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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.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 1 Global state: 1. Relapse. . . . . . Analysis 1.2. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 2 Global state: 2. Poor compliance with study protocol due to lack of efcacy, deterioration or psychosis. . . . . . . . . . . . . . . . . . . Analysis 1.3. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 3 Global state: 3. Needing additional antipsychotic medication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.4. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 4 Global state: 4. Needing additional benzodiazepines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.5. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 5 Adverse effects: 1. Clinically important specic adverse effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.6. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 6 Adverse effects: 2. Average change in QTc interval (ms) from baseline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.7. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 7 Adverse effects: 3. Physiological (serum) measures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.8. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 8 Leaving the study early. . . . . . Analysis 1.9. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 9 concomitant medication - anxiolytics. HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 5 5 6 10 12 13 16 19 20 20 29 46 48 49 50 50 51 57 58 60 61 61 62 62 62 62 63

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

[Intervention Review]

Aripiprazole versus placebo for schizophrenia


Ravindra B Belgamwar1 , Hany George G El-Sayeh2
1 Lymebrook

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

Contact address: Ravindra B Belgamwar, Lymebrook Mental Health Centre, Bradwell Hospital Site, Newcastle Under Lyme, Staffordshire, ST5 4LD, UK. ravindrab.belgamwar@northstaffs.nhs.uk. ravindrab.belgamwar@northstaffs.nhs.uk. 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. Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT 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, CENTRAL, 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% condence intervals (CI) on an intention-to-treat basis based on a xed-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 xed-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 signicantly decreased relapse in both the short (n = 310, 1 RCT, RR
Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1

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 signicant 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.

PLAIN LANGUAGE SUMMARY 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 nding on its efcacy in treating schizophrenia is unchanged from those found in the original review.

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 3

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 Placebo Poor compliance with 16 per 100 study protocol Relapse 61 per 100

Corresponding risk Aripiprazole 11 per 100 RR 0.72 (0.53 to 0.97) 2275 (8 studies) 573 (2 studies) ++OO low ++OO low ++OO low

40 per 100

RR 0.66 (0.57 to 0.75)

Weight gain (equal or 5.2 per 100 greater then 7% of baseline) Concomitant medication 84 per 100 (Anxiolytic - Lorazepam)

8.5 per 100

RR 2.33 (1.17 to 4.66)

615 (3 studies)

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.

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 4

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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BACKGROUND

How the intervention might work


Technical background

Description of the condition


Schizophrenia is one of the major psychiatric disorders; it affects individuals 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, schizophrenia 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 rst episode. The course of schizophrenia can be either continuous, or episodic, with progressive or stable decit, or there can be one or more episodes with complete or incomplete remission (ICD 10). Between 14% and 20% of patients will recover fully; others 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 ve years (NICE 2009). The mortality amongst people with schizophrenia is approximately 50% above the general population, partly related to high suicide rates, violent deaths and increased risk of physical health problems (NICE 2009).

Aripiprazole is said to be the prototype of a new third generation of antipsychotics, the so-called dopamine-serotonin system stabilisers (McQuade 2002). It is reported to exert its antipsychotic effects by acting as a partial agonist at D2 dopamine- and 5-HT1a serotonin 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 antagonist in pathways where an abundance of dopamine was producing psychosis. However, it would stimulate receptors as an agonist at sites in which low dopaminergic tone would produce side effects (e.g. areas mediating motor movement and prolactin release) (Rivas-Vasquez 2003). Aripiprazole, however, also has an afnity 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 ve 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). Aripiprazole has since been licensed in most countries worldwide, and is available as tablets, orally disintegrating tablets, oral solution and intramuscular injection.

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 antipsychotics 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 symptoms of schizophrenia and negative symptoms of schizophrenia. It has also been suggested that aripiprazole may be associated with fewer movement disorders (parkinsonism, dystonias, tardive dyskinesia), less weight gain and reduced negative effects on the heart (QTc interval abnormalities) and on glucose metabolism compared with standard antipsychotics (Rivas-Vasquez 2003).

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 prole 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 comparison has been split out of the old review and used to create a new review, one that assesses aripiprazoles efcacy and side effects compared to placebo. This placebo review will then become part of a family of aripiprazole reviews: Aripiprazole versus typical antipyschotics (Bhattacharjee 2008) and Aripiprazole versus other atypical antipsychotics (Komossa 2007).

OBJECTIVES
To review the effects of aripiprazole compared with placebo for people with schizophrenia or other psychotic disorders or affective psychotic disorders.
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Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

METHODS

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 nal analysis. If there was a substantive difference, we only analysed clearly randomised 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 crossover studies were eligible, but only data up to the point of rst 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 schizoaffective 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 different 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 dened in the individual studies) as the primary outcome measure.
Secondary outcomes

1. Death - suicide and natural causes 2. Global state 2.1 Relapse as dened in the individual studies. 2.2 Poor compliance with study protocol due to lack of efcacy, 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 negative 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 specic symptoms (positive symptoms of schizophrenia, negative symptoms of schizophrenia, depression, mania) 4.5 Average endpoint specic symptom score 4.6 Average change in specic 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 specic aspects of functioning, such as social or life skills 5.5 Average endpoint specic aspects of functioning, such as social or life skills 5.6 Average change in specic 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 specic aspects of behaviour 4.5 Average endpoint specic aspects of behaviour 4.6 Average change in specic aspects of behaviour 6. Adverse effects - general and specic (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, sexual side effects, anxiety, somnolence, disturbances of the gastrointestinal 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 specic adverse effects 6.5 Average endpoint specic adverse effects 6.6 Average change in specic adverse effects 7. Engagement with services 8. Satisfaction with treatment 8.1 Leaving the study early 8.2 Recipient of care not satised with treatment 8.3 Recipient of care average satisfaction score 8.4 Recipient of care average change in satisfaction scores 8.5 Carer not satised with treatment 8.6 Carer average satisfaction score 8.7 Carer average change in satisfaction scores
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Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 specic aspects of quality of life 9.5 Average endpoint specic aspects of quality of life 9.6 Average change in specic 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 specic aspects of cognitive functioning 10.5 Average endpoint specic aspects of cognitive functioning 10.6 Average change in specic aspects of cognitive functioning

RBB inspected all reports. HGE then re-inspected these in order to ensure reliable selection. We resolved any disagreement by discussion, 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 further information and added these trials to the list of those awaiting assessment. Data extraction and management

1. Extraction

Search methods for identication of studies

We electronically extracted initial data from the Aripripazole for schizophrenia review (El-Sayeh 2006). RBB independently extracted 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

Electronic searches 1. We searched The Cochrane Schizophrenia Groups Trials Register (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

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 modied 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 therapist). We realise that this is not often reported clearly, in Description of studies noted if this is the case or not. 2.3 Endpoint versus change data

1. Reference searching

We inspected the references of all identied 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

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 difcult in unstable and difcult 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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Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

2.4 Skewed data Continuous data on clinical and social outcomes are often not normally distributed. To avoid the pitfall of applying parametric 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 nite number zero, the standard deviation, when multiplied by two, is less than the mean (as otherwise 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 modied 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 nite 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 difcult 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.

2.8 Summary of ndings table We used the GRADE approach to interpret ndings (Schnemann 2008) and used GRADE proler (GRADEPRO) to import data from Review Manager 5 (RevMan) to create Summary of ndings tables. These tables provide outcome-specic information concerning 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 ndings 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 Interventions (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 nal 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 ndings for the main comparison.

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 signicant 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.

Measures of treatment effect

1. Binary data

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.

For binary outcomes we calculated a standard estimation of the risk ratio (RR) and its 95% condence 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 signicant results we had planned to calculate the number needed to treat to provide benet /to induce harm statistic (NNTB/H), and its 95% condence 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 ndings for the main comparison and calculations therein.
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Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

2. Continuous data

2. Binary

For continuous outcomes we estimated mean difference (MD) between groups. We would prefer not to calculate effect size measures (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 specic instruments.

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 Unit of analysis issues


Clinical heterogeneity 1. Cluster trials

If cluster studies had been appropriately analysed taking into account ICCs and relevant data documented in the report, synthesis 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 occurs if an effect (e.g. pharmacological, physiological or psychological) of the treatment in the rst phase is carried over to the second phase. As a consequence, on entry to the second phase the participants can differ systematically from their initial state despite a wash-out phase. For the same reason, cross-over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both effects are very likely in schizophrenia, we have only used data of the rst phase of cross-over studies.

First, we considered all the included studies within any comparison to judge clinical heterogeneity. We then visually inspected the graphs to investigate the possibility of statistical heterogeneity 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 heterogeneity.

Assessment of reporting biases Reporting biases arise when the dissemination of research ndings is inuenced 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.

3. Studies with multiple treatment groups

Where a study involved more than two treatment arms, if relevant, the additional treatment arms were presented in comparisons. Where the additional treatment arms were not relevant, these data were not reproduced.

Data synthesis

1. Analysis

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.

Where possible we employed a xed-effect model for analyses. We understand that there is no closed argument for preference for use of xed-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 xed-effect models, employing random-effects when we detected heterogeneity.
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Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 heterogeneity was present, we investigated reasons for this. If it substantially altered the results, we did not summate data, but presented the data separately and investigated reasons for heterogeneity. Sensitivity analysis We compared results for high doses (however high was dened in the study or, if such a denition was not presented, greater than 15 mg aripiprazole per day) to those for lower doses with regard to the primary outcome of relapse.

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 carried out another search on 13th of August 2008. RB inspected 359 electronic and 135 PDF reports from the rst 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 aripiprazole versus active control. J Xia inspected reports on the Chinese-language studies. Included studies

3. Included studies

3.1 Length of trials

RESULTS

Description of studies
See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classication. 1. Included studies We identied nine studies that we could include. All were described as randomised and as being double blind, although allocation 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, participants 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).

Schizophrenia is a lifelong illness that affects young people. Out of the nine included studies; six reported data on short-term followup of up to six weeks ( Adson 2003; Carson 2000; Csernansky 2003; Daniel 2000; Marcus 2005; Potkin 2003), one on mediumterm follow-up of 26 weeks (Carson 2004) and two studies involved the administration intramuscular preparation reported data on 24 hours period (Daniel 2004, Oren 2005). There are no studies 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 denitive 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 antipsychotics 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.
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Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 efcacy, deterioration or psychosis as a global outcome because, surprisingly, 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 reported in more than 5% to 10% of participants. This design precludes 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 signicant and Potkin 2003 reported the mean change in body weight. All but one included study provide usable data on leaving the study early.

This schizophrenia scale has 30 items, each of which can be dened on a seven-point scoring system varying from 1 - absent to 7 - extreme. This scale can be divided into three sub-scales for measuring the severity of general psychopathology, positive symptoms (PANSS-P) and negative symptoms (PANSS-N). A low score indicates 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 interviewers 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 trialists compare aripiprazole with both haloperidol and placebo. Outcomes such as death, clearly of interest, were reported in an obscure 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 Pharmaceuticals (UK) on the 27th October 2004 in Leeds, we requested further clarication 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 identied 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, specically on death which, on further evaluation, do not suggest an increased risk of mortality as indicated in the conference 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 functioning (CGI) and adverse effects (Simpson-Angus scale, Barnes Akathisia scale, Abnormal Involuntary Movement scale) and other outcome measures including changes in body weight, serum prolactin, 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
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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 Outcomes 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 improvement, by comparing the conditions of the person standardised against other people with the same diagnosis. A seven-point scoring system is usually used, with low scores showing decreased severity 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)

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 studies (aripiprazole versus active control without placebo arm). During our search, we came across several new studies in the pipeline

where aripiprazole is compared to another antipsychotic medication. We excluded nine other studies from the review. Three were review 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 administration 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.

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

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Allocation All included studies were said to be randomised. None of the included studies, however, explicitly detailed the method of randomisation. 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 (Jni P 2001). Therefore all trials were category B (moderate risk of bias - some doubt about the results - see Methods). This was conrmed by poor ratings on the Jadad Scale (see Characteristics of included studies) (Jadad 1996).

Overall much of the data we found could not be used because of poor reporting. Findings which are presented as graphs, in percentiles or just reported as P values are often of little use to a reviewer. 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 efcacy. 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.

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.

Effects of interventions
See: Summary of ndings for the main comparison From the original review Aripripazole for schizophrenia, we identied 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 Aripiprazole compared to placebo or any additional data on the existing included studies. The two update searches did not nd further studies but provided additional study data, particularly on side effects. We also identied two new studies (Carson 2008; Nyilas 2007) focusing on adolescent populations from conference posters. Since the ndings 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.

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, dened as those completing the trial). Although LOCF analyses are commonly used to account for missing observations, this technique could introduce bias as considerable assumptions are made about people who did not stay in the study. We saw no reporting of attempts to validate assumptions by following 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.

Comparison 1: ARIPIPRAZOLE versus PLACEBO

Selective reporting

1. Global state

Data reporting

1.1 Relapse

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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 signicantly 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 signicantly 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 efcacy, 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 compliance with study protocol, and several seemed to fall into a natural grouping reporting a poor global outcome. We have grouped these throughout the review. Overall people allocated to aripiprazole encountered this outcome signicantly 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 signicantly 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 signicantly 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).

2.2 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 signicant difference between the two groups.

2.4 General extrapyramidal symptoms, movement disorders, vomiting, anxiety, dyspepsia There appears to be no signicant 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 signicantly 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 information; 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); pharyngolaryngeal pain (n = 367, 1 RCT, RR 8.58 CI 0.52 to 142.92); all were statistically insignicant. One study (Adson 2003) reported asthenia, with no signicant difference amongst the groups (n = 420, 1 RCT, RR 0.94 CI 0.41 to 2.17).
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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 signicant difference.

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 signicant (n = 787, 2 RCTs, RR 2.44 CI 0.13 to 46.82, NNH 198). For average change - QTc interval (ms) from baseline, there appeared to be no signicant difference between 20 mg/day aripiprazole 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 signicant 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

Summary of main results


When compared with placebo, aripiprazole treated patients had fewer relapses, fewer people left study early and needed less additional antipsychotic medications. Where reported, both the group needed benzodiazepine/antianxiety medication (lorazepam) as an adjunct treatment in most of the patients.

1. Applicability of ndings 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 welldened schizophrenia or schizoaffective disorder. Such people are a minority in everyday care, where people who are not in hospital and suffer from less well dened illness, combined with problems such as depression and substance abuse, are the norm. The reader is subsequently left with the difcult decision as to whether the ndings of studies with such participants, interventions and outcomes, gathered in standardised highly developed inpatient settings, 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 medication, 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 intervention works in the short term (by 12 weeks) there is no guarantee that this means that the compound has long-term benets. 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 ndings to routine care. The design of the studies is clearly encouraging loss to follow-up. People leave for many reasons, often not specied, and their last observation is carried forward to the end. These data, sometimes with an assumption 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 trialists 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 unreported 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
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We noted that data were heterogenous on visual inspection of forest plot and had high I2 . Signicantly 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 combination was use in 85% of participants in both the groups (n = 787, OR 0.96 CI 0.61 to 1.52).

DISCUSSION

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

since it is not the individual compounds in a trial which are randomised, but the intention to give those individual compounds. Some trialists tended to report mean gures without giving standard 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, service outcomes, general functioning, behaviour, engagement with services, economic outcomes and cognitive functioning. The primary 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 restricting 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 difcult as results were often summarised. Several studies were reported multiple times. Without unique study identiers, this gives the impressions that there are more data than actually exist and facilitates erroneous double counting.

3.1.2 Poor compliance with study protocol due to lack of efcacy, deterioration or psychosis This category constituted patients leaving the study due to poor efcacy, those with deterioration in their mental state and those who developed frank psychosis. There was a signicant 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 signicantly less need for benzodiazepine medication in the aripiprazole treated patients (NNT 16). Two studies used intramuscular medication, however, and the outcomes 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. Comparison 1: aripiprazole versus placebo


3.2 Adverse effects

3.1 Global state

3.2.1 Clinically important specic 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 signicant differences in reported adverse effects in people taking placebo compared to those taking aripiprazole. No objective rating scales appeared to be used in measuring these symptoms, even though for certain symptoms such as anxiety and extrapyramidal side effects, these are commonly used in research. Potkin 2003 did repeatedly nd 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 extrapyramidal 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 active control group, how the level of signicant weight gain (seven percent) was decided upon. There was no mention of this gure in the methodology section of the included study reports and if
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3.1.1 Relapse Relapse, the primary outcome for this review, was only reported by Carson 2002 b and was dened 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 rst, 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. Nevertheless, it is genuinely heartening that aripiprazole helps avoid these degrees of deterioration and that the number needed to treat of ve is not very large in either the short or medium term.

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

it was decided on after the data were inspected, any results would be prone to bias.

symptoms rating scales). The studies rely on other factors, such as compliance and smaller numbers of relapses as a measure of efcacy.

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 measures 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 signicant difference in favour of aripiprazole 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 numerical 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 nding in favour of aripiprazole.

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 medication, 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 benets. 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 ndings to routine care. The design of the studies is clearly encouraging loss to follow-up. People leave for many reasons, often not specied, and their last observation is carried forward to the end. These data, sometimes with an assumption 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 trialists 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 unreported 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 randomised, but the intention to give those individual compounds. Some trialists tended to report mean gures without giving standard 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, service outcomes, general functioning, behaviour, engagement with services, economic outcomes and cognitive functioning. The primary 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 restricting what is reported seems odd. We note that the design of
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3.3 Leaving the study early

Signicantly 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 reects 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 signicantly affect the overall results.

Overall completeness and applicability of evidence


There is a lack of evidence on the efcacy of aripiprazole in schizophrenia (i.e. showing improvement of the schizophrenia

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 difcult, as results were often summarised. Several studies were multiply reported. Without unique study identiers this gives the impression that there are more data than actually exist and facilitates erroneous double counting. 2. Applicability of ndings 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 welldened schizophrenia or schizoaffective disorder. Such people are a minority in everyday care, where people who are not in hospital and suffer from less well-dened illness, combined with problems such as depression and substance abuse, are the norm. The reader is subsequently left with the difcult decision as to whether the ndings of studies with such participants, interventions and outcomes and standardised highly developed inpatient settings can still inform their daily practice.

1. No additional studies identied 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).

AUTHORS CONCLUSIONS 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 aripiprazole with active control. When compared with placebo, aripiprazole treated patients had fewer relapses and fewer left study early, and needed less additional antipsychotic medications. Overall it appears that aripiprazole has a better side effect prole; those that were signicantly more prevalent than in the placebo group included akathisia, nausea 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 production of prolactin, which can cause unpleasant breast pain and secretion) and glucose levels; on the limited evidence available (due to subjects leaving study early and fewer studies), aripiprazole appears to have a similar effect to that of placebo. The overall nding on its efcacy in treating schizophrenia is unchanged from what we found in the original review.

Quality of the evidence


1. All of the included studies were published in journals, although we obtained some data from conference proceedings and handsearching. 2. All included studies were sponsored by the pharmaceutical industry. 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 sections, 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.

2. For clinicians Aripripazole efcacy on global state was superior to placebo in one study. Aripripazole may offer signicant advantages over other atypicals in terms of outcomes, as it caused hyperprolactinaemia and raised QTc interval; thus, aripiprazoles effect appears to be similar to that of placebo. More studies are needed to replicate and validate these ndings. 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.
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Potential biases in the review process


There were no disagreement between authors on the numbers extracted.

Agreements and disagreements with other studies or reviews

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 nite resources, the lack of good quality data leaves managers and policy makers with difcult decisions to make.

participants. Data from graphs, P values of differences and statements of signicant or non-signicant 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. Specic As an antipsychotic agent with a novel mechanism of action, aripiprazole 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 longterm risks, including mortality, behaviour, satisfaction with treatment and cost-effectiveness, in comparison to typical and atypical antipsychotics, are a priority. Pragmatic entry criteria and nonblinding with hard endpoints may be helpful in decreasing the study attrition (Rowland 1998).

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 condent 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 requirement 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

ACKNOWLEDGEMENTS
The Cochrane Schizophrenia Group Editorial Base in Nottingham 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.

REFERENCES

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/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:176232. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets; medical review part 1. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:150. McEvoy J, Daniel D, Carson WH Jr, McQuade R, Marcus R. A randomized, double blind, placebo controlled, study of the efcacy 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: 895905.

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;1-2:2212. 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. Efcacy of aripiprazole in psychotic disorders: comparison with haloperidol and placebo. Journal of the European

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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College of Neuropsychopharmacology 2000;10(Suppl 3):S309. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 1. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:150. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 3. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:11175. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 4. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm Vol. 2002:176232. Kane J, Ingenito G, Ali M. Efcacy 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. Efcacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. Journal of Clinical Psychiatry 2002;9:76371. Kane JM, Ingenito G, Ali M. Efcacy of aripiprazole in psychotic disorders: comparison with haloperidol and placebo. International Journal of Neuropsychopharmacology 2000;Suppl 1:S124. Kane JM, Ingenito G, Ali M. Efcacy of aripiprazole in psychotic disorders: comparison with haloperidol and placebo. Proceedings of the 155th Annual Meeting of the American Psychiatric Association; 2002 May 18-23; Philadelphia, PA, USA. 2002. Kane JM, Ingenito G, Ali M. Efcacy of aripiprazole in psychotic disorders: comparison with haloperidol and placebo. Proceedings of the 53rd Annual Meeting of the American Psychiatric Association; 2000 May 13-18; 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. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 3. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm 2002:11175. 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 Annual Meeting of the American Psychiatric Association; 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 placebocontrolled 26-week study. Journal of Clinical Psychiatry 2003;64(9):104856. 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 longterm treatment with aripiprazole. Schizophrenia Research 2004;67(1):1923. Csernansky 2003 {unpublished data only} Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 1. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:150. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 2. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:51110. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 3. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:11175. 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 Neuropsychopharmacology 2000;Suppl 1:S157. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 1. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:150. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 3. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:11175. Saha AR, Petrie JL, Ali MW. Safety and efcacy prole 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
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Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

the 157th Annual Meeting of the American Psychiatric 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. Efcacy 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, ODonnell A, Carson W, McQuade R. The efcacy and safety of lower doses of Aripripazole for the treatment of patients with acute exacerbation of schizophrenia. CNS Spectr 2006;11 (9):691702. Marcus RN. Efcacy and safety of lower doses of aripiprazole. Proceedings of the 158th Annual Meeting of the American Psychiatric Association; 2005 May 21-26; 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;188:28192. Oren D, Marcus R, Kostic D, McQuade R, Iwamoto T, Archibald D. Efcacy 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 Annual Meeting of the American Psychiatric Association; 2002 May 18-23; Philadelphia, USA. 2002. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 1. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:150. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 3. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:11175. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 4. www.fda.gov/

cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:176232. 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;60:68190. Saha A, Carson W, Ali M, Dunbar G, Ingenito G. Efcacy 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, Ingenito G. Aripiprazole and risperidone versus placebo in schizophrenia and schizoaffective disorder. Schizophrenia Research 2002;3(Suppl 1):1856. Yeung P, McQuade RD, Carson WH, Saha A, Ali MW, Ingenito G. Aripiprazole and risperidone versus placebo in schizophrenia. European Psychiatry 2002;Suppl 1:102s. Yeung PP, Carson WH, Saha A, McQuade RD, Ali M, Stringfellow JC, Ingenito G. Efcacy 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 Neuropsychopharmacology 2002;Suppl 3:S288. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 3. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 11175. 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 the American Psychiatric Association; 2002 May 18-23; 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
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Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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, LItalien 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 of Neuropsychopharmacology 2004;14(Suppl 3):S275. 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 doubleblind 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;166:3919. 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. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 3. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:11175. Kujawa M, Saha AR, Ali MW, Jody DN, McQuade RD, Ingenito GG. Switching to aripiprazole monotherapy. Schizophrenia Research 2003;60:290. 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. Efcacy 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):2936. Chen 2005 b {published data only} Chen J-D, Zhao J-P, Li L-H, Guo X-F, Zhai J-G, Wang CY, 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):8458.

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):25966. Corey-Lisle 2006 {unpublished data only} Corey-Lisle PK, Kolotkin RL, Crosby RD, LItalien 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 Meeting of the American Psychiatric Association; 2006 May 20-25, Toronto, Canada. 2006. Fan 2005 a {published data only} Fan W-L, Yu C-M, Wen J-S. Efcacy analysis of aripiprazole and clozapine in the treatment of schizophrenia. Journal of North Sichuan Medical College 2005;20(4):3779. 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 2024, 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):8534. 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 2024, 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
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Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Annual Meeting of the American Psychiatric Association; 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):1556. McQuade R, Jody D, Kane J, Carson W, Kujawa M, Stringfellow J, Marcus R, Sanchez R, Meltzer HY. Efcacy and safety of aripiprazole versus perphenazine in treatmentresistant 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. Efcacy and safety of aripiprazole versus perphenazine in treatmentresistant 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. Proceedings of the 157th Annual Meeting of the American 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, GutierrezEsteinou 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):21323. Kern 2001 {published data only} Carson W, Cornblatt B, Saha A, Ali M, Kern R, Green M. Neurocognitive benets of aripiprazole versus olanzapine in stable psychosis. Journal of the European College of Neuropsychopharmacology 2002;Suppl 3:S291. 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. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 3. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:11175. 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 efcacy between aripiprazole and haloperidol in treatment of chronic schizophrenia and schizoaffective disorder: results for 16-week clinical study. Journal of the European College of Neuropsychopharmacology 2006;16 (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 longterm 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. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 1. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:150. Kasper S, Lerman MN, McQuade RD, Saha A, Carson WH, Ali M, Archibald D, Ingenito G, Marcus R, Pigott T. Efcacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. International Journal of Neuropsychopharmacology 2003;6(4):32537. 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 the 155th Annual Meeting of the American Psychiatric Association; 2002 May 18-23; Philadelphia, PA, USA.
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Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 the 156th Annual Meeting of the American Psychiatric 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 of Neuropsychopharmacology 2002;12(Suppl 3):S288. McQuade RD, Kujawa M, Saha AR, Ingenito GG, Ali MW, Luo X, Archibald DG, Carson WH. Aripiprazole for long-term maintenance treatment of schizophrenia. Schizophrenia Research 2003;60:295. 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):1589. Stock EG, Achibald DG, Tourkodimitris S, Kuwaja MJ, Marcus RN, Carson Jr WH. Long-term effects of aripiprazole on affective symptoms of schizophrenia. Proceedings of the 156th Annual Meeting of the American Psychiatric Association; 2003 May 17-22; San Francisco, USA. 2003. Kujawa 2003 {published data only} Kujawa M, Stringfellow J, Hardy S, Ali M, Iwamoto T, Lam S, Marcus R, Stock E. Efcacy, 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 efcacy of aripiprazole in patients with schizoaffective disorder. Proceedings of the 156th Annual Meeting of the American Psychiatric Association; 2003 May 17-22; San Francisco, USA. 2003. Kujawa 2004 {published data only} Kujawa MJ, McQuade RD, Jody DN, Carson WH, AbouGharbia N, Iwamoto T, Archibald DG, Stock EG. Longterm weight effects of aripiprazole vs olanzapine in a 26week, 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):1845. 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 NeuroPsychopharmacologicum 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. Dubitsky GM, Harris R, Laughren T, Hardeman S. Abilify (aripiprazole) tablets, medical review part 3. www.fda.gov/ cder/foi/nda/2002/21-436Abilify.htm. U.S. Food and Drug Administration CDER, 2002:111175. 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 the 156th Annual Meeting of the American Psychiatric 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):4756. Modell 2005 b {published data only} Modell S, Jody D, Kujawa M, Carson W, Stringfellow J, Iwamoto T, Marcus R, Stock E T. Efcacy of aripiprazole and perphenazine in severe schizophrenia resistant to
25

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

treatment with atypical antipsychotics. Journal of the European College of Neuropsychopharmacology 2004;14 (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, LItalien G, Vester-Blokland, McQuade RD, Carson WH, Marcus RN. Improvement of nonHDL cholesterol levels among patients randomized to aripiprazole versus olanzapine. Proceedings of the 159th Annual Meeting of the American Psychiatric Association; 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. Longterm 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, LItalien G, Weiden P. An economic evaluation of aripiprazole compared to olanzapine based on metabolic side-effect prole. Journal of the European College of Neuropsychopharmacology 2004;14 (Suppl 3):S279. Riera 2004 {published data only} LItalien 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. Investigators 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 Meeting of the American Psychiatric Association; 2004 May 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 efcacy of aripiprazole in patients with rst 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, LItalien 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 48; Nice, France. 2006. Hanssens L, LItalien 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, LItalien G, Marcus RN, McQuade RD,
26

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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. Proceedings of the 159th Annual Meeting of the American Psychiatric Association; 2006 May 20-25, Toronto, Canada. 2006. Hanssens L, LItalien 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. Proceedings of the 159th Annual Meeting of the American Psychiatric Association; 2006 May 20-25, Toronto, Canada. 2006. Hanssens L, LItalien 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. Proceedings of the 159th Annual Meeting of the American Psychiatric Association; 2006 May 20-25, Toronto, Canada. 2006. Hanssens L, LItalien 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, LItalien 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, LItalien 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. LItalien 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 Annual Meeting of the American Psychiatric Association; 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;31:4967. Stock EG. Aripiprazole versus olanzapine in schizophrenia: A 52-week, open-label study. Proceedings of the 158th Annual Meeting of the American Psychiatric Association; 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):1531. 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): 7789. 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): 2501. Wang 2005 j {published data only} Wang R, Liu Y, Ning Z. A controlled study of aripiprazole vs clozapine in the treatment of rst-episode schizophrenia. Journal of Clinical Psychosomatic Diseases 2005;11(4):3012. 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 rst-onset schizophrenia. Chinese Journal of Rehabilitation Theory and Practice 2006; 12(1):645. 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):334. Ye 2005 {published data only} Ye X-R, Xia X-L. A comparative study between aripiprazole and risperidone in treatment of rst-onset schizophrenia. Medical Journal of National Defending Forces in Southwest China 2005;15(6):6168. 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):501. 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):9235. 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): 72830. 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):27878.
27

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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): 11947. 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):4256.

Burris 2002 Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB. Aripiprazole, a novel antipsychotic, is a high-afnity partial agonist at human dopamine D2 receptors. Journal of Pharmacology and Experimental Therapeutics 2002;302(1):3819. Cannon 1996 Cannon M, Jones P. Schizophrenia. Journal of Neurology, Neurosurgery and Psychiatry 1996;60:60413. Carpenter 1994 Carpenter WT Jr, Buchanan RW. Schizophrenia. New England Journal of Medicine 1994;330:68190. Carson 2000 Carson WH, Kane JM, Ali M, Dunbar GC, Ingenito G. Efcacy of aripiprazole in psychotic disorders: comparison with haloperidol and placebo. European Neuropsychopharmacology 2000;10(Suppl 3):S309. Deeks 2000 Deeks J. Issues in the selection for meta-analyses of binary data. Proceedings of the 8th International Cochrane Colloquium; 2000 Oct 25-28th; Cape Town, South Africa. 2000. Egger 1997 Egger M, Davey-Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:62934. El-Sayeh 2006 El-Sayeh HG, Morganti C. Aripiprazole for schizophrenia. Cochrane Database of Systematic Reviews 2006, Issue 2. [DOI: 10.1002/14651858.CD004578.pub3] Elbourne 2002 Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta-analyses involving crossover trials: methodological issues. International Journal of Epidemiology 2002;31(1):1409. FDA 2002a U.S. Federal Drug Administration CDER. Abilify (aripiprazole) tablets, medical review. www.fda.gov/cder/ foi/nda/2002/21-436Abilify.htm 2002. Grunder 2006 Grunder G, Kungel M, Ebrecht M, Grcs T, Modell S. Aripiprazole: pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia. Pharmacopsychiatry 2006;39(Suppl 1):S215. Guy 1976 Guy W. Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology. revised. Rockville, MD: National Institute of Mental Health, 1976:21822. Higgins 2003 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327: 55760. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated
28

References to studies awaiting assessment


Carson 2008 {published and unpublished data} Carson WH, Nyilas M, Forbes RA, Pikalov A, McQuade RD, Ivanova S, Owen R, Ginsberg L, Wagner KD. Acute efcacy of aripripazole for the treatment of bipolar 1 disorder in paediatric patients. Schizophrenia Research 2008; 98:42. 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.

Additional references
Abilify 2006 Otsuka America Pharmaceutical Inc. Abilify (aripiprazole). www.abilify.com (accessed 10 April 2010). Altman 1996 Altman DG, Bland JM. Detecing skewness from summary information. BMJ 1996;313:1200. Anath 2003 Anath J, Venkatesh R, Burgoyne K, Augustines D, Corpuz V, Gunatilake S. Weight gain associated with atypical antipsychotic drugs: mechanisms and management. Expert Review of Neurotherapeutics 2003;3(1):5968. Arnt 1998 Arnt J, Skarsfeldt T. Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology 1988;18:63101. Bhattacharjee 2008 Bhattacharjee J, El-Sayeh HGG. Aripiprazole versus typical antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews 2008, Issue 1. [DOI: 10.1002/ 14651858.CD006617.pub2] Boissel 1999 Boissel JP, Cucherat M, Li W, Chatellier G, Gueyfer F, Buyse M, Boutitie F, Nony P, Haugh M, Mignot G. The problem of therapeutic efcacy indices. 3. Comparison of the indices and their use. Therapie 1999;54(4):40511.

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

September 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.. ICD 10 World Health Organization. ICD 10. http://apps.who.int/ classications/apps/icd/icd10online/ (accessed 10 April 2010). Jadad 1996 Jadad A, Moore A, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Controlled Clinical Trials 1996;17:112. Jni P 2001 Jni P, Altman DG, Egger M. Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ 2001;323(7303):426. Kay 1986 Kay SR, Opler LA, Fiszbein A. Positive and Negative Syndrome Scale (PANSS) Manual. North Tonawanda, NY: Multi-Health Systems, 1986. Komossa 2007 Komossa K, Rummel-Kluge C, Schmid F, Hunger H, Schwarz S, El-Sayeh HGG, Kissling W, Leucht S. Aripiprazole versus other atypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/14651858.CD006569.pub2] Leucht 2005 Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR. What does the PANSS mean?. Schizophrenia Research 2005;79(2-3):2318. [PUBMED: 15982856] Leucht 2005a Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel R. Clinical implications of Brief Psychiatric Rating Scale Scores. British Journal of Psychiatry 2005;187:36671.

Marshall 2000 Marshall M, Lockwood A, Adams C, Bradley C, Joy C, Fenton M. Unpublished rating scales - a major source of bias in randomised controlled trials of treatments for schizophrenia?. British Journal of Psychiatry 2000;176: 24952. NICE 2009 National Institute of Clinical Excellence. Core interventions in the treatment and management of schizophrenia in primary and secondary care (update). http:// www.nice.org.uk/guidance/CG82 2009. Overall 1962 Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Psychological Reports 1962;10:799812. Rivas-Vasquez 2003 Rivas-Vasquez RA. Aripiprazole: a novel antipsychotic with dopamine stabilising properties. Professional Psychology: Research and Practice 2003;34(1):10811. Rowland 1998 Roland M, Torgerson DJ. What are pragmatic trials?. BMJ 1998;316:285. Schnemann 2008 Schnemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, et al.Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2008:35983. Xia 2007 Xia J, Adams CE, Bhagat N, Bhagat V, Bhoopathi P, El-Sayeh H, Pinfold V, Takriti Y. The Leeds Outcomes Stakeholders Survey (LOSS) Study. Proceedings of the 15th Cochrane Colloquium; 2007 Oct 23-27; Sao Paulo. 2007. Indicates the major publication for the study

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CHARACTERISTICS OF STUDIES

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. 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 dened PANSS criteria. Exclusions: pregnancy, lactation, schizoaffective disorder, organic, bipolar disorders, hospitalisation for 14 days prior to screening, substance dependence within 3 months, suicide risk, unstable thyroid pathology, history of neuroleptic malignant syndrome, history of unstable medical condition 1. Aripiprazole: dose 10 mg/day. N = 106. 2. Aripiprazole: dose 15 mg/day. N = 106. 3. Aripiprazole: dose 20 mg/day. N = 100. 4. Placebo. N = 108. 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) 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.

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Unclear

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) High risk

Randomised, method not described


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Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Other bias Carson 2000 a Methods High risk

Double blind, no further details

Very high drop-out rate with limited details. Unclear Unclear

Unclear risk Unclear risk

Allocation: randomised, method not described. Blindness: double, no further details. Duration: 4 weeks, preceded by > 5 day washout period. Design: parallel, multicentre. Setting: hospital, USA. Consent: obtained. Loss: described. Diagnosis: schizophrenia or schizoaffective disorder (DSM-IV). N = 414. Age: mean ~ 39 years. Sex: M 288, F 126. History: acute relapse, mean age at rst episode ~ 22 years, mean number of previous hospitalisations ~ 10. Exclusions: other psychiatric disorders, history of violence or suicidal ideation/self-harm, signicant neurological abnormality, psychoactive drug or alcohol abuse/dependence, recent treatment with an investigational drug 1. Aripiprazole: dose 15 mg/day. N = 102. 2. Aripiprazole: dose 30 mg/day. N = 102. 3. Haloperidol: dose 10 mg/day. N = 104. 4. Placebo. N = 106. 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) Overall 40% discontinuation rate. No information given on standard deviations. Data reported in both OC and LOCF analyses.
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Participants

Interventions

Outcomes

Notes

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(Continued)

Jadad = 2. Risk of bias Bias Authors judgement Support for judgement Unclear

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) High risk

Randomised, method not described Double blind, method of blinding not described

Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Other bias Carson 2002 b Methods High risk

High attrition rate

Unclear risk Unclear risk

Unclear Unclear

Allocation: randomised, method not described. Blindness: double, no further details. Duration: 26 weeks, preceded by 3-14 day washout period. Design: parallel, multicentre. Setting: mixed in and out patients, multi-national. Consent: not described. Loss: High attrition rate. Diagnosis: schizophrenia. N = 310. Age: mean ~ 42 years. Sex: M 174, F 136. History: chronic stable, no signicant worsening of symptoms in past 3 months, diagnosis for > 2 years, baseline PANSS score mean ~ 82. Exclusions: not described. 1. Aripiprazole: dose 15 mg/day. N = 155. 2. Placebo: N = 155. 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 signicant laboratory measurements. Leaving the study early. Unable to use 32

Participants

Interventions

Outcomes

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(Continued)

Global state: CGI (no SDs). 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 efcacy and safety characteristics. Jadad = 2.

Risk of bias Bias Authors judgement Support for judgement Unclear

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) High risk

Randomised, method not described Double, no further details

Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Other bias Csernansky 2003 Methods High risk

High attrition rate, reasons for discontinuation given Unclear Unclear

Unclear risk Unclear risk

Allocation: randomised, method not described. Blindness: double. Duration: 4 weeks, preceded by 3-7 day placebo washout period. Design: parallel, multicentre. Setting: inpatient, USA. Consent: not described. Loss: described. 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
33

Participants

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(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. Leaving the study early. Unable to use Mental state: BPRS (no SDs). Global state: CGI (no usable data). 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.

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Unclear

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) High risk

Randomised, method not described Double, no further details

Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Other bias High risk

High attrition rate

Unclear risk Unclear risk

Unclear Unclear

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Daniel 2000 Methods Allocation: randomised, method not described. Blindness: double. Duration: 4 weeks, preceded by 3-7 day washout period. Design: parallel, multicentre. Setting: inpatient. Consent: not described. Loss: described. Diagnosis: schizophrenia (DSM-IV). N = 307. Age: 18-65 years, average ~ 38. 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: rst 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 1. Aripiprazole: dose 2 mg/day. N = 59. 2. Aripiprazole: dose 10 mg/day. N = 60. 3. Aripiprazole: dose 30 mg/day. N = 61. 4. Haloperidol: dose 10 mg/day after 5 mg/day 1+2). N = 63. 5. Placebo. N = 64. Leaving the study early. Unable to use Global state: CGI (no SDs). Mental state: BPRS, PANSS (no SDs). Adverse effects: reported adverse effects, extra-pyramidal side effects, mean weight gain, mean prolactin levels (no usable data) 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.

Participants

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Unclear

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) High risk

Randomised, method not described Unclear

Blinding (performance bias and detection Unclear risk bias) All outcomes
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Daniel 2000

(Continued)

Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Other bias Daniel 2004 Methods

Unclear risk

Unclear

Unclear risk Unclear risk

Unclear Unclear

Allocation: randomised, method not described. Blindness: double. Duration: 24hrs. Design: parallel, multicentre. Setting: inpatient. Consent: not described. Loss: described. Diagnosis: schizophrenia, schizoaffective disorder, schizophreniform disorder. N = 357*. Age: not described. Sex: not described. History: acute agitation. Exclusions: not described. 1. Aripiprazole IM: dose 1 mg/day. N = 57. 2. Aripiprazole IM: dose 5 mg/day. N = 62. 3. Aripiprazole IM: dose 10 mg/day. N = 56. 4. Aripiprazole IM: dose 15 mg/day. N = 58. 5. Haloperidol IM: dose 7.5 mg/day. N = 60. 6. Placebo IM. N = 62. Global state: poor compliance with study protocol due to lack of efcacy, deterioration, or psychosis. Leaving the study early. 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) *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.

Participants

Interventions

Outcomes

Notes

Risk of bias
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Daniel 2004

(Continued)

Bias

Authors judgement

Support for judgement Unclear

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) High risk

Randomised, method not described Double, no further details

Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Other bias Marcus 2005 Methods Low risk

95% completed study, details of loss of follow-up given appears to be Unclear

Low risk Unclear risk

Allocation: randomised, method not described. Blindness: double. Duration: 6 weeks. Design: parallel, multicentre. Setting: hospital, USA. Consent: not described. Loss: not described. Diagnosis: schizophrenia. N = 367. Age: unknown. Sex: unknown. History: acute relapse. Exclusions: not described. 1. Aripiprazole: dose 2 mg/day. N = 93. 2. Aripiprazole: dose 5 mg/day. N = 92. 3. Aripiprazole: dose 10 mg/day. N = 94. 4. Placebo. N = 88. Leaving the study early. Unable to use Global state: CGI (no SD). Mental state: PANSS (no SD), time to response (dened by CGI and PANSS) (no usable data). Adverse effects: self-reported > 5% participants (no usable data)

Participants

Interventions

Outcomes

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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 Authors judgement Support for judgement Unclear

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) High risk

Randomised, method not described Double, no further details

Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Other bias Oren 2005 Methods High risk

High attrition rate

Low risk Unclear risk

Appears to be Unclear

Allocation: randomised, block randomisation. Blindness: double. Duration: 24 hours. Design: parallel, multicentre. Setting: hospital. Consent: not described. Loss: described. Diagnosis: schizophrenia or schizoaffective disorder (DSM-IV). N = 448. Age: >/= 18 years. Sex: unknown. History: acute agitation, voluntarily hospitalised, able to comply and comprehend protocol, PEC score of >/= 15 and </= 32, and at least 2 components >/= 4 (moderate). Exclusions: not described. 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

Participants

Interventions

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Oren 2005

(Continued)

Outcomes

Global state: poor compliance with study protocol due to lack of efcacy, deterioration, or psychosis, requiring additional dose of antipsychotic medication, benzodiazepines. Leaving the study early. 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) 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.

Notes

Risk of bias Bias Authors judgement Support for judgement Via a central call-in system

Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Low risk

Randomised, permuted block randomisation Double, no further details

Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Low risk

96.6% competed study

Unclear risk

Secondary efcacy measures were not reported in details Unclear

Other bias Potkin 2003 Methods

Unclear risk

Allocation: randomised, method not described. Blindness: double. Duration: 4 weeks, preceded by 5-day placebo washout period. Design: parallel, multicentre. Setting: hospital, USA. Consent: described. Loss: described.

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Potkin 2003

(Continued)

Participants

Diagnosis: schizophrenia or schizoaffective disorder (DSM-IV). N = 404. Age: 18-65 years, average ~ 39. 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, suicidal attempts or ideation, signicant neurological abnormality, alcohol/psychoactive substance misuse within 1 month of study start, treatment with investigational drug within 4 weeks of washout phase, unstable/acute medical conditions, pregnancy, lactation 1. Aripiprazole: dose 20 mg/day. N = 101. 2. Aripiprazole: dose 30 mg/day. N = 101. 3. Risperidone: dose 2 mg day 1, 4 mg day 2, 6 mg/day thereafter. N = 99. 4. Placebo. N = 103. 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) Overall 40% discontinuation rate. No information given on standard deviations. Data was analysed in terms of OC and LOCF. Jadad = 2.

Interventions

Outcomes

Notes

Risk of bias Bias Authors judgement Support for judgement Unclear

Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) High risk

Randomised, method not described Double, no further details

Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) High risk

High attrition rate

Unclear risk

Unclear
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Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Potkin 2003

(Continued)

Other bias

Unclear risk

Unclear

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 Allain 2005 Auby 2002

Reason for exclusion Allocation: not randomised, an open label study Allocation: randomised. Participants: people with stable schizophrenia or schizoaffective disorder. Intervention: aripiprazole at multiple doses - no other comparator drug. Outcomes: no usable data. Allocation: not randomised, an open label study. Intervention: aripiprazole versus other antipsychotics, no placebo group Allocation: states it is randomised. Participants: states people with schizophrenia etc. Intervention: aripripazole versus olanzapine, no placebo group Allocation: not randomised, a review. 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 Allocation: randomised. Participants: people with schizophrenia or schizoaffective disorder. Intervention: aripiprazole at different regimens - no other comparator or placebo Intervention: aripripazole versus risperidol, no placebo control group Intervention: aripripazole versus risperidone, no placebo control group Allocation: not randomised, an open label study. Intervention: aripiprazole versus olanzapine, no placebo control group

Beuzen 2005

Blonde 2004

Carson 2002 a Carson W, McQuade 2003

Casey 2003

Chan 2007 Chen 2005 b Chrzanowski 2006

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(Continued)

Corey-Lisle 2006 Daniel 2006 Fan 2005 a Gismondi R, Mel2 Han 2005 a Hwang 2005 Jody 2004 Kane 2003

Allocation: not randomised, a naturalistic trial. Intervention: IM aripripazole versus IM haloperidol, no placebo control group Intervention: aripripazole versus clozapine, no placebo control group Intervention: aripripazole versus perphenazine, no placebo control group Intervention: aripripazole versus clozapine, no placebo control group Intervention: aripripazole versus risperidone, no placebo control group Allocation: not randomised, an open label study. 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 conrmation of treatment resistance, 2-10 day neuroleptic washout. Design: multicentre, parallel. Intervention: aripiprazole versus perphenazine, no placebo control group Intervention: aripripazole versus haloperidol, no placebo control group Intervention: aripripazole versus perphenazine, no placebo control group 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 Intervention: aripiprazole versus olanzapine, no placebo control group Intervention: aripiprazole versus haloperidol, no placebo control group Intervention: aripiprazole versus haloperidol, no placebo control group Intervention: a review article. 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.
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Kane 2006 d Kane 2007 a Kern 2001

Kim 2006 d Kujawa 2002 Kujawa 2003 Kujawa 2004

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

(Continued)

Diagnosis: schizophrenia. Intervention: aripripazole versus olanzapine, no placebo control group Liang 2005 Mai 2005 Mallikaarjun 2000 Intervention: aripiprazole versus haloperidol, no placebo control group Intervention: aripripazole versus risperidone, no placebo control group Allocation: randomised. Participants: healthy volunteers. Allocation: not randomised, review. Intervention: aripripazole versus haloperidol, no placebo control group Intervention: aripiprazole versus haloperidol, no placebo control group Intervention aripiprazole versus olanzapine, no placebo control group Intervention: aripripazole versus perphenazine, no placebo control group Intervention: aripiprazole versus olanzapine, no placebo control group Intervention: aripripazole versus olanzapine, no placebo group Intervention: aripiprazole versus haloperidol, no placebo control group Intervention: aripiprazole versus haloperidol, no placebo control Allocation: not randomised, review. Intervention: aripiprazole versus olanzapine, no placebo control group Intervention: aripiprazole versus standard care, no placebo control group Allocation: randomised. Participants: rst episode of schizophrenia or schizoaffective disorder occurring within 1 year of study. Intervention: aripiprazole at multiple doses - no other comparator drug or placebo Allocation: not randomised, an open-label study. Intervention: aripiprazole versus olanzapine, no placebo control group Allocation: not randomised, naturalistic trial. Intervention: aripiprazole versus olanzapine, no placebo control group Allocation: not randomised.

Marcus 2003 Marder 2004 McQuade 2002 McQuade 2003 Modell 2005 b N0025078569 Newcomer 2006 Octavio 2004 Octavio 2005 Petrie 1997 Ray 2005 Riera 2004 Saha 2004

Sanchez 2006

STAR 2006 Stock 2005 Stroup 2003

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(Continued)

Tandon 2006 Wang 2005 Wang 2005 j Wu 2005 d Xia 2005 Ye 2005 Zhang 2005 Zhang 2005 a Zhao 2005 Zhi 2005 Zhu 2005 Zhu 2005 a Zhu 2005 b

Intervention: aripiprazole versus other antipsychotics, no placebo control group Intervention: aripiprazole versus chlorpromazine, no placebo control group Intervention: aripiprazole versus clozapine, no placebo control group Intervention: aripripazole versus haloperidol, no placebo control group Intervention: aripiprazole versus chlorpromazine, no placebo control group Intervention: aripripazole versus risperidone, no placebo control group Intervention: aripiprazole versus sulpiride, no placebo control group Intervention: aripripazole versus risperidone, no placebo control group Intervention: aripripazole versus sulpiride, no placebo control group Intervention: aripripazole versus risperidone, no placebo control group Intervention: aripripazole versus risperidone, no placebo control group Intervention: aripripazole versus clozapine, no placebo control group Intervention: aripripazole versus risperidone, no placebo control group

Characteristics of studies awaiting assessment [ordered by study ID]


Carson 2008 Methods Participants 4 weeks randomised double blind controlled trial Paediatric age 10-17 years, with DSM-IV diagnosis of bipolar 1 disorder, manic or mixed episode with/with out psychotic symptoms (n = 296) Placebo versus aripiprazole 10 or 30 mg >= 50% change on Young mania rating scale

Interventions Outcomes Notes

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Nyilas 2007 Methods Participants Interventions Outcomes Notes 6 weeks multicentre, randomised double blind controlled trial Age 13-17 years, DSM-IV diagnosis of schizophrenia (n = 302) Placebo versus aripiprazole 10 or 30 mg Mean change on PANSS

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DATA AND ANALYSES

Comparison 1. ARIPIPRAZOLE versus PLACEBO

Outcome or subgroup title 1 Global state: 1. Relapse 1.1 short term 1.2 medium term 1.3 Acute (2 hr after IM) 2 Global state: 2. Poor compliance with study protocol due to lack of efcacy, deterioration or psychosis 3 Global state: 3. Needing additional antipsychotic medication 4 Global state: 4. Needing additional benzodiazepines 5 Adverse effects: 1. Clinically important specic adverse effects 5.1 anxiety 5.2 extrapyramidal symptoms - akathisia 5.3 extrapyramidal symptoms - general 5.4 extrapyramidal symptoms - needing antiparkinson medication at least once 5.5 headache 5.6 insomnia 5.7 nausea 5.8 vomiting 5.9 weight gain - > 7% over baseline 5.10 constipation 5.11 diarrhoea 5.12 dyspepsia 5.13 toothache 5.14 upper abdominal pain 5.15 infections 5.16 dizziness 5.17 sedation 5.18 skin rash 5.19 cough 5.20 pharyngolaryngeal pain 5.21 tachycardia 5.22 agitation

No. of studies 2 1 1 1 8

No. of participants 883 310 310 263 2275

Statistical method Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

Effect size 0.65 [0.57, 0.74] 0.59 [0.45, 0.77] 0.66 [0.53, 0.81] 0.71 [0.57, 0.89] 0.74 [0.59, 0.93]

1062

Risk Ratio (M-H, Fixed, 95% CI)

0.73 [0.57, 0.93]

2 9

683 23455

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.53 [0.30, 0.92] 1.17 [1.07, 1.28]

3 5 4 4

1035 1595 1298 1043

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.83 [0.62, 1.12] 1.78 [1.16, 2.74] 0.83 [0.47, 1.45] 0.83 [0.61, 1.14]

6 4 6 5 3 2 2 2 1 1 1 4 4 1 1 1 3 3

1962 1298 1962 1699 1035 787 787 787 367 367 367 1347 1347 367 367 367 1084 980

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

1.17 [0.94, 1.47] 1.09 [0.89, 1.33] 1.55 [1.07, 2.24] 1.46 [0.96, 2.23] 2.55 [1.35, 4.82] 1.42 [0.75, 2.69] 0.79 [0.40, 1.56] 0.89 [0.56, 1.41] 1.47 [0.43, 5.00] 4.13 [0.24, 72.63] 0.57 [0.20, 1.65] 1.34 [0.83, 2.14] 1.82 [1.06, 3.15] 3.47 [0.45, 26.50] 1.89 [0.43, 8.29] 8.58 [0.52, 142.92] 1.94 [0.89, 4.25] 0.61 [0.40, 0.92]
46

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

5.23 asthenia 5.24 QTc interval >= 450 or 10% above baseline 6 Adverse effects: 2. Average change in QTc interval (ms) from baseline 6.1 Aripiprazole 20 mg/day 6.2 Aripiprazole 30 mg/day 7 Adverse effects: 3. Physiological (serum) measures 7.1 cholesterol - total fasting >/= 200 mg/dl 7.2 cholesterol - total fasting >/= 200 mg/dl - long-term effect 7.3 cholesterol - total fasting >/= 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 8.1 due to any reason 8.2 due to adverse effects 9 concomitant medication anxiolytics

1 2 1

420 787 408

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

0.94 [0.41, 2.17] 2.44 [0.13, 46.82] 0.99 [-3.38, 5.37]

1 1 3 1 1

204 204 3515 310 310

Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

3.00 [-3.19, 9.19] -1.0 [-7.18, 5.18] 0.94 [0.86, 1.04] 1.04 [0.83, 1.30] 1.21 [0.98, 1.50]

1 1 1

310 310 310

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

1.22 [0.77, 1.93] 0.96 [0.70, 1.33] 0.74 [0.41, 1.33]

310

Risk Ratio (M-H, Fixed, 95% CI)

1.01 [0.80, 1.28]

310

Risk Ratio (M-H, Fixed, 95% CI)

1.0 [0.62, 1.61]

1 1 2

310 310 725

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.94 [0.67, 1.31] 0.86 [0.66, 1.12] 0.21 [0.11, 0.37]

9 9 9 2

5170 2585 2585 787

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) Odds Ratio (M-H, Fixed, 95% CI)

0.73 [0.61, 0.87] 0.73 [0.60, 0.87] 0.75 [0.42, 1.35] 0.96 [0.61, 1.52]

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

47

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 n/N

Placebo n/N

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio 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)


Heterogeneity: not applicable

155

155

32.5 %

0.59 [ 0.45, 0.77 ]

Total events: 50 (Aripiprazole), 85 (Placebo) 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)


Heterogeneity: not applicable

155

155

39.0 %

0.66 [ 0.53, 0.81 ]

Total events: 67 (Aripiprazole), 102 (Placebo) Test for overall effect: Z = 3.86 (P = 0.00011) 3 Acute (2 hr after IM) Oren 2005 79/175 56/88 28.5 % 0.71 [ 0.57, 0.89 ]

Subtotal (95% CI)


Heterogeneity: not applicable

175

88

28.5 %

0.71 [ 0.57, 0.89 ]

Total events: 79 (Aripiprazole), 56 (Placebo) Test for overall effect: Z = 2.96 (P = 0.0031)

Total (95% CI)

485

398

100.0 %

0.65 [ 0.57, 0.74 ]

Total events: 196 (Aripiprazole), 243 (Placebo) 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

Favours aripiprazole

Favours placebo

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

48

Analysis 1.2. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 2 Global state: 2. Poor compliance with study protocol due to lack of efcacy, deterioration or psychosis.
Review: Aripiprazole versus placebo for schizophrenia

Comparison: 1 ARIPIPRAZOLE versus PLACEBO Outcome: 2 Global state: 2. Poor compliance with study protocol due to lack of efcacy, deterioration or psychosis

Study or subgroup

Aripiprazole n/N

Placebo n/N 11/108 16/106 15/35 20/64 1/62 12/88 1/88 23/103

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

Adson 2003 Carson 2000 a Csernansky 2003 Daniel 2000 Daniel 2004 Marcus 2005 Oren 2005 Potkin 2003

24/312 30/204 8/34 24/180 1/235 49/279 0/175 32/202

12.2 % 15.7 % 11.0 % 22.0 % 1.2 % 13.6 % 1.5 % 22.7 %

0.76 [ 0.38, 1.49 ] 0.97 [ 0.56, 1.70 ] 0.55 [ 0.27, 1.12 ] 0.43 [ 0.25, 0.72 ] 0.26 [ 0.02, 4.16 ] 1.29 [ 0.72, 2.31 ] 0.17 [ 0.01, 4.10 ] 0.71 [ 0.44, 1.15 ]

Total (95% CI)

1621

654

100.0 %

0.74 [ 0.59, 0.93 ]

Total events: 168 (Aripiprazole), 99 (Placebo) Heterogeneity: Chi2 = 10.76, df = 7 (P = 0.15); I2 =35% Test for overall effect: Z = 2.55 (P = 0.011) Test for subgroup differences: Not applicable

0.5

0.7

1.5

Favours aripiprazole

Favours placebo

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

49

Analysis 1.3. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 3 Global state: 3. Needing additional antipsychotic medication.
Review: Aripiprazole versus placebo for schizophrenia

Comparison: 1 ARIPIPRAZOLE versus PLACEBO Outcome: 3 Global state: 3. Needing additional antipsychotic medication

Study or subgroup

Aripiprazole n/N

Placebo n/N 6/108 9/106 1/34 50/88

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

Adson 2003 Carson 2000 a Csernansky 2003 Oren 2005

12/312 9/204 4/35 72/175

10.1 % 13.4 % 1.1 % 75.3 %

0.69 [ 0.27, 1.80 ] 0.52 [ 0.21, 1.27 ] 3.89 [ 0.46, 33.02 ] 0.72 [ 0.56, 0.93 ]

Total (95% CI)

726

336

100.0 %

0.73 [ 0.57, 0.93 ]

Total events: 97 (Aripiprazole), 66 (Placebo) Heterogeneity: Chi2 = 2.92, df = 3 (P = 0.40); I2 =0.0% Test for overall effect: Z = 2.55 (P = 0.011) Test for subgroup differences: Not applicable

0.5

0.7

1.5

Favours aripiprazole

Favours placebo

Analysis 1.4. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 4 Global state: 4. Needing additional benzodiazepines.
Review: Aripiprazole versus placebo for schizophrenia

Comparison: 1 ARIPIPRAZOLE versus PLACEBO Outcome: 4 Global state: 4. Needing additional benzodiazepines

Study or subgroup

Aripiprazole n/N

Placebo n/N 4/108 17/88

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

Adson 2003 Oren 2005

11/312 14/175

20.8 % 79.2 %

0.95 [ 0.31, 2.93 ] 0.41 [ 0.21, 0.80 ]

Total (95% CI)

487

196

100.0 %

0.53 [ 0.30, 0.92 ]

Total events: 25 (Aripiprazole), 21 (Placebo) Heterogeneity: Chi2 = 1.58, df = 1 (P = 0.21); I2 =37% Test for overall effect: Z = 2.25 (P = 0.025) Test for subgroup differences: Not applicable

0.2

0.5

Favours aripiprazole

Favours placebo

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

50

Analysis 1.5. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 5 Adverse effects: 1. Clinically important specic adverse effects.
Review: Aripiprazole versus placebo for schizophrenia

Comparison: 1 ARIPIPRAZOLE versus PLACEBO Outcome: 5 Adverse effects: 1. Clinically important specic adverse effects

Study or subgroup

Aripiprazole n/N

Placebo n/N

Risk Ratio M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 anxiety Carson 2002 b Potkin 2003 Adson 2003 23/155 41/202 31/312 34/155 19/103 14/108 0.68 [ 0.42, 1.09 ] 1.10 [ 0.67, 1.80 ] 0.77 [ 0.42, 1.39 ]

Subtotal (95% CI)


Total events: 95 (Aripiprazole), 67 (Placebo)

669

366

0.83 [ 0.62, 1.12 ]

Heterogeneity: Chi2 = 2.04, df = 2 (P = 0.36); I2 =2% Test for overall effect: Z = 1.21 (P = 0.23) 2 extrapyramidal symptoms - akathisia Carson 2002 b Daniel 2004 Oren 2005 Potkin 2003 Adson 2003 14/155 9/235 1/175 40/202 25/312 12/155 1/62 1/88 9/103 4/108 1.17 [ 0.56, 2.44 ] 2.37 [ 0.31, 18.39 ] 0.50 [ 0.03, 7.94 ] 2.27 [ 1.14, 4.49 ] 2.16 [ 0.77, 6.08 ]

Subtotal (95% CI)


Total events: 89 (Aripiprazole), 27 (Placebo)

1079

516

1.78 [ 1.16, 2.74 ]

Heterogeneity: Chi2 = 2.76, df = 4 (P = 0.60); I2 =0.0% Test for overall effect: Z = 2.62 (P = 0.0088) 3 extrapyramidal symptoms - general Carson 2002 b Oren 2005 Potkin 2003 Adson 2003 7/155 3/175 7/202 13/312 10/155 3/88 0/103 7/108 0.70 [ 0.27, 1.79 ] 0.50 [ 0.10, 2.44 ] 7.68 [ 0.44, 133.24 ] 0.64 [ 0.26, 1.57 ]

Subtotal (95% CI)


Total events: 30 (Aripiprazole), 20 (Placebo)

844

454

0.83 [ 0.47, 1.45 ]

Heterogeneity: Chi2 = 3.16, df = 3 (P = 0.37); I2 =5% Test for overall effect: Z = 0.65 (P = 0.51) 4 extrapyramidal symptoms - needing antiparkinson medication at least once

0.1 0.2

0.5

10

Favours aripiprazole

Favours placebo

(Continued . . . )

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

51

(. . .
Study or subgroup Aripiprazole n/N Carson 2000 a Csernansky 2003 Daniel 2000 Adson 2003 23/204 6/34 41/180 24/312 Placebo n/N 13/106 10/35 19/64 8/108 Risk Ratio M-H,Fixed,95% CI

Continued) Risk Ratio

M-H,Fixed,95% CI 0.92 [ 0.49, 1.74 ] 0.62 [ 0.25, 1.51 ] 0.77 [ 0.48, 1.22 ] 1.04 [ 0.48, 2.24 ]

Subtotal (95% CI)


Total events: 94 (Aripiprazole), 50 (Placebo)

730

313

0.83 [ 0.61, 1.14 ]

Heterogeneity: Chi2 = 0.96, df = 3 (P = 0.81); I2 =0.0% Test for overall effect: Z = 1.14 (P = 0.26) 5 headache Carson 2002 b Daniel 2004 Oren 2005 Potkin 2003 Marcus 2005 Adson 2003 17/155 32/235 13/175 63/202 48/279 78/312 21/155 2/62 7/88 28/103 18/88 17/108 0.81 [ 0.44, 1.47 ] 4.22 [ 1.04, 17.13 ] 0.93 [ 0.39, 2.26 ] 1.15 [ 0.79, 1.67 ] 0.84 [ 0.52, 1.37 ] 1.59 [ 0.99, 2.56 ]

Subtotal (95% CI)


Total events: 251 (Aripiprazole), 93 (Placebo)

1358

604

1.17 [ 0.94, 1.47 ]

Heterogeneity: Chi2 = 8.31, df = 5 (P = 0.14); I2 =40% Test for overall effect: Z = 1.42 (P = 0.15) 6 insomnia Carson 2002 b Oren 2005 Potkin 2003 Adson 2003 67/155 10/175 53/202 54/312 63/155 9/88 23/103 14/108 1.06 [ 0.82, 1.38 ] 0.56 [ 0.24, 1.32 ] 1.17 [ 0.77, 1.80 ] 1.34 [ 0.77, 2.30 ]

Subtotal (95% CI)


Total events: 184 (Aripiprazole), 109 (Placebo)

844

454

1.09 [ 0.89, 1.33 ]

Heterogeneity: Chi2 = 2.98, df = 3 (P = 0.39); I2 =0.0% Test for overall effect: Z = 0.80 (P = 0.42) 7 nausea Carson 2002 b Daniel 2004 Oren 2005 Potkin 2003 Marcus 2005 Adson 2003 10/155 17/235 10/175 17/202 21/279 54/312 7/155 3/62 2/88 10/103 3/88 10/108 1.43 [ 0.56, 3.66 ] 1.50 [ 0.45, 4.94 ] 2.51 [ 0.56, 11.23 ] 0.87 [ 0.41, 1.82 ] 2.21 [ 0.67, 7.23 ] 1.87 [ 0.99, 3.54 ]

Subtotal (95% CI)

1358

604
0.1 0.2 0.5 1 2 5 10

1.55 [ 1.07, 2.24 ]

Favours aripiprazole

Favours placebo

(Continued . . . )
Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 52

(. . .
Study or subgroup Aripiprazole n/N Total events: 129 (Aripiprazole), 35 (Placebo) Heterogeneity: Chi2 = 3.45, df = 5 (P = 0.63); I2 =0.0% Test for overall effect: Z = 2.34 (P = 0.019) 8 vomiting Carson 2002 b Daniel 2004 Potkin 2003 Marcus 2005 Adson 2003 11/155 9/235 23/202 13/279 32/312 7/155 2/62 6/103 7/88 5/108 Placebo n/N Risk Ratio M-H,Fixed,95% CI

Continued) Risk Ratio

M-H,Fixed,95% CI

1.57 [ 0.63, 3.95 ] 1.19 [ 0.26, 5.35 ] 1.95 [ 0.82, 4.65 ] 0.59 [ 0.24, 1.42 ] 2.22 [ 0.89, 5.54 ]

Subtotal (95% CI)


Total events: 88 (Aripiprazole), 27 (Placebo)

1183

516

1.46 [ 0.96, 2.23 ]

Heterogeneity: Chi2 = 5.41, df = 4 (P = 0.25); I2 =26% Test for overall effect: Z = 1.77 (P = 0.076) 9 weight gain - > 7% over baseline Carson 2002 b Potkin 2003 Adson 2003 9/155 22/202 26/312 6/155 2/103 4/108 1.50 [ 0.55, 4.11 ] 5.61 [ 1.35, 23.39 ] 2.25 [ 0.80, 6.30 ]

Subtotal (95% CI)


Total events: 57 (Aripiprazole), 12 (Placebo)

669

366

2.55 [ 1.35, 4.82 ]

Heterogeneity: Chi2 = 2.29, df = 2 (P = 0.32); I2 =13% Test for overall effect: Z = 2.89 (P = 0.0039) 10 constipation Marcus 2005 Adson 2003 22/279 25/312 4/88 7/108 1.73 [ 0.61, 4.90 ] 1.24 [ 0.55, 2.78 ]

Subtotal (95% CI)


Total events: 47 (Aripiprazole), 11 (Placebo)

591

196

1.42 [ 0.75, 2.69 ]

Heterogeneity: Chi2 = 0.26, df = 1 (P = 0.61); I2 =0.0% Test for overall effect: Z = 1.08 (P = 0.28) 11 diarrhoea Marcus 2005 Adson 2003 9/279 17/312 6/88 5/108 0.47 [ 0.17, 1.29 ] 1.18 [ 0.44, 3.11 ]

Subtotal (95% CI)


Total events: 26 (Aripiprazole), 11 (Placebo)

591

196

0.79 [ 0.40, 1.56 ]

Heterogeneity: Chi2 = 1.64, df = 1 (P = 0.20); I2 =39% Test for overall effect: Z = 0.68 (P = 0.50) 12 dyspepsia Marcus 2005 Adson 2003 17/279 41/312 8/88 14/108
0.1 0.2 0.5 1 2 5 10

0.67 [ 0.30, 1.50 ] 1.01 [ 0.58, 1.79 ]

Favours aripiprazole

Favours placebo

(Continued . . . )
Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 53

(. . .
Study or subgroup Aripiprazole n/N Placebo n/N Risk Ratio M-H,Fixed,95% CI

Continued) Risk Ratio

M-H,Fixed,95% CI

Subtotal (95% CI)


Total events: 58 (Aripiprazole), 22 (Placebo)

591

196

0.89 [ 0.56, 1.41 ]

Heterogeneity: Chi2 = 0.68, df = 1 (P = 0.41); I2 =0.0% Test for overall effect: Z = 0.51 (P = 0.61) 13 toothache Marcus 2005 14/279 3/88 1.47 [ 0.43, 5.00 ]

Subtotal (95% CI)


Total events: 14 (Aripiprazole), 3 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.62 (P = 0.54) 14 upper abdominal pain Marcus 2005

279

88

1.47 [ 0.43, 5.00 ]

6/279

0/88

4.13 [ 0.24, 72.63 ]

Subtotal (95% CI)


Total events: 6 (Aripiprazole), 0 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.97 (P = 0.33) 15 infections Marcus 2005

279

88

4.13 [ 0.24, 72.63 ]

9/279

5/88

0.57 [ 0.20, 1.65 ]

Subtotal (95% CI)


Total events: 9 (Aripiprazole), 5 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 1.04 (P = 0.30) 16 dizziness Marcus 2005 Daniel 2004 Oren 2005 Adson 2003

279

88

0.57 [ 0.20, 1.65 ]

13/279 25/235 11/175 31/312

6/88 5/62 3/88 6/108

0.68 [ 0.27, 1.74 ] 1.32 [ 0.53, 3.31 ] 1.84 [ 0.53, 6.44 ] 1.79 [ 0.77, 4.17 ]

Subtotal (95% CI)


Total events: 80 (Aripiprazole), 20 (Placebo)

1001

346

1.34 [ 0.83, 2.14 ]

Heterogeneity: Chi2 = 2.68, df = 3 (P = 0.44); I2 =0.0% Test for overall effect: Z = 1.20 (P = 0.23) 17 sedation Marcus 2005 Daniel 2004 Oren 2005 Adson 2003 13/279 20/235 11/175 33/312 0/88 4/62 3/88 7/108 8.58 [ 0.52, 142.92 ] 1.32 [ 0.47, 3.72 ] 1.84 [ 0.53, 6.44 ] 1.63 [ 0.74, 3.58 ]

Subtotal (95% CI)


Total events: 77 (Aripiprazole), 14 (Placebo)

1001

346

1.82 [ 1.06, 3.15 ]

0.1 0.2

0.5

10

Favours aripiprazole

Favours placebo

(Continued . . . )
Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 54

(. . .
Study or subgroup Aripiprazole n/N Heterogeneity: Chi2 = 1.62, df = 3 (P = 0.66); I2 =0.0% Test for overall effect: Z = 2.16 (P = 0.031) 18 skin rash Marcus 2005 11/279 1/88 Placebo n/N Risk Ratio M-H,Fixed,95% CI

Continued) Risk Ratio

M-H,Fixed,95% CI

3.47 [ 0.45, 26.50 ]

Subtotal (95% CI)


Total events: 11 (Aripiprazole), 1 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 1.20 (P = 0.23) 19 cough Marcus 2005

279

88

3.47 [ 0.45, 26.50 ]

12/279

2/88

1.89 [ 0.43, 8.29 ]

Subtotal (95% CI)


Total events: 12 (Aripiprazole), 2 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.85 (P = 0.40) 20 pharyngolaryngeal pain Marcus 2005

279

88

1.89 [ 0.43, 8.29 ]

13/279

0/88

8.58 [ 0.52, 142.92 ]

Subtotal (95% CI)


Total events: 13 (Aripiprazole), 0 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 1.50 (P = 0.13) 21 tachycardia Daniel 2004 Adson 2003 Marcus 2005

279

88

8.58 [ 0.52, 142.92 ]

12/235 24/312 7/279

2/62 3/108 2/88

1.58 [ 0.36, 6.89 ] 2.77 [ 0.85, 9.01 ] 1.10 [ 0.23, 5.22 ]

Subtotal (95% CI)


Total events: 43 (Aripiprazole), 7 (Placebo)

826

258

1.94 [ 0.89, 4.25 ]

Heterogeneity: Chi2 = 0.93, df = 2 (P = 0.63); I2 =0.0% Test for overall effect: Z = 1.66 (P = 0.097) 22 agitation Oren 2005 Daniel 2004 Adson 2003 7/175 6/235 38/312 5/88 2/62 23/108 0.70 [ 0.23, 2.15 ] 0.79 [ 0.16, 3.83 ] 0.57 [ 0.36, 0.91 ]

Subtotal (95% CI)


Total events: 51 (Aripiprazole), 30 (Placebo)

722

258

0.61 [ 0.40, 0.92 ]

Heterogeneity: Chi2 = 0.24, df = 2 (P = 0.89); I2 =0.0% Test for overall effect: Z = 2.33 (P = 0.020) 23 asthenia Adson 2003 19/312 7/108
0.1 0.2 0.5 1 2 5 10

0.94 [ 0.41, 2.17 ]

Favours aripiprazole

Favours placebo

(Continued . . . )
Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 55

(. . .
Study or subgroup Aripiprazole n/N Placebo n/N Risk Ratio M-H,Fixed,95% CI

Continued) Risk Ratio

M-H,Fixed,95% CI

Subtotal (95% CI)


Total events: 19 (Aripiprazole), 7 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.15 (P = 0.88)

312

108

0.94 [ 0.41, 2.17 ]

24 QTc interval >= 450 or 10% above baseline Adson 2003 Marcus 2005 3/312 0/279 0/108 0/88 2.44 [ 0.13, 46.82 ] 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI)


Total events: 3 (Aripiprazole), 0 (Placebo)

591

196

2.44 [ 0.13, 46.82 ]

Heterogeneity: Chi2 = 0.0, df = 0 (P = 1.00); I2 =0.0% Test for overall effect: Z = 0.59 (P = 0.55)

Total (95% CI)

16634

6821

1.17 [ 1.07, 1.28 ]

Total events: 1486 (Aripiprazole), 573 (Placebo) Heterogeneity: Chi2 = 84.13, df = 67 (P = 0.08); I2 =20% Test for overall effect: Z = 3.37 (P = 0.00075) Test for subgroup differences: Chi2 = 46.94, df = 23 (P = 0.00), I2 =51%

0.1 0.2

0.5

10

Favours aripiprazole

Favours placebo

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

56

Analysis 1.6. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 6 Adverse effects: 2. Average change in QTc interval (ms) from baseline.
Review: Aripiprazole versus placebo for schizophrenia

Comparison: 1 ARIPIPRAZOLE versus PLACEBO Outcome: 6 Adverse effects: 2. Average change in QTc interval (ms) from baseline

Study or subgroup

Aripiprazole N Mean(SD)

Placebo N Mean(SD)

Mean Difference IV,Fixed,95% CI

Weight

Mean Difference 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)


Heterogeneity: not applicable

101

103

49.9 %

3.00 [ -3.19, 9.19 ]

Test for overall effect: Z = 0.95 (P = 0.34) 2 Aripiprazole 30 mg/day Potkin 2003 101 -3 (22) 103 -2 (23) 50.1 % -1.00 [ -7.18, 5.18 ]

Subtotal (95% CI)


Heterogeneity: not applicable

101

103

50.1 %

-1.00 [ -7.18, 5.18 ]

Test for overall effect: Z = 0.32 (P = 0.75)

Total (95% CI)

202

206

100.0 %

0.99 [ -3.38, 5.37 ]

Heterogeneity: Chi2 = 0.80, df = 1 (P = 0.37); I2 =0.0% Test for overall effect: Z = 0.45 (P = 0.66) Test for subgroup differences: Chi2 = 0.80, df = 1 (P = 0.37), I2 =0.0%

-10

-5

10

Favours aripiprazole

Favours placebo

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 1.7. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 7 Adverse effects: 3. Physiological (serum) measures.
Review: Aripiprazole versus placebo for schizophrenia

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

Study or subgroup

Aripiprazole n/N

Placebo n/N

Risk Ratio M-H,Fixed,95% CI

Weight

Risk Ratio M-H,Fixed,95% CI

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)


Heterogeneity: not applicable Test for overall effect: Z = 0.34 (P = 0.73)

155

155

14.6 %

1.04 [ 0.83, 1.30 ]

Total events: 78 (Aripiprazole), 75 (Placebo)

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)


Heterogeneity: not applicable

155

155

14.6 %

1.21 [ 0.98, 1.50 ]

Total events: 91 (Aripiprazole), 75 (Placebo) Test for overall effect: Z = 1.81 (P = 0.070) 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)


Heterogeneity: not applicable Test for overall effect: Z = 0.86 (P = 0.39) 4 glucose - plasma levels >/= 110mg/dl Carson 2002 b

155

155

5.3 %

1.22 [ 0.77, 1.93 ]

Total events: 33 (Aripiprazole), 27 (Placebo)

49/155

51/155

9.9 %

0.96 [ 0.70, 1.33 ]

Subtotal (95% CI)


Heterogeneity: not applicable Test for overall effect: Z = 0.24 (P = 0.81)

155

155

9.9 %

0.96 [ 0.70, 1.33 ]

Total events: 49 (Aripiprazole), 51 (Placebo)

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)


Heterogeneity: not applicable Test for overall effect: Z = 1.01 (P = 0.31)

155

155

4.5 %

0.74 [ 0.41, 1.33 ]

Total events: 17 (Aripiprazole), 23 (Placebo)

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
0.1 0.2 0.5 1 2 5 10

14.2 %

1.01 [ 0.80, 1.28 ]

Favours aripiprazole

Favours placebo

(Continued . . . )

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

58

(. . .
Study or subgroup Aripiprazole n/N Total events: 74 (Aripiprazole), 73 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.11 (P = 0.91) 7 low density lipoprotein cholesterol (LDL) >/= 160 mg/dl - long-term effect Carson 2002 b 28/155 28/155 5.4 % Placebo n/N Risk Ratio M-H,Fixed,95% CI Weight

Continued) Risk Ratio

M-H,Fixed,95% CI

1.00 [ 0.62, 1.61 ]

Subtotal (95% CI)


Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0)

155

155

5.4 %

1.00 [ 0.62, 1.61 ]

Total events: 28 (Aripiprazole), 28 (Placebo)

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)


Heterogeneity: not applicable Test for overall effect: Z = 0.37 (P = 0.71)

155

155

9.5 %

0.94 [ 0.67, 1.31 ]

Total events: 46 (Aripiprazole), 49 (Placebo)

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)


Heterogeneity: not applicable Test for overall effect: Z = 1.15 (P = 0.25)

155

155

13.6 %

0.86 [ 0.66, 1.12 ]

Total events: 60 (Aripiprazole), 70 (Placebo)

10 prolactin - increase to >/= 23 ng/ml or level above upper limit of normal Adson 2003 Potkin 2003 8/312 7/202 19/108 11/103 5.5 % 2.8 % 0.15 [ 0.07, 0.32 ] 0.32 [ 0.13, 0.81 ]

Subtotal (95% CI)

514

211

8.3 %

0.21 [ 0.11, 0.37 ]

Total events: 15 (Aripiprazole), 30 (Placebo) Heterogeneity: Chi2 = 1.67, df = 1 (P = 0.20); I2 =40% Test for overall effect: Z = 5.24 (P < 0.00001)

Total (95% CI)

1909

1606

100.0 %

0.94 [ 0.86, 1.04 ]

Total events: 491 (Aripiprazole), 501 (Placebo) Heterogeneity: Chi2 = 35.41, df = 10 (P = 0.00011); I2 =72% Test for overall effect: Z = 1.18 (P = 0.24) Test for subgroup differences: Chi2 = 33.96, df = 9 (P = 0.00), I2 =74%

0.1 0.2

0.5

10

Favours aripiprazole

Favours placebo

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Analysis 1.8. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 8 Leaving the study early.
Review: Aripiprazole versus placebo for schizophrenia

Comparison: 1 ARIPIPRAZOLE versus PLACEBO Outcome: 8 Leaving the study early

Study or subgroup

Aripiprazole n/N

Placebo n/N

Risk Ratio M-H,Random,95% CI

Risk Ratio M-H,Random,95% CI

1 due to any reason Adson 2003 Carson 2000 a Carson 2002 b Csernansky 2003 Daniel 2000 Daniel 2004 Marcus 2005 Oren 2005 Potkin 2003 200/312 76/204 84/155 13/34 67/180 8/235 128/279 5/175 37/202 78/108 48/106 110/155 23/35 35/64 3/62 44/88 1/88 51/103 0.89 [ 0.77, 1.02 ] 0.82 [ 0.63, 1.08 ] 0.76 [ 0.64, 0.91 ] 0.58 [ 0.36, 0.95 ] 0.68 [ 0.51, 0.91 ] 0.70 [ 0.19, 2.57 ] 0.92 [ 0.72, 1.17 ] 2.51 [ 0.30, 21.19 ] 0.37 [ 0.26, 0.53 ]

Subtotal (95% CI)

1776

809

0.73 [ 0.60, 0.87 ]

Total events: 618 (Aripiprazole), 393 (Placebo) Heterogeneity: Tau2 = 0.05; Chi2 = 26.46, df = 8 (P = 0.00088); I2 =70% Test for overall effect: Z = 3.37 (P = 0.00076) 2 due to adverse effects Adson 2003 Carson 2000 a Carson 2002 b Csernansky 2003 Daniel 2000 Daniel 2004 Marcus 2005 Oren 2005 Potkin 2003 19/312 17/204 16/155 0/34 10/180 2/235 7/279 1/175 4/202 6/108 11/106 13/155 0/35 1/64 0/62 6/88 0/88 12/103 1.10 [ 0.45, 2.67 ] 0.80 [ 0.39, 1.65 ] 1.23 [ 0.61, 2.47 ] 0.0 [ 0.0, 0.0 ] 3.56 [ 0.46, 27.23 ] 1.33 [ 0.06, 27.45 ] 0.37 [ 0.13, 1.07 ] 1.52 [ 0.06, 36.86 ] 0.17 [ 0.06, 0.51 ]

Subtotal (95% CI)


Total events: 76 (Aripiprazole), 49 (Placebo)

1776

809

0.75 [ 0.42, 1.35 ]

Heterogeneity: Tau2 = 0.30; Chi2 = 13.84, df = 7 (P = 0.05); I2 =49% Test for overall effect: Z = 0.95 (P = 0.34)

0.5

0.7

1.5

Favours aripiprazole

Favours placebo

(Continued . . . )

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

60

(. . .
Study or subgroup Aripiprazole n/N Placebo n/N Risk Ratio M-H,Random,95% CI

Continued) Risk Ratio

M-H,Random,95% CI

Total (95% CI)

3552

1618

0.73 [ 0.61, 0.87 ]

Total events: 694 (Aripiprazole), 442 (Placebo) Heterogeneity: Tau2 = 0.05; Chi2 = 40.14, df = 16 (P = 0.00074); I2 =60% Test for overall effect: Z = 3.41 (P = 0.00065) Test for subgroup differences: Chi2 = 0.02, df = 1 (P = 0.90), I2 =0.0%

0.5

0.7

1.5

Favours aripiprazole

Favours placebo

Analysis 1.9. Comparison 1 ARIPIPRAZOLE versus PLACEBO, Outcome 9 concomitant medication anxiolytics.
Review: Aripiprazole versus placebo for schizophrenia

Comparison: 1 ARIPIPRAZOLE versus PLACEBO Outcome: 9 concomitant medication - anxiolytics

Study or subgroup

Treatment n/N

Control n/N 91/108 76/88

Odds Ratio M-H,Fixed,95% CI

Weight

Odds Ratio M-H,Fixed,95% CI

Adson 2003 Marcus 2005

262/312 239/279

56.7 % 43.3 %

0.98 [ 0.54, 1.78 ] 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) Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.94); I2 =0.0% Test for overall effect: Z = 0.16 (P = 0.87) Test for subgroup differences: Not applicable

0.1 0.2

0.5

10

Favours treatment

Favours control

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

61

HISTORY
Protocol rst published: Issue 3, 2007 Review rst published: Issue 8, 2011

CONTRIBUTIONS OF AUTHORS
El-Sayeh HGG - initial protocol development, data extraction, analysis, writing review. Belgamwar RB - update review protocol development, data extraction, writing review.

DECLARATIONS OF INTEREST
Dr Ravindra Belgamwar - none. Dr Hany George El-Sayeh - none.

SOURCES OF SUPPORT Internal sources


North Staffordshire Combined Health Care NHS Trust, UK.

External sources
none, Not specied.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW


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 signicant 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 No changes to overall outcome lack of efcacy, deterioration or psychosis

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

Aripiprazole versus placebo for schizophrenia (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

62

(Continued)

1.5

Adverse effects on: anxiety, akathisia, extrapyramidal symp- No changes to overall outcome toms, headache, insomnia, weight gain, constipation, diarrhoea, dyspepsia, dizziness, sedation, asthenia and tachycardia

1.5 1.7.10

Adverse effects on: nausea, vomiting and agitation

Result favours placebo

Prolactin - increase to >/= 23 ng/ml or level above upper limit No changes to overall outcome of normal

1.8.1

Leaving the study early: due to any reason

No changes to overall outcome

1.8.2 1.9

Leaving the study early: due to adverse effects Concomitant medication - anxiolytics

No changes to overall outcome 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 reect changes in Cochrane methodology since our protocol was published, for example the inclsuion of a Summary of Findings table.

INDEX TERMS Medical Subject Headings (MeSH)


therapeutic

Antipsychotic Agents [adverse effects; therapeutic use]; Patient Dropouts [statistics & numerical data]; Piperazines [adverse effects; use]; Placebos [therapeutic use]; Quinolones [adverse effects; therapeutic use]; Randomized Controlled Trials as Topic; Schizophrenia [ drug therapy]

MeSH check words


Humans

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