World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, Part 1: Update 2012 on the ...
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The World Journal of Biological Psychiatry, 2012; 13: 318–378
GUIDELINES
World Federation of Societies of Biological Psychiatry (WFSBP)
Guidelines for Biological Treatment of Schizophrenia, Part 1:
Update 2012 on the acute treatment of schizophrenia and the
management of treatment resistance
ALKOMIET HASAN1, PETER FALKAI1, THOMAS WOBROCK1, JEFFREY LIEBERMAN2,
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BIRTE GLENTHOJ3, WAGNER F. GATTAZ4, FLORENCE THIBAUT5,
HANS-JÜRGEN MÖLLER6 & THE WFSBP TASK FORCE ON TREATMENT
GUIDELINES FOR SCHIZOPHRENIA∗
1Department of Psychiatry and Psychotherapy, University of Goettingen, Goettingen, Germany, 2Department of Psychiatry,
College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, Lieber Center for
Schizophrenia Research, New York, NY, USA, 3Center for Neuropsychiatric Schizophrenia Research & Center for
Clinical Intervention and Neuropsychiatric Schizophrenia Research, Copenhagen University Hospital, Psychiatric Center
Glostrup, Denmark, 4Department of Psychiatry, University of Sao Paulo, Brazil, 5University Hospital Ch. Nicolle,
For personal use only.
INSERM U 614, Rouen, France, and 6Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University,
Munich, Germany
Abstract
These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry Guide-
lines for Biological Treatment of Schizophrenia published in 2005. For this 2012 revision, all available publications pertain-
ing 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 and these
guidelines 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 identified lit-
erature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence
(A–F; Bandelow et al. 2008b, World J Biol Psychiatry 9:242). This first part of the updated guidelines covers the general
descriptions of antipsychotics and their side effects, the biological treatment of acute schizophrenia and the management
of treatment-resistant schizophrenia.
Key words: Schizophrenia, antipsychotics, evidence-based guidelines, treatment, acute phase treatment, treatment resistance,
biological treatment
∗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, Georg August University Goettingen, Von-
Siebold-Street 5, D-37075 Göttingen, Germany. Tel: 49 551 396610. Fax: 49 551 3922798. E-mail: ahasan@gwdg.de
(Received 16 May 2012 ; accepted 18 May 2012 )
ISSN 1562-2975 print/ISSN 1814-1412 online © 2012 Informa Healthcare
DOI: 10.3109/15622975.2012.696143Biological treatment of schizophrenia: part one 319
Preface recommended to further strengthen the therapeutic
effort. The goals and strategies of treatment vary
In 2005, the World Federation of Societies of
according to the phase and severity of illness. In the
Biological Psychiatry (WFSBP) Guidelines for Bio-
acute phase of treatment (lasting weeks to months),
logical Treatment of Schizophrenia (Part 1: Acute
which is defined by an acute psychotic episode,
treatment of schizophrenia) were published. Since
major goals are to develop an alliance with the patient
2005, new randomized clinical trials (RCT), open-
and family, to prevent harm, control disturbed
label trials and meta-analyses have been conducted
behaviour, reduce the severity of psychosis and asso-
and published, providing new evidence for the effi-
ciated symptoms (e.g., agitation, aggression, negative
cacy of biological treatment in schizophrenia. Knowl-
symptoms, affective symptoms), determine and
edge regarding the safety, tolerability and efficacy of
address the factors that led to the occurrence of the
approved antipsychotic drugs has increased and new
acute episode and to affect a rapid return to the best
antipsychotic drugs have been introduced. Further-
level of functioning. Special attention should be paid
more, combination strategies and treatment with
to the presence of suicidal ideation, intent or plan,
therapeutic agents other than antipsychotics have
and the presence of commanding hallucinations. The
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been further investigated and some new treatment
patient should be informed about the nature and
strategies have been developed.
management of the illness, including the benefits
Therefore, an update of the WFSBP Guidelines for
and side effects of the medication, in a form that is
Biological Treatment of Schizophrenia is imperative.
appropriate to his or her ability to assimilate the
information. In the acute treatment phase, the main
emphasis is on pharmacotherapeutic (and other
Executive summary of recommendations somatic) interventions. Therefore, antipsychotic
therapy should be initiated as a necessary part of a
General recommendations
comprehensive package of care that addresses the
This part remains partly unchanged and was adopted individual’s clinical, emotional and social needs.
For personal use only.
from the WFBSP 2005 guidelines and updated
where necessary. Specific treatment is indicated for
patients who meet diagnostic criteria for schizo- Specific treatment recommendations for the
phrenia, a schizophrenic episode or psychotic symp- acute treatment of schizophrenia and the
toms related to schizophrenic disorder (according to management of treatment resistance
DSM-IV or ICD-10). An assessment of mental and
physical health to evaluate relevant psychiatric and The separation into first- and second-generation
medical comorbid conditions, psychosocial circum- antipsychotics can be considered as arbitrary and
stances and quality of life should be undertaken there is the need to choose the suitable drug for a
regularly. When a person presents psychotic symp- certain clinical condition. However, to structure the
toms for the first time, a careful diagnostic evalua- text, especially with regard to the terms used
tion should be performed, including laboratory in nearly all clinical trials, the terms FGAs and
investigation and screening for drug abuse. Imaging SGAs are used, but the reader should be aware that
techniques (preferentially MRI, if not accessible these terms represent rather a pseudo-classification
CCT), in order to exclude organic brain disease than a clinically and scientifically meaningful
should be performed when somatic disease is clini- classification.
cally suspected (e.g., encephalitis, see part 3 of these
guidelines “Management of special circumstances
First-episode schizophrenia
and concomitant disorders”). However, CSF should
only be investigated if an organic brain disease In first-episode schizophrenia, antipsychotic phar-
(e.g., encephalitis, immune mediated disease) is macological treatments should be introduced with
expected. great care due to the higher risk of extrapyramidal
After the initial assessment of the patient’s diag- symptoms (EPS). Appropriate strategies include
nosis and establishment of a therapeutic alliance, a gradual introduction of antipsychotic medication
treatment plan must be formulated and imple- with the lowest possible effective dose, combined
mented. This formulation involves the selection of with careful explanation. The first-line use of both
the treatment modalities, the specific type(s) of treat- first-generation (FGA) and second generation (SGA)
ment, and the treatment setting(s). Periodic re- antipsychotic medication at the lower end of the
evaluation of the diagnosis and the treatment plan standard dose range are possible treatments for a
is essential. Engagement of the family and signifi- person experiencing a first episode of schizophrenia.
cant others, with the patient’s permission, is Antipsychotics should be chosen individually,320 A. Hasan et al.
respecting the patient’s mental and somatic condi- Treatment-resistant schizophrenia
tion with special attention to side effects. However,
Treatment-resistant schizophrenia can be defined as
due to the reduced risk of inducing extrapyramidal
a situation in which a significant improvement of
side effects, SGAs should be favoured in first-
psychopathology and/or other target symptoms has
episode schizophrenia patients. When using FGAs, a
not been demonstrated despite treatment with two
close monitoring of extrapyramidal side effects
different antipsychotics from at least two different
(especially acute dystonic reactions, parkinsonism
chemical classes (at least one should be an atypical
and akathisia at the beginning of the treatment, and
antipsychotic) at the recommended antipsychotic
tardive dyskinesia later during the treatment) is nec-
dosages for a treatment period of at least 2–8 weeks
essary. Metabolic parameters need to be closely con-
per drug (Kane et al. 1988b; Lehman et al. 2004;
trolled during treatment with antipsychotics. Skilled
McIlwain et al. 2011; NICE 2010).
nursing care, a safe and supportive environment, and
In assessing treatment-resistant schizophrenia or
liberal doses of benzodiazepines may be essential to
partial response to medication, multidimensional
relieve distress, insomnia and behavioural distur-
evaluation should consider persistent positive or
bances secondary to psychosis while antipsychotic
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negative symptoms, cognitive dysfunction with severe
medication takes effect. However, the combination
impairment, bizarre behaviour, recurrent affective
of benzodiazepines with a long half-time with antip-
symptoms, deficits in vocational and social function-
sychotics has only little evidence and this combina-
ing and a poor quality of life.
tion strategy seems to be associated with an increased
Adherence should be ensured, if necessary by
mortality in schizophrenia patients (Baandrup et al.
checking drug concentrations. In individuals with
2010).
clearly defined treatment-resistant schizophrenia,
clozapine should be introduced as the treatment of
choice because of its superior efficacy in this regard.
Multiple episode schizophrenia (relapse) Other treatment alternatives in case of non-response,
such as other SGAs, augmentation strategies (anti-
For personal use only.
Both, FGAs and SGAs generally have their place in
depressants, mood stabilisers) in relation to target
the treatment of acute schizophrenia. The selection
symptoms, combination of antipsychotics and elec-
of an antipsychotic medication should be guided
troconvulsive therapy, can be implemented in certain
by the patient’s previous experience of symptom
cases. However, limited evidence for the efficacy of
response and side effects, intended route of admin-
these strategies exists.
istration, the patient’s preferences for a particular
For patients presenting with catatonic features,
medication, the presence of comorbid medical con-
the option of ECT should be considered earlier when
ditions, and potential interactions with other pre-
insufficient response to benzodiazepines is observed.
scribed medications. Special attention needs to be
given to antipsychotic-related side effects.
The dose may be titrated as quickly as tolerated
Negative symptoms
to the target therapeutic dose of the antipsychotic
medication while monitoring the patient’s clinical The differentiation of primary and secondary nega-
status. Rapid dose escalation, high loading doses and tive symptoms is of particular importance for the
treatment with high doses above the mentioned dose treatment of schizophrenia. Primary negative symp-
range do not have proven superior efficacy, but have toms are considered a core symptom of schizophre-
been associated with increased side effects. nia, whereas secondary negative symptoms are a
In multiple episode schizophrenia the most com- consequence of positive symptoms (e.g., social with-
mon contributors to symptom relapse are antipsy- drawal because of paranoid ideas), neurological side
chotic medication non-adherence, substance use effects (extrapyramidal side effects, acute dystonia,
(see part 3 of these guidelines) and stressful life antipsychotic-induced parkinsonism and tardive
events, although relapses are not uncommon as a dyskinesia), depressive symptoms (e.g., post-
result of the natural course of the illness, despite psychotic or antipsychotic-induced depression) or
continuing treatment. If non-adherence is sus- environmental factors (e.g., social understimulation
pected, it is recommended that the reasons should due to hospitalisation) (Carpenter et al. 1985).
be evaluated and considered in the treatment For the treatment of secondary negative symp-
plan. It is recommended that pharmacological treat- toms, both FGAs and SGAs have a modest efficacy.
ment should be initiated promptly, because acute For primary negative symptoms treatment with cer-
psychotic exacerbations are associated with emo- tain SGAs (amisulpride, aripiprazole, clozapine,
tional distress, and a substantial risk of dangerous olanzapine, quetiapine, ziprasidone), but not with
behaviours. FGAs, is recommended with inconsistent evidenceBiological treatment of schizophrenia: part one 321
and with the need for more studies to prove the efficacy. (somatic) treatment of adults and they address rec-
There is some limited evidence for the efficacy of anti- ommendations in this field. The specific aim of these
depressants in the treatment of negative symptoms. guidelines is to evaluate the role of pharmacological
agents in the treatment and management of schizo-
phrenia, while the role of specific psychological
Treatment non-adherence interventions and specific service delivery systems is
covered only briefly. The effectiveness of somatic
One of the most common contributors to symptom
treatment is considered.
relapse is antipsychotic medication non-adherence in
The guidelines were developed by the authors and
schizophrenia patients. This is a general problem
arrived at by consensus with the WFSBP Task Force
in all medical disciplines, because patients balance
on Schizophrenia, consisting of international experts
between the advantages and disadvantages of their
in the field.
treatment (Goff et al. 2010). In schizophrenia patients
and patients with schizoaffective disorders almost half
of the patients take less than 70% of the prescribed
Methods of literature research
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doses (Goff et al. 2010). There are many reasons for
and data extraction
this treatment non-adherence: impaired insight, side
effects associated with the antipsychotic medication, In the development of these guidelines, the follow-
disorganized behaviour, the stigma of the diagnosis ing guidelines, consensus papers and sources were
and the feeling of not being ill when symptom remis- considered.
sion is achieved (Goff et al. 2010). Therefore, special
– American Psychiatric Association, Practice Guide-
attention needs to be paid to treatment-adherence in
line for the Treatment of Patients with Schizo-
schizophrenia patients, because antipsychotics are
phrenia, Second Edition (Lehman et al. 2004),
only effective if they are really taken.
and APA Guideline Watch: Practice Guideline for
the treatment of patients with schizophrenia
For personal use only.
(Dixon et al. 2009);
Management of side effects and long-term – Deutsche Gesellschaft für Psychiatrie, Psycho-
treatment of schizophrenia therapie und Nervenheilkunde. Praxisleitlinien
This is described in the second part of these guide- Psychiatrie und Psychotherapie: Schizophrenie
lines, which will be published soon. (DGPPN 2006);
– National Institute for Clinical Excellence: The
NICE Guideline on core interventions in the
Concomitant substance use disorders, treatment and management of schizophrenia in
depressive symptoms, pregnancy adults in primary and secondary care (updated
and risk of suicide edition) (NICE 2010);
– Royal Australian and New Zealand College of
This is described in the third part of these guidelines, Psychiatrists: Australian and New Zealand clinical
which will be published soon. practice guideline for the treatment of schizophre-
nia (RANZCP 2005);
– World Federation of Societies of Biological Psy-
Goal and target audience of the WFSBP
chiatry (WFSBP) Guidelines for Biological Treat-
Guidelines
ment of Schizophrenia, Part 1: Acute treatment of
These guidelines are intended for use in clinical schizophrenia (Falkai et al. 2005);
practice by all physicians investigating, diagnosing – World Federation of Societies of Biological Psy-
and treating patients with schizophrenia. Therefore, chiatry (WFSBP) Guidelines for Biological Treat-
a continuous update of contemporary knowledge of ment of Schizophrenia, Part 2: Long-term
various aspects of schizophrenia, with a particular treatment of schizophrenia (Falkai et al. 2006);
focus on treatment options, is provided. The aim of – The Schizophrenia Patient Outcome Research
these guidelines is to improve standards of care, Team (PORT): Updated Treatment Recommen-
diminish unacceptable variations in the provision dations 2009 (Kreyenbuhl et al. 2010) and The
and quality of care, and to support physicians in 2009 Schizophrenia PORT Psychopharmacologi-
clinical decisions. Although these guidelines favour cal Treatment Recommendations and Summary
particular treatments on the basis of the available evi- Statements (Buchanan et al. 2010);
dence, the treating physician remains responsible for – The Cochrane Library, Meta-analyses on the effi-
his assessment and treatment option. These guide- cacy of different drugs and interventions in schizo-
lines are primarily concerned with the biological phrenia (up to September 2011).322 A. Hasan et al.
– Reviews, meta-analyses, randomised clinical trials grade 1. When this treatment fails, all other grade
and open label-trials contributing to interventions 1 options should be tried first before switching
in schizophrenia patients identified by search in to treatments with recommendation grade 2”
the Medline data base (up to March 2012). For (Bandelow et al. 2008a) (see Table I).
special questions, case reports and case series
were taken into account.
– Individual clinical experience of the authors Acute-phase treatment of schizophrenia
and the members of the WFSBP Task Force on
This section was adopted from the first version of
Schizophrenia.
these guidelines and modified where necessary. In
the acute phase, the specific treatment goals are to
prevent harm, control disturbed behaviour, suppress
Evidence-based classification symptoms, affect a rapid return to the best level of
of recommendations functioning, develop an alliance with the patient and
Categories of evidence family, formulate short- and long-term treatment
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plans, and connect the patient with appropriate
The evidence-based grading of this update is based
aftercare in the community (Lehman et al. 2004).
on the WFSBP recommendations for grading evi-
Whichever treatments are offered, it is essential to
dence (Bandelow et al. 2008b), as used recently in
engage the patient in a collaborative, trusting and
other WFSBP Guidelines (Bandelow et al. 2008a;
caring working relationship at the earliest opportu-
Grunze et al. 2009). Daily treatment costs were not
nity (NICE 2002). Psychosocial interventions in this
taken into consideration due to the variability of
phase aim at reducing overstimulating or stressful
medication costs worldwide. Each treatment recom-
relationships and at developing supportive relation-
mendation was evaluated and discussed with respect
ships with the psychiatrist and other members of the
to the strength of evidence for its efficacy, safety,
treatment team (DGPPN 2006; Lehman et al. 2004).
tolerability and feasibility. It must be noted that the
For personal use only.
The patient should be provided with information on
strength of recommendation is related to the level of
the nature and management of the illness that is
efficacy and tolerability, but not necessarily impor-
appropriate to his or her ability to assimilate the
tance, of the treatment. Five major categories and
information. A patient has to be informed about the
three minor categories were used to determine the
benefits and side effects of the medication. The psy-
hierarchy of recommendations (related to the
chiatrist must realise that the degree of acceptance
described level of evidence) (see Table I).
of medication and information about it varies accord-
ing to the patient’s cognitive capacity, the degree of
the patient’s denial of the illness, and efforts made
Recommendation grades
by the psychiatrist to engage the patient and family
The recommendation grades are also based on the in a collaborative treatment relationship (Lehman
WFSBP recommendations and adopted from et al. 2004). Indications for hospitalisation include
the first revision of the WFSBP Guidelines for the the patient’s being considered to pose a serious threat
Pharmacological Treatment of Anxiety, Obsessive- of harm to self or others, being unable to care for
Compulsive and Post-Traumatic Stress Disorders self, needing constant supervision, and general med-
(Bandelow et al. 2008a). The aforementioned cate- ical or psychiatric problems that make outpatient
gories of evidence “are based on efficacy only, with- treatment unsafe or ineffective. Involuntary hospi-
out regard to other advantages or disadvantages of talisations are required if patients refuse to be admit-
the drugs, such as side effects or interactions” (Ban- ted, and if they meet the requirements of the local
delow et al. 2008a). However, these are important jurisdiction. Alternative treatment settings, such as
issues for the clinical practice, and therefore, recom- partial hospitalisation, home care, family crisis ther-
mendation grades were also used in these updated apy, crisis residential care, and assertive community
guidelines. For example, the evidence for the efficacy treatment, should be considered for patients who do
of clozapine in first-episode schizophrenia is good not need formal hospitalisation for their acute epi-
(Category of evidence A), but due to its side effect sodes (Lehman et al. 2004). In the acute treatment
profile it is not recommended as a first line treatment phase, the main emphasis is on pharmacotherapeutic
for first-episode schizophrenia (Recommendation (and other somatic) interventions. Therefore, antip-
Grade 2). According to the publication of Bandelow sychotic therapy should be initiated as early as pos-
and colleagues (2008a), “the recommendation grades sible as a necessary part of a comprehensive package
can be viewed as steps: The first step would be a of care that addresses the individual’s clinical, emo-
prescription of a medication with recommendation tional and social needs. The clinician responsible forBiological treatment of schizophrenia: part one 323
Table I. Categories of evidence and recommendation grades according to Bandelow and colleagues (2008 a,b).
Category of
Evidence Description
A Full Evidence From Controlled Studies is based on:
2 or more double-blind, parallel-group, randomized controlled studies (RCTs) showing
superiority to placebo (or in the case of psychotherapy studies, superiority to a
“psychological placebo” in a study with adequate blinding)
and
1 or more positive RCT showing superiority to or equivalent efficacy compared with
established comparator treatment in a three-arm study with placebo control or in a
well-powered non-inferiority trial (only required if such a standard treatment exists)
In the case of existing negative studies (studies showing non-superiority to placebo or i
nferiority to comparator treatment), these must be outweighed by at least 2 more positive
studies or a meta-analysis of all available studies showing superiority to placebo and non-
inferiority to an established comparator treatment. Studies must fulfil established
methodological standards. The decision is based on the primary efficacy measure.
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B Limited Positive Evidence From Controlled Studies is based on:
1 or more RCTs showing superiority to placebo (or in the case of psychotherapy
studies, superiority to a“psychological placebo”)
or
a randomized controlled comparison with a standard treatment without placebo
control with a sample size sufficient for a non-inferiority trial
and
no negative studies exist
C Evidence from Uncontrolled Studies or Case Reports/Expert Opinion
C1 Uncontrolled Studies. Evidence is based on:
1 or more positive naturalistic open studies (with a minimum of 5 evaluable patients)
or
For personal use only.
a comparison with a reference drug with a sample size insufficient for a non-inferiority trial
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 Based on
Grade
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
treatment and key worker should monitor both RCTs and meta-analyses published in the last
therapeutic progress and tolerability of the drug on 50 years. Antipsychotics are a chemically heteroge-
an ongoing basis. neous group and they are used in acute phase treat-
ment, in the treatment of special circumstances, in
long-term maintenance therapy and in the preven-
tion of relapse of schizophrenia.
Antipsychotics
Since the first publication of the WFSBP Guide-
Antipsychotics are the first-line treatment in all dif- lines for Biological Treatment of Schizophrenia, no
ferent stages of schizophrenia. Evidence for the effi- additional “old” first-generation antipsychotic (FGA)
cacy of antipsychotics is provided by a magnitude of agents have been introduced. In 2005, amisulpride,324 A. Hasan et al.
aripiprazole, clozapine, olanzapine, quetiapine, ris- Second-generation antipsychotics
peridone, ziprasidone and zotepine were available as
Following the introduction of SGAs, patients and
so called second-generation antipsychotics (SGA).
psychiatrists had hope of a new treatment period for
This update reviews all available and published data
schizophrenia. However, the postulated advantages
of these drugs and, in addition, includes the data
(better efficacy for positive and negative symptoms,
for paliperidone, iloperidone, asenapine, lurasidone
better outcomes for quality of life, better side effect
and sertindole (which was reintroduced in 2005 to
profile) in comparison to FGAs are discussed
Europe, but has no FDA approval).
controversially.
Effectiveness studies with some key methodolog-
Classification and efficacy of antipsychotics ical problems (Moller 2008) failed to show a clear
difference between certain FGAs and SGAs (Jones
First-generation antipsychotics
et al. 2006; Lieberman et al. 2005; McCue et al.
The efficacy of FGAs in reducing psychotic symp- 2006; Rosenheck et al. 2006). However, two meta-
toms in acute schizophrenia was mainly investigated analyses indicate that certain SGAs might have
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during the period from the 1960s to 1980s, by com- some advantages over other SGAs and FGAs with
paring one or more antipsychotic agents with either regard to certain dimensions (overall efficacy, spe-
a placebo or a sedative agent. These studies make cific psychopathology, relapse prevention and qual-
clear that FGAs are superior to a placebo or sedative ity of life) (Kishimoto et al. 2011; Leucht et al.
agent for the treatment of acute schizophrenia. More 2009b).
recently, the FGA haloperidol has been extensively Since the first publication of the WFSBP Guide-
investigated as a comparator in many RCTs. lines for Biological Treatment of Schizophrenia,
An elaborate review found superior efficacy of there have been several publications (RCTs, meta-
FGAs compared to placebo and, with the exception analyses) investigating the efficacy and tolerability
of mepazine and promazine, all of these agents were of new SGAs (paliperidone, iloperidone, asenapine,
For personal use only.
equally effective, although there were differences in lurasidone) in comparison to placebo (Canuso et al.
dose, potency and side effects of the different drugs 2009a,b; Citrome 2009; Cutler et al. 2008; Davidson
(Davis et al. 1989). In general, superiority over pla- et al. 2007; Kane et al. 2007a, 2011a; Marder et al.
cebo was confirmed by numerous double-blind 2007a; Meltzer et al. 2008a; Nakamura et al. 2009;
studies and reviews (Dixon et al. 1995; Kane and Nussbaum and Stroup 2008; Patrick et al. 2010;
Marder 1993). The 2005 guidelines concluded, Potkin et al. 2007). These studies have shown that
based on Cochrane reviews and NICE reviews, that these drugs are effective in the treatment of schizo-
chlorpromazine, flupenthixol, fluphenazine, pera- phrenia and superior to placebo.
zine, perphenazine, pimozide, sulpiride, thioridazine, Furthermore, since the first publication of the
trifluoperazine and zuclopenthixolacetate are similar WFSBP Guidelines for Biological Treatment of
in efficacy to other FGAs, and superior compared to Schizophrenia, many studies and meta-analyses have
placebo. However, this cannot be stated for some compared placebo to the following established SGAs:
drugs, despite having a very high affinity to D2- risperidone (Potkin et al. 2006, 2007; Rattehalli
receptors, such as benperidol, because of lacking et al. 2010a,b); aripiprazole (Cutler et al. 2006;
evidence (Leucht and Hartung 2002, 2005). More- El-Sayeh and Morganti 2006; El-Sayeh et al. 2006;
over, thioridazine and chlorpromazine are no longer Marder et al. 2007b; McEvoy et al. 2007; Volavka
commonly used. In particular, haloperidol is a potent et al. 2005); olanzapine (Duggan et al. 2005),
antipsychotic drug for the treatment of psychotic quetiapine (Arango and Bernardo 2005; Canuso
symptoms in acute schizophrenia and its efficacy and et al. 2009b; Potkin et al. 2006; Small et al. 2004),
safety has been confirmed in many studies and meta- zotepine (DeSilva et al. 2006)).
analyses over the years (Joy et al. 2006a; Kahn et al. These studies provide further evidence for the effi-
2008; Leucht et al. 2008, 2009b). Finally, an old, but cacy of symptom reduction in schizophrenia patients
methodologically good review, showed good efficacy and the drug’s superiority over placebo. However,
of FGAs in diminishing psychotic symptoms in long- one Cochrane meta-analysis showed only a marginal
term treatment and relapse prevention in schizo- benefit of the well-established SGA risperidone
phrenia patients (Davis 1975). In conclusion, FGAs (Rattehalli et al. 2010a) in comparison to placebo,
are effective in the treatment of schizophrenia despite risperidone’s efficacy and effectiveness hav-
(Category of Evidence A, Recommendation grade 1). ing been proven in many RCTs and other meta-
Low-potency FGAs are inferior to high-potency analyses (see below). In general, SGAs are effective
FGAs for the treatment of acute schizophrenia in the treatment of schizophrenia (Category of
(Category of Evidence A, Recommendation grade 1). Evidence A, Recommendation grade 1).Biological treatment of schizophrenia: part one 325
Comparing the efficacy of FGAs versus SGAs ziprasidone) and the primary outcome measure was
the discontinuation of treatment for any cause in a
The most important question for the pharmacologi-
sample of chronic schizophrenia patients. The overall
cal treatment of schizophrenia is whether to treat
rate of discontinuation ranged from 64 to 82% and,
initially and predominantly with SGAs (as recom-
according to the authors, this determines a limited
mended in nearly all guidelines released between
range of effectiveness. Participants receiving olan-
2004 and 2009) or to treat with FGAs. In the first
zapine had a significantly longer time to discontinu-
version of these guidelines it was determined that
ation compared to those receiving SGAs or the FGA
SGAs generally seemed to be preferable, although all
perphenazine. Olanzapine (64% discontinuation
antipsychotics have their place in the treatment of
rate) was superior to risperidone (74% discontinua-
acute schizophrenia.
tion rate), quetiapine (82% discontinuation rate)
Paradigms started to change after two large clini- and the FGA perphenazine (75% discontinuation
cal trials were published: the US based CATIE study rate), but these results did not survive statistical cor-
(funded by the National Institute of Mental Health) rections for multiple comparisons. The secondary
(Lieberman et al. 2005) and the UK-based CUt- outcome parameter “psychopathology scales”
World J Biol Psychiatry Downloaded from informahealthcare.com by 82.113.121.223 on 07/27/12
LASS study (funded by the National Health Ser- (PANSS positive/negative) did not differ across
vice) (Jones et al. 2006). These studies discussed that groups. The results of this large study need to be
certain SGAs are not superior to certain FGAs with discussed in the context of important methodologi-
regard to their effectiveness and that these FGAs and cal limitations which may limit their generalizability.
SGAs have an individual, but independently impor- This study had a very high drop-out rate (overall
tant side effect profile. Both RCTs included chroni- discontinuation rate of 64%), had a significant selec-
cally ill patients that were either having an acute tion bias in the FGA arm (exclusion of patients with
exacerbation of the disease or were changing their a history of tardive dyskinesia in the FGA arm),
antipsychotic medication due to different reasons included partially treatment refractory patients, had
(e.g., no response or side effects). used olanzapine in a broader dosage range than used
For personal use only.
However, for the correct understanding and inter- in clinical practice and had undergone a partial
pretation of these two studies, as well as other such unblinding (Glick 2006; Meltzer and Bobo 2006;
effectiveness studies, methodological problems Moller 2008; Naber and Lambert 2009).
related to effectiveness studies need to be addressed. The CUTLASS study (Jones et al. 2006) showed
In general, effectiveness studies (e.g., phase IV stud- no inferiority of a group of various FGAs (preferen-
ies) do not have a placebo arm and in many cases, tially sulpiride) compared to SGAs (risperidone,
do have the beta-error problem (failure to detect a olanzapine, amisulpride, zotepine, and quetiapine)
difference although there is one), do include patients in terms of quality of life (primary outcome) and
with a long and chronic disease course (and residual symptom reduction according to PANSS (secondary
symptoms) and do have problems associated with outcome) in a sample of chronic schizophrenia
the blinding procedure (Moller 2008). Specific patients. This study was criticised because of some
methodological problems that may afflict the differ- methodological shortcomings. The study sample was
ent studies and their impact on the results are quite small (N 227 included, N 185 for the fol-
discussed separately for each study below. low-up after 52 weeks), a high-quality blinding pro-
One study from the Veterans Affairs Medical cedure was not performed, SGAs and FGAs were
Centres (Rosenheck et al. 2003) compared the SGA compared as two homogenous groups, 49% of the
olanzapine with the FGA haloperidol (in addition to patients received sulpiride as FGA (sulpiride is con-
the anticholinergic drug benztropine) and found no sidered as the most atypical FGA) and only 59% of
significant difference between the drugs in relation the patients continued taking their initial medication
to study retention, improvement in PANSS scores, for 52 weeks (Moller 2008; Naber and Lambert
quality of life and extrapyramidal symptoms, but did 2009). However, the most important limitation is the
show the occurrence of more cognitive disturbances use quality of life as the primary outcome parameter
in patients treated with haloperidol and benzotro- since it is more closely associated with negative or
pine. The long duration of disease (approximately depressive symptoms than with psychotic symptoms
20 years), the flexible dosing scheme and the (Moller 2008).
prophylactic treatment with benzotopine are impor- In contrast to the two aforementioned studies, the
tant confounders, and this needs to be addressed open-label EUFEST study, which was funded by
when interpreting the results (Moller 2008). three pharmaceutical companies without having an
In the CATIE study (Lieberman et al. 2005), influence on study design, data collection, data anal-
the FGA perphenazine was compared with four ysis and publication (Kahn et al. 2008), was con-
different SGAs (olanzapine, quetiapine, risperidone, ducted on first-episode schizophrenia patients.326 A. Hasan et al.
Haloperidol was compared with four different SGAs With regard to the main outcome parameter (overall
(amisulpride, olanzapine, quetiapine, ziprasidone) efficacy) and PANSS (positive and negative), amisul-
and the primary outcome measure was treatment pride, clozapine, olanzapine and risperidone were
discontinuation. A secondary outcome measure better than FGAs with medium to small effect sizes.
was improvement of psychopathology according to Aripiprazole, quetiapine, sertindole, ziprasidone and
PANSS. Treatment discontinuation for any cause zotepine did not show superiority to FGAs in overall
was significantly higher in patients treated with halo- efficacy and in PANSS scores.
peridol. Treatment discontinuation as a consequence Another meta-analysis showed a modest superi-
of insufficient efficacy was also higher in the halo- ority in relapse prevention for SGAs when compared
peridol group, whereas the difference between halo- with FGAs (Kishimoto et al. 2011). In detail, risperi-
peridol and quetiapine was not significant (Kahn done, clozapine and olanzapine were superior to
et al. 2008). The secondary outcome measures, like FGAs with regard to the endpoint “relapse rate”.
improvement of symptoms according to PANSS and After 6 months, only risperidone was superior to
admission to hospital did not show a significant dif- FGAs, but pooled SGAs were superior to FGAs with
ference between groups. Haloperidol showed most regard to long term-relapse rates (6 months). Impor-
World J Biol Psychiatry Downloaded from informahealthcare.com by 82.113.121.223 on 07/27/12
extrapyramidal side effects and weight-gain was tantly, there was no trial in which any FGA was
highest for olanzapine (Kahn et al. 2008). superior to the SGA comparator (Kishimoto et al.
One randomised open-label study found haloperi- 2011)
dol, olanzapine and risperidone to be superior to In the 2005 guidelines the question, as to whether
aripiprazole, quetiapine and ziprasidone with regard SGAs, as a group, are superior to FGAs in their
to the time at which acute in-patient care became efficacy and effectiveness in the treatment of schizo-
necessary, but found no difference concerning phrenia was raised. Today, there is some evidence
changes in the scores of Brief Psychiatric Rating that FGAs and SGAs are comparable with regard to
Scale among drugs (McCue et al. 2006). Results efficacy and effectiveness (especially reduction of
might have been biased by the fact that the dosage PANSS scores). However, certain SGAs are have
For personal use only.
of haloperidol was higher than in other studies (16 some advantages with regard to motor side effects
mg/day) and that 47% of the patients in the halo- (Category of evidence A, Recommendation grade 1) and
peridol group also received anticholinergics for the certain SGAs seem to have some advantages with
treatment of motor side effects. In contrast, no regard to certain treatment domains compared to
patient from the olanzapine or aripiprazole group FGAs (improvement of positive symptoms, treat-
was treated with an additional anticholinergic drug ment discontinuation, relapse prevention) (Category
(Moller 2008). of evidence C3, Recommendation grade 4).
A statement of the World Psychiatric Associa- The side effect of each individual drug, and the
tion Pharmacopsychiatry Section reviewed specific and personal vulnerability, differ among all
approximately 1600 randomized controlled trials of antipsychotic drugs and have to be taken into con-
antipsychotic treatment in schizophrenia with regard sideration before choosing a certain antipsychotic for
to the effectiveness of 62 antipsychotic agents administration. In the early stages of treatment, acute
(Tandon et al. 2008). This analysis stated that both neurological side effects should be avoided. When
FGAs and SGAs are very heterogeneous drugs with designing long-term treatment (see part 2 of these
important differences in their individual side effect guidelines) neurological side effects need to be bal-
profiles. A modest and inconsistent superiority for anced against metabolic and other side effects.
the treatment of negative, cognitive, and depressive In the 2005 and 2006 guidelines, we made clear
symptoms was revealed for SGAs in comparison to that it has never been claimed that SGAs are gener-
FGAs. It was speculated that these differences were ally more efficacious than FGAs. We described an
probably driven by the equivalent efficacy of SGAs equal efficacy for positive symptoms, but discussed
and FGAs in the improvement of positive symptoms some advantages of SGAs in reducing negative,
but fewer motor side effects in the SGA group. depressive and cognitive symptoms and in the better
Finally, this analysis could not detect a different effi- EPS tolerability of SGAs. A detailed discussion of
cacy among the SGAs, but clozapine was superior to each antipsychotic agent and the efficacy on different
all other antipsychotic agents in treatment-resistant domains in different disease states can be found in
schizophrenia (see below) (Tandon et al. 2008). a separate section below. However, it is important to
One recently published meta-analysis by the note that SGAs do not represent a homogenous class
Cochrane schizophrenia group compared nine of drugs (Leucht et al. 2009b) and that certain side
SGAs with FGAs for different treatment domains, effects cannot be considered as typical for the whole
excluding all open-label studies (Leucht et al. 2009b). group of SGAs.Biological treatment of schizophrenia: part one 327
Summary statements Side effects
– FGAs and SGAs are effective in reducing psy- In recent years, the specific and individual side
chotic symptoms and in general no differences effects of different FGAs and SGAs have received
between drugs could be detected (Category of special attention (see Table II).
Evidence A, Recommendation grade 1) Differences in the risk of specific side effects of
– Some SGAs (as outlined and discussed in these antipsychotics are often predictable from the recep-
guidelines) might have some advantages in over- tor binding profiles of the various agents. Some side
all efficacy over other SGAs and FGAs (Category effects result from receptor-mediated effects within
of Evidence B/C3, Recommendation grades 3/4) the central nervous system (e.g., extrapyramidal side
– Some SGAs (as outlined and discussed in these effects, hyperprolactinemia, sedation) or outside the
guidelines) might be superior to FGAs in relapse central nervous system (e.g., constipation, hypoten-
prevention (Category of Evidence B/C3, Recom- sion), whereas other side effects are of unclear
mendation grades 3/4) pathophysiology (e.g., weight gain, hyperglycaemia)
– The increased risk of neurological side effects fol- (DGPPN 2006).
World J Biol Psychiatry Downloaded from informahealthcare.com by 82.113.121.223 on 07/27/12
lowing treatment with FGAs could favour certain It is important to note that both FGAs and SGAs,
SGAs (Category of Evidence C3, Recommendation depending on their individual receptor binding
grade 4) profiles share neurological side effects (acute and
– All side effects need to be taken into consider- long-term extrapyramidal symptoms, neuroleptic
ation. Special attention needs to be given to malignant symptoms), sedation, cardiovascular
motor side effects, metabolic side effects and effects, weight gain, metabolic side effects, anticho-
cardiovascular side effects. linergic, antiadrenergic and antihistaminergic effects,
hyperprolactinaemia and sexual dysfunctions.
Pharmacokinetics Neurological side effects
For personal use only.
Antipsychotics are mainly administered in oral forms, High-potency FGAs are known to have a high risk
but certain FGAs and SGAs can be administered as of inducing extrapyramidal side effects, acute dysto-
intravenous applications, as short-acting intramus- nia, antipsychotic-induced parkinsonism and tardive
cular preparations, or as long-acting injectable dyskinesia. Tardive dyskinesia, in particular, has a
preparations (see part two of these guidelines). close association with FGA treatment (Kasper et al.
Short-acting intramuscular FGAs reach a peak con- 2006) and it should be highlighted that tardive dys-
centration 30–60 min after the medication is admin- kinesia is often not reversible after discontinuation
istered, whereas oral medications reach a peak after of the antipsychotic treatment (see part two of these
2–to 3 h (Dahl 1990). As a result, the calming effect guidelines). SGAs induce fewer extrapyramidal side
of the FGAs may begin more quickly when the med- effects in a therapeutic dose range than FGAs and
ication is administered parenterally. However, this show a significant reduction in the risk of tardive
calming effect on agitation is different from the dyskinesia compared to FGAs (Correll et al. 2004;
antipsychotic effect, which may require several days Leucht et al. 1999). In a recent meta-analysis, all
or weeks. Oral concentrates are typically better and SGAs were associated with fewer extrapyramidal
more rapidly absorbed than pill preparations, and side effects than the well-established FGA haloperi-
often approximate intramuscular administration in dol (Leucht et al. 2009b). Compared to low-potency
their time to peak serum concentrations. FGAs, only clozapine had the advantage of lower
SGAs show similar pharmacokinetics to those of extrapyramidal side effects (Leucht et al. 2009b).
FGAs. SGAs are rapidly and completely absorbed However, at first glance the results of the CATIE
after oral administration but often undergo extensive study did not show significant differences among the
first-pass hepatic metabolism (Burns 2001). Time to different antipsychotic drugs (FGA: perphenazine;
peak plasma concentrations ranges from 1 to 10 h. SGA: olanzapine, risperidone, ziprasidone, quetiap-
Atypical agents are highly lipophilic, highly protein- ine) in the incidence of neurological side effects.
bound, and tend to accumulate in the brain and These findings are likely to have been biased by the
other tissues. Parenteral preparations are available inclusion criteria of the FGA study arm (Lieberman
for various SGAs (e.g., aripiprazole, olanzapine, et al. 2005; Miller et al. 2008; Moller 2008). The
ziprasidone). CUtLASS study found no difference between
The times for maximal plasma levels, the elimina- FGAs and SGAs in neurological side effects (Jones
tion half-time and the metabolism pathways of cer- et al. 2006), whereas the mostly administered FGA
tain FGAs and SGAs are presented in Table V. was sulpiride, a very atypical FGA (Moller 2008).328 A. Hasan et al.
Table II. Selected side effects of commonly used antipsychotics. Frequencies and severity of side effects refers to information obtained by drug companies, FDA, additional literature and other Haloperidol administration resulted in the presen-
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. Weight
Ziprasidone
tation of more signs of parkinsonism in patients
0/()
0/()
0/()
()
()
0
0
0
0
0
0
0
compared with SGA administration in the EUFEST
?
?
study (Kahn et al. 2008). In one large comparison
of risperidone and haloperidol in first-episode schizo-
phrenia patients, haloperidol induced significantly
Sertindole
more extrapyramidal signs and symptoms than ris-
0/()
0/()
()
()
()
()
()
()
()
()
peridone (Schooler et al. 2005). These findings are
supported by Cochrane reviews, providing further
evidence that the frequently-used haloperidol is
Risperidone
likely to cause neurological side effects (Joy et al.
0/
0/() 2006a). Findings of another Cochrane review sug-
()
()
()
0
gest that there is a dose-dependent effect of haloperi-
dol to induce extrapyramidal side effects. High doses
( 7.5 mg/day) are associated with an increased risk
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Quetiapine
of extrapyramidal side effects with no clear evidence
0/()
0/()
()
()
()
() for added efficacy (Donnelly et al. 2010).
0
0
?
It should be noted that low dosages of haloperidol
( 5 mg/day) might not be effective enough for the
treatment of schizophrenia (Zimbroff et al. 1997).
Paliperidone
However, one study did not show a difference
Antipsychotic medication
0/
0/()
()
()
()
between 2 and 8 mg of haloperidol (Oosthuizen
0
et al. 2004). Furthermore, even low dosages of halo-
peridol can induce more extrapyramidal side effects
than SGAs (Kahn et al. 2008; Leucht et al. 2009c;
For personal use only.
Olanzapine
Moller et al. 2008; Oosthuizen et al. 2003; Schooler
/
0/()
0/()
()
()
()
()
()
et al. 2005). A head-to-head comparison (meta-anal-
0
ysis) of different SGAs with the primary outcome
gain during 6 – 10 weeks: low (0–1.5 kg); medium (1.5 – 3 kg); high ( 3 kg).
parameter “use of antiparkinson medication’’ con-
firmed these findings (Rummel-Kluge et al. 2010a).
Clozapine
Risperidone treatment was found to be especially
()
()
()
0
0
0
0
0
linked to higher use of antiparkinson medication
compared to other SGAs. However, this difference
disappeared after exclusion of all studies with ris-
peridone 6 mg/day, indicating a dose-dependent
Aripiprazole
0/()
effect (Rummel-Kluge et al. 2010a). In this meta-
()
()
()
()
()
0
0
0
0
0
0
0
analysis clozapine and quetiapine resulted in signifi-
cantly less use of antiparkinsonian medication, but
these two drugs have not been compared directly
Amisulpride
(Rummel-Kluge et al. 2010a).
0/()
0/()
SGAs can cause extrapyramidal symptoms (see
0/
()
()
()
()
0
0
?
details below) and some studies have provided evi-
dence that even clozapine, and probably quetiapine,
can also induce dose-independent extrapyramidal
Haloperidol
side effects, but the risk is much lower compared to
0/()
that associated with FGAs. Especially the risk for
()
()
developing tardive dyskinesia is discussed to be lower
for certain SGAs compared to FGAs (Kasper et al.
2006).
Akathisia/Parkinsonism
Glucose abnormalities
Lipid abnormalities
Prolactin elevation
Tardive dyskinesia
QT-prolongation
Dysmenorrhoea
Agranulocytosis
Galaktorrhoea
Neuroleptic malignant syndrome (NMS)
Constipation
Hypotension
Weight Gain
guidelines.
Side effect
This rare condition was described in the previous
Sedation
Seizures
publication of these guidelines and, since 2005, some
MNS
new reports and reviews have been published dealingBiological treatment of schizophrenia: part one 329
with this important topic. Neuroleptic malignant Obesity, weight gain and
syndrome (NMS) is characterised by dystonia, rigid- metabolic side effects
ity, fever, autonomic instability, such as tachycardia,
Individuals suffering from schizophrenia are more
delirium, myoglobinuria and increased levels of cre-
likely to be overweight or obese than the general
atine kinase, leukocytes and hepatic enzymes. The
population. Therefore, in combination with other
prevalence of NMS is uncertain; it probably occurs
risk factors (e.g., smoking, reduced physical activity,
in less than 1% of patients treated with FGAs and
diabetes, hyperlipidemia), the risk of obesity, weight
is even more rare among patients treated with SGAs
gain and metabolic side effects is increased, with a
(Adityanjee et al. 1999; Strawn et al. 2007). How-
consequent rise in cardiovascular morbidity and
ever, NMS remains a risk for susceptible patients
mortality (Colton and Manderscheid 2006; Marder
receiving SGAs (El-Gaaly et al. 2009; Strawn 2006;
et al. 2004; Newcomer 2005; 2007). All antipsychot-
Strawn and Keck 2006; Strawn et al. 2007; Trollor
ics can induce weight gain, but certain antipsychotics
et al. 2009). Risk factors for NMS include acute
are more prone to do it so (Casey and Zorn 2001;
agitation, young age, male gender, preexisting neu-
De Hert et al. 2009).
rological disability, physical illness, dehydration,
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The results of the CATIE study indicate that olan-
rapid escalation of antipsychotic dosage, use of high-
zapine induces the highest weight gain of SGAs (clo-
potency medications and use of intramuscular prep-
zapine was not investigated) and the same finding
arations (Keck et al. 1989; Pelonero et al. 1998;
was revealed by the EUFEST-study (Kahn et al.
Strawn et al. 2007). In special cases clinical features
2008; Lieberman et al. 2005). In these studies, zip-
of NMS might be closer to those of a serotoninergic
rasidone seemed to have a positive effect on this
syndrome when certain SGA are used and the level
parameter (Kahn et al. 2008; Lieberman et al. 2005).
of severity is modest (Nisijima et al. 2007).
A 24-week, open-label, three-arm multicenter study
revealed a significant weight gain associated with
olanzapine, risperidone and quetiapine, with no dif-
Epileptic seizures ferences among these drugs (Newcomer et al. 2009).
For personal use only.
Patients suffering from schizophrenia have an An 8-week double-blind RCT found a larger increase
increased risk of epileptic seizure and this risk is in metabolic parameters (BMI; total cholesterol;
boosted by the intake of antipsychotic drugs (Alper LDL; triglycerides) in patients treated with olanzap-
et al. 2007). Epileptic seizures occur in an average ine when compared with risperidone, which had
of 0.5–0.9% of patients receiving antipsychotic med- some small benefits on metabolic parameters. Inter-
ications, with clozapine being associated with the estingly, study discontinuation in both drug groups
highest rate of incidence (approx. 3%) and a cumu- was linked to weight gain (Kelly et al. 2008).
lative risk (approx. 10%) after 4 years of treatment One meta-analysis found that amisulpride, clozap-
(Buchanan 1995; Devinsky et al. 1991; Pacia and ine, olanzapine, risperidone, sertindole and zotepine
Devinsky 1994). As confirmed by the approval have lead to more weight-gain than haloperidol
reports, the incidence of seizures caused by the (Leucht et al. 2009b). Aripiprazole and ziprasidone
newer antipsychotic drugs revealed the highest risk were not associated with greater weight gain and this
for seizures to be during treatment with clozapine. meta-analysis did not find a significant difference
The incidence of seizures in patients assigned to concerning weight gain between SGA and low-
newer antipsychotic drugs drug was 3.5% for clozap- potency FGAs (Leucht et al. 2009b). Another meta-
ine, 0.9% for olanzapine, 0.8% for quetiapine, 0.4– analysis from the same study group revealed that,
0.5% for ziprasidone, 0.4% for aripiprazole and within the group of SGAs, olanzapine and clozapine
0.3% for risperidone (Alper et al. 2007). For zotepine, lead to the most weight gain, followed by quetiapine,
an association with an increased risk of seizures has risperidone and amisulpride (intermediate to low
been described in other guidelines (DGPPN 2006). weight gain) and then by ziprasidone (lowest weight
One review found that, among FGAs, the highest gain) (Rummel-Kluge et al. 2010b). The finding of
risk for seizure provocation is associated with chlo- the highest weight gain in patients treated with olan-
rpromazine, and the lowest risk with haloperidol zapine and clozapine is supported by other publica-
(Hedges et al. 2003). However, EEG alterations tions (Newcomer 2007; Wu et al. 2006; Zipursky
following administration of both FGAs and SGAs et al. 2005). One meta-analysis found a small increase
and in untreated schizophrenia patients are a com- in the risk of diabetes in patients being treated with
mon finding, indicating a general potential risk for SGAs (clozapine, olanzapine, risperidone and que-
seizures, independent of antipsychotic treatment- tiapine) compared to FGAs (Smith et al. 2008).
type (Alper et al. 2007; Amann et al. 2003; Steinert The PORT guidelines identified that clozapine and
et al. 2011). olanzapine induced the highest weight gain/metabolicYou can also read
