Professional Documents
Culture Documents
GUIDELINES
Research, Copenhagen University Hospital, Psychiatric Center Glostrup, Denmark, 5Department of Psychiatry,
University of Sao Paulo, Brazil, and 6University Hospital Ch. Nicolle, Faculty of Medicine, INSERM, Rouen, France
For personal use only.
Abstract
These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry
(WFSBP) guidelines for biological treatment of schizophrenia published in 2006. For this 2012 revision, all available
publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-
based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically
meaningful. They are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia.
Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane
Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The iden-
tified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels
of evidence (A–F) and five levels of recommendation (1–5) (Bandelow et al. 2008a,b, World J Biol Psychiatry 9:242,
see Table 1). This second part of the updated guidelines covers long-term treatment as well as the management of relevant
side effects. These guidelines are primarily concerned with the biological treatment (including antipsychotic medication
and other pharmacological treatment options) of adults suffering from schizophrenia.
Key words: Schizophrenia, antipsychotics, evidence-based guidelines, long-term treatment, side effects
Executive summary of recommendations are required not only for patients suffering from
acute schizophrenia, but also in the stabilisation and
General recommendations
stable phase of the disease. The stabilisation period
This part remains partly unchanged; it has been follows the acute phase and constitutes a time-
adopted from the WFBSP 2006 guidelines and limited transition to continuing treatment in the
updated where necessary. Specific treatment strategies stable phase. The stable phase represents a prolonged
*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-Jürgen Möller (Germany), S. Mosolov (Russia), Driss Moussaoui (Marocco),
Jean-Pierre Olié (France), Antonio Pacheco Palha (Portugal), Asli Sarandöl (Turkey), Mitsumoto Sato (Japan), Heinrich Sauer (Germany),
Nina Schooler (USA), Bilgen Taneli (Turkey), Lars von Knorring (Sweden), Daniel Weinberger (USA), Shigeto Yamawaki (Japan).
Correspondence: Dr. med. Alkomiet Hasan, MD, Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University,
Nussbaumstr. 7, D-80336 Munich, Germany. Tel: ⫹ 49 89 5160 5505. Fax: ⫹ 49 89 5160 5530. E-mail: alkomiet.hasan@med.
uni-muenchen.de
and
no negative controlled studies exist
C2 Case Reports. Evidence is based on:
1 or more positive case reports
and
no negative controlled studies exist
C3 Evidence is based on the opinion of experts in the field or clinical experience
D Inconsistent Results
Positive RCTs are outweighed by an approximately equal number of negative studies
E Negative Evidence
The majority of RCTs studies or exploratory studies shows non-superiority to placebo (or in the
case of psychotherapy studies, superiority to a “psychological placebo”) or inferiority to
comparator treatment
F Lack of Evidence
Adequate studies proving efficacy or non-efficacy are lacking.
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
period of treatment and rehabilitation during which reduction, consolidate remission, and promote the
symptoms are under adequate control and the focus process of recovery. The main goals of treatment
is on improving functioning and recovery. The goals during the stable phase are to ensure that symptom
of long-term therapy have to be discussed with the remission or control is sustained, that the patient is
patient in the context of adequate background infor- maintaining or improving their level of functioning
mation, as well as her/his personal goals, in order to and quality of life, that monitoring for adverse treat-
find a common ground which will encourage an ment effects continues, and to prevent relapse. The
effective long-term medication strategy (shared- antipsychotic pharmacological therapy should be
decision making). In this regard, a treatment plan accompanied by psychosocial interventions.
must be formulated and implemented. A number of psychosocial treatments, including
During the stabilisation phase, the main goals of family intervention, supported employment, asser-
treatment are to facilitate continued symptom tive community treatment, skills training and
4 A. Hasan et al.
cognitive behaviour-oriented psychotherapy, have Antipsychotic medications are associated with dif-
been shown to be effective during the stable phase. fering levels of risk for various side effects, including
The selection of appropriate psychosocial treat- neurological, metabolic, sexual, endocrine, sedative
ments should be guided by the circumstances of and cardiovascular side effects (for a detailed
the individual patient’s needs and social context. description see Part 1 of this guideline update).
In the same way, psychopharmacological manage- These side effects may have an even greater influ-
ment must be individually tailored to the needs ence on the choice of long-term medication than in
and preferences of the patient, focusing on relapse the acute phase of treatment. Monitoring of side
prevention, symptom suppression and improve- effects is based on the side effect profile of the pre-
ment of subjective wellbeing and quality of life. scribed antipsychotic. During the stable phase, it is
important to monitor all patients routinely for all
extrapyramidal symptoms (EPS), weight gain, car-
diovascular and metabolic side effects. Monitoring
Specific treatment recommendations
for obesity-related health problems (e.g., high blood
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Long-term treatment is necessary for all patients pressure, lipid abnormalities and clinical symptoms
with schizophrenia. If the patient has shown of diabetes) and consideration of appropriate
improvements with a particular medication regi- interventions are recommended if necessary (see
men, continuation of that regimen with further Table III and Part 1 of these updated guidelines).
monitoring is recommended for at least 6 months Clinicians may consider regular monitoring of fast-
in the stabilisation phase. Premature dosage lower- ing glucose or haemoglobin A1c levels to detect
ing may lead to a recurrence of symptoms and emerging diabetes since patients often have multiple
relapse, whereas this question is recently discussed risk factors for diabetes, especially patients with
controversially (Takeuchi et al. 2012). Side effects obesity (De Hert et al. 2006, 2011a). FGAs and
have to be assessed and, if necessary, pharmaco- SGAs have specific side effect profiles and these pro-
therapy has to be adjusted. Antipsychotic medica- files have to be considered when planning a long-
For personal use only.
tions substantially reduce the risk of relapse in the term treatment. SGAs have clear advantages with
stable phase of illness and are strongly recom- respect to EPS (especially tardive dyskinesia).
mended for durations of 1–2 years in first-episode However, this advantage has to be weighed against
patients, 2–5 years in patients who have experienced other potentially dangerous side effects, e.g., meta-
one relapse, and for over 5 years (maybe even bolic or cardiac side effects (see Table II and Part 1
throughout life) in multi-episode patients. of these updated guidelines).
Antipsychotic monotherapy should be the pre- It is important to evaluate whether residual nega-
ferred treatment approach. Continuous dosing tive symptoms are in fact secondary to a parkinso-
strategies have shown superiority compared to nian syndrome or untreated major depression since
intermittent-dose approaches. Deciding on the dose interventions are available to address these causes of
of an antipsychotic medication during the stable negative symptoms. For primary negative symptoms,
phase is complicated by the fact that there is no treatment options include switching to an atypical
reliable strategy available to identify the minimum antipsychotic or augmentation strategies. Neverthe-
effective dose to prevent relapse. less, it should be noted that the evidence for the
There is no good evidence that high maintenance efficacy of these strategies is only limited (see Part 1
doses (e.g., for first-generation antipsychotics of these updated guidelines). Adjunctive medications
(FGAs) above 600 mg CPZ equivalents) are more are prescribed for comorbid conditions of patients in
effective in preventing relapse than standard doses. the stable phase. Comorbid major depression and
Therefore, a maintenance dosage below 600 CPZ obsessive-compulsive disorder may respond to anti-
equivalents is recommended. First-episode patients depressant medications, mood stabilisers may
may require lower doses for relapse prevention than address prominent mood lability, and benzodiaz-
multi-episode patients. epines are helpful for managing anxiety and insom-
Depot preparations (FGAs or SGAs, long-acting nia. However, the evidence for these treatment
antipsychotics) should be the application method of strategies is minimal and the combination therapy of
choice when a patient expresses a preference for such antipsychotics and benzodiazepines with a long half-
treatment because of its convenience, or as part of a time is discussed to increase mortality in schizophre-
treatment plan in which the avoidance of covert non- nia patients (Baandrup et al. 2010) (see Part 1 of
adherence with antipsychotic drugs is a clinical pri- this guideline update).
ority. In certain cases, patients should be actively Further treatment strategies, including appro-
motivated and educated about the benefits of using priate management of side effects, are extensively
depot preparations. discussed below.
Biological treatment of schizophrenia: Part 2 5
Ziprasidone
Goal and target audience of the WFSBP
0 ⫽ no risk; (⫹) ⫽ occasionally, may be no difference to placebo; ⫹ ⫽ mild (less 1%); ⫹⫹ ⫽ sometimes (less 10%), ⫹⫹⫹ frequently (⬎ 10%); ? ⫽ no statement possible due to lacking data.
0/(⫹)
0/(⫹)
0/(⫹)
guidelines
⫹⫹
(⫹)
(⫹)
0
0
0
0
0
0
0
?
?
These guidelines are intended for use in clinical
practice by all physicians investigating, diagnos-
ing and treating patients with schizophrenia. There-
Sertindole
0/(⫹)
⫹⫹
(⫹)
(⫹)
(⫹)
(⫹)
(⫹)
(⫹)
(⫹)
(⫹)
⫹
⫹
⫹
of various aspects of schizophrenia, with a particular
focus on treatment options, is provided. The aim of
these guidelines is to improve standards of care, to
diminish unacceptable variations in the provision
Risperidone
0/⫹⫹
⫹⫹
⫹⫹
⫹⫹
⫹⫹
(⫹)
(⫹)
(⫹)
⫹
0
Frequencies and severity of side effects refers to information obtained by drug companies, FDA, additional literature and other guidelines.
0/(⫹)
0/(⫹)
⫹⫹
⫹⫹
⫹⫹
(⫹)
(⫹)
(⫹)
(⫹)
⫹
0
0
?
0/⫹⫹
0/(⫹)
⫹⫹
⫹⫹
⫹⫹
⫹⫹
(⫹)
(⫹)
(⫹)
⫹
0
⫹/⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
0/(⫹)
0/(⫹)
⫹⫹
(⫹)
(⫹)
(⫹)
(⫹)
(⫹)
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹
(⫹)
(⫹)
(⫹)
0
0
0
considered:
0/(⫹)
(⫹)
(⫹)
(⫹)
(⫹)
(⫹)
⫹
⫹
0
0
0
0
0
0
0
0/(⫹)
⫹⫹
⫹⫹
⫹⫹
0/⫹
(⫹)
(⫹)
(⫹)
(⫹)
2009);
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
0/(⫹)
⫹⫹
⫹⫹
⫹⫹
(⫹)
(⫹)
⫹
⫹
Glucose abnormalities
QT prolongation
Dysmenorrhoea
Agranulocytosis
Weight Gain
Sedation
MNS
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
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EEG x x
Pregnancy test x x
schizophrenia is good (Category of evidence A), but If the patient has improved with a particular medica-
due to its side effect profile it is not recommended tion regimen, it is recommended that the regimen is
as a first line treatment for first-episode schizophre- continued for at least 6 months (Lehman et al. 2004;
nia (Recommendation Grade 2). According to the Falkai et al. 2006). It is also critical to assess continu-
publication of Bandelow and colleagues (2008a), ing side effects that may have been present in the
“the recommendation grades can be viewed as acute phase and to adjust pharmacotherapy accord-
steps: The first step would be a prescription of a ingly in order to minimise adverse side effects that
medication with recommendation grade 1. When may otherwise lead to medication nonadherence and
this treatment fails, all other grade 1 options should relapse.
be tried first before switching to treatments with The stable phase (lasting months to years)
recommendation grade 2” (Bandelow et al. 2008a) represents a prolonged period of treatment and
(see Table I). rehabilitation during which symptoms are under
adequate control and the focus is on improving
functioning and recovery. The main goals of treat-
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General aspects of long-term treatment ment during the stable phase are to ensure that
of schizophrenia symptom remission or control is sustained, that the
patient is maintaining or improving their level of
Indication and goals of long-term treatment
functioning and quality of life, that any increases in
for schizophrenia
symptom severity or relapse occurrence are effec-
The general aspects of this section have been tively treated, and that monitoring for adverse treat-
adopted from the last version of these guidelines ment effects continues. For most patients in the
and have been updated where necessary. Schizo- stable phase of schizophrenia, psychosocial inter-
phrenia is a heterogeneous condition that has a ventions are recommended as a useful adjunctive
varying course and outcome, and affects many treatment to pharmacological treatment to improve
aspects of a patient’s life. The care of most patients outcome. The main aims of pharmacological inter-
For personal use only.
with this disorder involves multiple efforts and a vention in the stable phase are to prevent relapse,
multidisciplinary team approach to reduce the fre- help keep an individual stable enough to live as nor-
quency, duration and severity of episodes, reduce mal a life as possible, and continue to promote the
the overall morbidity and mortality of the disorder, process of recovery (in the sense of a maintenance
and improve psychosocial functioning, indepen- or continuation therapy).
dence and quality of life. The goals of long-term treatment have to be
Specific treatment needs to be continued in the discussed with the patient and, if she/he agrees,
stabilisation and stable phase of schizophrenia and with family members, relatives, care givers and, in
long-term treatment is indicated for all patients with some cases, advocates, with the aim of providing
schizophrenia. Clinical issues consist of relapse pre- adequate information and with an understanding
vention and improvement of symptoms, including of the patient’s personal goals. When an agreement
the reduction of the demoralising effects of persistent is reached in the context of shared decision-making,
psychotic symptoms, treating depression and pre- a treatment plan must be formulated and imple-
venting suicide, reducing substance abuse and mented. Psychopharmacological management
smoking, and enhancing family relationships and must be individually tailored to the needs and
vocational rehabilitation. preferences of the patient, focusing on relapse pre-
The stabilisation period (usually lasting 3–6 vention, symptom suppression and improvement
months) follows the acute phase and constitutes a of subjective wellbeing and quality of life. Psycho-
time-limited transition to continuing treatment in therapeutic interventions remain supportive but
the stable phase. The primary goals in the stabilisa- may be less directive than in the acute phase.
tion phase are the consolidation of the therapeutic Educational programmes during this phase have
relationship, reduction of positive symptoms, been effective in teaching a wide range of schizo-
improvement of cognitive and negative symptoms, phrenia patients medication self-management
reduction of stress for the patient, improvement of (e.g., benefits of maintenance of antipsychotic
social deficits and consolidation of remission, pro- medication, how to cope with side effects), symp-
motion of insight and compliance, supporting the toms self-management (e.g., how to identify early
development of individual coping strategies, provi- warning signs of relapse, develop a relapse preven-
sion of support to minimise the likelihood of relapse, tion plan, refuse illicit substances and alcohol),
enhancement of the patient’s adaptation to life in the and basic social skills (APA 1997; Lehman et al.
community and promotion of the recovery process. 2004; Falkai et al. 2006).
8 A. Hasan et al.
Antipsychotic treatment the relative benefits of the drugs and their side effect
profiles and the past experience of the patient and
General aspects
the physician. Antipsychotic drugs should not be
Since the last publication of these guidelines, some prescribed concurrently and monotherapy should be
new studies investigating and comparing the efficacy favoured. For short periods of overlap in the case of
of FGAs and SGAs in the long-term treatment of switching, in the case of severe treatment resistance
schizophrenia have been published. Furthermore, or in order to combine different pharmacological
new long-acting antipsychotics have been launched effects (e.g., combined treatment with low-potency
to the market, providing additional treatment options FGA for sedation), a combination treatment is
for the long-term management of schizophrenia. acceptable (NICE 2002; Lehman et al. 2004;
The following statements are in accordance with RANZCP 2005; DGPPN 2006; Falkai et al. 2006).
the previous version of these guidelines and have Psychiatrists, who treat patients with more than one
been updated only where necessary. The efficacy of antipsychotic at the same time should be aware of
FGAs in relapse prevention was demonstrated in the drug interactions and that there have been practi-
World J Biol Psychiatry Downloaded from informahealthcare.com by Nyu Medical Center on 04/28/13
1970s (Davis 1975, 1985) and was confirmed for cally no studies examining the security of these com-
most SGAs later (Davis and Chen 2003; Leucht bination treatments.
et al. 2009a, 2012a,b; NICE 2010). These efficacies
have been shown for both first-episode schizophrenia
Methodological aspects
patients (Kane et al. 1982; Crow et al. 1986; Bradford
et al. 2003; Schooler et al. 2005; Gaebel et al. 2007) In contrast to the acute and short-term treatment of
and for multiple-episode schizophrenia patients schizophrenia, there are only few studies that have
(Davis 1975, 1985; Davis et al. 1993; Jeste et al. been conducted investigating maintenance therapy
1993; Gilbert et al. 1995; Leucht et al. 2003). Antip- and comparing FGAs and SGAs. As widely dis-
sychotic therapy should be continued as part of a cussed in the first part of these guidelines and in
comprehensive package of care that addresses the other publications (Leucht et al. 2009b; Glick et al.
For personal use only.
individual’s clinical, emotional and social needs 2011), the differentiation between FGAs and SGAs
(NICE 2002). Antipsychotic drugs are an indispens- raises some problems (“pseudoclassification”) and
able treatment option for most people in the recov- each antipsychotic has its individual side effect pro-
ery and stable phases of schizophrenia. The main aim file. This fact limits the comparability of different
here is to prevent relapse and help keep a person antipsychotics and needs to be considered when
stable enough to live as normal a life as possible reading these guidelines and the underlying original
(NICE 2002) with minimal side effects. Antipsy- publications.
chotics are also necessary for psychological treat- Another problem is that good meta-analyses
ments to be effective, and psychosocial interventions addressing questions of long-term antipsychotic
are always an essential addition to pharmacotherapy treatment are still rare – a situation that can be
(RANZCP 2005). explained by the small number of well-designed
Targets of long-term treatment include mainte- long-term clinical trials. Furthermore, main prob-
nance therapy to stabilise remission, prevent relapse, lems of meta-analyses are the comparability of the
and provide symptom suppression or even continued included studies (e.g., diagnostic differences, differ-
symptom improvement. Ongoing monitoring and ent observation periods, different dosages) and the
assessment during the stable phase are necessary fact that negative results are less frequently published
to determine whether the patient might benefit than positive results (publication bias) (Leucht et al.
from alterations to his or her treatment programme 2009c). The reader should be aware about the meth-
(Lehman et al. 2004), and whether potential dange- odological problems associated with meta-analyses
rous side effects are developing. However, the fre- and consider that meta-analyses can lead to a differ-
quency of assessments conducted by the psychiatrist ent interpretation of already available data (Leucht
or member of the team should depend on the et al. 2009c). Furthermore, long-term treatment
specific nature of the treatment and the expected needs to address other clinical variables than psycho-
fluctuations of the illness, as well as from the health pathology (e.g., neurocognition, drug acceptability,
care system of the particular country. For example, compliance, subthreshold episodes, substance abuse
patients given certain antipsychotics (e.g., clozapine) and many more) and many of the published long-
should be evaluated more frequently than patients term studies do have still too short observation peri-
on other antipsychotics. ods, which do not allow to draw final conclusions
The choice of antipsychotic drug should be made about long-term treatment in schizophrenia patients
jointly by the individual and the clinician responsible (Altamura and Glick 2010). These methodological
for treatment, based on an informed discussion of aspects are of great relevance for the understanding
Biological treatment of schizophrenia: Part 2 9
of the original publications and of the recommenda- of life. However, extrapyramidal symptoms were
tions made in these guidelines. more frequent in the haloperidol group. Although
the study was biased by a high drop-out rate of 68%,
the drop-out rate did not differ significantly between
FGAs and SGAs
drugs (Gaebel et al. 2007).
As described in the last version and in the recently In a double-blind international 2-year RCT, olan-
updated first part of these guidelines, differences zapine (mean dose 10.2 mg/day) and haloperidol
between FGAs and SGAs need to be viewed in the (mean dose 4.82 mg/day) were shown to have the
context of efficacy or effectiveness, side effects, the same efficacy in the primary outcome measure of
patient’s symptomatology and experience. A modern symptom reduction (Green et al. 2006). However,
antipsychotic therapy should provide a tailored ther- patients treated with olanzapine were found to be
apeutic regime with great attention to the side effects. less likely to discontinue the study and showed higher
In the case of long-term maintenance therapies, remission rates. It should be noted that the signifi-
intolerable side effects are an important factor related cantly longer duration of illness in the haloperidol
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to poor treatment adherence (Goff et al. 2010). group must be considered when interpreting these
Two pooled randomized, double-blind, multi- findings (Green et al. 2006).
centre 52-week studies (with similar study protocols) Another long-term 2-year randomized, double-
compared the long-term efficacy of aripiprazole and blind study compared haloperidol with risperidone
haloperidol in 1294 schizophrenia patients (Kasper in 63 patients with stable and chronic schizophrenia.
et al. 2003). This study showed comparable efficacy In addition to the antipsychotic treatment, study
of aripiprazole and haloperidol in reducing positive patients received “standard behavioural skills train-
symptoms, but a superiority of aripiprazole in reduc- ing or enhanced training with a case manager who
ing negative and affective symptoms. Furthermore, promoted patients’ use of their skills in the commu-
treatment with haloperidol was associated with more nity” (Marder et al. 2003). In this study, no differ-
motor side effects (Kasper et al. 2003). ences in the primary outcome parameter symptom
For personal use only.
A large double-blind, prospective long-term study reduction (Brief Psychiatric Rating Scale) could be
in stable outpatients suffering from chronic schizo- detected between the drugs. However, for the sec-
phrenia (mean duration of disease over 15 years), ondary outcome parameters, anxious-depression
revealed superiority of risperidone (modal daily dose cluster of the Brief Psychiatric Rating Scale and the
4.9 mg) with regard to treatment discontinuation, SCL-90-R self-report instrument, risperidone was
reduction of symptoms and extrapyramidal side superior compared to haloperidol. Furthermore,
effects when compared with haloperidol (modal risperidone induced fewer motor side effects and
daily dose 11.7 mg) (Csernansky et al. 2002). patients treated with haloperidol received more anti-
In a large (n ⫽ 555) double-blind, controlled, cholinergics and propanolol (for akathisia) (Marder
flexible-dose RCT, risperidone (mean modal dose et al. 2003).
3.3 mg/day) and haloperidol (mean modal dose One 12-month double-blind study from the
2.9 mg/day) were both found to lead to significant Veterans Affairs Medical Centres (Rosenheck et al.
improvements in global psychopathology without 2003) compared olanzapine with haloperidol (plus
difference between groups (Schooler et al. 2005). prophylactic benztropine for motor side effects) and
However, within the patients who achieved a clinical found no significant difference between the drugs in
improvement, the patients treated with risperidone relation to study retention, improvement in PANSS
had a significantly longer time to relapse. Patients scores, quality of life and extrapyramidal symptoms.
treated with haloperidol showed more extrapyrami- However, this study revealed that cognitive distur-
dal symptoms, while patients in the risperidone bances occurred more frequently in patients treated
group had a greater prolactin elevation. Treatment with haloperidol and benztropine. Olanzapine
with haloperidol resulted in less initial weight gain induced less motor side effects, but more weight gain
compared to treatment with risperidone, but this did compared to haloperidol (Rosenheck et al. 2003).
not remain significant at the study endpoint (Schooler Important confounders of his study are the long dis-
et al. 2005). eases course (approximately 20 years), the flexible
In a double-blind RCT with 159 remitted first- dosing scheme and the prophylactic treatment with
episode schizophrenia patients, no difference in the benztropine (Moller 2008). The latter biases the
primary outcome parameter “relapse prevention” study in favour of haloperidol and should not be
was found between haloperidol (4.1 mg/day) and common practice given the cognitive disturbances
risperidone (4.2 mg/day) (Gaebel et al. 2007). Both induced by anticholinergics.
drugs showed the same efficacy in the secondary In a flexible-dose double-blind 52-week RCT, no
outcome parameters symptom reduction and quality difference between chlorpromazine and clozapine
10 A. Hasan et al.
could be found with respect to rating scale measures of FGAs, and the effect size of zotepine was margin-
of symptom severity. However, patients receiving ally greater. Other SGAs revealed no clear superior-
clozapine remitted significantly faster and remained ity (Davis et al. 2003). No efficacy difference was
in remission longer than patients receiving chlorpro- detected when amisulpride, risperidone and olan-
mazine (Lieberman et al. 2003). zapine were directly compared to each other. In a
In various parts of the CATIE study (except from more recent meta-analysis (comparing FGAs to
Part 3; for details see Part 1 of these guidelines) SGAs, conducted mainly from short-term trials),
(Lieberman et al. 2005; Essock et al. 2006; Stroup SGAs were not pooled because the authors felt that
et al. 2006, 2007) some evidence was found to sug- they were too different to form a class (Leucht et al.
gest that olanzapine might be superior to the FGA 2009b, 2011b). In this new meta-analysis, only ris-
perphenanzine, as well as to other SGAs, in the peridone, olanzapine and sertindole (based on only
maintenance treatment of schizophrenia. The CUt- one study) were superior to FGAs in terms of relapse
LASS study (for details see Part 1 of these guide- prevention. For amisulpride, aripiprazole and clo-
lines), with a follow-up until week 52, indicated no zapine, no significant difference could be detected
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difference between a group of SGAs and a group of compared to FGAs and, for the other SGAs, no data
FGAs (preferentially sulpiride) in the long-term were available (Leucht et al. 2009b). However, these
treatment of schizophrenia (Jones et al. 2006). How- meta-analyses (Davis et al. 2003; Leucht et al. 2009b)
ever, both studies have important methodological primarily included short-term studies and the trans-
restrictions which have been discussed in the first lation of their results to long-term studies should be
part of these updated guidelines and elsewhere undertaken only with caution.
(Naber and Lambert 2009; Moller 2008). A meta-analysis (Leucht et al. 2003) including
One prospective observational trial with 374 only trials with a minimum 6 month duration showed
schizophrenia/schizoaffective patients and an obser- a superiority of SGAs when grouped together and
vation period of 24 months showed that olanzapine when compared to placebo, a superiority of certain
(mean daily dose 15 mg) has some superiority com- SGAs (risperidone, olanzapine and sertindole), and
For personal use only.
pared to risperidone (mean daily dose 4.9 mg) and a numeric, but not significant superiority for amisul-
quetiapine (mean daily dose 588 mg) with regard to pride and clozapine when compared to FGAs and a
the primary outcome measure (rehospitalisation of superiority of the grouped SGAs compared to FGAs.
patients after discharge from index hospitalisation) SGAs and FGAs showed no difference in terms of
(Kilian et al. 2012). However, the quetiapine group dropout-rate due to adverse effects. The authors dis-
needed higher chlorpromazine equivalent doses to cussed several confounding factors of this meta-
show similar effects compared to the other treatment analysis (e.g., the difficulty of defining relapse, the
groups (Kilian et al. 2012). fixed-dosage regime in the included trials) and con-
The EUFEST study (Kahn et al. 2008) was con- cluded that the “available data do not allow for any
ducted on first-episode schizophrenia patients and conclusions about whether this modest superiority
compared haloperidol with four different SGAs for the new antipsychotics in relapse prevention is
(amisulpride, olanzapine, quetiapine, ziprasidone) related to enhanced efficacy, better adherence, or a
with regard to the primary outcome measure treat- combination of these factors” (Leucht et al. 2003).
ment discontinuation. Treatment discontinuation for A more recent meta-analysis of randomized trials,
any reason was significantly higher in patients treated lasting 6 months or longer, compared FGAs with
with haloperidol. Treatment discontinuation as a SGAs in the long-term treatment of schizophrenia
consequence of insufficient efficacy was also higher (Kishimoto et al. 2011) and showed that SGAs,
in the haloperidol group, but the difference between when grouped together, were significantly superior
haloperidol and quetiapine was not significant (Kahn to FGAs with regard to relapse prevention. No study
et al. 2008). showed a superiority of the FGA comparator and
In the SOHO study (observational and non- this meta-analysis does not allow a conclusive com-
randomized), SGAs led to lower discontinuation parison among SGAs (Kishimoto et al. 2011). How-
rates and more remissions than FGAs and subjects ever, the authors discuss the results concerning the
reported increased subjective wellbeing following questions of whether SGAs form a meaningful group
treatment with SGAs (Lambert et al. 2006; Haro and whether mid- or low-potency FGAs differ from
et al. 2007). haloperidol (Kishimoto et al. 2011).
In a 2003 published meta-analysis of randomised A recent analysis of mid- and long-term outcome
short-term efficacy trials comparing SGAs and data of newer antipsychotics discusses some advan-
FGAs, and comparing between different SGAs, tages of SGAs in the long-term and maintenance
effect sizes of clozapine, amisulpride, risperidone treatment of schizophrenia (Glick et al. 2011). The
and olanzapine were found to be greater than those authors highlight the problems of the comparability
Biological treatment of schizophrenia: Part 2 11
of different antipsychotics and that during the main- reduced incidence of tardive dyskinesia and other
tenance treatment patients and the relatives focus on motor side effects (Moller 2008; Naber and Lambert
other issues (e.g., relief from disabling symptoms, 2009). In the CATIE study patients with tardive dys-
gaining works, building up relationships) than kinesia were excluded from the FGA arm (selection
during the acute treatment (Glick et al. 2011). Fur- bias) and in the CUtLASS study the most frequently
thermore, a consensus paper published by the Euro- chosen FGA was sulpiride. Sulpiride is an “atypical”
pean college of neuropsychopharmacology (ECNP) FGA and can be considered as an SGA. Further-
states that in controlled long-term studies, where the more, neither of these studies used haloperidol, the
secondary negative symptoms become less promi- mostly prescribed FGA in most developed countries,
nent, certain SGAs may have some advantages in as comparator (Naber and Lambert 2009). The find-
reducing negative symptoms (Montgomery and van ings of the large European first-episode study
Zwieten-Boot 2007). Please see Part 1 of these (EUFEST) confirm that treatment with haloperidol
guidelines for a detailed and evidence-based discus- might lead to significantly more motor side effects
sion of the treatment of primary and secondary and a significantly higher study discontinuation rate
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treatment, the risk of inducing tardive dyskinesia is tive in relapse prevention and should
lower following treatment with SGAs (Kasper et al. be offered to a patient suffering from
2006; Naber and Lambert 2009; Leucht et al. schizophrenia (Category of evidence A,
2011b). The metabolic side effect profile of certain Recommendation grade 1).
antipsychotics (see Part 1 of these guidelines) should – FGAs and SGAs do not show general
not be underestimated and long-term studies differences in reducing symptoms with long
specifically addressing this question are lacking. term treatment (Category of evidence A,
However, increasing rates of cardiovascular diseases Recommendation grade 1).
as consequences of metabolic syndrome are one of – Some evidence is available to support
main reasons for excess mortality in schizophrenia superiority of certain SGAs (as outlined in
patients and, therefore, special attention must be these guidelines) with regard to treatment
paid to these side effects (Newcomer 2007; Laursen discontinuation and relapse prevention
et al. 2009; De Hert et al. 2009, 2011a). (Category of Evidence B, Recommendation
Therefore, maintenance treatment should follow grade 3).
the basic rules of acute treatment: an antipsychotic – The reduced risk of inducing motor side
maintenance therapy should be balanced between effects (especially tardive dyskinesia) might
efficacy, compliance, the patient’s individual side favour certain SGAs (Category of evidence C,
effect profile and the patient’s experience with cer- Recommendation grade 4).
tain antipsychotics. – In the long-term treatment, where the second-
The risk of developing tardive dyskinesia following ary negative symptoms become less promi-
treatment with FGAs is well-established, but long- nent, certain SGAs may have some advantages
term complications following treatment with certain in reducing negative symptoms (Category of
SGAs are still not fully understood. Current studies evidence C, Recommendation grade 4).
cannot negate a risk for developing metabolic syn- – For long-term therapy, tardive dyskinesia
drome, diabetes and coronary heart disease associ- and metabolic side effects seem to have the
ated with long-term treatment with certain SGAs greatest impact on the patient’s wellbeing
(see Part 1 of these guidelines). and health – these side effects, among others
Even after the results of the CATIE and CUt- (see Part 1 of these guidelines), need to
LASS studies, the risk of tardive dyskinesia should be monitored continuously and treated as
not be underestimated because the widely discussed soon as possible (Category of evidence C,
limitations of these two studies may have led to a Recommendation grade 4).
12 A. Hasan et al.
– The choice of the antipsychotic should be A number of studies have investigated treatment
influenced by the same criteria recom- regimens where markedly lower dosages of FGAs
mended for starting a treatment (Good (oral and depot formulations) were used in mainte-
Clinical Practice). nance therapy than during acute treatment. The
– Maintenance treatment should be carried results showed that, compared with continuous ther-
forward with the antipsychotic drug which apy, relapse rates increased in most studies, espe-
led to the best response and which had the cially in low-dose studies (e.g., reduction of 25–50%
best individual side effect profile during the of the standard dose (Johnson et al. 1987; Schooler
acute episode (Good Clinical Practice). et al. 1997)), but were within acceptable limits (Kane
– Each antipsychotic selection procedure et al. 1982, 1983; Marder et al. 1984; Hogarty et al.
must be undertaken individually, respecting 1988; Johnson et al. 1987; Dixon et al. 1995; Schooler
the patient’s experience with certain drug et al. 1997).
classes and the individual side effect However, the lower dosages were associated with
profile. a more favourable side effect profile and better com-
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Starting dose Target dose first-episode Target dose multi-episode Maximal dosage
Antipsychotic (mg/day) DI1 (mg/day) (mg/day) (mg/day)2
SGA
Amisulpride 200 (1)–2 100–300 400–800 1200
Asenapine3 5 1 5–10 5–20 20
Aripiprazole 5–15 1 15–(30) 15–30 30
Clozapine4 25 2–(4) 100–250 300–800 900
Iloperidone3 1–2 2 4–16 4–24 32
Lurasidone3 20–40 1 40–80 40–120 120
Olanzapine 5–10 1 5–15 5–20 20
Paliperidone3 3–6 1 3–9 3–12 12
Quetiapine IR/XR 50 2/1 300–600 400–750 750
Sertindole 4 1 12–20 12–24 24
Risperidone 1–2 1–2 1–4 3–10 16
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In clinical practice some FGAs and SGAs are even dosed higher without sufficient evidence. This is especially the case during a long-term
treatment. Increasing the dosage may result in more side effects and this would consecutively lead to a reduced compliance.
3These antipsychotics have not been investigated in first-episode schizophrenia patients.
4Clozapine is usually not introduced in first-episode schizophrenia patients as first-line treatment.
group leads to significantly more relapses compared and their families to discontinue antipsychotic
to when medication is continued (Kane et al. 1982; medication after patients recover from an episode of
Crow et al. 1986; Hogarty and Ulrich 1998; Chen schizophrenia but, as discussed above, studies indi-
et al. 2010). Chronically ill patients who had been cate that the rate of relapse after an acute psychotic
stable for years, but stopped their medications, episode is relatively high. Given the fact that there
experienced significantly more relapses than patients are no reliable predictors of prognosis or drug
who stayed on their antipsychotics (Johnson 1976; response, pharmacological relapse prevention should
Cheung 1981; Odejide and Aderounmu 1982; be considered for every patient diagnosed with
Sampath et al. 1992; Leucht et al. 2011b). Further- schizophrenia. Possible exceptions are individuals
more, a vast majority of patients who do not undergo with very brief psychotic episodes without negative
any form of antipsychotic therapy experience a psychosocial consequences, and the uncommon
relapse within 3–5 years. Therefore, continuous patient for whom all available antipsychotics pose a
antipsychotic treatment for patients suffering from significant health risk (Fleischhacker and Hummer
multi-episode schizophrenia has been recommended 1997; NICE 2002; 2010).
by various publications (Kissling 1991; DGPPN
2006; Falkai et al. 2006). Up to 20% of individuals
will only experience a single episode, while a similar
Summary statements
or even higher percentage will experience a relapse
despite continued antipsychotic drug treatment Recommendations for treatment durations in schizo-
(Möller and van Zerssen 1995; Robinson et al. 1999; phrenia do not have a strong empirical basis and
Moller 2004; Falkai et al. 2006). An observational further studies are needed to provide better evidence-
study in outpatients with schizophrenia in 10 based recommendations. Most recommendations
European countries revealed a constant relapse are based on small studies, expert’s opinions and
rate throughout the observation period, indicating a clinical experience. However, there is a high risk of
disease-dependent relapse rate (Haro et al. 2007). relapse if patients stop their medication during the
Psychiatrists may experience pressure from patients first 1–2 years following acute psychosis.
14 A. Hasan et al.
– A continuous antipsychotic for at least one severe symptoms, such as tension and nervousness,
year for first-episode patients is recommended eating less, difficulty concentrating and remember-
(Category of evidence C, Recommendation ing, trouble in sleeping, and depression, and it may
grade 4). also include mild psychotic symptoms and idiosyn-
– For multiple-episode patients, maintenance cratic behaviours. Such changes preceding relapse
treatment duration of at least 2–5 years indicate either the emergence of new symptoms or
(in severe cases life-long treatment) should increases in symptoms that were already present at
be taken into consideration (Category of baseline. In addition to these symptoms, changes in
evidence C, Recommendation grade 4). observable behaviours are noted by some patients
– Nevertheless, the duration of treatment and families. Examples include social withdrawal,
should be determined on an individual basis, wearing makeup in excessive or bizarre ways, and
taking into account the patient’s motivation, loss of concern for one’s appearance (APA 1997).
the psychosocial situation and the additional Controlled studies have demonstrated that spe-
care being given. Indefinite continuation of cific programmes designed to educate patients and
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been demonstrated (Weiden et al. 2004). The devel- France, whereas in other countries (e.g., UK and
opment of long-acting depot antipsychotics has Australia) the long-acting antipsychotics are used
provided an important option, especially in the frequently (Patel et al. 2009; Leucht et al. 2011a).
management of partial nonadherence. Since the ini-
tial draft of these guidelines in 2006 and in addition
to the first long-acting SGA risperidone, two new First-generation depot antipsychotics
long-acting antipsychotics have been launched onto
the market (paliperidone palmitate and olanzapine Studies comparing the antipsychotic depot with
pamoate) and some new studies and meta-analyses placebo are very rare. Most reliable data are avail-
have been conducted. able from meta-analyses, which raise certain meth-
Long-acting depot antipsychotics mostly consist odological problems (Leucht et al. 2009c). Studies
of an ester of the antipsychotic agent in an oily solu- comparing depot medication against placebo could
tion which has to be administered by deep intramus- only be identified for bromperidol, fluphenazine,
cular injection. Following injection, the drug is slowly fluspirilene and haloperidol. From one Cochrane
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released from the injection site (an exception is ris- review, there is limited evidence that bromperidol
peridone). This results in relatively stable plasma decanoate is superior to placebo, but not superior
drug levels over long periods, allowing the injections to fluphenazine or haloperidol depot (Purgato and
to be given every 2–4 weeks. The advantages of long- Adams 2011). For haloperidol decanoate, only
acting depot antipsychotics have to be balanced sparse data exists, but there is suggestion that it
against some disadvantages. The following list has may improve symptoms in schizophrenia signifi-
been adopted and modified from a publication by cantly better than placebo and there are no clear
Nasrallah (2007) as well as the 2006 version of these differences between the oral and the depot formu-
guidelines. lation (Quaraishi et al. 1999). Depot fluphenazine
(decanoate or enanthate) has been studied exten-
sively and a Cochrane Review included a total of
For personal use only.
superiority of depot formulations by assuring scale (Kane et al. 2003). This finding is supported
adherence (Davis et al. 1994). by the results of two other 12-week, double-blind
Across the literature there has been discussion placebo-controlled studies, that demonstrated the
about whether the inclusion of inpatients and the superiority of long-acting risperidone with regard to
short duration of trials might have reduced the psychopathology and treatment response compared
advantages of depot medication (Leucht et al. 2011a). to placebo (Ciliberto et al. 2005; Lauriello et al.
Therefore, one recently published meta-analysis (10 2005).
RCTs) focused on long-term (ⱖ 1 year) RCTs com- In two studies (Harrison and Goa 2004; Chue
paring depot (8 first-generation depots, two second- et al. 2005), no differences between oral risperidone
generation depots) versus oral formulations in and risperidone microspheres could be detected in
outpatient settings (Leucht et al. 2011a). In this terms of efficacy, whereas one 12-week RCT showed
analysis, depot antipsychotics were superior to oral that risperidone given in the form of a long-acting
antipsychotics with regard to relapse, but not to injection was superior to oral risperidone with regard
rehospitalisation due to psychopathology, dropout to the PANSS positive subscore and side effects, but
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rates and non-adherence (Leucht et al. 2011a). not with respect to other PANSS scores (Bai et al.
Finally, the recent PORT guidelines recommend the 2006).
use of haloperidol decanoate and fluphenazine In the open-label phase III of the CATIE study,
decanoate for the maintenance treatment of schizo- no difference in efficacy between various SGAs,
phrenia (Buchanan et al. 2010). perphenazine, fluphenazine and risperidone, given
in a long-acting injectable form, could be found
(Stroup et al. 2009). Furthermore, long-acting
Summary statement injectable risperidone (25–50 mg) was not shown to
be superior to oral olanzapine (5–20 mg) after
– Currently, there is good evidence to support 13 weeks of treatment and after a 12-month follow
the use of FGA depot antipsychotics up (618 patients randomised and treated and
For personal use only.
for relapse prevention in schizophrenia 347 patients completed the trial) (Keks et al. 2007).
(Category of evidence A, Recommendation In the first published naturalistic long-term 2-year-
grade 1), but no clear difference in efficacy prospective study (e-STAR), a risperidone long-
between oral and depot formulations can be
acting injection was found to be superior to an oral
stated (Category of evidence A, Recommendation
SGA (risperidone or olanzapine) in terms of Clini-
grade 1).
cal Global Impression Severity and the number of
hospitalizations (Olivares et al. 2009). A long-term
2-year open-label study evaluated the switch from
Second-generation depot antipsychotics stable treatment with oral risperidone, olanzapine,
In 2006, long-acting risperidone was the only SGA or conventional neuroleptics to long-acting inject-
depot formulation. At the time of development of able risperidone or to oral quetiapine. Kaplan–
these guidelines, three different SGA depot formula- Meier estimates showed that the time until relapse
tions were available: risperidone microspheres, pali- was significantly longer for patients treated with
peridone palmitate and olanzapine pamoate. long-action injectable risperidone compared to
patients treated with oral quetiapine (Gaebel et al.
2010). However, in unstable patients, defined as
Risperidone microspheres (risperidone depot) those having been hospitalised within the previous
2 years or having an imminent risk for hospitalisa-
The preparation consists of an aqueous suspension tion, other results have been reported. This was
of microspheres comprising risperidone and a bio- tested in a large, recently published randomized
degradable copolymer, and the injection interval is study from the Veterans Affairs Clinical Centre
2 weeks. However, before applying the depot alone, (Rosenheck et al. 2011). Unstable patients were
there is a need for oral supplementation of oral ris- either treated with long-acting injectable risperi-
peridone for the first 3 weeks. With this mechanism, done every 2 weeks or with a psychiatrist’s choice
significant release of risperidone starts 3 weeks after of an oral antipsychotic. The analyses revealed that
the first injection, and is followed by gradual and the relapse rate after randomization was not sig-
sustained release for 4–6 weeks following the first nificantly lower among patients who received long-
injection (Harrison and Goa 2004). In a 12-week acting injectable risperidone than among those who
multicentre, double-blind RCT study, long-acting received oral antipsychotics, but that patients treated
risperidone was superior compared to placebo with with the depot had more adverse effects at the injec-
regard to psychopathology according to the PANSS tion site and more motor side effects (Rosenheck
Biological treatment of schizophrenia: Part 2 17
et al. 2011). One study based on observational data schizophrenia patients and elderly patients
from the Cohort for the General study of Schizo- suffering from schizophrenia (Category of
phrenia (CGS) showed that long-acting risperidone evidence B, Recommendation grade 3).
was especially prescribed in younger and more fre- – There is no evidence to support the com-
quently hospitalised patients (regardless of disease bination of galantamine and risperidone
severity). However, even after correction for these depot for the treatment of cognitive symptoms
factors, long-acting risperidone was associated with in schizophrenia (Category of evidence E).
a significant lower risk for hospitalisation compared
to other treatment options (non-use or other depot
formulations or oral formulation of FGAs or SGAs)
Paliperidone palmitate (paliperidone depot)
(Grimaldi-Bensouda et al. 2011).
Three studies with long-acting injectable risperi- Paliperidone palmitate is the depot formulation of
done have been conducted in special groups of oral paliperidone. It has low water solubility and dif-
schizophrenia patients: (1) first-episode schizophre- fuses slowly into systemic circulation following injec-
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nia patients; (2) elderly patients suffering from tion. Treatment with paliperidone palmitate does
schizophrenia; (3) schizophrenia patients with con- not require oral supplementation during the initia-
comitant drug abuse. tion of treatment (Hough et al. 2009). It was
In first-episode schizophrenia patients, long-acting approved by the FDA according to the results of
injectable risperidone was well tolerated and led to four short-term (9–13 weeks) studies comparing
more treatment adherence than oral risperidone in a paliperidone palmitate with placebo (20% intralipid
prospective RCT (Weiden et al. 2009). Another long- 200 mg/ml injectable) (Citrome 2010). These first
term 2-year open-label study with first-episode studies, showed that paliperidone palmitate is effec-
schizophrenia patients revealed that 64% of the tive in the treatment of schizophrenia in different
patients achieved remission and that 97% of the symptom domains (Citrome 2010). In a recently
patients maintained this status until study comple- published RCT, patients suffering from schizophre-
For personal use only.
tion (Emsley et al. 2008). A publication including nia were either randomised to placebo injection, to
subjects who participated in a foregoing 12-weeks an injection of 50 mg paliperidone palmitate or to
study showed that long-acting injectable risperidone 100 mg paliperidone palmitate on days 1, 8 and 36
is safe and well tolerated after 12 months of treat- (Kramer et al. 2010). Both dosages were superior to
ment in schizophrenia patients (Lindenmayer et al. placebo with regard to reduction of total PANSS
2007), and safety has also been demonstrated in scores, CGI scores and the factor “study discon-
elderly patients (ⱖ 65 years) (Kissling et al. 2007). In tinuation”. Furthermore, paliperidone palmitate
a subsample of schizophrenia patients with comorbid was well-tolerated and did not cause more motor
substance abuse, long-acting risperidone was supe- side effects (whereas the percentage of patients
rior to zuclopenthixol-depot in an open, randomized, receiving medication against motor side effects was
controlled 6-month study (Rubio et al. 2006). higher in the 100-mg group), but did cause signifi-
Finally, a 52-week double-blind, randomized study cantly more weight gain than placebo (Kramer et al.
showed that the combination of galantamine and 2010). In another study, schizophrenia patients were
long-acting injectable risperidone was not superior switched from a stable antipsychotic treatment to
to the combination of placebo and risperidone depot paliperidone palmitate in a 9-week, open-label phase.
in terms of the improvement in different cognitive Patients then received two intramuscular injections
domains (Lindenmayer and Khan 2011). of paliperidone palmitate (50mg) one-week apart,
followed by subsequent injections (25, 50 or 100mg
in a flexible-dose scheme) once monthly. Next, sta-
ble patients were either randomized to paliperidone
Summary statements
palmitate (at the stabilized dose) or to placebo in a
– There is good evidence to support the use double-blind study phase. Paliperidone palmitate
of long-acting injectable risperidone for was superior to placebo, both in a planned interim
the treatment of schizophrenia (Category of analysis and in the final analysis, with regard to the
evidence A, Recommendation grade 1). primary endpoint time-to-relapse (Hough et al.
– There is some evidence to support a 2010). A 13-week, double-blind study with 388
superiority of the depot compared to the schizophrenia patients compared three different
oral preparation (Category of evidence C, dosages of paliperidone palmitate (50, 100, 150 mg)
Recommendation grade 4). with placebo. In this study, only 100 mg paliperi-
– There is some evidence for the use of long- done palmitate showed a significant effect on the
acting injectable risperidone in first-episode reduction of PANSS scores (Gopal et al. 2010b).
18 A. Hasan et al.
Another 13-week study with a comparable design Olanzapine pamoate (olanzapine depot)
(25, 100, 150 mg paliperidone palmitate vs. pla-
This depot formulation consists of a crystalline salt-
cebo) showed a superiority for reducing PANSS
formulation composed of olanzapine and pamoic acid
score in all treatment groups compared to placebo
(pamoate) (Citrome 2009). In an 8-week, double-
in a sample of acutely exacerbated schizophrenia
blind study, schizophrenia patients were randomly
patients (Pandina et al. 2010). One further 13-week
assigned to receive 210 mg/2 weeks, 300 mg/2 weeks,
study compared 25, 50 and 100 mg paliperidone
or 405 mg/4 weeks of long-term injectable olanzap-
palmitate with placebo and showed a significant
ine or placebo/2 weeks. No other concomitant oral
improvement in all treatment groups compared to
antipsychotic treatment was permitted (Lauriello
placebo (Nasrallah et al. 2010). The first open-label
et al. 2008). After 3 days, the high dosages were
double-blind 1-year long-term study (extension of
superior to placebo with regard to reduction of
the double-blind study by Hough and colleagues
PANSS scores, and this superiority was reached for
(2010)) investigated a flexible dose of paliperidone
all three dosages after 1 week of treatment. However,
palmitate (Gopal et al. 2011). In this study, psycho-
olanzapine pamoate led to more sedation and weight
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and the risk decreases between hours 1 and 3 (⬍ 1 Dosages of depot formulations (see Table V)
in 10,000 injections after 3 h (Detke et al. 2010)).
According to the PORT guidelines, the recom-
After PDSS, the median time to recovery resolve
mended dosage range for fluphenazine decanoate is
from all symptoms is between 24 and 72 h – for seven
6.25 mg/2 weeks to 25 mg/2 weeks and, for haloperi-
patients unconsciousness was reported and the lon-
dol decanoate, is 50 mg/4 weeks to 200 mg/4 weeks.
gest period of unconsciousness was 12 h (Detke et al.
These recommendations have been based on both
2010). As olanzapine pamoate has a higher solubility
the findings of Kane and colleagues and an early
in blood than in muscle, the possibilities of acciden-
review by Dixon and colleagues (Dixon et al. 1995;
tal injections into a blood vessel or accidental entry
Kane et al. 2002).
of olanzapine pamoate directly into the bloodstream
One study investigated the equivalent switching
without a direct injection into the vessel (injury of a
dose from oral risperidone to long-acting risperi-
blood vessel during the injection process) have been
done injection in hospitalized patients. According
discussed (Citrome 2009; McDonnell et al. 2010).
to the findings of this study, switching doses are
Therefore, a proper injection technique (aspira-
suggested as follows: patients who were originally
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– There is good evidence to support the spheres were found to be appropriate for the long-
use of long-acting injectable olanzapine term treatment of schizophrenia and schizoaffective
(Category of evidence (A)/B, Recommenda- disorder (Simpson et al. 2006).
tion grade (2)/3). It should be mentioned Treatment with paliperidone palmitate can be
that we were not able to identify a compara- initiated after discontinuing previous treatment
tor study between olanzapine pamoate and with an oral antipsychotic (no oral supplementa-
another depot antipsychotic. tion is required) or at the next scheduled injection,
– The postinjection delirium sedation syn- and monthly thereafter, in patients switching from
drome needs to be considered as a possible another depot antipsychotic (including long-acting
severe side effect after every injection. injectable risperidone) (Gopal et al. 2010a). Pali-
– Each injection should follow the rules of peridone palmitate should be initiated with 150 mg
action described by the manufacturer and at day 1 and then with 100 mg at day 8 (⫾ 2 days).
after each injection, a three hour observa- Both injections should be applied to the same
tion period needs to be respected (Category muscle to reach adequate drug concentrations
of evidence C, Recommendation grade 4). quickly. After day 8, paliperidone should be injected
SGA
Risperidone microspheres 2 25 25–50
Paliperidone palmitate 4 25–75 25–150
Olanzapine pamoate 2–4 150–210/2 weeks 150–210/2 weeks
300–405/4 weeks 300–405/4 weeks
FGA
Flupentixol decanoate 2–3 20–40 20–100
Fluphenazine decanoate 2–4 6.25–37.5 12.5–50
Haloperidol decanoate 4 50–100 100–200
Perphenazine decanoate 2–4 12–100 50–200
Zuclopenthixol decanoate 2–4 100–200 200–400
20 A. Hasan et al.
every month (⫾ 7 days) with dosages in the range However, too rapid and too extreme dosage reduc-
of 25–150 mg (Gopal et al. 2010a). tion should be avoided.
For long-acting olanzapine injection, the oral-to- The reduced risk for tardive dyskinesia following
dose correspondence was explored in a 24-week treatment with FGAs might favour the use of SGAs,
study. Patients receiving oral olanzapine in a dose of although the risk of developing metabolic and car-
10 mg/day can be switched to 405 mg/4 weeks, and diovascular side effects following treatment with
patients receiving 15 or 20 mg/day can be switched some SGAs needs to be taken into consideration.
to 300 mg/2 weeks without increasing risk of relapse Certain SGAs (as described in these guidelines)
(Detke et al. 2011). Further analyses of the 24-week might be superior in terms of relapse prevention.
maintenance study described earlier (Kane et al. The reader should keep in mind that the catego-
2010) indicate that side effects and efficacy show a rization of antipsychotics into FGAs and SGAs
dose-association in schizophrenia patients treated (or typical and atypical antipsychotics) does not fol-
with long-acting olanzapine injection (Hill et al. low any clear neurobiological (apart from a higher
2011). D2-binding of FGAs compared to most SGAs)
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Other than the advice documented in this chapter, or clinical rules, and that the drug with the best
recommended dosage range might also be based on balance between efficacy and side effect profile and
recommendations given by the manufacturers. which is best tolerated (for compliance reasons)
should be chosen for long-term therapy. Antipsy-
chotics with the best profile for motor and meta-
bolic side effects do have some advantages, but
Summarised recommendations
there is not enough data to make clear evidence
for long-term treatment
based recommendations for a particular drug.
In first- and multiple-episode schizophrenia Switching strategies and the management of
patients, antipsychotic medications substantially treatment-resistance were described in the first part
reduce the risk of relapse in the stable phase of of these guidelines.
For personal use only.
illness and are strongly recommended. The choice As continuous dosing strategies have revealed
of long-term medication should be made jointly superiority compared to intermittent-dose strategies,
by the patient and the clinician based on adequate continuous oral or intramuscular administration of
information about the benefits and side effects an antipsychotic medication is preferable to other
(Lehman et al. 2004; NICE 2010; Leucht et al. treatment strategies.
2011b) – for the latter, tardive dyskinesia and In all cases, the prodromal signs of relapse should
metabolic side effects in particular need to be be regularly monitored and a dose adjustment made
addressed and monitored. if relapse is imminent. In stable remission, and if
If possible, family members, caregivers and in there are valid reasons against continuing long-term
some cases advocates should also be included medication (e.g., due to lack of acceptance), relapse
in the decision process. In long-term treatment/ prevention with intermittent antipsychotic treatment
maintenance treatment, the antipsychotic medica- and prodrome-based early intervention can be
tion which was able to achieve remission with the attempted, particularly in first-episode patients with
most favourable side effect profile should be given. a favourable prognosis. In this type of strategy, it is
Selecting the target dose of an antipsychotic med- important that the patient should detect his or her
ication during the stable phase is complicated by own early warning signs and establish an individual
the fact that there is no reliable strategy available crisis network.
to identify the minimum effective dose to prevent Depot preparations should be a treatment option
relapse. As outlined before, there is no evidence when a patient expresses a preference for such
that high maintenance doses (e.g., more than treatment in order to ensure compliance. As a con-
600 mg CPZ equivalents for FGAs) are more sequence of side effects or as a result of discus-
effective in preventing relapse than standard doses sions with the patient, low-dose continuous depot
(Bollini et al. 1994). However, it should be kept in medication may be advisable if oral medication is
mind that first-episode patients may require lower added in case of early prodromal signs of relapse.
doses in relapse prevention than multiple-episode For optimum effectiveness in preventing relapse,
patients. The lowest dose should be chosen at depot preparations should be prescribed within
which, preferably, no side effects occur, the risk of the standard recommended dosage and interval
relapse seems to be optimally reduced and, if symp- range. It may be good clinical practice that, before
toms are still present, suppression of these is opti- depot medication is applied, test doses of the oral
mised. Side effects have to be assessed and, if form should be used to avoid unexpected severe
necessary, pharmacotherapy has to be adjusted. side effects.
Biological treatment of schizophrenia: Part 2 21
dyskinesia, malignant neuroleptic syndrome), seda- have indicated that neurological side effects remain
tion, cardiovascular effects, weight gain, metabolic often undiagnosed and therefore untreated (Weiden
side effects, anticholinergic, antiadrenergic and anti- et al. 1987). Clinical psychiatrists should be trained
histaminergic effects, hyperprolactinaemia, agranu- to detect these potential severe symptoms. Neuro-
locytosis and sexual dysfunctions (see Part 1 of these logical side effects are linked to FGAs, but SGAs
guidelines). carry an associated risk as well.
Monitoring of side effects is based on the specific
side effect profile of the prescribed antipsychotic.
During the stable phase it is important to monitor Extrapyramidal side effects (see Table VI)
all patients routinely for weight gain (weight, waist Extrapyramidal side effects can be divided into acute
circumference), extrapyramidal symptoms, cardio- (acute dystonic reactions, parkinsonism, akathisia)
vascular and metabolic side effects. Great attention and chronic (tardive dyskinesia) categories. Acute
should be paid to monitoring of obesity-related extrapyramidal side effects are signs and symptoms
health problems (e.g., high blood pressure, lipid that occur in the first days and weeks of antipsy-
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abnormalities and clinical symptoms of diabetes). chotic medication administration, are dose depen-
Therefore, clinicians should also consider regular dent, and are reversible with medication dose
monitoring of fasting glucose or haemoglobin A1c reduction or discontinuation (APA 1997).
levels (HbA1c) to detect emerging metabolic syn-
drome and diabetes, since patients often have mul-
tiple risk factors for these syndromes, especially Acute dystonic reaction
patients with obesity. SGAs have clear advantages
with respect to motor side effects (especially tardive This side effect typically arises at the beginning of
dyskinesia) compared to FGAs. These advantages an antipsychotic treatment or when a dosage is
have to be weighed against other side effects, for increased. As outlined in Part 1 of these guidelines,
instance a higher risk of weight gain or diabetes it is more common in younger patients and it is
For personal use only.
mellitus with some agents. Adequate management related to high doses of antipsychotics (Singh et al.
of side effects may contribute to increased treat- 1990). Acute dystonic reactions respond dramati-
ment adherence and better outcome. Therefore, cally to the administration of anticholinergic or
strategies for the management of disabling side antihistaminic medication (APA 1997) (Category of
effects are reviewed and recommendations given in evidence C, Recommendation grade 4). Parenteral
the following section. In particular, the sections administration will have a more rapid onset of
“Neurological side effects” and “Metabolic side action than oral administration. If the first applica-
effects” received great attention during the update tion does not disrupt the acute dystonic reaction,
process due to the importance of these side effects anticholinergic or antihistaminic medication can be
and the volume of publications in this field. The given again.
section “Other side effects” contains statements
from the last version of these guidelines, which have
Parkinsonism
been updated where necessary. However, the reader
should be aware that studies with high scientific Parkinsonism usually develops several days or
quality in this area are rare and that management weeks after initiation of an antipsychotic treatment.
of side effects is still receiving less attention than Antipsychotic-induced parkinsonism generally
improving symptomatology. Special attention resolves itself after discontinuation of antipsychotic
should be given to the fact that many of the medication (Category of evidence C, Recommendation
statements are based on meta-analytical findings, grade 4), although some cases of persisting symptoms
which carry certain methodological problems (e.g., have been reported (Melamed et al. 1991). The pri-
comparability of included studies or underlying mary treatment of drug-induced parkinsonism con-
sample sizes), leading to different interpretations of sists of preventative and therapeutic dose reductions
experimental psychopharmacology studies (Leucht or the administration of certain SGAs (Category of
et al. 2009c). evidence C, Recommendation grade 4). If this is not
possible, administration of anticholinergic agents
(e.g., biperiden) or dopamine agonists should be con-
sidered. However, dopamine agonists, such as bro-
Neurological side effects
mocriptine, carry a potential risk of exacerbating
Neurological side effects are a great burden for psychosis, and anticholinergic drugs can cause anticho-
patients and it is strongly recommended that screen- linergic side effects. Thus, excessive doses and chronic
ing for these side effects takes place. Older studies use of these agents should be avoided or minimised.
Biological treatment of schizophrenia: Part 2 23
Table VI. Therapeutic options to manage antipsychotic side effects I (motor side effects and neuroleptic malignant syndrome). For
categories of evidence see main text.
Acute dystonic reactions • Select antipsychotic with low rate EPS • Oral or intravenous application of anticholinergic drug,
• Start with low dose e.g., 2.5–5 mg biperiden, if necessary repeat procedure after
• Increase dose slowly and stepwise 30 min, continue biperiden oral (maximal 12 mg/day)
Parkinsonism • Select antipsychotic with low risk for • Dose reduction or discontinuation of antipsychotic
parkinsonism medication
• Increase dose slowly and stepwise • Switch to SGA
• Oral application of anticholinergic drug
Akathisia • Select antipsychotic with low risk for • Dose reduction
akathisia • Oral application of beta-receptor-blocking agent
• Increase dose slowly and stepwise (e.g., propranolol 30–90 mg/day)
• Switch to certain SGAs
• Oral application of benzodiazepines
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2004b; Vinson and Drotts 2001) (Category of benefit of SGAs for the amelioration of tardive
evidence C, Recommendation grade 4). dyskinesia symptoms and state that there is no
Vitamin B6 was tested for the treatment of acute evidence to recommend SGAs for this purpose
neuroleptic-induced akathisia in a small placebo- (Buchanan et al. 2010). However, there are some
controlled RCT. According to the Barnes Akathisia studies, partly reviewed in the PORT guidelines that
Scale, Vitamin B6 was superior to placebo in reduc- might provide some hints towards a benefit of switch-
ing akathisia (Lerner et al. 2004). Another small ing to an SGA. In a small 12-week double-blind,
RCT in patients with neuroleptic-induced akathisia placebo-controlled study, the switch from an FGA
showed that both Vitamin B6 and mianserin were to either risperidone or placebo after a 4-week wash-
superior to placebo in reducing subjective distress. out period in patients suffering from schizophrenia
However, the differences reached only trend level and tardive dyskinesia was investigated (Bai et al.
in the objective assessments of akathisia (Miodownik 2003). In this study, risperidone (68% responder)
et al. 2006). There is some little evidence to sup- was superior to placebo (30% responder) in improv-
port the use of Vitamin B6 in akathisia (Category of ing tardive dyskinesia (Bai et al. 2003). In a 48-week
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treatment with antipsychotics, but can also occur either quetiapine or haloperidol. The patients in the
during a short-term treatment. SGAs, compared to quetiapine group showed significantly more improve-
FGAs have a benefit with regard to tardive dyski- ment in terms of tardive dyskinesia and scores of
nesia (Tenback et al. 2005, 2010; Kasper et al. motor side effects (Emsley et al. 2004), and this
2006; Correll and Schenk 2008). As outlined in the positive effect of quetiapine was replicated in another
supplementary material of the PORT guidelines, all small study (Cortese et al. 2008). One analysis from
SGAs have been reported to be associated with new the CATIE sample compared 200 schizophrenia
cases of tardive dyskinesia, but no difference in the patients with tardive dyskinesia and 997 patients
incidence of tardive dyskinesia exists among various without tardive dyskinesia who were randomly
SGAs (Buchanan et al. 2010). There is good evi- assigned to receive one of four SGAs (olanzapine,
dence to state that SGAs carry less risk for tardive quetiapine, risperidone, ziprasidone). This analysis
dyskinesia compared to FGAs (Category of evidence did not show a significant difference between drugs
A, Recommendation grade 1). in terms of a reduction of tardive dyskinesia, and
Cessation of the antipsychotic is the first-line rec- most patients showed either persistence of or fluc-
ommendation for the treatment of tardive dyskinesia tuations in symptoms (Caroff et al. 2011). Although
in other guidelines and in textbooks, but meta- there are some trends towards a positive effect
analyses of the Cochrane Schizophrenia group could of switching from an FGA to an SGA on tardive
not provide evidence for a positive effect of antipsy- dyskinesia, the evidence remains limited (Category of
chotic reduction/cessation as specific treatment for evidence C, Recommendation grade 4). This can be
tardive dyskinesia (Soares-Weiser and Rathbone explained by the lack of double-blinded RCTs and
2006). However, reducing antipsychotic dose is asso- by the very small sample sizes of the published stud-
ciated with the improvement of dyskinetic symp- ies. Furthermore, a switch of antipsychotics can lead
tomatology (Kane et al. 1983; Cookson 1987) in to worsening of symptoms.
studies with very small sample sizes. Reduction of A switch to clozapine is a frequently discussed
antipsychotics is associated with a high risk of relapse strategy for the treatment of tardive dyskinesia. In a
and this risk must be weighed against the sparse small open-label trial, seven schizophrenia patients
evidence of this therapeutic approach. with severe tardive dyskinesia were withdrawn from
The switch from one antipsychotic (usually their antipsychotic medication for 1 week and then
FGA) to another one (usually SGA) has been pro- treated with clozapine for 24 weeks. This strategy led
posed to have a beneficial effect on tardive dyski- to an improvement in tardive dyskinetic symptoms
nesia. The PORT guidelines discuss this potential (Bassitt and Louza Neto 1998), and these findings
Biological treatment of schizophrenia: Part 2 25
were confirmed in a 5-year follow-up study (Louza reports indicated that tetrabenazine might have a
and Bassitt 2005). A review including eight pub- positive impact on tardive dyskinesia (Leung and
lished studies indicated that tardive dyskinesia is Breden 2011) (Category of evidence C, Recommenda-
responsive to clozapine, but that methodological tion grade 4). In a naturalistic long-term follow-up
limitations of the studies limits the quality of the study with six patients, the combination of tetra-
data (Lieberman et al. 1991). This is in line with benazine, clonazepam and clozapine resulted in a
another small short-term study showing that clo- rapid improvement of tardive dyskinesia in patients
zapine might be effective for the treatment of tar- with severe, unsuccessfully controlled tardive dys-
dive dyskinesia (Spivak et al. 1997). A study with kinesia (Kimiagar et al. 2011). However, good stud-
humans and animals (oral dyskinesia; vacuous ies which would allow an evidence-based statement
chewing movements every 5 min) showed that to be made are also lacking for tetrabenazine.
patients with pre-existing tardive dyskinesia The benzamide derivate tiapride might have some
responded to treatment with long-term clozapine beneficial effects on tardive dyskinesia, but there are
(Tamminga et al. 1994). In summary, there is some insufficient well-designed studies to make a clear
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limited evidence for a beneficial effect of clozapine evidence-based statement (El-Sayeh et al. 2006)
on tardive dyskinesia, but double-blind RCTs are (Category of evidence F).
still lacking (Category of evidence C, Recommendation Apart from drug treatment, biological treatments
grade 4). have been tested for the treatment of tardive dyski-
Several other agents have been investigated with nesia. In a case series and in a case-report, ECT was
regard to their efficacy for improving tardive dyski- shown to have a beneficial effect on severe tardive
nesia. Vitamin E may have small benefits (Soares- dyskinesia (Hay et al. 1990; Ucok and Ucok 1996)
Weiser et al. 2011) (Category of evidence C, (Category of evidence C, Recommendation grade 4).
Recommendation grade 4), whereas the use of anti- Deep brain stimulation (DBS), which is a well-
cholinergic drugs is not recommended because of established treatment option in several movement
the lack of evidence and due to adverse effects disorders, like Parkinson’s disease and dystonia, has
For personal use only.
(Soares and McGrath 2000; Tammenmaa et al. the potential for a treatment possibility in severe tar-
2002) (Category of evidence F). Furthermore, there dive dyskinesia (Lyons 2011). To date, there are no
is no compelling evidence that benzodiazepines studies investigating DBS for tardive dyskinesia, but
decrease tardive dyskinesia in a sufficient manner case reports/case series (Trottenberg et al. 2005;
(Bhoopathi and Soares-Weiser 2006) and the risk of Sako et al. 2008) and the experience from movement
developing drug dependence is another important disorders give theoretical, but reasonable hope, that
limiting factor (Category of evidence F). One Cochrane DBS can improve tardive dyskinesia in severe cases
review (updated 2010 with no change of conclusion) (Category of evidence C, Recommendation grade 4).
studied the effects of a miscellaneous group of com- Furthermore, pallidotomy as a last resort treat-
pounds (botulinum toxin, endorphin, essential fatty ment could be a promising therapeutic approach in
acid, EX11582A, ganglioside, insulin, lithium, nalox- extremely severe cases of refractory antipsychotic-
one, oestrogen, periactin, phenylalanine, piracetam, induced tardive dyskinesia (Wang et al. 1997;Thobois
stepholidine, tryptophan, neurosurgery, or ECT) for et al. 2011) (Category of evidence C, Recommendation
the treatment of tardive dyskinesia and did not find grade 4).
any of them to be effective (Soares-Weiser and Joy In summary, treatment of tardive dyskinesia is dif-
2003) (Category of evidence F). ficult and no good data concerning different treat-
In the absence of reliable evidence, the possible ment strategies exists. However, in severe cases, the
benefits of calcium channel blockers in the treatment aforementioned strategies should be offered to
of tardive dyskinesia have to be balanced against the patients if switching to a SGA or to clozapine has
potential adverse effects, e.g., lowering of blood pres- no positive effect. In doing so, psychiatrists should
sure and even causing symptoms of tardive dyskine- be aware of the relatively small amount of evidence
sia to increase (Soares-Weiser and Rathbone 2004) supporting these strategies.
(Category of evidence F).
The effects of GABAegeric agonists (baclofen,
Neuroleptic malignant syndrome
gamma-vinyl-GABA, gamma-acetylenic-GABA, pro-
gabide, muscimol, sodium valproate and tetrahy- Neuroleptic malignant syndrome (Gurrera et al.
droisoxazolopyridine) on tardive dyskinesia are 2011) is characterised by dystonia, rigidity, fever
inconclusive and their use cannot be recommended (⬎ 100.4°F or 38°C on at least two occasions), auto-
(Alabed et al. 2011) (Category of evidence F). nomic instability such as tachycardia ⬎ 25% above
A review including three prospective studies, baseline, tachypnea ⬎ 50% above baseline, blood
eight add-on trials, one case series and eight case pressure elevation (⬎ 25% above baseline) and
26 A. Hasan et al.
fluctuation (ⱖ 20 mmHg (diastolic) or ⱖ 25 mmHg recommendations. One major conflict is that the
(systolic) change within 24 h), delirium, myoglobi- restart of antipsychotic treatment after NMS is
nuria and increased levels of creatine kinase (at least associated with a high risk (up to 30%) to develop
4 times the upper limit of normal) (Gurrera et al. NMS again (Caroff and Mann 1988; Pope et al.
2011), and of leukocytes and hepatic enzymes 1991; Strawn et al. 2007), but that most patients
(lactate dehydrogenase, aspartate transaminase) and need a long-term antipsychotic treatment. One pub-
a low iron serum level. However, no laboratory lication presented some general rules as precaution
parameter is specific for NMS. EEG can show signs to prevent the development NMS again (Strawn
of metabolic encephalopathy like generalized slowing et al. 2007):
(Caroff and Mann 1988; Strawn et al. 2007).
– Reports of pervious episodes should be
Biological measurements may help to distinguish
checked for accuracy
between NMS and serotonin syndrome which share
– Indications for antipsychotics should be
the same clinical features in some patients taking
clearly documented
neuroleptic and serotonin agonist medications simul-
– Alternative medications should be considered
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(Devinsky et al. 1991; Pacia and Devinsky 1994; An established weight management program
Buchanan 1995). (including a supplemented novel food replacement
The clinical management of seizures includes program, community-based teaching about shop-
treatment with benzodiazepines and anticonvulsant ping and healthy food preparation), which had been
agents (e.g., levetiracetam, valproic acid) and moni- modified for schizophrenia patients, was tested in a
toring of cardiovascular parameters. Carbamazepine RCT and revealed that such weight management
should not be used in combination with clozapine programs can stop weight gain or even reverse it in
due to its potentiation of neutropenia and agranulo- schizophrenia patients (Jean-Baptiste et al. 2007).
cytosis. In general, in the presence of seizures, a dose Furthermore, there are studies indicating that behav-
reduction is recommended, or a switch from clozap- ioural therapy and educational interventions have
ine or zotepine to another antipsychotic medication the potential to induce weight loss in schizophrenia
if the former option is not justified for clinical and patients treated with antipsychotics (Mauri et al.
psychopathological reasons. 2006; Ganguli 2007). In the last version of these
guidelines, we reviewed some studies that support
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increase their physical activity gradually in a stepwise evidence C, Recommendation grade 4), but good stud-
manner, in combination with dietary restriction to ies fulfilling standards of evidence are still lacking.
obtain negative energy balance (Ananth et al. 2004) However, physicians should encourage patients with
(see Table VII and recommendation Table II). obesity to participate in psychological interventions
that focus on nutrition, physical activity (aerobic
exercise) and self-monitoring (Category of evidence C,
Psychosocial interventions to reduce weight gain and to Recommendation grade 4).
improve metabolic parameters
Psychosocial interventions may have a small benefit
Pharmacological interventions to reduce weight gain
and lead to weight loss in schizophrenia patients,
although the evidence for this is limited (Birt 2003; The 2010 PORT guidelines describe three possible
Faulkner et al. 2007a,b). pharmacological interventions for the treatment of
Table VII. Therapeutic options to manage antipsychotic side effects II (metabolic side effects). For categories of evidence see main text.
Weight gain • Select antipsychotic with lower risk of weight gain • Psychosocial interventions (weight programs, diet programs,
behavioural therapy)
• Switch to another antipsychotic with a better metabolic side
effect profile (for details see main text)
• Add amantadine, H2-receptor antagonists (rosaglitazone)
• Add topiramate
Hyperlipidemia • Selecting antipsychotic with low risk of inducing • Psychosocial interventions (weight programs, diet programs,
hyperlipidemia behavioural therapy)
• Screening for risk factors, cholesterol and • Switch to another antipsychotic with a better metabolic side
triglycerides effect profile (for details see main text)
Diabetes • Screening for diabetes risk factors, fasting blood • Psychosocial interventions (weight programs, diet programs,
glucose, in some cases haemoglobin A1c behavioural therapy)
• Selecting antipsychotic with low risk of inducing • Switch to another antipsychotic with a better metabolic side
diabetes effect profile (for details see main text)
• Referring to a diabetologist for special pharmacological
treatment of diabetes
28 A. Hasan et al.
Recommendation Table II. Recommendations for the psychosocial short term trials the switch from various anti-
and pharmacological intervention to reduce weight gain and other psychotics to aripiprazole reduced weight gain or
metabolic side effects associated with antipsychotic treatment.
resulted in a significant weight loss (Casey et al.
Category of 2003; Ganguli et al. 2011). The switch from olan-
Intervention/Drug evidencea Recommendationb zapine to quetiapine resulted in a decline of
Psychosocial intervention C 41
mean weight gain and the switch from olanzapine/
Switch to aripiprazole A 22 risperidone to ziprasidone was promising in open-
Switch to ziprasidone B 32 label studies (Weiden et al. 2003a,b; Gupta et al.
Amantadine C 4 2004). In a long-term observation study, the switch
H2-receptor antagonists C 4 from olanzapine/risperidone to ziprasidone was
Metformin D 5
Modafinil F —
associated with sustained improvements in weight
Orlistat F — and metabolic parameters (Weiden et al. 2008).
Rosaglitazone F — However, the switch from an FGA to ziprasidone
Rosaglitazone ⫹ clozapine C 4 did not change any metabolic parameter (Weiden
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and psychotic relapse. Please see main text for specific switching not available.
strategies. A Cochrane review indicates that switching
antipsychotics to an agent with fewer metabolic
side effects can result in an improvement of these
antipsychotic-induced weight gain: (1) switching
parameters (Mukundan et al. 2010).
from one agent to another; (2) addition of another
The recently published results for aripiprazole
medication (see the discussed agents below) before
allow us to state that a switch to aripiprazole is a
the initiation of antipsychotic treatment; (3) addition
promising approach for treating antipsychotic-
of another medication (see below) during the antip-
induced weight gain (Category of evidence A,
sychotic treatment (Buchanan et al. 2010). Though
Recommendation grade 2). The switch to ziprasi-
some strategies seem to be promising, the evidence
done might have some advantages compared to
for these strategies is limited (Buchanan et al. 2010)
staying on risperidone/olanzapine, but the evidence
and every strategy can worsen the symptomatology
is limited (Category of evidence B, Recommendation
of the patient (Falkai et al. 2006).
grade 3). Before switching drugs, it should be taken
into consideration that switching from one antip-
sychotic to another carries the risk of symptom
Switching antipsychotics
worsening, as indicated by the findings of the
In a multicentre, double-blind RCT, 173 overweight CATIE study, for example (Essock et al. 2006;
schizophrenia patients were randomly assigned to a Rosenheck et al. 2009).
switch from olanzapine to aripiprazole or to stay on
olanzapine – the switch to aripiprazole resulted in an
Drug therapy for obesity
improvement in metabolic parameters and weight
(Newcomer et al. 2008). In non-psychiatric populations specific drug thera-
A randomized trial examined the effects of pies for obesity are recommended exclusively as part
switching from olanzapine, quetiapine or rispe- of an integral treatment plan in patients with a BMI
ridone to aripiprazole on metabolic parameters above 30 kg/m2, or in combination with obesity
and showed that patients switching antipsychotics related risk factors or diseases with a BMI above
(n ⫽ 89) had significantly weight reductions and 27 kg/m2. Different drugs have been tested to reduce
an improvement of metabolic parameters com- weight gain and improve metabolic parameters in
pared to patients staying on their antipsychotic schizophrenia patients, but most studies did not
drug (n ⫽ 98) (Stroup et al. 2011). In open-label show a benefit.
Biological treatment of schizophrenia: Part 2 29
Amantadine Metformin
Amantadine, a dopamine agonist, has a risk of wors- Metformin is an antidiabetic drug, used to treat type
ening psychosis (Ananth et al. 2004). Weight reduc- II diabetes, that increases sensitivity for insulin and
tion was reported with an open-label add-on can lead to consecutive weight loss in subjects with-
treatment of amantadine after 2 weeks in 10 patients out diabetes (Buchanan et al. 2010; Desilets et al.
taking FGAs (Correa et al. 1987). The effect of 2008). The combination of metformin with olanzap-
weight loss was also shown by an add-on treatment ine was either superior or inferior to placebo with
with 100–300 mg/day amantadine for 3–6 months in regard to weight gain and metabolic parameters
12 patients who gained excessive weight while taking (Baptista et al. 2006, 2007; Chen et al. 2008; Wu
olanzapine (Floris et al. 2001). In a small double- et al. 2008). However, the combination of metformin
blind, placebo-controlled study, amantadine was with olanzapine might be promising in the sub-
superior to placebo as an addition to olanzapine with population of first-episode patients, who are more
regard to weight loss (Graham et al. 2005). This was receptive for side effects (Wu et al. 2008). In another
confirmed by a placebo-controlled double-blind, study, no effect of metformin was reported in five
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16-week trial examining 60 patients with schizophre- patients who were undergoing long-term treatment
nia, schizophreniform or bipolar disorder. However, with haloperidol, fluphenazine, trifluperazine or ris-
the effect was no longer significant after 24 weeks peridone (Baptista et al. 2001). A meta-analysis
(Deberdt et al. 2005). including 12 studies indicated a small and modest
There is some minimal evidence to suggest that positive effect on weight gain and metabolic param-
amantadine can reduce antipsychotic-induced eters for the combination of metformin and olan-
weight gain (Category of evidence C, Recommendation zapine (Praharaj et al. 2011). Furthermore, the
grade 4). combination of metformin plus the oral anorexiant
sibutramine was not superior to placebo with regard
to metabolic parameters, except for preventing a
H2-receptor antagonists triglyceride increase (Baptista et al. 2008). A very
For personal use only.
either modafinil or placebo. No effect on metabolic RCTs combined with either olanzapine (Henderson
parameters in patients treated with modafinil was et al. 2005a) or clozapine (Henderson et al. 2007).
found (Henderson et al. 2011). One case report The combination with olanzapine reduced weight
and one study have investigated the impact of and improved metabolic parameters, whereas the
the psychostimulant modafinil on antipsychotic- combination with clozapine did not show a benefit
induced weight gain and other metabolic parameters. (Henderson et al. 2005a; Barinas-Mitchell et al.
The case report showed that the addition of 2006; Henderson et al. 2007).
modafinil to treatment with clozapine resulted in a There is little evidence that the combination of
significant weight loss (Henderson et al. 2005b). olanzapine and sibutramine might be helpful with
Currently, the addition of modafinil administration regard to metabolic parameters (Category of evidence
to clozapine treatment with the aim of reducing C, Recommendation grade 4), and the amount of data
antipsychotic-induced weight gain cannot be is insufficient to permit the formulation of a general
recommended (Category of evidence F). statement (Category of evidence F). However,
sibutramine can induce psychotic symptoms and
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16 weeks (Tchoukhine et al. 2011). One case report (Ko et al. 2005). In a randomised, double-blind,
suggests moderate weight loss after adding orlistat, placebo-controlled clinical trial, topiramate was
a lipase inhibitor reducing intestinal fat absorption, superior to placebo in controlling antipsychotic-
to amisulpride (Anghelescu et al. 2000). associated weight gain (Afshar et al. 2009). In
There are insufficient data to give a good another 12-week, randomized, open-label, parallel-
evidence-based recommendation for orlisat (Cate- group trial of topiramate in outpatients subjects with
gory of evidence F). schizophrenia, topiramate limited the olanzapine-
induced weight gain (Kim et al. 2006). This was
further confirmed in a 12-week, double-blind,
Rosaglitazone parallel-group study in drug-naive first-episode
schizophrenia patients. In this study 100 mg/day
In a small double-blind, placebo-controlled 12-week topiramate added to olanzapine was significantly
RCT, the antidiabetic agent rosaglitazone was not more effective in improving metabolic parameters
superior to placebo when combined with olanzapine and reducing weight gain than placebo added to
with regard to metabolic parameters (Baptista et al. olanzapine (Narula et al. 2010). The combination of
2009). However, another small 8-week double-blind, topiramate with clozapine did not lead to a weight
placebo-controlled RCT showed that the addition of loss in a double-blind, placebo-controlled RCT in
rosaglitazone to a treatment with clozapine is prom- which weight gain was not the primary outcome
ising with regard to insulin resistance and other parameter (Muscatello et al. 2011). In a report,
metabolic parameters (Henderson et al. 2009). topiramate, given at a dose of 125 mg/day over
There is only minimal evidence that the combi- 5 months, led to weight loss in a patient taking clo-
nation of clozapine and rosaglitazone might be zapine (Dursun and Devarajan 2000). However, in
helpful with regard to metabolic parameters another 12-week RCT in which weight gain was not
(Category of evidence C, Recommendation grade 4), the primary outcome parameter, topiramate and
but there is not enough evidence to make a general placebo did not differ with regard to this parameter
statement (Category of evidence F). (Tiihonen et al. 2005).
There is some evidence that topiramate might
improve metabolic parameters and antipsychotic-
Sibutramine
induced weight gain (Category of evidence C, Recom-
Sibutramine is approved for the treatment of obesity. mendation grade 4), and that especially the
It was tested in two double-blind, placebo-controlled combination of topiramate with olanzapine seems to
Biological treatment of schizophrenia: Part 2 31
or inflammatory markers (Borba et al. 2011). Fluox- cardiovascular and metabolic diseases or early death,
etine was not superior compared to placebo in reduc- smoking history, and exercise and dietary habits and
ing olanzapine-induced weight gain (Poyurovsky other treatments which may increase the risk is the
et al. 2002; Bustillo et al. 2003), but fluvoxamine first step in screening for these risk factors. Further-
could prevent clozapine-induced weight gain more, blood pressure, body weight, waist circumfer-
(Lu et al. 2004). However, both SSRIs have a high ence and body mass index have to be screened. Then,
interaction potential and could not be recommended baseline measures of fasting glucose and fasting lip-
for use for this purpose. ids, total cholesterol, LDL, HDL and triglyceride
levels must be collected (De Hert et al. 2009). These
measures have to be repeated in weeks 6 and 12 fol-
General aspects
lowing the beginning of treatment and then repeated
For personal use only.
The use of agents like phentermine, chlorphenter- annually. Weight and waist circumference should be
mine, sibutramine or phenylpropanolamine in indi- measured after 1 month and then repeated every
viduals with mental illness is limited because these 3 months. A weight gain ⬎ 7% than baseline occur-
drugs can lead to an exacerbation of psychotic symp- ring within a few months must alert the psychiatrist
toms. For this reason, these agents cannot be recom- and relatives. Specific recommendations and the
mended in patients with schizophrenia. As stated in management of special cases have been published
the 2010 PORT guidelines (Buchanan et al. 2010) elsewhere (De Hert et al. 2009).
and in a review from the schizophrenia research group This is in line with the recommendations from
(Faulkner et al. 2007b), a general recommendation the APA/ADA consensus development conference
for a drug intervention to reduce antipsychotic- on antipsychotic drugs and obesity and diabetes,
induced weight gain cannot be given. Furthermore, which demands baseline screening and ongoing
the aspect of worsening psychosis after adding one monitoring of metabolic parameters during treat-
or two other agents to the present antipsychotic ment with antipsychotics (APA 2004).The ADA/
medication needs to be addressed in future studies. APA consensus paper recommends screening at
However, as discussed above and in the first part of baseline, at weeks 4, 8 and 12, and then annually
these updated guidelines, a switch from one antipsy- (APA 2004). Furthermore, the following statement
chotic with an unfavourable metabolic profile to one should have great priority in the management
with a better profile (e.g., aripiprazole, ziprasidone) of metabolic side effects: “Clinicians should also
might be a promising therapeutic alternative. encourage patients to monitor and chart their own
However, despite the fact that there is only lim- weight. It is particularly important to monitor any
ited evidence that weight programmes (including alteration in weight following a medication change.
cognitive behavioural elements) lead to significant The patients’ psychiatric illness should not discour-
weight loss, physicians should encourage patients age clinicians from addressing the metabolic com-
with obesity to participate in psychological inter- plications for which these patients are at increased
ventions that focus on nutrition, physical acti- risk” (APA 2004). Patients and their carers should
vity and self-monitoring (Category of evidence C, be informed about the metabolic syndrome and the
Recommendation grade 4). Furthermore, families symptoms of diabetes, and patients should be mon-
and relatives should be informed about metabolic itored at regular intervals for the criteria of meta-
side effects and metabolic parameters should be bolic syndrome (see Alberti et al. 2009). The risks
checked regularly (see Table III). and consequences of metabolic syndrome and
32 A. Hasan et al.
diabetes have to be weighed against the control this predominantly applies to tricyclic neuroleptic
of psychotic symptoms if switching to another agents of the phenothiazine type (e.g., chlorpromaz-
agent with an assumed lower risk of diabetes is ine, promethazine, perazine and, especially, thior-
considered. This paragraph shows that there is a idazine) and to pimozide. Of the SGAs, sertindole
variance of recommendations and diagnostic algo- and ziprasidone were found to lengthen the QT
rithms regarding this important topic across guide- interval in a significant manner. QTc prolongation
lines. However, special attention should be paid to (QTc intervals above 450/470–500 ms or change
the regular monitoring of metabolic side effects from baseline more than 30–60 ms, dependent
(Table II). on publication and textbook) is associated with an
increased risk of torsade de pointes and transition
to ventricular fibrillation (Glassman and Bigger
Other side effects 2001; Roden 2004; Sumic et al. 2007; Semple and
Smyth 2009; Nielsen et al. 2011). If this occurs
Cardiovascular side effects (see Table VIII)
under antipsychotic treatment, the medication should
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portive measures include the use of support stock- Clozapine is associated with a risk of myocarditis
ings, increased dietary salt and advising patients who in 1 per 500 to 1 per 10,000 treated patients. If the
experience severe postural hypotension to avoid get- diagnosis is probable (typical symptoms can be:
ting up quickly and without assistance. Tachycardia chest pain, palpitations, dyspnea, reduced general
due to anticholinergic effects without hypotension condition, fever, symptoms of right-heart overload
can be managed with low doses of a peripherally like edema or respiratory distress), clozapine should
acting beta-blocker (Miller 2000). be stopped immediately and the patient referred
All antipsychotics may cause (dose-dependent) urgently to a specialist for internal medicine (Marder
cardiac side effects, at varying rates. Of the FGAs, et al. 2004).
Table VIII. Therapeutic options to manage antipsychotic side effects III (cardiovascular and haematological side effects). For categories
of evidence see main text.
Orthostatic • Starting with low dose, increase dose slowly • Physical activity
hypotension and stepwise • Switch to another antipsychotic with another receptor profile
• Selecting antipsychotic with low α- (for details see main text)
adrenergic receptor-blocking profile • (Application of oral dihydroergotamine (max. 6 mg/day)
or etilefrine (20–60 mg/day))
QTc prolongation • Selecting antipsychotic with low risk of • If QTc is ⬎ 450/470–500 ms or has increased more than
QTcprolongation 30–60 ms switching to another antipsychotic is indicated
• Evaluation of cardiac risk factors
• Control for pharmacological interactions
• Control of ECG
• Avoid combining drugs with a known risk
for QTc prolongation
Leukopenia • Controlling white blood cell count (WBC) • In case of agranulocytosis (⬍ 1000 granulocytes) immediately
stopping antipsychotic treatment
• Cooperate with a haematologist
• Prevent infections, monitoring WBC
• In some cases application of GM-CSF/G-CSF
• Clozapine treatment has to be stopped if leukocytes are
⬍ 3500 or granulocytes are ⬍ 1500
Biological treatment of schizophrenia: Part 2 33
Haematological side effects (see Table VIII) menstrual and sexual dysfunction, consideration
should be given to changing the medication to a
This part remains unchanged and is in accordance
prolactin-sparing agent. If the signs and symptoms
with the previous version of these guidelines. Agran-
disappear and the prolactin level decreases, an
ulocytosis is the most severe side effect of clozapine
endocrine workup can be avoided. Osteoporosis
and some other FGAs (e.g., chlorprothixen). In
should be considered as another important long-
some cases, however, the condition may also occur
term consequence of hyperprolactinemia (Holt
in association with other antipsychotic medications.
and Peveler 2011).
During clozapine treatment, a white blood-cell
Switching from a prolactin-elevating antipsychotic
(WBC) count ⬍ 2000/mm3 or absolute neutrophil
(e.g., risperidone, sulpiride) to a non-prolactin-
count (ANC) ⬍ 1000/mm3 indicates impending or
elevating antipsychotic (e.g., aripiprazole; quetiap-
current agranulocytosis; the clinician should stop
ine, olanzapine) seems to be a promising treatment
clozapine treatment immediately, check WBC and
(Kim et al. 2002; Casey et al. 2003; Kaneda et al.
differential counts daily, monitor for signs of
2004; Kinon et al. 2006; Lee et al. 2006; Potkin
infection, and consider bone marrow aspiration and
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Table IX. Therapeutic options to manage antipsychotic side effects IV (other side effects).
Combining aripiprazole with either risperidone or recommended (Lehman et al. 2004). As cataracts
quetiapine in one multicentre, double-blind, 16-week, were observed in beagles that were given quetiapine,
placebo-controlled study with 323 schizophrenia or psychiatrists should ask about the quality of distance
schizoaffective patients did not lead to a significant vision and about blurry vision, and should refer to
improvement in psychopathology compared to pla- an ocular evaluation annually or every 2 years
cebo, but was well-tolerated and reduced prolactin (Marder et al. 2004).
levels in the risperidone group (Kane et al. 2009a). Urinary tract problems such as urinary retention
The authors of the PORT guidelines reviewed dif- and urinary incontinence may be particularly pro-
ferent treatments for antipsychotic-induced sexual voked by antipsychotic medications with marked
dysfunctions and did not find enough evidence for a anticholinergic components such as phenothiazines
treatment recommendation (Buchanan et al. 2010). and those with cholinergic effects. Acute urinary
However, some minimal evidence, based on open- retention problems may be treated with low-dose
label studies or small double-blind RCTs, exists e.g. carbachol.
suggesting that drugs for the treatment of erectile Dry mouth and eyes, and constipation may result
World J Biol Psychiatry Downloaded from informahealthcare.com by Nyu Medical Center on 04/28/13
dysfunctions (sildenafil, vardenafil) might be effec- from adrenergic and anticholinergic stimulation,
tive for the treatment of antipsychotic-induced sex- often described during treatment with FGAs.
ual dysfunction, but good evidence is still lacking. Patients may be advised to use sugar free chewing
(Buchanan et al. 2010) (Category of evidence C, gum or drops against dry mouth. Usually patients
Recommendation grade 4). mostly suffer from the described autonomic side
effects when antipsychotic treatment is introduced
or doses are increased.
Others (see Table IX)
To treat constipation, patients should be advised
Apart from a statement regarding constipation, this to drink more, and in some cases administration
part remains unchanged and is in accordance with of lactulose may be useful. However, constipation
the previous version of these guidelines. Sialorrhea seems to be a frequent side effect (see Part 1 of
For personal use only.
and drooling occur relatively frequently with clozap- this updated guideline) and changing antipsycho-
ine treatment and are most likely due to decreased tics might be discussed in severe cases. Constipa-
saliva clearance related to impaired swallowing tion should be identified early to prevent paralytic
mechanisms, or possibly to muscarinic cholinergic ileus, bowel obstruction, faecal impaction, bowel
antagonist activity at the M4 receptor or to alpha- perforation and other severe complications (De
adrenergic agonist activity (Rabinowitz et al. 2001). Hert et al. 2010).
Therapeutic options for sialorrhea include the
application of pirenzepine 25–50 mg/day and dose
reduction of clozapine, if possible. Allergic and der-
Conclusion
matological effects, including photosensitivity, occur
infrequently but are most common with low-potency This update of the WFSBP guidelines for the long-
phenothiazine medications. Patients should be term biological treatment of schizophrenia and the
instructed to avoid excessive sunlight and use sun- management of side effects summarizes the available
screen (Lehman et al. 2004). Hepatic effects, such publications in this field and proves evidence-based
as elevated hepatic enzymes, may be triggered by a treatment recommendations.
number of antipsychotic medications, whereby this For the clinical psychiatrist, knowledge about
is usually asymptomatic. Direct hepatotoxicity or the efficacy of different antipsychotic drugs in the
cholestatic jaundice occur extremely rarely and are long-term treatment and the management of
particularly associated with low-potency phenothia- antipsychotic-induced side effects is of particular
zines (APA 2004; Lehman et al. 2004). importance. For long-term treatment especially, a
Ophthalmological effects due to pigment accumu- good balance between efficacy, side effects and
lation in the lens and cornea, retinopathies, corneal compliance must be achieved. Clinicians must keep
oedema, accommodation disturbances and glau- in mind that most patients are likely to require life-
coma have also been described as side effects of long treatment and this determines treatment strat-
antipsychotic medication. To prevent pigmentary egies with the optimal balance between efficacy and
retinopathies, corneal opacities and cataracts, tolerability. Both FGAs and SGAs are effective in
patients maintained on thioridazine and chlorprom- relapse prevention. SGAs do have some advantages
azine should have periodic ophthalmological exami- with regard to motor side effects and relapse
nations (approximately every 2 years for patients prevention. This could favour certain SGAs
with a cumulative treatment of more than 10 years); (as outlined in these guidelines) in the long-term
a maximum dose of 800 mg/day of thioridazine is treatment of schizophrenia.
Biological treatment of schizophrenia: Part 2 35
The management of neurological side effects, Vital, SmithKline Beecham, Wyeth, and Essex.
especially tardive dyskinesia, and metabolic side During the last 2 years, but not presently, Peter
effects is the greatest challenge for psychiatry. Before Falkai was a member of the advisory boards of
the introduction of the SGAs, schizophrenia patients Janssen-Cilag, AstraZeneca, Eli Lilly, and Lund-
suffered from severe neurological side effects and beck. He received research support by AstraZen-
nobody wants these times back. However, nobody eca. Thomas Wobrock has been a member of a
wants a future in which young schizophrenia patients speaker bureau for Alpine Biomed, AstraZeneca,
suffer from obesity, metabolic syndrome, diabetes Bristol Myers Squibb, Eli Lilly, I3G, Janssen-Cilag,
and coronary heart disease. Solving this problem is Novartis, Lundbeck, Sanofi-Aventis and Pfizer. He
the challenge of the future. received research support by AstraZeneca, I3G and
Antipsychotics with the best balance between AOK. Jeffrey Liebermann was/is a member of the
these side effects may have a benefit in the long-term advisory boards of Bioline, Intracellular Therapies,
treatment, but there is not enough evidence-based Alkermes, Lilly and Pierre Fabre. He received
data to make a conclusive statement. Even today, research support/grants by Allon, GlaxoSmith-
World J Biol Psychiatry Downloaded from informahealthcare.com by Nyu Medical Center on 04/28/13
there is unsatisfying evidence relating to different Kline, Lilly, Merck, Novartis, Pfizer, Psychogenics,
questions in the long-term treatment of schizophre- LTD, Sepracor and Targacept. He holds a patent
nia and these questions need to be addressed in large by Repligen. Birte Glenthoj and Wagner F. Gattatz
well-designed clinical trials. In recent years, some report no conflict of interest. Florence Thibaut is
important trials have been published, but each of a member of the Sertindol Study International
them has important methodological limitations. Safety Committee. Hans-Jürgen Möller has received
Several aspects, such as the well-known link grants or is a consultant for and on the speakership
between sponsorship and study outcome, the use of bureaus of AstraZeneca, Bristol-Meyers Squibb,
various dosage ranges among studies, the unpopular Eisai, Eli Lilly, GlaxoSmithKline, Janssen Cilag,
publication of negative results, different exclusion Lundbeck, Merck, Norvartis, Organon, Pfizer,
criteria (especially when investigating treatment- Sanofi-Aventis, Schering-Plough, Schwabe, Sepracor,
For personal use only.
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