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

Abstract

Objective: Schizophrenia is a severe mental disorder and many patients are treated in primary care settings. Apart from the pharmacological management of disease-associated symptoms, the detection and treatment of side effects is of the utmost importance in clinical practice. The purpose of this publication is to offer relevant evidence-based recommendations for the biological treatment of schizophrenia in primary care.

Methods: This publication is a short and practice-oriented summary of Parts I–III of the World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia. The recommendations were developed by the authors and consented by a task force of international experts. 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 additional 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.

Keywords:

• WFSBP treatment guidelines
• schizophrenia
• primary care

Introduction

Schizophrenia is a severe mental disorder characterized by various symptom domains including disturbances of perception (e.g., hallucinations), 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. Moreover, biological treatment of schizophrenia is essential for symptomatic and functional remission. The World Federation of Societies of Biological Psychiatry (WFSBP) has developed and published three guidelines for the biological treatment of schizophrenia. 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 disorders and pregnancy and lactation) were published (Hasan et al. 2015). However, due to their focus on biological treatments, these guidelines neither include recommendations for psychotherapeutic interventions and psychosocial care (e.g., cognitive behavioural therapy (CBT) or family interventions) nor for social psychiatric services (e.g., home treatment, assertive community 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 recommendations 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 settings, 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 following, 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 evaluation includes laboratory investigation, drug screening, brain imaging (preferentially MRI, if not accessible CT scan), EEG (in some countries needed as monitoring instrument during treatment) and CSF analyses (especially if acute inflammatory or autoimmune-mediated brain diseases are assumed). Diagnostic evaluation is needed for differential diagnosis purposes and clinical diagnosis is confirmed according to ICD-10 or DSM-5.

Antipsychotics have served as the basis of the biological treatment 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 having 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-generation antipsychotics (SGAs) with lower likelihoods to cause EPS. However, SGAs carry other risks like disturbances of glucose utilisation, 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 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 discussion 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 monitoring 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 treatment of acute schizophrenia, but the decision for one specific drug should follow a strict risk-benefit-evaluation. In first-episode patients, second-generation antipsychotics (SGAs) (e.g., amisulpride, olanzapine, quetiapine, risperidone) 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 relapsing 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 treatment, 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 antipsychotic efficacy and effectiveness of FGAs and SGAs (apart from clozapine) could be detected. However, SGAs seem to have advantages in terms of treatment discontinuation 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 experiences 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 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).

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

Many antipsychotics are available and a detailed description of the specific drugs can be found in the full version of these guidelines. 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 recommending that antipsychotics should be chosen individually by respecting 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 quetiapine are the best-approved SGAs, whereas haloperidol is the best approved FGA (see also comments above). For long-term maintenance 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.

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 recommendation 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.

Antipsychotic	Starting dose(mg/day)	Target dose first-episode(mg/day)	Target dose multi-episode(mg/day)	Maximal dosage(mg/day)^b
Amisulpride	200	100–300 (B, 2)	400–800 (A, 1)	1200
Asenapine^c	5	5–10 (F)	5–20 (A, 1)	20
Aripiprazole	5–15	15– (30) (B, 2)	15–30 (A, 1)	30
Clozapine^d	25	100–250 (A, 2)	300–800 (A, 1)	900
Haloperidol	1–10	1–4 (A, 2)	3–15 (A, 2)	30–100^a
Iloperidone^c	1–2	4–16 (F)	4–24 (A, 1)	32
Lurasidone^c	20–40	40–80 (F)	40–120 (B, 3)	120
Olanzapine	5–10	5–15 (A, 1)	5–20 (A, 1)	20
Paliperidone^c	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
Sertindole^c	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.

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 anhedonia 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, anhedonia due to extrapyramidal motor side effects or depression or apathy due to social under-stimulation. All antipsychotics (or treatment 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 primary negative symptoms. Regarding the augmentation with antidepressants 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 significant 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 recommendations 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 limited 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 established that depressive symptoms may improve in the course of time as psychotic symptoms improve and this effect of antipsychotic treatment should be waited for first. In case of persistent depressive symptoms, certain SGAs (e.g., amisulpride, aripiprazole, clozapine, olanzapine and quetiapine) seem to be superior to others (e.g., risperidone). The introduction of antidepressants may be warranted in cases where the criteria for a major depressive episode are fulfilled. When adding antidepressants a close monitoring of psychotic symptoms, suicidality, drug-drug interactions and ECG is necessary. Lithium is also recommended, whereas the efficacy has not been shown in all studies. 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 antipsychotic 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 treatment 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 recurring 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 treatment 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 antipsychotics should follow the same principles defined for oral antipsychotics. 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 manufacturer (e.g., risperidone/paliperidone before initiating paliperidone depot, aripiprazole before aripiprazole depot).

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

Treatment-resistant schizophrenia

In cases of treatment resistance, the adherence, the correct application of antipsychotics in terms of dosage and duration and other factors that may have an impact on the success of an antipsychotic treatment (e.g., drug abuse, drug–drug interactions, psychosocial stress, other environmental factors) need to be controlled. A switch from one FGA to another FGA is not recommended, 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 treatment resistance, clozapine is recommended in all available guidelines. 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 refractory schizophrenia as an add-on intervention to an ongoing antipsychotic 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 comprehensive evaluation of this topic. In brief, the management of pregnancy and lactation must be performed by a multi-professional team and several non-pharmacological aspects have to be considered. 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 antipsychotic 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 comorbidities 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 important 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 therapy 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 schizophrenia treatment, it has by now been well established that the differences 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 dysfunction) and cardiovascular side effects. Moreover, sedation as relevant side effect needs to be considered for certain antipsychotics. 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 professionals 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 obstructive pulmonary disease, cardiovascular disorders and infectious diseases. One recent population-wide study of 954,351 singletons 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 retrospective longitudinal US-Medicaid cohort of patients with schizophrenia 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 pneumonia (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 physical health in patients with schizophrenia needs further specific interventions such as dietary programs, surveillance programs 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 monitoring of physical health in schizophrenia patients are provided elsewhere (e.g., De Hert et al. 2011a). Frequent somatic comorbidities 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):

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 suggestions 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
Waist circumference	x	x		x	x
Blood pressure	x	x		x	x
Fasting plasma glucose	x			x	x
Fasting lipid profile	x			x	x
Blood cell count	x	x		x	x
ECG	x				x
EEG	x				x
Pregnancy test	x				x

• Obesity, diabetes, hypertonia, hyperlipidemia, cardiovascular 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 burdensome 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 adherence 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).

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	Treatment
Acute dystonic reactions	• Select antipsychotic with low rate EPS• Start with low dose• Increase dose slowly and stepwise	• 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)
Parkinsonism	• Select antipsychotic with low risk for parkinsonism• Increase dose slowly and stepwise	• Dose reduction or discontinuation of antipsychotic  medication• Switch to SGA• Oral application of anticholinergic drug
Akathisia	• Select antipsychotic with low risk for akathisia• Increase dose slowly and stepwise	• 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
Tardive Dyskinesia	• Select antipsychotic with low risk for tardive dyskinesia• Evaluate risk factors for tardive dyskinesia	• 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)
Neuroleptic malignant syndrome (NMS)	• Select antipsychotic with low risk for NMS	• 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

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 multifactorial etiopathogenesis including biological factors of schizophrenia, life-style modifications due to the illness, reduced activity 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 carefully (see Table 4).

• React to metabolic changes. On the basis of the EPA statement (De Hert et al. 2009), the WFSBP guidelines recommend that a weight gain >7% than baseline occurring within a few months must alert physicians and relatives.

• Provide psychosocial interventions such as awareness programs, diet plans, CBT to reduce weight and increase physical activity.

• Switch to an antipsychotic with a more favourable metabolic 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 sufficient 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-associated side effects, the monitoring of somatic comorbidities of patients suffering from schizophrenia should further bear the following 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.

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 comorbidity of schizophrenia and substance use disorder) should also be treated by a specialised treatment team providing interventions for both treatment conditions. Acute psychotic episodes, episodes 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 individualized as far as possible and should take aspects of efficacy and side effects into account. In this context, extrapyramidal, metabolic 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 specific 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 psychosocial 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

The authors would like to thank Anja Dorothée Streb, Department 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 from Servier). Hans-Jürgen Möller received honoraria for lectures 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.