Frontal brain volume reduction due to antipsychotic drugs?;Frontale Hirnvolumenminderung durch Antipsychotika?

Nervenarzt

Volumn 86, Issue 3, 2015, Pages 302-323

  Aderhold, V ^a   Weinmann, S ^b   Hagele C ^c   Heinz, A ^c  

^a UNIVERSITY OF GREIFSWALD   (Germany)

^b VIVANTES KLINIKUM AM URBAN   (Germany)

^c CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

Author keywords

Antipsychotic drugs; Brain atrophy; Grey matter; Schizophrenia; White matter

Indexed keywords

NEUROLEPTIC AGENT;

ATROPHY; BRAIN; CHEMICALLY INDUCED; DRUG EFFECTS; EVIDENCE BASED MEDICINE; HUMAN; ORGAN SIZE; PATHOLOGY; PATHOPHYSIOLOGY; SCHIZOPHRENIA; TREATMENT OUTCOME;

ANTIPSYCHOTIC AGENTS; ATROPHY; BRAIN; EVIDENCE-BASED MEDICINE; HUMANS; ORGAN SIZE; SCHIZOPHRENIA; TREATMENT OUTCOME;

EID: 84939876510     PISSN: 00282804     EISSN: 14330407     Source Type: Journal    
DOI: 10.1007/s00115-014-4027-5     Document Type: Article

References (152)

1. Huber G (1957) Pneumencephalographische und psychopathologische Bilder bei endogenen Psychosen. Springer, Berlin
2. Shenton MA, Dickey CC, Frumin M, McCarley RW (2001) A review of MRI findings in schizophrenia. Schizophr Res 49:1–52
3. Heinz A, Weinberger DR (2000) Schizophrenia: the neurodevelopmental hypothesis. Current concepts in psychiatry. Psychiatrie der Gegenwart. Springer, Berlin, S 89–104
4. Kalus P, Falkai P, Heinz A (2008) Strukturelle und funktionelle Hirnveränderungen bei schizophrenen Psychosen. Nervenarzt 79:275–278
5. Pantelis C, Yücel M, Wood SJ et al (2005) Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia. Schizophr Bull 31:672–696
6. Woods BT, Ward KE, Johnson EH (2005) Meta-analysis of the time-course of brain volume reduction in schizophrenia: implications for pathogenesis and early treatment. Schizophr Res 73:221–228
7. Selemon LD, Rajkowska G, Goldman-Rakic PS (1998) Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a 3-dimensional, stereologic counting method. J Comp Neurol 392:402–412
8. Os J van, Kapur S (2009) Schizophrenia. Lancet 374:635–645
9. NICE clinical guideline 82 (2009) Schizophrenia – core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. Developed by the National Collaborating Centre for Mental Health, Leicester
10. Madsen AL, Keidling N, Karle A et al (1998) Neuroleptics in progressive structural brain abnormalities in psychiatric illness. Lancet 352:784–785
11. Fusar-Poli P, Smieskova R, Kempton MJ et al (2013) Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neurosci Biobehav Rev 37:1680–1691
12. Borgwardt SJ, McGuire PK, Aston J et al (2008) Reductions in frontal, temporal and parietal volume associated with the onset of psychosis. Schizophr Res 106:108–114
13. Molina V, Reig S, Sanz J et al (2005) Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia. Schizophr Res 80:61–71
14. Heinz A (2002) Dopaminergic dysfunction in alcoholism and schizophrenia – psychopathological and behavioral correlates. Eur Psychiatry 17:9–16
15. Hulshoff Pol HE, Kahn RS (2008) What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr Bull 34:354–366
16. Navari S, Dazzan P (2009) Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings. Psychol Med 39:1763–1777
17. Smieskowa R, Fusar-Poli P, Allen P et al (2009) The effects of antipsychotics on the brain: what have we learnt from structural imaging of schizophrenia? – a systematic review. Curr Pharm Des 15:2535–2549
18. Moncrieff J, Leo J (2010) A systematic review of the effects of antipsychotic drugs on brain volume. Psychol Med 40:1409–1422
19. Bora E, Fornito A, Radua J et al (2011) Neuroanatomical abnormalities in schizophrenia: a multimodal voxelwise meta-analysis and meta-regression analysis. Schizophr Res 127:46–57
20. Chan RCK et al (2011) Brain anatomical abnormalities in high-risk individuals, first-episode, and chronic schizophrenia: an activation likelihood estimation meta-analysis of illness progression. Schizophr Bull 37:177–188
21. Olabi B, Ellison-Wright I, McIntosh AM et al (2011) Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol Psychiatry 70:88–96
22. Haijma SV, Van Haren N, Cahn W et al (2013) Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophr Bull 39:1129–1138
23. Shepherd AM, Laurens KR, Matheson SL et al (2012) Systematic meta-review and quality assessment of the structural brain alterations in schizophrenia. Neurosci Biobehav Rev 36:1342–1356
24. Scherk H, Falkai P (2006) Effects of antipsychotics on brain structure. Curr Opin Psychiatry 19:145–150
25. Gur RE, Cowell P, Turetsky BI et al (1998) A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry 55:145–152
26. Lieberman JA, Chakos M, Wu H et al (2001) Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry 49:487–499
27. Cahn W, Hulshoff Pol HE, Lems EB et al (2002) Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry 59:1002–1101
28. Lieberman JA, Tollefson GD, Charles C et al (2005) Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 62:361–370
29. Thompson PM, Bartzokis G, Hayashi KM et al (2009) Time-lapse mapping of cortical changes in schizophrenia with different treatments. Cereb Cortex 19:1107–1123
30. Haren NE van, Hulshoff Pol HE, Schnack HG et al (2007) Focal gray matter changes in schizophrenia across the course of the illness: a 5-year follow-up study. Neuropsychopharmacology 32:2057–2066
31. Haren NE van, Hulshoff Pol EH, Schnack GH et al (2008) Progressive brain volume loss in schizophrenia over the course of the illness: evidence of maturational abnormalities in early adulthood. Biol Psychiatry 63:106–113
32. Haren NE van, Schnack HG, Cahn W et al (2011) Changes in cortical thickness during the course of illness in schizophrenia. Arch Gen Psychiatry 68:871–880
33. Théberge J, Williamson KE, Aoyama N et al (2007) Longitudinal grey-matter and glutamatergic losses in first-episode schizophrenia. Br J Psychiatry 191:325–334
34. Aoyama N, Théberge J, Drost DJ et al (2011) Grey matter and social functioning correlates of glutamatergic metabolite loss in schizophrenia. Br J Psychiatry 198:448–456
35. Nakamura M, Salisbury DF, Hirayasu Y et al (2007) Neocortical gray matter volume in first-episode schizophrenia and first-episode affective psychosis: a cross-sectional and longitudinal MRI study. Biol Psychiatry 62:773–783
36. Ho BC, Andreasen NC, Nopoulos P et al (2003) Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Arch Gen Psychiatry 60:585–594
37. Ho B-C, Andreasen NC, Dawson JD, Wassink TH (2007) Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. Am J Psychiatry 164:1890–1899
38. Ho B-C, Andreasen NC, Ziebell S et al (2011) Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry 68:128–137
39. Andreasen NC, Liu D, Ziebell S et al (2013) Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: a prospective longitudinal MRI study. Am J Psychiatry 170:609–615
40. Schlagenhauf F, Dinges M, Beck A et al (2010) Switching schizophrenia patients from typical neuroleptics to aripiprazole: effects on working memory dependent functional activation. Schizophr Res 118:189–200
41. Cyranoski D (2011) Antipsychotic drugs could shrink patients‘ brains. Experts say findings should not dramatically change current prescription practices. Nature. doi:10.1038/news.2011.75 News (Published online 7 February 2011)
42. Andreasen NC, Nopoulos P, Magnotta V et al (2011) Progressive brain change in schizophrenia: a prospective longitudinal study of first-episode schizophrenia. Biol Psychiatry 70:672–679
43. Radua J, Borgwardt S, Crescini A et al (2012) Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication. Neurosci Biobehav Rev 36:2325–2333
44. Wang Q, Cheung C, Deng W et al (2013) White-matter microstructure in previously drug-naïve patients. Psychol Med 43:2301–2309
45. Leung M, Cheung C, Yu K et al (2011) Gray matter in first-episode schizophrenia before and after antipsychotic drug treatment. Anatomical likelihood estimation meta-analyses with sample size weighting. Schizophr Bull 37:199–211
46. Deng MY, McAlonan GM, Cheung C et al (2009) A naturalistic study of grey matter volume increase after early treatment in anti-psychotic naïve, newly diagnosed schizophrenia. Psychopharmacology (Berl) 206:437–446
47. Garver DL, Holcomb JA, Christensen JD (2005) Cerebral cortical gray expansion associated with two second-generation antipsychotics. Biol Psychiatry 58:62–66
48. Girgis RR, Diwadkar VA, Nutche JJ et al (2006) Risperidone in first-episode psychosis: a longitudinal, exploratory voxel-based morphometric study. Schizophr Res 82:89–94
49. Farrow TF, Whitford TJ, Williams LM et al (2005) Diagnosis-related regional gray matter loss over two years in first episode schizophrenia and bipolar disorder. Biol Psychiatry 58:713–723
50. Mané A, Falcon C, Mateos JJ et al (2009) Progressive gray matter changes in first episode schizophrenia: a 4-year longitudinal magnetic resonance study using VBM. Schizophr Res 114:136–143
51. Kasparek T, Prikryl R, Schwarz D et al (2009) Gray matter morphology and the level of functioning in one-year follow-up of first-episode schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry 33:1438–1446
52. Vita A, De Peri L, Deste G, Sacchetti E (2012) Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies. Transl Psychiatry 2:e190. doi:10.1038/tp.2012.116
53. Sheffield JM, Williams LE, Woodward ND, Heckers S (2013) Reduced gray matter volume in psychotic disorder patients with a history of childhood sexual abuse. Schizophr Res 143:185–191
54. Borgwardt S, McGuire P, Fusar-Poli P (2011) Gray matters! – mapping the transition to psychosis. Schizophr Res 133:63–67
55. Meisenzahl EM, Koutsouleris N, Gaser C et al (2008) Structural brain alterations in subjects at high-risk of psychosis: a voxel-based morphometric study. Schizophr Res 102:150–162
56. Pantelis C, Velakoulis D, McGorry PD et al (2003) Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 361:281–288
57. Boos HBM, Aleman A, Cahn W et al (2007) Brain volumes in relatives of patients with schizophrenia: a meta-analysis. Arch Gen Psychiatry 64:297–304
58. Goldman AL, Pezawas L, Mattay VS et al (2008) Heritability of brain morphology related to schizophrenia: a large-scale automated magnetic resonance imaging segmentation study. Biol Psychiatry 63:475–483
59. Borgwardt SJ, Picchioni MM, Ettinger U et al (2010) Regional gray matter volume in monozygotic twins concordant and discordant for schizophrenia. Biol Psychiatry 67:956–965
60. Baare WF, Oel CJ van, Hulshoff Pol HE et al (2001) Volumes of brain structures in twins discordant for schizophrenia. Arch Gen Psychiatry 58:33–40
61. Hietala J, Cannon TD, Erp TG van et al (2003) Regional brain morphology and duration of illness in never- medicated first-episode patients with schizophrenia. Schizophr Res 64:79–81
62. Ho BC, Alicata D, Ward J et al (2003) Untreated initial psychosis: relation to cognitive deficits and brain morphology in first-episode schizophrenia. Am J Psychiatry 160:142–148
63. Takahashi T, Suzuki M, Tanino R et al (2007) Volume reduction of the left planum temporale gray matter associated with long duration of untreated psychosis in schizophrenia: a preliminary report. Psychiatry Res 154:209–219
64. Lappin JM, Morgan K, Morgan C et al (2006) Gray matter abnormalities associated with duration of untreated psychosis. Schizophr Res 83:145–153
65. Malla AK, Bodnar M, Joober R, Lepage M (2011) Duration of untreated psychosis is associated with orbital-frontal grey matter volume reductions in first episode psychosis. Schizophr Res 125:13–20
66. Perkins DO, Gu H, Boteva K, Lieberman JA (2005) Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry 162:1785–1804
67. Rund BR, Melle I, Friis S et al (2007) The course of neurocognitive functioning in first-episode psychosis and its relation to premorbid adjustment, duration of untreated psychosis, and relapse. Schizophr Res 91:132–140
68. Goldberg TE, Burdick KE, McCormack J et al (2009) Lack of an inverse relationship between duration of untreated psychosis and cognitive function in first episode schizophrenia. Schizophr Res 107:262–266
69. Halim ND, Weickert CS, McClintock BW et al (2004) Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus. Neuropsychopharmacology 29:1063–1069
70. McClure RK, Phillips I, Jazayerli R et al (2006) Regional change in brain morphometry in schizophrenia associated with antipsychotic treatment. Psychiatry Res 148:121–132
71. Garver DL, Nair TR, Christensen JD et al (2000) Brain and ventricle instability during psychotic episodes of the schizophrenias. Schizophr Res 44:11–23
72. Boonstra G, Haren NE van, Schnack HG et al (2011) Brain volume changes after withdrawal of atypical antipsychotics in patients with first-episode schizophrenia. J Clin Psychopharmacol 31:146–153
73. Dazzan P, Morgan KD, Orr K et al (2005) Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the AESOP study. Neuropsychopharmacology 30:765–774
74. Joober R, Schmitz N, Malla A et al (2006) Is Olanzapine a brain-sparing medication? Arch Gen Psychiatry 63:1292
75. Tost H, Braus DF, Hakimi S et al (2010) Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. Nat Neurosci 13:920–922
76. Crespo-Facorro B, Roiz-Santiáñez R, Pérez-Iglesias R et al (2008) Effect of antipsychotic drugs on brain morphometry. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine. Prog Neuropsychopharmacol Biol Psychiatry 32:1936–1943
77. Roiz-Santiáñez R, Tordesillas-Gutiérrez D, Ortíz-García de la Foz V et al (2012) Effect of antipsychotic drugs on cortical thickness. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine. Schizophr Res 141:22–28
78. Schlagenhauf F, Wüstenberg T, Schmack K et al (2008) Switching schizophrenia patients from typical neuroleptics to olanzapine: effects on BOLD response during attention and working memory. Eur Neuropsychopharmacol 18:589–599
79. Hartz SM, Ho B-C, Andreasen NC et al (2010) G72 influences longitudinal change in frontal lobe volume in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 153B:640–647
80. Kobiella A, Reimold M, Ulsho DE et al (2011) How the serotonin transporter 5-HTTLPR polymorphism influences amygdala function: the roles of in vivo serotonin transporter expression and amygdala structure. Transl Psychiatry 1:e37. doi:10.1038/tp.2011.29
81. Van Haren NE, Koolschijn PC, Cahn W et al (2010) Cigarette smoking and progressive brain volume loss in schizophrenia. Eur Neuropsychopharmacol 20:454–458
82. Tregellas JR, Shatti S, Tanabe JL et al (2007) Gray matter volume differences and the effects of smoking on gray matter in schizophrenia. Schizophr Res 97:242–249
83. Mann K, Hermann D, Heinz A (2000) One hundred years of alcoholism: the twentieth century. Alcohol Alcohol 35:10–15
84. Mathalon DH, Pfefferbaum A, Lim KO et al (2003) Compounded brain volume deficits in schizophrenia-alcoholism comorbidity. Arch Gen Psychiatry 60:245–252
85. Rais M, Cahn W, Van Haren N et al (2008) Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients. Am J Psychiatry 165:490–496
86. Walter M, Denier N, Vogel M, Lang UE (2012) Effects of psychoactive substances in schizophrenia. Findings of structural and functional neuroimaging. Curr Top Med Chem 12:2426–2433
87. Ho B-C, Wassink TH, Ziebell S, Andreasen NC (2011) Cannabinoid receptor 1 gene polymorphisms and marijuana misuse interactions on white matter and cognitive deficits in schizophrenia. Schizophr Res 128:66–75
88. Dean CE (2006) Antipsychotic-associated neuronal changes in the brain: toxic, therapeutic, or irrelevant to the long-term outcome of schizophrenia? Prog Neuropsychopharmacol Biol Psychiatry 30:174–189
89. Konopaske GT, Dorph-Petersen K-A, Sweet RA et al (2008) Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry 63:759–765
90. Dorph-Petersen KA, Pierri JN, Perel JM et al (2005) 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 30:1649–166
91. Ukai W, Ozawa H, Tateno M et al (2004) Neurotoxic potential of haloperidol in comparison with risperidone: implication of Akt-mediated signal changes by haloperidol. J Neural Transm 111:667–681
92. Jarskog LF, Gilmore JH, Glantz LA et al (2007) Caspase-3 activation in rat frontal cortex following treatment with typical and atypical antipsychotics. Neuropsychopharmacology 32:95–102
93. Benes FM, Paskevich PA, Davidson J, Domesick YB (1985) Synaptic rearrangements in medial prefrontal cortex of haloperidol-treated rats. Brain Res 348:15–20
94. Selemon LD, Rajkowski G, Goldman-Rakic PS (1995) Abnormal high neuronal density in the schizophrenic cortex: a morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 52:805–818
95. Konopaske GT, Dorph-Petersen KA, Pierri JN et al (2006) Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology 32:1216–1223
96. Vernon AC, Natesan S, Modo M, Kapur S (2011) Effect of chronic antipsychotic treatment on brain structure: a serial magnetic resonance imaging study with ex vivo and postmortem confirmation. Biol Psychiatry 69:936–944
97. Vernon AC, Natesan S, Crum WR et al (2012) Contrasting effects of haloperidol and lithium on rodent brain structure: a magnetic resonance imaging study with postmortem confirmation. Biol Psychiatry 71:855–863
98. Heinz A, Schlagenhauf F (2010) Dopaminergic dysfunction in schizophrenia: salience attribution revisited. Schizophr Bull 36:472–485
99. Gonzalez R, Zamora J, Gomez-Camarero J et al (2008) Meta-analysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med 149:109–122
100. Haren NE van, Cahn W, Hulshoff Pol HE et al (2003) Brain volumes as predictor of outcome in recent-onset schizophrenia: a multi-center MRI study. Schizophr Res 64:41–52
101. Mitelman SA, Brickman AM, Shihabuddin L et al (2007) A comprehensive assessment of gray and white matter volumes and their relationship to outcome and severity in schizophrenia. Neuroimage 37:449–462
102. Andreasen NC, Moser DJ, O’Leary DS, Ho BC (2005) Longitudinal changes in neurocognition during the first decade of schizophrenia illness. International congress of schizophrenia research, S 348
103. Koutsouleris N, Davatzikos C, Borgwardt S et al (2013) Accelerated brain aging in schizophrenia and beyond: a neuroanatomical marker of psychiatric disorders. Schizophr Bull (Epub ahead of print)
104. Heinz A, Knable MB, Coppola R et al (1998) Psychomotor slowing, negative symptoms and dopamine receptor availability – an IBZM SPECT study in neuroleptic-treated and drug-free schizophrenic patients. Schizophr Res 31:19–26
105. Takahashi T, Wood SJ, Yung AR et al (2010) Superior temporal gyrus volume in antipsychotic-naive people at risk of psychosis. Br J Psychiatry 196(3):206–211
106. Job DE, Whalley HC, Johnstone EC, Lawrie SM (2005) Grey matter changes over time in high risk subjects developing schizophrenia. Neuroimage 25:1023–1030
107. Rais M, Cahn W, Schnack HG et al (2012) Brain volume reductions in medication-naive patients with schizophrenia in relation to intelligence quotient. Psychol Med 42:1847–1856
108. Chua SE, Cheung C, Cheung V et al (2007) Cerebral grey, white matter and csf in never-medicated, first-episode schizophrenia. Schizophr Res 89:12–21
109. Remington GJ, Prendergast P, Bezchlibnyk-Butler KZ (1997) Neuroleptic dosing in chronic schizophrenia: a 10-year follow-up. Can J Psychiatry 42:53–57
110. Barbui C, Nosè M, Mazzi MA et al (2006) Persistence with polypharmacy and excessive dosing in patients with schizophrenia treated in four European countries. Int Clin Psychopharmacol 21:355–362
111. Pandurangi AK, Dalkilic A (2008) Polypharmacy with second-generation antipsychotics: a review of evidence. J Psychiatr Pract 14:345–367
112. Samaha AN, Reckless GE, Seeman P et al (2008) Less is more: antipsychotic drug effects are greater with transient rather than continuous delivery. Biol Psychiatry 64:145–152
113. Howes OD (2012) The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 69:776–786
114. Elie D, Poirier M, Chianetta J et al (2010) Cognitive effects of antipsychotic dosage and polypharmacy: a study with the BACS in patients with schizophrenia and schizoaffective disorder. J Psychopharmacol 24:1037–1044
115. Vinogradov S, Fisher M, Warm H et al (2009) The cognitive cost of anticholinergic burden: decreased response to cognitive training in schizophrenia. Am J Psychiatry 166:1055–1062
116. Wojtalki JA, Eack SM, Pollock BG, Keshavan MS (2012) Prefrontal gray matter morphology mediates the association between serum anticholinergicity and cognitive functioning in early course schizophrenia. Psychiatry Res 204:61–67
117. Gilbert PL, Harris MJ, McAdams LA, Jeste DV (1995) Neuroleptic withdrawal in schizophrenic patients. A review of the literature. Arch Gen Psychiatry 52:173–188
118. Viguera AC, Baldessarini RJ, Hegarty JD et al (1997) Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment. Arch Gen Psychiatry 54:49–55
119. Baldessarini RJ, Viguera AC (1995) Neuroleptic withdrawal in schizophrenic patients. Arch Gen Psychiatry 52:189–192
120. Moncrieff J (2006) Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr Scand 114:3–13
121. Leucht S, Tardy M, Komossa K et al (2012) Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 379:2063–2071
122. Wunderink L, Nienhuis FJ, Sytema S et al (2007) Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry 68:654–661
123. Pharoah F, Mari J, Rathbone J, Wong W (2006) Family intervention for schizophrenia. Cochrane Database Syst Rev 4:CD000088. doi:10.1002/14651858.CD000088.pub2
124. Takeuchi H, Suzuki T, Uchida H et al (2012) Antipsychotic treatment for schizophrenia in the maintenance phase: a systematic review of the guidelines and algorithms. Schizophr Res 134:219–225
125. Lepping P, Sambhi RS, Whittington R et al (2011) Clinical relevance of findings in trials of antipsychotics: systematic review. Br J Psychiatry 198:341–345
126. Leucht S, Arbter D, Engel RR et al (2009) How effective are second-generation antipsychotic drugs? Mol Psychiatry 14:429–447
127. Newcomer JW (2005) Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 19(Suppl 1):1–93
128. Rummel-Kluge C, Komossa K, Schwarz S et al (2010) Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res 123:225–233
129. Foley DL, Morley KI (2011) Systematic review of early cardiometabolic outcomes of the first treated episode of psychosis. Arch Gen Psychiatry 68:609–616
130. Jin H, Shih PA, Golshan S et al (2013) Comparison of longer-term safety and effectiveness of 4 atypical antipsychotics in patients over age 40: a trial using equipoise-stratified randomization. J Clin Psychiatry 74:10–18
131. Reist C, Mintz J, Albers LJ et al (2007) Second- generation antipsychotic exposure and metabolic-related disorders in patients with schizophrenia: an observational pharmacoepidemiology study from 1988 to 2002. J Clin Psychopharmacol 27:46–51
132. Citrome LL, Holt RI, Zachry WM et al (2007) Risk of treatment-emergent diabetes mellitus in patients receiving antipsychotics. Ann Pharmacother 41:1593–603
133. Correll CU, Frederickson AM, Kane JM, Manu P (2006) Metabolic syndrome and the risk of coronary heart disease in 367 patients treated with second-generation antipsychotic drugs. J Clin Psychiatry 67:575–583
134. Maayan L, Correll CU (2011) Weight gain and metabolic risks associated with antipsychotic medications in children and adolescents. J Child Adolesc Psychopharmacol 21:517–535
135. Cohen D, Bonnot O, Bodeau N et al (2012) Adverse effects of second-generation antipsychotics in children and adolescents: a bayesian meta-analysis. J Clin Psychopharmacol 32:309–316
136. Bola JR, Lehtinen K, Cullberg J, Ciompi L (2009) Psychosocial treatment, antipsychotic postponement, and low-dose medication strategies in first-episode psychosis: a review of the literature. Psychosis 1:4–18
137. Carpenter WT, Buchanan RW, Kirkpatrick B, Breier AF (1999) Diazepam treatment of early signs of exacerbation in schizophrenia. Am J Psychiatry 156:299–303
138. Lerner V, Fotyanov M, Liberman M et al (1995) Maintenance medication for schizophrenia and schizoaffective patients. Schizophr Bull 21:693–701
139. Gaebel W, Riesbeck M, Wölwer W et al (2011) Relapse prevention in first-episode schizophrenia – maintenance vs intermittent drug treatment with prodrome-based early intervention: results of a randomized controlled trial within the German Research Network on Schizophrenia. J Clin Psychiatry 72:205–218
140. Marneros A, Pillmann F (2004) Acute and transient psychosis. Cambridge Univ Press
141. Harrow M, Jobe TH (2013) Does long-term treatment of schizophrenia with antipsychotic medications facilitate recovery? Schizophr Bull 39:962–965
142. Marshall M, Rathbone J (2011) Early intervention for psychosis. Cochrane Database Syst Rev 6:CD004718
143. Onwumere J, Bebbington P, Kuipers E (2011) Family interventions in early psychosis: specificity and effectiveness. Epidemiol Psychiatr Sci 20:113–119
144. Bird V, Premkumar P, Kendall T et al (2010) Early intervention services, cognitive- behavioural therapy and family intervention in early psychosis: systematic review. Br J Psychiatry 197:350–356
145. Yung AR, Nelson B (2011) Young people at ultra high risk for psychosis: a research update. Early Interv Psychiatry 5(Suppl 1):52–57
146. Linszen D, Dingemans P, Lenior M (2001) Early intervention and a five year follow up in young adults with a short duration of untreated psychosis: ethical implications. Schizophr Res 51:55–61
147. Amminger GP, Schäfer MR, Papageorgiou K et al (2010) Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry 67:146–154
148. Remington G, Seeman P, Feingold A et al (2011) „Extended“ antipsychotic dosing in the maintenance treatment of schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatry 72:1042–1048
149. Remington G, Seeman P, Shammi C et al (2005) „Extended“ antipsychotic dosing: rationale and pilot data. J Clin Psychopharmacol 25:611–613
150. Remington G, Kapur S (2010) Antipsychotic dosing: how much but also how often? Schizophr Bull 36:900–903
151. Ginovart N, Wilson AA, Hussey D et al (2009) D2-receptor upregulation is dependent upon temporal course of D2-occupancy: a longitudinal (11C)-raclopride PET study in cats. Neuropsychopharmacology 34:662–671
152. Majic T, Pluta J-P, Mell T et al (2010) Pharmakotherapie von neuropsychiatrischen Symptomen bei Demenz: Querschnitterhebung in 18 Berliner Seniorenwohnheimen. (The pharmacotherapy of neuropsychiatric manifestations of dementia: a cross-sectional study in 18 homes for the elderly in Berlin). Dtsch Arztebl Int 107:320–327