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The impact of clozapine on hospital use: asystematic review and meta-analysis

Land R, Siskind D, McArdle P, Kisely S, Winckel K, Hollingworth SA.The impact of clozapine on hospital use: a systematic review and meta-analysis.

Objective: The objective of this study was to perform a systematicreview and meta-analysis of studies reporting the impact of clozapineon hospital use in people with a psychotic illness.Method: PubMed, EMBASE, PsycINFO and the CochraneSchizophrenia Group Trials Register were systematically searched frominception to 12 October 2016. We included all trials and observationalstudies, except case reports.Results: Thirty-seven studies were included. Clozapine significantlyreduced the proportion of people hospitalised compared to controlmedicines (RR = 0.74; 95% CI: 0.69–0.80, P < 0.001, 22 studies,n = 44 718). There were significantly fewer bed days after clozapinetreatment compared to before clozapine treatment in both controlled(MD = �34.41 days; 95% CI: �68.22 to �0.60 days, P = 0.046,n = 162) and uncontrolled studies (MD = �52.86 days; 95% CI:�79.86 days to �25.86 days, P < 0.001, n = 2917). Clozapine andcontrol medicines had a similar time to rehospitalisation (�19.90 days;95% CI: �62.42 to 22.63 days, P = 0.36).Conclusion: Clozapine treatment reduced the number of peoplehospitalised and the number of bed days after treatment compared withbefore treatment. Clozapine has the potential to reduce acute hospitaluse among people with treatment refractory schizophrenia.

R. Land1, D. Siskind2,3,P. McArdle2,3, S. Kisely2,3,K. Winckel1,4,S. A. Hollingworth11School of Pharmacy, University of Queensland,Woolloongabba, 2School of Medicine, University ofQueensland, Herston, 3Metro South Addiction andMental Health Services, and 4Pharmacy Department,Princess Alexandra Hospital, Woolloongabba, Qld,Australia

Key words: schizophrenia; psychotic disorders;clozapine; hospital use; meta-analysis

Samantha A Hollingworth, School of Pharmacy,University of Queensland, 20 Cornwall St,Woolloongabba, Qld 4102, Australia.E-mail: [email protected]

Accepted for publication January 9, 2017

Significant outcomes

• Clozapine treatment is effective in reducing the proportion of people hospitalised and the number ofbed days after treatment compared to before treatment.

Limitations

• The paucity of randomised controlled trial data limits the interpretation of the results.

• Given reductions in the average length of stay in recent years, older studies may not be generalisableto current clinical situations.

Introduction

Schizophrenia is a heterogeneous syndrome classi-fied as one of the top 20 causes of disability by theWorld Health Organization with a globalprevalence of 7.2 per 1000 persons (1, 2). Themanagement of schizophrenia consists of non-pharmacological and pharmacological options.Non-pharmacological measures include somatictherapy and psychosocial interventions (3).

Antipsychotics are the main pharmacologicaltreatment option (4).

Antipsychotics do not benefit all, with 20% ofpeople with first-episode psychosis failing torespond to adequate trials of at least two differentantipsychotics (5). This is termed treatment refrac-tory schizophrenia (TRS), and estimates rangefrom 20% to 33% among all people withschizophrenia (6). The second-generation

1

Acta Psychiatr Scand 2017: 1–14 © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons LtdAll rights reservedDOI: 10.1111/acps.12700

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antipsychotic, clozapine, is the gold standard treat-ment for TRS, with superior efficacy for positivesymptoms (7) compared to first-generation andnon-clozapine second-generation antipsychotics.

Clozapine is associated, however, with rare butpotentially fatal (agranulocytosis, neutropenia,myocarditis, cardiomyopathy) and common trou-bling (metabolic syndrome, sedation, sialorrhea,constipation) adverse drug reactions (ADRs) (8).People prescribed clozapine require regular bloodtests to prevent the life-threatening haematologicalevents of agranulocytosis and neutropenia. Addi-tional monitoring is also required to prevent car-diovascular events such as myocarditis andcardiomyopathy (9).

Clinical trials often test medicines in ideal cir-cumstances, have short durations, recruit ahomogenous, low-risk set of subjects and may havesurrogate outcomes such as rating scales as end-points. Hence their generalisability to ‘real-world’consumers can be limited. Hospital use can be areliable endpoint to ascertain the ‘real-world’ effec-tiveness of antipsychotic treatment (10). This isbecause hospitalisation encompasses admissiondue to either treatment failure leading to psychosis,or due to adverse effects from treatment. A keygoal in therapy for many people with schizophre-nia is the avoidance of hospital admission. Hospi-tal admissions are often associated with badmemories, stigma, increased cost to the patient andgovernment and disrupted social integration inpeople with schizophrenia (11). It is pertinent toensure the ‘real-world’ effectiveness of clozapineoutweighs the potential harms.

Aim of the study

The aim of this study was to investigate the impactof clozapine on hospital use in people with a psy-chotic illness by conducting a systematic reviewand meta-analysis.

Material and methods

Protocol and registration

The review was registered with PROSPERO (regis-tration number: CRD42016038287), an interna-tional database of prospectively registeredsystematic reviews (12). We followed recommenda-tions for the Preferred Reporting Items for System-atic Reviews and Meta-Analyses (PRISMA)statement (13). Ethical approval was not requiredfor this manuscript as all included interventiondata had been previously published with ethicalapproval.

Eligibility criteria

We included all randomised controlled trials(RCTs) and observational studies, except casereports, that reported hospital use in people whohad a psychotic illness and were prescribed clozap-ine. We excluded studies if they had insufficientdata or examined a diagnosis other than a psy-chotic illness. Published data in all languages wereincluded and translated into English.

Search strategy

We searched PubMed, EMBASE, PsycINFO andthe Cochrane Schizophrenia Group Trials Registerfrom inception to 12 October 2016. In the case ofPubMed, we used the following terms: (clozapin*OR clozaril* OR denzapin* OR zaponex* ORclopine*) AND (schizophrenia OR schizoaffectiveOR psychosis OR psychotic) AND (hospital ORhospitalization OR hospitalisation OR rehospitali-sation OR rehospitalization OR admission ORadmitted OR bed OR in-patient).

Study selection

We included both randomised and non-rando-mised studies. We included controlled and uncon-trolled studies that reported on hospital use inpeople with a psychotic illness who were prescribedclozapine. One author (RL) screened all identifiedstudies at the title and abstract level. Studies thatmet the inclusion criteria based on title andabstract or that could not be excluded on the basisof information provided in the abstract werereviewed at full-text level by two authors (RL andPM). We contacted the first authors if data weremissing in the included studies.

Data collection process

One author (RL) extracted data which waschecked by two authors (PM and DS). Weresolved discrepancies at any stage of study selec-tion, data extraction and quality assessment byre-checking source studies. One author (DS) vali-dated the extracted data. Three authors analysedthe data (RL, DS and SK).

Data items

We extracted data on the following aspects: studydesign, study years, study duration, study setting,diagnostic tool, diagnoses, TRS definition, num-ber of participants, gender distribution, reasonfor hospitalisation, mean (standard deviation

2

Land et al.

[SD]) age, dose of clozapine and control medi-cine(s). We also extracted the summary of find-ings, statistical analyses, funding and conflict ofinterests. We converted doses of clozapine andcontrol medicines to chlorpromazine equivalents(14). They were used in separate meta-analyses tocompare clozapine and control medicines inchlorpromazine dose equivalents in order toexclude any potential bias due to discrepanciesbetween relative dosing of clozapine and controlmedicines.

Outcomes

The primary outcome was hospital use for any rea-son. This included the proportion of people hospi-talised, change in number of bed days afterclozapine or control medicine compared to before,and time to rehospitalisation. If multiple timepoints were reported in a study, we used the datafrom the last time point.

Study quality

Study quality was assessed by two authors (RLand PM). We assessed the quality of the RCTsusing the following criteria adapted from theCochrane Collaboration guidelines (15): (i) ade-quate generation of allocation sequence; (ii) blind-ing of allocation to conditions to participant and/or assessor; (iii) adequate random sequence gener-ation; (iv) prespecified primary outcome measures;(v) appropriate reporting on missing data; (vi) useof intention to treat analysis; and (vii) othersources of potential bias including pharmaceuticalcompany funding.

We assessed the quality of the observationalstudies using the following criteria adapted fromthe Newcastle–Ottawa Scale (16): (i) selection ofthe study groups; (ii) comparability of the groups;and (iii) ascertainment of outcome.

Statistical analyses

We used Review Manager (Cochrane) version 5.3for Mac and Comprehensive Meta-Analysis (Bio-stat) version 3.3 for the meta-analyses. We alsoused Win-Pepi (Brixton Health) for the cumulativeforest plot. We reported the risk ratio (RR) fordichotomous data. We calculated the mean differ-ence (MD) for continuous data.

We conducted sensitivity analyses for the studyduration, study years, effect of dosage, use of first-or second-generation antipsychotic control medici-nes, reason for hospital use, study quality and TRSdiagnosis.

We assessed heterogeneity using the I2 statistic,a measure that does not depend on the number ofstudies in the meta-analysis and hence has greaterpower to detect heterogeneity when the number ofstudies is small. It is calculated using the chi-squared statistic (Q) and its degrees of freedom(17). An estimate of 50% or greater indicates pos-sible heterogeneity, and scores of 75–100% indi-cate considerable heterogeneity.

We used the random-effects model for all theanalyses, as we could not definitely excludebetween-study variation, even in the absence ofstatistical heterogeneity, given the range of medici-nes under review. We tested for publication biasusing Egger’s regression asymmetry test where lowP-values suggest publication bias.

Results

Study selection

We found 4582 studies of interest in the initialsearch of the electronic databases, of which 3380titles and abstracts were screened. Of these, 276were potentially relevant and were reviewed at full-text level: 239 studies were excluded (Fig. 1) and37 studies were included in the systematic review.The sum of people in these 37 studies prescribedclozapine was 12 631 and 35 337 prescribed con-trol medicines. We contacted the first author fortwo studies about missing data, but were unable toobtain the data.

Study characteristics

We included 37 studies in the meta-analysis (18–54): three randomised controlled trials and 34observational studies (Table 1). Studies were pub-lished between 1990 and 2016. Studies reporteddata at time points ranging from 28 weeks to364 weeks. Twenty-two studies provided data onthe proportion of people hospitalised. There were15 studies that reported the number of bed daysusing two different study types: two were con-trolled before and after treatment studies and 13were uncontrolled before and after treatment stud-ies. Five studies provided data on the time torehospitalisation.

Two of the three RCTs were good quality (27,35) and one was moderate quality (38) using theCochrane Collaboration’s assessment of bias tool.The method of randomisation was not stated intwo studies (27, 35), with no description of themethod of allocation concealment. In the thirdstudy (38), the method of allocation concealmentwas described as being ‘open’. One study (35)

3

Clozapine and hospital use

reported double blinding, while the other two stud-ies (27, 38) were open label. One study (35) blindedthe outcome assessors to treatment status. Theother two studies used structured questionnaires toassess outcome. Two studies used intention to treatanalysis with a clear description of drop-outs.Fewer people prescribed clozapine dropped outcompared to control medicines; this was signifi-cantly different in one study (38) but not differentin the other (35).

Overall, of the 34 observational studies includedin the review, five (42, 46–48, 52) were considered

good quality, 21 (18–23, 26, 28, 30, 31, 33, 34, 36,39–41, 45, 50, 51, 53, 54) were considered moderatequality, and eight (24, 25, 29, 32, 37, 43, 44, 49)were considered poor quality on the Newcastle–Ottawa Scale. Studies were considered poor if theyincluded less than 20 people prescribed clozapineor failed to provide any participant characteristics,for example age, gender distribution, or dose.Most (n = 32) of the 34 studies had a moderaterisk of bias. Only three studies independently vali-dated the diagnosis, nine stated a diagnosis but didnot specify the diagnostic criteria, and the

Fig. 1. PRISMA flow chart of search and selection of included studies. [Colour figure can be viewed at wileyonlinelibrary.com]

4

Land et al.

Table1.

Studiesincluded

inthesystem

aticreview

with

studycharacteristics

Paper†

Country

Studydesign

Studyyears

Duration/Studysetting/

Reason

foradm

ission

Diagnostictool/

Diagnoses

Treatment

refractory

definition

Clozapine:numberof

participants/mean(SD)

age‡/

%male/CPZequivalent(SD)§

Controlm

edication/numberof


age‡/%

male/CPZequivalent(SD)§

Outcom

es

Ahnet

al.

(2005)

Korea

Observational

cohortstudy

NS

52w/Out-patients/

Psychiatric

condition

DSM-IV/TRS

3trials

300–600mg

CPZequivalent

12weeks

duration

117/32.4(0.7)/61.5/249.1(6.4)

N/A

Pre/postbeddays

Bitter

etal.(2013)

Hungary

Prospective

observational

cohortstudy

1/7/2007–

30/6/2008

52w/Out-patients/

Psychiatric

condition

ICD-10

(F20.0-F20.9)/

Schizophrenia

NS

790/48.3*/47/99.1*

Amisulpride/920/47.0*/38/248.7*

Aripiprazole/601/43.3*/38/337.2*

Olanzapine/1633/46.3*/41/236.7*

Quetiapine/1587/49.7*/35/337.4*

Risperidone/2480/50.6*/40/416.2*

RLAI/1095/45.6/44*/NS

Ziprasidone/461/45.7/35/207.6*

Peoplehospitalised

Breieret

al.

(2000)

USA

Prospective

observational

cohortstudy

1/1/1990–

1/1/1991

52w/Out-patients/NS

DSM-III-R/

Schizophrenia

NS

26/34(7)/74.3/509.2(112.1)

N/A

Pre/postbeddays

Castro&Elkis

(2007)

Brazil

Retrospective

observational

cohortstudy

1/12/1997–

31/12/1999

156w/Out-patients/

Psychiatric

condition

ICD-10/Schizophrenia

Multipletrials

Failureto

respond

31/35.6(9.5)/67.7/NS

Haloperidol/22/37.6(11.7)/45.5/NS

Risperidone/43/38.3(10.2)/39.5/NS

Peoplehospitalised

Timetorehospitalisation

Conley

etal.

(2003)

USA

Prospective

observational

cohortstudy

1/1/1997–

31/12/1997

52w/Out-patients/

Psychiatric

condition

DSM-IV/Schizophrenia

NS

41/36.9(9.4)/61/461.7(196.4)

Risperidone/149/38.0(14.5)/63/

398.2(188.1)

Olanzapine/103/39.7(9.4)/58/

412.1(131.6)

Haloperidoldec/59/35.1(8.9)/68/

530.1(363.0)

Fluphenazinedec/59/39.9(9.4)/

72/398.1(207.7)

Peoplehospitalised


Conley

etal.

(1999)

USA

Prospective

observational

cohortstudy

14/3/1994–

31/12/1996

88w/Out-patients/

Psychiatric

condition

NS/Schizophrenia

NS

49/38.6(11.5)/59.2/NS

Risperidone/75/41.6(14.0)/61.3/

470.5(213.6)

Peoplehospitalised


Dey etal.(2016)

New

Zealand

Retrospective

observational

cohortstudy

1/7/2009–

1/12/2011

104w/Out-patients/

NS

ICD-10

(F20–29)/

Schizophreniaor

relateddisorders

NS

90/NS/NS/NS

FGA/73/NS/NS/NS

LAI/69/NS/NS/NS

Peoplehospitalised

Dicksonet

al.

(1998)

Canada

Retrospective

observational

cohortstudy

NS

156w/Out-patients/

NS

DSM-III-R/TRS

NS

11/28.8(3.9)/90.9/NS

N/A

Pre/postbeddays

Drew

etal.

(1999)

Australia

Retrospective

observational

cohortstudy

NS

156w/Out-patients/

Psychiatric

condition

NS/Schizophrenia,

Schizoaffective

disorder

NS

37/NS/67.6†/469.9†

N/A

Pre/postbeddays

Essock

etal.

(1996)

USA

RCT

1/1/1991–

1/1/1993

104w/Out-patients/

NS

SCID

diagnosis/Schizophrenia,

Schizoaffectivedisorder

2trials

6weekduration

1000

mg/day

CPZequivalent

138/42

(12)/61/585.9†

Usualcare/89/40(11)/61/1386†

Peoplehospitalised

5


Table1.

(Continued)

Paper†

Country

Studydesign

Studyyears


Reason

foradm

ission

Diagnostictool/

Diagnoses

Treatment

refractory

definition

Clozapine:numberof


age‡/


Controlm

edication/numberof


age‡/%


Outcom

es

Frankenburg

etal.(1992)

USA

Retrospective

observational

cohortstudy

1/1/1987–

1/1/1989

28w/In-patients/

Psychiatric

condition

DSM-III-R

AxisID

isorders

(SCID-1)/Schizophrenia,

Schizoaffectivedisorder,

Atypicalpsychosis,

Bipolardisorder

3trials

Failureto

respond/

intolerant

75/30.9(7.9)/65.3/NS

N/A

Pre/postbeddays

Ghaemietal.

(1998)

USA

Retrospective

observational

cohortstudy

1992–1996

52w/Out-patients/

Psychiatric

condition

DSM-IV

criteria/Schizophrenia,


Bipolardisorder

NS

20/39.4(7.9)/70/NS

N/A

Pre/postbeddays

Hayhurstet

al.

(2002)

England

Retrospective

observational

cohortstudy

1/1/1995–

1/12/1998

104w/Out-patients/

NS

ICD-10/Schizophrenia,


NS

63/41.9(12.7)/65.1/489.9†

SGAorFGA

/63/43.2(11.9)/65.1/NS

Pre/postbeddays

Herceg

etal.

(2008)

Croatia

Retrospective

observational

cohortstudy

1/1/2003–

31/12/2004

104w/Out-patients/

Psychiatric

condition

ICD-10

andDS

M-IV/

Schizophrenia

NS

60/40.3(3.5)/60/219.4(29.4)

Haloperidol/130/44.0(3)/78/

933(187.8)

Fluphenazine/101/44.3(3.3)/57/

410.9(129.1)

Risperidone/67/37.8(3.8)/64/

349.1(53.41)

Olanzapine/40/36.1(3.9)/53/

359.2(34.6)

Peoplehospitalised


Honigfield

etal.(1990)

USA

Observational

cohortstudy

NS

104w/Out-patients/

NS

NS/TRS

NS

86/NS/NS/NS

Usualcare/86/NS/NS/NS

Peoplehospitalised

Kimet

al.

(2008A)¶

Korea

Prospective

observational

cohortstudy

NS

104w/Out-patients/

Psychiatric

condition


&Alcohol-use

disorder

2trials

6weekduration

1000

mg/day

CPZequivalent

Failuretorespond/

intolerant

25/39.5(9.4)/100/488.0(99.5)

Risperidone/36/38.7(10.5)/100/

654.8(230.8)

Peoplehospitalised

Kimet

al.

(2008B)††

Korea

Retrospective

observational

cohortstudy

1998–2007

156w/In-patients

&Out-patients/NS

DSM-IV-TR/Schizophrenia,


2trials

Failuretorespond

26/14.4(2.1)/46/300.6(115.4)

N/A

Pre/postbeddays

Lieberman

etal.(2003)

China

RCT

1/10/1995–

1/12/1998

52w/Out-patients/

Psychiatric

condition

DSM-IV/Schizophrenia,

Schizophreniform

NS

80/28.7(6.9)/52/456.6†

Chlorpromazine/80/28.7(6.9)/52/600†

Peoplehospitalised

Linet

al.

(2006)

Taiwan

Observational

cohortstudy

1/7/2001–

30/6/2002

104w/Out-patients/

Psychiatric

condition

NS/Schizophrenia

NS

61/37.2(8.0)/34.4/289.2

(150.6)

FGA/272/39.2(10.0)/54.8/

568.1(345.3)

Risperidone/49/41.5(14.5)/67.3/

300.4(121.3)

Peoplehospitalised


Luchinset

al.

(1998)

USA

Observational

cohortstudy

NS

52w/Out-patients/

NS

NS/Schizophrenia,


2trials

Failureto

respond/

intolerant

28/NS/57/NS

N/A

Pre/postbeddays

Meltze

retal.

(2010)

USA

RCT

1/2/1991–

1/2/1996

104w/Out-patients/

Psychiatric

condition

+other‡‡


TRSpatients

excluded

40/25.8(5.8)/67.5/254.96

(95.65)

FGA/45/24.4(5.0)/80.0/

441.6(342.20)

Peoplehospitalised

6

Land et al.

Table1.

(Continued)

Paper†

Country

Studydesign

Studyyears


Reason

foradm

ission

Diagnostictool/

Diagnoses

Treatment

refractory

definition

Clozapine:numberof


age‡/


Controlm

edication/numberof


age‡/%


Outcom

es

Meltze

retal.

(1993)

USA

Retrospective

observational

cohortstudy

1/4/1987–

1/3/1990

104w/Out-patients/

Anycondition

DSM-III-R/TRS

NS

37/31.5(6.9)/64.9/667.9

(183.4)

N/A

Pre/postbeddays

Naberet

al.

(1992)

Germany

Observational

cohortstudy

NS

104w/Out-patients/

NS

NS/Schizophrenia

NS

480/34

(12)/42.1/302.1(189.2)

N/A

Pre/postbeddays

Nielsen

etal.

(2012)

Denm

ark

Prospective

observational

cohortstudy

1/1/1997–

31/12/2005

104w/Out-patients/

Psychiatric

condition


3trials

633/NS/58.5/383.4†

N/A

Pre/postbeddays

Nyakyom

aet

al.(2010)

UKRetrospective

observational

cohortstudy

1/1/2000–

22/12/2006

104w/Out-patients/

NS

ICD-10

(F20-F25)/

Schizophrenia,


2trials

Failureto

respond/

intolerant

145/35.6(11.5)/77/NS

Non-clozapine

AP/40/39.3(11.4)/

80/NS

Peoplehospitalised

Percudani

etal.(1999)

Italy

Retrospective

observational

cohortstudy

1/5/1993

-1/5/1996

52w/Out-patients/

Psychiatric

condition

ICD-10

(F20.1-F20.8)/

Schizophrenia

2trials

Failureto

respond

12/34.8(7.4)/58.3/317.1(88.7)

N/A

Pre/postbeddays

Reid etal.(1998)

USA

Observational

cohortstudy

NS

234w/Out-patients/

Psychiatric

condition

NS/Schizophrenia,


NS

383/NS/NS/NS

FGA/233/NS/NS/NS

Peoplehospitalised

Revickietal.

(1990)

USA

Observational

cohortstudy

1984–1987

52w/Out-patients/

Psychiatric

condition

DSM-III/S

chizophrenia

2trials

Failureto

respond

Adequatedose

andduration

133/33.2(8.1)/65/NS

FGA/51/37(9)/56/NS

Peoplehospitalised

Ringback

Weitoft

etal.(2014)

Sweden

Retrospective

observational

cohortstudy

1/1/2006–

1/12/2009

156w/Out-patients/

Psychiatric

condition

ICD-10

F20,F25/

Schizophrenia,

Schizoaffective

disorder

NS

2138/46.8(22.6)/59.7/NS

Olanzapine/3747/47

(13.6)/58.3/NS

Risperidone/3212/48.5(13.5)/55.0/NS

Zuclopenthixol/1704/52.3(12.0)/

49.1/NS

Perphenazine/1511/52.9(12.3)/48.8/NS

Haloperidol/1181/52.5(13.0)/53.5/NS

Quetiapine/736/44.6(13.9)/47.3/NS

Aripiprazole/720/41.2(12.5)/57.4/NS

Flupentixol/669/53.2(11.9)/45.3/NS

Ziprasidone/397/45.4(11.7)/41.6/NS

Peoplehospitalised

Sernyak

etal.(2001)

USA

Observational

cohortstudy

1992–1995

156w/In-patients/

Psychiatric

condition

NS/Schizophrenia

NS

1415/43.0(9.3)/N

S/NS

N/A

Pre/postbeddays

Stroup

etal.

(2015)

USA

Retrospective

observational

cohortstudy

2001–2009

52w/Out-patients/

Psychiatric

condition

ICD-9-CM

290–319/TRS

Multipletrials

Failureto

respond

3123/38.6(11.9)/52/NS

Non-clozapine

AP/3123/39.2(12.1)/52/NS

Peoplehospitalised

Tayloret

al.

(2007)

UKRetrospective

observational

cohortstudy

1994–2002

156w/Out-patients/

Psychiatric

condition

NS/Schizophrenia,


NS

7/37.7(9.4)/57/NS

Olanzapine/15/47.6(11.8)/60/NS

Risperidone/14/42.2(11.2)/57/NS

Pre/postbeddays

7


Table1.

(Continued)

Paper†

Country

Studydesign

Studyyears


Reason

foradm

ission

Diagnostictool/

Diagnoses

Treatment

refractory

definition

Clozapine:numberof


age‡/


Controlm

edication/numberof


age‡/%


Outcom

es

Tayloret

al.

(2008)

UKRetrospective

observational

cohortstudy

2002–2005

156w/Out-patients/

Psychiatric

condition

ICD-10

(F2)/Schizophrenia,

Psychoses

NS

40/37(10.9)/65/492.5†

Amisulpride/95/41(12.3)/63/388.8†

Olanzapine/148/40(9.2)/64/391.7†

Quetiapine/78/41

(13.3)/38/378.3†

Risperidone/39/43(12.3)/62/507.0†

Peoplehospitalised

Thom

aset

al.(2015)

United

States

Observational

cohortstudy

1994–2003

52w/Out-patients/

Psychiatric

condition

ICD9threvision

code

295.xx/Schizophrenia

NS

DS:757/39.7(12.2)/61.3/NS

S:1174/40.4(12.5)/63.4/NS

DS:O

lanzapine/2322/39.9(12.2)/

58.1/NS

S:Olanzapine/3615/40.9(12.5)/60.5/NS

Peoplehospitalised

Tiihonen

etal.(2006)

Finland

Prospective

observational

cohortstudy

1/1/1995–

1/12/2001

364w/Out-patients/

Psychiatric

condition

ICD10F20,F25;

corresponding

to295in



NS

150/27.4*/NS/327.2*

Risperidone/240/30.7*/NS/416.2*

Olanzapine/197/28.6*/NS/236.7*

Perphenazineoral/104/32.7*/

NS/438.2*

Thioridazine/62/32.1*/NS/355.5*

Chlorpromazine/61/31.0*/NS/300*

Chlorprothixene/43/30.0 */NS/NS

Haloperidol/37/31.5*/NS/378.2*

Perphenazinedepot/3

5/34.9*/NS/NS

Levomepromazine/19/32.3*/NS/NS

Peoplehospitalised

Werneck

etal.(2011)

Brazil

Retrospective

observational

cohortstudy

1/12/1997–

31/12/2004

156w/Out-patients/

Psychiatric

condition


NS

59/38(9)/61/500.6(153.4)

FGAOral/50/41

(9)/30/NS

FGADepot/2

0/45

(12)/70/NS

Risperidone/63/39(11)/52/416.2(154.4)

AMS+

OLZ/36/36(9)/78/NS

SGA(non-clozapine)/14/30

(5)/64/NS

Peoplehospitalised

Williams

etal.(2006)

Canada

Prospective

observational

cohortstudy

1999–2000

104w/Out-patients/

Anycondition



Schizophreniform,

Psychosis

NS

51/NS/NS/360.3(160.2)

Risperidone/80/NS/NS/282.9(171.2)

Quetiapine/16/NS/NS/237.0(159.3)

Olanzapine/70/NS/NS/371.4(177.9)

SingleTypical/17/NS/NS/NS

MultipleTypical/4/NS/NS/NS

SingleTypical(depot)/24/NS/NS/NS

MultipleTypical(depot)/8/NS/NS/NS

Peoplehospitalised

NS,notstated;N/A,notapplicable;RCT,randomised

controlledtrial;w

,weeks;D

SM,D

iagnostic

andStatisticalManual,ICD,

InternationalClassificationofDiseases;SCID,

Structured

ClinicalInterviewforD

SMdisorders;TRS,TreatmentR

efrac-

torySchizophrenia;RLAI,risperidonelong-actinginjectable;dec,decanoate;FGA

,first-generationantipsychotic;LAI,long-actinginjectable;D

irectreason,attributabletocondition

ortreatment,Indirectreason,attributabletotreatmentside-effects

orself-injury;SGA

,second-generationantipsychotic;A

P,antipsychotic;D

S,delayedsw

itch;S,sw

itch;AM

S+OLZ,am

isulpride+

olanzapine.

†Leadauthorandyearofpublication.

‡SD=standarddeviation,*=medianvalueforage,†

=SD

notprovidedforage.

§CPZ

=chlorpromazineequivalents,meanchlorpromazineequivalentdosesandstandarddeviationofclozapineandcontrolm

edicationcalculated

usingpowertransformationfromAndreasonet

al.(2010),*=medianvaluefordose,†=SD

not

provided

fordose.

¶Kim

etal.2008A

=Timetorehospitalisationofclozapinevs.risperidoneinthenaturalistic

treatmentofcom

orbidalcohol-use

disorderandschizophrenia.

††Kimet

al.2008B

=Long-term

sustainedbenefitsofclozapinetreatmentinrefractoryearly

onsetschizophrenia:AretrospectivestudyinKorean

childrenandadolescents.

‡‡Other=medical,social,drug-abused-related,supervisionofcompliancereasons.

8

Land et al.

remaining 22 studies reported clinical diagnosesusing the International Classification of Diseases(55) or the Diagnostic and Statistical Manual (56).Fifteen of the 34 studies were mirror studies, com-paring clinical outcomes in a pretreatment periodand a post-clozapine treatment period. In theremaining studies, 12 had substantial differences inbaseline characteristics. In all 34 studies, the effectof clozapine use on hospitalisation was assessedusing patient records.

In studies where clozapine was compared tomore than one control medicine, the number ofparticipants in the clozapine group was dividedproportionally to the number of participants in thecontrol medicine group. This was done to avoiddouble counting clozapine participants.

Control medicines included first-generationantipsychotics such as chlorpromazine, chlorpro-thixene, haloperidol, fluphenazine, flupentixol,levomepromazine perphenazine, thioridazine andzuclopenthixol. Second-generation antipsychoticsincluded amisulpride, aripiprazole, olanzapine,risperidone, quetiapine and ziprasidone(Table 1).

Twelve studies provided definitions of TRS,two of which adhered to the criteria outlinedby Kane et al. (1988) (57). One study explicitlyexcluded people with TRS (38). Two studiesincluded diagnoses of schizophrenia or bipolardisorder (28, 29). One study explored the rela-tionship between clozapine and hospital use inpeople with schizophrenia and concomitantalcohol-use disorder (33).

The reasons for hospital use varied amongstudies: 24 studies defined hospital use for apsychiatric condition; one study defined hospitaluse for psychiatric and other conditions; twostudies defined hospital use for any reason; andten studies did not define the reason for hospi-tal use (Table 1).

People prescribed clozapine were significantlyyounger than people prescribed control medicines(MD �1.33 years, 95% confidence interval [CI]�2.21 to �0.49 years, P = 0.003, 18 studies,n = 33 286). There was no difference in durationof illness for clozapine compared to control(MD = 1.09 years; 95% CI: �0.40 to 2.57 years,P = 0.15, five studies, n = 658). People prescribedclozapine were significantly younger at onset of ill-ness than control (MD = �1.92 years; 95% CI:�2.87 to �0.98 years, P < 0.001, six studies,n = 1430). There was no difference in the meandaily dose in chlorpromazine equivalents in theclozapine group compared to the control group(MD = �93.63 mg; 95% CI: �204.20 mg to16.94 mg, P = 0.10, seven studies, n = 1684).

Proportion of people hospitalised

From the 37 studies included, 22 studies reportedthe proportion of people hospitalised, the remain-ing 15 studies did not report on this data. 9520people were prescribed clozapine, and 35 198 peo-ple were prescribed control medicines. Clozapinesignificantly reduced the proportion of people hos-pitalised compared to control medicines(RR = 0.74; 95% CI: 0.69–0.80, P < 0.001, 22studies, n = 44 718). Both the RCTs (RR = 0.62;95% CI: 0.41–0.94, P = 0.03, 3 studies, n = 369)and observational studies (RR = 0.75; 95% CI:0.69–0.81, P < 0.001, 19 studies, n = 44 349)favoured clozapine with regard to hospitalisation(Fig. 2). The heterogeneity for the RCTs was 0%and for the observational studies was 29%. Theheterogeneity for comparisons among controlmedicines ranged from 0% to 42%.

When we examined studies using second-genera-tion antipsychotics as the control medicine, clozap-ine significantly reduced the proportion of peoplehospitalised (RR = 0.75; 95% CI: 0.67–0.83,P < 0.001, 13 studies, n = 29 559). This resultremained significant in subanalyses by individualmedicines: risperidone (RR = 0.74; 95% CI: 0.60–0.93, P = 0.009, 12 studies, n = 8634); quetiapine(RR = 0.60; 95% CI 0.45–0.79, P = 0.0003, fourstudies, n = 2686); and olanzapine (RR = 0.82;95% CI: 0.69–0.97, P = 0.02, eight studies,n = 14 617) (Fig. 2).

In studies using first-generation antipsychoticsas the control medicine, clozapine significantlyreduced the proportion of people hospitalised

Fig. 2. Cumulative forest plot of the proportion of people hos-pitalised on clozapine vs. control medicines (risk ratio, 95%confidence interval).

9


(RR = 0.71; 95% CI: 0.65–0.77, P < 0.001, 13studies, n = 8344). There was no difference in theproportion of people hospitalised when clozapinewas compared to haloperidol (Fig. 2).

There was no difference in the proportion ofpeople hospitalised when we compared clozapineto antipsychotic depot treatment (first generationand second generation) (Fig. 2). When weexcluded studies reporting first-generation depotantipsychotics, clozapine significantly reduced theproportion of people hospitalised compared torisperidone long-acting injection (RR = 0.48; 95%CI: 0.32–0.72, P = 0.0004, one study, n = 1194). Ina sensitivity analysis which removed an outlyingstudy (52) comparing clozapine to perphenazinedepot, clozapine significantly reduced the propor-tion of people hospitalised (RR = 0.57; 95% CI:0.42–0.77, P = 0.0002, five studies, n = 1505).

We performed a series of prespecified sensitivityanalyses on study characteristics. Clozapine, com-pared to control medicines, reduced the proportionof people hospitalised to a greater extent in studydurations of less than one year (RR = 0.68; 95%CI: 0.59–0.78, P < 0.001, six studies, n = 24 391)compared to durations of more than one year(RR = 0.78; 95% CI: 0.71–0.85, P < 0.001, 16 stud-ies, n = 20 327). We considered the years when thestudies were conducted, but three studies did notprovide information (32, 33, 44). The proportion ofpeople hospitalised was significantly lower forclozapine compared to control medicines in studiesconducted before 2000 (RR = 0.76, 95% CI: 0.67–0.86, P < 0.001, 10 studies, n = 10 227) and studiesconducted after 2000 (RR = 0.77, 95% CI: 0.71–0.84, P < 0.001, nine studies, n = 33 642).

We explored the reasons for hospital use. Whenwe excluded studies that did not state a psychiatricreason for hospital use, the proportion of peoplehospitalised remained significantly lower for cloza-pine than control (RR = 0.75, 95% CI: 0.70–0.82,

P < 0.001, 16 studies, n = 43 674). Only one study(38) provided usable information on non-psychia-tric hospitalisations and found no differencebetween clozapine and control.

We investigated studies reporting the proportionof people hospitalised using chlorpromazine equiv-alent doses. There was no difference in the doseequivalents between clozapine and control medici-nes (MD = �53.53 mg; 95% CI: �145.66 mg to�38.59 mg, P = 0.25, seven studies, n = 1858).

When we considered people with only TRS, theproportion of people hospitalised was significantlylower for clozapine than control medicines(RR = 0.59; 95% CI: 0.45–0.78, P = 0.002, sevenstudies, n = 2381).

Pre- vs. post-treatment bed days

Fifteen observational studies compared the num-ber of bed days before and after treatment withmedicines. Two (30, 49) were controlled observa-tional studies with 70 people prescribed clozapineand 92 people prescribed control medicines. Thir-teen (18, 20, 25, 26, 28, 29, 34, 37, 39–41, 43, 47)studies were uncontrolled observational studieswith 2917 people prescribed clozapine.

People prescribed clozapine, compared to con-trol medicines, had significantly fewer bed daysafter treatment vs. before (MD = �34.41 days;95% CI: �68.22 to �0.60 days, P = 0.046,n = 162) (Fig. 3). People prescribed clozapine hadsignificantly fewer bed days after treatment com-pared to before treatment in 13 uncontrolled stud-ies (MD = �52.86 days; 95% CI: �79.86 days to�25.86 days, P < 0.001, n = 2917) (Fig. 4).

People who continued clozapine for more than2 years had significantly fewer bed days after treat-ment vs. before than those who discontinued cloza-pine within the 2 years (MD = �78.03 days; 95%CI: �118.68 days to �37.8 days, P < 0.001, three

Fig. 3. Forest plot of the number of bed days before starting treatment vs. after with clozapine (two controlled observational studies).

10

Land et al.

studies). We examined study duration in a sensitiv-ity analysis. There was three-fold difference in thenumber of bed days before treatment vs. aftertreatment for durations of less than one year(MD = �24.0 days; 95% CI: �32.4 days to�15.7 days, P < 0.001, six studies) compared tomore than one year (MD = �84.23 days; 95% CI:�133.08 days to �35.37 days, P = 0.001, sevenstudies). One study specifically included childrenand adolescents (34). When we excluded it, clozap-ine still significantly reduced the number of beddays after treatment compared to before treatment(MD = �52.09 days; 95% CI: �79.29 days to�24.88, P < 0.001, 12 studies).

Time to rehospitalisation

Five observational studies reported the time torehospitalisation (n = 243 clozapine; n = 1169 con-trol medicines). There was no difference betweenclozapine and control medicines in time to rehospi-talisation (MD = �19.90 days; 95 CI:�62.42 days to 22.63 days, P = 0.36, five studies,n = 1412). A subanalysis of control medicinesrevealed no difference between clozapine and indi-vidual control medicines in the time to rehospitali-sation. The heterogeneity was 86%.

In the one study that reported a study durationof less than one year, people treated with clozapinehad a significantly increased time to rehospitalisa-tion compared to combined controls (risperidone,

olanzapine, haloperidol decanoate and fluphena-zine decanoate) (MD = 36.86 days; 95% CI:1.02 days to 72.70 days, P = 0.04, one study,n = 412). In four studies with durations of morethan one year, however, there was no difference inthe time to rehospitalisation among treatments(MD = �48.72 days; 95% CI: �107.50–10.06 days, P = 0.10, four studies, n = 1000).

All five studies reported a psychiatric conditionas the reason for hospital use. People prescribedclozapine were on significantly lower chlorpro-mazine equivalent doses than control medicines(MD = �147.66 mg; 95% CI: �288.59 mg to�6.74 mg, P = 0.04, three studies, n = 1192). In theone study with only people with TRS, there was nodifference to the time to rehospitalisation(MD = �78.30 days; 95% CI:�186.58–29.99 days,P = 0.16, one study, n = 96). In the four studieswith an unknown TRS population, there was nodifference to the time to rehospitalisation (MD =�12.43 days; 95% CI: �57.53 days to 32.67 days,P = 0.59, four studies, n = 1316).

Publication bias

We were only able to test for publication bias fortwo outcomes: the proportion of people hospi-talised and bed days before and after clozapine.Using Egger’s regression asymmetry test, there wasno evidence of publication bias for either hospitali-sation (intercept = �0.05, 95% CI: �0.30 to 0.20,

Fig. 4. Forest plot of the number bed days before starting treatment vs. after with clozapine (13 uncontrolled observational studies).

11


P = 0.807) or bed days (intercept = �0.06, 95%CI �2.88 to 2.79, P = 0.96).

Discussion

To our knowledge, this study is the first systematicreview and meta-analysis to specifically investigatethe impact of clozapine on hospital use in peoplewith a psychotic illness. We included 37 studieswith 47 968 participants.

Clozapine was superior to control medicines inreducing the proportion of people hospitalised.This finding was consistent across study typesincluding RCTs and observational studies. Clozap-ine was superior to risperidone, quetiapine andolanzapine in reducing the proportion of peoplehospitalised. Clozapine treatment was not differentto depot treatment and haloperidol in reducing theproportion of people hospitalised. This was likelydue to the smaller number of studies rather than areal difference (Fig. 2). When we excluded first-generation depot antipsychotics in a sensitivityanalysis, however, clozapine was superior torisperidone long-acting injection in reducing theproportion of people hospitalised. Clozapine wassuperior to control medicines in reducing the pro-portion of people with TRS who were hospitalised.

Clozapine was superior in both controlled anduncontrolled before and after studies in reducingthe number of bed days after starting treatmentcompared to before treatment. People who contin-ued clozapine, compared to those who discontin-ued, had fewer bed days after treatment vs. beforetreatment.

Clozapine’s effectiveness in reducing hospitalisa-tions may be due in part to the need for ongoingregular haematological monitoring. This monitor-ing process usually entails monthly blood tests andclinic appointments (58) and may be greater thanmonitoring for other antipsychotics. It is possiblethat this greater ongoing monitoring and contactwith clinical services for people on clozapine mayallow earlier detection of mental state deteriora-tion and appropriate interventions to avert hospi-talisations.

Clozapine had no effect, compared to controlmedicines, on the time to rehospitalisation. Cloza-pine’s lack of effect may be explained by subse-quent re-titrations (if required) in peopleprescribed clozapine. They are often admitted tohospital if they have missed three days or more ofdosing (retitration) for the purpose of slowly start-ing clozapine with careful monitoring of bloodpressure, heart rate and other outcomes. It is possi-ble that a subgroup of people on clozapine hadincomplete response. Agid et al. 2011 (5) noted

that 25% of people with TRS had inadequateresponse to clozapine. As such, this subgroup mayhave been more likely to be rehospitalised.

The majority of studies were observational stud-ies, as such incomplete adherence may have beenresponsible for a failure to show any effect on timeto rehospitalisation and hospitalisation rates com-pared with antipsychotic depot treatment (firstgeneration and second generation) (Fig. 2).

Limitations

There were several limitations of this review. Manyof the studies were of various observational studydesigns and therefore lacked standardised method-ologies. Eight observational studies were deemed tobe poor quality, but a sensitivity analysis excludingthese studies made no difference to the results.Observational studies have inherent limitations suchas difficulty controlling for confounding variablesand a high risk of bias. Despite these limitations,observational studies can provide valuable informa-tion about the effectiveness, rather than efficacy, ofmedicines. It is likely that the people prescribedclozapine had a more severe psychotic illness thanthose prescribed control medicines. This confound-ing may have made clozapine seem less effective atreducing hospital use than it really is. Despite thedifferent study types, RCTs and observational stud-ies revealed consistent results in the meta-analyses.

Some analyses showed substantial heterogeneity.Although we explored this aspect with sensitivityanalyses and used a random-effects model through-out to incorporate heterogeneity into our analyses,our results should still be treated with caution. Inparticular, the results for the outcome of time torehospitalisation have a non-normal distribution.

A major limitation was the lack of dose informa-tion. People prescribed clozapine were on lowerchlorpromazine equivalent doses compared to con-trol medicines in the seven studies that providedinformation. It is possible that the lower doses ofclozapine may have underestimated the effective-ness of clozapine. No studies reported serum levelsof clozapine.

Some studies did not define the reason for hospi-tal use. It is important to cautiously interpret theresults of hospital use. People may be admitted tohospital for reasons other than schizophrenia andnot necessarily because they are experiencing arelapse or medicine failure. However, a sensitivityanalysis of studies with a psychiatric reason forhospital use showed that the proportion of peoplehospitalised remained significantly lower for cloza-pine than control. The lack of published data onthe frequency of hospital use for medical rather

12

Land et al.

than psychiatric reasons limits the opportunity todetermine this cohort’s general health. People onclozapine may have poorer general health due toits side-effect profile or other lifestyle factors (4),although they may also have better general healthgiven epidemiological studies show clozapinereduces overall mortality (59).

Most studies were published before 2005. Sincethat time, the average hospital duration hasdecreased (60) and so clozapine may no longerreduce bed days to the same extent. However, asensitivity analysis of the time at which the studywas conducted did not alter the results.

In conclusion, our findings have highlighted thesuperior benefit of clozapine treatment vs. controlmedicines in reducing the proportion of peoplehospitalised and the bed days after treatment com-pared with before treatment.

Acknowledgements

We would like to thank Helmut Land for his assistance intranslating articles.

Declaration of Interest

DS is supported in part by a National Health and MedicalResearch Council Early Career Fellowship (APP1111136).Other authors have no interests to declare.

References

1. World Health Organization. The World Health Report2001: Mental Health. New Understanding, New Hope.Switzerland; 2001 [cited 20 March 2016].

2. Saha S, Chant D, Welham J, McGrath J. A systematicreview of the prevalence of schizophrenia. PLoS Med2005;2:e141.

3. Lehman AF, Lieberman JA, Dixon LB et al. Practice guide-line for the treatment of patients with schizophrenia, sec-ond edition. Am J Psychiatr 2004;161:1.

4. Kahn RS, Sommer IE, Murray RM et al. Schizophrenia.Nat Rev Dis Primers 2015;1:15067.

5. Agid O, Arenovich T, Sajeev G et al. An algorithm-basedapproach to first-episode schizophrenia: response ratesover 3 prospective antipsychotic trials with a retrospectivedata analysis. J Clin Psychiatry 2011;72:1439–1444.

6. Barry SJ, Gaughan TM, Hunter R. Schizophrenia. BMJClinical Evidence 2012;28:2012.

7. Siskind D, McCartney L, Goldschlager R, Kisely S, Cloza-pine V. First- and second-generation antipsychotics intreatment-refractory schizophrenia: systematic review andmeta-analysis. Br J Psychiatry 2016;209:385–392.

8. Nielsen J, Damkier P, LublinH, TaylorD. Optimizing cloza-pine treatment. Acta Psychiatr Scand 2011;123:411–422.

9. Fakra E, Azorin JM. Clozapine for the treatment ofschizophrenia. Expert Opin Pharmacother 2012;13:1923–1935.

10. Burns T. Hospitalisation as an outcome measure inschizophrenia. Br J Psychiatry 2007;191:s37.

11. Abdel-Baki A, Lesage A, Nicole L, Cossette M, Salvat E,Lalonde P. Schizophrenia, an illness with bad outcome:myth or reality? Can J Psychiatry 2011;56:92–101.

12. Booth A, Clarke M, Dooley G et al. The nuts and bolts ofPROSPERO: an international prospective register of sys-tematic reviews. Syst Rev 2012;1:1–9.

13. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferredreporting items for systematic reviews and meta-analyses:the PRISMA statement. Ann Intern Med 2009;151:264–269.

14. Andreasen NC, Olsen S. Negative v positive schizophrenia:definition and validation. Arch Gen Psychiatry1982;39:789–794.

15. Higgins JP, Green S. Cochrane Handbook for SystematicReviews of Interventions, 2008.

16. Stang A. Critical evaluation of the Newcastle-Ottawa scalefor the assessment of the quality of nonrandomized studiesin meta-analyses. Eur J Epidemiol 2010;25:603–605.

17. The Cochrane Collaboration. Cochrane Handbook forSystematic Reviews of Interventions 5.1.0 [updated March2011], 2011 [updated 2011; cited]. Available from: http://handbook.cochrane.org/.

18. Ahn YM, Chang JS, Kim Y et al. Reduction in hospitalstay of chronic schizophrenic patients after long-termclozapine treatment. Int Clin Psychopharmacol2005;20:157–161.

19. Bitter I, Katona L, Zambori J et al. Comparative effective-ness of depot and oral second generation antipsychoticdrugs in schizophrenia: a nationwide study in Hungary.Eur Neuropsychopharmacol 2013;23:1383–1390.

20. Breier A, Buchanan RW, Irish D, Carpenter JRWT. Cloza-pine treatment of outpatients with schizophrenia: outcomeand long-term response patterns. Psychiatr Serv2000;51:1249–1253.

21. Castro AP, Elkis H. Rehospitalization rates of patientswith schizophrenia discharged on haloperidol, risperidoneor clozapine. Rev Bras Psiquiatr 2007;29:207–212.

22. Conley RR, Kelly DL, Love RC, McMahon RP. Rehospi-talization risk with second-generation and depot antipsy-chotics. Ann Clin Psychiatry 2003;15:23–31.

23. Conley RR, Love RC, Kelly DL, Bartko JJ. Rehospital-ization rates of patients recently discharged on a regimenof risperidone or clozapine. Am J Psychiatr 1999Jun;156:863–868.

24. Dey S, Menkes DB, Obertova Z, Chaudhuri S, Mellsop G.Correlates of rehospitalisation in schizophrenia. AustrPsychiatry 2016;24:356–359.

25. Dickson RA, Dalby JT, Williams R, Warden SJ. Hospitaldays in clozapine-treated patients. Can J Psychiatry1998;43:945–948.

26. Drew LR, Hodgson DM, Griffiths KM. Clozapine in com-munity practice: a 3-year follow-up study in the AustralianCapital Territory. Austr N Z J Psychiatry 1999;33:667–675.

27. Essock SM, Hargreaves WA, Covell NH, Goethe J. Cloza-pine’s effectiveness for patients in state hospitals: resultsfrom a randomized trial. Psychopharmacol Bull1996;32:683–697.

28. Frankenburg FR, Zanarini MC, Cole JO, McElroy SL.Hospitalization rates among clozapine-treated patients: aprospective cost-benefit analysis. Ann Clin Psychiatry1992;4:247–250.

29. Ghaemi SN, Ziegler DM, Peachey TJ, Goodwin FK. Cost-effectiveness of clozapine therapy for severe psychosis.Psychiatr Serv 1998;49:829–831.

30. Hayhurst K, Brown P, Lewis SW. The cost-effectiveness ofclozapine: a controlled, population-based, mirror-imagestudy. J Psychopharmacol 2002;16:169–175.

31. Herceg M, Jukic V, Vidovic D et al. Two-year rehospitaliza-tion rates of patients with newly diagnosed or chronic

13


http://handbook.cochrane.org/

http://handbook.cochrane.org/

schizophrenia on atypical or typical antipsychotic drugs: ret-rospective cohort study. CroatianMed J 2008;49:215–223.

32. Honigfeld G, Patin J. A two-year clinical and economicfollow-up of patients on clozapine. Hosp Community Psy-chiatry 1990 Aug;41:882–885.

33. Kim JH, Kim D, Marder SR. Time to rehospitalizationof clozapine versus risperidone in the naturalistic treat-ment of comorbid alcohol use disorder and schizophre-nia. Prog Neuropsychopharmacol Biol Psychiatry2008;32:984–988.

34. Kim Y, Kim BN, Cho SC, Kim JW, ShinMS. Long-term sus-tained benefits of clozapine treatment in refractory earlyonset schizophrenia: a retrospective study in Korean chil-dren and adolescents. Hum Psychopharmacol2008;23:715–722.

35. Lieberman JA, Phillips M, Gu H et al. Atypical and con-ventional antipsychotic drugs in treatment-naive first-epi-sode schizophrenia: a 52-week randomized trial ofclozapine vs chlorpromazine. Neuropsychopharmacology2003;28:995–1003.

36. Lin CH, Lin SC, Chen MC, Wang SY. Comparison of timeto rehospitalization among schizophrenic patients dis-charged on typical antipsychotics, clozapine or risperi-done. J Chin Med Assoc 2006;69:264–269.

37. Luchins DJ, Hanrahan P, Shinderman M, Lagios L, FichtnerCG. Initiating clozapine treatment in the outpatient clinic:service utilization and cost trends. Psychiatr Serv1998;49:1034–1038.

38. Meltzer HY, Bobo WV, Lee MA, Cola P, Jayathilake K.A randomized trial comparing clozapine and typical neu-roleptic drugs in non-treatment-resistant schizophrenia.Psychiatry Res 2010;177:286–293.

39. Meltzer HY, Cola P, Way L et al. Cost effectiveness ofclozapine in neuroleptic-resistant schizophrenia. Am JPsychiatr 1993;150:1630–1638.

40. Naber D, Holzbach R, Perro C, Hippius H. Clinical man-agement of clozapine patients in relation to efficacy andside-effects. Br J Psychiatry Suppl 1992;17:54–59.

41. Nielsen J, Nielsen RE, Correll CU. Predictors of clozapineresponse in patients with treatment-refractory schizophre-nia: results from a Danish Register Study. J Clin Psy-chopharmacol 2012 Oct;32:678–683.

42. Nyakyoma K, Morriss R. Effectiveness of clozapine use indelaying hospitalization in routine clinical practice: a2 year observational study. Psychopharmacol Bull2010;43:67–81.

43. Percudani M, Fattore G, Galletta J, Mita PL, Contini A,Altamura AC. Health care costs of therapy-refractoryschizophrenic patients treated with clozapine: a study in acommunity psychiatric service in Italy. Acta PsychiatrScand 1999;99:274–280.

44. Reid WH, Mason M. Psychiatric hospital utilization inpatients treated with clozapine for up to 4.5 years in astate mental health care system. J Clin Psychiatry1998;59:189–194.

45. Revicki DA, Luce BR, Weschler JM, Brown RE, AdlerMA. Cost-effectiveness of clozapine for treatment-resis-tant schizophrenic patients. Hosp Community Psychiatry1990;41:850–854.

46. Ringback WEITOFT G, Berglund M, Lindstrom EA, NilssonM, Salmi P, RosenM. Mortality, attempted suicide, re-hos-pitalisation and prescription refill for clozapine and otherantipsychotics in Sweden-a register-based study. Pharma-coepidemiol Drug Saf 2014;23:290–298.

47. Sernyak MJ, Rosenheck R, Desai R, Stolar M, Ripper G.Impact of clozapine prescription on inpatient resource uti-lization. J Nerv Ment Dis 2001;189:766–773.

48. Stroup TS, Gerhard T, Crystal S, Huang C, Olfson M.Comparative Effectiveness of Clozapine and StandardAntipsychotic Treatment in Adults With Schizophrenia.Am J Psychiatr 2016;173:166–173.

49. Taylor D, Hayhurst K, Kerwin R. A controlled, mirror-image study of second-generation antipsychotics in thetreatment of schizophrenia. Int Clin Psychopharmacol2007;22:133–136.

50. Taylor M, Shajahan P, Lawrie SM. Comparing the use anddiscontinuation of antipsychotics in clinical practice: anobservational study. J Clin Psychiatry 2008;69:240–245.

51. Thomas KL, Jiang Y, McCombs JS. Clozapine revisited:impact of clozapine vs olanzapine on health care use byschizophrenia patients on Medicaid. Ann Clin Psychiatry2015;27:90–99.

52. Tiihonen J, Wahlbeck K, Lonnqvist J et al. Effectiveness ofantipsychotic treatments in a nationwide cohort ofpatients in community care after first hospitalisation dueto schizophrenia and schizoaffective disorder: observa-tional follow-up study. BMJ 2006;333:224.

53. Werneck AP, Hallak JC, Nakano E, Elkis H. Time torehospitalization in patients with schizophrenia dischargedon first generation antipsychotics, non-clozapine secondgeneration antipsychotics, or clozapine. Psychiatry Res2011;188:315–319.

54. Williams R, Kopala L, Malla A, Smith G, Love L, BalshawR. Medication decisions and clinical outcomes in theCanadian National Outcomes Measurement Study inSchizophrenia. Acta Psychiatr Scand Suppl 2006;430:12–21.

55. World Health Organization. Manual of the international sta-tistical classification of diseases, injuries, and causes of death:based on the recommendations of the seventh revision Con-ference, 1955, and adopted by the ninth World HealthAssembly under the WHONomenclature Regulations, 1957.

56. American Psychiatric Association. Diagnostic and Statisti-cal Manual of Mental Disorders (DSM). Washington,DC; 2013.

57. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine forthe treatment-resistant schizophrenic: a double-blind com-parison with chlorpromazine. Arch Gen Psychiatry1988;45:789–796.

58. Nielsen J, Young C, Ifteni P et al. Worldwide differences inregulations of clozapine use. CNS Drugs 2016;30:149–161.

59. Tiihonen J, L€onnqvist J, Wahlbeck K et al. 11-year follow-up of mortality in patients with schizophrenia: a popula-tion-based cohort study (FIN11 study). Lancet2009;374:620–627.

60. Lay B, Nordt C, R€osslerW. Trends in psychiatric hospital-isation of people with schizophrenia: a register-basedinvestigation over the last three decades. Schizophr Res2007;97:68–78.

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