doi:10.1111/pcn.
12322
Schizophrenia in 2020: Trends in diagnosis and therapy
1,2
Wolfgang Gaebel, MD * and Jürgen Zielasek,
1
Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich Heine University, and 2WHO Collaborating
Center for Quality Assurance and Empowerment in Mental Health, Düsseldorf, Germany
Schizophrenia research is providing an increasing
number of studies and important insights into the
condition’s etiopathogenesis based on genetic, neu-
ropsychological and cranial neuroimaging studies.
However, research progress has not yet led to the
incorporation of such findings into the revised clas-
sification criteria of mental disorders or everyday
clinical practice. By 2020, schizophrenia will most
likely still be a clinically defined primary psychotic
disorder. While there is some hope that treatment
will be improved with new antipsychotic drugs, drugs
addressing negative symptoms, more refined psy-
chotherapy approaches and the introduction of
new treatment modalities like transcranial magnetic
LINICAL AND BASIC research has been provid-
C ing increasingly detailed information about the
etiopathogenesis, diagnosis, classification and treat-
ment of schizophrenia. The number of published
studies in schizophrenia research has been rapidly
increasing over the last 25 years and an analysis of
MEDLINE, a relevant database of international scien-
tific publications, shows that the increase of
schizophrenia-related publications since 1990 is
much larger than the increase of the total number of
all research publications included in MEDLINE (Fig. 1).
*Correspondence: Wolfgang Gaebel, MD, Department of Psychiatry
and Psychotherapy, LVR-Klinikum Düsseldorf, Bergische Landstr. 2,
D-40629 Düsseldorf, Germany. Email:
wolfgang.gaebel@uni-duesseldorf.de
Accepted 22 May 2015.
© 2015 The Authors
Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
1,2
MD
stimulation, an additional hope is to improve early
detection and prevention. As the results of new
research into the etiopathogenesis of schizophrenia
are promising to improve diagnosis, classification
and therapy in the future, a picture of complex
brain dysfunction is currently emerging requiring
sophisticated mathematical methods of analysis. The
imminent clinical challenge will be to develop com-
prehensive diagnostic and treatment modules
individually tailored to the time-variable needs of
patients and their families.
Key words: etiopathogenesis, classification, psycho-
ses, psychotic disorders, schizophrenia.
This indicates that schizophrenia research is
picking up pace. New genome-wide association
studies and sophisticated methods to analyze func-
tional neuroimaging data are being used. New detec-
tion methods, like magnetic resonance spectroscopy,
are being introduced in schizophrenia research. The
main challenges to clinical psychiatrists and research-
ers in the field of primary psychotic disorders are not
only to keep abreast of the rising stack of schizophre-
nia research publications on their desks, but also to
evaluate this vast amount of knowledge as regards its
pertinence to everyday clinical diagnostic and thera-
peutic practice. This review aims to: (i) describe the
major findings of schizophrenia research over the last
5–10 years, which may be of importance for shaping
the next 5 years of schizophrenia research and clinical
practice; and (ii) describe the scientific challenges to
the fields of schizophrenia research and clinical prac-
661
662 W. Gaebel and J. Zielasek Psychiatry and Clinical Neurosciences 2015; 69: 661–673

6000

5000

4000

3000

2000

1000

0
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Number of publications “schizophrenia” per year

Figure 1. Number of publications indexed in MEDLINE per year with the term ‘schizophrenia’ in the title and/or the abstract. The
number of annual publications related to ‘schizophrenia’ has quadrupled in the last 25 years from 958 in 1990 to 5054 in 2014.
The total number of all publications indexed in MEDLINE only rose from 408 502 in 1990 to 1 084 367 in 2014, which means that
the total number of all publications increased by a factor of approximately 2.5. Thus, the increase of the annual number of
publications about schizophrenia rose disproportionately faster than the general number of publications in MEDLINE. Date of
analysis: 26 February 2015.

tice for the next 5 years, and how these challenges
may be addressed.
TRENDS IN SCHIZOPHRENIA
CLASSIFICATION AND DIAGNOSIS 2020
ICD-11 and DSM-5: Revision of the
classification criteria for schizophrenia
This field has mainly been influenced by the work to
prepare a revised version of the Diagnostic and Statis-
tical Manual for Mental Disorders, which was pub-
lished by the American Psychiatric Association in
2013.1 In addition, there is a currently ongoing revi-
sion process of the 10th version of the clinical
diagnostic criteria for mental disorders (including
schizophrenia) of the World Health Organization
(WHO) International Classification of Disorders
(ICD). ICD-11 is due to be published in 2017 and at
the time of writing, a preliminary beta version of
ICD-11 was available for review on the Internet
(http://apps.who.int/classifications/icd11/browse/f/
en, last accessed 26 February 2015). The develop-
ment of both ICD-11 and DSM-5 were and are
characterized by disorder group-specific working
groups of clinical and research experts, who reviewed
the available evidence for classification issues
of schizophrenia, and prepared suggestions for
changes.2–4 Several common and divergent
approaches to the classification of schizophrenia in
DSM-5 and ICD-11 are evident. Both classification
systems omit the traditional clinical subtypes of

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Psychiatry and Clinical Neurosciences 2015; 69: 661–673 Schizophrenia in 2020 663

DSM-5

A. Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully
treated).
At least one of these must be (1), (2), or (3):

1. Delusions.
2. Hallucinations.
3. Disorganized speech (e.g., frequent derailment or incoherence).
4. Grossly disorganized or catatonic behavior.
5. Negative symptoms (i.e., diminished emotional expression or avolition).
B. Social/occupational dysfunction
C. Duration (6 months)
D. Schizoaffective and Mood Disorder Exclusion
E. Substance/General Medical Condition Exclusion
F. Relationship to a Pervasive Developmental Disorder

ICD-11

At least two of the following (one of which must be from the list of [a] to [d]) must be present (by patient report or observation by the
clinician or other informants) most of the time for a period of 1 month or more:

a. Persistent delusions (e.g., grandiose delusions, delusions of reference, persecutory delusions).

b. Persistent hallucinations (most commonly auditory, although they may be in any sensory modality).
c. Disorganized thinking (formal thought disorder) (e.g., tangentiality and loose associations,irrelevant speech, neologisms). When
severe, the person’s speech may be so incoherent as to be incomprehensible (‘word salad’).
d. Experiences of influence, passivity or control (e.g., the experience that thoughts are not generated by the person, are beingplaced
in one’s mind or withdrawn from one’s mind by others, or that thoughts are being broadcast to others).
e. Negative symptoms, such as affective flattening, alogia or paucity of speech, avolition, asociality and anhedonia.
f. Grossly disorganized behavior, which may be noted in any form of goal-directed activity (e.g., unpredictable or inappropriate
emotional responses, behavior that appears bizarre or purposeless).
g. Psychomotor disturbances, such as catatonic restlessness or agitation, posturing, waxy flexibility, negativism, mutism, or stupor.

Figure 2. Clinical diagnostic criteria for schizophrenia in DSM-51 and ICD-11 (preliminary beta version, to be finalized by 2017;
http://apps.who.int/classifications/icd11/browse/f/en, last accessed 26 February 2015).

schizophrenia (paranoid, hebephrenic), because a
number of studies indicated that such clinical
subtyping had little relevance for determining prog-
nosis or therapy. Similarly, first-rank symptoms were
de-emphasized in both classification systems follow-
ing studies, indicating that these had little prognostic
relevance.5 The classification in both systems will rely
on the assessment of the clinical symptoms of schizo-
phrenia, a minimum disease duration (different in
both systems: 6 months in DSM-5 and 1 month sug-
gested for ICD-11, Fig. 2), and the exclusion of other
somatic disorders or the effects of drugs or their with-
drawal as reasons for the appearance of psychotic
symptoms.
Importantly, DSM-5 requires the occurrence of
functional impairments as a mandatory diagnostic
criterion, whereas ICD-11 will not include this as a
mandatory criterion. This difference reflects differ-
ences of the general definition of a mental disorder in
the two classification systems, which includes func-
tional impairments in DSM-5, whereas WHO dis-
courages the use of functional impairments as criteria
for a mental disorder.
Both classification systems took steps in the direc-
tion of a ‘dimensional’ clinical assessment of schizo-
phrenia symptoms using severity ratings for positive
symptoms, negative symptoms, mood symptoms,
psychomotor symptoms and cognitive impairments,
with some differences in the details of the two
systems (Fig. 2). Of note, in both systems, affective
symptoms, catatonia and cognitive impairment now
form parts of the assessment of schizophrenia, with
catatonia not a clinical subtype of schizophrenia, but
one of the clinical manifestations without the status
of a separate clinical subtype. Recent research sug-
gests that the classification criteria of DSM-5 for cata-
tonia may not be sufficient and may lead to
underdiagnosis,6 which is one of the reasons that in

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Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
664 W. Gaebel and J. Zielasek Psychiatry and Clinical Neurosciences 2015; 69: 661–673

Symptom Specifiers ICD-11 DSM-5

0 Positive symptoms • Hallucinations
1 Negative symptoms • Delusions
2 Depressive symptoms • Disorganized speech
3 Manic symptoms • Abnormal psychomotor
4 Psychomotor symptoms behavior
5 Cognitive impairment • Negative symptoms
• Impaired cognition
• Depression
• Mania

Course Specifiers 0 First episode, currently in acute episode

(harmonized for use in both
ICD-11 and DSM-5)
1 First episode, currently in partial remission
2 First episode, currently in full remission
3 Multiple episodes, currentlly in acute episode Figure 3. Symptom and source
4 Multiple episodes, currentlly in partial remission specifiers of ICD-11 (beta version,
5 Multiple episodes, currentlly in full remission
http://apps.who.int/classifications/
6 Continuous
icd11/browse/f/en, last accessed 26
7 Unspecified
February, 2015) and DSM-5.1

ICD-11, more comprehensive clinical feature lists of
catatonia are currently being developed. An impor-
tant area of harmonization between ICD-11 and
DSM-5 regarding the schizophrenia criteria are the
novel course criteria, which were developed in close
collaboration of the development teams of both
systems, and which are now formulated in a way to
cover all disease stages (Fig. 3).
An attenuated psychosis syndrome was not consid-
ered as a new diagnostic entity in DSM-5 given the
lack of certainty about the progression rate of those
who experience such symptoms.7 The syndrome was
included as a condition for further study in the
appendix of DSM-5. ICD-11 will probably reach a
similar conclusion. However, the classification crite-
ria may need to be re-revised, as a Swiss study recently
showed that the current DSM-5 symptom list may
exclude persons who have a stable prodromal
syndrome, but no current progression, and who are
help-seeking.8
Notable is the absence of any etiopathogenetic
aspects in the schizophrenia classification criteria of
DSM-5 and the current suggestions for ICD-11. Obvi-
ously, the currently available evidence was not con-
sidered robust enough by the expert panels to warrant
the inclusion for example of genetic or other
biomarker information in the classification process
(with the exception of the ruling out of somatic dis-
orders, for example by using cranial neuroimaging
techniques to exclude a brain tumor as the reason for
the occurrence of psychotic symptoms in an indi-
vidual). Altogether, neither of the revision processes
led to major paradigmatic changes, but rather to
subtle moves in the direction of dimensional assess-
ments in the classification process and a clarification
of course and symptom specifiers.
Elucidation of the etiopathogenesis of
schizophrenia
Although the etiopathogenesis of schizophrenia is
still unknown, evidence from many lines of research
(genetic, psychophysiology, neurobiology etc.)
indicates that there are probably many roads of
etiopathogenesis leading to the diverse clinical mani-
festations of schizophrenia. Genetic research impli-
cates a large number of genetic variants in
schizophrenia, ranging from major copy number
variations to single gene polymorphisms. The multi-
tude of described genetic alterations (most of which
have a low penetrance) in patients with schizophre-
nia is large and several challenges have arisen:9–13
• The number of risk-associated loci in schizophrenia
is estimated to be at about 850 loci. All of these
genetic risk markers may explain around 10% of all
schizophrenia cases.
• Some rare copy number variations, especially those
involving partial deletions of the long arm of chro-
mosome 22 (22q11.2), show a high penetrance in
schizophrenia, but these cases only amount to
approximately 0.2–0.3% of all patients with
schizophrenia.

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Psychiatry and Clinical Neurosciences 2015; 69: 661–673
• Genome-wide association studies in schizophrenia
have added new risk loci and recently increased the
number of probably relevant genetic polymor-
phisms into the range of n = 8500, but also increas-
ing the explained variance of liability to about
32%.
• None of the genetic polymorphisms demonstrated
in schizophrenia is disease-specific or can be used
for individual diagnostic purposes or the classifi-
cation of schizophrenia.
Recent genome-wide association studies converge
on genes involved in the regulation of synaptic
activities, neurodevelopment and immune func-
tions.11 An interesting new aspect here is the finding
of immunity-related genes, which seems to
vindicate theories about an involvement of
neuroimmunologic processes in the pathogenesis of
schizophrenia.14,15 Also, there is now a subtype of
patients with symptoms of schizophrenia, who have
autoantibodies against the N-methyl-D-aspartate
receptor, and whose psychotic symptoms respond to
immunologic therapies.16 Clearly, more work is
needed to characterize the clinical features of this
subgroup of patients, in whom autoantibody testing
is needed to indicate immunologic therapy.
However, it is still largely unknown how much and
by which pathomechanisms such genetic or immu-
nologic variation contributes to the pathophysi-
ologic process of schizophrenia, except in the few
cases of antineuronal-antibody-associated psychosis,
in which the binding of the autoantibody to its
brain receptors seems to be implicated (although
this would still need to be elucidated in detail). One
of the common final pathways of the etiopathogen-
esis of schizophrenia is a disturbance of brain dopa-
mine neurotransmitter pathways, and investigations
to subtype schizophrenia by responsiveness to anti-
dopaminergic (antipsychotic) treatment are under-
way, which may lead to novel classification criteria
in the future.17 New technologies, like magnetic
resonance spectroscopy, are adding information on
dopamine and other neurotransmitters in the
pathogenesis of schizophrenia, but so far, this has
no immediate bearing on the individual diagnostic
process.18 Neuro/psychophysiological evidence
obtained using sophisticated graph-analytic proce-
dures to disentangle network structures in func-
tional or structural neuroimaging of the brain
indicates that there are complex, inter-individually
variable (and probably also time-dynamic) altera-
Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Schizophrenia in 2020 665
tions of the topological network structures, which
involve the normally observed modular structure of
connectivity of brain regions via hubs as central
nodes of communication channeling between
modules.19,20 Such analyses may open new roads to
therapeutic interventions by correcting altered con-
nectivity or modular brain topology using tech-
niques developed in neurology for the treatment of
Parkinson’s disease motor symptoms.19 However,
two aspects of caution need to be considered: (i) in
schizophrenia, it is still unclear if disturbed connec-
tivity and disturbed modular topology are the
causes or the consequences of the pathophysiology
of schizophrenia; and (ii) altered brain network
topologies may represent attempts by the brain to
compensate for schizophrenia-induced brain dys-
functions.21 Therefore, further studies are needed
to prove that such dysfunctions are causes of
symptoms, and not (beneficial) compensatory
mechanisms.
Besides such (neuro)biologic factors, psychosocial
factors are obviously also involved. Among the psy-
chological disease mechanisms, studies implicate
factors like aberrant salience,22 jumping to conclu-
sions23 and biases in evidence integration24 in the
formation of psychotic symptoms, and therapeuti-
cally addressing such psychological dysfunctions for
example with psychotherapeutic methods may lead
to novel therapies in the future, but will probably
not influence the diagnostic process in the next 5
years. Another aspect may emerge through research
on socioenvironmental pathogenic processes, which
may be detectable with techniques of epigenetic
changes like altered DNA-methylation25 or through
effects on the brain of socioenvironmental
factors.26,27 However, these approaches are still far
from clinical relevance. For clinical routine use, sen-
sitivity, specificity, and the positive and negative
predictive values would need to be available, and
such information is still lacking. Thus, while prog-
ress in the field of the etiopathogenesis of schizo-
phrenia has been considerable, it has supported
Bleuler’s assumption that schizophrenia will most
probably not have a unitary etiopathogenesis, and
that several pathogenic factors may converge to a
common final pathway like the disturbance of brain
neurotransmitter functions and brain network
topologies. While the elucidation of details of these
processes are pending, Bleuler’s formulation of the
schizophrenias in the plural form may be an
adequate reflection on these findings.
© 2015 The Authors
666 W. Gaebel and J. Zielasek
Deconstructing schizophrenia
For elucidating the etiopathogenesis of schizophre-
nia, it may be necessary to focus on the etiopatho-
genesis of specific psychotic symptoms rather than
on the complex complete clinical picture. While still
clinically useful, the concept of ‘schizophrenia’ may
obfuscate biological markers simply by providing
a too heterogenous population of individuals
with similar symptoms but of very different
etiopathogenetic background. Genetic and other
(neuro)biological endophenotypes may need to be
identified to establish objective markers of the pro-
cesses leading to particular psychotic symptoms
like hallucinations or delusions.28,29 However,
there will still be a long way from biomarkers/
endophenotypes to clinical practice.30 The National
Institutes of Mental Health has initiated a large-scale
research program to develop, for research purposes,
new ways of classifying mental disorders based on
dimensions of observable behavior and neurobio-
logical measures. The range of dimensions to be
assessed encompasses positive and negative valence
systems, cognitive systems, social systems and
arousal/regulatory systems, which will all be
assessed in a comprehensive analysis of the genetic
backgrounds of these systems, the cellular level, the
brain network level, physiology, behavior and
patient self-reports.31 This ambitious project has
yielded the first information on the pathophysiol-
ogy of hallucinations,32,33 but whether this ‘Research
Domain Criteria’ (RDoC) project will ultimately
lead to new (and more technology-driven?) classifi-
cation criteria remains to be seen and seems
unlikely to be fully operational for schizophrenia in
2020. An advantage of this approach is that it may
provide patient-driven analyses, and genetic-driven
analyses, which may then converge on common
pathways of disease development.34 The constraints
imposed upon research by the boundaries of tradi-
tional classification concepts, like ‘schizophrenia’,
can be overcome using the RDoC approach.
Addressing somatic comorbidity in the
diagnostic process
A final clinical-practical aspect for the diagnostic
process in patients with schizophrenia is the
increased attention to somatic comorbidity. The
increased mortality of patients with schizophrenia is
mainly caused by suicides and somatic disorders35 –
© 2015 The Authors
Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 661–673
the latter receiving due increased attention given the
high disease burden of somatic disorders in people
with schizophrenia and its role in excess mortality.36
This may be due to late diagnosis and
undertreatment, unhealthy lifestyles, and drug side-
effects, although it has also been shown that
adequate use of antipsychotic medication reduces
the ‘mortality gap’ of patients with schizophrenia.37
Therefore, any future program to improve the
quality of schizophrenia diagnostics will need to
include the aspect of attention to somatic
comorbidity.
SCHIZOPHRENIA 2020: TRENDS
IN THERAPY
Treatment modalities in schizophrenia have changed
with the concepts of schizophrenia over the decades
and are currently shaped by the biopsychosocial
model leading to three pillars of schizophrenia
therapy:
1 Biological therapeutic methods employing anti-
psychotic drugs, which act via blockade of brain
dopamine receptors and modulating effects on
other brain neurotransmitter systems.
2 Psychotherapeutic approaches increasingly
informed by research on specific psychological
aspects of the pathophysiology of schizophrenia as
mentioned before (like aberrant salience and
jumping to conclusions38 and cognitive training
techniques to overcome cognitive impairments,
for example of working memory functions).
3 Psychosocial treatments addressing aspects of
workplace rehabilitation (like supported employ-
ment programs).
Current trends in developing new treatments for
schizophrenia can be found in five areas:
1 Novel pharmacologic agents
2 Further development of psychotherapy for schizo-
phrenia
3 New somatic therapies like transcranial magnetic
stimulation or deep brain stimulation
4 Improving the quality of mental health care by
implementing guidelines and developing more
effective care models
5 Developing early need-based, personalized
interventions.
Psychiatry and Clinical Neurosciences 2015; 69: 661–673
Novel pharmacologic agents
Current antipsychotic therapy mainly relies on target-
ing brain dopamine D2 receptors, but novel drugs are
being developed that work via glutamate receptors,
glycine transporters or the alpha-7-nicotinic acetyl-
choline receptor.39 However, so far none of these
novel approaches has led to therapeutic break-
throughs. Besides hallucinations and delusions,
against which the current antipsychotic drugs show
sufficient activity, new therapeutic targets will be
‘negative’ symptoms like avolition and anhedonia,
and cognitive symptoms, like working memory
impairments. Another important aspect will be to
reduce the side-effects of the current antipsychotic
drugs, which may lead to dyskinesias, cardiac
arrhythmias or the metabolic syndrome, all of which
frequently limit the clinical acceptance of these drugs.
Another aspect is that pharmaceutical companies are
reducing their engagements for antipsychotic drug
developments, as developing drugs for brain disor-
ders like schizophrenia is complex, time-consuming
and expensive, and may thus appear as a less attrac-
tive area for investment compared to other areas of
drug development.40 Changing policies that regulate
market returns may be one way to address this chal-
lenge, and clearly another approach would be to
provide convincing results about the etiopathogen-
esis of schizophrenia to drug developers. Other
aspects could be to establish biomarkers for stratifi-
cation of schizophrenia patients, to develop predic-
tive models and to enhance data sharing and
collaboration.41 Such measures are urgently needed
to ascertain the future of drug development for the
treatment of schizophrenia.
Further development of psychotherapy
for schizophrenia
In the last 20 years, a number of studies have shown
that cognitive-behavioral psychotherapy is effective
to reduce the symptoms of schizophrenia, especially
when combined with antipsychotic drug therapy,
while psychodynamic therapy is not effective.42 Prog-
ress in the area of psychological therapies for schizo-
phrenia is currently emerging in that there is evidence
for psychotherapeutic treatment of specific symp-
toms of psychosis like auditory hallucinations43 or
mimic affect recognition.44 An important aspect will
be to implement such new psychotherapeutic strate-
gies in schizophrenia health care and everyday clini-
Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Schizophrenia in 2020 667
cal practice in order to overcome traditional but
outdated nihilistic attitudes towards the psycho-
therapy of schizophrenia.
New somatic therapies
One of the most promising approaches is the use of
repetitive transcranial magnetic stimulation (rTMS)
therapy to control the symptoms of psychosis.
However, the therapeutic efficacy of the currently
available protocols was limited in controlled, ran-
domized trials,45,46 and treatment effects were vari-
able on the different symptom dimensions with
some notable therapeutic effects for mimic affect rec-
ognition.47 It may be hoped that by carefully selecting
patients who are likely to respond to rTMS by using
clinical profiles or biomarkers, and by optimizing the
treatment protocols, this therapeutic alternative will
become more widely available and acceptable. For
example, a recent review showed that the stimulation
site and the stimulation type were important for
determining the efficacy of rTMS in reducing the
intensity of auditory hallucinations.48 Another area of
research is the development of deep brain stimula-
tion (DBS) techniques for the treatment of the symp-
toms of psychosis. This is mainly driven by the
observation that in Parkinson’s disease, the elucida-
tion of disturbed neurocircuitry led to the develop-
ment of DBS treatment algorithms. While modeling
studies showed that in principle this would be a fea-
sible therapeutic approach to correct the disturbed
brain network topology in schizophrenia,19 it
remains to be determined which patients may profit
and to address the potential side-effects of such new
therapies. Obviously, the invasiveness of the proce-
dure will be an issue and the emerging ethical issues
about invasive brain procedures in patients with psy-
chotic disorders need to be addressed.
Improving health care for people
with schizophrenia
While the previous sections have shown that the
developments of new pharmacologic antipsychotic
agents, of new psychotherapeutic methods and of
new somatic therapies addressing the disturbed
neurocircuitry in schizophrenia are underway, none
of these approaches is promising to provide short-
term success on a broad basis before 2020. Therefore,
alternatives are needed that may be more readily
available and one area of potential improvement of
© 2015 The Authors
668 W. Gaebel and J. Zielasek
the diagnosis and therapy of schizophrenia is the
optimization of the use of the currently available
evidence and therapeutic methods. First, there is still
a treatment gap indicating that only about half of all
patients with schizophrenia receive treatment. This
could be addressed by information campaigns about
the nature and symptoms of the disorder, the avail-
able treatment options and the mental health-care
services, which provide such services. Improving trust
in mental health-care services may be a central issue
here, as was shown by a recent review and recom-
mendations to increase trust in mental health-care
services developed in the framework of the Guidance
Project of the European Psychiatric Association.49
Along this line of reasoning, fighting stigma and dis-
crimination of people with mental disorders and the
people and institutions providing mental health care
will be important elements of such programs.50
Improving the quality of mental health care by
implementing guidelines
Another aspect will be to implement existing guide-
lines, which summarize the available evidence and
provide recommendations for clinical practice.
Schizophrenia guidelines are available worldwide51
and there is a need to increase their implementation
in clinical practice and to evaluate the efficacy of their
implementation. Research in this field is scarce but
indicates that guideline implementation and guide-
line adherence improve the outcome of schizophre-
nia health care.52,53
A novel health-care model for schizophrenia
Optimally, guideline implementation would be part
of a more comprehensive model to implement best-
evidence practices in mental health care, which may
also include developing new structures like enhanced
outpatient services and to tailor the therapeutic
program to patients’ individual – and time-variable –
needs. Such models may also help to close the treat-
ment gap, which indicates that approximately half of
all persons in need of schizophrenia treatment actu-
ally receive treatment.54 Such a new care model
should:
1 Be evidence-based and should be used to transfer
scientific progress quickly into clinical practice
2 Use all levels of information sources
3 Form an integrated network of local mental
health-care providers
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Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 661–673
4 Offer individualized, need-adapted and stage-
specific combinations of diagnostic and treatment
modules
5 Provide a ‘holistic’, person- and recovery-centered
approach addressing clinical symptoms, func-
tional abilities, quality of life, mental health lit-
eracy, trust in services and empowerment for the
patient and his/her family.
Such novel models of mental health care for
schizophrenia can be conceptualized integrating the
biopsychosocial model (Fig. 4).
This could then be used to devise an integrated
care model for patients with schizophrenia based
on evidence-informed diagnostic and treatment
modules that transgress traditional boundaries of in-
and outpatient care sectors, and which are tailored to
the disease-stage-specific needs of the individual
(Fig. 5).
These needs may vary greatly over time and the
main advantage of such a modular system is its flex-
ibility and adaptiveness to the most current mental
health care needs of the individual affected by schizo-
phrenia. It is also adaptable to different health-care
systems, in that different (national) mental health-
care systems may adopt different diagnostic or treat-
ment contents in the various models, considering the
regional or national availability of mental health-care
service types, traditions of mental health care and the
continuous evaluation of novel treatment strategies
in schizophrenia. Therefore, the contents of the
modules will have to be reviewed and adapted con-
stantly following new evidence or the introduction of
new service types.
Early need-based, personalized interventions
A final aspect regarding the mental health care aspect
which bridges into the area of basic research into the
etiopathogenesis of schizophrenia is the develop-
ment of personalized interventions in the early phase
of the disorder with a view to either completely
prevent or considerably ameliorate the initial phase
of psychosis. Currently, the clinical criteria for the
early phases of schizophrenia are being refined, but
biomarkers allowing individual risk predictions
would be needed to bring about decisive progress in
this field.55 One promising approach is to use cranial
neuroimaging data of persons at risk of developing
schizophrenia, and use machine-learning algorithms
to obtain computerized predictions based on
Psychiatry and Clinical Neurosciences 2015; 69: 661–673 Schizophrenia in 2020 669

Bio Psycho Social

Level of Personal and

Etiology Psychological
information mental health-care
Pathophysiology mechanisms
source system level

New therapies developed New therapies developed New therapies addressing

based on novel based on findings about recovery and empowerment,
Examples mechanisms of etiology the role of cognitive including and going beyond
of novel and pathophysiology, like processes in symptom classical outcome assessments
approaches information on brain formation like symptom assessments
network disturbances in Demonstrated efficacy of
schizophrenia elements of mental health care
like CMHT or supported
employment

Resulting Deep brain stimulation Cognitive training Comprehensive Community

health-care rTMS treatment for negative symptoms Mental Health Centers,
modules Assertive Community
Treatment, home treatment,
crisis intervention,
psychoeducation and
empowerment training

Figure 4. The biopsychosocial foundations of a novel health-care model for schizophrenia. CMHT, community mental health
treatment; rTMS, repetitive transcranial magnetic stimulation.

Examples of modules:
Acute Module
(e.g., clarification of
differential
diagnosis, initiation
of antipsychotic
medication)
Remission-stabilizing Chronic Phase Module
Module (e.g., cognitive training,
Relapse Module
(e.g., home supported employment,
(e.g., crisis
treatment if patient rehabilitation modules to
intervention)
does not attend to assess and improve recovery
appointments) and empowerment)

In-patient Out-patient In-patient Out-patient

Symptom First
severity episode

Relapse
Diagnostic
threshold

Partial Note that modules transgress

remission traditional boundaries of in-
and out-patient health-care
service sectors

Time [years]

Figure 5. Course-stage specific, individualized modular mental health-care model for schizophrenia.

© 2015 The Authors

Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
670 W. Gaebel and J. Zielasek
biomarkers.56 Transition outcomes can be correctly
predicted in about 80% of cases with the current
techniques, but clearly this needs to be improved
probably by using combinations of biomarkers in
order to become clinically more useful. Clinical
investigations show that there is a long prodromal
phase of many years before overt psychosis occurs,
and cognitive impairments and negative symptoms
like depression or avolition may be present earlier
than ‘positive’ symptoms like hallucinations and
delusions. Together with neuroimaging data, these
clinical features suggest that there is a prodromal
period antedating the dopamine-induced psychotic
state by many years, and that this prodromal phase
may be an opportunity for preventing disease pro-
gression.57 The challenge here is the identification of
persons at a high risk of developing schizophrenia,
and to determine which therapeutic approaches are
safe and effective at this disease stage.
CONCLUSIONS
The following four conceptual trends have become
evident from this review of the current state of the art
and foreseeable future developments of the diagno-
sis, classification and therapy of schizophrenia:
• The main informant for concepts, classification
and treatment will be research results on the etio-
pathogenesis of schizophrenia.
• Personalized early recognition using neuroimaging
will become a reality.
• Mental health care optimization will lead to
improved outcomes.
• There will be no utterly new principles of schizo-
phrenia concepts – but more and better evidence
for the current biopsychosocial conceptualization
of all mental disorders, including schizophrenia,
will emerge.
A major challenge will be to integrate the findings
from genetic research, neuroimaging, neurophysi-
ological studies and clinical trials into an evolving
coherent picture of the etiopathogenesis, classifica-
tion and treatment of schizophrenia. Different
methods of investigation and studies across tradi-
tional diagnostic boundaries will be necessary to
unravel the etiopathogenesis of the symptoms of
schizophrenia, to develop new classification criteria
that employ biomarkers, and to target therapy to
such disturbed neurobiological functions.34,58 Of the
© 2015 The Authors
Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 661–673
hundred genes identified as being associated with
schizophrenia, only one to two may be expected
to yield useful targets for novel therapeutic
approaches.59 Estimations based on neuroimaging
data indicate that there may be 100–1000 ‘hubs’,
which are brain centers connecting the ‘modules’ of
the brain, and that there may be on the order of 5000
to 5 million connections within modules and
between hubs that will need to be assessed.21 Another
aspect is that it will be necessary to not only analyze
biomarkers horizontally, that is, comparing healthy
controls with persons with schizophrenia, but also
vertically, that is, comparing whole sets of
biomarkers in individuals with and without schizo-
phrenia.30 Such combinatorial assessments may be
guided by target-identified objectives focusing, for
example, in one combinatorial study on synaptic
protein, synaptic functions and ensuing network
alterations, and in others focusing on immunological
aspects. Thus, several critical open questions remain:
• How can a coherent picture be conceptualized
given the highly complex, time-variable and
interindividually variable (neuro)biologic under-
pinnings of schizophrenia?
• How can compensatory mechanisms be distin-
guished from etiopathogenic factors?
• How can this information be used in individual
clinical cases to improve diagnosis or the selection
of the most effective therapeutic modalities?
Probably, deconstructing schizophrenia using the
RDoC approach in combination with improved
mental health care will be shaping the development
of schizophrenia diagnosis and therapy until 2020.
This phase will also be shaped by the current insight
that there is a bidirectional relation between sophis-
ticated advances in the diagnosis and treatment of
schizophrenia, and the mental health-care system in
the community: Scientific advances will change
mental health-care systems, and reforms in the
mental health-care systems will enhance scientific
advances, for example by providing access for more
people with schizophrenia to modern treatment
modalities and broadening the experience base about
the clinical use of innovative treatments.
In summary, the following conclusions can be
drawn:
• Even following the recent revisions of the classifi-
cation criteria of schizophrenia in DSM-5 and ICD-
Psychiatry and Clinical Neurosciences 2015; 69: 661–673
11, in 2020, schizophrenia will remain a clinically
defined primary psychotic disorder.
• Treatment can still be improved with new antipsy-
chotic drugs, drugs addressing negative symptoms,
new treatment modalities like rTMS and by
improving early detection and prevention.
• New research insights into the etiopathogenesis of
schizophrenia are promising to improve diagnosis,
classification and therapy in the future, although a
picture of complex brain dysfunction is emerging
requiring sophisticated mathematical methods of
analysis.
• The challenge is to develop comprehensive diag-
nostic and treatment modules individually tailored
to the time-variable needs of patients and their
families.
Schizophrenia has been and will be a developing
construct, which has diagnostic, prognostic and
therapy-indicating values and can therefore currently
not be abandoned. However, the road is now open
and the techniques and methods are available to
deconstruct schizophrenia based on symptoms or
biomarkers, which will hopefully lead to innovative
and improved diagnostic and therapeutic procedures.
Besides deconstructing schizophrenia and using com-
binatorial biomarker approaches, pragmatically
closing the existing treatment gap and improving the
quality of schizophrenia mental and somatic health
care are attainable goals for the next 5 years.
ACKNOWLEDGMENTS
The authors declare no conflicts of interest pertain-
ing to the preparation of this manuscript or its con-
tents. W.G. has received symposia support from
Janssen-Cilag GmbH, Neuss, Lilly Deutschland
GmbH, Bad Homburg, Servier Deutschland GmbH,
Munich and Sanofi-Aventis Deutschland GmbH,
Frankfurt am Main. W.G. is a member of the Faculty
of the Lundbeck International Neuroscience Foun-
dation (LINF), Denmark. J.Z. has received an author
honorarium for a review article by Servier Medical
Publishing.
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