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Schizophrenia in 2020: Trends in diagnosis and therapy Wolfgang Gaebel, MD1,2* and Jürgen Zielasek, MD1,2

1Department 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

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.

CLINICAL AND BASIC research has been provid- 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).

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-

*Correspondence: Wolfgang Gaebel, MD, Department of Psychiatry and Psychotherapy, LVR-Klinikum Düsseldorf, Bergische Landstr. 2, D-40629 Düsseldorf, Germany. Email: [email protected] Accepted 22 May 2015.

doi:10.1111/pcn.12322

mailto:[email protected]

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

6000

Number of publications “schizophrenia” per year

5000

4000

3000

2000

1000

2014201320122011201020092008200720062005200420032002200120001999199819971996199519941993199219911990 0

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.

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http://apps.who.int/classifications/icd11/browse/f/en

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

DSM-5

ICD-11

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):

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

b. Persistent hallucinationshallucinations (most commonly auditory, although they may be in any sensory modality).

c. Disorganized thinkingDisorganized 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 controlExperiences 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,Negative symptoms, such as affective flattening, alogia or paucity of speech, avolition, asociality and anhedonia.

f. Grossly disorganized behavior,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,Psychomotor disturbances, such as catatonic restlessness or agitation, posturing, waxy flexibility, negativism, mutism, or stupor.

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:

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).

Social/occupational dysfunction

Duration (6 months)

Schizoaffective and Mood Disorder Exclusion

Substance/General Medical Condition Exclusion

Relationship to a Pervasive Developmental Disorder

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).

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http://apps.who.int/classifications/icd11/browse/f/en

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.

Symptom SpecifiersSymptom Specifiers

Course SpecifiersCourse Specifiers

(harmonized for use in both

ICD-11 and DSM-5)

ICD-11

0 Positive symptoms

1 Negative symptoms

2 Depressive symptoms

3 Manic symptoms

4 Psychomotor symptoms

5 Cognitive impairment

0 First episode, currently in acute episode

1 First episode, currently in partial remission

2 First episode, currently in full remission

3 Multiple episodes, currentlly in acute episode

4 Multiple episodes, currentlly in partial remission

5 Multiple episodes, currentlly in full remission

6 Continuous

7 Unspecified

DSM-5

• Hallucinations

• Delusions

• Disorganized speech

• Abnormal psychomotor

behavior

• Negative symptoms

• Impaired cognition

• Depression

• Mania

Figure 3. Symptom and source specifiers of ICD-11 (beta version, http://apps.who.int/classifications/ icd11/browse/f/en, last accessed 26 February, 2015) and DSM-5.1

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• 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-

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.

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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 –

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.

666 W. Gaebel and J. Zielasek 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-

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

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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

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

668 W. Gaebel and J. Zielasek Psychiatry and Clinical Neurosciences 2015; 69: 661–673

Etiology

Pathophysiology

Psychological

mechanisms

Personal and

mental health-care

system level

New therapies developed

based on novel

mechanisms of etiology

and pathophysiology, like

information on brain

network disturbances in

schizophrenia

New therapies developed

based on findings about

the role of cognitive

processes in symptom

formation

New therapies addressing

recovery and empowerment,

including and going beyond

classical outcome assessments

like symptom assessments

Demonstrated efficacy of

elements of mental health care

like CMHT or supported

employment

Comprehensive Community

Mental Health Centers,

Assertive Community

Treatment, home treatment,

crisis intervention,

psychoeducation and

empowerment training

Deep brain stimulation

rTMS treatment

Cognitive training

for negative symptoms

Bio Psycho Social

Level of

information

source

Examples

of novel

approaches

Resulting

health-care

modules

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:

Symptom

severity

Diagnostic

threshold

First

episode

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

Partial

remission

Time [years]

Relapse

Note that modules transgress traditional boundaries of in- and out-patient health-care service sectors

Acute Module

(e.g., clarification of

differential

diagnosis, initiation

of antipsychotic

medication)

Chronic Phase Module

(e.g., cognitive training,

supported employment,

rehabilitation modules to

assess and improve recovery

and empowerment)

Relapse Module

(e.g., crisis

intervention)

Remission-stabilizing

Module

(e.g., home

treatment if patient

does not attend to

appointments)

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

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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

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-

670 W. Gaebel and J. Zielasek 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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