani S, Taniguchi K, Shibuya-Tayoshi S, Numata S et al. GABA concentration in schizophrenia patients and the effects of antipsychotic medication: a proton magnetic resonance spectroscopy study. Schizophr Res 2010; 117: 83.91.
85. Stevens JR. Neuropathology of schizophrenia. Arch Gen Psychiatry 1982; 39: 1131.1139.
86. de Jong S, van Eijk KR, Zeegers DW, Strengman E, Janson E, Veldink JH et al. PGC Schizophrenia (GWAS)Consortium. Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes. Eur J Hum Genet 2012; 20: 1004.1008.
87. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D et al. Common variants conferring risk of schizophrenia. Nature 2009; 460: 744.747.
88. Corvin A, Morris DW. Genome-wide association Studies: Findings at the major histo-compatibility complex locus in psychosis. Biol Psychiatry 2014; 75: 276.283.
89. McAllister AK. Major Histocompatibility Complex I in Brain Development and Schizophrenia. Biol Psychiatry 2014; 75: 262.268.
90. Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ. Functional requirement for class I MHC in CNS development and plasticity. Science 2000; 290: 2155.2159.
91. Shatz CJ. MHC class I: an unexpected role in neuronal plasticity. Neuron 2009; 64: 40.45.
92. Canetta SE, Brown AS. Prenatal infection, maternal immune activation, and risk for schizophrenia. Transl Neurosci 2012; 3: 320.327.
93. Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry 2011; 168: 1303.1310.
94. Steiner J, Walter M, Glanz W, Sarnyai Z, Bernstein HG, Vielhaber S et al. Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry 2013; 70: 271.278.
95. Hagberg H, Gressens P, Mallard C. Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol. 2012; 71: 444.457.
96. van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C] PK11195 positron emission tomography study. Biol Psychiatry 2008; 64: 820.822.
97. Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC. Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 2009; 50: 1801.1807.
98. Takano A, Arakawa R, Ito H, Tateno A, Takahashi H, Matsumoto R et al. Peripheral benzodiazepine receptors in patients with chronic schizophrenia: a PET study with [11C]DAA1106. Int J Neuropsychopharmacol 2010; 13: 943.950.
99. Chauveau F, Van Camp N, Dolle F, Kuhnast B, Hinnen F, Damont A et al. Comparative evaluation of the translocator protein radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a rat model of acute neuroinflammation. J Nucl Med 2009; 50: 468.476.
100. Monji A, Kato T, Kanba S. Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci 2009; 63: 257.265.
101. Narayan S, Tang B, Head SR, Gilmartin TJ, Sutcliffe JG, Dean B et al. Molecular profiles of schizophrenia in the CNS at different stages of illness. Brain Res 2008; 1239: 235.248.
102. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2011; 70: 663.671.
103. Feigenson KA, Kusnecov AW, Silverstein SM. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev 2014; 38: 72.93.
104. Papadia S, Soriano FX, Leveille F, Martel MA, Dakin KA, Hansen HH et al. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat Neurosci 2008; 11: 476.487.
105. Smith SE, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 2007; 27: 10695.10702.
106. Behrens MM, Ali SS, Dugan LL. Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J Neurosci 2008; 28: 13957.13966.
107. Muller N, Schwarz M. Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox Res 2006; 10: 131.148.
108. Mayer ML, Westbrook GL, Vyklicky L Jr. Sites of antagonist action on N-methyl-Daspartic acid receptors studied using fluctuation analysis and a rapid perfusion technique. J Neurophysiol 1988; 60: 645.663.
109. Coyle JT. Nitric oxide and symptom reduction in schizophrenia. JAMA Psychiatry 2013; 70: 664.665.
110. Meyer U, Feldon J. Neural basis of psychosis-related behaviour in the infection model of schizophrenia. Behav Brain Res 2009; 204: 322.334.
111. Pasternak O, Westin CF, Bouix S, Seidman LJ, Goldstein JM, Woo TU et al. Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset. J Neurosci 2012; 32: 17365.17372.
112. Egerton A, Fusar-Poli P, Stone JM. Glutamate and psychosis risk. Curr Pharm Des 2012; 18: 466.478.
113. Demjaha A, Murray RM, McGuire PK, Kapur S, Howes OD. Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. Am J Psychiatry 2012; 169: 1203.1210.
114. Fillman SG, Cloonan N, Miller LC, Weickert CS. Markers of inflammation in the prefrontal cortex of individuals with schizophrenia. Mol Psychiatry 2013; 18: 133.
115. Kato T, Monji A, Hashioka S, Kanba S. Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro. Schizophr Res 2007; 92: 108.115.
116. Kato TA, Monji A, Mizoguchi Y, Hashioka S, Horikawa H, Seki Y, Kasai M, Utsumi H, Kanba S. Anti-Inflammatory properties of antipsychotics via microglia modulations: are antipsychotics a 'fire extinguisher' in the brain of schizophrenia? Mini Rev Med Chem 2011; 11: 565.574.
117. Zheng LT, Hwang J, Ock J, Lee MG, Lee WH, Suk K. The antipsychotic spiperone attenuates inflammatory response in cultured microglia via the reduction of proinflammatory cytokine expression and nitric oxide production. J Neurochem 2008; 107: 1225.1235.
118. Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008; 371: 1085.1097.
119. Robinson D. First-episode schizophrenia. CNS Spectr 2010; 15: 4.7.
120. Robinson DG, Woerner MG, Alvir JM, Geisler S, Koreen A, Sheitman B et al. Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 1999; 156: 544.549.
121. Agid O, Arenovich T, Sajeev G, Zipursky RB, Kapur S, Foussias G et al. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry 2011; 72: 1439.1444.
122. Singh SP, Singh V. Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia. CNS Drugs 2011; 25: 859.885.
123. Heresco-Levy U, Javitt DC. Comparative effects of glycine and D-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis. Schizophr Res 2004; 66: 89.96.
124. Hashimoto K, Malchow B, Falkai P, Schmitt A. Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci 2013; 263: 367.377.
125. Goff DC, Lamberti JS, Leon AC, Green MF, Miller AL, Patel J et al. A placebocontrolled add-on trial of the Ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology 2008; 33: 465.472.
126. Lane HY, Liu YC, Huang CL, Chang YC, Liau CH, Perng CH et al. Sarcosine (Nmethylglycine) treatment for acute schizophrenia: a randomized, doubleblind study. Biol Psychiatry 2008; 63: 9.12.
127. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andregv BV et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 2007; 13: 1102.1107.
128. Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S et al. A multicenter, inpatient, phase 2, double-blind, placebocontrolled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol 2011; 31: 349.355.
129. Gill KM, Grace AA. The role of 5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia. Curr Pharm Des advance online publication, 15 December 2013 (e-pub ahead of print).
130. Vinkers CH, Mirza NR, Olivier B, Kahn RS. The inhibitory GABA system as a therapeutic target for cognitive symptoms in schizophrenia: investigational agents in the pipeline. Expert Opin Investig Drugs 2010; 19: 1217.1233.
131. Insel TR. Rethinking schizophrenia. Nature 2010; 468: 187.193.
132. Sommer IE, van Westrhenen R, Begemann MJ, de Witte LD, Leucht S, Kahn RS. Efficacy of Anti-inflammatory Agents to Improve Symptoms in Patients With Schizophrenia: An Update. Schizophr Bull 2014; 40: 181.191.
133. Carmeli C, Knyazeva MG, Cuenod M, Do KQ. Glutathione precursor N-acetylcysteine modulates EEG synchronization in schizophrenia patients: a doubleblind, randomized, placebo-controlled trial. PLoS One 2012; 7: e29341.
134. Lavoie S, Murray MM, Deppen P, Knyazeva MG, Berk M, Boulat O et al. Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology 2008; 33: 2187.2199.
135. Amminger GP, Schafer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry 2010; 67: 146.154.
136. Mossaheb N, Schafer MR, Schlogelhofer M, Klier CM, Cotton SM, McGorry PD, Amminger GP. Effect of omega-3 fatty acids for indicated prevention of young patients at risk for psychosis: when do they begin to be effective? Schizophr Res 2013; 148: 163.167.
137. Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci 2013; 34: 167.177.
138. Schmaal L, Berk L, Hulstijn KP, Cousijn J, Wiers RW, van den Brink W. Efficacy of N-acetylcysteine in the treatment of nicotine dependence: a double-blind placebo-controlled pilot study. Eur Addict Res 2011; 17: 211.216.
139. Schneider ML, Kwan BM. Psychological need satisfaction, intrinsic motivation and affective response to exercise in adolescents. Psychol Sport Exerc 2013; 14: 776.785.
140. Scheewe TW, Backx FJ, Takken T, Jorg F, van Strater AC, Kroes AG et al. Exercise therapy improves mental and physical health in schizophrenia: a randomised controlled trial. Acta Psychiatr Scand 2013; 127: 464.473.
141. Radom-Aizik S, Zaldivar FP Jr, Haddad F, Cooper DM. Impact of brief exercise on circulating monocyte gene and microRNA expression: Implications for atherosclerotic vascular disease. Brain Behav Immun 2014; 39: 121.129.
142. Di Raimondo D, Tuttolomondo A, Butta C, Casuccio A, Giarrusso L, Miceli G et al. Metabolic and anti-inflammatory effects of a home-based programme of aerobic physical exercise. Int J Clin Pract 2013; 67: 1247.1253.
143. Abdel-Baki A, Brazzini-Poisson V, Marois F, Letendre E, Karelis AD. Effects of aerobic interval training on metabolic complications and cardiorespiratory fitness in young adults with psychotic disorders: a pilot study. Schizophr Res 2013; 149: 112.115.
144. Scheewe TW, van Haren NE, Sarkisyan G, Schnack HG, Brouwer RM, de Glint M et al. Exercise therapy, cardiorespiratory fitness and their effect on brain volumes: a randomised controlled trial in patients with schizophrenia and healthy controls. Eur Neuropsychopharmacol 2013; 23: 675.685.
145. Pajonk FG, Wobrock T, Gruber O, Scherk H, Berner D, Kaizl I et al. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry 2010; 67: 133.143.
146. Daskalakis ZJ, Moller B, Christensen BK, Fitzgerald PB, Gunraj C, Chen R. The effects of repetitive transcranial magnetic stimulation on cortical inhibition in healthy human subjects. Exp Brain Res 2006; 174: 403.412.
147. de Jesus DR, Favalli GP, Hoppenbrouwers SS, Barr MS, Chen R, Fitzgerald PB et al. Determining optimal rTMS parameters through changes in cortical inhibition. Clin Neurophysiol 2013; 124: 1309.1320.
148. Luber B, Kinnunen LH, Rakitin BC, Ellsasser R, Stern Y, Lisanby SH. Facilitation of performance in a working memory task with rTMS stimulation of the precuneus: frequency-and time-dependent effects. Brain Res 2007; 1128: 120.129.
149. Luber B, Steffener J, Tucker A, Habeck C, Peterchev AV, Deng ZD et al. Extended remediation of sleep deprived-induced working memory deficits using fMRIguided transcranial magnetic stimulation. Sleep 2013; 36: 857.871.
150. Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 2008; 63: 801.808.
151. Zakharyan R, Boyajyan A. Inflammatory cytokine network in schizophrenia. World J Biol Psychiatry 2014; 15: 174.187.
152. Dickerson F, Stallings C, Origoni A, Boronow J, Yolken R. C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr Res 2007; 93: 261.265.
153. Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Yang S et al. C-reactive protein is elevated in schizophrenia. Schizophr Res 2013; 143: 198.202.
154. Vuksan-Cusa B, Sagud M, Jakovljevic M, Peles AM, Jaksic N, Mihaljevic S et al. Association between C-reactive protein and homocysteine with the subcomponents of metabolic syndrome in stable patients with bipolar disorder and schizophrenia. Nord J Psychiatry 2013; 67: 320.325.
155. Allen P, Chaddock CA, Howes OD, Egerton A, Seal ML, Fusar-Poli P et al. Abnormal relationship between medial temporal lobe and subcortical dopamine function in people with an ultra high risk for psychosis. Schizophr Bull. 2012; 38: 1040.9.
156. Bloemen OJN, de Koning MB, Gleich T, Meijer J, de Haan L, Linszen DH et al. Striatal dopamine D2/3 receptor binding following dopamine depletion in subjects at Ultra High Risk for psychosis. Eur Neuropsychopharmacol 2013; 23: 126.132.
157. Egerton A, Chaddock CA, Winton-Brown TT, Bloomfield MAP, Bhattacharyya S, Allen P et al. Presynaptic striatal dopamine dysfunction in people at ultra-high risk for psychosis: findings in a second cohort. Biol Psychiatry 2013; 74: 106.112.
158. Fusar-Poli P, Howes OD, Allen P, Broome M, Valli I, Asselin MC et al. Abnormal frontostriatal interactions in people with prodromal signs of psychosis: a multimodal imaging study. Arch Gen Psychiatry 2010; 67: 683.691.
159. Fusar-Poli P, Howes OD, Allen P, Broome M, Valli I, Asselin MC et al. Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis. Mol. Psychiatry 2011; 16: 67.75.
160. Hirvonen J, van Erp TGM, Huttunen J, Aalto S, Nagren K, Huttunen M et al. Increased caudate dopamine D2 receptor availability as a genetic marker for schizophrenia. Arch Gen Psychiatry 2005; 62: 371.378.
161. Howes O, Bose S, Turkheimer F, Valli I, Egerton A, Stahl D et al. Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Mol Psychiatry 2011a; 16: 885.886.
162. Suridjan I, Rusjan P, Addington J, Wilson AA, Houle S, Mizrahi R. Dopamine D2 and D3 binding in people at clinical high risk for schizophrenia, antipsychoticnaive patients and healthy controls while performing a cognitive task. J Psychiatry Neurosci 2013; 38: 98.106.
163. Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y et al. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002; 22: 3708.3719.
164. Abi-Dargham A, Xu X, Thompson JL, Gil R, Kegeles LS, Urban N et al. Increased prefrontal cortical D1 receptors in drug naive patients with schizophrenia: a PET study with [11C]NNC112. J Psychopharmacol (Oxford) 2012; 26: 794.805.
165. Buchsbaum MS, Christian BT, Lehrer DS, Narayanan TK, Shi B, Mantil J et al. D2/ D3 dopamine receptor binding with [F-18]fallypride in thalamus and cortex of patients with schizophrenia. Schizophr Res 2006; 85: 232.244.
166. Corripio I, Perez V, Catafau AM, Mena E, Carrio I, Alvarez E. Striatal D2 receptor binding as a marker of prognosis and outcome in untreated first-episode psychosis. Neuroimage 2006; 29: 662.666.
167. Corripio I, Escarti MJ, Portella MJ, Perez V, Grasa E, Sauras RB et al. Density of striatal D2 receptors in untreated first-episode psychosis: an I123-IBZM SPECT study. Eur Neuropsychopharmacol 2011; 21: 861.866.
168. Glenthoj BY, Mackeprang T, Svarer C, Rasmussen H, Pinborg LH, Friberg L et al. Frontal Dopamine D2/3 Receptor Binding in Drug-Naive First-Episode Schizophrenic Patients Correlates with Positive Psychotic Symptoms and Gender. Biological Psychiatry 2006; 60: 621.629.
169. Graff-Guerrero A, Mamo D, Shammi CM, Mizrahi R, Marcon H, Barsoum P et al. The effect of antipsychotics on the high-affinity state of D2 and D3 receptors: a positron emission tomography study With [11C]-(+)-PHNO. Arch Gen Psychiatry 2009a; 66: 606.615.
170. Graff-Guerrero A, Mizrahi R, Agid O, Marcon H, Barsoum P, Rusjan P et al. The dopamine D2 receptors in high-affinity state and D3 receptors in schizophrenia: a clinical [11C]-(+)-PHNO PET study. Neuropsychopharmacology 2009b; 34: 1078.1086.
171. Hietala J, Syvalahti E, Vuorio K, Rakkolainen V, Bergman J, Haaparanta M et al. Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. Lancet 1995; 346: 1130.1131.
172. Hietala J, Syvlahti E, Vilkman H, Vuorio K, Rkklinen V, Bergman J et al. Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia. Schizophr Res 1999; 35: 41-50.
173. Hsiao MC, Lin KJ, Liu CY, Tzen KY, Yen TC. Dopamine transporter change in drugnaive schizophrenia: an imaging study with 99mTc-TRODAT-1. Schizophr Res 2003; 65: 39-46.
174. Karlsson P, Farde L, Halldin C, Sedvall G. PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia. Am J Psychiatry 2002; 159: 761-767.
175. Laakso A, Vilkman H, Alakare B, Haaparanta M, Bergman J, Solin O et al. Striatal dopamine transporter binding in neuroleptic-naive patients with schizophrenia studied with positron emission tomography. Am J Psychiatry 2000; 157: 269-271.
176. Lavalaye J, Linszen DH, Booij J, Dingemans PM, Reneman L, Habraken JB et al. Dopamine transporter density in young patients with schizophrenia assessed with [123]FP-CIT SPECT. Schizophr Res 2001; 47: 59-67.
177. Lehrer DS, Christian BT, Kirbas C, Chiang M, Sidhu S, Short H et al. 18F-fallypride binding potential in patients with schizophrenia compared to healthy controls. Schizophr Res 2010; 122: 43-52.
178. Lindstrm LH, Gefvert O, Hagberg G, Lundberg T, Bergstrm M, Hartvig P et al. Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(beta-11C) DOPA and PET. Biol Psychiatry 1999; 46: 681-688.
179. Mateos JJ, Lomea F, Parellada E, Font M, Fernandez E, Pavia J et al. Decreased striatal dopamine transporter binding assessed with [123I] FP-CIT in first-episode schizophrenic patients with and without short-term antipsychotic-induced parkinsonism. Psychopharmacology (Berl) 2005; 181: 401-406.
180. Mateos JJ, Lomea F, Parellada E, Font M, Fernndez E, Pavia J et al. Striatal dopamine transporter density decrease in first episode schizophrenic patients treated with risperidone. Rev Esp Med Nucl 2006; 25: 159-165.
181. Mateos JJ, Lomea F, Parellada E, Mireia F, Fernandez-Egea E, Pavia J et al. Lower striatal dopamine transporter binding in neuroleptic-naive schizophrenic patients is not related to antipsychotic treatment but it suggests an illness trait. Psychopharmacology (Berl) 191: 805-811.
182. Nozaki S, Kato M, Takano H, Ito H, Takahashi H, Arakawa R et al. Regional dopamine synthesis in patients with schizophrenia using L-[beta-11C]DOPA PET. Schizophr Res 2009; 108: 78-84.
183. Safont G, Corripio I, Escart MJ, Portella MJ, Prez V, Ferrer M et al. Cannabis use and striatal D2 receptor density in untreated first-episode psychosis: an in vivo SPECT study. Schizophr Res 2011; 129: 169-171.
184. Schmitt GJE, Meisenzahl EM, Frodl T, La Fougre C, Hahn K, Mller HJ et al. The striatal dopamine transporter in first-episode, drug-naive schizophrenic patients: evaluation by the new SPECT-ligand[99mTc]TRODAT-1. J Psychopharmacol (Oxford) 2005; 19: 488-493.
185. Schmitt GJE, Frodl T, Dresel S, la Fougre C, Bottlender R, Koutsouleris N et al. Striatal dopamine transporter availability is associated with the productive psychotic state in first episode, drug-naive schizophrenic patients. Eur Arch Psychiatry Clin Neurosci 2006; 256: 115-121.
186. Schmitt GJE, la Fougre C, Dresel S, Frodl T, Hahn K, Mller HJ et al. Dual-isotope SPECT imaging of striatal dopamine: first episode, drug nave schizophrenic patients. Schizophr Res 2008; 101: 133-141.
187. Schmitt GJE, Meisenzahl EM, Frodl T, La Fougre C, Hahn K, Mller HJ et al. Increase of striatal dopamine transmission in first episode drug-naive schizophrenic patients as demonstrated by [(123)I]IBZM SPECT. Psychiatry Res 2009; 173: 183-189.
188. Schmitt GJE, Dresel S, Frodl T, la Fougre C, Boerner R, Hahn K et al. Dual-isotope SPECT imaging of striatal dopamine: a comparative study between never-treated and haloperidol-treated first-episode schizophrenic patients. Eur Arch Psychiatry Clin Neurosci 2012; 262: 183-191.
189. Talvik M, Nordstrm AL, Olsson H, Halldin C, Farde L. Decreased thalamic D2/D3 receptor binding in drug-naive patients with schizophrenia: a PET study with [11C]FLB 457. Int. J Neuropsychopharmacol 2003; 6: 361-370.
190. Talvik M, Nordstrm AL, Okubo Y, Olsson H, Borg J, Halldin C et al. Dopamine D2 receptor binding in drug-nave patients with schizophrenia examined with raclopride-C11 and positron emission tomography. Psychiatry Res 2006; 148: 165-173.
191. Yang YK, Yu L, Yeh TL, Chiu NT, Chen PS, Lee IH. Associated alterations of striatal dopamine D2/D3 receptor and transporter binding in drug-naive patients with schizophrenia: a dual-isotope SPECT study. Am J Psychiatry 2004; 161: 1496-1498.
192. Yasuno F, Suhara T, Okubo Y, Sudo Y, Inoue M, Ichimiya T et al. Low dopamine d (2) receptor binding in subregions of the thalamus in schizophrenia. Am J Psychiatry 2004; 161: 1016-1022.
193. Bloemen OJN, Gleich T, de Koning MB, da Silva Alvis F, de Haan L, Linszen DH et al. Hippocampal glutamate levels and striatal dopamine D(2/3) receptor occupancy in subjects at ultra high risk of psychosis. Biol Psychiatry 2011; 70: e1-2, author reply e3.
194. Fusar-Poli P, Stone JM, Broome MR, Valli I, Mechelli A, McLean MA et al. Thalamic glutamate levels as a predictor of cortical response during executive functioning in subjects at high risk for psychosis. Arch. Gen. Psychiatry 2011; 68: 881-890.
195. Purdon SE, Valiakalayil A, Hanstock CC, Seres P, Tibbo P. Elevated 3T proton MRS glutamate levels associated with poor Continuous Performance Test (CPT-0X) scores and genetic risk for schizophrenia. Schizophr Res 2008; 99: 218-224.
196. Valli I, Stone J, Mechelli A, Bhattacharyya S, Raffin M, Allen P et al. Altered medial temporal activation related to local glutamate levels in subjects with prodromal signs of psychosis. Biol Psychiatry 2011; 69: 97-99.
197. Bartha R, al-Semaan YM, Williamson PC, Drost DJ, Malla AK, Carr TJ et al. A short echo proton magnetic resonance spectroscopy study of the left mesialtemporal lobe in first-onset schizophrenic patients. Biol Psychiatry 1999; 45: 1403-1411.
198. De la Fuente-Sandoval C, Len-Ortiz P, Azcrraga M, Stephano S, Favila R, Daz-Galvis L et al. Glutamate levels in the associative striatum before and after 4 weeks of antipsychotic treatment in first-episode psychosis: a longitudinal proton magnetic resonance spectroscopy study. JAMA Psychiatry 2013; 70: 1057-1066.
199. Ohrmann P, Siegmund A, Suslow T, Spitzberg K, Kersting A, Arolt V et al. Evidence for glutamatergic neuronal dysfunction in the prefrontal cortex in chronic but not in first-episode patients with schizophrenia: a proton magnetic resonance spectroscopy study. Schizophr Res 2005; 73: 153-157.
200. Ohrmann P, Siegmund A, Suslow T, Pedersen A, Spitzberg K, Kersting A et al. Cognitive impairment and in vivo metabolites in first-episode neuroleptic-naive and chronic medicated schizophrenic patients: a proton magnetic resonance spectroscopy study. J Psychiatr Res 2007; 41: 625-634.
201. Olbrich HM, Valerius G, Rüsch N, Buchert M, Thiel T, Hennig J et al. Frontolimbic glutamate alterations in first episode schizophrenia: evidence from a magnetic resonance spectroscopy study. World J Biol Psychiatry 2008; 9: 59-63.
202. Thberge J, Bartha R, Drost DJ, Menon RS, Malla A, Takhar J et al. Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. Am J Psychiatry 2002; 159: 1944-1946.
203. Thberge J, Williamson KE, Aoyama N, Drost DJ, Manchanda R, Malla AK et al. Longitudinal grey-matter and glutamatergic losses in first-episode schizophrenia. Br J Psychiatry 2007; 191: 325-334.
204. Wood SJ, Berger GE, Wellard RM, Proffitt T, McConchie M, Velakoulis D et al. A 1H-MRS investigation of the medial temporal lobe in antipsychotic-nave and early-treated first episode psychosis. Schizophr Res 2008; 102: 163-170.
205. Arnold SE, Trojanowski JQ, Gur RE, Blackwell P, Han LY, Choi C. Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch. Gen. Psychiatry 1998; 55: 225-232.
206. Bayer TA, Buslei R, Havas L, Falkai P. Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci. Lett 1999; 271: 126-128.
207. Bruton CJ, Crow TJ, Frith CD, Johnstone EC, Owens DG, Roberts GW. Schizophrenia and the brain: a prospective clinico-neuropathological study. Psychol Med 1990; 20: 285-304.
208. Busse S, Busse M, Schiltz K, Bielau H, Gos T, Brisch R et al. Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for disease courserelated immune alterations? Brain Behav Immun 2012; 26: 1273-1279.
209. Falke E, Han LY, Arnold SE. Absence of neurodegeneration in the thalamus and caudate of elderly patients with schizophrenia. Psychiatry Res 2000; 93: 103-110.
210. Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T et al. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry 2013; 18: 206-214.
211. Fisman M. The brain stem in psychosis. Br J Psychiatry 1975; 126: 414-422.
212. Kurumaji A, Wakai T, Toru M. Decreases in peripheral-type benzodiazepine receptors in postmortem brains of chronic schizophrenics. J Neural Transm 1997; 104: 1361-1370.
213. Nasrallah HA, McCalley-Whitters M, Bigelow LB, Rauscher FP. A histological study of the corpus callosum in chronic schizophrenia. Psychiatry Res 1983; 8: 251-260.
214. Radewicz K, Garey LJ, Gentleman SM, Reynolds R. Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. J Neuropathol Exp Neurol 2000; 59: 137-150.
215. Rao JS, Kim H-W, Harry GJ, Rapoport SI, Reese EA. Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophr Res 2013; 147: 24-31.
216. Roberts GW, Colter N, Lofthouse R, Bogerts B, Zech M, Crow TJ. Gliosis in schizophrenia: a survey. Biol Psychiatry 1986; 21: 1043-1050.
217. Roberts GW, Colter N, Lofthouse R, Johnstone EC, Crow TJ. Is there gliosis in schizophrenia? Investigation of the temporal lobe. Biol Psychiatry 1987; 22: 1459-1468.
218. Steiner J, Mawrin C, Ziegeler A, Bielau H, Ullrich O, Bernstein H-G et al. Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired cerebral lateralization. Acta Neuropathol 2006; 112: 305-316.
219. Steiner J, Bernstein H-G, Bielau H, Farkas N, Winter J, Dobrowolny H et al. S100Bimmunopositive glia is elevated in paranoid as compared to residual schizophrenia: a morphometric study. J Psychiatr Res 2008a; 42: 868-876.
220. Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C et al. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res 2008b; 42: 151-157.
221. Stevens CD, Altshuler LL, Bogerts B, Falkai P. Quantitative study of gliosis in schizophrenia and Huntingtons chorea. Biol Psychiatry 1988a; 24: 697-700.
222. Stevens J, Casanova M, Bigelow L. Gliosis in schizophrenia. Biol Psychiatry 1988b; 24: 727-731.
223. Togo T, Akiyama H, Kondo H, Ikeda K, Kato M, Iseki E et al. Expression of CD40 in the brain of Alzheimer's disease and other neurological diseases. Brain Res 2000; 885: 117-121.
224. Wierzba-Bobrowicz T, Lewandowska E, Kosno-Kruszewska E, Lechowicz W, Pasennik E, Schmidt-Sidor B. Degeneration of microglial cells in frontal and temporal lobes of chronic schizophrenics. Folia Neuropathol 2004; 42: 157-165.
225. Wierzba-Bobrowicz T, Lewandowska E, Lechowicz W, Stepień T, Pasennik E. Quantitative analysis of activated microglia, ramified and damage of processes in the frontal and temporal lobes of chronic schizophrenics. Folia Neuropathol 2005; 43: 81-89.