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Home , Alois Alzheimer, Arnold Pick, Dementia, Dementia praecox, Emil Kraepelin, Franz Nissl

Molecular (2015) 20, 671–676 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp

REVIEW Kraepelin revisited: from degeneration to failed regeneration

P Falkai1, MJ Rossner1,2, TG Schulze3, A Hasan1, MM Brzózka1, B Malchow1, WG Honer4 and A Schmitt1,5

One hundred years after its conceptual definition as ‘ Praecox’ by , schizophrenia is still a serious psychiatric illness that affects young adults and leads to in at least half of patients. The key treatment issue is partial or non-response, especially of negative symptoms. The illness is also associated with different degrees of cognitive dysfunction, particularly in verbal and working ; the resulting functional impairment may lead to unemployment and an inability to maintain stable relationships. Patients’ cognitive dysfunction led Kraepelin to the assumption that schizophrenia is a form of juvenile dementia caused by a degenerative process of the . Postmortem studies and a plethora of imaging studies do not support the notion of a degenerative process, but such a process is supported by the recently published, largest genome-wide association study on schizophrenia. More than a 100 hits were described, converging on pathways that have a significant role in metabolism in immune modulation, calcium signalling and synaptic plasticity. This review suggests that research should focus on animal models based on risk genes like transcription factor 4 and study the effects of exposure to environmental stressors relevant for schizophrenia. The use of relevant end points like pre-pulse inhibition or cognitive dysfunction will allow us to gain an understanding of the molecular pathways in schizophrenia and consequently result in improved treatment options, especially for the disabling aspects of this illness.

Molecular Psychiatry (2015) 20, 671–676; doi:10.1038/mp.2015.35; published online 31 March 2015

INTRODUCTION In the 6th edition of his textbook ‘Psychiatrie’,1 published in More than 100 years after its conceptual definition as ‘Dementia 1899, Kraepelin (Figure 1) grouped most of the insanities into two Praecox’ by Emil Kraepelin, schizophrenia is still a serious large categories: and manic-depressive illness psychiatric illness. The introduction of in (the so-called ). Dementia Praecox was 1953 helped improve outcome significantly; however, since then characterised by the following features: there have been only limited developments in long-term out- come. Paralleling human studies and animal experiments may ● It was primarily a disorder of intellectual functioning, whereas lead to a deeper understanding of the pathophysiology of manic-depressive illness was primarily a disorder of schizophrenia and subsequently to causal treatment options for or mood. patients. This review, written by a group of researchers from the ● It had a deteriorating course and a poor prognosis, whereas Department of Psychiatry at the University Hospital in , manic-depressive illness had a course of acute exacerbations once chaired by E Kraepelin himself (1903–1922), puts its focus on followed by complete remissions. , and thus offers a conceptual framework of schizo- phrenia from ethological factors through brain mechanisms and functional consequences in patients to related animal models. : DEMENTIA PRAECOX AS A DEGENERATIVE DISORDER E KRAEPLIN: ‘DEMENTIA PRAECOX’ AND COGNITIVE E Kraepelin categorised patients with a major psychiatric illness on DYSFUNCTION the basis of their long-term course. At admission, a score sheet The term Dementia Praecox, which refers to ‘premature dementia’ (‘Zählkarte’) was compiled for each patient that contained all the or ‘precocious madness’, was first used in this Latin form in 1891 necessary information to allow Kraepelin and his team to classify by (1851–1924), a professor of psychiatry at the patients at the end of the hospital stay and in the years of follow- German branch of in . It was popularised up. In addition to his work on classifying mental illness to identify by E Kraepelin in his textbooks published in 1893, 1896 and 1899, aetiological subgroups, Kraepelin encouraged talented young in which he referred to a chronic, deteriorating psychotic illness people to come to the department in Munich and supported their characterised by rapid cognitive disintegration, usually beginning research on mental disorders. In addition to (1860– in the late teens or early adulthood. 1919), who invented the cell staining method now bearing his

1Department of Psychiatry and ; Ludwig-Maximilians-University, Munich, ; 2Max-Planck-Institute of Experimental , Goettingen, Germany; 3Institute for Psychiatric Phenomics and Genomics; Ludwig-Maximilians-University, Munich, Germany; 4Department of Psychiatry; University of British Columbia, Canada and 5Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo, Sao Paulo, Brazil. Correspondence: Professor P Falkai, Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU), Nussbaumstrasse 7, München 80336, Germany. E-mail: [email protected] Received 26 September 2014; revised 11 February 2015; accepted 24 February 2015; published online 31 March 2015 Kraepelin revisited P Falkai et al 672 affectivity and ambivalence) and that the biological was much more prevalent in the population than previously assumed because of its ‘simple’ and especially ‘latent’ forms.

SCHIZOPHRENIA TODAY: STILL A WITH AN UNFAVOURABLE OUTCOME? More than a 100 years after Kraepelin popularised the term Dementia Praecox, schizophrenia still has an unfavourable prognosis. The worldwide prevalence is 1% and the first onset is usually in young adults aged between 20 and 35.5,6 Only 20% of patients are employed in the primary labour market and only 30% are able to maintain a stable relationship.7 The introduction of by Delay and Deniker in 1953 significantly helped to improve the severity of acute symptoms and prevent relapses in many patients. Nevertheless, 60 years later 450% of patients still do not show remission but have residual of significant functional relevance.8,9 After reconstruct- ing the prodromal stages of first-episode schizophrenia and performing a systematic follow-up, Häfner and an der Heiden were able to show that patients who develop the illness between the ages of 36 and 59 demonstrate a significant loss of their ability to maintain unsheltered work years before their first admission (‘social prognosis’). Treating these patients improved the social prognosis to some extent; however, in the end only ~ 30% were able to maintain unsheltered work, compared with 80% at the beginning of the illness.7 This study showed clearly that negative symptoms, consisting of affective and cognitive domains, contribute substantially to this unfavourable long-term outcome. The stability of the cognitive deficits, particularly episodic and verbal memory, was convincingly shown in 5- and 10-year follow- up studies of first-episode schizophrenia.10

UNDERSTANDING COGNITIVE DYSFUNCTION IN Figure 1. Emil Kraepelin, 1921 at the Department of Psychiatry, SCHIZOPHRENIA: HUMAN STUDIES Munich. As outlined above, cognitive dysfunction is one key to the unfavourable outcome in schizophrenia and may be independent name, it was A Alzheimer who systematically investigated the of the long-term course of both positive and negative fi postmortem brains of patients with Dementia Praecox. In his rst symptoms.11,12,13 Recent studies suggest that cognitive distur- publication he described the thinning of the neocortical layers, 2 bance in schizophrenia contributes to relapses and also has a role which he interpreted as a sign of a destructive process. These and in the likelihood of remission. Understanding the underlying other investigations brought E Kraepelin in 1913 to the following neurobiology of cognitive dysfunction is critical to improve ‘ conclusions: These considerations force us to draw the direct outcome, and parallel investigations of patients and animal models conclusion that there must be a manifest destruction of the cortex. form the best strategy to improve such understanding (Figure 2). In those cases that have been investigated more closely by reliable Family and adoption studies show that the risk to develop means, regular alterations have actually been demonstrated for schizophrenia has a large genetic contribution of up to 80%. In which there is no other explanation. [....]. We therefore reach the recent years, large-scale collaborative genome-wide association conclusion that in Dementia Praecox there is severe damage to or studies have identified well over 100 genes that may contribute to destruction of the nervous cortical elements, which may be the pathophysiology of schizophrenia.14 Interestingly, these genes compensated for in individual cases, but which mostly results in a converge on pathways that have a significant role in immune ’ 3 peculiar, persistent impairment of the psyche . modulation (major histocompatibility complex), calcium signalling (CACNA1C and CACNB) and regulating neuronal plasticity and adult EUGEN BLEULER: THE AND COGNITIVE neurogenesis (microRNA MIR137 (which codes for miR-137)and IMPAIRMENT transcription factor 4, TCF4), both of which are components of the regenerative capacities of the brain. The major histocompatibility fi ‘ In 1908, E Bleuler rede ned Dementia Praecox as the Group of complex region has a significant role in schizophrenia and is ’ Schizophrenias , that is, a group of disorders characterised by a associated with delayed episodic memory,15 but this locus captures dysfunction of different psychic domains in phases of illness and 16 4 a large genomic region and displays substantial diversity. The remission. Like E Kraepelin, he argued that Dementia Praecox (‘the immune-related major histocompatibility complex class I mole- schizophrenias’) was fundamentally a physical disease process cules may have a role in neurodevelopment and are known to characterised by exacerbations and remissions. Nobody was ever regulate regenerative processes such as synaptic plasticity and completely ‘cured’ of schizophrenia and there was always some synaptic response to neuronal activity up to adulthood.17,18 sort of lasting cognitive weakness or defect that was manifest in Structural and functional alterations in specific brain networks behaviour. Unlike Kraepelin, he believed that the overall prognosis of schizophrenia patients may be a hallmark of the underlying was not uniformly grim, that ‘dementia’ was a secondary symptom pathophysiology. To address this, we reviewed magnetic reso- not directly caused by the underlying biological process (three nance imaging (MRI) findings in schizophrenia and thereby other ‘fundamental symptoms’ were deficits in associations, focussed on high-quality meta-analyses based on a highly

Molecular Psychiatry (2015), 671 – 676 © 2015 Macmillan Publishers Limited Kraepelin revisited P Falkai et al 673 standardized literature extraction and evaluation. We focused on in regenerative capacities, an additional neurodegenerative or results from structural and functional MRI studies and did not even neurotoxic process of untreated cannot be consider the large body of evidence from positron emission excluded.39,40 In contrast, results of volume reductions in tomography and spectroscopy studies for reasons of space. individuals at ultra-high risk and first-episode schizophrenia A recent meta-analysis of 317 studies from 1998–2012 patients25,26,29 and longitudinal studies showing no progression comprising 9000 schizophrenia patients revealed general grey of cognitive deficits in the course of schizophrenia over a period of matter and volume reductions in schizophrenia up to 10 years10 support the hypothesis of a primary neurode- patients.19 Another meta-analysis compared structural abnormal- velopmental deficit, which may lay the foundation for disturbed ities found in 42 schizophrenia studies (comprising 2058 patients regenerative capacities during adulthood. with schizophrenia and 2131 comparison participants) with those found in 14 bipolar studies (comprising 366 patients with and 497 comparison participants) and demonstrated UNDERSTANDING COGNITIVE DYSFUNCTION IN circumscribed volume reduction in structures in SCHIZOPHRENIA: ANIMAL EXPERIMENTS schizophrenia but not in bipolar disorder.20 A meta-analysis of 45 Changes in synaptic plasticity in the hippocampus of patients with studies found an overlap of brain abnormalities in schizophrenia schizophrenia could be followed by a reduction in long-term and bipolar disorder, although grey matter volume deficits were potentiation (LTP) and also long-term or an impaired more prominent in schizophrenia.21 Finally, a meta-analysis of 15 regulation of both in terms of meta-plasticity, with implications for voxel-based diffusion tensor imaging studies showed reduced the functioning of the episodic memory system (see Figure 2, left- fractional anisotropy in left frontal and left temporal deep white hand side). However, all of these assumptions are indirect and not matter in schizophrenia patients. These findings point towards as tightly connected as they could be if derived from an animal disconnectivity in two white matter tracts, one interconnecting model. Providing a close link between postmortem and in vivo the , thalamus and cingulate gyrus and the other findings in schizophrenia patients and animal models of schizo- interconnecting the frontal lobe, insula, hippocampus and phrenia, including differences in LTP and behaviour, is a temporal lobe.22 Despite the well-established problems of challenging task. The question that immediately arises is whether integrating methodologically different studies into a meta- a suitable animal model is able to mimic at least certain defined analysis, these publications strongly indicate that the temporal aspects of the clinical picture (for example, cognitive dysfunction) lobe structures, namely the hippocampus and amygdala, are or neurobiological features (for example, deficits in pre-pulse among the brain regions most involved in schizophrenia. A recent inhibition) or both. study was able to demonstrate in truly first-episode schizophrenia As outlined above, large genome-wide association studies have with limited life-time exposure to antipsychotics that left identified a number of risk genes, which might likely contribute to a hippocampal volume reduction was specifically correlated with genetic vulnerability for schizophrenia.14 One of these is the TCF4 immediate recall of verbal memory performance, pointing gene, a homologue of which is widely expressed in the central towards episodic memory dysfunction.23 This finding comple- (CNS) of mice, including the cortex and hippo- ments data from the literature showing a similar correlation in campus, and which seems to be important in brain development. patients with temporal lobe . In addition to a hypoactiva- Like many other transcription factors, TCF4 has been shown to be tion of frontal regions, a meta-analysis of 11 resting-state involved in regulating neuronal maturation and thus to contribute functional MRI studies reported a hypoactivation of the left to the regenerative capacities of the brain. Its expression is hippocampus.24 Furthermore, several meta-analyses demon- sustained in the adult CNS and has a pivotal role in cognition.41,42 strated bilateral volume reduction of the hippocampus Of interest is that a haploinsufficiency of the TCF4 gene causes so- (left4right) in several phases of schizophrenia,25,26 a finding called Pitt–Hopkins . Patients with Pitt–Hopkins syndrome that is supported by results from postmortem studies.27,28 Even show features of a neurodevelopmental disorder, including individuals at ultra-high risk to develop schizophrenia present enlarged ventricles, severe mental retardation and breathing decreased volumes of the left hippocampus, but this finding was abnormalities, emphasising the crucial role of TCF4 in normal CNS not related to transition to psychosis.29 Recent stereological development.43 TCF4 messenger RNA is upregulated in schizo- investigations demonstrated that the volume decrease (4–6%) phrenia patients and in patient-derived human-induced pluripotent was not caused by neuronal cell loss accompanied by stem cell when compared with controls.44,45 Thus, human astrogliosis.30 Remarkably, this study found a selective reduction studies support the hypothesis that even a moderate alteration in in oligodendrocyte numbers in the polymorph layer of the TCF4 expression levels may lead to prominent CNS dysfunction.43 dentate gyrus (CA4 region) in schizophrenia, which could support These findings are substantiated by evidence from animal studies the notion of disturbed macroconnectivity in this disorder.30 addressing certain endophenotypes of psychiatric . Trans- Furthermore, the thinning of the dentate gyrus, accompanied by a genic mice moderately overexpressing Tcf4tg postnatally in brain reduced number of granule cells,31 would imply that hippocampal regions (cortex and hippocampus) involved in and changes seen in schizophrenia might partially be a consequence memory processes (Tcf4tg mice) display cognitive impairment in of disturbed neuroregenerative mechanisms in the human brain. fear-associated learning and attentional dysfunction.41,42 This Biological regeneration has been defined as the reconstitution of a malfunction may be related to a disturbed interaction between lost or injured part of an organism.32 Possible mechanisms of lost the hippocampus and prefrontal cortex. Moreover, linking to regenerative capacities in schizophrenia involve disturbed phenotypes described for a significant proportion of schizophrenia neurogenesis,33,34 impaired synaptic plasticity35 and dysfunction patients, Tcf4tg animals display deficits in sensorimotor gating, as of the dynamic interplay between neurons and oligodendrocytes, revealed by the pre-pulse inhibition test.41 leading to deficits in axonal function.36 Such a hypothesis is Taken together, data obtained from human and animal studies supported by a plethora of evidence demonstrating reduced provide growing evidence about the role of TCF4 not only in CNS synaptic proteins of the soluble NSF-attachment protein receptor development but foremost in higher order information proces- complex, hippocampal presynaptic proteins37 and dysregulation sing, including cognition and sensorimotor gating.43 Considering of structural synaptic elements in the temporal lobes in that not only genetic but also environmental factors contribute to schizophrenia.38 The converging lines of evidence suggest that the development of schizophrenia, it is noteworthy that the episodic memory dysfunction in schizophrenia might well be cognitive performance of Tcf4tg mice can be modulated by caused by the disturbance of synaptic and neuronal plasticity and different environmental conditions (Brzózka, Badowska, Rossner, disconnectivity. However, in addition to our concept of a failure unpublished data).

© 2015 Macmillan Publishers Limited Molecular Psychiatry (2015), 671 – 676 Kraepelin revisited P Falkai et al 674 Human model Animal model

Risk genes Epigenetic regulation basic domain CNVs (e.g. NRG1,TCF4) Genetic and epigenetic helix 1 Genetic factors: TCF4 factors loop helix 2

Place of birth Obstetric complicationsViral Migration Environmental factors Housing conditions Cannabis enriched environment social defeat single housing

Hippocampus volume Interaction Hi ↔ PfCx

Tcf4tg

Oligodendrocytes

Cellular level Synaptic plasticity pA

ms pA pA LTP

ms ms

Word replication rate in VLMT Spatial learning Water maze

enriched single social environment housing defeat I have forgotten… Episodic memory in SZ Figure 2. From genetic to environmental risk factors: parallels in humans and animal models. CNV, copy number variation; Hi, hippocampus; LTP, long-term potentiation; PfCx, prefrontal cortex; SZ, schizophrenia; TCF4, transcription factor 4; VLMT, verbal learning and memory test.

SCHIZOPHRENIA: A DISTURBANCE OF REGENERATION? GABAergic neurotransmission and to the brain-derived neurotrophic 58 As outlined above, there is an ongoing debate about whether factor genotype and were present in medicated and unmedicated 52 52 schizophrenia is or is not primarily a degenerative disorder with patients as well as in first-degree relatives. 59 irreversible structural and functional abnormalities that increase On the basis of findings such as these, Pajonk et al. performed over time. The presence of a degenerative process would support a MRI study of exercise in patients with multi-episode schizo- the concept of Dementia Praecox as described by E Kraepelin, phrenia. Schizophrenia patients and a control group of healthy involving cognitive dysfunction and lack of recovery as critical individuals performed indoor cycling three times a week for illness elements. One of the key questions therefore is whether or 30 min over 3 months; a second, non-exercise control group of not the structural and functional changes seen in patients with schizophrenia patients played table football at the same schizophrenia, for example, in the hippocampal formation, are frequency and for the same period of time. After indoor cycling, patients showed a hippocampal volume increase of ~ 10%, reversible. Data from animals and healthy humans demonstrate a accompanied by an increase of the n-acetylaspartate/creatinine volume increase of the hippocampus, especially in the dentate ratio in magnetic resonance spectroscopy and an improvement in gyrus, and improved memory as a consequence of wheel running 59 46,47,48 the short-term memory index. This is consistent with recent data and physical exercise. Postmortem investigations show that from high-field MRI showing increased hippocampal volumes in wheel running enhances neurogenesis and synaptogenesis in 49,50,51 wheel-running rats but no changes in the cortex. These studies mice. Furthermore, studies using different techniques of support the notion that structural and functional changes seen in noninvasive brain stimulation point towards reduced LTP- and 52 multi-episode patients may be reversible even after many years of long-term depression-like plasticity in schizophrenia patients. illness and are therefore rather a consequence of disturbed LTP plasticity in the model system of the primary motor cortex was regenerative capacities of the brain than a classical degenerative shown to be reduced in schizophrenia by using paired-associative process. stimulation (a kind of spike-dependent plasticity)53 after a cortical reorganisation (use-dependent plasticity)54 and anodal transcranial direct-current stimulation (a kind of non-focal and EPIGENETIC DYSREGULATION: THE UNDERLYING CAUSE? N-methyl-D-aspartate receptor-dependent plasticity).55 Vice versa, Environmental influences on the development of the illness and its long-term depression-like plasticity was reduced after 1 Hz repetitive treatment seem to have been understudied in recent years in both transcranial magnetic stimulation (focal plasticity)56 and cathodal patients and animal models.60 However, accumulating data transcranial direct-current stimulation (non-focal plasticity);57 these suggest that epigenetic regulation is disturbed in psychiatric deficits were linked to impairments in both glutamatergic and disorders.61 In schizophrenia, microRNAs may act through post-

Molecular Psychiatry (2015), 671 – 676 © 2015 Macmillan Publishers Limited Kraepelin revisited P Falkai et al 675 transcriptional and even transcriptional control mechanisms to 8 Marengo J. Classifying the courses of schizophrenia. Schizophr Bull 1994; 20: cause large effects on synaptic LTP and axonal guidance. For 519–536. example, several schizophrenia risk genes such as TCF4 and 9 Lambert M, Karow A, Leucht S, Schimmelmann BG, Naber D. Remission in schizo- 62 phrenia: validity, frequency, predictors, and patients' perspective 5 years later. CACNA1C are targets of miR-137. Furthermore, it is interesting 12 – that in schizophrenia an altered histone code increased histone Dialogies Clin Neurosci 2010; :393 407. 10 Hoff AL, Svetina C, Shields G, Stewart J, DeLisi LE. Ten year longitudinal study of deacetylase (HDAC)/DNA methyltransferase levels and an altered neuropsychological functioning subsequent to a first episode of schizophrenia. 63–66 DNA methylation can be found as well. Against this back- Schizophr Res 2005; 78:27–34. ground it is notable that potent HDAC inhibitors can reverse 11 Green MF. What are the functional consequences of neurocognitive deficits in Alzheimer-like changes in an animal model.67 Valproic acid is a schizophrenia? Am J Psychiatry 1996; 153: 321–330. potent HDAC inhibitors that modulates different subtypes of 12 Silverstein SM, Schenkel LS, Valone C, Nuernberger SW. Cognitive deficits and HDACs; however, extremely high doses would be needed to obtain psychiatric rehabilitation outcomes in schizophrenia. Psychiatr Q 1998; 69: – a significant change in epigenetic regulation in the target areas of 169 191. fi 13 Goff DC, Hill M, Barch D. The treatment of cognitive impairment in schizophrenia. the human brain. Speci c HDAC inhibitors are used in oncology, Pharmacol Biochem Behav 2010; 99:245–253. but they may have unfavourable side effects that are intolerable 14 Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological for patients with schizophrenia, and many issues regarding insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511: safety, drug interactions, brain permeability, target selectivity, dose 421–427. ranges and treatment duration are still unanswered.61 15 Walters JT, Rujescu D, Franke B, Giegling I, Vásquez AA, Hargreaves A. The role of the major histocompatibility complex region in cognition and brain structure: a schizophrenia GWAS follow-up. Am J Psychiatry 2013; 170:877–885. CONCLUSION 16 Corvin A, Morris DW. Genome-wide association studies: findings at the major 75 – 4 histocompatibility complex locus in psychosis. Biol Psychiatry 2014; :276 283. In summary, 100 years after its introduction the concept of 17 McAllister AK. Major histocompatibility complex I in brain development and Dementia Praecox is still alive. Sadly, 60 years after the schizophrenia. Biol Psychiatry 2014; 75: 262–268. introduction of antipsychotic agents recovery is still unsatisfactory 18 Pribiag H, Stellwagen D. Neuroimmune regulation of homeostatic synaptic plas- in 450% of patients. Negative symptoms and most importantly ticity. Neuropharmacology 2014; 78:13–22. cognitive dysfunction seem to be at the core of this unfavourable 19 Haijma SV, Van Haren N, Cahn W, Koolschijn PC, Hulshoff Pol HE, Kahn RS. Brain outcome and therefore need to be targeted in research to achieve volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophr Bull 39 – better treatment options. On the basis of animal data and imaging 2013; :1129 1138. 20 Ellison-Wright I, Bullmore E. Anatomy of bipolardisorder and schizophrenia: a data from patients it seems unlikely that schizophrenia is meta-analysis. Schizophr Res 2010; 117:1–12. characterised by a classical degenerative process. More likely is 21 De Peri L, Crescini A, Deste G, Fusar-Poli P, Sacchetti E, Vita A. Brain structural that—of the outlined risk gene pathways—environmental stres- abnormalities at the onset of schizophrenia and bipolar disorder: a meta-analysis sors lead to long-lasting dysfunction, reducing the ability of the of controlled magnetic resonance imaging studies. Curr Pharm Des 2012; 18: human brain to regenerate. Impaired oligodendrocyte function, 486–494. synaptogenesis and probably reduced neurogenesis, with result- 22 Ellison-Wright I, Bullmore E. Meta-analysis of diffusion tensor imaging studies in 108 – ing deficits in structural and functional micro- and macroconnec- schizophrenia. Schizophr Res 2009; :3 10. tivity, point to a disturbance of the regenerative capacity of the 23 Hasan A, Wobrock T, Falkai P, Schneider-Axmann T, Guse B, Backens M et al. Hippocampal integrity and in first-episode schizophrenia: a human brain in schizophrenia. This possibility must be considered multidimensional study. World J Biol Psychiatry 2014; 15: 188–199. if hopes to improve treatment options and outcome for patients 24 Kühn S, Gallinat J. Resting-state brain activity in schizophrenia and major with schizophrenia are to be fulfilled. depression: a quantitative meta-analysis. Schizophr Bull 2013; 39:358–365. 25 Adriano F, Caltagirone C, Spalletta G. Hippocampal volume reduction in first- episode and chornic schizophrenia: a review and meta-analysis. Neuroscientist CONFLICT OF INTEREST 2012; 18:180–200. The authors declare no conflict of interest. 26 Shepherd AM, Laurens KR, Matheson SL, Carr VJ, Green MJ. Systematic meta- review and quality assessment of the structural brain alterations in schizophrenia. Neurosci Biobehav Rev 2012; 36: 1342–1356. ACKNOWLEDGMENTS 27 Bogerts B, Falkai P, Haupts M, Greve B, Ernst S, Tapernon-Franz U et al. 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