WFBSP SZ Guidelines Part2 2013 Long Tgerm Schi

8/13/2019 WFBSP SZ Guidelines Part2 2013 Long Tgerm Schi

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GUIDELINES

World Federation of Societies of Biological Psychiatry (WFSBP)

Guidelines for Biological Treatment of Schizophrenia, Part 2:

Update 2012 on the long-term treatment of schizophrenia

and management of antipsychotic-induced side effects

ALKOMIET HASAN1, PETER FALKAI1, THOMAS WOBROCK2, JEFFREY LIEBERMAN3,BIRTE GLENTHOJ4, WAGNER F. GATTAZ5, FLORENCE THIBAUT6& HANS-JRGEN MLLER1, WFSBP Task force on Treatment Guidelines for Schizophrenia*

1Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany, 2Centre of Mental Health,

Darmstadt-Dieburg Clinics, Darmstadt, Germany, 3Department of Psychiatry, College of Physicians and Surgeons,

Columbia University, New York State Psychiatric Institute, Lieber Center for Schizophrenia Research, New York, USA,4Center for Neuropsychiatric Schizophrenia Research & Center for Clinical Intervention and Neuropsychiatric Schizophrenia

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

AbstractThese 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 availablepublications 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 scientificallymeaningful. 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 CochraneLibrary, 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 levelsof evidence (AF) and five levels of recommendation (15) (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 relevantside effects. These guidelines are primarily concerned with the biological treatment (including antipsychotic medicationand 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

General recommendations

This part remains partly unchanged; it has beenadopted from the WFBSP 2006 guidelines and

updated where necessary. Specific treatment strategies

are required not only for patients suffering fromacute schizophrenia, but also in the stabilisation andstable phase of the disease. The stabilisation periodfollows the acute phase and constitutes a time-limited transition to continuing treatment in the

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), StevenRichard 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), PatrickMcGorry (Australia), Herbert Meltzer (USA), Hans-Jrgen Mller (Germany), S. Mosolov (Russia), Driss Moussaoui (Marocco),

Jean-Pierre Oli (France), Antonio Pacheco Palha (Portugal), Asli Sarandl (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: [email protected]

(Received 5 October 2012; accepted 10 October 2012)

The World Journal of Biological Psychiatry, 2013; 14: 244

ISSN 1562-2975 print/ISSN 1814-1412 online 2013 Informa HealthcareDOI: 10.3109/15622975.2012.739708


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Biological treatment of schizophrenia: Part 2 3

reduction, consolidate remission, and promote the

process of recovery. The main goals of treatmentduring the stable phase are to ensure that symptomremission or control is sustained, that the patient ismaintaining or improving their level of functioningand quality of life, that monitoring for adverse treat-ment effects continues, and to prevent relapse. Theantipsychotic pharmacological therapy should beaccompanied by psychosocial interventions.

A number of psychosocial treatments, includingfamily intervention, supported employment, asser-tive community treatment, skills training and

period of treatment and rehabilitation during which

symptoms are under adequate control and the focusis on improving functioning and recovery. The goalsof long-term therapy have to be discussed with thepatient in the context of adequate background infor-mation, as well as her/his personal goals, in order tofind a common ground which will encourage aneffective long-term medication strategy (shared-decision making). In this regard, a treatment planmust be formulated and implemented.

During the stabilisation phase, the main goals oftreatment are to facilitate continued symptom

Table I. Categories of evidence and recommendation grades according to Bandelow and colleagues (2008a, b).

Category of Evidence Description

A Full Evidence From Controlled Studies is based on:Two or more double-blind, parallel-group, randomized controlled studies (RCTs) showing

superiority to placebo (or in the case of psychotherapy studies, superiority to a psychologicalplacebo in a study with adequate blinding)

and

One or more positive RCT showing superiority to or equivalent efficacy compared withestablished comparator treatment in a three-arm study with placebo control or in awell-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 inferiorityto comparator treatment), these must be outweighed by at least two more positive studies or ameta-analysis of all available studies showing superiority to placebo and non-inferiority to anestablished comparator treatment. Studies must fulfil established methodological standards.The decision is based on the primary efficacy measure.

B Limited Positive Evidence From Controlled Studies is based on:One or more RCTs showing superiority to placebo (or in the case of psychotherapy studies,

superiority to a psychological placebo)ora randomized controlled comparison with a standard treatment without placebo control with a

sample size sufficient for a non-inferiority trialand

no negative studies existC 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

a comparison with a reference drug with a sample size insufficient for a non-inferiority trialand

no negative controlled studies existC2 Case Reports. Evidence is based on:

1 or more positive case reportsand

no negative controlled studies existC3 Evidence is based on the opinion of experts in the field or clinical experience

D Inconsistent ResultsPositive RCTs are outweighed by an approximately equal number of negative studies

E Negative EvidenceThe 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 tocomparator treatment

F Lack of EvidenceAdequate studies proving efficacy or non-efficacy are lacking.

Recommendation Grade Based on1 Category A evidence and good risk-benefit ratio2 Category A evidence and moderate risk-benefit ratio3 Category B evidence4 Category C evidence5 Category D evidence


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4 A. Hasan et al.

Antipsychotic medications are associated with dif-fering levels of risk for various side effects, includingneurological, metabolic, sexual, endocrine, sedativeand cardiovascular side effects (for a detaileddescription see Part 1 of this guideline update).These side effects may have an even greater influ-ence on the choice of long-term medication than in

the acute phase of treatment. Monitoring of sideeffects is based on the side effect profile of the pre-scribed antipsychotic. During the stable phase, it isimportant to monitor all patients routinely for allextrapyramidal symptoms (EPS), weight gain, car-diovascular and metabolic side effects. Monitoringfor obesity-related health problems (e.g., high bloodpressure, lipid abnormalities and clinical symptomsof diabetes) and consideration of appropriateinterventions are recommended if necessary (seeTable III and Part 1 of these updated guidelines).Clinicians may consider regular monitoring of fast-ing glucose or haemoglobin A1c levels to detectemerging diabetes since patients often have multiplerisk factors for diabetes, especially patients withobesity (De Hert et al. 2006, 2011a). FGAs andSGAs have specific side effect profiles and these pro-files have to be considered when planning a long-term treatment. SGAs have clear advantages withrespect to EPS (especially tardive dyskinesia).However, this advantage has to be weighed againstother potentially dangerous side effects, e.g., meta-bolic or cardiac side effects (see Table II and Part 1of these updated guidelines).

It is important to evaluate whether residual nega-

tive symptoms are in fact secondary to a parkinso-nian syndrome or untreated major depression sinceinterventions are available to address these causes ofnegative symptoms. For primary negative symptoms,treatment options include switching to an atypicalantipsychotic or augmentation strategies. Neverthe-less, it should be noted that the evidence for theefficacy of these strategies is only limited (see Part 1of these updated guidelines). Adjunctive medicationsare prescribed for comorbid conditions of patients inthe stable phase. Comorbid major depression andobsessive-compulsive disorder may respond to anti-depressant medications, mood stabilisers may

address prominent mood lability, and benzodiaz-epines are helpful for managing anxiety and insom-nia. However, the evidence for these treatmentstrategies is minimal and the combination therapy ofantipsychotics and benzodiazepines with a long half-time is discussed to increase mortality in schizophre-nia patients (Baandrup et al. 2010) (see Part 1 ofthis guideline update).

Further treatment strategies, including appro-priate management of side effects, are extensivelydiscussed below.

cognitive behaviour-oriented psychotherapy, havebeen shown to be effective during the stable phase.The selection of appropriate psychosocial treat-ments should be guided by the circumstances ofthe individual patients needs and social context.In the same way, psychopharmacological manage-ment must be individually tailored to the needs

and preferences of the patient, focusing on relapseprevention, symptom suppression and improve-ment of subjective wellbeing and quality of life.

Specific treatment recommendations

Long-term treatment is necessary for all patientswith schizophrenia. If the patient has shownimprovements with a particular medication regi-men, continuation of that regimen with furthermonitoring is recommended for at least 6 monthsin the stabilisation phase. Premature dosage lower-ing may lead to a recurrence of symptoms andrelapse, whereas this question is recently discussedcontroversially (Takeuchi et al. 2012). Side effectshave to be assessed and, if necessary, pharmaco-therapy has to be adjusted. Antipsychotic medica-tions substantially reduce the risk of relapse in thestable phase of illness and are strongly recom-mended for durations of 12 years in first-episodepatients, 25 years in patients who have experiencedone relapse, and for over 5 years (maybe eventhroughout life) in multi-episode patients.

Antipsychotic monotherapy should be the pre-

ferred treatment approach. Continuous dosingstrategies have shown superiority compared tointermittent-dose approaches. Deciding on the doseof an antipsychotic medication during the stablephase is complicated by the fact that there is noreliable strategy available to identify the minimumeffective dose to prevent relapse.

There is no good evidence that high maintenancedoses (e.g., for first-generation antipsychotics(FGAs) above 600 mg CPZ equivalents) are moreeffective in preventing relapse than standard doses.Therefore, a maintenance dosage below 600 CPZequivalents is recommended. First-episode patients

may require lower doses for relapse prevention thanmulti-episode patients.

Depot preparations (FGAs or SGAs, long-actingantipsychotics) should be the application method ofchoice when a patient expresses a preference for suchtreatment because of its convenience, or as part of atreatment plan in which the avoidance of covert non-adherence with antipsychotic drugs is a clinical pri-ority. In certain cases, patients should be activelymotivated and educated about the benefits of usingdepot preparations.


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Goal and target audience of the WFSBP

guidelines

These guidelines are intended for use in clinicalpractice by all physicians investigating, diagnos-ing and treating patients with schizophrenia. There-fore, a continuous update of contemporary knowledge

of various aspects of schizophrenia, with a particularfocus on treatment options, is provided. The aim ofthese guidelines is to improve standards of care, todiminish unacceptable variations in the provisionand quality of care, and to support physicians inclinical decisions. Although these guidelines favourparticular treatments on the basis of the availableevidence, the treating physician remains responsiblefor his assessment and treatment option. Theseguidelines are primarily concerned with the biologi-cal (somatic) treatment of adults and they addressrecommendations in this field. The specific aim ofthese guidelines is to evaluate the role of pharmaco-

logical agents in the treatment and management ofschizophrenia, while the role of specific psychologi-cal interventions and specific service delivery sys-tems is covered only briefly. The effectiveness ofsomatic treatment s also considered.

The guidelines were developed by the authors andarrived at by consensus with the WFSBP Task Forceon Schizophrenia, consisting of international expertsin the field.

Methods of literature research

and data extraction

In the development of these guidelines, the followingguidelines, consensus papers and sources wereconsidered:

American Psychiatry Association, Practice Guidelinefor the Treatment of Patients with schizophre-nia (APA 1997), American Psychiatric Associa-tion, Practice Guideline for the Treatment ofPatients with Schizophrenia, Second Edition(Lehman et al. 2004), and APA GuidelineWatch: Practice Guideline for the treatment ofpatients with schizophrenia (Dixon et al.2009);

Deutsche Gesellschaft fr Psychiatrie, Psychothera-pie und Nervenheilkunde. Praxisleitlinien Psy-chiatrie und Psychotherapie: Schizophrenie(DGPPN 2006);

National Institute for Clinical Excellence: The NICEGuideline on core interventions in the treat-ment and management of schizophrenia inadults in primary and secondary care (updatededition) (NICE 2010);

Royal Australian and New Zealand College of Psy-chiatrists: Australian and New Zealand clinicalT

ableII.Selectedsideeffectsofcom

monlyusedantipsychotics.

Antipsychoticmedication

Sideeffect

Haloper

idol

Amisulpride

Aripiprazole

Clozapine

Olanzapine

Paliperidon

e

Quetiapine

Risperidone

Sertindole

Ziprasidone

Akathisia/Parkinsonism

0/

0

0/()

0/

0/()

0/

0

/()

0/()

Tardivedyskinesia

()

()

0

()

()

?

()

()

?

Seizures

0

()

0

0

0

0

()

0

QTprolongation

()

()

()

()

()

()

()

Glucoseabnormalities

()

()

0

0

Lipidabnormalities

()

()

0

0

Constipation

0

0

Hypotension

0

()

()

()

0

Agranulocytosis

0/()

0/()

0/()

0/()

0/()

0/()

0/()

0

/()

0/()

WeightGain

()

()

Prolactinelevation

0

0

()

()

()

0

Galaktorrhoea

0

0

0

()

0

Dysmenorrhoea

0

0

()

()

()

Sedation

0/()

0

/

()

0/()

MNS

?

()

()

()

()

()

()

()

?

Frequenciesandseverityofsideeffe

ctsreferstoinformationobtainedbydrugcompanies,FDA,additionalliteratureandotherguidelines.

0norisk;()occasionally,maybenodifferencetoplacebo;mild(less

1%);sometimes(less10%),frequently(10%);?nostatementpossible

duetolackingdata.

Weightgainduring610weeks:

low(01.5kg);medium(1.53kg);

high(3kg).


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6 A. Hasan et al.

Evidence-based classificationof recommendations

Categories of evidence

The evidence-based grading of this update is basedon the WFSBP recommendations for grading evi-dence (Bandelow et al. 2008b), as used recently inother WFSBP guidelines (Bandelow et al. 2008a;Grunze et al. 2009). Daily treatment costs were nottaken into consideration due to the variability ofmedication costs worldwide. Each treatment recom-mendation was evaluated and discussed with respectto the strength of evidence for its efficacy, safety,tolerability and feasibility. It must be noted that thestrength of recommendation is related to the level ofefficacy and tolerability, but not necessarily impor-tance, of the treatment. Five major categories andthree minor categories were used to determine thehierarchy of recommendations (related to thedescribed level of evidence) (see Table I).

Recommendation grades

The recommendation grades are also based on theWFSBP recommendations and adopted fromthe first revision of the WFSBP Guidelines for the

Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders(Bandelow et al. 2008a). The aforementioned cate-gories of evidence are based on efficacy only, with-out regard to other advantages or disadvantagesof the drugs, such as side effects or interactions(Bandelow et al. 2008a). However, these areimportant issues for the clinical practice, and there-fore, recommendation grades were also usedin these updated guidelines. For example, the evi-dence for the efficacy of clozapine in first-episode

practice guideline for the treatment of schizo-phrenia (RANZCP 2005);

World Federation of Societies of Biological Psy-chiatry (WFSBP) Guidelines for BiologicalTreatment of Schizophrenia, Part 1: Acutetreatment of schizophrenia (Falkai et al.2005);

World Federation of Societies of Biological Psy-chiatry (WFSBP) Guidelines for BiologicalTreatment of Schizophrenia, Part 2: Long-term treatment of schizophrenia (Falkai et al.2006);

World Federation of Societies of Biological Psychia-try (WFSBP) Guidelines for Biological Treat-ment of Schizophrenia, Part 1: Update 2012 onthe acute treatment of schizophrenia and themanagement of treatment resistance (Hasanet al. 2012);

The Schizophrenia Patient Outcome Research Team(PORT): UpdatedTreatment Recommendations2009 (Kreyenbuhl et al. 2010) and The 2009Schizophrenia PORT PsychopharmacologicalTreatment Recommendations and SummaryStatements (Buchanan et al. 2010);

The Cochrane Library, Meta-analyses on the effi-

cacy of different drugs and interventions inschizophrenia (up to August 2012).

Reviews, meta-analyses, randomised clinical trialsand open label-trials contributing to interven-tions in schizophrenia patients identified bysearch in the Medline data base (up to August2012). For special questions, case reports andcase series were taken into account.

Individual clinical experience by the authorsand the members of the WFSBP Task Force onSchizophrenia.

Table III. Monitoring for patients on second-generation antipsychotics. More frequent assessments maybe warranted based on clinical status. Especially during a long-term treatment (e.g., lifelong treatment),the monitoring process has to be adapted individually. These monitoring intervals are one suggestionwhich needs to be modified with regard to the administered antipsychotic and the national guidelines.Patients treated with clozapine need a special monitoring. Compared to the first part of these updatedguidelines, this table was modified (waist circumference) as a result of an expert-based consent.

Baseline 4 Weeks 8 Weeks 12 Weeks Annually

Personal/Family History x xWeight (BMI) x x x x xWaist circumference x x x xBlood pressure x x x xFasting plasma glucose x x xFasting lipid profile x x xBlood cell count x x x xECG x xEEG x xPregnancy test x x

BMI, Body mass index; ECG, electrocardiogram; EEG, electroencephalogram.Modified according to APA (2004) and De Hert et al. (2009).


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If the patient has improved with a particular medica-tion regimen, it is recommended that the regimen iscontinued for at least 6 months (Lehman et al. 2004;Falkai et al. 2006). It is also critical to assess continu-ing side effects that may have been present in theacute phase and to adjust pharmacotherapy accord-ingly in order to minimise adverse side effects that

may otherwise lead to medication nonadherence andrelapse.

The stable phase (lasting months to years)represents a prolonged period of treatment andrehabilitation during which symptoms are underadequate control and the focus is on improvingfunctioning and recovery. The main goals of treat-ment during the stable phase are to ensure thatsymptom remission or control is sustained, that thepatient is maintaining or improving their level offunctioning and quality of life, that any increases insymptom severity or relapse occurrence are effec-tively treated, and that monitoring for adverse treat-ment effects continues. For most patients in thestable phase of schizophrenia, psychosocial inter-ventions are recommended as a useful adjunctivetreatment to pharmacological treatment to improveoutcome. The main aims of pharmacological inter-vention in the stable phase are to prevent relapse,help keep an individual stable enough to live as nor-mal a life as possible, and continue to promote theprocess of recovery (in the sense of a maintenanceor continuation therapy).

The goals of long-term treatment have to bediscussed with the patient and, if she/he agrees,

with family members, relatives, care givers and, insome cases, advocates, with the aim of providingadequate information and with an understandingof the patients personal goals. When an agreementis reached in the context of shared decision-making,a treatment plan must be formulated and imple-mented. Psychopharmacological managementmust be individually tailored to the needs andpreferences of the patient, focusing on relapse pre-vention, symptom suppression and improvementof subjective wellbeing and quality of life. Psycho-therapeutic interventions remain supportive butmay be less directive than in the acute phase.

Educational programmes during this phase havebeen effective in teaching a wide range of schizo-phrenia patients medication self-management(e.g., benefits of maintenance of antipsychoticmedication, how to cope with side effects), symp-toms self-management (e.g., how to identify earlywarning signs of relapse, develop a relapse preven-tion plan, refuse illicit substances and alcohol),and basic social skills (APA 1997; Lehman et al.2004; Falkai et al. 2006).

schizophrenia is good (Category of evidence A), butdue to its side effect profile it is not recommendedas a first line treatment for first-episode schizophre-nia (Recommendation Grade 2). According to thepublication of Bandelow and colleagues (2008a),the recommendation grades can be viewed assteps: The first step would be a prescription of a

medication with recommendation grade 1. Whenthis treatment fails, all other grade 1 options shouldbe tried first before switching to treatments withrecommendation grade 2 (Bandelow et al. 2008a)(see Table I).

General aspects of long-term treatment

of schizophrenia

Indication and goals of long-term treatment

for schizophrenia

The general aspects of this section have beenadopted from the last version of these guidelinesand have been updated where necessary. Schizo-phrenia is a heterogeneous condition that has avarying course and outcome, and affects manyaspects of a patients life. The care of most patientswith this disorder involves multiple efforts and amultidisciplinary team approach to reduce the fre-quency, duration and severity of episodes, reducethe overall morbidity and mortality of the disorder,and improve psychosocial functioning, indepen-dence and quality of life.

Specific treatment needs to be continued in the

stabilisation and stable phase of schizophrenia andlong-term treatment is indicated for all patients withschizophrenia. Clinical issues consist of relapse pre-vention and improvement of symptoms, includingthe reduction of the demoralising effects of persistentpsychotic symptoms, treating depression and pre-venting suicide, reducing substance abuse andsmoking, and enhancing family relationships andvocational rehabilitation.

The stabilisation period (usually lasting 36months) follows the acute phase and constitutes atime-limited transition to continuing treatment inthe stable phase. The primary goals in the stabilisa-

tion phase are the consolidation of the therapeuticrelationship, reduction of positive symptoms,improvement of cognitive and negative symptoms,reduction of stress for the patient, improvement ofsocial deficits and consolidation of remission, pro-motion of insight and compliance, supporting thedevelopment of individual coping strategies, provi-sion of support to minimise the likelihood of relapse,enhancement of the patients adaptation to life in thecommunity and promotion of the recovery process.


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8 A. Hasan et al.

the relative benefits of the drugs and their side effectprofiles and the past experience of the patient andthe physician. Antipsychotic drugs should not beprescribed concurrently and monotherapy should befavoured. For short periods of overlap in the case ofswitching, in the case of severe treatment resistanceor in order to combine different pharmacological

effects (e.g., combined treatment with low-potencyFGA for sedation), a combination treatment isacceptable (NICE 2002; Lehman et al. 2004;RANZCP 2005; DGPPN 2006; Falkai et al. 2006).Psychiatrists, who treat patients with more than oneantipsychotic at the same time should be aware ofdrug interactions and that there have been practi-cally no studies examining the security of these com-bination treatments.

Methodological aspects

In contrast to the acute and short-term treatment ofschizophrenia, there are only few studies that havebeen conducted investigating maintenance therapyand comparing FGAs and SGAs. As widely dis-cussed in the first part of these guidelines and inother publications (Leucht et al. 2009b; Glick et al.2011), the differentiation between FGAs and SGAsraises some problems (pseudoclassification) andeach antipsychotic has its individual side effect pro-file. This fact limits the comparability of differentantipsychotics and needs to be considered whenreading these guidelines and the underlying originalpublications.

Another problem is that good meta-analysesaddressing questions of long-term antipsychotictreatment are still rare a situation that can beexplained by the small number of well-designedlong-term clinical trials. Furthermore, main prob-lems of meta-analyses are the comparability of theincluded studies (e.g., diagnostic differences, differ-ent observation periods, different dosages) and thefact that negative results are less frequently publishedthan positive results (publication bias) (Leucht et al.2009c). The reader should be aware about the meth-odological problems associated with meta-analysesand consider that meta-analyses can lead to a differ-

ent interpretation of already available data (Leuchtet al. 2009c). Furthermore, long-term treatmentneeds to address other clinical variables than psycho-pathology (e.g., neurocognition, drug acceptability,compliance, subthreshold episodes, substance abuseand many more) and many of the published long-term studies do have still too short observation peri-ods, which do not allow to draw final conclusionsabout long-term treatment in schizophrenia patients(Altamura and Glick 2010). These methodologicalaspects are of great relevance for the understanding

Antipsychotic treatment

General aspects

Since the last publication of these guidelines, somenew studies investigating and comparing the efficacyof FGAs and SGAs in the long-term treatment ofschizophrenia have been published. Furthermore,

new long-acting antipsychotics have been launchedto the market, providing additional treatment optionsfor the long-term management of schizophrenia.

The following statements are in accordance withthe previous version of these guidelines and havebeen updated only where necessary. The efficacy ofFGAs in relapse prevention was demonstrated in the1970s (Davis 1975, 1985) and was confirmed formost SGAs later (Davis and Chen 2003; Leuchtet al. 2009a, 2012a,b; NICE 2010). These efficacieshave been shown for both first-episode schizophreniapatients (Kane et al. 1982; Crow et al. 1986; Bradfordet al. 2003; Schooler et al. 2005; Gaebel et al. 2007)and for multiple-episode schizophrenia patients(Davis 1975, 1985; Davis et al. 1993; Jeste et al.1993; Gilbert et al. 1995; Leucht et al. 2003). Antip-sychotic therapy should be continued as part of acomprehensive package of care that addresses theindividuals clinical, emotional and social needs(NICE 2002). Antipsychotic drugs are an indispens-able treatment option for most people in the recov-ery and stable phases of schizophrenia. The main aimhere is to prevent relapse and help keep a personstable enough to live as normal a life as possible(NICE 2002) with minimal side effects. Antipsy-

chotics are also necessary for psychological treat-ments to be effective, and psychosocial interventionsare always an essential addition to pharmacotherapy(RANZCP 2005).

Targets of long-term treatment include mainte-nance therapy to stabilise remission, prevent relapse,and provide symptom suppression or even continuedsymptom improvement. Ongoing monitoring andassessment during the stable phase are necessaryto determine whether the patient might benefitfrom alterations to his or her treatment programme(Lehman et al. 2004), and whether potential dange-rous side effects are developing. However, the fre-

quency of assessments conducted by the psychiatristor member of the team should depend on thespecific nature of the treatment and the expectedfluctuations of the illness, as well as from the healthcare system of the particular country. For example,patients given certain antipsychotics (e.g., clozapine)should be evaluated more frequently than patientson other antipsychotics.

The choice of antipsychotic drug should be madejointly by the individual and the clinician responsiblefor treatment, based on an informed discussion of


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of life. However, extrapyramidal symptoms weremore frequent in the haloperidol group. Althoughthe study was biased by a high drop-out rate of 68%,the drop-out rate did not differ significantly betweendrugs (Gaebel et al. 2007).

In a double-blind international 2-year RCT, olan-zapine (mean dose 10.2 mg/day) and haloperidol

(mean dose 4.82 mg/day) were shown to have thesame efficacy in the primary outcome measure ofsymptom reduction (Green et al. 2006). However,patients treated with olanzapine were found to beless likely to discontinue the study and showed higherremission rates. It should be noted that the signifi-cantly longer duration of illness in the haloperidolgroup must be considered when interpreting thesefindings (Green et al. 2006).

Another long-term 2-year randomized, double-blind study compared haloperidol with risperidonein 63 patients with stable and chronic schizophrenia.In addition to the antipsychotic treatment, studypatients received standard behavioural skills train-ing or enhanced training with a case manager whopromoted patients use of their skills in the commu-nity (Marder et al. 2003). In this study, no differ-ences in the primary outcome parameter symptomreduction (Brief Psychiatric Rating Scale) could bedetected between the drugs. However, for the sec-ondary outcome parameters, anxious-depressioncluster of the Brief Psychiatric Rating Scale and theSCL-90-R self-report instrument, risperidone wassuperior compared to haloperidol. Furthermore,risperidone induced fewer motor side effects and

patients treated with haloperidol received more anti-cholinergics and propanolol (for akathisia) (Marderet al. 2003).

One 12-month double-blind study from theVeterans Affairs Medical Centres (Rosenheck et al.2003) compared olanzapine with haloperidol (plusprophylactic benztropine for motor side effects) andfound no significant difference between the drugs inrelation to study retention, improvement in PANSSscores, quality of life and extrapyramidal symptoms.However, this study revealed that cognitive distur-bances occurred more frequently in patients treatedwith haloperidol and benztropine. Olanzapine

induced less motor side effects, but more weight gaincompared to haloperidol (Rosenheck et al. 2003).Important confounders of his study are the long dis-eases course (approximately 20 years), the flexibledosing scheme and the prophylactic treatment withbenztropine (Moller 2008). The latter biases thestudy in favour of haloperidol and should not becommon practice given the cognitive disturbancesinduced by anticholinergics.

In a flexible-dose double-blind 52-week RCT, nodifference between chlorpromazine and clozapine

of the original publications and of the recommenda-tions made in these guidelines.

FGAs and SGAs

As described in the last version and in the recentlyupdated first part of these guidelines, differences

between FGAs and SGAs need to be viewed in thecontext of efficacy or effectiveness, side effects, thepatients symptomatology and experience. A modernantipsychotic therapy should provide a tailored ther-apeutic regime with great attention to the side effects.In the case of long-term maintenance therapies,intolerable side effects are an important factor relatedto poor treatment adherence (Goff et al. 2010).

Two pooled randomized, double-blind, multi-centre 52-week studies (with similar study protocols)compared the long-term efficacy of aripiprazole andhaloperidol in 1294 schizophrenia patients (Kasperet al. 2003). This study showed comparable efficacyof aripiprazole and haloperidol in reducing positivesymptoms, but a superiority of aripiprazole in reduc-ing negative and affective symptoms. Furthermore,treatment with haloperidol was associated with moremotor side effects (Kasper et al. 2003).

A large double-blind, prospective long-term studyin stable outpatients suffering from chronic schizo-phrenia (mean duration of disease over 15 years),revealed superiority of risperidone (modal daily dose4.9 mg) with regard to treatment discontinuation,reduction of symptoms and extrapyramidal sideeffects when compared with haloperidol (modal

daily dose 11.7 mg) (Csernansky et al. 2002).In a large (n555) double-blind, controlled,flexible-dose RCT, risperidone (mean modal dose3.3 mg/day) and haloperidol (mean modal dose2.9 mg/day) were both found to lead to significantimprovements in global psychopathology withoutdifference between groups (Schooler et al. 2005).However, within the patients who achieved a clinicalimprovement, the patients treated with risperidonehad a significantly longer time to relapse. Patientstreated with haloperidol showed more extrapyrami-dal symptoms, while patients in the risperidonegroup had a greater prolactin elevation. Treatment

with haloperidol resulted in less initial weight gaincompared to treatment with risperidone, but this didnot remain significant at the study endpoint (Schooleret al. 2005).

In a double-blind RCT with 159 remitted first-episode schizophrenia patients, no difference in theprimary outcome parameter relapse preventionwas found between haloperidol (4.1 mg/day) andrisperidone (4.2 mg/day) (Gaebel et al. 2007). Bothdrugs showed the same efficacy in the secondaryoutcome parameters symptom reduction and quality


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10 A. Hasan et al.

of FGAs, and the effect size of zotepine was margin-ally greater. Other SGAs revealed no clear superior-ity (Davis et al. 2003). No efficacy difference wasdetected when amisulpride, risperidone and olan-zapine were directly compared to each other. In amore recent meta-analysis (comparing FGAs toSGAs, conducted mainly from short-term trials),

SGAs were not pooled because the authors felt thatthey were too different to form a class (Leucht et al.2009b, 2011b). In this new meta-analysis, only ris-peridone, olanzapine and sertindole (based on onlyone study) were superior to FGAs in terms of relapseprevention. For amisulpride, aripiprazole and clo-zapine, no significant difference could be detectedcompared to FGAs and, for the other SGAs, no datawere available (Leucht et al. 2009b). However, thesemeta-analyses (Davis et al. 2003; Leucht et al. 2009b)primarily included short-term studies and the trans-lation of their results to long-term studies should beundertaken only with caution.

A meta-analysis (Leucht et al. 2003) includingonly trials with a minimum 6 month duration showeda superiority of SGAs when grouped together andwhen compared to placebo, a superiority of certainSGAs (risperidone, olanzapine and sertindole), anda numeric, but not significant superiority for amisul-pride and clozapine when compared to FGAs and asuperiority of the grouped SGAs compared to FGAs.SGAs and FGAs showed no difference in terms ofdropout-rate due to adverse effects. The authors dis-cussed several confounding factors of this meta-analysis (e.g., the difficulty of defining relapse, the

fixed-dosage regime in the included trials) and con-cluded that the available data do not allow for anyconclusions about whether this modest superiorityfor the new antipsychotics in relapse prevention isrelated to enhanced efficacy, better adherence, or acombination of these factors (Leucht et al. 2003).A more recent meta-analysis of randomized trials,lasting 6 months or longer, compared FGAs withSGAs in the long-term treatment of schizophrenia(Kishimoto et al. 2011) and showed that SGAs,when grouped together, were significantly superiorto FGAs with regard to relapse prevention. No studyshowed a superiority of the FGA comparator and

this meta-analysis does not allow a conclusive com-parison among SGAs (Kishimoto et al. 2011). How-ever, the authors discuss the results concerning thequestions of whether SGAs form a meaningful groupand whether mid- or low-potency FGAs differ fromhaloperidol (Kishimoto et al. 2011).

A recent analysis of mid- and long-term outcomedata of newer antipsychotics discusses some advan-tages of SGAs in the long-term and maintenancetreatment of schizophrenia (Glick et al. 2011). Theauthors highlight the problems of the comparability

could be found with respect to rating scale measuresof symptom severity. However, patients receivingclozapine remitted significantly faster and remainedin remission longer than patients receiving chlorpro-mazine (Lieberman et al. 2003).

In various parts of the CATIE study (except fromPart 3; for details see Part 1 of these guidelines)

(Lieberman et al. 2005; Essock et al. 2006; Stroupet al. 2006, 2007) some evidence was found to sug-gest that olanzapine might be superior to the FGAperphenanzine, as well as to other SGAs, in themaintenance treatment of schizophrenia. The CUt-LASS study (for details see Part 1 of these guide-lines), with a follow-up until week 52, indicated nodifference between a group of SGAs and a group ofFGAs (preferentially sulpiride) in the long-termtreatment of schizophrenia (Jones et al. 2006). How-ever, both studies have important methodologicalrestrictions which have been discussed in the firstpart of these updated guidelines and elsewhere(Naber and Lambert 2009; Moller 2008).

One prospective observational trial with 374schizophrenia/schizoaffective patients and an obser-vation period of 24 months showed that olanzapine(mean daily dose 15 mg) has some superiority com-pared to risperidone (mean daily dose 4.9 mg) andquetiapine (mean daily dose 588 mg) with regard tothe primary outcome measure (rehospitalisation ofpatients after discharge from index hospitalisation)(Kilian et al. 2012). However, the quetiapine groupneeded higher chlorpromazine equivalent doses toshow similar effects compared to the other treatment

groups (Kilian et al. 2012).The EUFEST study (Kahn et al. 2008) was con-ducted on first-episode schizophrenia patients andcompared haloperidol with four different SGAs(amisulpride, olanzapine, quetiapine, ziprasidone)with regard to the primary outcome measure treat-ment discontinuation. Treatment discontinuation forany reason was significantly higher in patients treatedwith haloperidol. Treatment discontinuation as aconsequence of insufficient efficacy was also higherin the haloperidol group, but the difference betweenhaloperidol and quetiapine was not significant (Kahnet al. 2008).

In the SOHO study (observational and non-randomized), SGAs led to lower discontinuationrates and more remissions than FGAs and subjectsreported increased subjective wellbeing followingtreatment with SGAs (Lambert et al. 2006; Haroet al. 2007).

In a 2003 published meta-analysis of randomisedshort-term efficacy trials comparing SGAs andFGAs, and comparing between different SGAs,effect sizes of clozapine, amisulpride, risperidoneand olanzapine were found to be greater than those


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reduced incidence of tardive dyskinesia and othermotor side effects (Moller 2008; Naber and Lambert2009). In the CATIE study patients with tardive dys-kinesia were excluded from the FGA arm (selectionbias) and in the CUtLASS study the most frequentlychosen FGA was sulpiride. Sulpiride is an atypicalFGA and can be considered as an SGA. Further-

more, neither of these studies used haloperidol, themostly prescribed FGA in most developed countries,as comparator (Naber and Lambert 2009). The find-ings of the large European first-episode study(EUFEST) confirm that treatment with haloperidolmight lead to significantly more motor side effectsand a significantly higher study discontinuation rate(Kahn et al. 2008).

Keeping these conflicting points of view in mind,an evidence-based long-term treatment for schizo-phrenia should be based on an individually tailoredmedication strategy with special attention to tardivedyskinesia and metabolic side effects.

Summary statements

Antipsychotics (FGAs and SGAs) are effec-tive in relapse prevention and shouldbe offered to a patient suffering fromschizophrenia (Category of evidence A,Recommendation grade 1).

FGAs and SGAs do not show generaldifferences in reducing symptoms with longterm treatment (Category of evidence A,

Recommendation grade 1).Some evidence is available to supportsuperiority of certain SGAs (as outlined inthese guidelines) with regard to treatmentdiscontinuation and relapse prevention(Category of Evidence B, Recommendation

grade 3).

The reduced risk of inducing motor sideeffects (especially tardive dyskinesia) mightfavour certain SGAs (Category of evidence C,Recommendation grade 4).

In the long-term treatment, where the second-ary negative symptoms become less promi-

nent, certain SGAs may have some advantagesin reducing negative symptoms (Category ofevidence C, Recommendation grade 4).

For long-term therapy, tardive dyskinesiaand metabolic side effects seem tohave thegreatest impact on the patients wellbeingand healththese side effects, among others(see Part 1 of these guidelines), need tobe monitored continuously and treated assoon as possible (Category of evidence C,Recommendation grade 4).

of different antipsychotics and that during the main-tenance treatment patients and the relatives focus onother issues (e.g., relief from disabling symptoms,gaining works, building up relationships) thanduring the acute treatment (Glick et al. 2011). Fur-thermore, a consensus paper published by the Euro-pean college of neuropsychopharmacology (ECNP)

states that in controlled long-term studies, where thesecondary negative symptoms become less promi-nent, certain SGAs may have some advantages inreducing negative symptoms (Montgomery and vanZwieten-Boot 2007). Please see Part 1 of theseguidelines for a detailed and evidence-based discus-sion of the treatment of primary and secondarynegative symptoms.

Another important aspect for the maintenancetreatment of schizophrenia is the treatment of sui-cidality and there is some evidence that certainantipsychotics are superior to others in reducing sui-cidal behaviour in schizophrenia (Meltzer et al. 2003;Crocq et al. 2010). This important topic will bediscussed in the third part of these guidelines.

In accordance to the acute treatment of schizo-phrenia, long-term treatment recommendations needto address the question of side effects. For long-termtreatment, the risk of inducing tardive dyskinesia islower following treatment with SGAs (Kasper et al.2006; Naber and Lambert 2009; Leucht et al.2011b). The metabolic side effect profile of certainantipsychotics (see Part 1 of these guidelines) shouldnot be underestimated and long-term studiesspecifically addressing this question are lacking.

However, increasing rates of cardiovascular diseasesas consequences of metabolic syndrome are one ofmain reasons for excess mortality in schizophreniapatients and, therefore, special attention must bepaid to these side effects (Newcomer 2007; Laursenet al. 2009; De Hert et al. 2009, 2011a).

Therefore, maintenance treatment should followthe basic rules of acute treatment: an antipsychoticmaintenance therapy should be balanced betweenefficacy, compliance, the patients individual sideeffect profile and the patients experience with cer-tain antipsychotics.

The risk of developing tardive dyskinesia following

treatment with FGAs is well-established, but long-term complications following treatment with certainSGAs are still not fully understood. Current studiescannot negate a risk for developing metabolic syn-drome, diabetes and coronary heart disease associ-ated with long-term treatment with certain SGAs(see Part 1 of these guidelines).

Even after the results of the CATIE and CUt-LASS studies, the risk of tardive dyskinesia shouldnot be underestimated because the widely discussedlimitations of these two studies may have led to a


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12 A. Hasan et al.

A number of studies have investigated treatmentregimens where markedly lower dosages of FGAs(oral and depot formulations) were used in mainte-nance therapy than during acute treatment. Theresults showed that, compared with continuous ther-apy, relapse rates increased in most studies, espe-cially in low-dose studies (e.g., reduction of 2550%

of the standard dose (Johnson et al. 1987; Schooleret al. 1997)), but were within acceptable limits (Kaneet al. 1982, 1983; Marder et al. 1984; Hogarty et al.1988; Johnson et al. 1987; Dixon et al. 1995; Schooleret al. 1997).

However, the lower dosages were associated witha more favourable side effect profile and better com-pliance. Other studies have shown that high mainte-nance doses (e.g., more than 600 mg CPZ equivalentsfor FGAs) are not superior to lower dosages, and onestudy demonstrated that dosages below 375 mg/dayCPZ equivalents are suitable for relapse prevention(Bollini et al. 1994).

In one recently published, well-designed clinicaltrial, dosage reduction of risperidone during main-tenance treatment resulted in significantly morerelapses than continuation with the initial stabilisa-tion dose (Wang et al. 2010). As described above,there is a need for more studies aimed at ascertainingthe optimal dose for maintenance therapy (especiallywith SGAs).

Taking the balance of relapse prevention and sideeffects into consideration, maintenance therapyshould be designed in accordance with the stabilisa-tion dose as long as there is a good control of relapse

and no serious side effects (see Table IV) (Categoryof Evidence C, Recommendation grade 4)for at least 1year (details for first-episode and multiple episodepatients see below).

Duration of long-term treatment

Schizophrenia is a chronic disease with a recurrentdisease course in the majority of cases. Therefore, themain targets of long-term and maintenance treat-ments are relapse prevention. The length of adequatetreatment duration remains unresolved and different

definitions of relapse across studies make the com-parability of results difficult. Placebo-controlledRCTs and discontinuation studies have clearlyshown that antipsychotics (FGAs and SGAs) arehighly effective in relapse prevention (see above).

First-episode schizophrenia patients may requiremaintenance therapy of a shorter duration thanmulti-episode patients. According to Leucht and col-leagues (2010), study durations in first-episodepatients are restricted to 2 years and there is evi-dence that antipsychotic withdrawal in such a patient

The choice of the antipsychotic should beinfluenced by the same criteria recom-mended for starting a treatment (GoodClinical Practice).

Maintenance treatment should be carriedforward with the antipsychotic drug whichled to the best response and which had the

best individual side effect profile during theacute episode(Good Clinical Practice).Each antipsychotic selection proceduremust be undertaken individually, respectingthe patients experience with certain drugclasses and the individual side effectprofile.

As discussed in these guidelines and in otherpublications, FGAs and SGAs are not two totallyindependent drug classes and today it is sometimesnot possible to clearly categorize an antipsychoticinto one particular class. Most antipsychotic agents,

as long as carefully prescribed, do have their placein the maintenance therapy of schizophrenia. Antip-sychotic agents with clear disadvantages, intolerableside effects and with no evidence-based data forefficacy have been described in Part 1 of theseguidelines. These drugs should be avoided.

Dosages for long-term treatment

Discussions concerning the adequate dosages forlong-term maintenance treatment have been contro-versial and evidence from dose reduction studies

remains insufficient. The general statement acrossguidelines is that, if a first-episode patient hasimproved with a particular medication regimen, con-tinuation of that regimen with monitoring are rec-ommended, if possible, for at least 6 months in thestabilisation phase, and at least 12 years when alowered dose is administered (Lehman et al. 2004;DGPPN 2006; Falkai et al. 2006). Premature lower-ing of dose may lead to a recurrence of symptomsand relapse. However, some authors discuss thisstatement controversially (Takeuchi et al. 2012) andthere is a need for further studies investigating thequestion of dosages and dosage-reduction for long-

term treatment.In general, first-episode patients do need lower

maintenance dosages than multi-episode patients(Category of Evidence C, Recommendation grade 4),but the reader should be aware that the empiricalbasis for this recommendation is still sparse. Thisrecommendation is based on the observations thatfirst-episode patients are more vulnerable to devel-oping side effects and require a lower dosage to showa response to antipsychotic treatment (see Part 1 ofthese guidelines).


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and their families to discontinue antipsychoticmedication after patients recover from an episode of

schizophrenia but, as discussed above, studies indi-cate that the rate of relapse after an acute psychoticepisode is relatively high. Given the fact that thereare no reliable predictors of prognosis or drugresponse, pharmacological relapse prevention shouldbe considered for every patient diagnosed withschizophrenia. Possible exceptions are individualswith very brief psychotic episodes without negativepsychosocial consequences, and the uncommonpatient for whom all available antipsychotics pose asignificant health risk (Fleischhacker and Hummer1997; NICE 2002; 2010).

Summary statements

Recommendations for treatment durations in schizo-phrenia do not have a strong empirical basis andfurther studies are needed to provide better evidence-based recommendations. Most recommendationsare based on small studies, experts opinions andclinical experience. However, there is a high risk ofrelapse if patients stop their medication during thefirst 12 years following acute psychosis.

group leads to significantly more relapses comparedto when medication is continued (Kane et al. 1982;

Crow et al. 1986; Hogarty and Ulrich 1998; Chenet al. 2010). Chronically ill patients who had beenstable for years, but stopped their medications,experienced significantly more relapses than patientswho stayed on their antipsychotics (Johnson 1976;Cheung 1981; Odejide and Aderounmu 1982;Sampath et al. 1992; Leucht et al. 2011b). Further-more, a vast majority of patients who do not undergoany form of antipsychotic therapy experience arelapse within 35 years. Therefore, continuousantipsychotic treatment for patients suffering frommulti-episode schizophrenia has been recommendedby various publications (Kissling 1991; DGPPN

2006; Falkai et al. 2006). Up to 20% of individualswill only experience a single episode, while a similaror even higher percentage will experience a relapsedespite continued antipsychotic drug treatment(Mller and van Zerssen 1995; Robinson et al. 1999;Moller 2004; Falkai et al. 2006). An observationalstudy in outpatients with schizophrenia in 10European countries revealed a constant relapserate throughout the observation period, indicating adisease-dependent relapse rate (Haro et al. 2007).Psychiatrists may experience pressure from patients

Table IV. Recommended dosage (orally) of selected antipsychotics in long-term treatment.

AntipsychoticStarting dose

(mg/day) DI1Target dose first-episode

(mg/day)Target dose multi-episode

(mg/day)Maximal dosage

(mg/day)2

SGAAmisulpride 200 (1)2 100300 400800 1200Asenapine3 5 1 510 520 20Aripiprazole 515 1 15(30) 1530 30Clozapine4 25 2(4) 100250 300800 900Iloperidone3 12 2 416 424 32Lurasidone3 2040 1 4080 40120 120Olanzapine 510 1 515 520 20Paliperidone3 36 1 39 312 12Quetiapine IR/XRSertindole

504

2/11

3006001220

4007501224

75024

Risperidone 12 12 14 310 16Ziprasidone 40 2 4080 80160 160Zotepine 2550 2(4) 50150 100250 450FGAChlorpromazine 50150 24 300500 3001000 1000Fluphenazine 0.410 23 2.410 1020 20(40)Flupenthixol 210 13 210 1020 60Haloperidol 110 (1)2 14 315 100

Perazine 50150 12 100300 200600 1000Perphenazine 424 13 636 1242 56Pimozide 14 2 14 212 16Zuclopenthixol 250 13 210 2550 75

1DI (dose intervals): recommended distribution of the daily dose one 1, twice2, etc.2Maximal approved dosage in many countries (approved by national committees, these dosages may vary between different countries).In clinical practice some FGAs and SGAs are even dosed higher without sufficient evidence. This is especially the case during a long-termtreatment. 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.


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14 A. Hasan et al.

severe symptoms, such as tension and nervousness,eating less, difficulty concentrating and remember-ing, trouble in sleeping, and depression, and it mayalso include mild psychotic symptoms and idiosyn-cratic behaviours. Such changes preceding relapseindicate either the emergence of new symptoms orincreases in symptoms that were already present at

baseline. In addition to these symptoms, changes inobservable behaviours are noted by some patientsand families. Examples include social withdrawal,wearing makeup in excessive or bizarre ways, andloss of concern for ones appearance (APA 1997).

Controlled studies have demonstrated that spe-cific programmes designed to educate patients andfamilies about prodromal symptoms and earlyintervention when symptoms occur can be helpfulin reducing relapse rates (APA 1997; Lehman et al.2004) (Category of evidence B, Recommendation

grade 3). One aspect of early intervention may alsobe to reinstall pharmacological treatment if it hadbeen previously withdrawn, or to increase the doseof the antipsychotic currently being administered.The use of benzodiazepines may be helpful inreducing the anxiety and tension often associatedwith the start of a relapse (Carpenter et al. 1999;Lehman et al. 2004) (Category of evidence C, Recom-mendation grade 4).

Long-acting depot medication

(see Recommendation Table I)

Poor and partial adherence to oral antipsychotictreatment occurs in more than 40% of patients(Cramer and Rosenheck 1998) and is a major prob-lem associated with the long-term management ofschizophrenia. A direct relationship between partialmedication adherence and hospitalisation risk has

A continuous antipsychotic for at least oneyear for first-episode patients is recommended(Category of evidence C, Recommendation

grade 4).For multiple-episode patients, maintenancetreatment duration of at least 25 years(in severe cases life-long treatment) should

be taken into consideration (Category ofevidence C, Recommendation grade 4).Nevertheless, the duration of treatmentshould be determined on an individual basis,taking into account the patients motivation,the psychosocial situation and the additionalcare being given. Indefinite continuation ofantipsychotic medications is recommendedfor patients with a history of serious suicideattempts or violent, aggressive behaviourand very frequent relapses (Category ofevidence C, Recommendation grade 4).

Treatment strategies (continuous treatment vs.

intermittent treatment)

Intermittent dosing therapy with neuroleptic agentsand incremental dose reductions until discontinua-tion (tapering off), careful observation and earlyrepeated dose increases at the first signs of diseasewere shown to be inferior to continued treatmentas they result in a higher frequency of relapse andhospital admissions in first-episode and multiple-episode schizophrenia patients (Schooler 1993;Schooler et al. 1997; Wunderink et al. 2007; Gaebel

et al. 2002, 2011; Takeuchi et al. 2012).Therefore, continuous antipsychotic treatment

for relapse prevention is strongly recommended(Category of evidence A, Recommendation grade 1)and intermittent strategies should be avoided. Thelatter might only be appropriate for individuals withschizophrenia who are unwilling to accept a con-tinuous maintenance regimen or if there are con-traindications for continuous maintenance therapy(NICE 2010). Furthermore, intermittent dosingtherapy requires early intervention strategies.

Early intervention

This part has been adopted from the first version ofthese guidelines and updated where necessary. Earlyintervention when prodromal symptoms appear canbe effective in preventing relapse and rehospitalisa-tion, and is part of psychiatric management. Studieshave shown that relapse is usually preceded by theappearance of prodromal symptoms, which may lasta few days, several weeks, or longer. The prodromalphase of relapse usually consists of moderate to

Recommendation Table I. Recommendations for the antipsychotictreatment of schizophrenia patients with long-acting injectables.

Depot antipsychotic Category of evidencea Recommendationb

FGAs A 1Risperidone A 1Paliperidone A 1Olanzapine (A)/B (2)/31

aCategory of evidence: Category of evidence where Afullevidence from controlled studies (see Table I).bSafety ratingrecommendation grade derived from categoriesof evidence and additional aspects of safety, tolerability, andinteraction potential.1Olanzapine pamoate was recently launched and it is associatedwith the postinjection delirium sedation syndrome. Furthermore,we could not identify a comparator study between olanzapinepamoate and another depot antipsychotic. For these reasons, thehighest category of evidence cannot currently be stated (see maintext for details).


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France, whereas in other countries (e.g., UK andAustralia) the long-acting antipsychotics are usedfrequently (Patel et al. 2009; Leucht et al. 2011a).

First-generation depot antipsychotics

Studies comparing the antipsychotic depot withplacebo are very rare. Most reliable data are avail-able from meta-analyses, which raise certain meth-odological problems (Leucht et al. 2009c). Studiescomparing depot medication against placebo couldonly be identified for bromperidol, fluphenazine,fluspirilene and haloperidol. From one Cochranereview, there is limited evidence that bromperidoldecanoate is superior to placebo, but not superiorto fluphenazine or haloperidol depot (Purgato andAdams 2011). For haloperidol decanoate, onlysparse data exists, but there is suggestion that itmay improve symptoms in schizophrenia signifi-cantly better than placebo and there are no cleardifferences between the oral and the depot formu-lation (Quaraishi et al. 1999). Depot fluphenazine(decanoate or enanthate) has been studied exten-sively and a Cochrane Review included a total of70 studies. This meta-analysis indicated that flu-phenazine depot is superior to placebo with regardto long-term relapse rates, but failed to show thissuperiority in medium-term studies (6 months to1 year). Furthermore, fluphenazine decanoateseems to be superior to fluphenazine enanthate,but no clear differences between the depot and oral

forms of fluphenazine could be detected (Davidet al. 2005). In one trial, fluspirilene failed to showsuperiority over placebo, but a meta-analysisincluding 12 RCTs indicated that fluspirilene isnot inferior to other depot antipsychotics (Abhijn-han et al. 2007). However, the evidence for otherFGA depot formulations is assumed because theiroral forms displayed sufficient effectiveness in pre-venting relapse. A systematic meta-review for depotantipsychotics discussed the problem of testingdepot antipsychotics versus placebo because of theavailability of effective treatment regimes (Adamset al. 2001). However, the limited data indicate

that depot antipsychotics are effective in prevent-ing relapse in schizophrenia, and this finding issupported from a magnitude of studies testing onedepot antipsychotic against another. According tothis meta-review, only a slight advantage of depotmedication over oral medication could be con-cluded with weak evidence. Furthermore, no clearadvantages of one depot over another could befound (Adams et al. 2001). This is in line with thefindings of the Cochrane Reviews, but contrary tothe findings of an early meta-analysis discussing a

been demonstrated (Weiden et al. 2004). The devel-opment of long-acting depot antipsychotics hasprovided an important option, especially in themanagement of partial nonadherence. Since the ini-tial draft of these guidelines in 2006 and in additionto the first long-acting SGA risperidone, two newlong-acting antipsychotics have been launched onto

the market (paliperidone palmitate and olanzapinepamoate) and some new studies and meta-analyseshave been conducted.

Long-acting depot antipsychotics mostly consistof an ester of the antipsychotic agent in an oily solu-tion which has to be administered by deep intramus-cular injection. Following injection, the drug is slowlyreleased from the injection site (an exception is ris-peridone). This results in relatively stable plasmadrug levels over long periods, allowing the injectionsto be given every 24 weeks. The advantages of long-acting depot antipsychotics have to be balancedagainst some disadvantages. The following list hasbeen adopted and modified from a publication byNasrallah (2007) as well as the 2006 version of theseguidelines.

Advantages of long-acting antipsychotics:

Improved complianceLess need to remind patients to take theirmedicationLowest effective dose principle more safelyachieved (step-wise reduction)Avoidance of gastrointestinal absorption

problemsCircumvention of liver first-pass metabolismReduced risk of accidental or deliberateoverdose

Disadvantages of long-acting antipsychotics:

Diminished flexibility of administrationAdjustment to the optimal dosage is aprotracted and uncertain processDelayed disappearance of distressing sideeffects after discontinuation of medication

Occasional local tissue reactions at the site of the injection (risk of pain, oedema, pru-ritis, sometimes a palpable mass).

Nevertheless, some patients already receiving depotantipsychotics prefer this method of applicationbecause they consider depot antipsychotics to bemore convenient compared to oral antipsychotics(Walburn et al. 2001).

Although effective in improving treatment adher-ence and reducing relapse rates, these drugs arerarely prescribed in some countries like, US or


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16 A. Hasan et al.

scale (Kane et al. 2003). This finding is supportedby the results of two other 12-week, double-blindplacebo-controlled studies, that demonstrated thesuperiority of long-acting risperidone with regard topsychopathology and treatment response comparedto placebo (Ciliberto et al. 2005; Lauriello et al.2005).

In two studies (Harrison and Goa 2004; Chueet al. 2005), no differences between oral risperidoneand risperidone microspheres could be detected interms of efficacy, whereas one 12-week RCT showedthat risperidone given in the form of a long-actinginjection was superior to oral risperidone with regardto the PANSS positive subscore and side effects, butnot with respect to other PANSS scores (Bai et al.2006).

In the open-label phase III of the CATIE study,no difference in efficacy between various SGAs,perphenazine, fluphenazine and risperidone, givenin a long-acting injectable form, could be found(Stroup et al. 2009). Furthermore, long-actinginjectable risperidone (2550 mg) was not shown tobe superior to oral olanzapine (520 mg) after13 weeks of treatment and after a 12-month followup (618 patients randomised and treated and347 patients completed the trial) (Keks et al. 2007).In the first published naturalistic long-term 2-year-prospective study (e-STAR), a risperidone long-acting injection was found to be superior to an oralSGA (risperidone or olanzapine) in terms of Clini-cal Global Impression Severity and the number ofhospitalizations (Olivares et al. 2009). A long-term

2-year open-label study evaluated the switch fromstable treatment with oral risperidone, olanzapine,or conventional neuroleptics to long-acting inject-able risperidone or to oral quetiapine. KaplanMeier estimates showed that the time until relapsewas significantly longer for patients treated withlong-action injectable risperidone compared topatients treated with oral quetiapine (Gaebel et al.2010). However, in unstable patients, defined asthose having been hospitalised within the previous2 years or having an imminent risk for hospitalisa-tion, other results have been reported. This wastested in a large, recently published randomized

study from the Veterans Affairs Clinical Centre(Rosenheck et al. 2011). Unstable patients wereeither treated with long-acting injectable risperi-done every 2 weeks or with a psychiatrists choiceof an oral antipsychotic. The analyses revealed thatthe relapse rate after randomization was not sig-nificantly lower among patients who received long-acting injectable risperidone than among those whoreceived oral antipsychotics, but that patients treatedwith the depot had more adverse effects at the injec-tion site and more motor side effects (Rosenheck

superiority of depot formulations by assuringadherence (Davis et al. 1994).

Across the literature there has been discussionabout whether the inclusion of inpatients and theshort duration of trials might have reduced theadvantages of depot medication (Leucht et al. 2011a).Therefore, one recently published meta-analysis (10

RCTs) focused on long-term (1 year) RCTs com-paring depot (8 first-generation depots, two second-generation depots) versus oral formulations inoutpatient settings (Leucht et al. 2011a). In thisanalysis, depot antipsychotics were superior to oralantipsychotics with regard to relapse, but not torehospitalisation due to psychopathology, dropoutrates and non-adherence (Leucht et al. 2011a).Finally, the recent PORT guidelines recommend theuse of haloperidol decanoate and fluphenazinedecanoate for the maintenance treatment of schizo-phrenia (Buchanan et al. 2010).

Summary statement

Currently, there is good evidence to supportthe use of FGA depot antipsychoticsfor relapse prevention in schizophrenia(Category of evidence A, Recommendation

grade 1),but no clear difference in efficacybetween oral and depot formulations can bestated(Category of evidence A, Recommendation

grade 1).

Second-generation depot antipsychotics

In 2006, long-acting risperidone was the only SGAdepot formulation. At the time of development ofthese guidelines, three different SGA depot formula-tions were available: risperidone microspheres, pali-peridone palmitate and olanzapine pamoate.

Risperidone microspheres (risperidone depot)

The preparation consists of an aqueous suspensionof microspheres comprising risperidone and a bio-

degradable copolymer, and the injection interval is2 weeks. However, before applying the depot alone,there is a need for oral supplementation of oral ris-peridone for the first 3 weeks. With this mechanism,significant release of risperidone starts 3 weeks afterthe first injection, and is followed by gradual andsustained release for 46 weeks following the firstinjection (Harrison and Goa 2004). In a 12-weekmulticentre, double-blind RCT study, long-actingrisperidone was superior compared to placebo withregard to psychopathology according to the PANSS


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schizophrenia patients and elderly patientssuffering from schizophrenia (Category ofevidence B, Recommendation grade 3).

There is no evidence to support the com-bination of galantamine and risperidonedepot for the treatment of cognitive symptomsin schizophrenia(Category of evidence E).

Paliperidone palmitate (paliperidone depot)

Paliperidone palmitate is the depot formulation oforal paliperidone. It has low water solubility and dif-fuses slowly into systemic circulation following injec-tion. Treatment with paliperidone palmitate doesnot require oral supplementation during the initia-tion of treatment (Hough et al. 2009). It wasapproved by the FDA according to the results offour short-term (913 weeks) studies comparingpaliperidone palmitate with placebo (20% intralipid200 mg/ml injectable) (Citrome 2010). These firststudies, showed that paliperidone palmitate is effec-tive in the treatment of schizophrenia in differentsymptom domains (Citrome 2010). In a recentlypublished RCT, patients suffering from schizophre-nia were either randomised to placebo injection, toan injection of 50 mg paliperidone palmitate or to100 mg paliperidone palmitate on days 1, 8 and 36(Kramer et al. 2010). Both dosages were superior toplacebo with regard to reduction of total PANSSscores, CGI scores and the factor study discon-tinuation. Furthermore, paliperidone palmitate

was well-tolerated and did not cause more motorside effects (whereas the percentage of patientsreceiving medication against motor side effects washigher in the 100-mg group), but did cause signifi-cantly more weight gain than placebo (Kramer et al.2010). In another study, schizophrenia patients wereswitched from a stable antipsychotic treatment topaliperidone palmitate in a 9-week, open-label phase.Patients then received two intramuscular injectionsof paliperidone palmitate (50mg) one-week apart,followed by subsequent injections (25, 50 or 100mgin a flexible-dose scheme) once monthly. Next, sta-ble patients were either randomized to paliperidone

palmitate (at the stabilized dose) or to placebo in adouble-blind study phase. Paliperidone palmitatewas superior to placebo, both in a planned interimanalysis and in the final analysis, with regard to theprimary endpoint time-to-relapse (Hough et al.2010). A 13-week, double-blind study with 388schizophrenia patients compared three differentdosages of paliperidone palmitate (50, 100, 150 mg)with placebo. In this study, only 100 mg paliperi-done palmitate showed a significant effect on thereduction of PANSS scores (Gopal et al. 2010b).

et al. 2011). One study based on observational datafrom the Cohort for the General study of Schizo-phrenia (CGS) showed that long-acting risperidonewas especially prescribed in younger and more fre-quently hospitalised patients (regardless of diseaseseverity). However, even after correction for thesefactors, long-acting risperidone was associated with

a significant lower risk for hospitalisation comparedto other treatment options (non-use or other depotformulations or oral formulation of FGAs or SGAs)(Grimaldi-Bensouda et al. 2011).

Three studies with long-acting injectable risperi-done have been conducted in special groups ofschizophrenia patients: (1) first-episode schizophre-nia patients; (2) elderly patients suffering fromschizophrenia; (3) schizophrenia patients with con-comitant drug abuse.

In first-episode schizophrenia patients, long-actinginjectable risperidone was well tolerated and led tomore treatment adherence than oral risperidone in aprospective RCT (Weiden et al. 2009). Another long-term 2-year open-label study with first-episodeschizophrenia patients revealed that 64% of thepatients achieved remission and that 97% of thepatients maintained this status until study comple-tion (Emsley et al. 2008). A publication includingsubjects who participated in a foregoing 12-weeksstudy showed that long-acting injectable risperidoneis safe and well tolerated after 12 months of treat-ment in schizophrenia patients (Lindenmayer et al.2007), and safety has also been demonstrated inelderly patients (65 years) (Kissling et al. 2007). In

a subsample of schizophrenia patients with comorbidsubstance abuse, long-acting risperidone was supe-rior to zuclopenthixol-depot in an open, randomized,controlled 6-month study (Rubio et al. 2006).

Finally, a 52-week double-blind, randomized studyshowed that the combination of galantamine andlong-acting injectable risperidone was not superiorto the combination of placebo and risperidone depotin terms of the improvement in different cognitivedomains (Lindenmayer and Khan 2011).

Summary statementsThere is good evidence to support the useof long-acting injectable risperidone forthe treatment of schizophrenia(Category ofevidence A, Recommendation grade 1).

There is some evidence to support asuperiority of the depot compared to theoral preparation (Category of evidence C,Recommendation grade 4).

There is some evidence for the use of long-acting injectable risperidone in first-episode


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18 A. Hasan et al.

Olanzapine pamoate (olanzapine depot)

This depot formulation consists of a crystalline salt-formulation composed of olanzapine and pamoic acid(pamoate) (Citrome 2009). In an 8-week, double-blind study, schizophrenia patients were randomlyassigned to receive 210 mg/2 weeks, 300 mg/2 weeks,

or 405 mg/4 weeks of long-term injectable olanzap-ine or placebo/2 weeks. No other concomitant oralantipsychotic treatment was permitted (Laurielloet al. 2008). After 3 days, the high dosages weresuperior to placebo with regard to reduction ofPANSS scores, and this superiority was reached forall three dosages after 1 week of treatment. However,olanzapine pamoate led to more sedation and weightgain than placebo (Lauriello et al. 2008). In a24-week double-blind study, schizophrenia patientswho were stable on an oral olanzapine treatment (10,15, or 20 mg/day) were randomised to treatmentwith one of three different dosages of long-term

injectable olanzapine (150 mg/2 weeks, 405 mg/4 weeks, 300 mg/2 weeks), to a low reference doseof the depot (45 mg/ 4 weeks), or to their stabilisa-tion dose of oral olanzapine (Kane et al. 2010).Analyses showed that the majority of oral olanzapine-treated patients (93%), as well as most olanzapinelong-acting injection-treated patients receiving high(95%), medium (90%), low (84%), and very lowdoses (69%), remained exacerbation free, with thetherapeutic 4-week regimen (medium dose) andpooled 2-week regimen (low and high doses) dem-onstrating efficacy similar to that of oral olanzapineas well as to each other (Kane et al. 2010). Thestandard doses were superior to the very low doses,and metabolic side effects increased with increasingdosages of olanzapine (Kane et al. 2010).

Postinjection delirium sedation syndrome (PDSS)

A rare, but potential harmful, side effect was observedduring the clinical trials with the long-acting olan-zapine injection. The postinjection delirium sedationsyndrome (PDSS) is mainly characterized by symp-toms associated with olanzapine overdose. Thissymptom cluster includes dizziness, confusion, dis-

orientation, slurred speech, altered gait, weakness,muscle spasms, possible seizure, and varying degreesof sedation (Detke et al. 2010). However, othersymptoms of an olanzapine overdose, like hypoten-sion or respiratory depression, have not been reportedafter injection of the olanzapine depot (Detke et al.2010). It should be noted that the PDSS can occurafter any injection regardless how many prioruneventful injections the patient may have had(Citrome 2009). The risk for PDSS is greatest withinthe first hour after injection (1 in 1000 injections),

Another 13-week study with a comparable design(25, 100, 150 mg paliperidone palmitate vs. pla-cebo) showed a superiority for reducing PANSSscore in all treatment groups compared to placeboin a sample of acutely exacerbated schizophreniapatients (Pandina et al. 2010). One further 13-weekstudy compared 25, 50 and 100 mg paliperidone

palmitate with placebo and showed a significantimprovement in all treatment groups compared toplacebo (Nasrallah et al. 2010). The first open-labeldouble-blind 1-year long-term study (extension ofthe double-blind study by Hough and colleagues(2010)) investigated a flexible dose of paliperidonepalmitate (Gopal et al. 2011). In this study, psycho-pathology improved during the open-label extensionand 100 mg paliperidone palmitate was adminis-tered most frequently (Gopal et al. 2011). However,the authors did not compare relapse rates across thedifferent dosages of paliperidone palmitate.

Comparative studies (one double-blind 13-weekRCT and one open-label study) have shown pali-peridone palmitate not to be inferior to long-terminjectable risperidone, and that both drugs seemto have a related side effect profile (Li et al. 2011;Pandina et al. 2011). A 53-week, Phase III double-blind study in acute symptomatic patients confirmedthere to be no inferiority of paliperidone palmitatecompared to long-term injectable risperidone(Fleischhacker et al. 2011).

A subgroup analysis with severely ill schizophreniapatients (according to CGI) showed paliperidonepalmitate to be superior to placebo by day 4 of treat-

ment (Alphs et al. 2011). A post hoc analysis of a13-week, double-blind placebo-controlled studyindicated that, in patients who received oral risperi-done but who remained symptomatic, paliperidonepalmitate was superior to placebo with regard toimprovements in PANSS total scores, CGI scoresand scores of personal and social performance (Sliwaet al. 2011).

Summary statements

In summary, there is good evidence to sup-

port the use of long-acting injectable pali-peridone for the treatment of schizophrenia(Category of evidence A, Recommendation

grade 1).

There is no evidence that allows us to statea superiority of the depot compared tooral paliperidone (Category of evidence A,Recommendation grade 1).

Paliperidone depot seems to be as effectiveas risperidone depot (Category of evidence

A, Recommendation grade 1).


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Dosages of depot formulations (see Table V)

According to the PORT guidelines, the recom-mended dosage range for fluphenazine decanoate is6.25 mg/2 weeks to 25 mg/2 weeks and, for haloperi-dol decanoate, is 50 mg/4 weeks to 200 mg/4 weeks.These recommendations have been based on both

the findings of Kane and colleagues and an earlyreview by Dixon and colleagues (Dixon et al. 1995;Kane et al. 2002).

One study investigated the equivalent switchingdose from oral risperidone to long-acting risperi-done injection in hospitalized patients. Accordingto the findings of this study, switching doses aresuggested as follows: patients who were originallyon an oral risperidone dose of 3 mg/day shouldreceive 25 mg of long-acting risperidone injection,those taking an oral dose of 35 mg/day shouldreceive 37.5 mg, and those taking an oral dose of5 mg/day should receive 50 mg of long-acting

risperidone injection (Bai et al. 2007). A 1-yeardouble-blind RCT compared 25 and 50 mg oflong-acting risperidone in stable patients sufferingfrom schizophrenia and found a numeric, but nota statistically significant, difference between bothdosages. In total, 2550 mg risperidone micro-spheres were found to be appropriate for the long-term treatment of schizophrenia and schizoaffectivedisorder (Simpson et al. 2006).

Treatment with paliperidone palmitate can beinitiated after discontinuing previous treatmentwith an oral antipsychotic (no oral supplementa-tion is required) or at the next scheduled injection,and monthly thereafter, in patients switching fromanother depot antipsychotic (including long-actinginjectable risperidone) (Gopal et al. 2010a). Pali-peridone palmitate should be initiated with 150 mgat day 1 and then with 100 mg at day 8 (2 days).Both injections should be applied to the samemuscle to reach adequate drug concentrationsquickly. After day 8, paliperidone should be injected

and the risk decreases between hours 1 and 3 (1in 10,000 injections after 3 h (Detke et al. 2010)).After PDSS, the median time to recovery resolvefrom all symptoms is between 24 and 72 h for sevenpatients unconsciousness was reported and the lon-gest period of unconsciousness was 12 h (Detke et al.2010). As olanzapine pamoate has a higher solubility

in blood than in muscle, the possibilities of acciden-tal injections into a blood vessel or accidental entryof olanzapine pamoate directly into the bloodstreamwithout a direct injection into the vessel (injury of ablood vessel during the injection process) have beendiscussed (Citrome 2009; McDonnell et al. 2010).

Therefore, a proper injection technique (aspira-tion of several seconds to ensure that no vessel hasbeen hit, deep intramuscular injection) and observa-tion of the patients for at least three hours by profes-sional healthcare personnel must be strictly adheredto (Citrome 2009; McDonnell et al. 2010). Otherrules of action are described by the manufacturerand by other reviews (Detke et al. 2010; McDonnellet al. 2010).

Summary statements

There is good evidence to support theuse of long-acting injectable olanzapine(Category of evidence (A)/B, Recommenda-

tion grade (2)/3). It should be mentionedthat we were not able to identify a compara-tor study between olanzapine pamoate andanother depot antipsychotic.The postinjection delirium sedation syn-drome needs to be considered as a possiblesevere side effect after every injection.Each injection should follow the rules ofaction described by the manufacturer andafter each injection, a three hour observa-tion period needs to be respected(Categoryof evidence C, Recommendation grade 4).

Table V. Recommended dosages of depot antipsychotic medications in long-term treatment.

Antipsychotic

DI (dose

intervals, weeks)

First-episode

patients (mg)

Multi-episode

patients (mg)

SGARisperidone microspheres 2 25 2550Paliperidone palmitate 4 2575 25150Olanzapine pamoate 24 150210/2 weeks

300405/4 weeks150210/2 weeks300405/4 weeks

FGAFlupentixol decanoate 23 2040 20100Fluphenazine decanoate 24 6.2537.5 12.550Haloperidol decanoate 4 50100 100200Perphenazine decanoate 24 12100 50200Zuclopenthixol decanoate 24 100200 200400


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20 A. Hasan et al.

However, too rapid and too extreme dosage reduc-tion should be avoided.

The reduced risk for tardive dyskinesia followingtreatment with FGAs might favour the use of SGAs,although the risk of developing metabolic and car-diovascular side effects following treatment withsome SGAs needs to be taken into consideration.

Certain SGAs (as described in these guidelines)might be superior in terms of relapse prevention.

The reader should keep in mind that the catego-rization of antipsychotics into FGAs and SGAs(or typical and atypical antipsychotics) does not fol-low any clear neurobiological (apart from a higherD2-binding of FGAs compared to most SGAs)or clinical rules, and that the drug with the bestbalance between efficacy and side effect profile andwhich 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 h

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