Schizophrenia

Background: The lifetime prevalence of schizophrenia is 1%. Schizophrenia is among the most severe mental illnesses and gives rise to the highest treatment costs per patient of any disease. It is characterized by frequent relapses, marked impairment of quality of life, and reduced social and work participation.

Methods: The group entrusted with the creation of the German clinical practice guideline was chosen to be representative and pluralistic in its composition. It carried out a systematic review of the relevant literature up to March 2018 and identified a total of 13 389 publications, five source guidelines, three other relevant German clinical practice guidelines, and four reference guidelines.

Results: As the available antipsychotic drugs do not differ to any great extent in efficacy, it is recommended that acute antipsychotic drug therapy should be side-effect-driven, with a number needed to treat (NNT) of 5 to 8. The choice of treatment should take motor, metabolic, sexual, cardiac, and hematopoietic considerations into account. Ongoing antipsychotic treatment is recommended to prevent relapses (NNT: 3) and should be re-evaluated on a regular basis in every case. It is also recommended, with recommendation grades ranging from strong to intermediate, that disorder- and manifestation-driven forms of psychotherapy and psychosocial therapy, such as cognitive behavioral therapy for positive or negative manifestations (effect sizes ranging from d = 0.372 to d = 0.437) or psycho-education to prevent relapses (NNT: 9), should be used in combination with antipsychotic drug treatment. Further aspects include rehabilitation, the management of special treatment situations, care coordination, and quality management. A large body of evidence is available to provide a basis for guideline recommendations, particularly in the areas of pharmacotherapy and cognitive behavioral therapy.

Conclusion: The evidence-based diagnosis and treatment of persons with schizophrenia should be carried out in a multiprofessional process, with close involvement of the affected persons and the people closest to them.

Schizophrenia is one of the most severe mental illnesses. It has a point prevalence of 4.6 per 1000 inhabitants, a lifetime prevalence of around 1%, and the median reported incidence is 15 cases per 100 000 inhabitants (see [1] for details). Approximately two thirds of newly arising cases of schizophrenia occur before 45 years of age, i.e., in young to middle-aged adults. With regard to the clinical presentation, schizophrenia is characterized by a heterogeneous phenotype and a variable course, so one should really speak of a group of diseases, “the schizophrenias.” However, in accordance with the criteria for diagnosis and classification we used the singular “schizophrenia” for the guidelines. The disease is characterized by psychopathological disorders of perception, ego functions, affectivity, energy, and psychomotor function and by events that occur at particular junctures in the disease course (1). The latter is inter- and intraindividually variable: there may be one single episode, recurring episodes with no symptoms at all in between, relapses of increasing severity, or continuous illness with no periodic absence of symptoms. Although self-limiting episodes of schizophrenia are known to occur, the majority of episodes require multiprofessional treatment. The diagnosis is made in operationalized manner according to ICD-10 criteria. It is not only very important to differentiate schizophrenia from other mental illnesses; somatic diseases must also be considered as comorbidites or as causes for secondary psychoses.

One important factor that has, so far, received little attention is the very high mortality rate. Studies show that schizophrenia reduces life expectancy by anything from 10 to 25 years (2, 3). There are many reasons for the elevated mortality: increased suicidality (especially in the early years of illness), the occurrence of somatic diseases, underdiagnosis of somatic diseases, deficient self-care, and inadequate psychiatric/psychotherapeutic treatment, as well as aspects of treatment-associated adverse effects (1, 4, 5). Around 10% of persons in whom schizophrenia is diagnosed for the first time attempt suicide in the 12 months following diagnosis, and one can conclude, depending on the individual survey, that 5 to 15% of persons with a schizophrenia spectrum disorder kill themselves (6, 7, 8, 9, 10, 11, 12). An example of the underdiagnosis of somatic comorbidities is provided by a Swedish cohort study of 6 097 838 adults (including 8277 with schizophrenia): In both women (hazard ratio 3.33, 95% confidence interval [2.73; 4.05]) and men (2.20 [1.83; 2.65]) with schizophrenia, death due to ischemic heart disease occurred more frequently than in the rest of the population. Furthermore, the likelihood of timely diagnosis was significantly lower in those with schizophrenia (26.3% versus 43.7%). The figures for cancer disease were similar (13). Other clinically relevant characteristics that are associated with schizophrenia and are often interrelated are marked stigmatization; associations with previous trauma and experience of violence (the mean proportion of persons with schizophrenia who fulfill the criteria for post-traumatic stress disorder [PTSD] is as high as 30% [14]); a high prevalence of comorbid substance dependency (principally tobacco (prevalence up to 80% [15]), alcohol, and cannabis (mean prevalences ~25% [16]); high rates of unemployment and homelessness (~12% of homeless persons have a psychotic disease [17]); and reduced social participation.

The new German clinical practice guidelines

The clinical practice guidelines on schizophrenia published in 2019 represent a comprehensive revision and expansion of the two previous versions from 1998 and 2006. Each of these earlier documents was conceived, developed, and published as patient-centered, evidence-based, and consensus-based guidelines in accordance with the rules and standards of the Association of the Scientific Medical Societies in Germany (AWMF) (1).

Methods

The guideline revision was undertaken by a committee of persons representative of the intended users, divided into a steering group, an extended steering group, a consensus group, and an additional expert group (eBox 1). For the purpose of revision the subject matter was divided into modules, each dealt with by a dedicated working group in a multistage process (see [18]):

Box 1

What are the most important changes in the revised guidelines?

eBox 1

Professional societies, interest groups, and persons involved in the revision of the guideline

• Formulation and agreement of clinical issues within the guidelines group
• Identification and methodological evaluation of existing guidelines on schizophrenia (for the purpose of guideline adaptation)
• Systematic search of the literature with regard to questions not adequately answered by guideline adaptation (start date: 3 March  2016, last research: 1 March 2018)
• Systematic selection and evaluation of the evidence
• Formulation of recommendations and suggestions for recommendation grades by the module working groups and the steering group according to the PICO (patient population, intervention, comparison, outcome) scheme (19)
• Adoption of the recommendations and structured consensus building (consensus conferences and written Delphi process)
• Internal and external reviewing and adoption of the guidelines

Table

Three selected topics in the field of antipsychotic psychotherapy with the underlying meta-analyses and other source documents

Only guidelines of high methodological quality on relevant topics were used as sources (20, 21, 22, 23, 24). Domain 3 (Methodological Rigour of Development) of the German Instrument for Methodological Guideline Appraisal (DELBI) was used for assessment. Gradations of evidence and wordings of recommendations from these source guidelines were adapted for use in the revised guidelines. Further sources of recommendations on dependency-specific topics were two AWMF clinical practice guidelines (15, 25). An overview of the guidelines from Germany and other countries that were used, together with related AWMF guidelines, can be found in eTable 1. Moreover, for some of the guideline recommendations systematic de novo research was carried out (eFigure 1), while for other recommendations not based on evidence clinical consensus points were compiled.

Figure

Treatment algorithm derived from the revised German clinical practice guidelines (focus on pharmacology)

eFigure 1

Flow chart of systematic literature survey

eTable 1

National and international source guidelines, reference guidelines, and other related guidelines used in compiling the revision

Updated content in the revised guidelines

The modular structure of the guidelines is intended to enable future revision on the lines of the “living guidelines” principle. Box 1 summarizes the most important changes in the revised clinical practice guidelines, described in more detail below.

Diagnosis and differential diagnosis

As stated above, schizophrenia is diagnosed according to the operationalized criteria of ICD-10 (eFigure 2). However, the guidelines give a glimpse of the changes that can be anticipated in ICD-11. One particular innovation is the possibility of describing the course of the illness on the basis of symptom domains (positive symptoms, negative symptoms, cognitive disorders, psychomotor disorders, and affective disorders) (26). Much more importance is attached in the revised guidelines to aspects of organic differential diagnosis: recommendations were agreed with the intention of on the one hand detecting rare organic causes of schizophrenia (e.g., autoimmune encephalitis) in timely fashion, and on the other hand diagnosing the frequently occurring somatic comorbidities and integrating them into the overall treatment plan. eBox 2 presents the accompanying somatic disorders most commonly found in persons with schizophrenia, with the data expressed in terms of prevalence rates, incidence rates, or odds ratios.

eBox 3

Detection and management of adverse drug reactions

Box 2

Findings of selected meta-analyses published after the end of the literature survey

eBox 2

Relevant somatic comorbidities

eFigure 2

Algorithms for psychopathological and somatic differential diagnosis

General treatment principles

Modern psychiatric/psychotherapeutic treatment of persons with schizophrenia should always be multiprofessional, and all those involved in the treatment should maintain an empathetic, appreciative attitude. According to the guidelines, the “general goal of treatment [is] a person broadly free of symptoms of illness who is capable of living in a self-determined manner, has been informed about the therapeutic options, and is in the position to weigh up the risks and benefits thereof” (1). To achieve this, the elements of pharmacotherapy, psychotherapy, and psychosocial treatments should be offered in terms of an overall treatment plan with the close involvement of the person with schizophrenia together with their relatives or other reference persons. According to the evidence and consensus opinion, antipsychotic drug treatment alone is generally insufficient, as is renunciation of antipsychotic pharmacotherapy. Other forms of treatment, such as the use of antidepressants or neurostimulation procedures (e.g., electroconvulsive therapy), are reserved for particular indications (e.g., depressive syndromes or clozapine resistance).

Treatment with antipsychotics

Antipsychotics are highly effective with regard to the goals relevant to the disease (e.g., reduction of psychotic symptoms, prevention of relapse). For example, the largest meta-analysis with the highest quality methods shows a number needed to treat (NNT) of 3 for 1-year prevention of relapse (relapse rate 27% with antipsychotic treatment, 64% with placebo) (27). In respect of the therapeutic response in terms of reduction of psychotic experiences, another large-scale and high-quality meta-analysis shows an NNT of 5 or 8 for a minimal or good response (51%/23% with antipsychotic treatment, 30%/14% with placebo) (28). One basic innovation in the new German clinical practice guidelines is the emphasis on adverse effect–guided selection of the antipsychotic substances—abolishing the general prioritization of a specific substance group. Based on an adaptation of a NICE guideline (20) and on a meta-analysis (29), the following definition was formulated: “We recommend offering antipsychotics at a dose that is within the range recommended by the respective international consensuses and is as low as possible and as high as necessary (lowest possible dose)”. A low dose should be chosen particularly in patients suffering their first episode of schizophrenia, who are more vulnerable to adverse effects and overall respond better to low dosages. It is important that treatment to reduce psychotic symptoms be offered in the form of antipsychotic monotherapy. The recommendation of monotherapy is justified especially on grounds of better tractability and a lower risk of adverse effects and drug interactions. Moreover, nearly all of the source studies and meta-analyses investigated antipsychotics given as monotherapy.

For the first time, and uniquely worldwide, clinical consensus point (CCP) recommendations on the discontinuation of antipsychotic medication were agreed. This should not be defined as the primary course of action, however, because of the low recommendation grade (“may be considered”) compared with administration of antipsychotics to prevent relapse (“we recommend”). Nevertheless, suggestions, recommendations, and strategies are now in place for dealing with the routinely expressed request from both patients and their relatives for antipsychotic medication to be stopped. It is important, in clinical practice, to state that treatment does not end with discontinuation of the medication. On the contrary, regular, coordinated outpatient psychiatric and/or psychotherapeutic follow-up visits should continue for at least 2 years, with two goals: (1) early detection of signs and symptoms of an impending relapse (e.g., sleep disorders, a brief psychotic episode, depressive symptoms, inner unrest); (2) implementation of interventions to help manage stress or structure daily activities. It is vital for treatment to continue beyond supervised discontinuation of drug intake.

In contrast to the guideline recommendation of monotherapy, however, in clinical practice the use of polypharmacy is growing, particularly later in the disease course (30). This discrepancy between clinical practice and evidence was addressed as follows: According to the revised guidelines, a combination of two antipsychotics should be given (recommendation grade CCP) only after the failure of three previous attempts at antipsychotic treatment of adequate dosage and duration—including a course of clozapine—as monotherapy (recommendation 43, recommendation grade A, and recommendation 46, recommendation grade A). The addition of a second antipsychotic or an antidepressant for the temporary treatment of unrest, sleep disorders, elevated prolactin concentration, or depressive symptoms is considered separately in the guidelines—this special situation does not fall under the described recommendation to offer monotherapy, but when any additional substance is given, one must bear in mind the possible increase in adverse effects and monitor the patient accordingly. The Table and eTable 2 summarize the meta-analyses cited in the guidelines and list the corresponding recommendations. The Figure shows a treatment algorithm, derived from relevant recommendations, which focuses on antipsychotic treatment.

eTable 2

Supplement to the Table. Further selected topics in the field of antipsychotic drug therapy with the underlying meta-analyses and other source documents

Psychotherapy and psychosocial treatments

The revised clinical practice guidelines place far more emphasis on psychotherapy. Combination of treatment with an antipsychotic substance and cognitive behavioral therapy (CBT) is recommended for all persons with schizophrenia (effect size for positive symptoms: d = 0.372; for negative symptoms: d = 0.437). CBT should be offered (recommendation grade A). If CBT begins while the patient is in the hospital, it should be continued on an outpatient basis after discharge; the duration of treatment should be ≥ 16 sessions, and for optimization of treatment effects and in cases with more complex treatment goals ≥ 25 sessions should be offered (recommendation grade B). The inpatient and outpatient psychotherapeutic care available for persons with schizophrenia in Germany is clearly inadequate, although it remains unclear whether the previously very low rates of psychotherapy in this population have been increased by the extension of the indication to all phases of the disease by the Federal Joint Committee (G-BA) in 2014 (art. 26 para. 2 no. 4 of the G-BA’s Psychotherapy Guidelines) (1). Other psychotherapeutic procedures with recommendation grade A are psychoeducation (NNT = 9 in prevention of relapse), family interventions, cognitive remediation (a cognitive training and education process), and social competence training. The various procedures should be offered individually, depending on the indications in each case. eTable 3 shows the matrix of psychotherapeutic and psychosocial treatment procedures that can be offered depending on the indications and individual preferences. New in the revised guidelines is the recommendation (grade B) that CBT also be offered to those who reject antipsychotic drug treatment.

eTable 4

Detection and treatment of metabolic adverse events

eTable 5

Follow-up visits in antipsychotic treatment

eTable 6

The typical adverse effects of antipsychotics, according to the revised clinical practice guidelines

eTable 3

Matrix of the recommendations for psychotherapeutic and psychosocial treatment procedures, with selected underlying source publications, relevant statistical measures, and recommendation grades

Management of adverse drug reactions

A large number of preparation-specific adverse drug reactions may be caused by antipsychotics, and these potential side effects must always be borne in mind when prescribing this type of medication. Accordingly, the clinical practice guidelines focus on adverse event–guided prescription of antipsychotic drugs. The following groups of adverse events must be particularly closely respected and monitored:

• Motor reactions
• Metabolic reactions
• Sexual dysfunction/prolactin-associated reactions
• Cardiac reactions
• Disorders of the hematopoietic system.

Specifically for metabolic reactions, the guidelines group approved new evidence-based recommendations in terms of a stepwise procedure for detection and treatment. eBox 3 defines a general stepwise process for the recognition and treatment of adverse events, while eTable 4 presents concrete recommendations for the detection and treatment of metabolic syndrome, a very common occurrence in persons with schizophrenia. eTable 5 shows the follow-up visits as defined by the guidelines group for persons receiving antipsychotic treatment, and eTable 6 lists the preparation-specific adverse events.

Problems in coordination of care

In practice, various problems may arise in coordination among caregivers. These can affect the transition from inpatient care to the post-hospital setting (day clinic, outpatient clinic, specialist medical care in the community), coordination in the area of outpatient care (specialist-centered treatment, psychotherapists, primary-care physicians, other parties), or the challenge of hospital admission in an acute phase of illness characterized by decreased or lacking insight. The new module 5 (coordination of care) is dedicated to these and other aspects of optimized organization of patient care. For example, one recommendation (grade CCP) is that whenever treatment by a multiprofessional team is required or intensification of psychopharmacological, psychotherapeutic, or psychosocial measures becomes necessary, it should be considered whether transfer to a specialized and multiprofessional psychiatric hospital outpatient service (Psychiatrische Institutsambulanz, PIA), or to a community care network in which more complex treatment programs are available if needed, might be beneficial (1). In another recommendation (CCP, strong consensus) the guidelines group defined indications for hospital admission. Inpatient treatment should be offered to all patients who would benefit from the diagnostic and therapeutic resources available in the hospital setting or from the special protection offered by the hospital in the case of acute danger to themselves or others. This would include, for example:

• Treatment resistance
• Acute suicidality
• States of severe delusion or anxiety
• Lack of proper nutrition or self-care
• Marked apathy or adynamia
• Domestic circumstances hindering remission and recovery
• Treatment of complicating comorbidities
• Complex treatment situations
• Unexplained somatic comorbidities
• Severe adverse drug reactions
• Other problems not amenable to outpatient care.

This incomplete list makes it clear that in patients who present acute danger to themselves or others, or lack insight, one must consider hospitalization under the terms of the Care Act and the laws of the federal state concerned. It also becomes apparent that the guidelines group has defined factors such as the lack of options for care, but most importantly somatic and mental comorbidities, as indications for admission to the hospital. These latter points routinely lead to discussions with the medical service of the health insurance providers in Germany (MDK) on whether hospital beds are being utilized unnecessarily.

Summary

The revised German clinical practice guidelines on schizophrenia contain recommendations on both the diagnostic work-up and the pharmacological, psychotherapeutic, and psychosocial treatment of persons with schizophrenia over their entire life span. To conform with the guidelines, the treatment of persons with schizophrenia must be multiprofessional with a basic attitude of empathy, respect, and appreciation on the part of the caregivers. The aim is to render those affected able to enjoy “full and equal enjoyment of all human rights and fundamental freedoms” (article  1, UN CRPD).

Clinical practice guidelines in the Deutsches Ärzteblatt, as in numerous other specialist journals, are not subject to a peer review procedure, since such guidelines represent texts that have already been evaluated, discussed, and broadly agreed upon multiple times by experts (peers).

Acknowledgments

We thank all the individuals and groups whose long-term, continuous, and constructive commitment made it possible to draw up this guideline. Thanks are due to the German Association for Psychiatry, Psychotherapy and Psychosomatics for its substantive, structural and financial support of the entire guideline process, without which revision of the guideline could not have been achieved.

We are particularly grateful to Prof. Kopp (AWMF-Institute for Medical Knowledge Management) for her balanced moderation and advice during the entire guideline development process.

Conflict of interest statement
Prof. Hasan has received consultancy honoraria from Lundbeck, Otsuka, Janssen, and Roche as well as speaker’s fees from Desitin, Lundbeck, Otsuka and Janssen. He is the editor of the WFSBP guideline on schizophrenia. He is a member of an IFCN guideline group on rTMS treatment of neurological and mental illnesses.

Prof. Falkai has received consultancy honoraria from Janssen, Richter Pharma, Servier, and Sage as well as speaker’s fees from Otsuka, Lundbeck, Janssen, and Richter Pharma.

Prof. Gaebel is a member of the Lundbeck International Neuroscience Foundation (LINF).

Dr. Lehmann states that no conflict of interest exists.

Translated from the original German by David Roseveare

Corresponding author
Prof. Dr. med. Alkomiet Hasan
Bezirkskrankenhaus Augsburg, Klinik für Psychiatrie
Psychotherapie und Psychosomatik der Universität Augsburg
Medizinische Fakultät der Universität Augsburg
Dr.-Mack-Str. 1, 86156 Augsburg, Germany

Cite this as:
Hasan A, Falkai P, Lehmann I, Gaebel W: Clinical practice guideline: Schizophrenia. Dtsch Arztebl Int 2020; 117: 412–9.
DOI: 10.3238/arztebl.2020.0412

►Supplementary material

For eReferences please refer to:
www.aerzteblatt-international.de/ref2420

eTables, eBoxes and eFigures:
www.aerzteblatt-international.de/20m0412

References

1. Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN): S3-Leitlinie Schizophrenie. AWMF-Register Nr. 038–009. www.awmf.org/leitlinien/detail/ll/038-009.html (last accessed on 15 March 2019).

2. Simon GE, Stewart C, Yarborough BJ, et al.: Mortality rates after the first diagnosis of psychotic disorder in adolescents and young adults. JAMA Psychiatry 2018; 75: 254–60

3. Plana-Ripoll O, Pedersen CB, Agerbo E, et al.: A comprehensive analysis of mortality-related health metrics associated with mental disorders: a nationwide, register-based cohort study. Lancet 2019; 394: 1827–35

4. DeHert M, Correll CU, Bobes J, et al.: Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care. World Psychiatry 2011; 10: 52–77

5. De Hert M, Cohen D, Bobes J, et al.: Physical illness in patients with severe mental disorders. II. Barriers to care, monitoring and treatment guidelines, plus recommendations at the system and individual level. World Psychiatry 2011; 10: 138–51

6. Caldwell CB, Gottesman II: Schizophrenics kill themselves too: a review of risk factors for suicide. Schizophrenia Bull 1990; 16: 571–89

7. Siris SG: Suicide and schizophrenia. J Psychopharmaco 2001; 15: 127–35

8. Meltzer HY: Suicide in schizophrenia, clozapine, and adoption of evidence-based medicine. J Clin Psychiatry 2005; 66: 530–3

9. Pompili M, Amador XF, Girardi P, et al.: Suicide risk in schizophrenia: learning from the past to change the future. Ann Gen Psychiatry 2007; 6: 10

10. Pompili M, Lester D, Grispini A, et al.: Completed suicide in schizophrenia: evidence from a case-control study. Psychiatry Res 2009; 167: 251–7

11. Hasan A, Falkai P, Wobrock T, et al.: World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia. Part 3: update 2015 management of special circumstances: depression, suicidality, substance use disorders and pregnancy and lactation. World J Biol Psychiatry 2015; 16: 142–70

12. Nordentoft M, Jeppesen P, Abel M, et al.: OPUS study: suicidal behaviour, suicidal ideation and hopelessness among patients with first-episode psychosis. One-year follow-up of a randomised controlled trial. Br J Psychiatry Suppl 2002; 43: s98–106

13. Crump C, Winkleby MA, Sundquist K, Sundquist J: Comorbidities and mortality in persons with schizophrenia: a Swedish national cohort study. Am J Psychiatry 2013; 170: 324–33

14. Buckley PF, Miller BJ, Lehrer DS, Castle DJ: Psychiatric comorbidities and schizophrenia. Schizophrenia Bull 2009; 35: 383–402

15. Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN): S3-Leitlinie: Screening, Diagnostik und Behandlung des schädlichen und abhängigen Tabakkonsums 2015. www.awmf.org/leitlinien/detail/ll/076-006.html (last accessed on 19 January 2020).

16. Hunt GE, Large MM, Cleary M, Lai HMX, Saunders JB: Prevalence of comorbid substance use in schizophrenia spectrum disorders in community and clinical settings, 1990–2017: systematic review and meta-analysis. Drug Alcohol Depend 2018; 191: 234–58

17. Fazel S, Khosla V, Doll H, Geddes J: The prevalence of mental disorders among the homeless in western countries: systematic review and meta-regression analysis. PLoS Med 2008; 5: e225

18. Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN): S3-Leitlinie Schizophrenie: Leitlinienreport. www.awmf.org/uploads/tx_szleitlinien/038-009m_S3_Schizophrenie_2019-03.pdf (last accessed on 19 January 2020).

19. Richardson WS, Wilson MC, Nishikawa J, Hayward RS: The well-built clinical question: a key to evidence-based decisions. ACP journal club 1995; 123: A12–3.

20. National Institute for Health and Care Excellence (NICE): NICE clinical guideline 178 – Psychosis and schizophrenia in adults: treatment and management – Issued: February 2014, last modified: March 2014. guidance.nice.org.uk/cg178 (last accessed on 27 December 2019).

21. National Institute for Health and Care Excellence (NICE): Psychosis and schizophrenia in children and young people: recognition and management. www.ncbi.nlm.nih.gov/books/NBK299073/ (last accessed on 19 January 2020).

22. National Institute for Health and Care Excellence (NICE): Violence and aggression: short-term management in mental health, health and community settings. 2015.www.nice.org.uk/guidance/ng10 (last accessed on 19 January 2020).

23. Scottish Intercollegiate Guidelines Network (SIGN): SIGN 131. Management of schizophrenia. A national clinical guideline 2013. www.sign.ac.uk/sign-131-management-of-schizophrenia (last accessed on 14 July 2019).

24. Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN): S3 Leitlinie Psychosoziale Therapien bei schweren psychischen Erkrankung – 2013er Version und Teile der revidierten 2018er Version lagen der Leitliniengruppe vor. 2013/18. www.awmf.org/leitlinien/detail/ll/076-001.html (last accessed on 19 January 2020).

25. Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN): Screening, Diagnose und Behandlung alkoholbezogener Störungen: Springer; 2016. www.awmf.org/leitlinien/detail/ll/038-020.html (last accessed on 19 January 2020).

26. Gaebel W: Status of psychotic disorders in ICD-11. Schizophr Bull 2012; 38: 895–8

27. Leucht S, Tardy M, Komossa K, et al.: Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012; 379: 2063–71

28. Leucht S, Leucht C, Huhn M, et al.: Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry 2017; 174: 927–42

29. Uchida H, Suzuki T, Takeuchi H, Arenovich T, Mamo DC: Low dose vs standard dose of antipsychotics for relapse prevention in schizophrenia: meta-analysis. Schizophr Bull 2011; 37: 788–99

30. Gallego JA, Bonetti J, Zhang J, Kane JM, Correll CU: Prevalence and correlates of antipsychotic polypharmacy: a systematic review and meta-regression of global and regional trends from the 1970s to 2009. Schizophr Res 2012; 138: 18–28

31. Leucht S, Crippa A, Siafis S, Patel MX, Orsini N, Davis JM: Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry 2019: appiajp201919010034

32. Leucht S, Cipriani A, Spineli L, et al.: Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–62

33. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al.: Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 2019; 394: 939–51

34. Schneider-Thoma J, Efthimiou O, Huhn M, et al.: Second-generation antipsychotic drugs and short-term mortality: a systematic review and meta-analysis of placebo-controlled randomised controlled trials. Lancet Psychiatry 2018; 5: 653–63

35. Bighelli I, Salanti G, Huhn M, et al.: Psychological interventions to reduce positive symptoms in schizophrenia: systematic review and network meta-analysis. World Psychiatry 2018; 17: 316–29

36. McCutcheon RA, Pillinger T, Mizuno Y, et al.: The efficacy and heterogeneity of antipsychotic response in schizophrenia: a meta-analysis. Mol Psychiatry 2019. [Epub ahead of print

37. Pillinger T, McCutcheon RA, Vano L, et al.: Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry 2020; 7: 64–77

38. Zhu Y, Li C, Huhn M, et al.: How well do patients with a first episode of schizophrenia respond to antipsychotics: a systematic review and meta-analysis. Eur Neuropsychopharmacol 2017; 27: 835–44

39. Deutsche Gesellschaft für Psychiatrie und Psychotherapie und Nervenheilkunde (DGPPN): S3 Praxisleitlinien in Psychiatrie und Psychotherapie. Band 1 – Behandlungsleitlinie Schizophrenie. Darmstadt: Steinkopff-Verlag 2006.

e1. De Hert M, Sermon J, Geerts P, Vansteelandt K, Peuskens J, Detraux J: The use of continuous treatment versus placebo or intermittent treatment strategies in stabilized patients with Schizophrenia: A systematic review and meta-analysis of randomized controlled trials with first- and second-generation antipsychotics. CNS Drugs 2015; 29: 637–58

e2. Samara MT, Leucht C, Leeflang MM, et al.: Early improvement as a predictor of later esponse to antipsychotics in schizophrenia: a diagnostic test review. Am J Psychiatry 2015; 172: 617–29

e3. Samara MT, Dold M, Gianatsi M, et al.: Efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia: a network meta-analysis. JAMA Psychiatry 2016; 73: 199–210

e4. Siskind D, McCartney L, Goldschlager R, Kisely S: Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry 2016; 209: 385–92

e5. Buchanan RW, Kreyenbuhl J, Kelly DL, et al.: The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophrenia Bull 2010; 36: 71–93

e6. Hasan A, Falkai P, Wobrock T, et al.: World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry 2012; 13: 318–78

e7. Dold M, Fugger G, Aigner M, Lanzenberger R, Kasper S: Dose escalation of antipsychotic drugs in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Res 2015; 166: 187–93

e8. Galling B, Roldan A, Hagi K, et al.: Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry 2017; 16: 77–89

e9. Wang Y, Xia J, Helfer B, Li C, Leucht S: Valproate for schizophrenia. Cochrane Database Syst Rev 2016; 11: CD004028

e10. Leucht S, Helfer B, Dold M, Kissling W, McGrath JJ: Lithium for schizophrenia. Cochrane Database Syst Rev 2015: CD003834

e11. Correll CU, Rubio JM, Inczedy-Farkas G, Birnbaum ML, Kane JM, Leucht S: Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry 2017; 74: 675–84

e12. Helfer B, Samara MT, Huhn M, et al.: Efficacy and safety of antidepressants added to antipsychotics for schizophrenia: a systematic review and meta-analysis. Am J Psychiatry 2016; 173: 876–86

e13. Xia J, Merinder LB, Belgamwar MR: Psychoeducation for schizophrenia. Cochrane Database Syst Rev 2011: CD002831

e14. Bird V, Premkumar P, Kendall T, Whittington C, Mitchell J, Kuipers E: Early intervention services, cognitive-behavioural therapy and family intervention in early psychosis: systematic review. Br J Psychiatry 2010; 197: 350–6

e15. Wykes T, Steel C, Everitt B, Tarrier N: Cognitive behavior therapy for schizophrenia: effect sizes, clinical models, and methodological rigor. Schizophr Bull 2008; 34: 523–37

e16. Eichner C, Berna F: Acceptance and efficacy of metacognitive training (MCT) on positive symptoms and delusions in patients with schizophrenia: a meta-analysis taking into account important moderators. Schizophr Bull 2016; 42: 952–62

e17. Pinquart M, Oslejsek B, Teubert D: Efficacy of systemic therapy on adults with mental disorders: a meta-analysis. Psychother Res 2016; 26: 241–57

e18. Turner DT, McGlanaghy E, Cuijpers P, van der Gaag M, Karyotaki E, MacBeth A: A meta-analysis of social skills training and related interventions for psychosis. Schizophr Bull 2017

e19. Rosenbaum B, Harder S, Knudsen P, et al.: Supportive psychodynamic psychotherapy versus treatment as usual for first-episode psychosis: two-year outcome. Psychiatry 2012; 75: 331–41

e20. Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P: A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry 2011; 168: 472–85

e21. Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN): S3 Leitlinie Psychosoziale Therapien bei schweren psychischen Erkrankungen. www.awmf.org/leitlinien/detail/ll/038-020.html (last accessed on 19 January 2020).

e22. Correll CU, Solmi M, Veronese N, et al.: Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3 211 768 patients and 113 383 368 controls. World Psychiatry 2017; 16: 163–80

e23. Leucht S, Burkard T, Henderson J, Maj M, Sartorius N: Physical illness and schizophrenia: a review of the literature. Acta Psychiatr Scand 2007; 116: 317–33

e24. Olfson M, Gerhard T, Huang C, Crystal S, Stroup TS: Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry 2015; 72: 1172–81

e25. Galling B, Roldan A, Nielsen RE, et al.: Type 2 diabetes mellitus in youth exposed to antipsychotics: a systematic review and meta-analysis. JAMA Psychiatry 2016; 73: 247–59

e26. Bitter I, Czobor P, Borsi A, et al.: Mortality and the relationship of somatic comorbidities to mortality in schizophrenia. A nationwide matched-cohort study. Eur Psychiatry 2017; 45: 97–103

e27. Vancampfort D, Correll CU, Galling B, et al.: Diabetes mellitus in people with schizophrenia, bipolar disorder and major depressive disorder: a systematic review and large scale meta-analysis. World Psychiatry 2016; 15: 166–74

e28. Vancampfort D, Stubbs B, Mitchell AJ, et al.: Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis. World Psychiatry 2015; 14: 339–47

e29. Li H, Li J, Yu X, et al.: The incidence rate of cancer in patients with schizophrenia: a meta-analysis of cohort studies. Schizophr Res 2018; 195: 519–28

e30. Vancampfort D, Wampers M, Mitchell AJ, et al.: A meta-analysis of cardio-metabolic abnormalities in drug naive, first-episode and multi-episode patients with schizophrenia versus general population controls. World Psychiatry 2013; 12: 240–50

e31. Stubbs B, Vancampfort D, De Hert M, Mitchell AJ: The prevalence and predictors of type two diabetes mellitus in people with schizophrenia: a systematic review and comparative meta-analysis. Acta Psychiatr Scand 2015; 132: 144–57

e32. Mitchell AJ, Vancampfort D, De Herdt A, Yu W, De Hert M: Is the prevalence of metabolic syndrome and metabolic abnormalities increased in early schizophrenia? A comparative meta-analysis of first episode, untreated and treated patients. Schizophr Bull 2013; 39: 295–305

e33. Zareifopoulos N, Bellou A, Spiropoulou A, Spiropoulos K: Prevalence of comorbid chronic obstructive pulmonary disease in individuals suffering from schizophrenia and bipolar disorder: a systematic review. COPD 2018; 15: 612–20

e34. Kuo CJ, Yang SY, Liao YT, et al.: Second-generation antipsychotic medications and risk of pneumonia in schizophrenia. Schizophr Bull 2013; 39: 648–57

e35. Hughes E, Bassi S, Gilbody S, Bland M, Martin F: Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness: a systematic review and meta-analysis. Lancet Psychiatry 2016; 3: 40–8

e36. Stubbs B, Vancampfort D, Veronese N, et al.: The prevalence and predictors of obstructive sleep apnea in major depressive disorder, bipolar disorder and schizophrenia: a systematic review and meta-analysis. J Affect Disord 2016; 197: 259–67

e37. Clancy MJ, Clarke MC, Connor DJ, Cannon M, Cotter DR: The prevalence of psychosis in epilepsy; a systematic review and meta-analysis. BMC Psychiatry 2014; 14: 75

e38. Yang M, Chen P, He MX, et al.: Poor oral health in patients with schizophrenia: a systematic review and meta-analysis. Schizophr Res 2018; 201: 3–9

e39. Liao CH, Chang CS, Chang SN, et al.: The association of peptic ulcer and schizophrenia: a population-based study. J Psychosom Res 2014; 77: 541–6

e40. De Hert M, Dekker JM, Wood D, Kahl KG, Holt RI, Moller HJ: Cardiovascular disease and diabetes in people with severe mental illness position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC). Eur Psychiatry 2009; 24: 412–24

e41. Mukundan A, Faulkner G, Cohn T, Remington G: Antipsychotic switching for people with schizophrenia who have neuroleptic-induced weight or metabolic problems. Cochrane Database Syst Rev 2010; CD006629 MEDLINE

e42. Alvarez-Jimenez M, Hetrick SE, Gonzalez-Blanch C, Gleeson JF, McGorry PD: Non-pharmacological management of antipsychotic-induced weight gain: systematic review and meta-analysis of randomised controlled trials. Br J Psychiatry 2008; 193: 101–7

e43. Teasdale SB, Ward PB, Rosenbaum S, Samaras K, Stubbs B: Solving a weighty problem: systematic review and meta-analysis of nutrition interventions in severe mental illness. Br J Psychiatry 2017; 210: 110–8

e44. de Silva VA, Suraweera C, Ratnatunga SS, Dayabandara M, Wanniarachchi N, Hanwella R: Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry 2016; 16: 341

e45. Mizuno Y, Suzuki T, Nakagawa A, et al.: Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis. Schizophr Bull 2014; 40: 1385–403

e46. Siskind DJ, Leung J, Russell AW, Wysoczanski D, Kisely S: Metformin for clozapine associated obesity: a systematic review and meta-analysis. PloS One 2016; 11: e0156208

e47. Mahmood S, Booker I, Huang J, Coleman CI: Effect of topiramate on weight gain in patients receiving atypical antipsychotic agents. J Clin Psychopharmacol 2013; 33: 90–4

e48. Zheng W, Xiang YT, Xiang YQ, et al.: Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr Scand 2016; 134: 385–98

e49. Müller MJ, Benkert O: Antipsychotika. In: Benkert O, Hippius H, (eds.): Kompendium der Psychiatrischen Pharmakotherapie. Berlin, Heidelberg: Springer Verlag 2017; 269–488

e50. Correll CU: Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. J Am Acad Child Adolesc Psychiatry 2008; 47: 9–20

e51. Schimmelmann BG, Schmidt SJ, Carbon M, Correll CU: Treatment of adolescents with early-onset schizophrenia spectrum disorders: in search of a rational, evidence-informed approach. Curr Opin Psychiatry 2013; 26: 219–30