International Journal of Psychiatry in Clinical Practice

ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: https://www.tandfonline.com/loi/ijpc20

World Federation of Societies of Biological

Psychiatry (WFSBP) guidelines for biological
treatment of schizophrenia – a short version for
primary care

Alkomiet Hasan, Peter Falkai, Thomas Wobrock, Jeffrey Lieberman, Birte

Glenthøj, Wagner F. Gattaz, Florence Thibaut, Hans-Jürgen Möller & WFSBP
Task Force on Treatment Guidelines for Schizophrenia

To cite this article: Alkomiet Hasan, Peter Falkai, Thomas Wobrock, Jeffrey Lieberman, Birte
Glenthøj, Wagner F. Gattaz, Florence Thibaut, Hans-Jürgen Möller & WFSBP Task Force on
Treatment Guidelines for Schizophrenia (2017) World Federation of Societies of Biological
Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia – a short version
for primary care, International Journal of Psychiatry in Clinical Practice, 21:2, 82-90, DOI:
10.1080/13651501.2017.1291839

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INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE, 2017
VOL. 21, NO. 2, 82–90
http://dx.doi.org/10.1080/13651501.2017.1291839

REVIEW ARTICLE

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for

biological treatment of schizophrenia – a short version for primary care
Alkomiet Hasana, Peter Falkaia, Thomas Wobrockb,c, Jeffrey Liebermand, Birte Glenthøje, Wagner F. Gattazf,
Florence Thibautg , Hans-Ju €rgen Mo€llera and WFSBP Task Force on Treatment Guidelines for Schizophrenia
a
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany; bCentre of Mental Health, Darmstadt-Dieburg
Clinics, Groß-Umstadt, Germany; cDepartment of Psychiatry and Psychotherapy, Georg-August-University, Goettingen, Germany; dDepartment of
Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, Lieber Center for Schizophrenia
Research, New York, NY, USA; eCenter for Neuropsychiatric Schizophrenia Research & Center for Clinical Intervention and Neuropsychiatric
Schizophrenia Research, Copenhagen University Hospital, Psychiatric Center Glostrup, Copenhagen, Denmark; fDepartment of Psychiatry,
University of Sao Paulo, Sao Paulo, Brazil; gUniversity Hospital Cochin-Tarnier, Faculty of Medicine Paris Descartes, INSERM U 894, Centre
Psychiatry and Neurosciences, Paris, France

ABSTRACT ARTICLE HISTORY

Objective: Schizophrenia is a severe mental disorder and many patients are treated in primary care set- Received 9 January 2017
tings. Apart from the pharmacological management of disease-associated symptoms, the detection and Revised 26 January 2017
treatment of side effects is of the utmost importance in clinical practice. The purpose of this publication is Accepted 27 January 2017
to offer relevant evidence-based recommendations for the biological treatment of schizophrenia in pri-
mary care. KEYWORDS
Methods: This publication is a short and practice-oriented summary of Parts I–III of the World Federation WFSBP treatment
of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia. The rec- guidelines; schizophrenia;
ommendations were developed by the authors and consented by a task force of international experts. primary care
Guideline recommendations are based on randomized-controlled trials and supplemented with non-
randomized trials and meta-analyses where necessary.
Results: Antipsychotics of different chemical classes are the first-line pharmacological treatments for
schizophrenia. Specific circumstances (e.g., suicidality, depression, substance dependence) may need add-
itional treatment options. The pharmacological and non-pharmacological management of side effects is of
crucial importance for the long-term treatment in all settings of the healthcare system.
Conclusions: This summary of the three available evidence-based guidelines has the potential to support
clinical decisions and can improve treatment of schizophrenia in primary care settings.

Introduction Moreover, biological treatment of schizophrenia is essential for

Schizophrenia is a severe mental disorder characterized by various
symptom domains including disturbances of perception (e.g., hal-
lucinations), thinking (e.g., delusions), affect (e.g., blunted or
inappropriate affect) and cognition (e.g., social cognition, working
memory) (WHO 2016). According to the WHO, schizophrenia is
one of the leading causes of disability in developed countries
(WHO 2008) and the median prevalence is reported to be 4.6/
1.000 (4.0/1.000 for life-time prevalence) (Saha et al. 2005).
Characteristics of schizophrenia and other schizophrenia-spectrum
disorders are frequent relapses, physical and mental comorbidity
as well as social and vocational exclusion.
Therefore, evidence-based treatment strategies that can be
applied without time lag between diagnosis and initiation of
treatment for all areas of the healthcare system are needed.
symptomatic and functional remission. The World Federation of
Societies of Biological Psychiatry (WFSBP) has developed and pub-
lished three guidelines for the biological treatment of schizophre-
nia. In 2012, the guidelines on the acute treatment and the
management of side effects were published (Hasan et al. 2012),
followed in 2013 by the guidelines on the long-term treatment
and management of antipsychotic-induced side effects (Hasan
et al. 2013). Finally, in 2015, the guidelines on the management of
special circumstances (depression, suicidality, substance use disor-
ders and pregnancy and lactation) were published (Hasan et al.
2015). However, due to their focus on biological treatments, these
guidelines neither include recommendations for psychothera-
peutic interventions and psychosocial care (e.g., cognitive behav-
ioural therapy (CBT) or family interventions) nor for social
psychiatric services (e.g., home treatment, assertive community

CONTACT Alkomiet Hasan alkomiet.hasan@med.uni-muenchen.de Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich,
Germany, Nussbaumstr. 7, D-80336 Munich, Germany
A. Carlo Altamura (Italy), Nancy Andreasen (USA), Thomas R.E. Barnes (UK); M. Emin Ceylan (Turkey), Jorge Ciprian Ollivier (Argentina), Timothy Crow (UK), Aysen
Esen Danaci (Turkey), Anthony David (UK), Michael Davidson (Israel), Bill Deakin (UK), Helio Elkis (Brazil), Lars Farde (Sweden), Wolfgang Gaebel (Germany), Bernd
Gallhofer (Germany), Jes Gerlach (Denmark), Steven Richard Hirsch (UK), Carlos Roberto Hojaij (Australia), Michael Hwang (USA), Hai Gwo Hwo (Taiwan), Assen
Verniaminov Jablensky (Australia), Marek Jarema (Poland), John Kane (USA), Takuja Kojima (Japan), Veronica Larach (Chile), Jeffrey Lieberman (USA), Patrick McGorry
(Australia), Herbert Meltzer (USA), Hans-J€urgen M€oller (Germany), Sergey Mosolov (Russia), Driss Moussaoui (Marocco), Jean-Pierre Olie (France), Antonio Pacheco
Palha (Portugal), Asli Sarand€ol (Turkey), Mitsumoto Sato (Japan), Heinrich Sauer (Germany), Nina Schooler (USA), Bilgen Taneli (Turkey), Lars von Knorring (Sweden),
Daniel Weinberger (USA) and Shigeto Yamawaki (Japan).
ß 2017 Informa UK Limited, trading as Taylor & Francis Group

treatment). This does by no means implicate that psychosocial
treatments should not be recommended. Psychosocial treatments
are an essential pillar of schizophrenia treatment as outlined in
detail in other guidelines (e.g., NICE 2014).
This publication represents a practical summary of the
WFSBP guidelines for the biological treatment of schizophrenia
and aims at providing the essential evidence-based recommen-
dations for the application in general practice and primary
healthcare settings. For a description of the methodology and a
detailed overview of all evidence-based recommendations, the
authors wish to refer to the complete version of the guidelines
(Hasan et al. 2012, 2013, 2015). Whereas acute schizophrenia
patients are usually treated in specialized in- or outpatient set-
tings, we nevertheless wish to highlight the important role of
primary care settings. Primary care settings have a crucial role
e.g., for early treatment, for transmission of acute and untreated
patients to specialized psychiatric care as well as for the long-
term management, including the management of somatic
comorbidities and physical health (Jones et al. 2015). In the fol-
lowing, the essential recommendations from all parts of the
WFSBP guidelines for the biological treatment of schizophrenia
will be summarised and novel literature has been added where
necessary.
General aspects
After the onset of first signs of schizophrenia, especially acute
psychotic symptoms such as disorganisation and rapid cognitive
decline, a careful diagnostic evaluation is warranted. This evalu-
ation includes laboratory investigation, drug screening, brain
imaging (preferentially MRI, if not accessible CT scan), EEG (in
some countries needed as monitoring instrument during treat-
ment) and CSF analyses (especially if acute inflammatory or auto-
immune-mediated brain diseases are assumed). Diagnostic
evaluation is needed for differential diagnosis purposes and clin-
ical diagnosis is confirmed according to ICD-10 or DSM-5.
Antipsychotics have served as the basis of the biological treat-
ment of schizophrenia for approximately 60 years now. In terms
of their chemical structure, the antipsychotics, formerly named
neuroleptics, are a heterogeneous group of psychoactive drugs
(e.g., phenothiazines, thioxanthenes, butyrophenones).
Conventional or so-called first-generation antipsychotics (FGAs)
can be classified according to their affinity to D2-receptors into
high- and low-potency medications with high-potency agents hav-
ing a better antipsychotic efficacy when comparing the minimal
effective dose in milligram, but causing more extrapyramidal
motor side effects (EPS). Motor side effects, limited efficacy in
improving negative symptoms and subjective dysphoria during
treatment with FGAs have led to the development of second-gen-
eration antipsychotics (SGAs) with lower likelihoods to cause EPS.
However, SGAs carry other risks like disturbances of glucose util-
isation, lipid metabolism and weight gain. This effect has been
also described for certain conventional antipsychotics, but seems
to be even more pronounced in distinct SGAs.
Acute antipsychotic treatment should be initiated in all
patients as soon as possible after the diagnosis and should follow
several general principles (Hasan et al. 2012):
 A therapeutic alliance should be established, a treatment
plan must be formulated and implemented and with the
patient’s permission family members and significant other
persons should be involved.
 Antipsychotic medication should be gradually introduced
and prescribed at the lowest possible effective dose and
combined with careful explanation. In multiple episode
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 83
patients, the dose may be titrated as quickly as tolerated
with a careful monitoring of side effects and clinical status.
In general, the titration should be performed as slowly as
possible.
 Antipsychotics should be selected after a face-to-face dis-
cussion with the patient and if desired together with the
relatives with respect to the patient’s mental health and
somatic condition.
 Special attention needs to be paid to antipsychotic
induced side effects. This applies particularly to motor and
metabolic side effects (including obesity and premature
diabetes). Other side effects which also require close moni-
toring are cardiovascular side effects (especially QTc-
prolongation, myocarditis), hyperprolactinemia and sexual
dysfunction as well as other side effects (see below and
the full version of the guidelines).
 All antipsychotics principally have their place in the treat-
ment of acute schizophrenia, but the decision for one spe-
cific drug should follow a strict risk-benefit-evaluation. In
first-episode patients, second-generation antipsychotics
(SGAs) (e.g., amisulpride, olanzapine, quetiapine, risperi-
done) should be preferred to high-potency first-generation
antipsychotics (FGAs) (e.g., haloperidol, perphenazine) as
first-line treatment. This recommendation is driven by the
reduced risk for motor side effects and not by clinically
relevant differences in efficacy or effectiveness. However,
in several countries (e.g., Denmark, Sweden), olanzapine is
not recommended anymore as first-line treatment due to
its specific metabolic side effects. In patients with a relaps-
ing disease course, the choice should be guided by the
patient’s preferences, previous experience of response and
tolerability, intended route of administration as well as
potential interactions with other drugs.
The long-term treatment of schizophrenia with antipsychotics
should follow the same principles described for the acute treat-
ment, but additional aspects need to be considered (Hasan et al.
2013):
 All antipsychotics are effective for relapse prevention and
no clinically relevant differences in the long-term anti-
psychotic efficacy and effectiveness of FGAs and SGAs
(apart from clozapine) could be detected. However, SGAs
seem to have advantages in terms of treatment discon-
tinuation and the reduced risk to develop long-term
motor side effects might favour certain SGAs. Metabolic
side effects of certain SGAs may limit a long-term
application.
 Antipsychotics should be chosen by following the same
criteria as for the initiation of treatment, taking into
account the patient’s preferences and previous experien-
ces with a special focus on efficacy/effectiveness and side
effects
 If possible, antipsychotics administered during the acute
episode should be used for maintenance treatment as
well.
 Dosages should be titrated at the lowest possible range
with the best risk-benefit ratio. Early-episode patients
usually need lower dosages than patients with a longer
disease course.
Specific treatment recommendations
For all WFSBP guidelines, specific categories of evidence have
been defined as outlined in Table 1 (Bandelow et al. 2012). Apart
from the evidence grades, the guidelines define recommendation
84 A. HASAN ET AL.
Table 1. Categories of evidence and recommendation grades (Bandelow et al.
2012). Table 2 gives the categories of evidence for all recommended drugs. For
a detailed definition of the evidence and recommendation grades, see Hasan
et al. (2012).
Category of evidence Description
A Full evidence from controlled studies
B Limited positive evidence from controlled
studies
C Evidence from uncontrolled studies or case
reports/expert opinion
C1 Uncontrolled studies
C2 Case reports
C3 Based on the opinion of experts in the field
or clinical experience
D Inconsistent results
E Negative evidence
F Lack of evidence
Recommendation grade Based on
1 Category A evidence and good risk-benefit
ratio
2 Category A evidence and moderate risk-
benefit ratio
3 Category B evidence
4 Category C evidence
5 Category D evidence
grades based on both the evidence and the risks of a given
drug. For example, clozapine is an effective drug in all stages
of schizophrenia including first-episode schizophrenia (category
of evidence A), but due the specific side effects and
possible treatment complications (agranulocytosis, myocarditis) it
is not recommended as first-line treatment (recommendation
grade 2).
Many antipsychotics are available and a detailed description of
the specific drugs can be found in the full version of these guide-
lines. The separation into FGAs and SGAs was made by following
the structure of the nomenclature in the underlying clinical trials
and to provide a better overview. Current discussions prefer a
risk–benefit orientated classification of antipsychotics rather than
a straightforward classification into only two subgroups (Leucht
et al. 2013). Such an approach has e.g., been adopted by the
recent NICE (NICE 2014) or the PORT guidelines (Buchanan et al.
2010). The WFSBP guidelines have a related strategy recommend-
ing that antipsychotics should be chosen individually by respect-
ing the patient’s mental and somatic condition and with special
attention to side effects. However, for many clinical situations,
more specific recommendations need to be provided as outlined
below.
Antipsychotic treatment of first-episode schizophrenia
FGAs and SGAs are effective in the treatment of first-episode
schizophrenia, but not for all drugs specific first-episode studies
are available (see Table 2). The WFSBP guidelines recommend
with limited evidence SGAs as the first-line use in first-episode
patients due to their lower risk of motor side effects compared
with FGAs. In this population, olanzapine, risperidone and quetia-
pine are the best-approved SGAs, whereas haloperidol is the best
approved FGA (see also comments above). For long-term mainten-
ance treatment, SGAs should be preferred. One recently published
randomized-controlled trial (RCT) (Robinson et al. 2015) provides
evidence for an application of aripiprazole in this population. This
trial was not available at the time of the last update of the
WFSBP guidelines. Clozapine should not be used in non-
treatment-refractory first-episode schizophrenia.
Antipsychotic treatment of multi-episode schizophrenia
All available FGAs and SGAs are effective in the treatment of
multi-episode schizophrenia (see Table 2) and the decision for a
certain drug should be guided by the aforementioned general
aspects for antipsychotic treatment. The WFSBP guidelines point
out that SGAs might be superior to FGAs in terms of treatment
discontinuation.
Treatment of negative symptoms
Negative symptoms such as amotivation, blunted affect or anhe-
donia are difficult-to-treat symptoms and have a critical impact on
outcome (Kirkpatrick et al. 2006; An der Heiden and Hafner 2010).
In addition, primary negative symptoms need to be distinguished
from secondary negative symptoms (Carpenter et al. 1985). The
former are core symptoms of schizophrenia, whereas secondary
negative symptoms are a consequence of other symptoms or side
effects of treatment. Examples for secondary negative symptoms
are e.g., social withdrawal due to severe paranoid ideas, anhedo-
nia due to extrapyramidal motor side effects or depression or
apathy due to social under-stimulation. All antipsychotics (or treat-
ment modifications related to these drugs) are effective in the
treatment of secondary negative symptoms, whereas the evidence
for the treatment of primary negative symptoms is limited.
However, SGAs may have a subtle advantage over FGAs in the
treatment of primary negative symptoms and FGAs should be
avoided in patients suffering from primary negative symptoms.
Especially amisulpride and olanzapine, but also quetiapine and
ziprasidone were shown to be effective for the treatment of pri-
mary negative symptoms. Regarding the augmentation with anti-
depressants the best evidence is available for an add-on
treatment with mirtazapine, which should be weighed against its
known metabolic side effects.
Treatment of cognitive symptoms
Cognitive symptoms also rank among the core symptoms within
the complex symptomatology of schizophrenia and have a signifi-
cant impact on course and outcome (Green et al. 2000; Carbon &
Correll 2014). As cognitive symptoms and negative symptoms
overlap (Harvey et al. 2006) and since only few studies investigate
the efficacy of antipsychotic treatment on cognitive measures as
primary outcomes, the WBFSP guidelines provide recommenda-
tions for this topic only to a limited extent. Antipsychotics seem
to have a small beneficial effect of cognition in schizophrenia
patients, whereas the comparisons between different drug classes
reveal inconclusive results. However, it may be criticised that re-
test effects of cognitive testing may drive the main effects in
these analyses. As no study favours FGAs for this indication, the
WFSBP guidelines recommend the application of SGAs with lim-
ited evidence.
Treatment of depressive symptoms and suicidality
Depressive symptoms and suicidality are frequent comorbidities of
schizophrenia. Depressive symptoms should be quantified by
using the Calgary Depression Scale for Schizophrenia (Addington
et al. 1990) and it is not recommended to switch antipsychotics or
to introduce an antidepressant immediately. It has been estab-
lished that depressive symptoms may improve in the course of
time as psychotic symptoms improve and this effect of anti-
psychotic treatment should be waited for first. In case of persist-
ent depressive symptoms, certain SGAs (e.g., amisulpride,
 INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 85

Table 2. Recommended dosage (orally) of selected antipsychotics. This table is derived from the first part of the WFSBP guidelines for
the biological treatment of schizophrenia (Hasan et al. 2012) and adopted where necessary. Categories of evidence and recommenda-
tion grades are in brackets (e.g., (A, 1). Note that all drugs are approved for the antipsychotic treatment of schizophrenia, but not all
drugs have been specifically investigated in first-episode schizophrenia. However, for certain drugs (e.g., amisulpride), evidence from
open effectiveness studies (Kahn et al. 2008) is available. Certain drugs (e.g., amisulpride, paliperidone) are not approved or are not
available for the treatment of schizophrenia in all countries. Therefore, they should generally be considered as recommendation grade
2 in these countries as outlined in the complete versions of the guidelines. However, for the sake of clarity, this differentiation has not
been made for this summary paper. Moreover, it is evident that also first-episode patients may need higher dosages in their acute
stage of the illness and this table aims to provide target dosages for the maintenance treatment. In general, the antipsychotic dosage
chosen should be as low as possible with special attention to treatment-associated side effects. Also note that rapid dose escalation,
high loading doses and high-dose treatment above references ranges are usually not more effective than other strategies, but instead
result in burdensome side effects.
Starting dose Target dose first-episode Target dose multi-episode Maximal dosage
Antipsychotic (mg/day) (mg/day) (mg/day) (mg/day)b
Amisulpride 200 100–300 (B, 2) 400–800 (A, 1) 1200
Asenapinec 5 5–10 (F) 5–20 (A, 1) 20
Aripiprazole 5–15 15– (30) (B, 2) 15–30 (A, 1) 30
Clozapined 25 100–250 (A, 2) 300–800 (A, 1) 900
Haloperidol 1–10 1–4 (A, 2) 3–15 (A, 2) 30–100a
Iloperidonec 1–2 4–16 (F) 4–24 (A, 1) 32
Lurasidonec 20–40 40–80 (F) 40–120 (B, 3) 120
Olanzapine 5–10 5–15 (A, 1) 5–20 (A, 1) 20
Paliperidonec 3–6 3–9 (F) 3- 12 (A,) 12
Quetiapine IR/XR 50 300–600 (A, 1) 400–750 (A, 1) 750
Risperidone 1–2 1–4 (A, 1) 3–10 (A, 1) 16
Sertindolec 4 4–12 (F) 12–24 (A, 1) 24
Ziprasidone 40 40–80 (B, 2) 80–160 (A, 1) 160
Zotepine 25–50 50–150 (F) 100–250 (B, 3) 450
a
In certain countries 100 mg is the approved dosage – however, such high dosages should not be used in clinical practice and dosages
should not exceed 15 mg.
b
Maximal approved dosage in many countries. In clinical practice, some FGAs and SGAs are even higher dosed without sufficient
evidence.
c
These antipsychotics have not been investigated in first-episode schizophrenia patients.
d
Clozapine is usually not introduced in first-episode schizophrenia patients and should only be used in treatment-resistant cases.

aripiprazole, clozapine, olanzapine and quetiapine) seem to be
superior to others (e.g., risperidone). The introduction of antide-
pressants may be warranted in cases where the criteria for a
major depressive episode are fulfilled. When adding antidepres-
sants a close monitoring of psychotic symptoms, suicidality,
drug-drug interactions and ECG is necessary. Lithium is also rec-
ommended, whereas the efficacy has not been shown in all stud-
ies. The management of suicidality includes regular assessment of
suicidal thoughts and ideation, of the hospitalisation conditions as
well as of the antipsychotic treatment (efficacy and side effects) in
general. The WFSBP guidelines recommend clozapine for the
treatment of suicidality with moderate evidence. In patients with
mood symptoms, the procedures described for depression should
be applied.
Switching antipsychotics
In cases of antipsychotic non-response, a switch to another anti-
psychotic from a different class should be considered after 2–8
weeks. The WFSBP guidelines defined the lower end of this period
after 2 weeks, but other guidelines recommend an at least 4
weeks trial with one antipsychotic. This question is controversially
discussed in the field, whereas one yet unpublished RCT (Leucht
et al. 2016) and one meta-analysis (Samara et al. 2015) support
the idea of an early switch.
Duration of maintenance treatment and treatment strategies
On one hand, the question on the duration of antipsychotic treat-
ment is highly relevant, but sufficient studies are lacking. On the
other hand, it is evident that the discontinuation of antipsychotic
treatment significantly increases the relapse risk (Leucht et al.
2012). Based on expert opinion, the WFSBP guidelines recommend
a continuous antipsychotic maintenance treatment for at least
1 year after the first-episode and for 2–5 years in case of a recur-
ring course. However, the duration of treatment has to be
adjusted on an individual basis integrating many factors such as
the patient’s motivation, the psychosocial situation, the course of
disease and the specific needs of the given patient. The WFSBP
guidelines do not recommend intermittent treatment strategies
and highlight the importance of a continuous antipsychotic treat-
ment with a high evidence grade. This recommendation was
based on several RCTs and it is strengthened even further by new
meta-analyses which have been recently published (Sampson
et al. 2013; De Hert et al. 2015).
Long-acting injectables (LAI) (depot antipsychotics)
LAI (depot antipsychotics) (see Table 3) improve the adherence of
schizophrenia patients and can be recommended for maintenance
treatment with good evidence. However, no clear differences in
efficacy between oral and depot formulations, neither in FGA nor
SGA depots, can be stated. The application of depot antipsy-
chotics should follow the same principles defined for oral antipsy-
chotics. Before starting treatment with LAI, the oral formulation
has to be given for a defined time period for safety reasons
according to the specific recommendations of each single manu-
facturer (e.g., risperidone/paliperidone before initiating paliperi-
done depot, aripiprazole before aripiprazole depot).
Treatment-resistant schizophrenia
In cases of treatment resistance, the adherence, the correct appli-
cation of antipsychotics in terms of dosage and duration and
86 A. HASAN ET AL.
Table 3. Long-acting injectables. This table was extended according to the
WFSBP guideline (Hasan et al. 2013) because several new SGA depots have since
been launched. Categories of evidence and recommendation grades are in
brackets (e.g., (A, 1)). They were defined specifically for this publication on the
basis of the recommendations made for the oral antipsychotics. For olanzapine,
the highest category of evidence could not be stated due to the risk of post-
injection delirium sedation syndrome. Although highly effective, FGA depots
have not received the highest recommendation grade due to the elevated risk
of motor side effects during the long-term treatment.
Antipsychotic Dose intervals (weeks) Dosage (mg)
SGA
Aripiprazole (A, 1) 4 300–400
Risperidone microspheres (A, 1) 2 25–50
Paliperidone palmitate (A, 1) 4/12 25–150/175–525
Olanzapine pamoate (A/B, 2/3) 2/4 150–210/300–405
FGA
Flupentixol decanoate (A, 2) 2–3 20–100
Fluphenazine decanoate (A, 2) 2–4 6.25–50
Haloperidol decanoate (A, 2) 4 50–200
Perphenazine decanoate (A, 2) 2–4 12–200
Zuclopenthixol decanoate (A, 2) 2–4 100–400
other factors that may have an impact on the success of an anti-
psychotic treatment (e.g., drug abuse, drug–drug interactions, psy-
chosocial stress, other environmental factors) need to be
controlled. A switch from one FGA to another FGA is not recom-
mended, but a switch from a FGA to a SGA or a SGA to another
SGA can be considered if symptoms have not improved following
the first antipsychotic trial. However, in cases of confirmed treat-
ment resistance, clozapine is recommended in all available guide-
lines. If possible, clozapine drug levels above 350 ng/ml should be
achieved. Patients who do not tolerate clozapine may be switched
to olanzapine or risperidone. Other strategies are detailed in the
full version of the guidelines.
Electroconvulsive therapy (ECT) and schizophrenia
ECT is recommended with limited evidence for treatment refrac-
tory schizophrenia as an add-on intervention to an ongoing anti-
psychotic treatment. In catatonia, ECT is one important
therapeutic alternative and recommended in such cases. One
recently published open-label randomized-controlled trial (Petrides
et al. 2015) and one new meta-analysis highlight the role of ECT
(Lally et al. 2016) as augmentation treatment in clozapine-non-
responding schizophrenia patients. ECT is also recommended with
low evidence for severe depression and suicidality associated with
schizophrenia.
Pregnancy and lactation
The WFSBP guidelines (Hasan et al. 2015) provide a comprehen-
sive evaluation of this topic. In brief, the management of preg-
nancy and lactation must be performed by a multi-professional
team and several non-pharmacological aspects have to be consid-
ered. If antipsychotic treatment is necessary, the initiation should
be delayed as long as possible, the dosages should be titrated at
a minimal level, therapeutic drug monitoring should be performed
closely. If antipsychotics have to be introduced for the first time,
the following drugs should be favoured: haloperidol, risperidone,
olanzapine and quetiapine. Patients who had a successful anti-
psychotic treatment in the past should receive the antipsychotic
agent that has shown a sufficient efficacy before as long as no
contraindications are present. In principle, breastfeeding should
be avoided during antipsychotic treatment.
Substance-use disorders
Substance-use disorders are the most frequent psychiatric comor-
bidities in schizophrenia. The highest prevalence rates are
reported for tobacco and alcohol dependency. However, the use
of illegal drugs such as cannabis, amphetamines and others is also
a major clinical issue in this patient group. As the management of
substance-use disorders is mainly performed by specialized
centres, only the recommendations for tobacco dependency are
summarized for this primary care guideline. Tobacco dependency
concerns a significant number of schizophrenia patients and is
one of the major contributors to somatic comorbidities and excess
mortality of schizophrenia. Therefore, smoking cessation is import-
ant in order to improve the long-term outcome of schizophrenia
and should be an essential part of the treatment plan. Smoking
cessation should be initiated in stable schizophrenia patients and
here cognitive intervention as well as nicotine replacement ther-
apy can be recommended. Treatment can be supported with
bupropion (increase in side effects must be monitored), whereas
the data for varenicline were inconclusive when the guidelines
were published. However, the recently published large-scale
EAGLES study showed the safety and efficacy of varenicline in
patients with psychiatric disorders including schizophrenia
(Anthenelli et al. 2016).
Management of antipsychotic-induced side effects
All effective drugs in medicine have an individual side effect
profile and side effects have to be weighed against efficacy
and the need for treatment in clinical practice. For schizophre-
nia treatment, it has by now been well established that the dif-
ferences in tolerability/side effects between antipsychotics are
larger than the differences in efficacy. Therefore, antipsychotic
treatment has to follow a comprehensive risk–benefit evaluation
and monitoring of side effects. The most burdensome side
effects are motor, metabolic, hormonal (including sexual dys-
function) and cardiovascular side effects. Moreover, sedation as
relevant side effect needs to be considered for certain antipsy-
chotics. Constipation, convulsive seizures, blood count changes,
myocarditis or cardiomyopathy are also clinically relevant since
they could result in life-threatening conditions. Apart from the
antipsychotic-induced side effects, psychiatrists and all professio-
nals involved in the management of schizophrenia should be
aware of the significant excess mortality of schizophrenia, which
can be explained by somatic comorbidities like chronic obstruct-
ive pulmonary disease, cardiovascular disorders and infectious
diseases. One recent population-wide study of 954,351 single-
tons of which 4,371 developed schizophrenia showed that
95.6% had a somatic general hospital contact before the first
diagnosis of schizophrenia (Sorensen et al. 2015). A retrospect-
ive longitudinal US-Medicaid cohort of patients with schizophre-
nia with 1,138,853 individuals showed that schizophrenia
patients were >3.5 times more likely to die than age-matched
adults in the general population, with the highest increase in
standardized mortality ratios for COPD (9.9), influenza and pneu-
monia (7.0), diabetes mellitus (4.2) and cardiovascular diseases
(3.7) (Olfson et al. 2015). Suicides had a SMR of 3.9 (Olfson
et al. 2015). These cohort studies are examples for the complex
interaction of somatic comorbidities and schizophrenia and
highlight that GPs have a crucial role for early diagnosis and
treatment of such comorbidities. Therefore, the monitoring and
treatment of antipsychotic-induced side effects is intimately
related to improved physical health (De Hert et al. 2011a,
2011b; Olfson et al. 2015). However, the improvement of

Table 4. Recommended monitoring schedule for antipsychotic treatment (Hasan
et al. 2013). The recommendations in this table were modified according to
(APA 2004; De Hert et al. 2009) and on the basis of an expert-based consent.
More frequent assessments may be warranted based on clinical status (e.g.,
patients with metabolic syndrome or with a history of agranulocytosis).
Especially during a long-term treatment (e.g., lifelong treatment), the monitoring
process has to be adapted individually. These monitoring intervals are sugges-
tions which needs to be modified with regard to the administered antipsychotic
and the national guidelines; e.g., patients treated with clozapine or sertindole
need special monitoring.
Baseline 4 Weeks 8 Weeks 12 Weeks Annually
Personal/family history x x
Weight (BMI) x x x x x ring within a few months must alert physicians and
Waist circumference x x x x
Blood pressure x x x x
Fasting plasma glucose x x x grams, diet plans, CBT to reduce weight and increase
Fasting lipid profile x x x
Blood cell count x x x x
ECG x x
EEG x x
Pregnancy test x x
physical health in patients with schizophrenia needs further spe-
cific interventions such as dietary programs, surveillance pro-
grams and a specific treatment of somatic comorbidities. In
clinical practice, an assessment of several parameters to monitor
potential antipsychotic-induced or disorder-related side effects
should be implemented (see Table 4). Guidelines for the moni-
toring of physical health in schizophrenia patients are provided
elsewhere (e.g., De Hert et al. 2011a). Frequent somatic comor-
bidities in schizophrenia patients among many others are
(Leucht et al. 2007; De Hert et al. 2011a, 2011b; Laursen et al.
2011; Olfson et al. 2015):
 Obesity, diabetes, hypertonia, hyperlipidemia, cardiovascu-
lar disorders and metabolic syndrome
 Respiratory tract diseases, especially chronic obstructive
pulmonary disease and pneumonia
 Certain cancers, especially lung, breast and gastrointestinal
cancers, but not cancer in general
 Musculoskeletal diseases, including osteoporosis
 Stomatognathic diseases
 Infections (bacterial and viral diseases)
Management of motor side effects
Extrapyramidal motor side effects occur frequently, are burden-
some and remain underdiagnosed in clinical practice. Therefore,
physicians involved in the treatment of schizophrenia patients
should screen patients on a regular basis for motor side effects.
Motor side effects impact quality of life, result in poor adher-
ence and may have deleterious consequences (e.g., suicidality).
For an overview of the therapeutic options for the prevention
and management of antipsychotic-induced motor side effects,
see Table 5 and full version of the WFSBP guidelines (Hasan
et al. 2013).
Management of metabolic side effects
Metabolic side effects such as obesity, change in metabolic
parameters or diabetes have a strong impact on the physical
health in schizophrenia patients and contribute significantly to the
excess mortality in this illness. However, these side effects are not
only a consequence of antipsychotic treatment but have a multi-
factorial etiopathogenesis including biological factors of schizo-
phrenia, life-style modifications due to the illness, reduced activity
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 87
due to the symptomatology and other treatment aspects (De Hert
et al. 2011b). Therefore, monitoring and prevention are the most
important key factors to reduce the risk of developing metabolic
side effects. In summary, the following aspects need to be
considered:
 Monitor the development of metabolic side effects care-
fully (see Table 4).
 React to metabolic changes. On the basis of the EPA state-
ment (De Hert et al. 2009), the WFSBP guidelines
recommend that a weight gain >7% than baseline occur-
relatives.
 Provide psychosocial interventions such as awareness pro-
physical activity.
 Switch to an antipsychotic with a more favourable meta-
bolic profile. However, physicians should be aware that
every antipsychotic switch is associated with an increased
risk for symptom deterioration or relapse. The WFSBP
guidelines recommend aripiprazole and ziprasidone for
this propose, but also other antipsychotics with a more
favourable metabolic profile than the one causing the side
effects should be considered.
 Add metformin to an ongoing antipsychotic treatment.
The WFSBP guidelines were inconclusive regarding this
recommendation, whereas recent publications provide suf-
ficient data for a recommendation (Mizuno et al. 2014; Wu
et al. 2016). However, negative results have been reported
and the addition of metformin does not render a strict
monitoring and management of metabolic side effect
unnecessary.
A more elaborative discussion of this topic can be found in the
full version of the WFSBP guideline (Hasan et al. 2013) or the EPA
statement on cardiovascular disease and diabetes in people with
severe mental illness (De Hert et al. 2009).
Other side effects
Physicians and other professionals involved in the treatment of
schizophrenia patients are responsible for the monitoring and
management of many other side effects and treatment-associated
complications far beyond motor and metabolic side effects. These
side effects are
 Orthostatic hypotension
 QTc prolongation and other ECG changes
 Leukopenia
 Dry mouth
 Sialorrhea
 Sexual dysfunction and other hormonal side effects (e.g.,
osteoporosis)
 Constipation
 Urinary retention
 Change in liver enzymes
Prevention and management strategies for these side effects
are listed in detail in the full version of the WFSBP guidelines
(Hasan et al. 2013). Moreover, apart from these treatment-associ-
ated side effects, the monitoring of somatic comorbidities of
patients suffering from schizophrenia should further bear the fol-
lowing possibilities in mind: development of premature cancer
(e.g., lung cancer, bladder cancer), development of a chronic
obstructive pulmonary disease or obstructive sleep apnoea, in
other words, conditions linked to the high rate of tobacco
dependency. Finally, schizophrenia patients have an increased risk
for infectious diseases.
88 A. HASAN ET AL.

Table 5. Therapeutic options to manage motor side effects and neuroleptic malignant syndrome. This table was fully adapted as citation from the WFSBP guideline
(Hasan et al. 2013). For categories of evidence and a detailed description of the recommended interventions, see WFSBP guideline.
Side effect Prevention
Acute dystonic reactions  Select antipsychotic with low rate EPS
 Start with low dose
 Increase dose slowly and stepwise
Parkinsonism  Select antipsychotic with low risk for parkinsonism
 Increase dose slowly and stepwise
Akathisia  Select antipsychotic with low risk for akathisia
 Increase dose slowly and stepwise
Tardive Dyskinesia  Select antipsychotic with low risk for tardive dys-
kinesia
 Evaluate risk factors for tardive dyskinesia
Neuroleptic malignant syndrome (NMS)  Select antipsychotic with low risk for NMS
Treatment
 Oral or intravenous application of anticholinergic drug,
e.g., 2.5–5 mg biperiden, if necessary repeat procedure
after 30 min, continue biperiden oral (maximal 12 mg/d)
 Dose reduction or discontinuation of antipsychotic
medication
 Switch to SGA
 Oral application of anticholinergic drug
 Dose reduction
 Oral application of beta-receptor-blocking agent
(e.g., propranolol 30–90 mg/d)
 Switch to certain SGAs
 Oral application of benzodiazepines
 Trial of an anticholinergic or an antihistaminic agent
 Application of vitamin B6
 Application of trazodone
 Switch to clozapine (alternatively to certain other SGAs)
 Application of vitamin E
 (Application of tiapride)
 ECT (only case reports and case series)
 Deep brain stimulation (treatment in severe cases)
 Pallidotomy (last resort treatment in extremely
severe cases)
 Intensive care management
 Stop antipsychotic treatment
 (Application of dantrolene i.v. (2.5–10 mg/kg body
weight daily)
 (Application of lorazepam 4–8 mg i.v./d)
 In single cases ECT

When should a patient be referred to specialist care?
All patients suffering from schizophrenia should receive specialist
care at any one time (preferably at the time of the first diagnosis).
No less, patients suffering from double diagnosis (e.g., the comor-
bidity of schizophrenia and substance use disorder) should also
be treated by a specialised treatment team providing interven-
tions for both treatment conditions. Acute psychotic episodes, epi-
sodes with risk for personal harm or risk for others or with risk for
suicidality should be treated in specialists care as well.
Conclusions
The management and treatment of schizophrenia is challenging.
Therefore, physicians and other professionals should adhere to
available national and international guidelines. All sectors of the
healthcare system have to work in an interdisciplinary manner in
order to provide the best possible care for schizophrenia patients
and their families. Antipsychotic treatment should be individual-
ized as far as possible and should take aspects of efficacy and
side effects into account. In this context, extrapyramidal, meta-
bolic and cardiovascular side effects are the most important in
terms of quality of life, long-term outcome and mortality.
However, other side effects should not be underestimated.
Psychosocial interventions including CBT and family interventions
are the second important pillar of schizophrenia treatment. A
combination of evidence-based antipsychotic treatment and the
aforementioned psychosocial interventions should be provided to
every patient with schizophrenia.
Key points
 This short version of the three major WFSBP evidence-
based treatment guidelines may improve the treatment
and management of schizophrenia in primary care.
 First-line pharmacological treatment for schizophrenia
patients are antipsychotics, whereas the decision for a spe-
cific drug should be based on an individual discussion
with the patient. It should respect the patient’s mental
and somatic condition and pay special attention to side
effects.
 A combination of antipsychotic treatment and psycho-
social interventions must be offered to every patient with
schizophrenia.
 The evidence of WFSBP recommendations is based on
randomized controlled trials which do not entirely overlap
with the clinical reality. However, also effectiveness studies
were taken into consideration, which may be more related
to clinical practice than efficacy studies.
Acknowledgement
e Streb, Department
The authors would like to thank Anja Dorothe
of Psychiatry and Psychotherapy, Ludwig-Maximilians University
Munich for general and editorial assistance in preparing these
guidelines.
Disclosure statement
The development of these guidelines was not supported by any
pharmaceutical company. Alkomiet Hasan has received paid
speakership by Desitin, Otsuka, Lundbeck and Janssen Cilag. He
was member of the Roche, Lundbeck and Janssen Cilag Advisory
Board. Since 2010, no invitations to scientific meetings were
accepted. Peter Falkai was the honorary speaker for Janssen-Cilag,
AstraZeneca, Eli Lilly, Bristol-Myers-Squibb, Lundbeck, Pfizer, Bayer
Vital, SmithKline Beecham, Wyeth and Essex. During the last 5
years, but not presently, he was a member of the advisory boards
of Janssen-Cilag, AstraZeneca, Eli Lilly and Lundbeck. Thomas

Wobrock received paid speakership by Alpine Biomed,
AstraZeneca, Cerbomed, Bristol-Myers-Squibb, Eli Lilly, I3G,
Janssen-Cilag, Novartis, Lundbeck, Sanofi-Aventis, Otsuka and
Pfizer, and has accepted travel or hospitality not related to a
speaking engagement from AstraZeneca, Bristol-Myers-Squibb, Eli
Lilly, Janssen-Cilag and Sanofi-Synthelabo longer than 5 years ago;
he is a member of the advisory board of Janssen-Cilag as well as
Otsuka/Lundbeck and has received a research grant from
AstraZeneca, I3G, and AOK (health insurance company). Jeffrey
Liebermann was/is a member of the advisory boards of Bioline,
Intracellular Therapies, Alkermes, Lilly and Pierre Fabre. He
received research support/grants by Allon, GlaxoSmithKline, Lilly,
Merck, Novartis, Pfizer, Psychogenics, LTD, Sepracor and
Targacept. He holds a patent by Repligen. Birte Glenthøj is leader
of a Lundbeck Foundation Center of Excellence for Clinical
Intervention and Neuropsychiatric Schizophrenia Research (CINS)
which is partially financed by an independent grant from the
Lundbeck Foundation based on international review and partially
financed by the Mental Health Services in the Capital Region of
Denmark, the University of Copenhagen, and other foundations.
Wagner F. Gattaz reports no conflict of interest. Florence Thibaut
was a member of the Sertindole Study International Safety
Committee before 2010, she is currently Editor-in-Chief of
Dialogues in Clinical Neuroscience (the journal receives a grant
€rgen Mo€ller received honoraria for lectures
from Servier). Hans-Ju
or for advisory activities or received grants by the following
pharmaceutical companies: Astra-Zeneca, Eli Lilly, Janssen,
Lundbeck, Pfizer, Schwabe, Servier, Otsuka and Takeda. He was
president or in the Executive Board of the following organisations:
CINP, ECNP, WFSBP, EPA and chairman of the WPA-section on
Pharmacopsychiatry.
ORCID
Florence Thibaut http://orcid.org/0000-0002-0204-5435
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