Molecular Psychiatry (2015), 16

2015 Macmillan Publishers Limited All rights reserved 1359-4184/15

www.nature.com/mp

REVIEW
Kraepelin revisited: schizophrenia from degeneration to
failed regeneration
P Falkai1, MJ Rossner1,2, TG Schulze3, A Hasan1, MM Brzzka1, B Malchow1, WG Honer4 and A Schmitt1,5

One hundred years after its conceptual denition as Dementia Praecox by Emil Kraepelin, schizophrenia is still a serious psychiatric
illness that affects young adults and leads to disability 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 memory; 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 human brain. 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 signicant role in dopamine
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 advance online publication, 31 March 2015; doi:10.1038/mp.2015.35

INTRODUCTION In the 6th edition of his textbook Psychiatrie,1 published in

More than 100 years after its conceptual denition as Dementia
Praecox by Emil Kraepelin, schizophrenia is still a serious
psychiatric illness. The introduction of antipsychotic drugs in
1953 helped improve outcome signicantly; however, since then
there have been only limited developments in long-term out-
come. Paralleling human studies and animal experiments may
lead to a deeper understanding of the pathophysiology of
schizophrenia and subsequently to causal treatment options for
patients. This review, written by a group of researchers from the
Department of Psychiatry at the University Hospital in Munich,
once chaired by E Kraepelin himself (19031922), puts its focus on
cognition, and thus offers a conceptual framework of schizo-
phrenia from ethological factors through brain mechanisms and
functional consequences in patients to related animal models.
E KRAEPLIN: DEMENTIA PRAECOX AND COGNITIVE
DYSFUNCTION
The term Dementia Praecox, which refers to premature dementia
or precocious madness, was rst used in this Latin form in 1891
by Arnold Pick (18511924), a professor of psychiatry at the
German branch of Charles University in Prague. It was popularised
by E Kraepelin in his textbooks published in 1893, 1896 and 1899,
in which he referred to a chronic, deteriorating psychotic illness
characterised by rapid cognitive disintegration, usually beginning
in the late teens or early adulthood.
1899, Kraepelin (Figure 1) grouped most of the insanities into two
large categories: Dementia Praecox and manic-depressive illness
(the so-called Kraepelinian dichotomy). Dementia Praecox was
characterised by the following features:
It was primarily a disorder of intellectual functioning, whereas
manic-depressive illness was primarily a disorder of affect
or mood.
It had a deteriorating course and a poor prognosis, whereas
manic-depressive illness had a course of acute exacerbations
followed by complete remissions.
ALOIS ALZHEIMER: DEMENTIA PRAECOX AS A DEGENERATIVE
DISORDER
E Kraepelin categorised patients with a major psychiatric illness on
the basis of their long-term course. At admission, a score sheet
(Zhlkarte) was compiled for each patient that contained all the
necessary information to allow Kraepelin and his team to classify
patients at the end of the hospital stay and in the years of follow-
up. In addition to his work on classifying mental illness to identify
aetiological subgroups, Kraepelin encouraged talented young
people to come to the department in Munich and supported their
research on mental disorders. In addition to Franz Nissl (1860
1919), who invented the cell staining method now bearing his

1
Department of Psychiatry and Psychotherapy; Ludwig-Maximilians-University, Munich, Germany; 2Max-Planck-Institute of Experimental Medicine, Goettingen, Germany;
3
Institute for Psychiatric Phenomics and Genomics; Ludwig-Maximilians-University, Munich, Germany; 4Department of Psychiatry; University of British Columbia, Canada and
5
Laboratory 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, Mnchen 80336, Germany.
E-mail: Peter.Falkai@med.uni-muenchen.de
Received 26 September 2014; revised 11 February 2015; accepted 24 February 2015
 Kraepelin revisited
P Falkai et al
2
Figure 1. Emil Kraepelin, 1921 at the Department of Psychiatry,
Munich.
name, it was A Alzheimer who systematically investigated the
postmortem brains of patients with Dementia Praecox. In his rst
publication he described the thinning of the neocortical layers,
which he interpreted as a sign of a destructive process.2 These and
other investigations brought E Kraepelin in 1913 to the following
conclusions: These considerations force us to draw the direct
conclusion that there must be a manifest destruction of the cortex.
In those cases that have been investigated more closely by reliable
means, regular alterations have actually been demonstrated for
which there is no other explanation. [....]. We therefore reach the
conclusion that in Dementia Praecox there is severe damage to or
destruction of the nervous cortical elements, which may be
compensated for in individual cases, but which mostly results in a
peculiar, persistent impairment of the psyche.3
EUGEN BLEULER: THE SCHIZOPHRENIAS AND COGNITIVE
IMPAIRMENT
In 1908, E Bleuler redened Dementia Praecox as the Group of
Schizophrenias, that is, a group of disorders characterised by a
dysfunction of different psychic domains in phases of illness and
remission.4 Like E Kraepelin, he argued that Dementia Praecox (the
schizophrenias) was fundamentally a physical disease process
characterised by exacerbations and remissions. Nobody was ever
completely cured of schizophrenia and there was always some
sort of lasting cognitive weakness or defect that was manifest in
behaviour. Unlike Kraepelin, he believed that the overall prognosis
was not uniformly grim, that dementia was a secondary symptom
not directly caused by the underlying biological process (three
other fundamental symptoms were decits in associations,
Molecular Psychiatry (2015), 1 6
affectivity and ambivalence) and that the biological disease was
much more prevalent in the population than previously assumed
because of its simple and especially latent forms.
SCHIZOPHRENIA TODAY: STILL A COGNITIVE DISORDER 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 rst 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 antipsychotics by Delay and Deniker in 1953
signicantly 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
syndromes of signicant functional relevance.8,9 After reconstruct-
ing the prodromal stages of rst-episode schizophrenia and
performing a systematic follow-up, Hfner and an der Heiden
were able to show that patients who develop the illness between
the ages of 36 and 59 demonstrate a signicant loss of their ability
to maintain unsheltered work years before their rst 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 decits, particularly episodic and
verbal memory, was convincingly shown in 5- and 10-year follow-
up studies of rst-episode schizophrenia.10
UNDERSTANDING COGNITIVE DYSFUNCTION IN
SCHIZOPHRENIA: HUMAN STUDIES
As outlined above, cognitive dysfunction is one key to the
unfavourable outcome in schizophrenia and may be independent
of the long-term course of both positive and negative
symptoms.11,12,13 Recent studies suggest that cognitive distur-
bance in schizophrenia contributes to relapses and also has a role
in the likelihood of remission. Understanding the underlying
neurobiology of cognitive dysfunction is critical to improve
outcome, and parallel investigations of patients and animal models
form the best strategy to improve such understanding (Figure 2).
Family and adoption studies show that the risk to develop
schizophrenia has a large genetic contribution of up to 80%. In
recent years, large-scale collaborative genome-wide association
studies have identied well over 100 genes that may contribute to
the pathophysiology of schizophrenia.14 Interestingly, these genes
converge on pathways that have a signicant role in immune
modulation (major histocompatibility complex), calcium signalling
(CACNA1C and CACNB) and regulating neuronal plasticity and adult
neurogenesis (microRNA MIR137 (which codes for miR-137) and
transcription factor 4, TCF4), both of which are components of the
regenerative capacities of the brain. The major histocompatibility
complex region has a signicant role in schizophrenia and is
associated with delayed episodic memory,15 but this locus captures
a large genomic region and displays substantial diversity.16 The
immune-related major histocompatibility complex class I mole-
cules may have a role in neurodevelopment and are known to
regulate regenerative processes such as synaptic plasticity and
synaptic response to neuronal activity up to adulthood.17,18
Structural and functional alterations in specic brain networks
of schizophrenia patients may be a hallmark of the underlying
pathophysiology. To address this, we reviewed magnetic reso-
nance imaging (MRI) ndings in schizophrenia and thereby
focussed on high-quality meta-analyses based on a highly
2015 Macmillan Publishers Limited

standardized literature extraction and evaluation. We focused on
results from structural and functional MRI studies and did not
consider the large body of evidence from positron emission
tomography and spectroscopy studies for reasons of space.
A recent meta-analysis of 317 studies from 19982012
comprising 9000 schizophrenia patients revealed general grey
matter and hippocampus volume reductions in schizophrenia
patients.19 Another meta-analysis compared structural abnormal-
ities found in 42 schizophrenia studies (comprising 2058 patients
with schizophrenia and 2131 comparison participants) with those
found in 14 bipolar studies (comprising 366 patients with bipolar
disorder and 497 comparison participants) and demonstrated
circumscribed volume reduction in temporal lobe structures in
schizophrenia but not in bipolar disorder.20 A meta-analysis of 45
studies found an overlap of brain abnormalities in schizophrenia
and bipolar disorder, although grey matter volume decits were
more prominent in schizophrenia.21 Finally, a meta-analysis of 15
voxel-based diffusion tensor imaging studies showed reduced
fractional anisotropy in left frontal and left temporal deep white
matter in schizophrenia patients. These ndings point towards
disconnectivity in two white matter tracts, one interconnecting
the frontal lobe, thalamus and cingulate gyrus and the other
interconnecting the frontal lobe, insula, hippocampus and
temporal lobe.22 Despite the well-established problems of
integrating methodologically different studies into a meta-
analysis, these publications strongly indicate that the temporal
lobe structures, namely the hippocampus and amygdala, are
among the brain regions most involved in schizophrenia. A recent
study was able to demonstrate in truly rst-episode schizophrenia
with limited life-time exposure to antipsychotics that left
hippocampal volume reduction was specically correlated with
immediate recall of verbal memory performance, pointing
towards episodic memory dysfunction.23 This nding comple-
ments data from the literature showing a similar correlation in
patients with temporal lobe epilepsy. In addition to a hypoactiva-
tion of frontal regions, a meta-analysis of 11 resting-state
functional MRI studies reported a hypoactivation of the left
hippocampus.24 Furthermore, several meta-analyses demon-
strated bilateral volume reduction of the hippocampus
(left4right) in several phases of schizophrenia,25,26 a nding
that is supported by results from postmortem studies.27,28 Even
individuals at ultra-high risk to develop schizophrenia present
decreased volumes of the left hippocampus, but this nding was
not related to transition to psychosis.29 Recent stereological
investigations demonstrated that the volume decrease (46%)
was not caused by neuronal cell loss accompanied by
astrogliosis.30 Remarkably, this study found a selective reduction
in oligodendrocyte numbers in the polymorph layer of the
dentate gyrus (CA4 region) in schizophrenia, which could support
the notion of disturbed macroconnectivity in this disorder.30
Furthermore, the thinning of the dentate gyrus, accompanied by a
reduced number of granule cells,31 would imply that hippocampal
changes seen in schizophrenia might partially be a consequence
of disturbed neuroregenerative mechanisms in the human brain.
Biological regeneration has been dened as the reconstitution of a
lost or injured part of an organism.32 Possible mechanisms of lost
regenerative capacities in schizophrenia involve disturbed
neurogenesis,33,34 impaired synaptic plasticity35 and dysfunction
of the dynamic interplay between neurons and oligodendrocytes,
leading to decits in axonal function.36 Such a hypothesis is
supported by a plethora of evidence demonstrating reduced
synaptic proteins of the soluble NSF-attachment protein receptor
complex, hippocampal presynaptic proteins37 and dysregulation
of structural synaptic elements in the temporal lobes in
schizophrenia.38 The converging lines of evidence suggest that
episodic memory dysfunction in schizophrenia might well be
caused by the disturbance of synaptic and neuronal plasticity and
disconnectivity. However, in addition to our concept of a failure
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Kraepelin revisited
P Falkai et al
3
in regenerative capacities, an additional neurodegenerative or
even neurotoxic process of untreated psychosis cannot be
excluded.39,40 In contrast, results of volume reductions in
individuals at ultra-high risk and rst-episode schizophrenia
patients25,26,29 and longitudinal studies showing no progression
of cognitive decits in the course of schizophrenia over a period of
up to 10 years10 support the hypothesis of a primary neurode-
velopmental decit, which may lay the foundation for disturbed
regenerative capacities during adulthood.
UNDERSTANDING COGNITIVE DYSFUNCTION IN
SCHIZOPHRENIA: ANIMAL EXPERIMENTS
Changes in synaptic plasticity in the hippocampus of patients with
schizophrenia could be followed by a reduction in long-term
potentiation (LTP) and also long-term depression or an impaired
regulation of both in terms of meta-plasticity, with implications for
the functioning of the episodic memory system (see Figure 2, left-
hand side). However, all of these assumptions are indirect and not
as tightly connected as they could be if derived from an animal
model. Providing a close link between postmortem and in vivo
ndings in schizophrenia patients and animal models of schizo-
phrenia, including differences in LTP and behaviour, is a
challenging task. The question that immediately arises is whether
a suitable animal model is able to mimic at least certain dened
aspects of the clinical picture (for example, cognitive dysfunction)
or neurobiological features (for example, decits in pre-pulse
inhibition) or both.
As outlined above, large genome-wide association studies have
identied a number of risk genes, which might likely contribute to a
genetic vulnerability for schizophrenia.14 One of these is the TCF4
gene, a homologue of which is widely expressed in the central
nervous system (CNS) of mice, including the cortex and hippo-
campus, and which seems to be important in brain development.
Like many other transcription factors, TCF4 has been shown to be
involved in regulating neuronal maturation and thus to contribute
to the regenerative capacities of the brain. Its expression is
sustained in the adult CNS and has a pivotal role in cognition.41,42
Of interest is that a haploinsufciency of the TCF4 gene causes so-
called PittHopkins syndrome. Patients with PittHopkins syndrome
show features of a neurodevelopmental disorder, including
enlarged ventricles, severe mental retardation and breathing
abnormalities, emphasising the crucial role of TCF4 in normal CNS
development.43 TCF4 messenger RNA is upregulated in schizo-
phrenia patients and in patient-derived human-induced pluripotent
stem cell neurons when compared with controls.44,45 Thus, human
studies support the hypothesis that even a moderate alteration in
TCF4 expression levels may lead to prominent CNS dysfunction.43
These ndings are substantiated by evidence from animal studies
addressing certain endophenotypes of psychiatric diseases. Trans-
genic mice moderately overexpressing Tcf4tg postnatally in brain
regions (cortex and hippocampus) involved in learning and
memory processes (Tcf4tg mice) display cognitive impairment in
fear-associated learning and attentional dysfunction.41,42 This
malfunction may be related to a disturbed interaction between
the hippocampus and prefrontal cortex. Moreover, linking to
phenotypes described for a signicant proportion of schizophrenia
patients, Tcf4tg animals display decits in sensorimotor gating, as
revealed by the pre-pulse inhibition test.41
Taken together, data obtained from human and animal studies
provide growing evidence about the role of TCF4 not only in CNS
development but foremost in higher order information proces-
sing, including cognition and sensorimotor gating.43 Considering
that not only genetic but also environmental factors contribute to
the development of schizophrenia, it is noteworthy that the
cognitive performance of Tcf4tg mice can be modulated by
different environmental conditions (Brzzka, Badowska, Rossner,
unpublished data).
Molecular Psychiatry (2015), 1 6
 Kraepelin revisited
P Falkai et al
4
Human model Animal model

CNVs Risk genes Epigenetic regulation basic domain

(e.g. NRG1,TCF4) Genetic and epigenetic helix 1 Genetic factors: TCF4
factors loop helix 2

environment

single housing

social defeat
Place of birth O ns

enriched
bstetric Viral infectio
abis Migrat ion compli
Ca n n c ati o n Environmental factors Housing conditions
s

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

As outlined above, there is an ongoing debate about whether
schizophrenia is or is not primarily a degenerative disorder with
irreversible structural and functional abnormalities that increase
over time. The presence of a degenerative process would support
the concept of Dementia Praecox as described by E Kraepelin,
involving cognitive dysfunction and lack of recovery as critical
illness elements. One of the key questions therefore is whether or
not the structural and functional changes seen in patients with
schizophrenia, for example, in the hippocampal formation, are
reversible. Data from animals and healthy humans demonstrate a
volume increase of the hippocampus, especially in the dentate
gyrus, and improved memory as a consequence of wheel running
and physical exercise.46,47,48 Postmortem investigations show that
wheel running enhances neurogenesis and synaptogenesis in
mice.49,50,51 Furthermore, studies using different techniques of
noninvasive brain stimulation point towards reduced LTP- and
long-term depression-like plasticity in schizophrenia patients.52
LTP plasticity in the model system of the primary motor cortex was
shown to be reduced in schizophrenia by using paired-associative
stimulation (a kind of spike-dependent plasticity)53 after a cortical
reorganisation paradigm (use-dependent plasticity)54 and anodal
transcranial direct-current stimulation (a kind of non-focal and
N-methyl-D-aspartate receptor-dependent plasticity).55 Vice versa,
long-term depression-like plasticity was reduced after 1 Hz repetitive
transcranial magnetic stimulation (focal plasticity)56 and cathodal
transcranial direct-current stimulation (non-focal plasticity);57 these
decits were linked to impairments in both glutamatergic and
factor genotype58 and were present in medicated and unmedicated
patients52 as well as in rst-degree relatives.52
On the basis of ndings such as these, Pajonk et al.59 performed
a MRI study of exercise in patients with multi-episode schizo-
phrenia. Schizophrenia patients and a control group of healthy
individuals performed indoor cycling three times a week for
30 min over 3 months; a second, non-exercise control group of
schizophrenia patients played table football at the same
frequency and for the same period of time. After indoor cycling,
patients showed a hippocampal volume increase of ~ 10%,
accompanied by an increase of the n-acetylaspartate/creatinine
ratio in magnetic resonance spectroscopy and an improvement in
the short-term memory index.59 This is consistent with recent data
from high-eld MRI showing increased hippocampal volumes in
wheel-running rats but no changes in the cortex. These studies
support the notion that structural and functional changes seen in
multi-episode patients may be reversible even after many years of
illness and are therefore rather a consequence of disturbed
regenerative capacities of the brain than a classical degenerative
process.
EPIGENETIC DYSREGULATION: THE UNDERLYING CAUSE?
Environmental inuences on the development of the illness and its
treatment seem to have been understudied in recent years in both
patients and animal models.60 However, accumulating data
suggest that epigenetic regulation is disturbed in psychiatric
disorders.61 In schizophrenia, microRNAs may act through post-

Molecular Psychiatry (2015), 1 6 2015 Macmillan Publishers Limited


transcriptional and even transcriptional control mechanisms to
cause large effects on synaptic LTP and axonal guidance. For
example, several schizophrenia risk genes such as TCF4 and
CACNA1C are targets of miR-137.62 Furthermore, it is interesting
that in schizophrenia an altered histone code increased histone
deacetylase (HDAC)/DNA methyltransferase levels and an altered
DNA methylation can be found as well.6366 Against this back-
ground it is notable that potent HDAC inhibitors can reverse
Alzheimer-like changes in an animal model.67 Valproic acid is a
potent HDAC inhibitors that modulates different subtypes of
HDACs; however, extremely high doses would be needed to obtain
a signicant change in epigenetic regulation in the target areas of
the human brain. Specic HDAC inhibitors are used in oncology,
but they may have unfavourable side effects that are intolerable
for patients with schizophrenia, and many issues regarding drug
safety, drug interactions, brain permeability, target selectivity, dose
ranges and treatment duration are still unanswered.61
CONCLUSION
In summary, 4100 years after its introduction the concept of
Dementia Praecox is still alive. Sadly, 60 years after the
introduction of antipsychotic agents recovery is still unsatisfactory
in 450% of patients. Negative symptoms and most importantly
cognitive dysfunction seem to be at the core of this unfavourable
outcome and therefore need to be targeted in research to achieve
better treatment options. On the basis of animal data and imaging
data from patients it seems unlikely that schizophrenia is
characterised by a classical degenerative process. More likely is
thatof the outlined risk gene pathwaysenvironmental stres-
sors lead to long-lasting dysfunction, reducing the ability of the
human brain to regenerate. Impaired oligodendrocyte function,
synaptogenesis and probably reduced neurogenesis, with result-
ing decits in structural and functional micro- and macroconnec-
tivity, point to a disturbance of the regenerative capacity of the
human brain in schizophrenia. This possibility must be considered
if hopes to improve treatment options and outcome for patients
with schizophrenia are to be fullled.
CONFLICT OF INTEREST
The authors declare no conict of interest.
ACKNOWLEDGMENTS
This work is supported by the Deutsche Forschungsgemeinschaft via the Clinical
Research Group 241 Genotypephenotype relationships and neurobiology of the
longitudinal course of psychosis (http://www.kfo241.de; grant number FA 241/16-1,
SCHU 1603/5-1 and RO 4076/1-1). The authors thank Jacquie Klesing, Board-certied
Editor in the Life Sciences, for editing assistance with the manuscript.
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