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Rev Psiquiatr Salud Ment (Barc.) 2009;2(1):5-28
1888-9891/$ - see front matter 2008 SEP and SEPB. Published by Elsevier Espaa, S.L. All rights reserved.
www.elsevier.es/saludmental
Revista de Psiquiatray Salud Mental
Revista de
Psiquiatray Salud Mental
rgano Ofcialde la SociedadEspaola
de Psiquiatray de la SociedadEspaola
de Psiquiatra Biolgica
www.elsevier.es/saludmental
Volumen 2,Nmero1. Enero-Marzo2009
EDITORIAL
Necesidad deproteger yomentar lasalud sicaen personasconenermedad mentalgrave
ORIGINALES
Comparacin delaefcaciadelasormasarmacuticasdeliberacin
retardada(depot)ylasoralesdelos antipsicticostpicosyatpicoscomercializadosen Espaaparapacientesdiagnosticadosdeesquizorenia
Implicacionesclnicasdelaedad deiniciodeltrastornobipolar I:dossubgruposcon dierentepronstico
Polimorfsmosserotoninrgicoscomopredictoresdelagravedad clnica
deltrastornodepnico
REVISIN
Trastornobipolar:queectotiene elcumplimientoteraputicoen elriesgo
deconductassuicidas?
ARTCULO ESPECIAL
Enermedad cardiovascular y diabetesen personascon enermedad mentalgrave
AGENDA
*Corresponding authorE-mail: jmharo@fsjd.org (J.M. Haro).
ORIGINAL
Comparing the efcacy of ong-acting pharmaceutica forms
(depot) ersus ora forms of the atypica and conentiona
antipsychotics marketed in Spain for treating patients
with schizophrenia
Anna Fernndez Snchez, Aejandra Pinto-Meza and Josep Maria Haro*
Research and Development Unit, Sant Joan de Du-Mental Health Services, Sant Joan de Du Foundation, Barcelona, Spain
Received September 2, 2008; accepted October 13, 2008
KEYWORDSOral antipsychotics;
Schizophrenia;
Systematic review
Astract
Introduction and objectives: Currently in Spain, 4 depot antipsychotics are available:ufenazine, pipotiazine, zuclopentixol and risperidone. The objectives of the presentstudy are: a) to evaluate the efcacy of depot vs. oral forms of typical and atypicalantipsychotics available in Spain for treating patients with schizophrenia; b) to comparethe efcacy of different depot antipsychotics; c) to evaluate cost-effectiveness of typicaland atypical depot and oral antipsychotics.Methods: Systematic review of the literature between January 1980 and March 2007.Pharmaceutical companies of depot preparations were contacted aiming to includeunpublished material.Results: A total of 15 studies were included (13 journal manuscripts and 2 posters providedby the industry). Concordance between evaluators was moderate-high. The quality ofselected studies was moderate-low. There were no differences in the efcacy betweendepot and oral risperidone. Efcacy of depot risperidone was higher than oral olanzapine(there were no differences regarding tolerability) and higher and better tolerated thanoral zuclopentixol. The evidence was controversial when comparing the ef cacy of depotand oral ufenazine. There were no differences when comparing the efcacy betweendepot ufenazine and oral pimozide. Depot zuclopentixol was more ef cient than the oral
preparation for treating patients with schizophrenia and violent behaviour. Finally, therewere no differences regarding the ef cacy and tolerability between depot pipotiazine anddepot ufenazine and between depot clopentixol and depot ufenazine.Conclusions: There is few high-quality scientic evidence comparing depot and oralantipsychotics or different depot antipsychotics available in Spain. Selected evidencedoes not allow to conclude that depot antipsychotics are more effective and bettertolerated than oral ones. 2008 Sociedad Espaola de Psiquiatra and Sociedad Espaola de Psiquiatra Biolgica.Published by Elsevier Espaa, S.L. All rights reserved.
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6 A. Fernndez Snchez et al
Introduction
Schizophrenia is a serious mental illness that generateslarge economic costs due to its chronic nature and canhave a great impact on the patients personality andability to adapt socially.1-5 Approximately one personin every hundred will suffer schizophrenia over their
lifetime, although the greatest incidence is observed inpeople around the age of 20.6 Despite being many factorsinvolved in its treatment, antipsychotic medicationis undoubtedly a key element. Besides reducing thesymptoms of the disorder, antipsychotics are also used asongoing treatment aimed to avoid relapses.7 Schizophrenicpatients who do not take antipsychotics have a relapserate of approximately 10% per month.8,9 If this ratepersists over time, total relapse is a fact after a year.On the other hand, the relapse rate in patients treatedwith antipsychotics is approximately 1.5% per monthfor inpatients and 3 to 4% per month for outpatients.9As the number of relapses and the non-treated periods
increase, the prognosis worsens as do the long termresults. Patients who suffer relapses do not recover theirprevious condition of social adjustment.10
Conventional delayed release antipsychotics (depot)were developed in the 1970s with the intention of improvinglong term treatment of schizophrenia. The main advantageof the depot presentations over oral antipsychotics is that
they facilitate completion of the prescribed treatment.11
Depot antipsychotics assure more predictable plasmaticconcentrations of the active pharmaceutical ingredient,since variability associated with absorption and hepaticbiotransformation are avoided.12 The practitioner also hasincreased control of the handling of the antipsychotic andis therefore in a better position to adjust doses to reachoptimum levels. Another advantage is that if the patientmisses an injection, for whatever reason, there is no abruptinterruption. This makes a relapse less likely.12 Among thedisadvantages of depot antipsychotics is the pain in theinjection area, the patients rejection to puncturing andthe feeling of being controlled.13
PAlAbRAS ClAvEDepot antipsychotics;
Antipsicticos depot;
Antipsicticos orales;
Esquizofrenia;
Revisin sistemtica
Comparacin de a ecacia de as formas farmacuticas de ieracin retardada(depot) y as oraes de os antipsicticos tpicos y atpicos comerciaizados en Espaa
para pacientes diagnosticados de esquizofrenia
Resumen
Introduccin y objetivos: Actualmente en Espaa se comercializan 4 antipsicticos depot:ufenazina, pipotiazina, zuclopentixol y risperidona. Los objetivos del presente estudioson: a) evaluar la e cacia de las formas depot y las orales de los antipsicticos tpicosy atpicos comercializados en Espaa en pacientes diagnosticados de esquizofrenia;b) comparar la e cacia de los diferentes antipsicticos depot, y c) evaluar el coste-efectividad de los antipsicticos tpicos y atpicos depot frente a los orales.Mtodos: Revisin sistemtica de la evidencia entre enero de 1980 y marzo de 2007.Tambin se contact con las empresas farmacuticas que comercializan las formas depotcon el objetivo de incluir los trabajos an no publicados.Resultados: Se incluyeron 15 trabajos (13 artculos publicados y 2 pster facilitados porfarmacuticas). La concordancia entre evaluadores fue moderada-alta. La calidad delos trabajos fue moderada-baja. No hubo diferencias en la ecacia de la risperidonadepot frente a la oral. La risperidona depot sera ms ecaz que la olanzapina oral(pero no habra diferencias respecto de su tolerabilidad) y ms e caz y mejor toleradaque el zuclopentixol oral. La evidencia es contradictoria al comparar la ecacia de la
ufenazina depot y la oral. No habra diferencias en la ecacia de ufenazina depot frentea pimozida oral. El zuclopentixol depot sera ms efectivo que el oral en el tratamientode los pacientes con esquizofrenia y conducta violenta. Finalmente, no se encuentrandiferencias en la ecacia y la tolerabilidad de la pipotiazina depot y la ufenazina depoty entre clopentixol depot y ufenazina depot.Conclusiones: Hay poca evidencia cientca de calidad en que se comparen antipsicticosdepot y orales o diferentes antipsicticos depot entre s comercializados en Espaa. Laevidencia seleccionada no permite concluir que los antipsicticos depot sean superioresa los orales en cuanto a ecacia y tolerabilidad. 2008 Sociedad Espaola de Psiquiatra y Sociedad Espaola de Psiquiatra Biolgica.Publicado por Elsevier Espaa, S.L. Todos los derechos reservados.
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Efcacy of depot antipsychotics versus oral forms marketed in Spain for schizophrenia 7
Despite the widespread acceptance that depotpreparations favour the completion of treatment, the patientcan still suffer relapses even when medication is assuredby the injection. There is a discussion about which depotantipsychotic diminishes relapses and rehospitalisation themost, when compared with the oral antipsychotics.
Second generation or atypical antipsychotics were developedin the 1980s to offer a more effective and tolerable treatmentto schizophrenic patients. These antipsychotics have provento be at least just as effective as the conventional ones forthe treatment of positive symptoms.14 Some studies havealso shown slight improvement in the negative symptoms andsome recovery in cognitive aspects15,16 which could reduce thechances of suicide17 and of substance abuse.18 Furthermore,it has been indicated that the atypical antipsychotics couldhelp to stabilise mood, have sedative properties19 and couldprotect against relapses in greater proportion to typicalantipsychotics.20 Comparatively, atypical antipsychotics aremore expensive than the traditional ones.
At the late 1990s, the rst atypical depot antipsychotic(risperidone) began development and to date, it has been
established that it is just as effective as the oral preparationand well tolerated by schizophrenic patients.21-23
Four depot antipsychotics are currently being marketedin Spain: Modecate (active ingredient: uphenazine),Lonseren (active ingredient: pipotiazine), Clopixol (activeingredient: zuclopenthixol) and Risperdal (active ingredient:risperidone).
The aims of the following systematic review are: a)evaluate the efcacy of the delayed release pharmaceuticaltypes (depot) and the oral types of antipsychotics (typicaland atypical) marketed in Spain for patients diagnosed withschizophrenia; b) compare the effectiveness of the differentdepot antipsychotics sold in Spain in patients diagnosedwith schizophrenia, and c) appraise the cost-efciency ofthe depot types versus the oral pharmaceutical forms ofantipsychotics (typical and atypical) commercialised inSpain in patients diagnosed with schizophrenia.
Method
A systematic review of the literature available wascarried out in the following data bases: MEDLINE (PubMed),PSYCINFO, ISI Web of Knowledge (with a transversal searchin MEDLINE, Current Contents Connect, Web of Science,Zoological Records, BIOSIS Previews, Derwent InnovationsIndex, ISI Proceedings), Cochrane Plus Library (Cochrane
Database of Systematic Reviews, Register of RandomisedClinical Trials, Health Technology Assessment Database [HTA]and NHS Economic Evaluation Database [NHS EED]) andBiological Sciences.
The pharmaceutical companies that market thedepot forms in Spain were also contacted to review anyunpublished papers.
All the literature published from January 1980 and March2007 was reviewed. The search strategy was as follows:(Phenothiazines [MeSH] [Phenothiazine is a MeSH word thatincludes the active ingredient uphenazine. Both terms weresearched to assure that this active ingredient was includedunder both names] OR pipothiazine [substance name]OR
Clopenthixol [MeSH] [Clopenthixol is the MeSH term of theactive ingredient zuclopenthixol] OR Fluphenazine [MeSH]OR Risperidone [MeSH]) AND (Randomized ControlledTrials [MeSH]) AND (Schizophrenia [MeSH]) AND (Delayed-Action Preparations [MeSH] OR depot).
As a sensitivity analysis, the same search was performed,excluding the MESH term randomized controlled trial inorder to avoid excluding articles which were randomisedbut did not include this term as MESH.
As a control measure, a second search was performedunder the supervision of a documentalist from thenancial entity, the Catalan Agency for Health TechnologyAssessment, (AATRM). This search strategy was applied onlyto the PubMed and PSYCINFO databases. After the search,there were no additional studies detected that had notbeen observed in the rst.
Once the search was undertaken and after reading thetitles and the abstracts, three researchers (AF, AP and CB)chose the relevant articles. For this review, the scienticevidence assessment was limited to those articles which:
1. Were randomised clinical trials or cost-efciencyreviews.
2. Compared a depot pharmaceutical format sold in Spainwith any other typical or atypical oral antipsychoticmedication.
3. Included the comparison between different depotmedications sold in Spain. Therefore, articles that, forexample, compared any of the four active ingredientsmarketed in Spain with the active ingredient haloperidolin its depot form or with uphenthixol or perphenazinewere excluded since none of these is approved by theSpanish Agency of Medicine and Healthcare Products(AEMPS).
4. Were written in English, French, Spanish, Italian orPortuguese.
5. Took into account trials on adult patients.6. Contemplated some of the following result gauges: use of
services (hospitalisations, emergency visits), improvementof the symptoms (evaluated through validated PANSS orGCI surveys) or of economic costs. Studies that evaluatedthe quality of life, therapeutic completion or adverseeffects as main assessment criteria were also taken intoconsideration.
As a control measure in the search, the referencesincluded in the systematic reviews collected in the Cochranedatabase were checked manually.
The selected articles were masked (the journal name,authors, institutions and any other identifying features wereremoved) and sent to three experts in methodology andschizophrenia (JMH, VP, JB) who independently evaluatedthe quality of the articles using the Jadad three-pointscale.24 The points were listed with a description of therandomised assignation (rated with 2 points), double-blind(2 points) and data inclusion of treatment abandonmentand discontinued monitoring (1 point).
Besides assessing the quality of the articles, the reviewersalso gathered other data from the articles using a list drawnup by the research team aimed at increasing objectivity,reliability and accuracy. The list included the following:
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8 A. Fernndez Snchez et al
Article reference (number assigned for its identication,as it was masked).
Design type. Sample. Average age. Sex (%). Sample size. Active ingredient, administration method and individual
dosage of each one. Result measurement. Monitoring period. Results (with variability and statistical signicance
indicators). Jadad quality evaluation scale. Remarks.
Each expert reviewer received the material togetherwith a completed example. Consensus was met in the eventof discrepancies between the experts.
Resuts
The rst PubMed search (including the MeSH termrandomized controlled trial) returned 11 articles. Whenthis MeSH term was excluded, the search returned 135matches. Searches in PSYCINFO resulted in 190 documents.Searches in the Cochrane Library returned 130 documentsamong systematic reviews, clinical trials and economicappraisals. The search in the ISI Web of Knowledge recovered175 documents. The Biological Sciences search did notreturn any relevant ndings. Finally, the pharmaceuticalcompanies consulted furnished us with 21 studies presentedat congresses that had not been published to date.
The total number of documents detected was 651. Afterexcluding duplicates from the databases and eliminatingstudies which, from the title or the abstract, did notcomply with the inclusion criteria, a total of 34 documentswere selected that clearly complied with all of the criterianeeded or that required a review of the full text to decide
TABLE 1 Seected studies and assessment of their quaity
Author (year) Format Score on the Jadad
scale (0-5))
Depot versus oral risperidone
Bai et al26 (2006) Article 3
Bai et al27 (2006) Poster study 2
Chue et al28 (2004) Article 4
Depot risperidone versus oral olanzapineRabinowitz et al29 (2006) Poster study 1
Depot versus oral uphenazine
Levine et al30 (1980) Article 3
Schooler et al31 (1980) Article 4
Depot uphenazine versus oral pimozide
McCreadie et al33 (1982) Article 4
McCreadie et al32 (1980) Article 4
Depot versus oral zuclopenthixol
Arango et al25 (2006) Article 2
Depot versus depot
Rubio et al34 (2006) Article. Compares depot zuclopenthixol 3
with depot risperidone
Leong et al35
(1989) Article. Compares depot pipotiazine 2with depot uphenazine
Albert et al36 (1980) Article. Compares depot pipotiazine 3
with depot uphenazine
Walker37 (1983) Article. Compares depot clopenthixol* 3
with depot uphenazine
Cost-efciency studies
De Graeve et al38 (2005) Article. Compares depot risperidone with
oral olanzapine and depot haloperidol
Yang et al39 (2005) Article. Compares depot risperidone
with oral olanzapine and depot haloperidol
*Clopenthixol is a synonym of zuclopenthixol.
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Efcacy of depot antipsychotics versus oral forms marketed in Spain for schizophrenia 9
whether they met the requirements or not. These 34 studieswere sent to the independent expert reviewers.
Of the 34 preselected studies, 15 were included inthis review since they met the inclusion criteria (clinicaltrials or cost-efciency studies and the comparisonscontemplated active ingredients and administration methodscommercialised in Spain). Of these 15 studies, 13 were articlespublished in scientic journals and 2 were papers provided bypharmaceutical companies presented at scientic congressesthat had not yet been published. Of the 13 articles, 11 wererandomised clinical trials and 2 were cost-efciency studies.Table 1 summarises the selected studies and the qualityassessment.
Quaity of the seected studies
Concordance between the expert reviewers resultedmoderately-high; 12 out of 13 clinical trials were evaluatedby 3 experts (the article by Arango et al25 was rated by onlyone as it was included after the shipping of the documentsto the other experts). Out of the 12 evaluated by everyone,
7 obtained the same score on the Jadad scale.Of the 13 clinical trials, 9 exceeded or equalled the
minimum quality score (3 points). The 2 cost-efciencystudies were based on panels of experts and systematicreview of the literature.
Studies comparing depot and ora presentations
Table 2 summarises the detailed evidence collected by thedifferent studies comparing depot and oral antipsychotics.
Depot ersus ora risperidone
Three studies compare depot and oral risperidone. Onewas a poster. The rst study, by Bai et al,26 compared49 inpatients with a diagnosis of schizophrenia accordingto the DSM-IV criteria that were randomised in bothpresentations of risperidone and monitored for 12 weeks.The measure of results is a reduction in symptoms(efciency) and adverse effects (safety) as well as improvedquality of life (tolerability). The authors conclusions arethat, comparing the measurements at the start and end ofthe follow-up, depot risperidone is safer since it reducesthe adverse effects evaluated on the Udvalg for KliniskeUndergolser scale (UKU) (2.12 3.46 versus 0.13 2.17;p = 0.037). The group taking depot risperidone also showeda reduction in prolactin concentrations at 4 weeks (13.4
24.5 versus 6.7 27.9ng/ml; p = 0.009) and 12 weeks (19.3 19.1 versus 3.1 26.6ng/ml; p = 0.001). Patients takingdepot risperidone presented signicant changes in the socialfunctioning items of the SF-36 survey and increased theirscores (7.5 20.1 versus 11 31.1; p = 0.017). No changeswere detected in the remaining SF-36 items. In relationto efciency, patients taking depot risperidone presenteddeterioration in the positive symptoms evaluated with thePositive and Negative Syndrome Scale (PANSS) (0.72 3.52versus 1.24 3.81; p = 0.022). No other differences werenoted in the remaining scales.
The second study, by Bai et al27 was carried out with45 inpatients with a diagnosis of schizophrenia and monitored
for 48 weeks. The working procedure is as described above.These data, presented in the shape of a poster, show thatthe depot risperidone continues displaying a reduction inadverse effects evaluated with the UKU (2.3 versus 0.6;p = 0.002) as well as of the prolactin concentrations (17.4versus 8.8; p < 0.001). By the same token, after 48 weeksof monitoring, the group taking depot risperidone displayeda worsening of the positive symptomatology evaluated withthe PANSS (0.1 versus 1.4; p = 0.039).
The study by Chue et al28 included 640 patients withschizophrenia who, after being stabilised with oralrisperidone, were randomised with the oral or depotpresentations. The result measurements used evaluatedthe symptomatology (efciency) and the adverse effects(safety). It was designed as a non-inferiority trial, in whichthe aim was to nd no differences between the groups. Nodifferences were found between the groups; both displayedan improvement with respect to the baseline measurement.The authors conclude that the change can be made fromoral to depot risperidone since there are no differences inefciency and tolerance. Furthermore, the pain caused by
the injection is perceived as low (18-20 out of 100 on ananalogical scale).
Depot risperidone ersus ora oanzapine
The study by Rabinowitz et al,29 presented as a poster,is a non-inferiority design in which 618 patients diagnosedwith schizophrenia or schizoaffective disorder takingoral olanzapine were randomised with this treatment ordepot risperidone. The result measurements includedsymptomatology (efciency) and adverse effects(tolerability). The authors conclude after 12 months thatthere were more patients in the depot risperidone groupdisplaying a > 20% reduction in symptomatology evaluatedwith the PANSS (odds ratio [OR] = 2.36; 95% condenceinterval [CI], 1.63-3.43). This tendency was maintaineduntil the end of the study (week 53) (OR = 1.46; 95% CI,1.09-1.95). No signicant differences were detected inrespect to adverse effects. The authors concluded that thedepot risperidone was not inferior to the oral olanzapinein the short term.
Depot uphenazine ersus ora uphenazine
The study by Levine et al30 is an article that evaluates67 patients with schizophrenia in which the discontinuationof treatment and its continuation with the oral format or
a placebo are compared. The result measurements arerelapses (efciency) and adverse effects (tolerability). Theauthors conclude that the relapses are more frequent inthe group that discontinues treatment than in the groupcontinuing treatment. On comparing the groups thatcontinue treatment (n = 27), the depot group relapsed lessthan the one that was on oral medication (67.65 versus81.81%). The group taking depot uphenazine presentedless proportion of involuntary movements than the grouptaking oral uphenazine.
The Schooler et al31 study is an article which studies 214randomised participants after a period with oral uphenazine,with oral or depot uphenazine. The result measurements
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Efcacy of depot antipsychotics versus oral forms marketed in Spain for schizophrenia 11
TABLE2
Evidencetable.
Depot
antipsychoticsversusoralantipsycho
ticsmarketedinSpain(Continuation)
Results
Active
Author
Design
Sample
Inclusion
Active
AbandonmentSymptom
atology
Adverse
Useof
Quality
ingredient
(year)
size
criteria
ingredientdose
effects
services
oflife
Depot
versusoral
risperidone
(Continueso
nthefollowingpage)
Chue
etal28
(2004)
randomly
grouped
as
continuing
oraltrea
tment
orchang
ing
toadepot.
Followed
-up
for48weeks
(secondpart
oftheprevious
article)
Randomised
clinicalt
rial.
Double-b
lind,
multicen
tred.
Non-infe
riority
(thesam
plesize
iscalculated
withapotential
of90%).
After
an8-week
periodof
stabilisation
withoral
risperido
ne,
theyare
randomisedto
depotor
oral.
12week
follow-
up
(48%males;
44.79.2
)
642
randomised.
2participants
areabandon
beforestarting
thestudy;
321withoral
risperidone
(63%male;
ages
39.90.6
);
319withdepot
risperidone
(65.6
%male;
aged
40.10.6
)
theone
theywere
on(25,
37.5
or50mg)is
administered
every
fortnight.
Schizophrenia
diagnosis
accordingto
DSM-IV.
PANSS
>49.
Normal
biochemical
values
ofthe
symptoms,2
duetoadverse
effectsand
1withdrew
consent
Oralrisperidone
group:same
doseasbefore
+placebo
injectionevery
fortnight.
Depot
risperidone
group:daily
oralplacebo
dose+injection
of25,
50or
75mgevery
fortnight.
From
the
oralgroup,
271finalised
(84%);4.7
%
didnot
continue
dueto
adverse
effects;
4%didnot
consentto
treatment.
Inadequate
response:
2.5
%.
256
finishedin
thedepot
risperidone
group
(80%).5.6
%
didnot
finishdue
toadverse
effects.
5.3
%
didnotgive
TotalPAN
SS:
differences
before-after.
Oralrispe
ridone:
6.30.
7;
p0.05
).No
differenc
esin
severityeither
TotalBPR
Sscore:
theimprovement
inthe100mg
depotpip
otiazine
groupwa
s19.7
%.
Theimpr
ovement
inthe150mg
depotpip
otiazine
groupwa
s16.9
%.
Thedepo
t
fluphenazine
improved
7.2
%
after39weeks.
Insignificant
tendency
(p0.0
5).No
changesare
detectedin
akinesia
(p>0.0
5),
akathisia
(p>0.0
5),
Parkinsons
(p>0.0
5)and
dystonia
(p>0.0
5)
Thereareno
differences
between
thethree
groupsinthe
frequencyof
extrapyramidal
symptoms.
Tendencyto
moresymptoms
inthe150mg
pipotiazine
group.
Not
significant
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20 A. Fernndez Snchez et al
TABLE3
Evidencetable.
Depot
antipsychoticsversusoralantipsycho
ticsmarketedinSpain(Continuation)
Results
Active
Author
Design
Sample
Inclusion
Active
Abandonment
Symptom
atology
dverse
Useof
Qualityoflife
ingredient
(year)
size
criteria
ingredient
effects
services
doses
Depotc
lopenthixol
versusdepot
fluphenazine
(Continueso
nthefollowingpage)
Walker37
(1983)
Randomised
clinicalt
rial,
double-b
lind;
24weeks
monitori
ng
precededby
12open
weeks
inwhich
doseis
adjusted
Ofthe45
participants
livinginthe
community,
6abandoned.
Thesample
wasof39(19,
clopenthixol;
20,fluphenazine)
Chronic
schizophrenia.
Nocriteria
mentioned
Clopenthixol:
100mg/month
to400mg/
fortnightly.
Fluphenazine
12.5mg/month
to37.5mg
every3weeks
6abandoned
(lossof
follow-up);
total:39
participants
isfavourable
improvem
ent
withpipo
tiazine
inthelas
tmonth
(p