belgamwar 2011 aripiprazole vs placebo schizophrenia

Aripiprazole versus placebo for schizophrenia (Review)

Belgamwar RB, El-Sayeh HGG

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2011, Issue 8

http://www.thecochranelibrary.com

Aripiprazole versus placebo for schizophrenia (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

5BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

16DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

46DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 1 Global state: 1. Relapse. . . . . . 48

Analysis 1.2. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 2 Global state: 2. Poor compliance with study

protocol due to lack of efficacy, deterioration or psychosis. . . . . . . . . . . . . . . . . . . 49

Analysis 1.3. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 3 Global state: 3. Needing additional

antipsychotic medication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Analysis 1.4. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 4 Global state: 4. Needing additional

benzodiazepines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Analysis 1.5. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 5 Adverse effects: 1. Clinically important

specific adverse effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Analysis 1.6. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 6 Adverse effects: 2. Average change in QTc

interval (ms) from baseline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Analysis 1.7. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 7 Adverse effects: 3. Physiological (serum)

measures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Analysis 1.8. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 8 Leaving the study early. . . . . . 60

Analysis 1.9. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 9 concomitant medication - anxiolytics. 61

61HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

63INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iAripiprazole versus placebo for schizophrenia (Review)


[Intervention Review]

Aripiprazole versus placebo for schizophrenia

Ravindra B Belgamwar1, Hany George G El-Sayeh2

1Lymebrook Mental Health Centre, Newcastle Under Lyme, UK. 2Briary Wing, Harrogate District Hospital, Harrogate, UK

Contact address: Ravindra B Belgamwar, Lymebrook Mental Health Centre, Bradwell Hospital Site, Newcastle Under Lyme, Stafford-

shire, ST5 4LD, UK. [email protected]. [email protected].

Editorial group: Cochrane Schizophrenia Group.

Publication status and date: New, published in Issue 8, 2011.

Review content assessed as up-to-date: 19 September 2010.

Citation: Belgamwar RB, El-Sayeh HGG. Aripiprazole versus placebo for schizophrenia. Cochrane Database of Systematic Reviews

2011, Issue 8. Art. No.: CD006622. DOI: 10.1002/14651858.CD006622.pub2.


A B S T R A C T

Background

First generation ’typical’ antipsychotics such as chlorpromazine and haloperidol have been the mainstay of treatment up until the

introduction of the second generation ’atypical’ antipsychotics such as risperidone and olanzapine. Typical and atypical antipsychotics

do provide a treatment response for most people with schizophrenia, whether a reduction in psychotic episodes or a lessening in the

severity of their illness. However, a proportion of people still do not respond adequately to antipsychotic medication. Additionally,

atypical and especially typical antipsychotics are associated with serious adverse effects, which can often compromise compliance with

medication and therefore increase the incidences of relapse. In this review we examine the effects of aripiprazole compared with placebo.

Objectives

To evaluate the effects of aripiprazole compared with placebo for people with schizophrenia and schizophrenia-like psychoses.

Search strategy

We searched the Cochrane Schizophrenia Group Trials Register (January 2008) which is based on regular searches of BIOSIS, CEN-

TRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. For this update, we carried out an initial search in May 2007 and a second

search in August 2008.

Selection criteria

We included all randomised trials comparing aripiprazole with placebo in people with schizophrenia or schizophrenia-like psychosis.

Data collection and analysis

We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an

intention-to-treat basis based on a fixed-effect model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate.

For continuous data, we calculated mean differences (MD) again based on a fixed-effect model.

Main results

Despite the fact that 2585 people participated in nine randomised aripiprazole studies, we were unable to extract any usable data on

death, service outcomes, general functioning, behaviour, engagement with services, satisfaction with treatment; economic outcomes or

cognitive functioning. In general, study attrition was very large for all studies over four weeks’ duration. There was high attrition in

most of the included studies. Fewer people left the aripiprazole group compared with those in the placebo group (n = 2585, 9 RCTs,

RR 0.73 CI 0.60 to 0.87). Compared with placebo, aripiprazole significantly decreased relapse in both the short (n = 310, 1 RCT, RR

1Aripiprazole versus placebo for schizophrenia (Review)


mailto:[email protected]

mailto:[email protected]

0.59 CI 0.45 to 0.77) and medium term (n = 310, 1 RCT, RR 0.66 CI 0.53 to 0.81). It also produced better compliance with study

protocol (n = 2275, 8 RCTs, RR 0.74 CI 0.59 to 0.93). Aripiprazole may decrease prolactin levels below those expected from placebo

(n = 305, 2 RCT, RR 0.21 CI 0.11 to 0.37). Insomnia (~23%) and headaches (~15%) were commonly reported in both groups, with

no significant difference.

Authors’ conclusions

Aripiprazole may be effective for the treatment of schizophrenia. Aripiprazole has a lower risk of raised prolactin and prolongation of

the QTc interval. Clearly reported pragmatic short-, medium- and long-term randomised controlled trials should be undertaken to

determine its position in everyday clinical practice.

P L A I N L A N G U A G E S U M M A R Y

Aripiprazole versus placebo for schizophrenia

Schizophrenia is one of the major psychiatric disorders; it affects individuals’ thinking, perception, affect and behaviour. It can occur in

around 1% of the population. Aripiprazole is one of the newer antipsychotic medications introduced for the treatment of schizophrenia.

When compared with placebo, people taking aripiprazole had fewer relapses, smaller numbers of participants left study early, and needed

less additional antipsychotic medications. Insomnia and headache were the most commonly reported side effects, but were not much

difference to placebo. Side effects such as akathisia, nausea and weight gain occurred more in the aripripazole group as compared to

placebo. There has been a worry with newer antipsychotic medications and their effect on conductance problems in the heart, impaired

glucose levels and excessive production of prolactin (which can cause unpleasant breast pain and secretion). On the limited evidence

available (due to participants leaving early and fewer studies) aripiprazole appears to have a similar effect to that of placebo. The overall

finding on its efficacy in treating schizophrenia is unchanged from those found in the original review.



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Aripiprazole compared with placebo for schizophrenia

Patient or population: people with schizophrenia or like psychosis

Settings: outpatient, inpatient

Intervention: aripiprazole oral or IM

Comparison: placebo oral or IM

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No of Participants

(studies)

Quality of the evidence

(GRADE)

Comments

Assumed risk Corresponding risk

Placebo Aripiprazole

Poor compliance with

study protocol

16 per 100 11 per 100 RR 0.72 (0.53 to 0.97) 2275

(8 studies)

++OO

low

Relapse 61 per 100 40 per 100 RR 0.66 (0.57 to 0.75) 573 (2 studies) ++OO

low

Weight gain (equal or

greater then 7% of base-

line)

5.2 per 100 8.5 per 100 RR 2.33 (1.17 to 4.66) 615

(3 studies)

++OO

low

Concomitant medication

(Anxiolytic - Lorazepam)

84 per 100 85 per 100 OR 0.96 (0.61 TO 1.52) 787

(2 studies)

++OO

low

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the

assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; RR: risk ratio; OR: odds ratio; GRADE: GRADE Working Group grades of evidence (see explanations)

GRADE Working Group grades of evidence.

High quality (++++): further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality (+++O): further research is likely to have an important impact on our confidence in the estimate of effect and may

change the estimate.

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Low quality (++OO): further research is very likely to have an important impact on our confidence in the estimate of effect and is likely

to change the estimate.

Very low quality (+OOO): we are very uncertain about the estimate.

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B A C K G R O U N D

Description of the condition

Schizophrenia is one of the major psychiatric disorders; it affects in-

dividuals’ thinking, perception, affect and behaviour. The lifetime

prevalence of schizophrenia is reported to be between 0.4% and

1.4% across populations (Cannon 1996). Typically, schizophre-

nia is preceded by prodromal symptoms such as deterioration in

functioning, unusual behaviour, disturbed communications etc.;

these changes can be gradual. But a number of individuals may

not have any prodromal symptoms and present with an acute first

episode. The course of schizophrenia can be either continuous,

or episodic, with progressive or stable deficit, or there can be one

or more episodes with complete or incomplete remission (ICD

10). Between 14% and 20% of patients will recover fully; oth-

ers will show improvement, but will have recurrences. The early

stages of schizophrenia are characterised by repeated exaggeration

of symptoms, with a high proportion responding to the initial

treatment of antipsychotic medications. Around 80% will relapse

within five years (NICE 2009). The mortality amongst people

with schizophrenia is approximately 50% above the general pop-

ulation, partly related to high suicide rates, violent deaths and in-

creased risk of physical health problems (NICE 2009).

Description of the intervention

’Atypical’ or ’second generation’ antipsychotics include drugs such

as clozapine, olanzapine, risperidone, quetiapine, amisulpiride and

ziprasidone. Initially, these were said to differ from typical antipsy-

chotics in that they were found not to cause movement disorders

(catalepsy) in rats at clinically effective doses (Arnt 1998). These

atypical drugs, however, are far from ideal, and problematic adverse

effects do occur. With the exception of ziprasidone, most atypicals

are associated with weight gain (Anath 2003). Clozapine, which is

used for people whose illness is ’treatment-resistant’, may induce

life-threatening decreases in white blood cells (agranulocytosis) as

well as heart problems (acute myocarditis, cardiomyopathy) and

diabetes (Rivas-Vasquez 2003). Atypical antipsychotics are costly

but may be better tolerated than older anitpyschotics, with less

frequent extrapyramidal symptoms are reported. Aripiprazole is

reported to cause little or no elevation of prolactin concentration.

Aripiprazole is claimed to be at least as effective for positive symp-

toms of schizophrenia and negative symptoms of schizophrenia.

It has also been suggested that aripiprazole may be associated with

fewer movement disorders (parkinsonism, dystonias, tardive dysk-

inesia), less weight gain and reduced negative effects on the heart

(QTc interval abnormalities) and on glucose metabolism com-

pared with standard antipsychotics (Rivas-Vasquez 2003).

How the intervention might work

Technical background

Aripiprazole is said to be the prototype of a new third generation of

antipsychotics, the so-called dopamine-serotonin system stabilis-

ers (McQuade 2002). It is reported to exert its antipsychotic effects

by acting as a partial agonist at D2 dopamine- and 5-HT1a sero-

tonin receptors, and as an antagonist at 5-HT2 serotonin receptors

(Grunder 2006). It has been postulated that, through the above

receptor site actions, and hence dopamine and serotonin system

stabilisation, a partial D2 agonist would be able to act as an antag-

onist in pathways where an abundance of dopamine was produc-

ing psychosis. However, it would stimulate receptors as an agonist

at sites in which low dopaminergic tone would produce side ef-

fects (e.g. areas mediating motor movement and prolactin release)

(Rivas-Vasquez 2003). Aripiprazole, however, also has an affinity

to other receptors including D3, D4, 5-HT2c, 5-HT7, alpha-1

adrenergic and H1 histamine receptors (Burris 2002). When taken

orally, aripiprazole has bioavailability of 87% and peak plasma

concentration occurring at three to five hours; the recommended

target dose for aripiprazole is 10 mg to 15 mg per day (dose range

10 mg to 30 mg) (Abilify 2006). Phase III trials were initially

conducted in Japan in 1995, and the drug was granted approved

status for the treatment of schizophrenia by the Food and Drug

Adminstration (USA) on 15 November 2002 (FDA 2002a). Arip-

iprazole has since been licensed in most countries worldwide, and

is available as tablets, orally disintegrating tablets, oral solution

and intramuscular injection.

Why it is important to do this review

Aripiprazole is one of the newer antipsychotic medications; it is

marketed as having a different mechanism of action and a better

side effect profile compared to others, particularly with regard to

weight gain and prolactin levels. This review looks at, and updates

data from a single comparison of a previous systematic review,

Aripiprazole for schizophrenia (El-Sayeh 2006). A single compar-

ison has been split out of the old review and used to create a

new review, one that assesses aripiprazole’s efficacy and side effects

compared to placebo. This placebo review will then become part

of a family of aripiprazole reviews: Aripiprazole versus typical an-

tipyschotics (Bhattacharjee 2008) and Aripiprazole versus other

atypical antipsychotics (Komossa 2007).

O B J E C T I V E S

To review the effects of aripiprazole compared with placebo for

people with schizophrenia or other psychotic disorders or affective

psychotic disorders.



M E T H O D S

Criteria for considering studies for this review

Types of studies

We included all relevant randomised controlled trials. Where a trial

was described as ’double-blind’, but it was implied that the study

was randomised, we included the trial in a sensitivity analysis. If

there was no substantive difference within primary outcomes (see

’types of outcome measures’) when these ’implied randomisation’

studies were added, then we included these in the final analysis.

If there was a substantive difference, we only analysed clearly ran-

domised trials and described the results of the sensitivity analysis

in the text. We excluded quasi-randomised studies, such as those

allocating by using alternate days of the week. Randomised cross-

over studies were eligible, but only data up to the point of first

cross-over because of the instability of the problem behaviours and

the likely carryover effects of all treatments.

Types of participants

We included people with schizophrenia and other types of

schizophrenia-like psychosis (e.g. schizophreniform and schizoaf-

fective disorders), irrespective of the diagnostic criteria used. There

is no clear evidence that the schizophrenia-like psychoses are

caused by fundamentally different disease processes or require dif-

ferent treatment approaches (Carpenter 1994).

Types of interventions

1. Aripiprazole: any dose or form of application.

2. Placebo or no treatment.

Types of outcome measures

We grouped outcomes into the acute (up to one week), short term

(up to 12 weeks), medium term (13 to 26 weeks) and long term

(more than 26 weeks).

Primary outcomes

We chose relapse (as defined in the individual studies) as the pri-

mary outcome measure.

Secondary outcomes

1. Death - suicide and natural causes

2. Global state

2.1 Relapse as defined in the individual studies.

2.2 Poor compliance with study protocol due to lack of efficacy,

deterioration or psychosis.

2.3 Needing additional antipsychotic medication.

2.4 Needing additional benzodiazepines.

3. Service outcomes

3.1 Hospitalisation

3.2 Time to hospitalisation

4. Mental state (with particular reference to the positive and neg-

ative symptoms of schizophrenia)

4.1 No clinically important change in general mental state

4.2 Average endpoint general mental state score

4.3 Average change in general mental state scores

4.4 No clinically important change in specific symptoms (positive

symptoms of schizophrenia, negative symptoms of schizophrenia,

depression, mania)

4.5 Average endpoint specific symptom score

4.6 Average change in specific symptom scores

5. General functioning.

5.1 No clinically important change in general functioning

5.2 Average endpoint general functioning score

5.3 Average change in general functioning scores

5.4 No clinically important change in specific aspects of function-

ing, such as social or life skills

5.5 Average endpoint specific aspects of functioning, such as social

or life skills

5.6 Average change in specific aspects of functioning, such as social

or life skills

4. Behaviour

4.1 No clinically important change in general behaviour

4.2 Average endpoint general behaviour score

4.3 Average change in general behaviour scores

4.4 No clinically important change in specific aspects of behaviour

4.5 Average endpoint specific aspects of behaviour

4.6 Average change in specific aspects of behaviour

6. Adverse effects - general and specific (particularly movement

disorders, and those known to occur with newer antipsychotic

medications such as weight gain, glucose imbalance, hypotension,

QTc changes, tachycardia, raised prolactin, blood dyscrasias, sex-

ual side effects, anxiety, somnolence, disturbances of the gastroin-

testinal tract and headache)

6.1 Clinically important general adverse effects

6.2 Average endpoint general adverse effect score

6.3 Average change in general adverse effect scores

6.4 Clinically important specific adverse effects

6.5 Average endpoint specific adverse effects

6.6 Average change in specific adverse effects

7. Engagement with services

8. Satisfaction with treatment

8.1 Leaving the study early

8.2 Recipient of care not satisfied with treatment

8.3 Recipient of care average satisfaction score

8.4 Recipient of care average change in satisfaction scores

8.5 Carer not satisfied with treatment

8.6 Carer average satisfaction score

8.7 Carer average change in satisfaction scores



9. Quality of life

9.1 No clinically important change in quality of life

9.2 Average endpoint quality of life score

9.3 Average change in quality of life scores

9.4 No clinically important change in specific aspects of quality

of life

9.5 Average endpoint specific aspects of quality of life

9.6 Average change in specific aspects of quality of life

10. Cognitive functioning

10.1 No clinically important change in cognitive functioning

10.2 Average endpoint cognitive functioning score

10.3 Average change in cognitive functioning scores

10.4 No clinically important change in specific aspects of cognitive

functioning

10.5 Average endpoint specific aspects of cognitive functioning

10.6 Average change in specific aspects of cognitive functioning

Search methods for identification of studies

Electronic searches

1. We searched The Cochrane Schizophrenia Groups Trials Reg-

ister (January 2007); An initial search was done in May 2007 and

second search was in August 2008, using the phrase:

[aripiprazole* or abilitat* or abilify* in title or *aripiprazole* or

*abilitat* or *abilify* in abstract, index terms of REFERENCE]

or [aripiprazole* in interventions of STUDY]

This register is compiled by systematic searches of major databases,

hand searches and conference proceedings (see Group Module).

2. The US Food and Drugs Administration (August 2003 and

January 2007). For this update HGE searched the whole site in

August 2008 site using the phrases ’aripiprazole’ and ’abilify’.

Searching other resources

1. Reference searching

We inspected the references of all identified studies for more trials.

2. Personal contact

Where necessary, we contacted authors of trials for missing data,

and additional unpublished studies.

Data collection and analysis

Selection of studies

RBB inspected all reports. HGE then re-inspected these in order

to ensure reliable selection. We resolved any disagreement by dis-

cussion, and where doubt remained, we acquired the full article

for further inspection. Once we obtained the full articles, we (RBB

and HGE) decided whether the studies met the review criteria. If

we could not resolve disagreement by discussion, we sought fur-

ther information and added these trials to the list of those awaiting

assessment.

Data extraction and management

1. Extraction

We electronically extracted initial data from the Aripripazole for

schizophrenia review (El-Sayeh 2006). RBB independently ex-

tracted additional data from selected trials, while HGE separately

re-examined the information. When disputes arose we attempted

to resolve these by discussion. When this was not possible and

further information was necessary to resolve the dilemma, we did

not enter data and added the trial to the list of those awaiting

assessment.

2. Management

2.1 Forms

We extracted data onto standard, simple forms.

2.2 Scale-derived data

We included continuous data from rating scales only if:

a. the psychometric properties of the measuring instrument have

been described in a peer-reviewed journal (Marshall 2000); and

b. the measuring instrument has not been written or modified by

one of the trialists for that particular trial.

Ideally the measuring instrument should either be i. a self-report

or ii. completed by an independent rater or relative (not the thera-

pist). We realise that this is not often reported clearly, in Descrip-

tion of studies noted if this is the case or not.

2.3 Endpoint versus change data

There are advantages of both endpoint and change data. Change

data can remove a component of between-person variability from

the analysis. On the other hand calculation of change needs two

assessments (baseline and endpoint) which can be difficult in un-

stable and difficult to measure conditions such as schizophrenia.

We decided to primarily use endpoint data, and only use change

data if the former were not available. We combined endpoint and

change data in the analysis as we used mean differences (MD)

rather than standardised mean differences throughout (Higgins

2011).



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2.4 Skewed data

Continuous data on clinical and social outcomes are often not

normally distributed. To avoid the pitfall of applying paramet-

ric tests to non-parametric data, we aimed to apply the following

standards to all data before inclusion: a) standard deviations and

means are reported in the paper or obtainable from the authors;

b) when a scale starts from the finite number zero, the standard

deviation, when multiplied by two, is less than the mean (as oth-

erwise the mean is unlikely to be an appropriate measure of the

centre of the distribution, (Altman 1996); c) if a scale started from

a positive value (such as PANSS which can have values from 30

to 210) the calculation described above was modified to take the

scale starting point into account. In these cases skew is present

if 2SD>(S-S min), where S is the mean score and S min is the

minimum score. Endpoint scores on scales often have a finite start

and end point and these rules can be applied. When continuous

data are presented on a scale that includes a possibility of negative

values (such as change data), it is difficult to tell whether data are

skewed or not. We entered skewed data from studies of less than

200 participants in additional tables rather than into an analysis.

Skewed data pose less of a problem when looking at mean if the

sample size is large, we entered such data into syntheses.

2.5 Common measure

To facilitate comparison between trials, we intended to convert

variables that can be reported in different metrics, such as days in

hospital (mean days per year, per week or per month) to a common

metric (e.g. mean days per month).

2.6 Conversion of continuous to binary

Where possible, we made efforts to convert outcome measures

to dichotomous data. This can be done by identifying cut-off

points on rating scales and dividing participants accordingly into

’clinically improved’ or ’not clinically improved’. It is generally

assumed that if there is a 50% reduction in a scale-derived score

such as the Brief Psychiatric Rating Scale (BPRS, Overall 1962)

or the Positive and Negative Syndrome Scale (PANSS, Kay 1986),

this could be considered as a clinically significant response (Leucht

2005; Leucht 2005a). If data based on these thresholds were not

available, we used the primary cut-off presented by the original

authors.

2.7 Direction of graphs

Where possible, we entered data in such a way that the area to

the left of the line of no effect indicated a favourable outcome for

aripiprazole. Where keeping to this made it impossible to avoid

outcome titles with clumsy double-negatives (e.g. ’Not improved’)

we reported data where the left of the line indicates an unfavourable

outcome. This was noted in the relevant graphs.

2.8 Summary of findings table

We used the GRADE approach to interpret findings (Schünemann

2008) and used GRADE profiler (GRADEPRO) to import data

from Review Manager 5 (RevMan) to create ’Summary of findings’

tables. These tables provide outcome-specific information con-

cerning the overall quality of evidence from each included study

in the comparison, the magnitude of effect of the interventions

examined, and the sum of available data on all outcomes we rated

as important to patient-care and decision making. We selected the

following main outcomes for inclusion in the summary of findings

table:

• Poor compliance with study protocol

• Relapse

• Weight gain (equal or greater then 7% of baseline)

• Concomitant medication (Anxiolytic - Lorazepam)

Assessment of risk of bias in included studies

RBB worked independently to assess risk of bias by using criteria

described in the Cochrane Handbook for Systematic Reviews of In-

terventions (Higgins 2011) to assess trial quality. This set of criteria

is based on evidence of associations between overestimate of effect

and high risk of bias of the article such as sequence generation,

allocation concealment, blinding, incomplete outcome data and

selective reporting.

If the raters disagreed, we made the final rating by consensus, with

the involvement of another member of the review group. Where

inadequate details of randomisation and other characteristics of

trials were provided, we contacted authors of the studies in order

to obtain further information. We reported non-concurrence in

quality assessment, but if disputes arose as to which category a

trial was to be allocated, again, we achieved resolution was by

discussion.

The level of risk of bias was noted in both the text of the review

and in the Summary of findings for the main comparison.

Measures of treatment effect

1. Binary data

For binary outcomes we calculated a standard estimation of the

risk ratio (RR) and its 95% confidence interval (CI). It has been

shown that RR is more intuitive (Boissel 1999) than odds ratios

and that odds ratios tend to be interpreted as RR by clinicians

(Deeks 2000). For statistically significant results we had planned

to calculate the number needed to treat to provide benefit /to

induce harm statistic (NNTB/H), and its 95% confidence interval

(CI) using Visual Rx (http://www.nntonline.net/) taking account

of the event rate in the control group. This, however, has been

superseded by Summary of findings for the main comparison and

calculations therein.



http://www.ims.cochrane.org/revman/gradepro

http://www.ims.cochrane.org/revman

2. Continuous data

For continuous outcomes we estimated mean difference (MD) be-

tween groups. We would prefer not to calculate effect size mea-

sures (standardised mean difference SMD). However, if scales of

very considerable similarity were used, we presumed there was a

small difference in measurement, and we would have calculated

effect size and transformed the effect back to the units of one or

more of the specific instruments.

Unit of analysis issues

1. Cluster trials

If cluster studies had been appropriately analysed taking into ac-

count ICCs and relevant data documented in the report, synthe-

sis with other studies would have been possible using the generic

inverse variance technique.

2. Cross-over trials

A major concern of cross-over trials is the carry-over effect. It oc-

curs if an effect (e.g. pharmacological, physiological or psycholog-

ical) of the treatment in the first phase is carried over to the second

phase. As a consequence, on entry to the second phase the par-

ticipants can differ systematically from their initial state despite a

wash-out phase. For the same reason, cross-over trials are not ap-

propriate if the condition of interest is unstable (Elbourne 2002).

As both effects are very likely in schizophrenia, we have only used

data of the first phase of cross-over studies.

3. Studies with multiple treatment groups

Where a study involved more than two treatment arms, if rele-

vant, the additional treatment arms were presented in compar-

isons. Where the additional treatment arms were not relevant,

these data were not reproduced.

Dealing with missing data

1. Overall loss of credibility

At some degree of loss to follow-up data must lose credibility (Xia

2007). We were forced to make a judgment where this was likely

for the trials included in this review. Should more than 40% of

data be unaccounted for by eight weeks, we did not reproduce

these data or use them within analyses.

2. Binary

Where attrition for a binary outcome is between 0% and 40%,

and outcomes of these people are described, we included these data

as reported. Where the outcomes of such people were not clearly

described, we assumed the worst primary outcome, and rates of

adverse effects similar to those who did continue to have their data

recorded.

Assessment of heterogeneity

Clinical heterogeneity

First, we considered all the included studies within any compar-

ison to judge clinical heterogeneity. We then visually inspected

the graphs to investigate the possibility of statistical heterogene-

ity and supplemented this using, primarily, the I2. This provides

an estimate of the percentage of variability due to heterogeneity

rather than chance alone. Where the I2 estimate was greater than

or equal to 70%, we interpreted this as indicating the presence of

high levels of heterogeneity (Higgins 2003). If inconsistency had

been high, data would not have been summated, but we would

have presented them separately and investigated reasons for het-

erogeneity.

Assessment of reporting biases

Reporting biases arise when the dissemination of research findings

is influenced by the nature and direction of results (Egger 1997).

We are aware that funnel plots may be useful in investigating

reporting biases but are of limited power to detect small-study

effects. We did not use funnel plots for outcomes where there were

10 or fewer studies, or where all studies were of similar sizes. In

other cases, where funnel plots were possible, we sought statistical

advice in their interpretation.

Data synthesis

1. Analysis

Where possible we employed a fixed-effect model for analyses. We

understand that there is no closed argument for preference for

use of fixed-effect or random-effects models. The random-effects

method incorporates an assumption that the different studies are

estimating different, yet related, intervention effects. While this

seem accurate to us, the random-effects method does put added

weight onto the smaller of the studies - those trials that are most

vulnerable to bias. For this reason we favour using fixed-effect

models, employing random-effects when we detected heterogene-

ity.



2. General

Where possible, we entered data in such a way that the area to

the left of the line of no effect indicated a favourable outcome for

aripiprazole.

Subgroup analysis and investigation of heterogeneity

We did not carry out any subgroup analysis. We visually inspected

graphs to investigate the possibility of statistical heterogeneity. We

supplemented this by using primarily the I2 statistic. This provides

an estimate of the percentage of variability due to heterogeneity

rather than chance alone. Where the I2 estimate was greater than

or equal to 75%, we interpreted this as indicating the presence of

considerable levels of heterogeneity (Higgins 2003). Where het-

erogeneity was present, we investigated reasons for this. If it sub-

stantially altered the results, we did not summate data, but pre-

sented the data separately and investigated reasons for heterogene-

ity.

Sensitivity analysis

We compared results for high doses (however ’high’ was defined

in the study or, if such a definition was not presented, greater than

15 mg aripiprazole per day) to those for lower doses with regard

to the primary outcome of relapse.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies; Characteristics of studies awaiting classification.

1. Included studies

We identified nine studies that we could include. All were de-

scribed as randomised and as being double blind, although allo-

cation concealment was not adequately described in all studies.

Two main reasons for exclusion were non-randomised studies and

studies with active control without a placebo arm.

For substantive descriptions of the studies please see

Characteristics of included studies and Characteristics of excluded

studies .

2. Studies waiting assessment

Two studies currently await assessment. In both studies, partic-

ipants were adolescents. Nyilas 2007 is a six-week multi-centre

double blind randomised controlled trial; participants were 13 to

17 years old with a DSM-IV diagnosis of schizophrenia (N = 302).

Carson 2008 is a randomised placebo controlled trial on paediatric

participants (aged 10 to 17) with a DSM-IV diagnosis of bipolar

1 disorder (N = 296).

We have already contacted the lead authors for more information

on these trials; at the time of writing this report we have not

received study data.

Results of the search

For this placebo review we conducted an initial electronic search

on 15th May 2007; as there was a delay in writing report we car-

ried out another search on 13th of August 2008. RB inspected 359

electronic and 135 PDF reports from the first search, as well as 239

electronic reports and 237 PDF reports from the second search.

The original aripiprazole review had 15 studies; we included nine

studies from this review, excluding the other six as they were arip-

iprazole versus active control. J Xia inspected reports on the Chi-

nese-language studies.

Included studies

3. Included studies

3.1 Length of trials

Schizophrenia is a lifelong illness that affects young people. Out of

the nine included studies; six reported data on short-term follow-

up of up to six weeks ( Adson 2003; Carson 2000; Csernansky

2003; Daniel 2000; Marcus 2005; Potkin 2003), one on medium-

term follow-up of 26 weeks (Carson 2004) and two studies in-

volved the administration intramuscular preparation reported data

on 24 hours period (Daniel 2004, Oren 2005). There are no stud-

ies reporting on long term follow up i.e. above 26 weeks.

3.2 Participants

Three of the nine included studies involved participants without

clearly operationalised diagnoses (Carson 2002 b; Daniel 2004;

Marcus 2005). All nine trials included people with a diagnosis of

schizophrenia. Four studies included people with schizophrenia

and/or schizoaffective disorder (Carson 2000 a; Daniel 2004; Oren

2005; Potkin 2003). The majority of participants in most studies

were male, and had a mean age in their late thirties to early forties.

In four trials we could not elicit definitive exclusion criteria from

available reports (Carson 2002 b; Daniel 2004; Marcus 2005;

Oren 2005). Adson 2003 and Potkin 2003 required people taking

part in the trial to have had a history of response to other antipsy-

chotics excluding clozapine. Daniel 2000 excluded people with a

history of resistance to anti-psychotic medication. Most people in

these studies were moderately to severely ill and many were acutely

ill.



3.3 Setting

Eight of the nine studies were described as occurring in hospital

or inpatient settings (Adson 2003; Carson 2000 a; Csernansky

2003; Daniel 2000; Daniel 2004; Marcus 2005; Oren 2005;

Potkin 2003). One trial took place in out-patient or mixed settings

(Carson 2002 b).

3.4 Study size

All the studies included between 200 and 500 participants except

Csernansky 2003, which randomised only 103 participants.

3.5 Interventions

The trialists administered aripiprazole in a wide range of doses

from 1 mg to 30 mg per day, with placebo as a comparator. Most

drugs were given orally, except in two studies in which medication

was given intramuscularly (Daniel 2004; Oren 2005).

3.6 Outcomes

Carson 2002 b compared aripiprazole with placebo and reported

usable data on global state and mean change in CGI. No other

study explicitly reported usable data on this outcome. We have

used ’poor compliance with study protocol due to lack of efficacy,

deterioration or psychosis’ as a global outcome because, surpris-

ingly, there were no more data relevant to global outcomes to be

found in any of the reports.

Studies reported usable data on adverse effects spontaneously re-

ported in more than 5% to 10% of participants. This design pre-

cludes reporting of important less frequent effects. Two studies

reported usable weight gain data; in Carson 2002 b weight gain

of at least 7% was documented as being clinically significant and

Potkin 2003 reported the mean change in body weight.

All but one included study provide usable data on leaving the study

early.

3.6.1 Outcome scales

We have provided details of only the scales that provided usable

data. We have outlined reasons for exclusions of data under ’Out-

comes’ in the Characteristics of included studies

3.6.1.1 Global state - Clinical Global Impression Scale - CGI Scale

(Guy 1976)

This is used to assess both severity of illness and clinical improve-

ment, by comparing the conditions of the person standardised

against other people with the same diagnosis. A seven-point scor-

ing system is usually used, with low scores showing decreased sever-

ity and/or overall improvement. A CGI-I (CGI-Improvement)

score was also validated for used in this review. Carson 2002 b

reported usable data for this outcome.

3.6.1.2 Mental state - Positive and Negative Syndrome Scale -

PANSS (0)

This schizophrenia scale has 30 items, each of which can be de-

fined on a seven-point scoring system varying from 1 - absent to 7

- extreme. This scale can be divided into three sub-scales for mea-

suring the severity of general psychopathology, positive symptoms

(PANSS-P) and negative symptoms (PANSS-N). A low score in-

dicates lesser severity. Kane 2003 reported data from this scale.

3.6.1.3 Quality of life - Quality of Life Scale - QLS, (Carpenter

1994)

This is a semi-structured interview administered and rated by

trained clinicians. It contains 21 items rated on a seven-point scale

based on the interviewer’s judgement of patient functioning. A

total QLS and four sub-scale scores are calculated, with higher

scores indicating less impairment.

3.6.2 Redundant data

Enormous efforts are invested in studies rating and recording data

that are then reported in such a way as to render them useless

for reviews such as this. For example, in Carson 2000 the trial-

ists compare aripiprazole with both haloperidol and placebo. Out-

comes such as death, clearly of interest, were reported in an ob-

scure manner so we could not be sure of either the number of

deaths or the groups in which they took place. We are only sure

that they did take place. At a meeting held with workers from the

Outcomes Research department of Bristol-Myers Squibb Pharma-

ceuticals (UK) on the 27th October 2004 in Leeds, we requested

further clarification on numerous data that appeared on the FDA

web site. In particular, we were concerned by the high death rates

observed in the two studies we identified by FDA study number. It

was jointly agreed that this information (as well as other important

data) would be provided to us when located by company staff. We

did not hear from the company again until we published a short

version of this review at a conference (El-Sayeh 2006). Thereafter,

in May 2006, one author (H E-S) and editor (CEA) met with

representatives of Bristol-Myers Squibb Pharmaceuticals. These

representatives were most helpful in clarifying data on the FDA

web site, specifically on death which, on further evaluation, do

not suggest an increased risk of mortality as indicated in the con-

ference review (El-Sayeh 2006). They also encouraged the review

authors to ask for more data. We have amended this version and

hope to do so again in light of more data provided by industry,

especially on those studies that await assessment.

Carson 2000 a reported continuous measures of global state (CGI)

but no variances are reported. The same applies to their repeated

measures of mental state (BPRS, BPRS-PANNS), general func-

tioning (CGI) and adverse effects (Simpson-Angus scale, Barnes

Akathisia scale, Abnormal Involuntary Movement scale) and other

outcome measures including changes in body weight, serum pro-

lactin, and QTc interval changes. This poor reporting is by no

means unique to Carson 2000 a (see ’Outcomes’, Characteristics

of included studies). Participants in trials may be appalled to know

how much of their data has been rendered useless. It is possible



that there is a systematic bias in which data, such as the simple

binary outcome of death, are not reported well.

3.6.3 Missing outcomes

We found no usable outcomes for the following categories: death,

service outcomes, general functioning, behaviour, engagement

with services, satisfaction with treatment, economic outcomes or

cognitive functioning.

3.6.4 Primary outcomes

Our primary outcome of relapse was only reported in Carson 2002

b, which compares aripiprazole with placebo. All other outcomes

in this review were of secondary importance to the review authors

but we do recognise that they may be of primary interest to others.

Excluded studies

The original review had 15 included studies and six excluded stud-

ies (aripiprazole versus active control without placebo arm). Dur-

ing our search, we came across several new studies in the pipeline

where aripiprazole is compared to another antipsychotic medica-

tion.

We excluded nine other studies from the review. Three were re-

view articles (Carson 2002 a; Petrie 1997; Kujawa 2003). We

excluded one study because participants were healthy volunteers

(Mallikaarjun 2000). We excluded Auby 2002 because, although

randomised, it evaluated one dose of aripiprazole versus another

and also reported no data that we could include. We will contact

the authors for further information. We excluded Stroup 2003

from the study because participants who received aripiprazole in

this trial were not randomised at that stage. We excluded Marcus

2003 since the study described was a review of other short-term

studies, not an original research article. We excluded Casey 2003

and Saha 2004 from this version of the review, as different admin-

istration regimens of aripiprazole were randomised rather than the

new drug versus others or placebo.

Risk of bias in included studies

We have provided information on summary of risk of bias across

all included studies in Figure 1 and Figure 2

Figure 1. Methodological quality graph: review authors’ judgements about each methodological quality

item presented as percentages across all included studies.



Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.



Allocation

All included studies were said to be randomised. None of the in-

cluded studies, however, explicitly detailed the method of ran-

domisation. No studies stated that those in charge of allocation

were blind to the participant list. This concealment of allocation

has repeatedly been shown to be of key importance in excluding

selection biases (Jüni P 2001). Therefore all trials were category B

(moderate risk of bias - some doubt about the results - see Meth-

ods). This was confirmed by poor ratings on the Jadad Scale (see

Characteristics of included studies) (Jadad 1996).

Blinding

Nine studies were described as being double-blind (Carson 2000

a; Carson 2002 b; Csernansky 2003; Daniel 2000; Daniel 2004;

Marcus 2005; McQuade 2003; Oren 2005; Potkin 2003). Adson

2003 was described as double-blind, but people who showed no

improvement or worsening of their symptoms by the third week

were offered the option of open-label treatment with aripiprazole

during the last three weeks of the study. In none of the studies was

testing of the blinding reported. Since blinding is recognised to be

important for minimising observation bias, it could be expected

that testing of this blinding be considered a priority.

Incomplete outcome data

Loss to follow-up

Several of the included studies reported data in terms of a last

observation carried forwards (LOCF) analysis and an OC analysis

(observed cases, defined as those completing the trial). Although

LOCF analyses are commonly used to account for missing ob-

servations, this technique could introduce bias as considerable as-

sumptions are made about people who did not stay in the study.

We saw no reporting of attempts to validate assumptions by fol-

lowing up people who did leave the study early. In some included

studies, rates of participants leaving early were more than 40%.

Using LOCF, 40% of the data on certain outcomes are assumed

and would lead to bias in the overall results.

The reasons for loss to follow-up are reasonably well reported and

we have documented these in the outcomes.

Selective reporting

Data reporting

Overall much of the data we found could not be used because of

poor reporting. Findings which are presented as graphs, in per-

centiles or just reported as P values are often of little use to a re-

viewer. Many studies failed to provide standard deviations when

reporting mean changes on a particular outcome measure

Other potential sources of bias

Aripiprazole being a relatively newer drug, it is not surprising that

all the trials were run by the drug company. Two studies with IM

preparation had 24-hour follow-up and a low rate of drop-out.

All other included studies have above four weeks follow-up and a

higher drop-out rate. The most common reason for drop-out in

both the arms of treatment was lack of efficacy.

The rates of attrition for individual studies are as follows: Adson

2003 0.66 (i.e. 34% of patients completed study); Carson 2000

a 0.40; Carson 2002 b 0.62; Csernansky 2003 0.48; Daniel 2000

0.40; Daniel 2004 0.05; Marcus 2005 0.47; Oren 2005 0.03; and

Potkin 2003 0.40.

Effects of interventions

See: Summary of findings for the main comparison

From the original review Aripripazole for schizophrenia, we iden-

tified 9 studies where aripripazole was compared with placebo; we

included all 9 studies. We carried out update searches in May 2007

and August 2008 to see if there are any new studies on Aripipra-

zole compared to placebo or any additional data on the existing

included studies. The two update searches did not find further

studies but provided additional study data, particularly on side

effects.

We also identified two new studies (Carson 2008; Nyilas 2007)

focusing on adolescent populations from conference posters. Since

the findings from these studies have been presented as graphs, in

percentiles or just reported as P values, we have not been able to

include them in the analysis at this stage. We contacted authors

for additional information but unable to get the data. This is

particularly unfortunate given that this age group is an important

subset of the general population, and research data and studies are

often lacking.

Comparison 1: ARIPIPRAZOLE versus PLACEBO

1. Global state

1.1 Relapse



Relapse was the primary outcome for this review. Only one

aripiprazole versus placebo comparison contained relevant data.

Carson 2002 b provided usable data for short-term (up to 12

weeks) relapse. There were significantly fewer relapses for people

given aripiprazole compared with those in the placebo group (n =

310, 1 RCT, RR 0.59 CI 0.45 to 0.77, NNT 5 CI 3.2 to 10.7).

The same study provided usable data for medium-term (13 to 26

weeks) relapse. Again the aripiprazole group had significantly less

relapse compared with people given placebo (n = 310, 1 RCT, RR

0.66 CI 0.53 to 0.81, NNT 5 CI 3.0 to 8.5).

1.2 Poor compliance with study protocol due to lack of

efficacy, deterioration or psychosis

Two studies with IM preparation had follow-up at 24 hours and

a low rate of leaving the study early. All other studies (one-week

to 12-week duration) gave several reasons for the poor compli-

ance with study protocol, and several seemed to fall into a natu-

ral grouping reporting a poor global outcome. We have grouped

these throughout the review. Overall people allocated to aripipra-

zole encountered this outcome significantly less than those given

placebo (n = 2275, 8 RCTs, RR 0.74 CI 0.59 to 0.93, NNT 21

CI 12.7 to 60.5).

1.3 Needing additional antipsychotic medication

Four studies reported this outcome, one acute (up to one week)

and other three from short term (one week to 12 week). There was

significantly less need for additional antipsychotic medication in

those randomised to aripiprazole compared to those given placebo

(n = 1062, 4 RCTs, RR 0.73 CI 0.57 to 0.93, NNT 16 CI 8.9 to

73.2).

1.4 Needing additional benzodiazepines

Two studies, one from acute (up to one week) and one from short

term (one week to 12 week) reported this outcome. There was

significantly less need for additional benzodiazepine treatment in

those randomised to aripiprazole compared to those given placebo

(n = 683, 2 RCT, RR 0.53 CI 0.3 to 0.92, NNT 18).

Caution is advised in interpreting these results: in two studies

lorazepam was given as an anxiolytics and was received by 85% of

patients in both arms (section 4).

2. Adverse effects

2.1 Insomnia and headaches

Insomnia (~23%) (n = 1298, 4 RCTs, RR 1.09 CI 0.89 to 1.33,

NNH 46) and headaches (~15%) (n = 1962, 6 RCTs, RR 1.17 CI

0.94 to 1.47, NNH 33) were commonly reported in both groups

with no significant difference.

2.2 Akathisia, nausea, sedation, weight gain

People on aripiprazole were more likely to develop akathisia (n =

1595, 5 RCTs, RR 1.78 CI 1.16 to 2.74, NNH 34); nausea (n =

1962, 6 RCTs, RR 1.55 CI 1.07 to 2.24, NNH 27); sedation (n

= 1347, 4 RCTs, RR 1.82 CI 1.06 to 3.15, NNH 23); and weight

gain of equal to or greater than 7% of baseline weight (n = 615, 3

RCTs, RR 2.55 CI 1.35 to 4.82, NNH 20).

2.3 Constipation, dizziness, tachycardia, diarrhoea

Constipation was experienced by 7.3% of patients (n = 787, 2

RCTs, RR 1.42 CI 0.75 to 2.69, NNH 43); dizziness by 7.4%

of patients (n = 1347, 4 RCTs, RR 1.34 CI 0.83 to 2.14, NNH

33); tachycardia by 4.6% (n = 1084, 3 RCTs, RR 1.94 CI 0.89 to

4.25, NNH 41); and diarrhoea by 4% (n = 887, 2 RCTs, RR 0.79

CI 0.40 to 1.56, NNH 55). There was no significant difference

between the two groups.

2.4 General extrapyramidal symptoms, movement disorders,

vomiting, anxiety, dyspepsia

There appears to be no significant difference between the two

comparator groups in terms of reported general extrapyramidal

symptoms (n = 1298, 4 RCTs, RR 0.83 CI 0.47 to 1.45, NNH

118); needing anti-parkinsonian medication (n = 1043, 4 RCTs,

RR 0.83 CI 0.61 to 1.14, NNH 33); vomiting (n = 1699, 5 RCTs,

RR 1.46 CI 0.96 to 2.33, NNH 46); anxiety (n = 1035, 3 RCTs,

RR 0.83 CI 0.62 to 1.12, NNH 25); and dyspepsia (n = 887, 2

RCTs, RR 0.88 CI 0.50 to 1.40, NNH 36).

2.5 Agitation

Agitation was less in the aripiprazole group (n = 980, 3 RCTs,

RR 0.61 CI 0.40 to 0.92, NNH 22). Aripripazole appeared to

produce significantly less rise in serum prolactin (increase to >/

= 23ng/ml) than placebo (n = 725, 2 RCT, RR 0.21 CI 0.11 to

0.37, NNT 9).

2.6 Additional side effects

One study (Marcus 2005) reported detailed side effects informa-

tion; these included toothache (n = 367, 1 RCTs, RR 1.47 CI

0.43 to 5.00); upper abdominal pain (n = 367, 1 RCTs, RR 4.13

CI 0.24 to 72.63); Infections (n = 367, 1 RCT, RR 0.57 CI 0.20

to1.65); skin rash (n = 367, 1 RCT, RR 3.47 CI 0.45 to 26.5);

cough (n = 367, 1 RCT, RR 1.89 CI 0.43 to 8.29); pharyngola-

ryngeal pain (n = 367, 1 RCT, RR 8.58 CI 0.52 to 142.92); all

were statistically insignificant. One study (Adson 2003) reported

asthenia, with no significant difference amongst the groups (n =

420, 1 RCT, RR 0.94 CI 0.41 to 2.17).



2.7 QTc interval

Two studies reported QTc interval of 450 or more or 10% above

baseline; 3 patients in the aripiprazole group showed these changes

whilst none from the placebo group. The difference was not sig-

nificant (n = 787, 2 RCTs, RR 2.44 CI 0.13 to 46.82, NNH 198).

For average change - QTc interval (ms) from baseline, there ap-

peared to be no significant difference between 20 mg/day aripipra-

zole and placebo on this continuous outcome measure (n = 204,

1 RCT, WMD 3.00 CI -3.19 to 9.19) and for the higher dose of

aripiprazole (30 mg/day) (n = 204, 1 RCT, WMD -1.00 CI -7.18

to 5.18), the standard deviations are very large and data could be

skewed.

2.8 Physiological (serum) measures

Physiological (serum) measures were reported by one study

(Carson 2002 b).

At 26 weeks there was no significant difference between groups on

total fasting cholesterol >/= 200 mg/dl (n = 310, 1 RCT, RR 1.21

CI 0.98 to1.50, NNH 10); total fasting cholesterol level >= 240

mg/dl (n = 310, 1 RCT, RR 1.22 CI 0.77 to 1.93, NNH 26); the

glucose levels of >/= 110mg/dl (n = 310, 1 RCT, RR 0.96 CI 0.7

to 1.33); haemoglobin 1AC (incidence >/= upper limit of normal)

(n = 310, 1 RCT, RR 0.74 CI 0.41 to 1.33); levels of low density

lipoprotein (>/= 130mg/dl) (n = 310, 1 RCT, RR 1.01 CI 0.80

to 1.28) and low density lipoprotein (>/= 160mg/dl) (n = 310, 1

RCT, RR 1.0 CI 0.62 to 1.61).

The same study measured triglycerides >= 200 mg/dl (n = 310,

1 RCT, RR 0.94 CI 0.67 to 1.31) and high density lipoprotein

(n = 310, 1 RCT, RR 0.86 CI 0.66 to 1.12) with no difference

amongst the groups.

3. Leaving the study early

We noted that data were heterogenous on visual inspection of

forest plot and had high I2. Significantly fewer people left (for any

reason) the aripiprazole group compared with those in the placebo

group (n = 2585, 9 RCTs, RR 0.73 CI 0.60 to 0.87, NNT 8,

95% CI 5.6 to 10.3). When the reason for leaving was recorded

as being due to adverse effects, there was no difference between

groups (n = 2585, 9 RCTS, RR 0.75 CI 0.42 to 1.35).

4. Concomitant medication

Two studies (Adson 2003; Marcus 2005) reported concomitant

use of anxiolytics and what appears to be lorazepam. This com-

bination was use in 85% of participants in both the groups (n =

787, OR 0.96 CI 0.61 to 1.52).

D I S C U S S I O N

Summary of main results

When compared with placebo, aripiprazole treated patients had

fewer relapses, fewer people left study early and needed less addi-

tional antipsychotic medications. Where reported, both the group

needed benzodiazepine/antianxiety medication (lorazepam) as an

adjunct treatment in most of the patients.

1. Applicability of findings

All the included studies occurred as multicentre trials in North

American and European settings. Clinicians should take this into

consideration when thinking of using aripiprazole in very different

settings of care.

The majority of trials involved inpatient participants with little in

the way of physical and psychiatric co-morbidity and with well-

defined schizophrenia or schizoaffective disorder. Such people are

a minority in everyday care, where people who are not in hospital

and suffer from less well defined illness, combined with problems

such as depression and substance abuse, are the norm. The reader

is subsequently left with the difficult decision as to whether the

findings of studies with such participants, interventions and out-

comes, gathered in standardised highly developed inpatient set-

tings, can still inform their daily practice.

2. Limited data, confusing data

The collection and quality of the data reported were very variable.

With the exception of one trial, no studies reported outcomes over

12 weeks. Aripiprazole is a relatively new antipsychotic medica-

tion, so it is not surprising that long-term studies are rare at this

point, but it is to be hoped that they are planned. Even if an in-

tervention works in the short term (by 12 weeks) there is no guar-

antee that this means that the compound has long-term benefits.

Data were often not used because of high drop-out rates. The

enormous degree of loss to follow-up is common in similar studies

of other compounds, but rare in everyday practice. This also casts

doubt on the applicability of findings to routine care. The design

of the studies is clearly encouraging loss to follow-up. People leave

for many reasons, often not specified, and their last observation is

carried forward to the end. These data, sometimes with an assump-

tion on over 50% of people are, nevertheless, acceptable to the

regulatory authorities. Until this ends, pharmaceutical companies

will see little reason to change their practices, as compounds such

as aripiprazole or any other new drug will gain licenses for clinical

use even if 40% to 60% of their data is unavailable. Often the tri-

alists do not have an obligation to follow people up for longer than

the period during which they took the medication. One possible

consequence of this might be that an extreme adverse reaction to

discontinuation of an intervention, such as death, would go un-

reported if it occurred a week after the treatment stopped. Data

beyond the discontinuation of the medications used within the

trial are collected but not reported. This data should be reported



since it is not the individual compounds in a trial which are ran-

domised, but the intention to give those individual compounds.

Some trialists tended to report mean figures without giving stan-

dard deviations. This renders averages meaningless and of no use

to review authors.

We found it disappointing that, despite considerable investment

in clinical trials, no outcome data were available on death, ser-

vice outcomes, general functioning, behaviour, engagement with

services, economic outcomes and cognitive functioning. The pri-

mary outcome of this review was relapse and data were available

on this in the aripiprazole-placebo comparison. Other outcomes

were of secondary importance to the review authors, but we have

reported what we can in order to present the most complete data

set possible for the reader.

Several trials only reported adverse effects which occurred in at

least 5% to 10% of participants, which could exclude potentially

serious less frequent outcomes. Randomised trials are limited in

their ability to highlight important rare outcomes, so further re-

stricting what is reported seems odd. We note that the design of

the trials did not limit reporting of positive outcomes to only those

that occurred at least 5% to 10% of the time.

Some data were obtained from conference proceedings and posters.

This made extraction difficult as results were often summarised.

Several studies were reported multiple times. Without unique

study identifiers, this gives the impressions that there are more

data than actually exist and facilitates erroneous double counting.

3. Comparison 1: aripiprazole versus placebo

3.1 Global state

3.1.1 Relapse

Relapse, the primary outcome for this review, was only reported

by Carson 2002 b and was defined in one of three ways: i. a CGI

rating of minimally worse; ii. a PANSS rating of moderately severe

on hostility or uncooperativeness on two successive days; or iii. >/

= 20% increase in total PANSS score from randomisation. This

implies first, that these measures of severity of illness are indeed

markers of a relapse and second, that the measures agree on the

severity of illness needed to constitute a relapse. We are not sure

that these scores on these measures really would constitute what

clinicians or recipients of care would call relapse. We think that

the ratings listed above would be moderate deterioration rather

than an event that would be universally recognised as relapse. Nev-

ertheless, it is genuinely heartening that aripiprazole helps avoid

these degrees of deterioration and that the number needed to treat

of five is not very large in either the short or medium term.

3.1.2 Poor compliance with study protocol due to lack of

efficacy, deterioration or psychosis

This category constituted patients leaving the study due to poor

efficacy, those with deterioration in their mental state and those

who developed frank psychosis. There was a significant difference

in favour of aripiprazole with regard to this outcome, although the

number needed to treat is high (NNT 21 CI 12 to 60).

3.1.3 Needing additional antipsychotic medication

Few people needed ’rescue’ antipsychotics in the aripiprazole group

as compared to placebo. It has to be seen as encouraging that

aripiprazole does seem to have some antipsychotic activity within

the four studies.

3.1.4 Needing additional benzodiazepines

There appeared to be significantly less need for benzodiazepine

medication in the aripiprazole treated patients (NNT 16). Two

studies used intramuscular medication, however, and the out-

comes were only reported over the short term (up to 24 hours)

(Daniel 2004; Oren 2005).

This needs to be taken in context as in two studies (Adson 2003;

Marcus 2005), the majority (85%) of the patients in both arms

received lorazepam as an anti-anxiety drug. This may suggest that

in the short term, there is a need for an additional benzodiazepine

similar to placebo.

3.2 Adverse effects

3.2.1 Clinically important specific adverse effects

Overall results from the included studies suggest that the akathisia,

nausea and weight gain were more common in those treated with

aripiprazole; there were no significant differences in reported ad-

verse effects in people taking placebo compared to those taking

aripiprazole. No objective rating scales appeared to be used in mea-

suring these symptoms, even though for certain symptoms such as

anxiety and extrapyramidal side effects, these are commonly used

in research. Potkin 2003 did repeatedly find more adverse effects

than Carson 2002 b and, although there is nothing in the methods

of the papers to suggest this, it may be that the former study used

more sensitive measures of adverse effects. Potkin 2003 did seem

to suggest that aripiprazole may be associated with extrapyrami-

dal symptoms, vomiting and weight gain. Although no different

from placebo, about 17% of people given aripiprazole were also

medicated with antiparkinson medication. It was unclear from all

studies, both those in this comparison and those including an ac-

tive control group, how the level of significant weight gain (seven

percent) was decided upon. There was no mention of this figure

in the methodology section of the included study reports and if



it was decided on after the data were inspected, any results would

be prone to bias.

3.2.2 Average change in QT interval (ms) from baseline (high

= poor)

From these data it does not seem that 20 mg/day or 30 mg/day of

aripiprazole affects the heart in this way.

3.2.3 Physiological (serum) measures

All data, mostly from Carson 2002 b, suggest little effect on mea-

sures of glucose and lipids. Patients with schizophrenia do have

higher risk of cardiovascular and metabolic disorders, and some

newer antipsychotic medications increase this risk. Aripripazole,

however, seems to have a neutral effect.

There did appear to be a significant difference in favour of arip-

iprazole in terms of the numbers of people with a rise in serum

prolactin to at least 23 ng/ml (NNT 9 CI 6.2 to 15.7). This may

have clinical implications in terms of the problems caused by high

prolactin, such as galactorrhoea. Potkin 2003 suggested that nu-

merical decline in the prolactin levels in the aripiprazole group is

consistent with partial agonism at the D2 receptors and mirror

results from their pre-clinical trials. However data were missing for

baseline mean serum prolactin levels in 8/103 people allocated to

placebo and 21/202 people given aripiprazole. We have assumed

that these people did not have raised prolactin, but if they did

and we were incorrect in our assumption, there would be no clear

finding in favour of aripiprazole.

3.3 Leaving the study early

Significantly fewer people left the aripiprazole group compared

with placebo (NNT 8 CI 5.6 to 10.3) for any reason. These data

are heterogeneous and if the two studies with the most extreme

results are removed (Csernansky 2003; Potkin 2003), data become

more homogeneous and much less favourable for aripiprazole. We

do not see obvious reasons for heterogeneity. However, nearly half

of all trial participants chose to leave early. This reflects negatively

on study design and means that much of the remaining data are

uninformative. Adverse effects did not seem to be a reason for

study attrition, although again data were heterogeneous. There is

no evidence from these studies that aripiprazole is a major cause of

unacceptable short-term adverse effects. Results from the (Carson

2002 b) study provided more accurate data, but this did not sig-

nificantly affect the overall results.

Overall completeness and applicability ofevidence

There is a lack of evidence on the efficacy of aripiprazole in

schizophrenia (i.e. showing improvement of the schizophrenia

symptoms rating scales). The studies rely on other factors, such

as compliance and smaller numbers of relapses as a measure of

efficacy.

1. Limited data, confusing data

The collection and quality of the data reported were very variable.

With the exception of one trial, no studies reported outcomes over

12 weeks. Aripiprazole is a relatively new antipsychotic medica-

tion, so it is not surprising that long-term studies are rare at this

point. However, it is to be hoped that they are planned. Even if

an intervention works in the short term (by 12 weeks) there is

no guarantee that this means that the compound has long-term

benefits.

Data were often not usable because of high drop-out rates. The

enormous degree of loss to follow-up is common in similar studies

of other compounds, but rare in everyday practice. This also casts

doubt on the applicability of findings to routine care. The design

of the studies is clearly encouraging loss to follow-up. People leave

for many reasons, often not specified, and their last observation is

carried forward to the end. These data, sometimes with an assump-

tion on over 50% of people are, nevertheless, acceptable to the

regulatory authorities. Until this ends, pharmaceutical companies

will see little reason to change their practices, as compounds such

as aripiprazole or any other new drug will gain licenses for clinical

use even if 40% to 60% of their data are unavailable. Often the tri-

alists do not have an obligation to follow people up for longer than

the period during which they took the medication. One possible

consequence of this might be that an extreme adverse reaction to

discontinuation of an intervention, such as death, would go un-

reported if it occurred a week after the treatment stopped. Data

beyond the discontinuation of the medications used within the

trial are collected but not reported. This data should be reported

since it is not the individual compounds in a trial which are ran-

domised, but the intention to give those individual compounds.

Some trialists tended to report mean figures without giving stan-

dard deviations. This renders averages meaningless and of no use

to review authors.

We found it disappointing that, despite considerable investment

in clinical trials, no outcome data were available on death, ser-

vice outcomes, general functioning, behaviour, engagement with

services, economic outcomes and cognitive functioning. The pri-

mary outcome of this review was relapse and data were available

on this in the aripiprazole-placebo comparison. Other outcomes

were of secondary importance to the review authors, but we have

reported what we can in order to present the most complete data

set possible for the reader.

Several trials only reported adverse effects which occurred in at

least 5% to 10% of participants, which could exclude potentially

serious less frequent outcomes. Randomised trials are limited in

their ability to highlight important rare outcomes, so further re-

stricting what is reported seems odd. We note that the design of



the trials did not limit reporting of positive outcomes to only those

that occurred at least 5% to 10% of the time.

We obtained some of the data from conference proceedings and

posters. This made extraction difficult, as results were often sum-

marised. Several studies were multiply reported. Without unique

study identifiers this gives the impression that there are more data

than actually exist and facilitates erroneous double counting.

2. Applicability of findings

All the included studies occurred as multicentre trials in North

American and European settings. Clinicians should take this into

consideration when thinking of using aripiprazole in very different

settings of care.

The majority of trials involved inpatient participants with little in

the way of physical and psychiatric co-morbidity and with well-

defined schizophrenia or schizoaffective disorder. Such people are

a minority in everyday care, where people who are not in hospital

and suffer from less well-defined illness, combined with problems

such as depression and substance abuse, are the norm. The reader

is subsequently left with the difficult decision as to whether the

findings of studies with such participants, interventions and out-

comes and standardised highly developed inpatient settings can

still inform their daily practice.

Quality of the evidence

1. All of the included studies were published in journals, although

we obtained some data from conference proceedings and hand-

searching.

2. All included studies were sponsored by the pharmaceutical in-

dustry.

3. Schizophrenia is a chronic condition and the long-term effect

of an antipsychotic medication is important. We noted that the

duration of follow-up was relatively short (i.e. less then 12 weeks

except for one study where the follow-up was for 26 weeks). Lack

of long-term studies limited the overall quality of evidence.

4. All studies reported being double blind in their methods sec-

tions, but did not give any further details.

5. High rates of participants leaving the studies early is another

important factor limiting the quality of evidence.

6. We noted variation in the data reporting amongst studies.

Potential biases in the review process

There were no disagreement between authors on the numbers

extracted.

Agreements and disagreements with otherstudies or reviews

1. No additional studies identified for this update of the original

aripiprazole for schizophrenia review.

2. Number needed to treat calculation showed variation to the

original review even with the same data. Following discussion with

the co-author we used the online calculation method for all results

(http://www.graphpad.com/quickcalcs/NNT1.cfm).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

1. For people with schizophrenia

For this update, we found no new studies comparing aripiprazole

with placebo to add to those included in the original review and

update. However, we noted several new studies comparing arip-

iprazole with active control.

When compared with placebo, aripiprazole treated patients had

fewer relapses and fewer left study early, and needed less addi-

tional antipsychotic medications. Overall it appears that aripipra-

zole has a better side effect profile; those that were significantly

more prevalent than in the placebo group included akathisia, nau-

sea and weight gain.

There have been concerns in the medical community about the

effects of atypical antipsychotics on conductance problems in the

heart (QTc interval), increased prolactin levels (excessive produc-

tion of prolactin, which can cause unpleasant breast pain and se-

cretion) and glucose levels; on the limited evidence available (due

to subjects leaving study early and fewer studies), aripiprazole ap-

pears to have a similar effect to that of placebo. The overall finding

on its efficacy in treating schizophrenia is unchanged from what

we found in the original review.

2. For clinicians

Aripripazole efficacy on global state was superior to placebo in

one study. Aripripazole may offer significant advantages over other

atypicals in terms of outcomes, as it caused hyperprolactinaemia

and raised QTc interval; thus, aripiprazole’s effect appears to be

similar to that of placebo. More studies are needed to replicate

and validate these findings. In two studies, lorazepam was given to

85% of the patients in both arms, suggesting a need for additional

medication. Long-term studies are required to see how long this

is necessary.



3. For managers/policy makers

Aripiprazole is another new atypical antipsychotic drug and it does

seem to have an effect on some people with serious mental illnesses

such as schizophrenia. It appears to be tolerated well. Despite

the fact that thousands of people have been randomised in trials

of aripiprazole, there are no data on service outcomes and few

medium- or long-term data. In the context of finite resources, the

lack of good quality data leaves managers and policy makers with

difficult decisions to make.

Implications for research

1. General

As with all similar studies, public registration of a study before

anyone is randomised would ensure that participants could be

confident that people would know that the study had at least taken

place. Unique study numbers would help researchers to identify

single studies from multiple publications and reduce the risk of

duplicating the reporting of data. Compliance with CONSORT

(Moher 2001), both on the part of authors and editors, would help

to clarify methodology and many outcomes. Failure to comply

results in both loss of data and confusion in the results, neither of

which help clinicians, patients or managers.

Intention-to-treat analysis should be performed on all outcomes

and all trial data should be made easily accessible. A minimal re-

quirement should be that all data should, at least, be presented as

numbers. In addition, continuous data should be presented with

means, standard deviations (or standard errors) and the number of

participants. Data from graphs, P values of differences and state-

ments of significant or non-significant differences are of limited

value. Unfortunately, in spite of the large numbers of participants

randomised, we were unable to use most of the data in the trials

included in this review due to the high drop-out rates observed as

well as poor data reporting.

2. Specific

As an antipsychotic agent with a novel mechanism of action, arip-

iprazole is an interesting compound, but pragmatic, real world,

randomised controlled trials should be carried out to determine its

value in standard clinical practice. Studies of medium- and long-

term risks, including mortality, behaviour, satisfaction with treat-

ment and cost-effectiveness, in comparison to typical and atypical

antipsychotics, are a priority. Pragmatic entry criteria and non-

blinding with hard endpoints may be helpful in decreasing the

study attrition (Rowland 1998).

A C K N O W L E D G E M E N T S

The Cochrane Schizophrenia Group Editorial Base in Notting-

ham produces and maintains standard text for use in the methods

section of their reviews. We have used this text as the basis of what

appears here and adapted it as required.

We thank Mark Fenton, Judith Wright and Samantha Roberts for

their assistance in the literature searches, and Jun Xia for reviewing

Chinese studies. We would also like to thank Clive Adams, Claire

Irving, Bethany York and John Rathbone for their support during

this review.

R E F E R E N C E S

References to studies included in this review

Adson 2003 {unpublished data only}

Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify

(aripiprazole) tablets, medical review part 4. www.fda.gov/

cder/foi/nda/2002/21-436˙Abilify.htm. U.S. Food and

Drug Administration CDER, 2002:176–232.∗ Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify

(aripiprazole) tablets; medical review part 1. www.fda.gov/


Drug Administration CDER, 2002:1–50.

McEvoy J, Daniel D, Carson WH Jr, McQuade R, Marcus

R. A randomized, double blind, placebo controlled, study

of the efficacy and safety of aripripazole 10, 15, 0r 20 mg/

day for the treatment of patients with acute exacerbations of

the schizophrenia. Journal of Psychiatric Research 2007;41:

895–905.

Carson 2000 a {published data only}

Anutosh S, Ali MW, Ingenito G, Carson WH. Controlled

study of aripiprazole and haloperidol in schizophrenia.

European Psychiatry 2002;Suppl 1:103s.

Carson WH, Ali M, Dunbar G, Ingenito G, Saha AR. A

double-blind, placebo-controlled trial of aripiprazole and

haloperidol. Schizophrenia Research 2001;1-2:221–2.

Carson WH, Ali M, Saha AR, Dunbar GC, Ingenito G. A

double-blind, placebo-controlled trial of aripiprazole and

haloperidol in patients with schizophrenia or schizoaffective

disorder. Proceedings of the 39th Annual Meeting of the

American College of Neuropsychopharmacology; 2000 Dec

10-14; San Juan; Puerto Rico. 2000.∗ Carson WH, Kane JM, Ali M, Dunbar GC, Ingenito G.

Efficacy of aripiprazole in psychotic disorders: comparison

with haloperidol and placebo. Journal of the European



College of Neuropsychopharmacology 2000;10(Suppl 3):S309.











cder/foi/nda/2002/21-436˙Abilify.htm Vol. 2002:176–232.

Kane J, Ingenito G, Ali M. Efficacy of aripiprazole in

psychotic disorders: comparison with haloperidol and

placebo. Schizophrenia Research 2000;1:39.

Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito

GG, Zimbroff DL, Ali MW. Efficacy and safety of

aripiprazole and haloperidol versus placebo in patients

with schizophrenia and schizoaffective disorder. Journal of

Clinical Psychiatry 2002;9:763–71.

Kane JM, Ingenito G, Ali M. Efficacy of aripiprazole in


placebo. International Journal of Neuropsychopharmacology

2000;Suppl 1:S124.



placebo. Proceedings of the 155th Annual Meeting of

the American Psychiatric Association; 2002 May 18-23;

Philadelphia, PA, USA. 2002.



placebo. Proceedings of the 53rd Annual Meeting of


Chicago, USA. 2000.

Carson 2002 b {published data only}

Carson W, McQuade R, Saha A, Torbeyns A, Stock E.

Aripiprazole versus placebo for relapse prevention in patients

with chronic schizophrenia. Journal of the European College

of Neuropsychopharmacology 2002;12(Suppl 3):S288.

Carson W, Pigott T, Saha A, Ali M, McQuade RD, Torbeyns

AF, Stock E. Aripiprazole versus placebo in the treatment

of stable, chronic schizophrenia. Proceedings of the156th

Annual Meeting of the American Psychiatric Association;

2003 May 17-22; San Francisco, USA. 2003.∗ Carson WH, Pigott TA, Saha AR, Ali MW, McQuade

RD, Torbeyns AF, Stock EG. Aripiprazole vs placebo in the

treatment of chronic schizophrenia. International Journal of

Neuropsychopharmacology 2002;Suppl 1:S187.

Casey D, Saha A, Marcus R, Carson WH, McQuade RD,

Torbeyns AF, Stock E. Aripiprazole versus placebo for

relapse prevention in patients with chronic schizophrenia.

Schizophrenia Research 2003;60:276.



cder/foi/nda/2002/21-436˙Abilify.htm 2002:111–75.

Marder SR, Jody D, Kaplita S, Saha A, Carson W, Torbeyns

A, Stock EG. Glycemic control and plasma lipids in long-

term treatment with aripiprazole. Proceedings of the 156th


2003 May 17-22; San Francisco, USA 2003.

Pigott TA, Carson WH, Saha AR, Torbeyns AF, Stock EG,

Ingenito GG. Aripiprazole for the prevention of relapse in

stabilized patients with chronic schizophrenia: a placebo-

controlled 26-week study. Journal of Clinical Psychiatry

2003;64(9):1048–56.

Pigott TA, Saha AR, Ali MW, McQuade RD, Torbeyns

AF, William HC, Stock EG. Aripiprazole versus placebo

in the treatment of chronic schizophrenia. Proceedings of

the 155th Annual Meeting of the American Psychiatric

Association; 2002 May 18-23; Philadelphia, PA, USA.

2002.

Stock E, Marder SR, Jody D, Kaplita S, Saha A, Carson

W, Torbeyns A. Plasma lipids levels and glycemic control

in long-term treatment with aripiprazole. Journal of the

European College of Neuropsychopharmacology 2003;13(4):

S327.

Torbeyns A, Marder SR, Carson W, Jody D, Kaplita S, Saba

A, Stock E. Glycemic control and plasma lipids in long-

term treatment with aripiprazole. Schizophrenia Research

2004;67(1):192–3.

Csernansky 2003 {unpublished data only}∗ Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify












Daniel 2000 {published data only}∗ Daniel DG, Saha AR, Ingenito G, Carson WH,

Dunbar G. Aripiprazole, a novel antipsychotic: overview

of a phase II study result. International Journal of










Saha AR, Petrie JL, Ali MW. Safety and efficacy profile of

aripiprazole, a novel antipsychotic. Schizophrenia Research

1999;1-3:295.

Daniel 2004 {published data only}

Daniel DG, Stock EG, Wilber CH, Marcus RN, Carson

Jr WH, Manos G, Iwamoto T. Intramuscular aripiprazole

in acutely agitated psychotic patients. Proceedings of




Association; 2004 May 1-6; New York, USA. 2004.

Kungel M, Daniel D, Stock E, Wilber R, Marcus R,

Carson W, Manos G, Iwamoto T. Efficacy and safety of

intramuscular aripiprazole in acutely agitated patients with

psychosis. Thematic Conference of the World Psychiatric

Association on “Treatments in Psychiatry: An Update”;

2004 Nov 10-13; Florence, Italy. 2004.

Marcus 2005 {published data only}

Cutler A, Marcus R, Sterling A, Hardy A, O’Donnell A,

Carson W, McQuade R. The efficacy and safety of lower

doses of Aripripazole for the treatment of patients with

acute exacerbation of schizophrenia. CNS Spectr 2006;11

(9):691–702.

Marcus RN. Efficacy and safety of lower doses of

aripiprazole. Proceedings of the 158th Annual Meeting of


Atlanta, USA. 2005.

Oren 2005 {published data only}

Andrezina R, Josiassen R, Marcus R, Oren D, Manos

G, Stcok E, Carson W, Iwamoto T. Intramuscular

aripripazole for the treatment of acute agitation in patients

with schizophrenia or schizoaffective disorder: a double

blind, placebo controlled comparison with intramuscular

haloperidol. Psychopharmacology 2006;188:281–92.

Oren D, Marcus R, Kostic D, McQuade R, Iwamoto

T, Archibald D. Efficacy and safety of intramuscular

aripiprazole, haloperidol or placebo in acutely agitated

patients with schizophrenia or schizoaffective disorder.

Schizophrenia Bulletin 2005;31:499.

Yocca F. Intramuscular aripiprazole in acute schizophrenia:

a pivotal phase-three study. Proceedings of the 158th annual

meeting of the American Psychiatric Association; 2005 May

21-26; Atlanta, USA. 2005.

Potkin 2003 {published data only}

Carson WH, Saha AR, Ali M, Dunbar GC, Ingenito G.

Aripiprazole and risperidone versus placebo in schizophrenia

and schizoaffective disorder. Proceedings of the Annual

Meeting of the American Psychiatric Association; 2001 May

5-10; LA, USA. Marathon Multimedia, 2001.

Carson WH, Saha AR, Mirza A, Dunbar GC, Ingenito G.

Aripiprazole and risperidone versus placebo in schizophrenia

and schizoaffective disorder. Proceedings of the 155th


2002 May 18-23; Philadelphia, USA. 2002.













Potkin SG, Kujawa M, Carson WH, Saha AR, Ali M,

Ingenito G. Aripiprazole and risperidone versus placebo in

schizophrenia and schizoaffective disorder. Schizophrenia

Research 2003;60:300.∗ Potkin SG, Saha AR, Kuwaja MJ, Carson WH, Ali

M, Stock E, Stringfellow J, Ingenito G, Marder SR.

Aripiprazole, an antipsychotic with a novel mechanism

of action, and risperidone vs placebo and schizoaffective

disorder. Archives of General Psychiatry 2003;60:681–90.

Saha A, Carson W, Ali M, Dunbar G, Ingenito G. Efficacy

and safety of aripiprazole and risperidone vs. placebo in

patients with schizophrenia and schizoaffective disorder.

Proceedings of the 7th World Congress of Biological

Psychiatry; 2001 Jul 1-6; Berlin, Germany. 2001.

Yeung P, Kujawa M, Carson WH, Saha A, Alid M,


schizophrenia and schizoaffective disorder. Schizophrenia

Research 2002;3(Suppl 1):185–6.

Yeung P, McQuade RD, Carson WH, Saha A, Ali MW,


schizophrenia. European Psychiatry 2002;Suppl 1:102s.

Yeung PP, Carson WH, Saha A, McQuade RD, Ali M,

Stringfellow JC, Ingenito G. Efficacy of aripiprazole, a novel

antipsychotic, in schizophrenia and schizoaffective disorder:

results of a placebo-controlled trial with risperidone.

European Neuropsychopharmacology 2001;11(3):259.

References to studies excluded from this review

Allain 2005 {published and unpublished data}∗ Allain H. A prospective, multicenter, open-label

study of aripiprazole in the management of patients

with schizophrenia in general psychiatric practices

(Broad Effectiveness Trial With Aripiprazole- BETA).

www.clinicaltrials.gov 2005.

Auby 2002 {published data only}∗ Auby P, Saha A, Ali M, Ingenito G, Wilber R,

Bramer S. Safety and tolerability of aripiprazole at doses

higher than 30 mg. Journal of the European College of





Drug Administration CDER, 111–75.

Saha AR, Ali MW, Ingenito GG, Wilber R, Luo X, Bramer

S. Safety and tolerability of aripiprazole at doses higher than

30 mg. International Journal of Neuropsychopharmacology

2002;Suppl 1:S185.

Saha AR, Ali MW, Ingenito GG, Wilber R, Luo X, Bramer

S. Safety and tolerability of aripiprazole at doses higher

than 30 mg. Proceedings of the 155th Annual Meeting of


Philadelphia, PA, USA. 2002.

Beuzen 2005 {published data only}

Beuzen J-N, Pans M, Modell S, Hagens P, McQuade R,

Iwamoto T, Carson W. Naturalistic study of aripiprazole



treatment. Proceedings of the XIII World Congress of

Psychiatry; 2005 10-15th Sept; Cairo, Egypt. 2005.

Blonde 2004 {published data only}

Blonde L, Ray S, Corey-Lisle PK, Cislo PR, L’Italien G.

The risk of new-onset type 2 diabetes and coronary heart

disease in chronic schizophrenic patients treated with

aripiprazole and olanzapine. Journal of the European College


Carson 2002 a {published data only}∗ Carson WH, Ingenito GG, McQuade RD, Stock

EG, Iwamoto T. [Schizophrenia; safety/tolerability of

aripiprazole]. Proceedings of the XIIth World Congress of

Psychiatry; 2002 Aug 24-29; Yokohama, Japan. 2002.

Carson W, McQuade 2003 {published data only}

Carson W, McQuade R, Abou-Gharbia N, Iwamoto

T, Archibald D, Stock E. Long-term weight effects of

aripiprazole and olanzapine: results from a 26-week double-

blind comparison study. Journal of the European College of

Neuropsychopharmacology 2004;14(Suppl 3):S259.

Casey 2003 {published data only}∗ Casey D, Saha AR, Ali MW, Jody DN, Kujawa MJ, Stock

EG, Ingenito GG. Switching to aripiprazole monotherapy.

International Journal of Neuropsychopharmacology 2002;

Suppl 1:S187.

Casey DE, Carson WH, Saha AR, Liebeskind A, Ali MW,

Jody D, Ingenito GG. Switching patients to aripiprazole

from other antipsychotic agents: a multicenter randomised

study. Psychopharmacology 2003;166:391–9.

Casey DE, Saha AR, Ali MW, Jody D, Kujawa MJ, Stock

EG, Ingenito GG. Switching to aripiprazole monotherapy.

Proceedings of the 155th Annual Meeting of the American

Psychiatric Association; 2002 May 18-23; Philadelphia, PA,

USA. 2002.





Kujawa M, Saha AR, Ali MW, Jody DN, McQuade RD,

Ingenito GG. Switching to aripiprazole monotherapy.


Medori R, Gharbia N, Saha A, Ali M, Stock E, Ingenito

G. Switching to aripiprazole monotherapy. Journal of the

European College of Neuropsychopharmacology 2002;Suppl 3:

S292.

Chan 2007 {published data only}

Chan H-Y, Lin W-W, Lin S-K, Hwang T-J, Su T-P, Chiang

S-C, Hwu H-G. Efficacy and safety of aripiprazole in the

acute treatment of schizophrenia in Chinese patients with

risperidone as an active control: a randomized trial. Journal

of Clinical Psychiatry 2007;68(1):29–36.

Chen 2005 b {published data only}

Chen J-D, Zhao J-P, Li L-H, Guo X-F, Zhai J-G, Wang C-

Y, Xie S-P, Gao C-G, Ding Y, Chen Y-G. A multicenter,

randomized and double-blind controlled clinical trial of

aripiprazole in treatment of schizophrenia. Chinese Journal

of New Drugs and Clinical Remedies 2005;24(11):845–8.

Chrzanowski 2006 {published data only}

Chrzanowski WK, Marcus RN, Torbeyns A, Nyilas M,

McQuade RD. Effectiveness of long-term aripiprazole

therapy in patients with acutely relapsing or chronic, stable

schizophrenia: a 52-week, open-label comparison with

olanzapine. Psychopharmacology 2006;189(2):259–66.

Corey-Lisle 2006 {unpublished data only}

Corey-Lisle PK, Kolotkin RL, Crosby RD, L’Italien GJ.

Changes in weight and weight-related quality of life in

aripiprazole versus standard-of-care treatment. Proceedings

of the 159th Annual Meeting of the American Psychiatric

Association; 2006 May 20-25, Toronto, Canada. 2006.

Daniel 2006 {unpublished data only}

Daniel DG, Crandall D, Manos G, McQuade RD,

Gutierrez-Esteinou R, Pikalov AA, Oren D. Transitioning

from intramuscular (IM) to oral aripiprazole in patients

with schizophrenia. Proceedings of the 159th Annual


20-25, Toronto, Canada. 2006.

Fan 2005 a {published data only}

Fan W-L, Yu C-M, Wen J-S. Efficacy analysis of aripiprazole

and clozapine in the treatment of schizophrenia. Journal of

North Sichuan Medical College 2005;20(4):377–9.

Gismondi R, Mel2 {published data only}

Gismondi R, Meltzer H, Kujawa M, Carson W, Stringfellow

J, Iwamoto T, Marcus R, Stock E. Aripiprazole versus

perphenazine in treatment-resistant schizophrenia.

Proceedings of the XXIVth Collegium Internationale

Neuro-Psychopharmacologicum Congress; 2004 June 20-

24, Paris, France 2004.

Han 2005 a {published data only}

Han P, Zhang Y-H, Zhang Y-Q. A controlled study of

schizophrenia treated with aripiprazole and clozapine.

Chinese Journal of Rehabilitation Theory and Practice 2005;

11(10):853–4.

Hwang 2005 {published data only}

Hwang TJ, Chan HY, Lin WW, Lin SK, Hwu HG, Cheng

MY, Forbes R. Aripiprazole versus risperidone in the

treatment of acutely relapsed patients with schizophrenia

in Taiwan: a randomized controlled trial. Journal of the

European College of Neuropsychopharmacology 2005;15

(Suppl 3):S497.

Jody 2004 {published data only}

Jody D, Tandon R, Stock E, Riera L, Kujawa M, Lam

S, Pans M, Iwamoto T, Carson W. A naturalistic study

of aripiprazole treatment in a general psychiatric setting.

Proceedings of the XXIVth Collegium Internationale

Neuro-Psychopharmacologicum Congress; 2004 June 20-

24, Paris, France 2004.

Kane 2003 {unpublished data only}∗ Kane J, Carson W, Kujawa M, Stringfellow J, Marcus R,

Sanchez R, Meltzer HY. Aripiprazole vs. perphenazine in

treatment-resistant schizophrenia. Proceedings of the 156th




2003 May 17-22; San Francisco, USA. 2003.

Kane J, Carson Wh, Kujawa M, Stringfellow J, Marcus

R, Sanchez R, Iwamoto T, Meltzer H. Aripiprazole in

treatment-resistant schizophrenia: a 6-week double- blind

comparison study versus perphenazine. Schizophrenia

Research 2004;67(1):155–6.

McQuade R, Jody D, Kane J, Carson W, Kujawa M,

Stringfellow J, Marcus R, Sanchez R, Meltzer HY. Efficacy

and safety of aripiprazole versus perphenazine in treatment-

resistant schizophrenia. Journal of the European College of

Neuropsychopharmacology 2003;13(4):S326.

McQuade R, Jody D, Kane J, Carson W, Kujawa M,

Stringfellow J, Marcus R, Sanchez R, Meltzer HY. Efficacy

and safety of aripiprazole versus perphenazine in treatment-

resistant schizophrenia. Journal of the European College of

Neuropsychopharmacology 2003;13(4):S326.

Meltzer HY, Kujawa MJ, Carson Jr WH, Stringfellow

J, Iwamoto T, Marcus RN, Stock EG. Aripiprazole and

perphenazine in severe treatment-resistant schizophrenia.


Psychiatric Association; 2004 May 1-6; New York, USA.

2004.

Sanchez R, Meltzer HY, Marcus RN, Stringfellow J,

Carson WH, Kane JM. Aripiprazole versus perphenazine in

treatment - resistant schizophrenia. Schizophrenia Bulletin

2005;31:502.

Kane 2006 d {published and unpublished data}

Kane JM, Swyzen W, Wu X, McQuade R, Gutierrez-

Esteinou R, Van Tran Q, Marcus R. Long-term symptomatic

remission in schizophrenia patients treated with aripiprazole

or haloperidol. Proceedings of the 159th Annual Meeting

of the American Psychiatric Association; 2006 May 20-25,

Toronto, Canada. 2006.

Kane 2007 a {published data only}

Kane JM, Meltzer HY, Carson WH Jr, McQuade RD,

Marcus RN, Sanchez R, Aripiprazole Study Group.

Aripiprazole for treatment-resistant schizophrenia: results of

a multicenter, randomized, double-blind, comparison study

versus perphenazine. Journal of Clinical Psychiatry 2007;68

(2):213–23.

Kern 2001 {published data only}

Carson W, Cornblatt B, Saha A, Ali M, Kern R, Green M.

Neurocognitive benefits of aripiprazole versus olanzapine

in stable psychosis. Journal of the European College of


Cornblatt B, Kern RS, Carson WH, Ali MW, Luo X,

Green M. Neurocognitive effects of aripiprazole versus

olanzapine in stable psychosis. International Journal of

Neuropsychopharmacology 2002;Suppl 1:s185.

Cornblatt B, Kern RS, Carson WH, Stock E, Ali

M, Ingenito G, Green MF. Neurocognitive effects of

aripiprazole versus olanzapine in patients with stable

psychosis. Journal of Psychopharmacology 2002;16(3):A15.

Cornblatt B, Kern RS, Carson WH, Stock E, Ali

M, Ingenito G, Green MF. Neurocognitive effects of

aripiprazole versus olanzapine in patients with stable

psychosis. Schizophrenia Research 2002;3(Suppl 1):27.




Drug Administration CDER, 2002:111–75.∗ Kern RS, Cornblatt B, Carson WH, Dunbar G, Ali M,

Ingenito G, Green MF. An open-label comparison of the

neurocognitive effects of aripiprazole versus olanzapine in

patients with stable psychosis. Schizophrenia Research 2001;

1-2:234.

Kern RS, Cornblatt B, Carson WH, Stock E, Saha AR,

Ali MW, Ingenito G, Green MF. Neurocognitive effects:

aripiprazole vs olanzapine in stable psychosis. European

Psychiatry 2002;Suppl 1:104s.

Kim 2006 d {published data only}

Kim JG, Cho DH, Lee SJ, Lee JK, Wang KS, Seo YI, Choi

SJ, Joo MJ, Kim HD, Lee KH, Kwon YJ, Han KR. The

comparison of efficacy between aripiprazole and haloperidol

in treatment of chronic schizophrenia and schizoaffective

disorder: results for 16-week clinical study. Journal of the


(Suppl 4):S417.

Kujawa 2002 {published data only}

Archibald DG, Manos G, Stock E, Jody D, Tourkodimitris

S, Marcus R, Iwamoto T, Yamamoto Y. Effects of long-

term aripiprazole therapy on the negative symptoms of

schizophrenia. Schizophrenia Research 2004;67(1):155.

Archibald DG, Manos G, Tourkodimitris S, Iwamoto T,

Carson WH, Stock E, Marcus R. Reduction in negative

symptoms of schizophrenia during long-term therapy with

aripiprazole. Schizophrenia Research 2003;60:271.





Kasper S, Lerman MN, McQuade RD, Saha A, Carson

WH, Ali M, Archibald D, Ingenito G, Marcus R, Pigott

T. Efficacy and safety of aripiprazole vs. haloperidol

for long-term maintenance treatment following acute

relapse of schizophrenia. International Journal of

Neuropsychopharmacology 2003;6(4):325–37.

Kostic D, Manos G, Stock E, Jody D, Archibald D,

Tourkodimitris S, Marcus R. Long-term effects of

aripiprazole on the negative symptoms of schizophrenia.

Journal of the European College of Neuropsychopharmacology

2003;13(4):S328.∗ Kujawa M, Saha AR, Ingenito GG, Ali MW, Luo X,

Archibald DG, Carson WH. Aripiprazole for long-term

maintenance treatment of schizophrenia. International

Journal of Neuropsychopharmacology 2002;Suppl 1:S186.

Kujawa MJ, Saha AR, Ingenito GG, Ali MW, Luo X,

Archibald DG, William Jr HC. Aripiprazole for long-term

maintenance treatment in schizophrenia. Proceedings of


Association; 2002 May 18-23; Philadelphia, PA, USA.



2002.

Manos G, Stock EG, Jody D, Archibald DG, Tourkodimitris

S, Marcus RN. Long-term effects of aripiprazole on the

negative symptoms of schizophrenia. Proceedings of


Association; 2003 May 17-22; San Francisco, USA. 2003.

McQuade R, Carson W, Saha A, Ingenito G, Ali M,

Archibald D. Aripiprazole for long-term maintenance

treatment of schizophrenia. Journal of the European College


McQuade RD, Kujawa M, Saha AR, Ingenito GG, Ali

MW, Luo X, Archibald DG, Carson WH. Aripiprazole

for long-term maintenance treatment of schizophrenia.


Saha AR, Carson WH, Mcquade RD, Stock EG, Inada I,

Ali MW. Long-term aripiprazole therapy in schizophrenia.

Proceedings of the XIIth World Congress of Psychiatry;

2002 Aug 24-29; Yokohama, Japan. 2002.

Stock E, Archibald DG, Tourkodimitris S, Kujawa M,

Marcus R, Carson W, Iwamoto T. Long-term effects of

aripiprazole and haloperidol on affective symptoms of

schizophrenia. Schizophrenia Research 2004;67(1):158–9.

Stock EG, Achibald DG, Tourkodimitris S, Kuwaja

MJ, Marcus RN, Carson Jr WH. Long-term effects of

aripiprazole on affective symptoms of schizophrenia.


Psychiatric Association; 2003 May 17-22; San Francisco,

USA. 2003.


Kujawa M, Stringfellow J, Hardy S, Ali M, Iwamoto T,

Lam S, Marcus R, Stock E. Efficacy, safety, and tolerability

of aripiprazole in patients with schizoaffective disorder.

Schizophrenia Research 2004;67(1):156.

Kujawa MJ, Stringfellow J, Hardy S, Ali M, Marcus RN,

Stock EG. The efficacy of aripiprazole in patients with

schizoaffective disorder. Proceedings of the 156th Annual


17-22; San Francisco, USA. 2003.


Kujawa MJ, McQuade RD, Jody DN, Carson WH, Abou-

Gharbia N, Iwamoto T, Archibald DG, Stock EG. Long-

term weight effects of aripiprazole vs olanzapine in a 26-

week, double-blind study. Proceedings of the XXIVth

Collegium Internationale Neuro-Psychopharmacologicum

Congress; 2004 June 20-24, Paris, France 2004.

Liang 2005 {published data only}

Liang J, Chen D. Aripiprazole and haloperidol in the

treatment of schizophrenia. China Pharmaceuticals 2005;14

(6):82.

Mai 2005 {published data only}

Mai G-Y, Cai G-H, Huang J-M. Comparative study on

the effect of aripiprazole and risperidone on schizophrenia.

Chinese Journal of Rehabilitation 2005;20(3):184–5.

Mallikaarjun 2000 {published data only}∗ Mallikaarjun S, Salazar DE, Bramer SL. Pharmacokinetics,

tolerability, and safety of aripiprazole following single and

multiple oral dose administration. Journal of the European

College of Neuropsychopharmacology 2000;Suppl 3:S306.

Mallikaarjun S, Salazar DE, Bramer SL. The

pharmacokinetics, tolerability, and safety of aripiprazole

following single and multiple oral dose administration.

International Journal of Neuropsychopharmacology 2000;

Suppl 1:S123.

Marcus 2003 {published data only (unpublished sought but not used)}

Marcus RN, Kostic D, Stringfellow J, Hardy S, Carson

WH, Stock EG. Effects of aripiprazole on excitement

and hostility: Symptoms of schizophrenia. Proceedings

of the 156th Annual Meeting of the American Psychiatric

Association; 2003 17-22 May; San Francisco, USA. 2003.

Marder 2004 {published data only}

Marder SR, Archibald DG, Manos G, Stock EG, Jody DN,

Tourkodimitris S, Marcus RN, Iwamoto T, Yamomoto

Y, Carson WH. Long-term effects of aripiprazole therapy

on the negative symptoms of schizophrenia. Proceedings

of the XXIVth Collegium Internationale Neuro-

Psychopharmacologicum Congress; 2004 June 20-24; Paris,

France 2004.

McQuade 2002 {published data only}

McQuade R, Carson W, Saha A, Ingenito G, Ali M,

Archibald D. Aripiprazole for long-term maintenance

treatment of schizophrenia. Journal of the European College

of Neuropsychopharmacology 2002;12(S3):S288.

McQuade 2003 {unpublished data only}

Abou Gharbia N, McQuade R, Jody D, Kujawa M, Carson

W, Iwamoto T, Archibald D, Stock E. Comparative study

of the long-term effects of aripiprazole and olanzapine

treatment on body weight. Proceedings of the Thematic

Conference of the World Psychiatric Association on

“Treatments in Psychiatry: An Update”; 2004 Nov 10-13;

Florence, Italy. 2004.





Jody D, Mcquade Rd, Kujawa M, Carson W, Iwamoto

T, Archibald D, Stock E. Long-term weight effects of

aripiprazole versus olanzapine. Schizophrenia Research 2004;

67(1):187.∗ McQuade RD, Jody DN, Kujawa MJ, Carson WH,

Iwamoto T, Archibald DG, Stock EG. Long-term weight

effects of aripiprazole versus olanzapine. Proceedings of


Association; 2003 May 17-22; San Francisco, USA. 2003.

McQuade RD, Stock E, Marcus R, Jody D, Gharbia NA,

Vanveggel SAD, Carson WH. A comparison of weight

change during treatment with olanzapine or aripiprazole:

results from a randomized, double-blind study. Journal of

Clinical Psychiatry 2004;65(Suppl 18):47–56.

Modell 2005 b {published data only}

Modell S, Jody D, Kujawa M, Carson W, Stringfellow J,

Iwamoto T, Marcus R, Stock E T. Efficacy of aripiprazole

and perphenazine in severe schizophrenia resistant to



treatment with atypical antipsychotics. Journal of the


(Suppl 3):S265.

N0025078569 {published data only}

N0025078569. A multi-centre, d-b, randomised

comparative study of aripiprazole and olanzapine in the

treatment of patients with acute schizophrenia. National

Research Register 2001; Vol. 1.

Newcomer 2006 {unpublished data only}

Newcomer JW, L’Italien G, Vester-Blokland, McQuade

RD, Carson WH, Marcus RN. Improvement of non-

HDL cholesterol levels among patients randomized to

aripiprazole versus olanzapine. Proceedings of the 159th


2006 May 20-25, Toronto, Canada. 2006.

Octavio 2004 {published data only}

Octavio I, Stock EG, Archibald DG, Tourkodimitris S,

Kujawa MJ, Marcus R, Carson WH, Iwamoto T. Long-

term effects of aripiprazole on affective symptoms of

schizophrenia. Proceedings of the XXIVth Collegium

Internationale Neuro-Psychopharmacologicum Congress;

2004 June 20-24 Paris, France 2004.

Octavio 2005 {published data only}

Octavio I, Stock E, Archibald D, Tourkodimitris S, Kujawa

M, Marcus R, Carson W, Iwamoto T. Long-term effects

of aripiprazole on affective symptoms of schizophrenia.

Journal of the European College of Neuropsychopharmacology

2004;14(Suppl 3):S261.

Petrie 1997 {published and unpublished data}∗ Petrie JL, Saha JR, McEvoy JP. Aripiprazole, a new typical

antipsychotic: phase 2 clinical trial result. Proceedings of

the 10th European College of Neuropsychopharmacology

Congress; Sep 13-17; Vienna, Austria. 1997.

Ray 2005 {published data only}

Ray S, Corey-Lisle PK, Cislo PR, L’Italien G, Weiden

P. An economic evaluation of aripiprazole compared to

olanzapine based on metabolic side-effect profile. Journal of

the European College of Neuropsychopharmacology 2004;14

(Suppl 3):S279.

Riera 2004 {published data only}

L’Italien GJ, Tandon R, Han J, Li H, Ray S, Carson W.

Schizophrenic patients treated with aripiprazole exhibit

improved overall effectiveness compared to patients treated

with atypical antipsychotics. Proceedings of the Thematic

Conference of the World Psychiatric Association on

“Treatments in Psychiatry: An Update”; 2004 Nov 10-13;

Florence, Italy. 2004.

McQuade RD. Investigator assessment of clinical

parameters after initiating aripiprazole therapy. Proceedings

of the 158th Anual Meeting of the American Psychiatric

Association; 2005 May 21-26; Atlanta, USA. 2005.

Octavio I, Tandon R, Stock E, Riera L, Kujawa M, Lam

S, Pans M, Iwamoto T, Carson W. A naturalistic study

of aripiprazole treatment in a general psychiatric setting.

Proceedings of the Thematic Conference of the World

Psychiatric Association on “Treatments in Psychiatry: An

Update”; 2004 Nov 10-13; Florence, Italy. 2004.

Riera L, Hu R, Stock E, Nyilas M, Torbeyns A, Borian F,

Gentile K, Carson W, Iwamoto T. Broad effectivness trial

with aripiprazole. Proceedings of the 157th Annual Meeting

of the American Psychiatric Association; 2004 May 1-6;

New York, USA. 2004.

Tandon R, Han J, Litalien G, Ray S, Carson Jr WH.

Investigator’s assessment questionnaire of antipsychotics’

effectiveness. Proceedings of the 157th Annual Meeting of

the American Psychiatric Association; 2004 May 1-6; New

York, USA. 2004.

Tandon R, Stock EG, Kujawa MJ, Torbeyns AF, Borian

FE, Riera L, McQuade RD. Broad effectiveness trial

with aripiprazole. Proceedings of the 55th Institute on

Psychiatric Services of the American Psychiatric Association;

2003 October/November; Boston, USA. 2003.

Tandon R, Stock EG, Riera L, Kujawa MJ, Lam S, Pans

M, Iwamoto T. A naturalistic trial with aripiprazole in a

general psychiatric setting. Proceedings of the 157th Annual


1-6; New York, USA. 2004.

Saha 2004 {published data only}

Saha AR, Brown D, McEvoy J, Ali M, Abou-Gharbia N,

Stock S, Iwamoto T. Tolerability and efficacy of aripiprazole

in patients with first episode schizophrenia: An open label

pilot study. Proceedings of the 12th Biennial Winter

Workshop on Schizophrenia; 2004 Feb 7-13; Davos,

Switzwerland. 2004.

Sanchez 2006 {published data only}

Sanchez R, Kostic D, Stock E, Torbeyns AF, Kerselaers

W, Nyilas M, McQuade R, Carson WH, Marcus RN.

Aripiprazole vs olanzapine in patients with acutely relapsing

or chronic, stable schizophrenia: a 52-week open-label

extension study. Proceedings of the 13th Biennial Winter

Workshop on Schizophrenia Research; 2006 Feb 4-10,

Davos, Switzerland. 2006.

STAR 2006 {published and unpublished data}

Corey-Lisle P, Kolotkin RL, Crosby RD, L’Italien G.

Changes in weight and weight-related quality of life in

aripiprazole versus standard-of-care treatment. Proceedings

of the 14th Congress of the Association of European

Psychiatrists; 2006 March 4-8; Nice, France. 2006.

Hanssens L, Biro E, Dillenschneider A, Spitzerova H,

McQuade R, Iwamoto T. Reasons for participation and

preference of medicine in community-treated schizophrenic

patients in a naturalistic setting (schizophrenia trial of

aripiprazole: star study). Proceedings of the 14th Congress

of the Association of European Psychiatrists; 2006 March 4-

8; Nice, France. 2006.

Hanssens L, L’Italien G, Marcus RN, McQuade R, Carson

WH, Beuzen JN. Effectiveness of aripiprazole versus

olanzapine, quetiapine, or risperidone: sub-analysis of a

large, randomized, naturalistic study (STAR). Journal of the

European College of Neuropsychopharmacology 2006;16(4):

S421.

Hanssens L, L’Italien G, Marcus RN, McQuade RD,



Carson WH, Beuzen J-N. Evaluation of quality of life in

community-treated schizophrenic patients: a naturalistic

open-label study comparing aripiprazole to standard-of-care.


Psychiatric Association; 2006 May 20-25, Toronto, Canada.

2006.

Hanssens L, L’Italien G, Marcus RN, McQuade RD,

Carson WH, Beuzen J-N. Reasons for switching among

community-treated schizophrenic patients in a naturalistic

setting : schizophrenia trial of aripiprazole: STAR study.



2006.

Hanssens L, L’Italien G, Marcus RN, McQuade RD, Carson

WH, Beuzen J-N. Sexual dysfunction in a naturalistic

open label study of aripiprazole and standard of care in the

management of community-treated schizophrenic patients.



2006.

Hanssens L, L’Italien G, McQuade R, Iwamoto T, Pans

M. Evaluation of quality of life in community-treated

schizophrenic patients: a naturalistic open-label study

comparing aripiprazole to standard care (schizophrenia

trial of aripiprazole: star study). Proceedings of the 14th

Congress of the Association of European Psychiatrists; 2006

March 4-8; Nice, France. 2006.

Kerwin R, L’Italien G, Hanssens L, Marcus RN,

McQuade R, Carson WH, Beuzen JN. Effectiveness

of aripiprazole versus standard of care treatment in

patients with schizophrenia: the Schizophrenia Trial of

Aripiprazole (STAR) study. Journal of the European College

of Neuropsychopharmacology 2006;16(4):S411.

Kerwin R, L’Italien G, Hanssens L, Marcus RN, McQuade

RD, Beuzen J-N. Effectiveness of aripiprazole versus

standard of care: schizophrenia trial of aripiprazole (STAR

trial). Proceedings of the 159th Annual Meeting of the

American Psychiatric Association; 2006 May 20-25,

Toronto, Canada. 2006.

L’Italien G, Hanssens L, Marcus RN, McQuade RD, Carson

WH, Beuzen J-N. Metabolic effects of aripiprazole versus

standard of care (the STAR trial). Proceedings of the 159th


2006 May 20-25, Toronto, Canada. 2006.

Stock 2005 {published data only}

McQuade R, Kostic D, Marcus R, Carson W, Torbeyns A,

Kerselaers W, Yocca F. Aripiprazole versus olanzapine in a

52-week open label extension study. Schizophrenia Bulletin

2005;31:496–7.

Stock EG. Aripiprazole versus olanzapine in schizophrenia:

A 52-week, open-label study. Proceedings of the 158th


2005 May 21-26; Atlanta, USA. 2005.

Stroup 2003 {published data only}

Stroup TS, McEvoy JP, Swartz MS, Byerly MJ, Glick

ID, Canive JM, McGee MF, Simpson GM, Stevens MC,

Lieberman JA. The National Institute of Mental Health

Clinical Antipsychotic Trials of Intervention Effectiveness

(CATIE) project: schizophrenia trial design and protocol

development. Schizophrenia Bulletin 2003;29(1):15–31.

Tandon 2006 {published data only}

Tandon R, Marcus RN, Stock EG, Riera LC, Kostic D,

Pans M, McQuade RD, Nyilas M, Iwamoto T, Crandall

DT. A prospective, multicenter, randomized, parallel-group,

open-label study of aripiprazole in the management of

patients with schizophrenia or schizoaffective disorder in

general psychiatric practice: Broad Effectiveness Trial With

Aripiprazole (BETA). Schizophrenia Research 2006;84(1):

77–89.

Wang 2005 {published data only}

Wang G-P, Xie R, Pei G-X. A comparative study between

aripiprazole and chlorpromazine in the treatment of

schizophrenia. Shandong Archives of Psychiatry 2005;18(4):

250–1.

Wang 2005 j {published data only}

Wang R, Liu Y, Ning Z. A controlled study of aripiprazole

vs clozapine in the treatment of first-episode schizophrenia.

Journal of Clinical Psychosomatic Diseases 2005;11(4):301–2.

Wu 2005 d {published data only}

Wu J-D, Li Y-D, Song Z-W. Effect of aripiprazole or haldol

on intelligence and memory in the first-onset schizophrenia.

Chinese Journal of Rehabilitation Theory and Practice 2006;

12(1):64–5.

Xia 2005 {published data only}

Xia S-Y, Hua P, Nie Y-B. A treatment study of schizophrenia

with aripiprazole and chlorpromazine. Practical Clinical

Medicine 2005;6(10):33–4.

Ye 2005 {published data only}

Ye X-R, Xia X-L. A comparative study between aripiprazole

and risperidone in treatment of first-onset schizophrenia.

Medical Journal of National Defending Forces in Southwest

China 2005;15(6):616–8.

Zhang 2005 {published data only}

Zhang Y, Gu Z, Sun A. Aripiprazole on the quality of life

of patients with schizophrenia. Journal of Jining Medical

College 2005;28(4):50–1.

Zhang 2005 a {published data only}

Zhang Y, Liu X, Li X-Y, Wang W. Aripiprazole and

risperidone in the treatment of schizophrenia. Chinese

Journal of Behavioural Medical Sciences 2005;14(10):923–5.

Zhao 2005 {published data only}

Zhao Z-Z, Li X-L, Zou Z-M. A comparative study on

aripiprazole and sulpiride in treating schizophrenia whose

predominant clinical features were negative symptoms.

Medical Journal of Chinese People Health 2005;17(12):

728–30.

Zhi 2005 {published data only}

Zhi S-L. Comparison study of aripiprazole and risperidone

on schizophrenia. Modern Journal of Integrated Traditional

Chinese and Western Medicine 2005;14(21):2787–8.



Zhu 2005 {published data only}

Zhu L, Wu H, Huang S, Liu X-X. Aripiprazole and

risperidone in the treatment of schizophrenia-control study.

Nervous Diseases and Mental Hygiene 2005;5(4):282.

Zhu 2005 a {published data only}

Zhu P-J, Cheng Z-E, Zhang J, Zhu P-L, Zhan X-M.

Clinical study of therapeutic effects of aripiprazole in

treatment of patients with schizophrenia. Chinese Journal

of Clinical Pharmacology and Therapeutics 2005;10(10):

1194–7.

Zhu 2005 b {published data only}

Zhu L, Wu H, Huang S, Liu X-X. Aripiprazole and

risperidone in the treatment of schizophrenia. Shanghai

Medical and Pharmaceutical Journal 2005;26(9):425–6.

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Nyilas 2007 {unpublished data only}

Nyilas M, Findling RL, Johnson B, Forbes RA, Pikalov

A, Marcus R, Carson WH, Robb A. Proceedings of

the 46th Annual Meeting of the American College of

Neuropsychopharmacology; 2007 Dec 9-13; Florida, USA.

2007.

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Adson 2003

Methods Allocation: randomised.

Blindness: double (in treatment responders).

Duration: 6 weeks, preceded by > 2 day wash-out period.

Design: parallel, multicentre.

Setting: hospital, North America.

Consent: not described.

Loss: described.

Participants Diagnosis: schizophrenia (DSM-IV).

N = 420.

Age: over 18, average ~ 41 years.

Sex: M 327, F 93.

History: acute relapse, response to previous neuroleptics other than clozapine, outpatient

> 3 months in past year, PANSS total > 60, and > 4 on 2 defined PANSS criteria.

Exclusions: pregnancy, lactation, schizoaffective disorder, organic, bipolar disorders, hos-

pitalisation for 14 days prior to screening, substance dependence within 3 months, sui-

cide risk, unstable thyroid pathology, history of neuroleptic malignant syndrome, history

of unstable medical condition

Interventions 1. Aripiprazole: dose 10 mg/day. N = 106.

2. Aripiprazole: dose 15 mg/day. N = 106.


4. Placebo. N = 108.

Outcomes Leaving the study early.

Unable to use -

Death: suicide and natural causes (incomplete data).

Mental state: PANSS total , PANSS-derived BPRS core score, PANSS negative score (no

SDs)

Notes Greater than 60% discontinuation rate.

Patients not responding by week 3 were offered open-label aripiprazole for weeks 4-6.

Original protocol amended to provide two secondary outcome criteria.

Data reported in both OC and LOCF analyses.

Jadad = 2.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Unclear

Allocation concealment (selection bias) High risk Randomised, method not described



Adson 2003 (Continued)

Blinding (performance bias and detection

bias)

All outcomes

Unclear risk Double blind, no further details

Incomplete outcome data (attrition bias)

All outcomes

High risk Very high drop-out rate with limited de-

tails.

Selective reporting (reporting bias) Unclear risk Unclear

Other bias Unclear risk Unclear

Carson 2000 a

Methods Allocation: randomised, method not described.

Blindness: double, no further details.

Duration: 4 weeks, preceded by > 5 day washout period.


Setting: hospital, USA.

Consent: obtained.

Loss: described.

Participants Diagnosis: schizophrenia or schizoaffective disorder (DSM-IV).

N = 414.

Age: mean ~ 39 years.

Sex: M 288, F 126.

History: acute relapse, mean age at first episode ~ 22 years, mean number of previous

hospitalisations ~ 10.

Exclusions: other psychiatric disorders, history of violence or suicidal ideation/self-harm,

significant neurological abnormality, psychoactive drug or alcohol abuse/dependence,

recent treatment with an investigational drug



3. Haloperidol: dose 10 mg/day. N = 104.


Outcomes Leaving the study early

Unable to use -

Death: suicide and natural causes (incomplete data).

Global state: CGI (no SDs).

Mental state: BPRS, BPRS-PANSS derived (no SDs).

General functioning: CGI (no SDs).

Adverse effects: SAS, Barnes Akathisia scale, Abnormal Involuntary Movement scale,

other outcome measures including changes in body weight, serum prolactin, and QTc

interval changes (no usable/standard deviation data)

Notes Overall 40% discontinuation rate.

No information given on standard deviations.

Data reported in both OC and LOCF analyses.



Carson 2000 a (Continued)

Jadad = 2.

Risk of bias



bias)




bias)

All outcomes

Unclear risk Double blind, method of blinding not de-

scribed


All outcomes

High risk High attrition rate



Carson 2002 b


Blindness: double, no further details.

Duration: 26 weeks, preceded by 3-14 day washout period.


Setting: mixed in and out patients, multi-national.


Loss: High attrition rate.

Participants Diagnosis: schizophrenia.

N = 310.

Age: mean ~ 42 years.

Sex: M 174, F 136.

History: chronic stable, no significant worsening of symptoms in past 3 months, diagnosis

for > 2 years, baseline PANSS score mean ~ 82.

Exclusions: not described.


2. Placebo: N = 155.

Outcomes Global state: relapse.

Adverse effects: adverse events above 10%, weight gain > 7%, fasting plasma glucose

>/= 110 mg/dl, Hb 1AC >/= upper limit of normal, clinically significant laboratory

measurements.

Leaving the study early.

Unable to use -



Carson 2002 b (Continued)


Mental state: PANSS, PANSS-derived BPRS (no SDs).

Adverse effects: change in weight, change in serum prolactin, SAS, AIMS, Barnes

Akathisia rating scale, change in QTc interval, change in fasting plasma glucose, change

in Hb 1AC from baseline (no usable/SDs)

Notes Limited data given on standard deviations.

Different numbers of patients were analysed for efficacy and safety characteristics.

Jadad = 2.

Risk of bias



bias)




bias)

All outcomes

Unclear risk Double, no further details


All outcomes

High risk High attrition rate, reasons for discontinu-

ation given



Csernansky 2003


Blindness: double.

Duration: 4 weeks, preceded by 3-7 day placebo washout period.


Setting: inpatient, USA.


Loss: described.

Participants Diagnosis: schizophrenia (DSM-III-R).

N = 103.

Age: 18-65 years, average ~ 36.

Sex: M 91, F 12.

History: acute relapse, BPRS score > 30 & score of > 4 on 2 of 4 positive symptoms,

evidence of previous response to antipsychotic medication.

Exclusions: > moderate motor symptoms as measured by SAS, AIMS and Barnes

Akathisia scale, other primary diagnoses, substance dependence within 2 months, cardiac



Csernansky 2003 (Continued)

patients, acute/unstable medical conditions

Interventions 1. Aripiprazole (OPC-14597): dose 5 mg/day 1+2, 10 mg/day 3+4, 15 mg/day 5+6, 20

mg/day 7-12, 30 mg/day 13-28. N = 34.

2. Haloperidol: dose 5 mg/day 1+2, 10 mg/day 3+4, 15 mg/day 5+6, 20 mg/day 7-12,

20 mg/day 13-28. N = 34.

3. Placebo. N = 35.


Unable to use -

Mental state: BPRS (no SDs).

Global state: CGI (no usable data).

Notes Overall 48.5% discontinuation rate.

Limited information on standard deviations.

Considered a ’negative’ study by the FDA.

Data reported in OC and LOCF analyses.

Jadad = 2.

Risk of bias



bias)




bias)

All outcomes



All outcomes






Daniel 2000


Blindness: double.

Duration: 4 weeks, preceded by 3-7 day washout period.


Setting: inpatient.


Loss: described.

Participants Diagnosis: schizophrenia (DSM-IV).

N = 307.


Sex: M 247, F 60.

History: acute relapse, BPRS score > 36 & score of > 2 on 4 criteria, antipsychotic

medication taken for > 72 hours prior to randomisation.

Exclusions: first episode of schizophrenia, refractory to antipsychotics, moderate to severe

EPS, dyskinesia or akathisia, substance abuse, cardiac disease, acute or unstable medical

condition, pregnancy, lactation, women not using adequate contraception




4. Haloperidol: dose 10 mg/day after 5 mg/day 1+2). N = 63.

5. Placebo. N = 64.


Unable to use -


Mental state: BPRS, PANSS (no SDs).

Adverse effects: reported adverse effects, extra-pyramidal side effects, mean weight gain,

mean prolactin levels (no usable data)

Notes Over 40% overall discontinuation rate.

No data given on standard deviations.

Marked sex differential in participants.

Data reported in both LOCF and OC analyses.

Jadad = 2.

Risk of bias



bias)




bias)

All outcomes




Daniel 2000 (Continued)


All outcomes




Daniel 2004


Blindness: double.

Duration: 24hrs.


Setting: inpatient.


Loss: described.

Participants Diagnosis: schizophrenia, schizoaffective disorder, schizophreniform disorder.

N = 357*.

Age: not described.

Sex: not described.

History: acute agitation.


Interventions 1. Aripiprazole IM: dose 1 mg/day. N = 57.

2. Aripiprazole IM: dose 5 mg/day. N = 62.



5. Haloperidol IM: dose 7.5 mg/day. N = 60.

6. Placebo IM. N = 62.

Outcomes Global state: poor compliance with study protocol due to lack of efficacy, deterioration,

or psychosis.


Adverse effects: reported in > 5% participants, extrapyramidal symptoms

Unable to use -

Behaviour: PEC score - mean change (no SD), CAB score- mean change (no SD), ACES

- (no SD), response - > 40% reduction in PEC score (unvalidated sub-scale), requiring

additional dose of antipsychotic medication, benzodiazepines (incomplete data)

Notes *Two participants not accounted for.

Limited data reported on standard deviations.

Data reported in LOCF analyses.

Jadad = 2.

Only adverse effects occurring in over 5% participants recorded.

Not all outcomes reported at 24 hrs.

Risk of bias



Daniel 2004 (Continued)



bias)




bias)

All outcomes



All outcomes

Low risk 95% completed study, details of loss of fol-

low-up given

Selective reporting (reporting bias) Low risk appears to be


Marcus 2005


Blindness: double.

Duration: 6 weeks.




Loss: not described.

Participants Diagnosis: schizophrenia.

N = 367.

Age: unknown.

Sex: unknown.

History: acute relapse.





4. Placebo. N = 88.


Unable to use -

Global state: CGI (no SD).

Mental state: PANSS (no SD), time to response (defined by CGI and PANSS) (no usable

data).

Adverse effects: self-reported > 5% participants (no usable data)



Marcus 2005 (Continued)

Notes Greater than 40% discontinuation rate.

Limited data on standard deviations given.

Data reported in LOCF analyses.

Jadad = 2.

Risk of bias



bias)




bias)

All outcomes



All outcomes


Selective reporting (reporting bias) Low risk Appears to be


Oren 2005

Methods Allocation: randomised, block randomisation.

Blindness: double.

Duration: 24 hours.


Setting: hospital.


Loss: described.


N = 448.

Age: >/= 18 years.

Sex: unknown.

History: acute agitation, voluntarily hospitalised, able to comply and comprehend pro-

tocol, PEC score of >/= 15 and </= 32, and at least 2 components >/= 4 (moderate).


Interventions 1. Aripiprazole IM: dose 10 mg/day. N = 175.

2. Placebo IM. N = 88.

3. Haloperidol IM: dose 6.5 mg/day. N = 185.

Allowed concomitant medication of up to 4 mg lorazepam or equivalent



Oren 2005 (Continued)

Outcomes Global state: poor compliance with study protocol due to lack of efficacy, deterioration,

or psychosis, requiring additional dose of antipsychotic medication, benzodiazepines.


Adverse effects: reported in > 5% participants, extrapyramidal symptoms

Unable to use -

Global state: CGI (no SD)

Behaviour: PEC score - mean change (no SD), CAB score - mean change (no SD), ACES

- (no data), response - > 40% reduction in PEC score (unvalidated sub-scale)

Notes Limited information given on standard deviations.

Data was analysed in LOCF.

Jadad = 2.

Adverse effects reported occurring in >/= 5% participants.

Not all outcomes recorded over 24 hrs.

Risk of bias



bias)

Low risk Via a central call-in system

Allocation concealment (selection bias) Low risk Randomised, permuted block randomisa-

tion


bias)

All outcomes



All outcomes

Low risk 96.6% competed study

Selective reporting (reporting bias) Unclear risk Secondary efficacy measures were not re-

ported in details


Potkin 2003


Blindness: double.

Duration: 4 weeks, preceded by 5-day placebo washout period.



Consent: described.

Loss: described.



Potkin 2003 (Continued)


N = 404.


Sex: M 283, F 121.

History: acute relapse, responsive to antipsychotic medication other than clozapine,

outpatient for > 3 months in past year, PANSS > 60 & score > 2 on psychotic symptom

sub-scale, adequate time interval since receiving previous anti-psychotic.

Exclusions: other psychiatric disorders requiring medication, history of violence, suici-

dal attempts or ideation, significant neurological abnormality, alcohol/psychoactive sub-

stance misuse within 1 month of study start, treatment with investigational drug within

4 weeks of washout phase, unstable/acute medical conditions, pregnancy, lactation



3. Risperidone: dose 2 mg day 1, 4 mg day 2, 6 mg/day thereafter. N = 99.


Outcomes Leaving the study early

Adverse effects: self-reported > 5% participants, mean change in body weight, mean

change in serum prolactin, mean change in QTc interval

Unable to use -

Global state: CGI - much, or very much improved (no SD).

Mental state: PANSS - 30% decrease in baseline score, PANSS-derived BPRS (no SD).

Adverse effects: SAS, Barnes Akathisia Rating scale, AIMS, vital signs (no usable data/

SD)

Notes Overall 40% discontinuation rate.

No information given on standard deviations.

Data was analysed in terms of OC and LOCF.

Jadad = 2.

Risk of bias



bias)




bias)

All outcomes



All outcomes





Potkin 2003 (Continued)


BAS: Barnes Akathesia Rating Scale

SAS: Simpson Angus Scale

CGI-I: CGI Improvement Scale

CGI-S: CGI Severity Scale

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Allain 2005 Allocation: not randomised, an open label study

Auby 2002 Allocation: randomised.

Participants: people with stable schizophrenia or schizoaffective disorder.

Intervention: aripiprazole at multiple doses - no other comparator drug.

Outcomes: no usable data.

Beuzen 2005 Allocation: not randomised, an open label study.

Intervention: aripiprazole versus other antipsychotics, no placebo group

Blonde 2004 Allocation: states it is randomised.

Participants: states people with schizophrenia etc.

Intervention: aripripazole versus olanzapine, no placebo group

Carson 2002 a Allocation: not randomised, a review.

Carson W, McQuade 2003 Allocation: randomised.

Blindness: double.

Participants: people with schizophrenia.

Intervention: aripiprazole: dose 15-30 mg/day. N = 156. Olanzapine: dose 10-20 mg/day. N = 161.

No placebo group

Casey 2003 Allocation: randomised.

Participants: people with schizophrenia or schizoaffective disorder.

Intervention: aripiprazole at different regimens - no other comparator or placebo

Chan 2007 Intervention: aripripazole versus risperidol, no placebo control group

Chen 2005 b Intervention: aripripazole versus risperidone, no placebo control group

Chrzanowski 2006 Allocation: not randomised, an open label study.

Intervention: aripiprazole versus olanzapine, no placebo control group



(Continued)

Corey-Lisle 2006 Allocation: not randomised, a naturalistic trial.

Daniel 2006 Intervention: IM aripripazole versus IM haloperidol, no placebo control group

Fan 2005 a Intervention: aripripazole versus clozapine, no placebo control group

Gismondi R, Mel2 Intervention: aripripazole versus perphenazine, no placebo control group

Han 2005 a Intervention: aripripazole versus clozapine, no placebo control group

Hwang 2005 Intervention: aripripazole versus risperidone, no placebo control group

Jody 2004 Allocation: not randomised, an open label study.

Kane 2003 Allocation: randomised, method not described

Blindness: double (during treatment phase).

Duration: 6 weeks, preceded by 14-day patient screening, 2-day neuroleptic washout, 4-6 weeks’

confirmation of treatment resistance, 2-10 day neuroleptic washout.

Design: multicentre, parallel.

Intervention: aripiprazole versus perphenazine, no placebo control group

Kane 2006 d Intervention: aripripazole versus haloperidol, no placebo control group

Kane 2007 a Intervention: aripripazole versus perphenazine, no placebo control group

Kern 2001 Allocation: randomised, method not described.

Blindness: open label.

Duration: 26 weeks.

Design: multicentre, parallel.

Setting: outpatient.

Participants: N = 256*. Age: 18-65 years, average ~ 40 years. Sex: M 164, F 92.

Diagnosis: schizophrenia or schizoaffective disorder.

History: chronic stable, not hospitalised for > 2 months prior to randomisation, previously on stable

dose of antipsychotic for > 2 months


Kim 2006 d Intervention: aripiprazole versus haloperidol, no placebo control group

Kujawa 2002 Intervention: aripiprazole versus haloperidol, no placebo control group

Kujawa 2003 Intervention: a review article.

Kujawa 2004 Allocation: randomised, method not described.

Blindness: double.

Duration: 26 weeks.

Design: parallel, multi-centre.

Participants: N = 317. Age: average ~ 38 years. Sex: M 229, F 88.



(Continued)

Diagnosis: schizophrenia.

Intervention: aripripazole versus olanzapine, no placebo control group

Liang 2005 Intervention: aripiprazole versus haloperidol, no placebo control group

Mai 2005 Intervention: aripripazole versus risperidone, no placebo control group

Mallikaarjun 2000 Allocation: randomised.

Participants: healthy volunteers.

Marcus 2003 Allocation: not randomised, review.

Marder 2004 Intervention: aripripazole versus haloperidol, no placebo control group

McQuade 2002 Intervention: aripiprazole versus haloperidol, no placebo control group

McQuade 2003 Intervention aripiprazole versus olanzapine, no placebo control group

Modell 2005 b Intervention: aripripazole versus perphenazine, no placebo control group

N0025078569 Intervention: aripiprazole versus olanzapine, no placebo control group

Newcomer 2006 Intervention: aripripazole versus olanzapine, no placebo group

Octavio 2004 Intervention: aripiprazole versus haloperidol, no placebo control group

Octavio 2005 Intervention: aripiprazole versus haloperidol, no placebo control

Petrie 1997 Allocation: not randomised, review.

Ray 2005 Intervention: aripiprazole versus olanzapine, no placebo control group

Riera 2004 Intervention: aripiprazole versus standard care, no placebo control group

Saha 2004 Allocation: randomised.

Participants: first episode of schizophrenia or schizoaffective disorder occurring within 1 year of study.

Intervention: aripiprazole at multiple doses - no other comparator drug or placebo

Sanchez 2006 Allocation: not randomised, an open-label study.


STAR 2006 Allocation: not randomised, naturalistic trial.

Stock 2005 Intervention: aripiprazole versus olanzapine, no placebo control group

Stroup 2003 Allocation: not randomised.



(Continued)

Tandon 2006 Intervention: aripiprazole versus other antipsychotics, no placebo control group

Wang 2005 Intervention: aripiprazole versus chlorpromazine, no placebo control group

Wang 2005 j Intervention: aripiprazole versus clozapine, no placebo control group

Wu 2005 d Intervention: aripripazole versus haloperidol, no placebo control group

Xia 2005 Intervention: aripiprazole versus chlorpromazine, no placebo control group

Ye 2005 Intervention: aripripazole versus risperidone, no placebo control group

Zhang 2005 Intervention: aripiprazole versus sulpiride, no placebo control group

Zhang 2005 a Intervention: aripripazole versus risperidone, no placebo control group

Zhao 2005 Intervention: aripripazole versus sulpiride, no placebo control group

Zhi 2005 Intervention: aripripazole versus risperidone, no placebo control group

Zhu 2005 Intervention: aripripazole versus risperidone, no placebo control group

Zhu 2005 a Intervention: aripripazole versus clozapine, no placebo control group

Zhu 2005 b Intervention: aripripazole versus risperidone, no placebo control group

Characteristics of studies awaiting assessment [ordered by study ID]

Carson 2008

Methods 4 weeks randomised double blind controlled trial

Participants Paediatric age 10-17 years, with DSM-IV diagnosis of bipolar 1 disorder, manic or mixed episode with/with out

psychotic symptoms (n = 296)

Interventions Placebo versus aripiprazole 10 or 30 mg

Outcomes >= 50% change on Young mania rating scale

Notes



Nyilas 2007

Methods 6 weeks multicentre, randomised double blind controlled trial

Participants Age 13-17 years, DSM-IV diagnosis of schizophrenia (n = 302)

Interventions Placebo versus aripiprazole 10 or 30 mg

Outcomes Mean change on PANSS

Notes



D A T A A N D A N A L Y S E S

Comparison 1. ARIPIPRAZOLE versus PLACEBO

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Global state: 1. Relapse 2 883 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.57, 0.74]

1.1 short term 1 310 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.45, 0.77]

1.2 medium term 1 310 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.53, 0.81]

1.3 Acute (2 hr after IM) 1 263 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.57, 0.89]

2 Global state: 2. Poor compliance

with study protocol due to lack

of efficacy, deterioration or

psychosis

8 2275 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.59, 0.93]

3 Global state: 3. Needing

additional antipsychotic

medication


4 Global state: 4. Needing

additional benzodiazepines


5 Adverse effects: 1. Clinically

important specific adverse

effects


5.1 anxiety 3 1035 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.62, 1.12]

5.2 extrapyramidal symptoms

- akathisia



- general



- needing antiparkinson

medication at least once


5.5 headache 6 1962 Risk Ratio (M-H, Fixed, 95% CI) 1.17 [0.94, 1.47]

5.6 insomnia 4 1298 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.89, 1.33]

5.7 nausea 6 1962 Risk Ratio (M-H, Fixed, 95% CI) 1.55 [1.07, 2.24]

5.8 vomiting 5 1699 Risk Ratio (M-H, Fixed, 95% CI) 1.46 [0.96, 2.23]

5.9 weight gain - > 7% over

baseline


5.10 constipation 2 787 Risk Ratio (M-H, Fixed, 95% CI) 1.42 [0.75, 2.69]

5.11 diarrhoea 2 787 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.40, 1.56]

5.12 dyspepsia 2 787 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.56, 1.41]

5.13 toothache 1 367 Risk Ratio (M-H, Fixed, 95% CI) 1.47 [0.43, 5.00]

5.14 upper abdominal pain 1 367 Risk Ratio (M-H, Fixed, 95% CI) 4.13 [0.24, 72.63]

5.15 infections 1 367 Risk Ratio (M-H, Fixed, 95% CI) 0.57 [0.20, 1.65]

5.16 dizziness 4 1347 Risk Ratio (M-H, Fixed, 95% CI) 1.34 [0.83, 2.14]

5.17 sedation 4 1347 Risk Ratio (M-H, Fixed, 95% CI) 1.82 [1.06, 3.15]

5.18 skin rash 1 367 Risk Ratio (M-H, Fixed, 95% CI) 3.47 [0.45, 26.50]

5.19 cough 1 367 Risk Ratio (M-H, Fixed, 95% CI) 1.89 [0.43, 8.29]

5.20 pharyngolaryngeal pain 1 367 Risk Ratio (M-H, Fixed, 95% CI) 8.58 [0.52, 142.92]

5.21 tachycardia 3 1084 Risk Ratio (M-H, Fixed, 95% CI) 1.94 [0.89, 4.25]

5.22 agitation 3 980 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.40, 0.92]



5.23 asthenia 1 420 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.41, 2.17]

5.24 QTc interval >= 450 or

10% above baseline


6 Adverse effects: 2. Average

change in QTc interval (ms)

from baseline

1 408 Mean Difference (IV, Fixed, 95% CI) 0.99 [-3.38, 5.37]

6.1 Aripiprazole 20 mg/day 1 204 Mean Difference (IV, Fixed, 95% CI) 3.00 [-3.19, 9.19]

6.2 Aripiprazole 30 mg/day 1 204 Mean Difference (IV, Fixed, 95% CI) -1.0 [-7.18, 5.18]

7 Adverse effects: 3. Physiological

(serum) measures


7.1 cholesterol - total fasting

>/= 200 mg/dl



>/= 200 mg/dl - long-term

effect



>/= 240mg/dl long-term effect


7.4 glucose - plasma levels >/=

110mg/dl


7.5 haemoglobin 1AC -

incidence >/= upper limit of

normal


7.6 low density lipoprotein

cholesterol (LDL) - >/= 130

mg/dl


7.7 low density lipoprotein

cholesterol (LDL) >/= 160

mg/dl - long-term effect


7.8 triglycerides >/= 200

mg/dl long-term effect


7.9 high density lipoprotein <

40 mg/dl long-term effect


7.10 prolactin - increase to

>/= 23 ng/ml or level above

upper limit of normal


8 Leaving the study early 9 5170 Risk Ratio (M-H, Random, 95% CI) 0.73 [0.61, 0.87]

8.1 due to any reason 9 2585 Risk Ratio (M-H, Random, 95% CI) 0.73 [0.60, 0.87]

8.2 due to adverse effects 9 2585 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.42, 1.35]

9 concomitant medication -

anxiolytics

2 787 Odds Ratio (M-H, Fixed, 95% CI) 0.96 [0.61, 1.52]



Analysis 1.1. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 1 Global state: 1. Relapse.

Review: Aripiprazole versus placebo for schizophrenia

Comparison: 1 ARIPIPRAZOLE versus PLACEBO

Outcome: 1 Global state: 1. Relapse

Study or subgroup Aripiprazole Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 short term

Carson 2002 b 50/155 85/155 32.5 % 0.59 [ 0.45, 0.77 ]

Subtotal (95% CI) 155 155 32.5 % 0.59 [ 0.45, 0.77 ]

Total events: 50 (Aripiprazole), 85 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 3.86 (P = 0.00011)

2 medium term

Carson 2002 b 67/155 102/155 39.0 % 0.66 [ 0.53, 0.81 ]

Subtotal (95% CI) 155 155 39.0 % 0.66 [ 0.53, 0.81 ]




3 Acute (2 hr after IM)

Oren 2005 79/175 56/88 28.5 % 0.71 [ 0.57, 0.89 ]

Subtotal (95% CI) 175 88 28.5 % 0.71 [ 0.57, 0.89 ]




Total (95% CI) 485 398 100.0 % 0.65 [ 0.57, 0.74 ]


Heterogeneity: Chi2 = 1.11, df = 2 (P = 0.57); I2 =0.0%

Test for overall effect: Z = 6.22 (P < 0.00001)

Test for subgroup differences: Chi2 = 1.09, df = 2 (P = 0.58), I2 =0.0%

0.2 0.5 1 2 5

Favours aripiprazole Favours placebo



Analysis 1.2. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 2 Global state: 2. Poor

compliance with study protocol due to lack of efficacy, deterioration or psychosis.



Outcome: 2 Global state: 2. Poor compliance with study protocol due to lack of efficacy, deterioration or psychosis



Adson 2003 24/312 11/108 12.2 % 0.76 [ 0.38, 1.49 ]

Carson 2000 a 30/204 16/106 15.7 % 0.97 [ 0.56, 1.70 ]

Csernansky 2003 8/34 15/35 11.0 % 0.55 [ 0.27, 1.12 ]

Daniel 2000 24/180 20/64 22.0 % 0.43 [ 0.25, 0.72 ]

Daniel 2004 1/235 1/62 1.2 % 0.26 [ 0.02, 4.16 ]

Marcus 2005 49/279 12/88 13.6 % 1.29 [ 0.72, 2.31 ]

Oren 2005 0/175 1/88 1.5 % 0.17 [ 0.01, 4.10 ]

Potkin 2003 32/202 23/103 22.7 % 0.71 [ 0.44, 1.15 ]

Total (95% CI) 1621 654 100.0 % 0.74 [ 0.59, 0.93 ]


Heterogeneity: Chi2 = 10.76, df = 7 (P = 0.15); I2 =35%


Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2




Analysis 1.3. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 3 Global state: 3. Needing

additional antipsychotic medication.



Outcome: 3 Global state: 3. Needing additional antipsychotic medication



Adson 2003 12/312 6/108 10.1 % 0.69 [ 0.27, 1.80 ]

Carson 2000 a 9/204 9/106 13.4 % 0.52 [ 0.21, 1.27 ]

Csernansky 2003 4/35 1/34 1.1 % 3.89 [ 0.46, 33.02 ]

Oren 2005 72/175 50/88 75.3 % 0.72 [ 0.56, 0.93 ]

Total (95% CI) 726 336 100.0 % 0.73 [ 0.57, 0.93 ]





0.5 0.7 1 1.5 2


Analysis 1.4. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 4 Global state: 4. Needing

additional benzodiazepines.



Outcome: 4 Global state: 4. Needing additional benzodiazepines



Adson 2003 11/312 4/108 20.8 % 0.95 [ 0.31, 2.93 ]

Oren 2005 14/175 17/88 79.2 % 0.41 [ 0.21, 0.80 ]

Total (95% CI) 487 196 100.0 % 0.53 [ 0.30, 0.92 ]





0.2 0.5 1 2 5




Analysis 1.5. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 5 Adverse effects: 1. Clinically

important specific adverse effects.



Outcome: 5 Adverse effects: 1. Clinically important specific adverse effects

Study or subgroup Aripiprazole Placebo Risk Ratio Risk Ratio


1 anxiety

Carson 2002 b 23/155 34/155 0.68 [ 0.42, 1.09 ]

Potkin 2003 41/202 19/103 1.10 [ 0.67, 1.80 ]

Adson 2003 31/312 14/108 0.77 [ 0.42, 1.39 ]

Subtotal (95% CI) 669 366 0.83 [ 0.62, 1.12 ]




2 extrapyramidal symptoms - akathisia

Carson 2002 b 14/155 12/155 1.17 [ 0.56, 2.44 ]

Daniel 2004 9/235 1/62 2.37 [ 0.31, 18.39 ]

Oren 2005 1/175 1/88 0.50 [ 0.03, 7.94 ]

Potkin 2003 40/202 9/103 2.27 [ 1.14, 4.49 ]

Adson 2003 25/312 4/108 2.16 [ 0.77, 6.08 ]

Subtotal (95% CI) 1079 516 1.78 [ 1.16, 2.74 ]




3 extrapyramidal symptoms - general

Carson 2002 b 7/155 10/155 0.70 [ 0.27, 1.79 ]

Oren 2005 3/175 3/88 0.50 [ 0.10, 2.44 ]

Potkin 2003 7/202 0/103 7.68 [ 0.44, 133.24 ]

Adson 2003 13/312 7/108 0.64 [ 0.26, 1.57 ]

Subtotal (95% CI) 844 454 0.83 [ 0.47, 1.45 ]




4 extrapyramidal symptoms - needing antiparkinson medication at least once

0.1 0.2 0.5 1 2 5 10


(Continued . . . )



(. . . Continued)Study or subgroup Aripiprazole Placebo Risk Ratio Risk Ratio


Carson 2000 a 23/204 13/106 0.92 [ 0.49, 1.74 ]

Csernansky 2003 6/34 10/35 0.62 [ 0.25, 1.51 ]

Daniel 2000 41/180 19/64 0.77 [ 0.48, 1.22 ]

Adson 2003 24/312 8/108 1.04 [ 0.48, 2.24 ]

Subtotal (95% CI) 730 313 0.83 [ 0.61, 1.14 ]




5 headache

Carson 2002 b 17/155 21/155 0.81 [ 0.44, 1.47 ]

Daniel 2004 32/235 2/62 4.22 [ 1.04, 17.13 ]

Oren 2005 13/175 7/88 0.93 [ 0.39, 2.26 ]

Potkin 2003 63/202 28/103 1.15 [ 0.79, 1.67 ]

Marcus 2005 48/279 18/88 0.84 [ 0.52, 1.37 ]

Adson 2003 78/312 17/108 1.59 [ 0.99, 2.56 ]

Subtotal (95% CI) 1358 604 1.17 [ 0.94, 1.47 ]




6 insomnia

Carson 2002 b 67/155 63/155 1.06 [ 0.82, 1.38 ]

Oren 2005 10/175 9/88 0.56 [ 0.24, 1.32 ]

Potkin 2003 53/202 23/103 1.17 [ 0.77, 1.80 ]

Adson 2003 54/312 14/108 1.34 [ 0.77, 2.30 ]

Subtotal (95% CI) 844 454 1.09 [ 0.89, 1.33 ]




7 nausea

Carson 2002 b 10/155 7/155 1.43 [ 0.56, 3.66 ]

Daniel 2004 17/235 3/62 1.50 [ 0.45, 4.94 ]

Oren 2005 10/175 2/88 2.51 [ 0.56, 11.23 ]

Potkin 2003 17/202 10/103 0.87 [ 0.41, 1.82 ]

Marcus 2005 21/279 3/88 2.21 [ 0.67, 7.23 ]

Adson 2003 54/312 10/108 1.87 [ 0.99, 3.54 ]

Subtotal (95% CI) 1358 604 1.55 [ 1.07, 2.24 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )








8 vomiting

Carson 2002 b 11/155 7/155 1.57 [ 0.63, 3.95 ]

Daniel 2004 9/235 2/62 1.19 [ 0.26, 5.35 ]

Potkin 2003 23/202 6/103 1.95 [ 0.82, 4.65 ]

Marcus 2005 13/279 7/88 0.59 [ 0.24, 1.42 ]

Adson 2003 32/312 5/108 2.22 [ 0.89, 5.54 ]

Subtotal (95% CI) 1183 516 1.46 [ 0.96, 2.23 ]




9 weight gain - > 7% over baseline

Carson 2002 b 9/155 6/155 1.50 [ 0.55, 4.11 ]

Potkin 2003 22/202 2/103 5.61 [ 1.35, 23.39 ]

Adson 2003 26/312 4/108 2.25 [ 0.80, 6.30 ]

Subtotal (95% CI) 669 366 2.55 [ 1.35, 4.82 ]




10 constipation

Marcus 2005 22/279 4/88 1.73 [ 0.61, 4.90 ]

Adson 2003 25/312 7/108 1.24 [ 0.55, 2.78 ]

Subtotal (95% CI) 591 196 1.42 [ 0.75, 2.69 ]




11 diarrhoea

Marcus 2005 9/279 6/88 0.47 [ 0.17, 1.29 ]

Adson 2003 17/312 5/108 1.18 [ 0.44, 3.11 ]

Subtotal (95% CI) 591 196 0.79 [ 0.40, 1.56 ]




12 dyspepsia

Marcus 2005 17/279 8/88 0.67 [ 0.30, 1.50 ]

Adson 2003 41/312 14/108 1.01 [ 0.58, 1.79 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )





Subtotal (95% CI) 591 196 0.89 [ 0.56, 1.41 ]




13 toothache

Marcus 2005 14/279 3/88 1.47 [ 0.43, 5.00 ]

Subtotal (95% CI) 279 88 1.47 [ 0.43, 5.00 ]




14 upper abdominal pain

Marcus 2005 6/279 0/88 4.13 [ 0.24, 72.63 ]

Subtotal (95% CI) 279 88 4.13 [ 0.24, 72.63 ]




15 infections

Marcus 2005 9/279 5/88 0.57 [ 0.20, 1.65 ]

Subtotal (95% CI) 279 88 0.57 [ 0.20, 1.65 ]




16 dizziness

Marcus 2005 13/279 6/88 0.68 [ 0.27, 1.74 ]

Daniel 2004 25/235 5/62 1.32 [ 0.53, 3.31 ]

Oren 2005 11/175 3/88 1.84 [ 0.53, 6.44 ]

Adson 2003 31/312 6/108 1.79 [ 0.77, 4.17 ]

Subtotal (95% CI) 1001 346 1.34 [ 0.83, 2.14 ]




17 sedation

Marcus 2005 13/279 0/88 8.58 [ 0.52, 142.92 ]

Daniel 2004 20/235 4/62 1.32 [ 0.47, 3.72 ]

Oren 2005 11/175 3/88 1.84 [ 0.53, 6.44 ]

Adson 2003 33/312 7/108 1.63 [ 0.74, 3.58 ]

Subtotal (95% CI) 1001 346 1.82 [ 1.06, 3.15 ]


0.1 0.2 0.5 1 2 5 10


(Continued . . . )







18 skin rash

Marcus 2005 11/279 1/88 3.47 [ 0.45, 26.50 ]

Subtotal (95% CI) 279 88 3.47 [ 0.45, 26.50 ]




19 cough

Marcus 2005 12/279 2/88 1.89 [ 0.43, 8.29 ]

Subtotal (95% CI) 279 88 1.89 [ 0.43, 8.29 ]




20 pharyngolaryngeal pain

Marcus 2005 13/279 0/88 8.58 [ 0.52, 142.92 ]

Subtotal (95% CI) 279 88 8.58 [ 0.52, 142.92 ]




21 tachycardia

Daniel 2004 12/235 2/62 1.58 [ 0.36, 6.89 ]

Adson 2003 24/312 3/108 2.77 [ 0.85, 9.01 ]

Marcus 2005 7/279 2/88 1.10 [ 0.23, 5.22 ]

Subtotal (95% CI) 826 258 1.94 [ 0.89, 4.25 ]




22 agitation

Oren 2005 7/175 5/88 0.70 [ 0.23, 2.15 ]

Daniel 2004 6/235 2/62 0.79 [ 0.16, 3.83 ]

Adson 2003 38/312 23/108 0.57 [ 0.36, 0.91 ]

Subtotal (95% CI) 722 258 0.61 [ 0.40, 0.92 ]




23 asthenia

Adson 2003 19/312 7/108 0.94 [ 0.41, 2.17 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )





Subtotal (95% CI) 312 108 0.94 [ 0.41, 2.17 ]




24 QTc interval >= 450 or 10% above baseline

Adson 2003 3/312 0/108 2.44 [ 0.13, 46.82 ]

Marcus 2005 0/279 0/88 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 591 196 2.44 [ 0.13, 46.82 ]




Total (95% CI) 16634 6821 1.17 [ 1.07, 1.28 ]




Test for subgroup differences: Chi2 = 46.94, df = 23 (P = 0.00), I2 =51%

0.1 0.2 0.5 1 2 5 10




Analysis 1.6. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 6 Adverse effects: 2. Average

change in QTc interval (ms) from baseline.



Outcome: 6 Adverse effects: 2. Average change in QTc interval (ms) from baseline

Study or subgroup Aripiprazole Placebo Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Aripiprazole 20 mg/day

Potkin 2003 101 1 (24) 103 -2 (21) 49.9 % 3.00 [ -3.19, 9.19 ]

Subtotal (95% CI) 101 103 49.9 % 3.00 [ -3.19, 9.19 ]



2 Aripiprazole 30 mg/day

Potkin 2003 101 -3 (22) 103 -2 (23) 50.1 % -1.00 [ -7.18, 5.18 ]

Subtotal (95% CI) 101 103 50.1 % -1.00 [ -7.18, 5.18 ]



Total (95% CI) 202 206 100.0 % 0.99 [ -3.38, 5.37 ]




-10 -5 0 5 10




Analysis 1.7. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 7 Adverse effects: 3. Physiological

(serum) measures.



Outcome: 7 Adverse effects: 3. Physiological (serum) measures



1 cholesterol - total fasting >/= 200 mg/dl

Carson 2002 b 78/155 75/155 14.6 % 1.04 [ 0.83, 1.30 ]

Subtotal (95% CI) 155 155 14.6 % 1.04 [ 0.83, 1.30 ]




2 cholesterol - total fasting >/= 200 mg/dl - long-term effect

Carson 2002 b 91/155 75/155 14.6 % 1.21 [ 0.98, 1.50 ]

Subtotal (95% CI) 155 155 14.6 % 1.21 [ 0.98, 1.50 ]




3 cholesterol - total fasting >/= 240mg/dl long-term effect

Carson 2002 b 33/155 27/155 5.3 % 1.22 [ 0.77, 1.93 ]

Subtotal (95% CI) 155 155 5.3 % 1.22 [ 0.77, 1.93 ]




4 glucose - plasma levels >/= 110mg/dl

Carson 2002 b 49/155 51/155 9.9 % 0.96 [ 0.70, 1.33 ]

Subtotal (95% CI) 155 155 9.9 % 0.96 [ 0.70, 1.33 ]




5 haemoglobin 1AC - incidence >/= upper limit of normal

Carson 2002 b 17/155 23/155 4.5 % 0.74 [ 0.41, 1.33 ]

Subtotal (95% CI) 155 155 4.5 % 0.74 [ 0.41, 1.33 ]




6 low density lipoprotein cholesterol (LDL) - >/= 130 mg/dl

Carson 2002 b 74/155 73/155 14.2 % 1.01 [ 0.80, 1.28 ]

Subtotal (95% CI) 155 155 14.2 % 1.01 [ 0.80, 1.28 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )



(. . . Continued)Study or subgroup Aripiprazole Placebo Risk Ratio Weight Risk Ratio





7 low density lipoprotein cholesterol (LDL) >/= 160 mg/dl - long-term effect

Carson 2002 b 28/155 28/155 5.4 % 1.00 [ 0.62, 1.61 ]

Subtotal (95% CI) 155 155 5.4 % 1.00 [ 0.62, 1.61 ]




8 triglycerides >/= 200 mg/dl long-term effect

Carson 2002 b 46/155 49/155 9.5 % 0.94 [ 0.67, 1.31 ]

Subtotal (95% CI) 155 155 9.5 % 0.94 [ 0.67, 1.31 ]




9 high density lipoprotein < 40 mg/dl long-term effect

Carson 2002 b 60/155 70/155 13.6 % 0.86 [ 0.66, 1.12 ]

Subtotal (95% CI) 155 155 13.6 % 0.86 [ 0.66, 1.12 ]




10 prolactin - increase to >/= 23 ng/ml or level above upper limit of normal

Adson 2003 8/312 19/108 5.5 % 0.15 [ 0.07, 0.32 ]

Potkin 2003 7/202 11/103 2.8 % 0.32 [ 0.13, 0.81 ]

Subtotal (95% CI) 514 211 8.3 % 0.21 [ 0.11, 0.37 ]



Test for overall effect: Z = 5.24 (P < 0.00001)

Total (95% CI) 1909 1606 100.0 % 0.94 [ 0.86, 1.04 ]




Test for subgroup differences: Chi2 = 33.96, df = 9 (P = 0.00), I2 =74%

0.1 0.2 0.5 1 2 5 10




Analysis 1.8. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 8 Leaving the study early.



Outcome: 8 Leaving the study early

Study or subgroup Aripiprazole Placebo Risk Ratio Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI

1 due to any reason

Adson 2003 200/312 78/108 0.89 [ 0.77, 1.02 ]

Carson 2000 a 76/204 48/106 0.82 [ 0.63, 1.08 ]

Carson 2002 b 84/155 110/155 0.76 [ 0.64, 0.91 ]

Csernansky 2003 13/34 23/35 0.58 [ 0.36, 0.95 ]

Daniel 2000 67/180 35/64 0.68 [ 0.51, 0.91 ]

Daniel 2004 8/235 3/62 0.70 [ 0.19, 2.57 ]

Marcus 2005 128/279 44/88 0.92 [ 0.72, 1.17 ]

Oren 2005 5/175 1/88 2.51 [ 0.30, 21.19 ]

Potkin 2003 37/202 51/103 0.37 [ 0.26, 0.53 ]

Subtotal (95% CI) 1776 809 0.73 [ 0.60, 0.87 ]


Heterogeneity: Tau2 = 0.05; Chi2 = 26.46, df = 8 (P = 0.00088); I2 =70%


2 due to adverse effects

Adson 2003 19/312 6/108 1.10 [ 0.45, 2.67 ]

Carson 2000 a 17/204 11/106 0.80 [ 0.39, 1.65 ]

Carson 2002 b 16/155 13/155 1.23 [ 0.61, 2.47 ]

Csernansky 2003 0/34 0/35 0.0 [ 0.0, 0.0 ]

Daniel 2000 10/180 1/64 3.56 [ 0.46, 27.23 ]

Daniel 2004 2/235 0/62 1.33 [ 0.06, 27.45 ]

Marcus 2005 7/279 6/88 0.37 [ 0.13, 1.07 ]

Oren 2005 1/175 0/88 1.52 [ 0.06, 36.86 ]

Potkin 2003 4/202 12/103 0.17 [ 0.06, 0.51 ]

Subtotal (95% CI) 1776 809 0.75 [ 0.42, 1.35 ]




0.5 0.7 1 1.5 2


(Continued . . . )




n/N n/N M-H,Random,95% CI M-H,Random,95% CI

Total (95% CI) 3552 1618 0.73 [ 0.61, 0.87 ]





0.5 0.7 1 1.5 2


Analysis 1.9. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 9 concomitant medication -

anxiolytics.



Outcome: 9 concomitant medication - anxiolytics

Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio


Adson 2003 262/312 91/108 56.7 % 0.98 [ 0.54, 1.78 ]

Marcus 2005 239/279 76/88 43.3 % 0.94 [ 0.47, 1.89 ]

Total (95% CI) 591 196 100.0 % 0.96 [ 0.61, 1.52 ]

Total events: 501 (Treatment), 167 (Control)




0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control



H I S T O R Y

Protocol first published: Issue 3, 2007

Review first published: Issue 8, 2011

C O N T R I B U T I O N S O F A U T H O R S

El-Sayeh HGG - initial protocol development, data extraction, analysis, writing review.

Belgamwar RB - update review protocol development, data extraction, writing review.

D E C L A R A T I O N S O F I N T E R E S T

Dr Ravindra Belgamwar - none.

Dr Hany George El-Sayeh - none.

S O U R C E S O F S U P P O R T

Internal sources

• North Staffordshire Combined Health Care NHS Trust, UK.

External sources

• none, Not specified.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

Apart from two studies (Daniel 2004; Oren 2005), all other studies had high attrition rates. We have included these studies in the

analysis and reported attrition rates. Adson 2003 had a very high attrition rate (higher than 40%); this study had been included in the

original review and is one of the initial aripripazole studies used for gaining its licence. As its inclusion necessitates a deviation from the

protocol, we performed sensitivity analysis to see whether its exclusion makes a significant difference in overall outcome of the results.

The sensitivity analysis is reported by producing a summary table as below.

Outcome Authors’ view after comparing test for overall results with and

without Adson 2003

1.2 Global state: 2. Poor compliance with study protocol due to

lack of efficacy, deterioration or psychosis

No changes to overall outcome

1.3 Global state: 3. Needing additional antipsychotic medication No changes to overall outcome

1.4 Global state: 4. Needing additional benzodiazepines No changes to overall outcome



(Continued)

1.5 Adverse effects on: anxiety, akathisia, extrapyramidal symp-

toms, headache, insomnia, weight gain, constipation, diar-

rhoea, dyspepsia, dizziness, sedation, asthenia and tachycar-

dia


1.5 Adverse effects on: nausea, vomiting and agitation Result favours placebo

1.7.10 Prolactin - increase to >/= 23 ng/ml or level above upper limit

of normal


1.8.1 Leaving the study early: due to any reason No changes to overall outcome

1.8.2 Leaving the study early: due to adverse effects No changes to overall outcome

1.9 Concomitant medication - anxiolytics No changes to overall outcome

We included data on use of concomitant medication for antipsychotics and benzodiazepines.

We have also updated the format and content of the methods section to reflect changes in Cochrane methodology since our protocol

was published, for example the inclsuion of a ’Summary of Findings’ table.

I N D E X T E R M SMedical Subject Headings (MeSH)

Antipsychotic Agents [adverse effects; ∗therapeutic use]; Patient Dropouts [statistics & numerical data]; Piperazines [adverse effects;∗therapeutic use]; Placebos [therapeutic use]; Quinolones [adverse effects; ∗therapeutic use]; Randomized Controlled Trials as Topic;

Schizophrenia [∗drug therapy]

MeSH check words

Humans



belgamwar 2011 aripiprazole vs placebo schizophrenia

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