Aripiprazole versus other atypical antipsychotics for schizophrenia

  • Comment
  • Review
  • Intervention

Authors


Abstract

Background

In most western industrialised countries, second generation (atypical) antipsychotics are recommended as first-line drug treatments for people with schizophrenia. In this review, we specifically examine how the efficacy and tolerability of one such agent - aripiprazole - differs from that of other comparable second generation antipsychotics.

Objectives

To review the effects of aripiprazole compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychoses.

Search methods

We searched the Cochrane Schizophrenia Group Trials Register (November 2012), inspected references of all identified studies for further trials and contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information.

Selection criteria

We included all randomised clinical trials (RCTs) comparing aripiprazole (oral) with oral and parenteral forms of amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine for people with schizophrenia or schizophrenia-like psychoses.

Data collection and analysis

We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. Where possible, we calculated illustrative comparative risks for primary outcomes. For continuous data, we calculated mean differences (MD), again based on a random-effects model. We assessed risk of bias for each included study and used GRADE approach to rate quality of evidence.

Main results

We now have included 174 trials involving 17,244 participants. Aripiprazole was compared with clozapine, quetiapine, risperidone, ziprasidone and olanzapine. The overall number of participants leaving studies early was 30% to 40%, limiting validity (no differences between groups).

When compared with clozapine, there were no significant differences for global state (no clinically significant response, n = 2132, 29 RCTs, low quality evidence); mental state (BPRS, n = 426, 5 RCTs, very low quality evidence); or leaving the study early for any reason (n = 240, 3 RCTs, very low quality evidence). Quality of life score using the WHO-QOL-100 scale demonstrated significant difference, favouring aripiprazole (n = 132, 2 RCTs, RR 2.59 CI 1.43 to 3.74, very low quality evidence). General extrapyramidal symptoms (EPS) were no different between groups (n = 520, 8 RCTs,very low quality evidence). No study reported general functioning or service use.

When compared with quetiapine, there were no significant differences for global state (n = 991, 12 RCTs, low quality evidence); mental state (PANSS positive symptoms, n = 583, 7 RCTs, very low quality evidence); leaving the study early for any reason (n = 168, 2 RCTs, very low quality evidence), or general EPS symptoms (n = 348, 4 RCTs, very low quality evidence). Results were significantly in favour of aripiprazole for quality of life (WHO-QOL-100 total score, n = 100, 1 RCT, MD 2.60 CI 1.31 to 3.89, very low quality evidence). No study reported general functioning or service use.

When compared with risperidone, there were no significant differences for global state (n = 6381, 80 RCTs, low quality evidence); or leaving the study early for any reason (n = 1239, 12 RCTs, very low quality evidence). Data were significantly in favour of aripiprazole for improvement in mental state using the BPRS (n = 570, 5 RCTs, MD 1.33 CI 2.24 to 0.42, very low quality evidence); with higher adverse effects seen in participants receiving risperidone of general EPS symptoms (n = 2605, 31 RCTs, RR 0.39 CI 0.31 to 0.50, low quality evidence). No study reported general functioning, quality of life or service use.

When compared with ziprasidone, there were no significant differences for global state (n = 442, 6 RCTs, very low quality evidence); mental state using the BPRS (n = 247, 1 RCT, very low quality evidence); or leaving the study early for any reason (n = 316, 2 RCTs, very low quality evidence). Weight gain was significantly greater in people receiving aripiprazole (n = 232, 3 RCTs, RR 4.01 CI 1.10 to 14.60, very low quality evidence). No study reported general functioning, quality of life or service use.

When compared with olanzapine, there were no significant differences for global state (n = 1739, 11 RCTs, very low quality evidence); mental state using PANSS (n = 1500, 11 RCTs, very low quality evidence); or quality of life using the GQOLI-74 scale (n = 68, 1 RCT, very low quality of evidence). Significantly more people receiving aripiprazole left the study early due to any reason (n = 2331, 9 RCTs, RR 1.15 CI 1.05 to 1.25, low quality evidence) and significantly more people receiving olanzapine gained weight (n = 1538, 9 RCTs, RR 0.25 CI 0.15 to 0.43, very low quality evidence). None of the included studies provided outcome data for the comparisons of 'service use' or 'general functioning'.

Authors' conclusions

Information on all comparisons is of limited quality, is incomplete and problematic to apply clinically. The quality of the evidence is all low or very low. Aripiprazole is an antipsychotic drug with an important adverse effect profile. Long-term data are sparse and there is considerable scope for another update of this review as new data emerge from ongoing larger, independent pragmatic trials.

Résumé scientifique

Aripiprazole versus autres antipsychotiques atypiques dans le traitement de la schizophrénie

Contexte

Dans la plupart des pays industrialisés occidentaux, les antipsychotiques de deuxième génération (atypiques) sont recommandés en tant que traitements médicamenteux de première ligne pour les personnes atteintes de schizophrénie. Dans cette revue, nous avons spécifiquement examiné l'efficacité et la tolérabilité de l'un de ces agents – l'aripiprazole - par rapport à d'autres antipsychotiques de deuxième génération comparables.

Objectifs

Faire la revue des effets de l'aripiprazole par rapport à d'autres antipsychotiques atypiques chez les patients atteints de schizophrénie et de psychoses apparentées.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre des essais du groupe Cochrane sur la schizophrénie (novembre 2012), examiné les références bibliographiques de toutes les études identifiées pour obtenir des essais et contacté les sociétés pharmaceutiques concernées, les agences d'approbation des médicaments et les auteurs des essais pour obtenir des informations supplémentaires.

Critères de sélection

Nous avons inclus tous les essais cliniques randomisés (ECR) comparant l'aripiprazole (par voie orale) les formes orales et parentérales de l'amisulpride, la clozapine, l'olanzapine, la quétiapine, la rispéridone, le sertindole, la ziprasidone et la zotépine chez des patients atteints de schizophrénie ou de psychoses apparentées.

Recueil et analyse des données

Les données ont été extraites indépendamment. Pour les données dichotomiques, nous avons calculé les rapports de risque (RR) et leurs intervalles de confiance (IC) à 95%, sur une base d'intention de traiter à partir d'un modèle à effets aléatoires. Lorsque cela était possible, nous avons calculé des risques significatifs comparatifs pour les critères de jugement principaux. Pour les données continues, nous avons calculé, les différences moyennes (DMP), de nouveau sur la base d'un modèle à effets aléatoires. Nous avons évalué le risque de biais pour chaque étude incluse et utilisé l'approche GRADE pour évaluer la qualité des preuves.

Résultats principaux

Nous avons maintenant inclus 174 essais impliquant 17244 participants. L'aripiprazole était comparée à la clozapine, la quétiapine, la rispéridone, la ziprasidone et l'olanzapine. Le nombre total de participants abandonnant les études prématurément était de 30 % à 40%, ce qui limite la validité (pas de différences entre les groupes).

Par rapport à la clozapine, il n'y avait aucune différence significative concernant l'état général (pas de réponse cliniquement significative, n = 2132, 29 ECR, preuves de faible qualité; l'état mental (score BPRS, n = 426, 5 ECR, preuves de très faible qualité); ou les arrêts prématurés toutes raisons confondues (n = 240, 3 ECR, preuves de très faible qualité). Le score de qualité de vie à l'aide de l'échelle WHO-QOL-100 a montré une différence significative, en faveur de l'aripiprazole (n = 132, 2 ECR, RR 2,59 IC entre 1,43 et 3,74, preuves de très faible qualité). Les symptômes extrapyramidaux (SE) n'étaient pas différents entre les groupes (n = 520, 8 ECR , preuves de très faible qualité). Aucune étude n'a rapporté le fonctionnement global ou l'utilisation des services.

Par rapport à la quétiapine, il n'y avait aucune différence significative concernant l'état général (n = 991, 12 ECR, preuves de très faible qualité); l'état mental (les symptômes positifs PANSS, n = 583, 7 ECR, preuves de très faible qualité); l'abandon précoce de l'étude toutes raisons confondues (n = 168, 2 ECR, preuves de très faible qualité), les symptômes extrapyramidaux (n = 348, 4 ECR, preuves de très faible qualité). Les résultats ont été significativement en faveur de l'aripiprazole pour la qualité de vie (WHO-QOL-100 score total, n = 100, 1 ECR, DM 2,60 IC entre 1,31 et 3,89, preuves de très faible qualité). Aucune étude n'a rapporté le fonctionnement global ou l'utilisation des services.

Par rapport à la rispéridone, il n'y avait aucune différence significative concernant l'état général (n = 6381, 80 ECR, preuves de faible qualité) ou les arrêts prématurés toutes raisons confondues (n = 1239, 12 ECR, preuves de très faible qualité). Les données ont été significativement en faveur de l'aripiprazole pour l'amélioration de l'état mental en utilisant le score BPRS (n = 570, 5 ECR, DM 1,33 IC entre 2,24 et 0,42, preuves de très faible qualité); avec une augmentation plus importante des effets indésirables constatés chez les participants recevant de la rispéridone en ce qui concerne les symptômes extrapyramidaux (n = 2605, 31 ECR, RR de 0,39, IC entre 0,31 et 0,50, preuves de faible qualité). Aucune étude n'a rapporté le fonctionnement global, la qualité de vie ou l'utilisation des services.

Par rapport à la ziprasidone, il n'y avait aucune différence significative concernant l'état général (n = 442, 6 ECR, preuves de très faible qualité); l'état mental en utilisant le score BPRS (n = 247, 1 ECR, preuves de très faible qualité) et les arrêts prématurés toutes raisons confondues (n = 316, 2 ECR, preuves de très faible qualité). La prise de poids était significativement supérieure chez les personnes recevant de l'aripiprazole (n = 232, 3 ECR, RR 4,01 IC entre 1,10 et 14,60, preuves de très faible qualité). Aucune étude n'a rapporté le fonctionnement global, la qualité de vie ou l'utilisation des services.

Comparé à l'olanzapine, il n'y avait aucune différence significative concernant l'état général (n = 1739, 11 ECR, preuves de très faible qualité), l'état mental à l'échelle PANSS (n = 1500, 11 ECR, preuves de très faible qualité) ou la qualité de vie à l'aide de l'échelle GQOLI-74 (n = 68, 1 ECR, preuves de très faible qualité). Significativement plus de personnes recevant de l'aripiprazole abandonnaient l'étude prématurément pour une raison quelconque (n = 2331, 9 ECR, RR de 1,15, IC entre 1,05 et 1,25, preuves de faible qualité) et significativement plus de personnes recevant de l'olanzapine prenaient du poids (n = 1538, 9 ECR, RR 0,25 IC entre 0,15 et 0,43, preuves de très faible qualité). Aucune des études incluses ne rapportait des données de résultats pour les comparaisons de « l'utilisation des services » ou du «fonctionnement global».

Conclusions des auteurs

Les informations sur toutes les comparaisons sont de qualité limitée, incomplètes et problématiques pour être appliquées cliniquement. La qualité des preuves est, pour l'ensemble, faible ou très faible. L'aripiprazole est un médicament antipsychotique avec des effets indésirables importants. Les données à long terme sont rares laissant un champ considérable pour une nouvelle mise à jour de cette revue lorsque de nouvelles données émergeront d'essais en cours de plus grande taille, indépendants et pragmatiques.

Notes de traduction

Translated by: French Cochrane Centre

Translation supported by: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Plain language summary

Aripiprazole versus other atypical antipsychotics

In many countries in the industrialised world there has been a huge growth in the prescription of medication for people with mental health problems, taken orally as a tablet or by injection. Atypical and second generation antipsychotic drugs have become ever more popular, because they are thought to help people with mental health problems who do not respond quite so well to initial treatment. These newer drugs hold the promise of both reducing symptoms, such as hearing voices or seeing things, and reducing problematic side effects, such as sleepiness, weight gain, and shaking.

However, there is little research and comparison of the ways in which drugs differ from one another. This review examines the effectiveness of aripiprazole with other new antipsychotics.

Originally the review included 12 research trials. After an update search carried out in November 2012, 162 trials were added. Most of these trials were from China and although new data were added to the review, overall conclusions did not change. The review now has five comparisons with aripiprazole being compared with clozapine, olanzapine, quetiapine, risperidone and ziprasidone.

For people with schizophrenia it may be important to know that aripiprazole may not be as good or effective as olanzapine but that it has less side effects. Aripiprazole is similar in effectiveness to risperidone and somewhat better than ziprasidone. Aripiprazole had less side- effects than olanzapine and risperidone (such as weight gain, sleepiness, heart problems, shaking and increased cholesterol levels). Aripiprazole was not as good as ziprasidone for dealing with restlessness or people’s inability to sit still. Comparison with other antipsychotic drugs as a group showed that people preferred taking aripiprazole. However, people with schizophrenia as well as mental health professionals and policy makers should know that the evidence is limited and mostly of low or very low quality. More trials and research is required, including on outcomes such as: quality of life; the views of service users and carers; and patient preference.

This plain language summary has been written by a consumer from Rethink Mental Illness, Benjamin Gray. Email: ben.gray@rethink.org

Résumé simplifié

Aripiprazole versus autres antipsychotiques atypiques

Dans de nombreux pays industrialisés, il y a eu une énorme croissance de la prescription de médicaments pour les personnes souffrant de problèmes de santé mentale, pris par voie orale en comprimé ou par injection. Les antipsychotiques dits atypiques ou de deuxième génération sont devenus de plus en plus populaires, car ils sont supposés aider les personnes souffrant de problèmes de santé mentale qui ne répondent pas assez bien à un traitement initial. Ces nouveaux médicaments maintiennent l'espoir de réduire les symptômes, tels que le fait d'entendre des voix ou de voir des choses et de réduire les effets secondaires, tels que la somnolence, la prise de poids et les tremblements.

Cependant, il existe peu de recherches et de comparaisons sur la manière dont les médicaments diffèrent les uns des autres. Cette revue examine l'efficacité de l'aripiprazole par rapport à d'autres nouveaux antipsychotiques.

La revue d'origine incluait 12 essais de recherche. Après une recherche de mise à jour effectuée en novembre 2012, 162 essais ont été ajoutés. La plupart de ces essais provenaient de Chine et bien que de nouvelles données ont été ajoutées à la revue, dans l'ensemble les conclusions n'ont pas changé. La revue comporte maintenant cinq comparaisons avec l'aripiprazole par rapport à la clozapine, l'olanzapine, la quétiapine, la rispéridone et la ziprasidone.

Pour les personnes atteintes de schizophrénie il peut être important de savoir que l'aripiprazole pourrait ne pas être aussi bénéfique ou efficace que l'olanzapine mais qu'elle provoque moins d'effets secondaires. L'aripiprazole est similaire dans l'efficacité à la rispéridone et légèrement plus efficace que la ziprasidone. L'aripiprazole a moins d'effets secondaires que l'olanzapine et la rispéridone (tels que la prise de poids, la somnolence, les problèmes cardiaques, les tremblements et l"augmentation des niveaux de cholestérol). L'aripiprazole n'était pas aussi efficace que la ziprasidone pour lutter contre l'agitation ou l'incapacité à rester tranquille. La comparaison avec d'autres médicaments antipsychotiques en tant que groupe a montré que les personnes ont préféré l’aripiprazole. Cependant, les personnes atteintes de schizophrénie ainsi que les professionnels de santé mentale et les décideurs politiques devraient savoir que les preuves sont limitées et généralement de qualité faible ou très faible. D'autres essais et recherches sont nécessaires, notamment sur les critères de jugement, tels que : la qualité de vie; le point de vue des patients et des soignants et la préférence du patient.

Ce résumé en langage simplifié a été rédigé par un usager de Rethink Mental Illness, Benjamin Gray. Email: ben.gray@rethink.org

Notes de traduction

Translated by: French Cochrane Centre

Translation supported by: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Laički sažetak

Usporedba aripiprazola i ostalih atipičnih antipsihotika za liječenje shizofrenije

U mnogim industrijaliziranim zemljama povećava se broj propisanih lijekova osobama s mentalnim bolestima, bilo da su u obliku tableta za primjenu na usta ili injekcija. Atipični i antipsihotici druge generacije postali su još popularniji jer se smatra da pomažu osobama s mentalnim bolestima koji ne odgovaraju dovoljno na prvotnu terapiju. Ti noviji lijekovi obećavaju smanjenje simptoma poput zvučnih i vizualnih halucinacija te problematičnih nuspojava poput pospanosti, povećanja tjelesne mase i drhtanja.

Međutim, postoji malo istraživanja i usporedbi načina na koji se antipsihotici međusobno razlikuju. Ovaj Cochrane sustavni pregled ispituje učinkovitost aripiprazola u usporedbi s drugim novim antipsihoticima.

Sustavni pregled je u svojoj prvoj verziji uključio 12 studija. Nakon novog pretraživanja literature, obavljenog u studenom 2012., dodane su 162 nove studije. Većina tih studija je provedena u Kini i iako su novi podaci dodani sustavnom pregledu, zaključci se nisu promijenili. Sustavni pregled sad sadrži usporedbu aripiprazola s pet lijekova: klozapinom, olanzapinom, kvetiapinom, risperidonom i ziprasidonom.

Za oboljele od shizofrenije može biti važno saznanje da aripiprazol nije toliko učinkovit kao olanzapin, ali ima manje nuspojava. Podjednako je učinkovit kao risperidon i čini se da je učinkovitiji od ziprasidona. Aripiprazol je imao manje nuspojava od risperidona i risperidona (poput povećanja tjelesne mase, pospanosti, kardioloških problema, drhtanja i povišene razine kolesterola. Aripiprazol nije bio učinkovit kao ziprasidon za sprečavanje nemira ili nemogućnosti mirnog sjedenja. Usporedba s drugim antipsihoticima pokazala je da su pacijenti preferirali aripiprazol. Međutim, osobe oboljele od shizofrenije kao i zdravstveni radnici i osobe koje izrađuju smjernice bi trebali znati da su dokazi ograničeni i većinom niske ili vrlo niske kvalitete. Potrebno je više studija i istraživanja, uključujući ishode poput: kvalitete života; pacijenata i osoba koje se brinu oko njih; i preferenciju pacijenata.

Ovaj laički sažetak Cochrane sustavnog pregleda napisao je Benjamin Grey iz udruge Rethink Mental Illnes. Kontakt: ben.gray@rethink.org

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Adam Galkovski
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Streszczenie prostym językiem

Arypiprazol a inne atypowe leki przeciwpsychotyczne

W wielu krajach uprzemysłowionej części świata nastąpił ogromny wzrost liczby leków przepisywanych dla osób z problemami psychicznymi; leki te są podawane w postaci tabletek - doustnie lub w postaci iniekcji. Atypowe leki przeciwpsychotyczne drugiej generacji stały się bardziej popularne, ponieważ uważa się, że są one skuteczne u osób z problemami psychicznymi, które nie odpowiadają już tak dobrze na pierwotne leczenie. Nowsze leki zmniejszą zarówno objawy, takie jak słyszenie głosów lub widzenie rzeczy jak i kłopotliwe skutki uboczne, takie jak senność, zwiększenie masy ciała i drżenie.

Istnieje jednak niewiele badań i zestawień różnic pomiędzy poszczególnymi lekami. Przegląd ten bada skuteczność arypiprazolu w porównaniu z innymi nowymi lekami przeciwpsychotycznymi.

Pierwotnie przegląd obejmował 12 badań naukowych. Po zaktualizowanym wyszukiwaniu przeprowadzonym w listopadzie 2012 r. dodano 162 badania. Większość z nich pochodziła z Chin, i chociaż do przeglądu zostały dodane nowe dane, ogólne wnioski nie uległy zmianie. Przegląd zawiera obecnie pięć porównań arypiprazolu z klozapiną, olanzapiną, kwetiapiną, rysperydonem i zyprazydonem.

Dla osób cierpiących na schizofrenię istotną wydaje się być informacja, że arypiprazol choć może nie jest tak dobry czy skuteczny jak olanzapina, ma od niej mniej skutków ubocznych. Arypiprazol jest podobny w skuteczności do rysperydonu i nieco lepszy niż zyprazydon. Ma on mniej skutków ubocznych niż olanzapina i rysperydon (takich jak przyrost masy ciała, senność, problemy z sercem, drżenie i zwiększenie stężenia cholesterolu). Arypiprazol nie był jednak tak skuteczny jak zyprazydon w zmniejszaniu niepokoju lub niezdolności do "usiedzenia w miejscu". Porównanie z innymi lekami przeciwpsychotycznymi jako grupą wykazało, że pacjenci woleli zażywać arypiprazol. Jednakże zarówno osoby ze schizofrenią, jak i specjaliści w zakresie zdrowia psychicznego oraz decydenci powinni wiedzieć, że jakość danych ogranicza się głównie do niskiej lub bardzo niskiej. Potrzeba większej ilości badań, w tym oceniających wpływ stosowania leków na: jakość życia, opinie uczestników badania i ich opiekunów oraz preferencje pacjentów.

To streszczenie zostało napisane przez korzystającego z usług systemu opieki zdrowotnej Benjamina Gray'a, użytkownika i eksperta w Rethink Mental Illness. E-mail: ben.gray@rethink.org

Uwagi do tłumaczenia

Tłumaczenie Dawid Storman Redakcja Katarzyna Mistarz

Summary of findings(Explanation)

Summary of findings for the main comparison. COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE for schizophrenia
  1. 1 Risk: moderate risk approximately equates to that of the control group risk in the study population.
    2 Risk of bias: rated 'serious' - majority of the included studies had inadequate study design - unclear randomisation, allocation concealment and blinding. Some also had selective reporting concerns.
    3 Imprecision: rated 'serious' - most of these included studies are of small samples with small effect size and wide confidence interval. The combined effect was not statistically significant.
    4 Imprecision: rated 'serious' - we were unable to obtain direct binary measure of mental state, thus used BPRS score as an indicator.
    5 Publication bias: rated 'strongly suspected' - only a small number of studies favouring intervention group were identified.
    6 Indirectness: rated 'serious' - we were unable to obtain direct binary measure of quality of life, thus employed WHO-QOL-100 rating score as an indicator.

COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE for schizophrenia
Patient or population: patients with schizophrenia
Settings: inpatient and outpatient
Intervention: COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE
Global state: No clinically significant response
Follow-up: up to 12 weeks
Low1 RR 1.05
(0.87 to 1.27)
2132
(29 studies)
⊕⊕⊝⊝
low 2,3
 
100 per 1000 105 per 1000
(87 to 127)
Moderate1
150 per 1000 157 per 1000
(131 to 190)
High1
200 per 1000 210 per 1000
(174 to 254)
Mental state: as measured by BPRS
BPRS (high score = poor)
 The mean mental state: as measured by BPRS in the intervention groups was
0.22 lower
(1.44 lower to 1 higher)
 426
(5 studies)
⊕⊝⊝⊝
very low 2,3,4,5
 
Leaving the study early - Any reason
Follow-up: up to 12 weeks
Low1 RR 1.41
(0.46 to 4.29)
240
(3 studies)
⊕⊝⊝⊝
very low 2,3
 
0 per 1000 0 per 1000
(0 to 0)
Moderate1
50 per 1000 70 per 1000
(23 to 214)
High1
100 per 1000 141 per 1000
(46 to 429)
Quality of life: as measured by WHO-QOL-100
WHO-QOL-100 (low score = poor)
Follow-up: up to 12 weeks
 The mean quality of life: as measured by WHO-QOL-100 in the intervention groups was
2.59 higher
(1.43 to 3.74 higher)
 132
(2 studies)
⊕⊝⊝⊝
very low 6
 
Adverse effects: extrapyramidal effects
Follow-up: up to 12 weeks
Low1 RR 1.91
(0.75 to 4.85)
520
(8 studies)
⊕⊝⊝⊝
very low 2,3,5
 
0 per 1000 0 per 1000
(0 to 0)
Moderate1
50 per 1000 96 per 1000
(38 to 242)
High1
100 per 1000 191 per 1000
(75 to 485)
General functioning - not measuredSee commentSee commentNot estimable-See commentNo study measured or reported this outcome.
Service use - not measuredSee commentSee commentNot estimable-See commentNo study measured or reported this outcome.
*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;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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: We are very uncertain about the estimate.

Summary of findings 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE for schizophrenia

Summary of findings 2. COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE for schizophrenia
  1. 1 Risk: moderate risk approximately equates to that of the control group risk in the study population.
    2 Risk of bias: rated 'serious' – majority of the included studies had inadequate study design - unclear randomisation, allocation concealment and blinding. A large proportion of them also had selective reporting concerns.
    3 Imprecision: rated 'serious' – most of these included studies are of small samples with small effect size and wide confidence interval. The 95% confidence interval of the combined estimated effect was not statistically significant.
    4 Imprecision and risk of bias: rated 'serious' - most of the studies included are of small sample size, the overall pooled estimate of effect is not significant.
    5 Inconsistency: rated 'serious' - unexplained heterogeneity is high (70%).
    6 Indirectness: rated 'serious' - we were unable to obtain direct binary measure of mental state, thus used the best approximate measure available as an indicator.
    7 Publication bias: rated 'strongly suspected' - only small number of studies were identified - publication bias likely.
    8 Imprecision and publication bias: rated 'serious' - only small number of studies with poor methodological design favouring intervention group were identified - publication bias likely
    9 Risk of bias: rated 'serious' – the only included study has unclear study design (randomisation, allocation concealment, blinding were unclear) and concerns of selective reporting.
    10 Indirectness: rated 'serious' - we are unable to obtain a direct binary measure of quality of life, thus used the best available proximate measure of WHO-QOL-100 as an indicator.
    11 Imprecision: rated 'very serious' - only one study is available on this outcome. The sample size is small and the CI of effect estimate is wide.
    12 Inconsistency: rated 'serious' - unexplained heterogeneity is around 53%.
    13 Imprecision: rated 'serious' - overall event rate is small (<300).

COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE for schizophrenia
Patient or population: patients with schizophrenia
Settings: inpatient and outpatient
Intervention: COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE
Global state: No clinically significant response (as defined by original studies) Low1 RR 0.92
(0.64 to 1.32)
991
(12 studies)
⊕⊕⊝⊝
low 2,3
 
50 per 1000 46 per 1000
(32 to 66)
Moderate1
100 per 1000 92 per 1000
(64 to 132)
High1
150 per 1000 138 per 1000
(96 to 198)
Mental state: as assessed by PANSS positive symptom scale score
PANSS positive symptom subscale (high score = poor)
Follow-up: up to 12 weeks
 The mean mental state: as assessed by PANSS positive symptom scale score in the intervention groups was
0.97 lower
(2.34 lower to 0.41 higher)
 583
(7 studies)
⊕⊝⊝⊝
very low 4,5,6,7
 
Leaving the study early
Follow-up: up to 12 weeks
Low1 RR 0.8
(0.22 to 2.87)
168
(2 studies)
⊕⊝⊝⊝
very low 2,8
 
0 per 1000 0 per 1000
(0 to 0)
Moderate1
50 per 1000 40 per 1000
(11 to 143)
High1
100 per 1000 80 per 1000
(22 to 287)
Quality of life: as measured by WHO-QOL-100
Follow-up: up to 12 weeks
 The mean quality of life: as measured by WHO-QOL-100 in the intervention groups was
2.6 higher
(1.31 to 3.89 higher)
 100
(1 study)
⊕⊝⊝⊝
very low 8,9,10,11
 
Adverse effects: extrapyramidal symptoms
Follow-up: up to 12 weeks
Low1 RR 2.8
(0.64 to 12.31)
348
(4 studies)
⊕⊝⊝⊝
very low 2,7,12,13
 
0 per 1000 0 per 1000
(0 to 0)
Moderate1
50 per 1000 140 per 1000
(32 to 616)
High1
100 per 1000 280 per 1000
(64 to 1000)
General functioning - not measuredSee commentSee commentNot estimable-See commentNo study measured or reported this outcome.
Service use - not measuredSee commentSee commentNot estimable-See commentNo study measured or reported this outcome.
*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;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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: We are very uncertain about the estimate.

Summary of findings 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE for schizophrenia

Summary of findings 3. COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE for schizophrenia
  1. 1 Risk: moderate risk approximately equates to that of the control group risk of the study population.
    2 Risk of bias: rated 'serious' - majority of the included studies had inadequate study design - unclear randomisation, allocation concealment and blinding. A large proportion of them also had selective reporting concerns.
    3 Imprecision: rated 'serious' - 95% CI around the pool estimate of effect was not statistically significant.
    4 Risk of bias: rated 'serious' - only a small number of publications with poor methodological design favouring intervention group were identified - publication bias likely.
    5 Indirectness: rated 'serious' - we were unable to find direct binary measure of mental state, thus used the best available data as an indicator.
    6 Publication bias: rated 'strongly suspected' - overall event number is small (<300) and the pooled effect estimate is not statistically significant.
    7 Imprecision: rated 'serious' - overall event number is small (<300).
    8 Publication bias: rated 'strongly suspected' - most of the studies identified were of poor methodological quality favouring intervention group - publication bias likely.

COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE for schizophrenia
Patient or population: patients with schizophrenia
Settings: inpatient and outpatient
Intervention: COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE
Global state: No clinically significant response (as defined by the original studies) Low1 RR 1.08
(0.96 to 1.21)
6381
(80 studies)
⊕⊕⊝⊝
low 2,3
 
50 per 1000 54 per 1000
(48 to 61)
Moderate1
100 per 1000 108 per 1000
(96 to 121)
High1
150 per 1000 162 per 1000
(144 to 182)
Mental state: as measured by BPRS
BPRS (high score = poor)
Follow-up: up to 12 weeks
 The mean mental state: as measured by BPRS in the intervention groups was
1.33 lower
(2.24 to 0.42 lower)
 570
(5 studies)
⊕⊝⊝⊝
very low 4,5,6
 
Leaving the study early
Follow-up: up to 12 weeks
Low1 RR 1.02
(0.79 to 1.32)
1239
(12 studies)
⊕⊝⊝⊝
very low 6,7
 
0 per 1000 0 per 1000
(0 to 0)
Moderate1
100 per 1000 102 per 1000
(79 to 132)
High1
150 per 1000 153 per 1000
(119 to 198)
Quality of life - not measuredSee commentSee commentNot estimable-See commentNo study measured or reported this outcome.
Adverse effects: extrapyramidal symptoms
Follow-up: up to 12 weeks
Low1 RR 0.39
(0.31 to 0.5)
2605
(31 studies)
⊕⊕⊝⊝
low 2,8
 
100 per 1000 39 per 1000
(31 to 50)
Moderate1
300 per 1000 117 per 1000
(93 to 150)
High1
400 per 1000 156 per 1000
(124 to 200)
General functioning - not measuredSee commentSee commentNot estimable-See commentNo study measured or reported this outcome.
Service use - not measuredSee commentSee commentNot estimable-See commentNo study measured or reported this outcome.
*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;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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: We are very uncertain about the estimate.

Summary of findings 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE for schizophrenia

Summary of findings 4. COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE for schizophrenia
  1. 1 Risk: moderate risk approximately equates to that of the control group risk in the study population.
    2 Risk of bias: rated 'serious' - majority of the included studies had inadequate study design - unclear randomisation, allocation concealment and blinding. A large proportion of them also had selective reporting concerns.
    3 Imprecision: rated 'serious' - the total event number is small (<300) and that the 95% CI of the pooled best estimate of effect is not statistically significant.
    4 Publication bias: rated 'strongly suspected' - only a small number of trials with small sample size were identified. It is likely that these trials with low methodological quality would have exaggerated intervention effect.
    5 Risk of bias: rated 'serious' - the only included study has serious concern with selective reporting and unclear allocation concealment and incomplete outcome.
    6 Indirectness: rated 'serious' - we were unable to find direct binary measure of mental state, thus used BPRS score as an indicator.
    7 Imprecision: rated 'serious' - only one study is identified, the estimate of effect is not statistically significant.
    8 Publication bias: rated 'strongly suspected' - only small number of trials with poor methodological quality were identified - publication bias likely.

COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE for schizophrenia
Patient or population: patients with schizophrenia
Settings: inpatient and outpatient
Intervention: COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE
Global state: No clinically significant response (as defined by the original studies) Low1 RR 0.97
(0.62 to 1.52)
442
(6 studies)
⊕⊝⊝⊝
very low 2,3,4
 
100 per 1000 97 per 1000
(62 to 152)
Moderate1
150 per 1000 146 per 1000
(93 to 228)
High1
200 per 1000 194 per 1000
(124 to 304)
Mental state: as measured with BPRS
BPRS (high score = poor)
Follow-up: up to 12 weeks
 The mean mental state: as measured with BPRS in the intervention groups was
2.2 lower
(4.97 lower to 0.57 higher)
 247
(1 study)
⊕⊝⊝⊝
very low 5,6,7
 
Leaving the study early
Follow-up: up to 12 weeks
Low1 RR 0.94
(0.66 to 1.34)
316
(2 studies)
⊕⊝⊝⊝
very low 2
 
150 per 1000 141 per 1000
(99 to 201)
Moderate1
250 per 1000 235 per 1000
(165 to 335)
High1
350 per 1000 329 per 1000
(231 to 469)
Quality of life - not measuredSee commentSee commentNot estimable-See commentNo study measured or reported this outcome.
Adverse effects: weight gain
Follow-up: up to 12 weeks
Low1 RR 4.01
(1.1 to 14.6)
232
(3 studies)
⊕⊝⊝⊝
very low 2,3,8
 
0 per 1000 0 per 1000
(0 to 0)
Moderate1
40 per 1000 160 per 1000
(44 to 584)
High1
100 per 1000 401 per 1000
(110 to 1000)
General functioning - not measuredSee commentSee commentNot estimable-See commentNo study measured or reported this outcome.
Service use - not measuredSee commentSee commentNot estimable-See commentNo study measured or reported this outcome.
*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;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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: We are very uncertain about the estimate.

Summary of findings 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE for schizophrenia

Summary of findings 5. COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE for schizophrenia
  1. 1 Risk: moderate risk approximately equates to that of the control group risk of the study population.
    2 Risk of bias: rated 'serious' - majority of the included studies had inadequate study design - unclear randomisation, allocation concealment and blinding. Some of them also had selective reporting concerns.
    3 Imprecision: rated 'serious' - total number of events is small (<300) and that the 95% CI of pooled estimate of effect is not statistically significant.
    4 Publication bias: rated 'strongly suspected' - only small number of trials with small sample size were identified. It is likely that these small studies with poor methodological quality have negatively affected on the estimate of treatment effect.
    5 Indirectness: rated 'serious' - we are unable to find direct binary measure of mental state, thus used PANSS score as an indicator.
    6 Imprecision: rated 'serious' - the overall pooled estimate of effect was not statistically significant and with wide confidence interval.
    7 Publication bias: rated 'strongly suspected' - only a small number of studies with poor methodological deign were identified - publication bias likely.
    8 Risk of bias: rated 'serious' - unclear randomisation, allocation concealment, blinding and serious concern with selective reporting.
    9 Indirectness: rated 'serious' - we are unable to find direct binary measure of quality of life, thus used GQOLI-74 score as an indicator.
    10 Imprecision: rated 'very serious' - only one study with serious methodological concerns was identified and the estimate of effect is not significant.

COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE for schizophrenia
Patient or population: patients with schizophrenia
Settings: inpatient and outpatient
Intervention: COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE
Global state: No clinically significant response
Follow-up: up to 12 weeks
Low1 RR 1.06
(0.96 to 1.17)
1739
(11 studies)
⊕⊝⊝⊝
very low 2,3,4
 
200 per 1000 212 per 1000
(192 to 234)
Moderate1
350 per 1000 371 per 1000
(336 to 409)
High1
500 per 1000 530 per 1000
(480 to 585)
Mental state: as measured with PANSS
PANSS (high score = poor)
Follow-up: up to 12 weeks
 The mean mental state: as measured with PANSS in the intervention groups was
0.61 higher
(0.23 lower to 1.46 higher)
 1500
(11 studies)
⊕⊝⊝⊝
very low 2,5,6,7
 
Leaving the study early
Follow-up: up to 12 weeks
Low1 RR 1.15
(1.05 to 1.25)
2331
(9 studies)
⊕⊕⊝⊝
low 2,7
 
200 per 1000 230 per 1000
(210 to 250)
Moderate1
350 per 1000 402 per 1000
(367 to 438)
High1
500 per 1000 575 per 1000
(525 to 625)
Quality of life: as measured with GQOLI-74
GQOLI-74 (low score = poor)
 The mean quality of life: as measured with gqoli-74 in the intervention groups was
1.26 lower
(6.37 lower to 3.85 higher)
 68
(1 study)
⊕⊝⊝⊝
very low 7,8,9,10
 
Adverse effects: weight gain
Follow-up: up to 12 weeks
Low1 RR 0.25
(0.15 to 0.43)
1538
(9 studies)
⊕⊝⊝⊝
very low 2,3,7
 
100 per 1000 25 per 1000
(15 to 43)
Moderate1
200 per 1000 50 per 1000
(30 to 86)
High1
300 per 1000 75 per 1000
(45 to 129)
General functioning - not measuredSee commentSee commentNot estimable-See commentNo study measured or reported this outcome.
Service use - not measuredSee commentSee commentNot estimable-See commentNo study measured or reported this outcome.
*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;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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: We are very uncertain about the estimate.

Background

Description of the condition

Schizophrenia is usually a chronic and disabling psychiatric disorder, which afflicts approximately one per cent of the population worldwide, affecting  male and female patients in similar proportions. The annual incidence of schizophrenia averages 15 per 100,000 population  and the risk of developing the illness over one's lifetime averages 0.7% (Tandon 2008). Its typical manifestations include  'positive' symptoms such as fixed, false beliefs (delusions) and perceptions without cause (hallucinations), 'negative' symptoms such as apathy and lack of drive, disorganisation of behaviour and thought, and catatonic symptoms such as mannerisms and bizarre posturing (Carpenter 1994). The degree of suffering and disability is considerable with 80% to 90% of those affected not working (Marvaha 2004) and up to 10% dying prematurely (Tsuang 1978). In the age group of 15 to 44 years, schizophrenia is among the top 10 leading causes of disease-related disability in the world (WHO 2001). Conventional antipsychotic drugs, such as chlorpromazine and haloperidol, have traditionally been used as first line antipsychotics for people with schizophrenia (Kane 1993). The introduction and subsequent use of clozapine in the United States of America identified that clozapine seemed to be more effective, and was associated with fewer movement disorders than existing agents such as chlorpromazine (Kane 1988). These results boosted the development and marketing of new/second/atypical generation antipsychotics (SGAs).

Description of the intervention

There is no good definition of what constitutes an atypical/second generation antipsychotic, but they were initially said to differ from older generation drugs in that they did not cause movement disorders (catalepsy) in rats at clinically effective doses (Arnt 1998). The terms new or second generation to describe clozapine, a very old drug, are equally poor descriptors. According to treatment guidelines (APA 2004; Gaebel 2006), SGAs include drugs such as amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine. It is unclear whether some old and inexpensive compounds such as sulpiride, perazine or even low-dose chlorpromazine, have similar properties (Möller 2000). High expectations were raised for these SGAs as regards their alleged superiority in a number of areas such as compliance, cognitive functioning, negative symptoms, movement disorders, quality of life and efficacy in treatment-resistant schizophrenia.

How the intervention might work

Aripiprazole is said to be the prototype of a new and third generation of antipsychotics; the so called dopamine-serotonin system stabilisers. 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 agonist at 5-HT2 serotonin receptors. 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, yet it would stimulate receptors as an agonist at sites in which low dopaminergic tone would produce adverse effects (e.g. areas mediating motor movement and prolactin release (Rivas-Vasquez 2003)). Aripiprazole, however, also has an affinity to other receptors including D3, D4, 5-HT2c, 5HT7, alpha-1 adrenergic and histamine receptors. This may explain adverse effects associated with this compound such as somnolence, headache, gastrointestinal upset and light headedness (FDA 2002). The recommended target dose for aripiprazole is 10-15 mg per day (dose range 10-30 mg/day). Phase III trials were initially conducted in Japan in 1995 and the drug was granted Approved Status by the FDA (USA) on the 15 November 2002 for the treatment of schizophrenia. Aripiprazole has since been licensed in most countries worldwide.

Why it is important to do this review

The debate as to how far the second generation antipsychotic drugs improve these outcomes compared to conventional antipsychotics continues (Duggan 2005) and results from recent studies were sobering (Jones 2006; Lieberman 2005). Nevertheless, in some parts of the world, particularly  in western industrialised countries, SGAs have become the mainstay of treatment. Second generation antipsychotics also differ in terms of their costs. Amisulpride and risperidone, for example, are already generic in many countries. Therefore, the question as to whether they differ from each other in their clinical efficacy becomes increasingly important. In this review we aim to summarise evidence from randomised controlled trials comparing aripiprazole with other SGAs. This  acts as a continuum to the comparisons previously published by EL-Sayeh 2006, Leucht 2008 and  Komossa 2009.

This review was published in early 2013 with a vast number of Chinese studies in awaiting classification, thus we have updated it again in June 2013.

Objectives

To review the effects of aripiprazole compared with other second generation/atypical antipsychotics for people with schizophrenia.

Methods

Criteria for considering studies for this review

Types of studies

We included both open and double-blinded, randomised controlled trials. We included open trials as we felt that important data that could potentially have an impact on the results might otherwise be overlooked. Where a trial was described as "double-blind" but it was only implied that the study was randomised, we included these trials in a sensitivity analysis. If there was no substantive difference within primary outcomes (see Types of outcome measures) when these 'implied randomisation' studies were added, then we included these in the final analysis. If there was a substantive difference, we only used 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.

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 oral form of application, any dose.

2. Other new/atypical antipsychotic drugs

These include amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine: any oral or parenteral form of application, any dose.

Types of outcome measures

We grouped outcomes into the short term (up to 12 weeks), medium term (13-26 weeks) and long term (over 26 weeks).

Primary outcomes
1. Global state

No clinically important response - as defined by the individual studies (e.g. global impression less than much improved or less than 50% reduction on a rating scale) - medium term

2. General functioning

No clinically important change in general functioning - medium term

3. Adverse effects

Clinically important specific adverse effects - medium term

Secondary outcomes

1. Global state

1.1 No clinically important change in global state (as defined by individual studies)
1.2 Relapse (as defined by the individual studies)

2. Mental state

2.1 No clinically important change in general mental state score
2.2 Average endpoint general mental score
2.3 Average change in general mental state score
2.4 No clinically important change in specific symptoms (positive symptoms of schizophrenia, negative symptoms of schizophrenia)
2.5 Average endpoint specific symptom score
2.6 Average change in specific symptom score

3. Leaving the studies early

3.1 Any reason, adverse events, inefficacy of treatment

4. Quality of life/satisfaction with treatment

4.1 No clinically important change in general quality of life
4.2 Average endpoint general quality of life score
4.3 Average change in general quality of life score

5. General functioning

5.1 No clinically important change in general functioning,- short and long term
5.2 Average endpoint general functioning score
5.3 Average change in general functioning score

6. Cognitive functioning

6.1 No clinically important change in overall cognitive functioning
6.2 Average endpoint of overall cognitive functioning score
6.3 Average change of overall cognitive functioning score

7. Service use

7.1 Number of patients hospitalised

8. Adverse effects

8.1 Number of participants with at least one adverse effect
8.2 Clinically important specific adverse effects (cardiac effects, death, movement disorders, prolactin increase and associated effects, weight gain, effects on white blood cell count), short and long term
8.3 Average endpoint in specific adverse effects
8.4 Average change in specific adverse effects

9. 'Summary of findings' table

We used the GRADE approach to interpret findings (Schünemann 2008) and used the GRADE profiler to import data from Review Manager (RevMan) to create 'Summary of findings' tables. These tables provide outcome-specific 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 findings' tables.

  1. Global state

  2. Mental state

  3. Leaving the study early

  4. Quality of Life

  5. Adverse effects

  6. General functioning

  7. Service use

Search methods for identification of studies

No language restriction was applied within the limitations of the search tools.

Electronic searches

1. Update search

We searched the Cochrane Schizophrenia Group Trials Register (5 November 2012) using the phrase:

[ ( (aripiprazol* AND (amisulprid* OR clozapin* OR olanzapin* OR quetiapin* OR risperidon* OR sertindol* OR ziprasidon* OR zotepin*)) in title, abstract or index terms of REFERENCE) or ( (aripiprazol* AND (amisulprid* OR clozapin* OR olanzapin* OR quetiapin* OR risperidon* OR sertindol* OR ziprasidon* OR zotepin*)) in interventions of STUDY)]

The Cochrane Schizophrenia Group’s Trials Register is compiled by systematic searches of major databases, handsearches of journals and conference proceedings (see Group Module). Incoming trials are assigned to relevant existing or new review titles.

2. Previous electronic search

Please see Appendix 1.

Searching other resources

1. Reference searching

We inspected the reference lists of all studies identified in the search for more trials.

2. Personal contact

Where possible, we contacted the first author of each included study for missing information.

3. Drug companies

We contacted the manufacturers of all atypical antipsychotics included for additional data in the 2011 update.

Data collection and analysis

For previous data collection and analysis methods please see Appendix 2.

Selection of studies

Review author TS inspected the reports for this update. TS resolved any doubts by discussion with other review authors, and where there was still doubt, TS acquired the full article for further inspection. Once the full articles were obtained, TS decided whether the studies met the review criteria. Twenty per cent of the references were randomly checked by HXM for reliability. Any disagreements were resolved by discussion. For any persistent disagreement, TS sought further information from authors of studies and added these trials to the list of those awaiting assessment. (See also Figure 1, Figure 2 and Figure 3 for detailed flow chart of the selection process).

Figure 1.

Study flow diagram: original search

Figure 2.

Study flow diagram: update 2011

Figure 3.

Study flow diagram: update 2012

Data extraction and management

1. Extraction

For this update, TS and HXM extracted data from included studies. If data were presented only in graphs and figures, TS and HXM extracted data whenever possible. When further information was necessary, TS contacted authors of studies in order to obtain missing data or for clarification. If studies were multicentre, where possible, TS extracted data relevant to each component centre separately.

2. Management
2.1 Forms

We extracted data onto standard, simple forms.

2.2 Scale-derived data

We included continuous data from rating scales only if:
a. the psychometric properties of the measuring instrument have been described in a peer-reviewed journal (Marshall 2000); and
b. the measuring instrument has not been written or modified by one of the trialists for that particular trial.

Ideally, the measuring instrument should either be i. a self-report or ii. completed by an independent rater or relative (not the therapist). We realise that this is not often reported clearly; we have noted whether or not this is the case in Description of studies.

2.3 Endpoint versus change data

There are advantages of both endpoint and change data. Change data can remove a component of between-person variability from the analysis. On the other hand, calculation of change needs two assessments (baseline and endpoint), which can be difficult in unstable and difficult to measure conditions such as schizophrenia. We decided primarily to 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 (SMD) throughout (Higgins 2011, Chapter 9.4.5.2).

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 (SDs) and means are reported in the paper or obtainable from the authors;

b) when a scale starts from the finite number zero, the SD, 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 the Positive and Negative Syndrome Scale (PANSS, (Kay 1986)), which can have values from 30 to 210), we modified the calculation described above to take the scale starting point into account. In these cases skew is present if 2 SD > (S-S min), where S is the mean score and S min is the minimum score.

Endpoint scores on scales often have a finite start and end point and these rules can be applied. We entered skewed endpoint data from studies of fewer than 200 participants in as other data within the data and analyses 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 endpoint data into syntheses.

When continuous data are presented on a scale that includes a possibility of negative values (such as change data), it is difficult to tell whether data are skewed or not; we entered skewed change data into analyses regardless of the size of study.

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 PANSS (Kay 1986), this could be considered as a clinically significant response (Leucht 2005a; Leucht 2005). If data based on these thresholds were not available, we used the primary cut-off presented by the original authors.

2.7 Direction of graphs

Where possible, we entered data in such a way that the area to the left of the line of no effect indicated a favourable outcome for aripiprazole.

Assessment of risk of bias in included studies

For this update, review author TS worked independently by using criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to assess trial quality. This new 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.

Where inadequate details of randomisation and other characteristics of trials were provided we contacted the authors of the studies in order to obtain additional information.

We have noted the level of risk of bias in both the text of the review and in the Summary of findings for the main comparison; Summary of findings 2; Summary of findings 3; Summary of findings 4; Summary of findings 5.

Measures of treatment effect

1. Binary data

For binary outcomes, we calculated a standard estimation of the risk ratio (RR) and its 95% confidence interval (CI). It has been shown that RR is more intuitive (Boissel 1999) than odds ratios and that odds ratios tend to be interpreted as RR by clinicians (Deeks 2000). The Number Needed to Treat/Harm (NNT/H) statistic with its CI is intuitively attractive to clinicians but is problematic both in its accurate calculation in meta-analyses and interpretation (Hutton 2009). For binary data presented in the 'Summary of findings' tables, where possible, we calculated illustrative comparative risks.

2. Continuous data

For continuous outcomes, we estimated the 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 calculated effect size and transformed the effect back to the units of one or more of the specific instruments.

Unit of analysis issues

1. Cluster trials

Studies increasingly employ 'cluster randomisation' (such as randomisation by clinician or practice), but analysis and pooling of clustered data poses problems. Authors often fail to account for intra-class correlation in clustered studies, leading to a 'unit of analysis' error (Divine 1992) whereby P values are spuriously low, CIs unduly narrow and statistical significance overestimated. This causes type I errors (Bland 1997; Gulliford 1999).

No cluster-randomised trials were identified in our search; however, if reviews in the future include such trials, where clustering is not accounted for in primary studies, we will present data in a table, with a (*) symbol to indicate the presence of a probable unit of analysis error. In subsequent versions of this review, we will seek to contact first authors of such studies to obtain intra-class correlation coefficients (ICCs) for their clustered data and to adjust for this by using accepted methods (Gulliford 1999). Where clustering is been incorporated into the analysis of primary studies, we will present these data as if from a non cluster-randomised study, but adjust for the clustering effect.

We have sought statistical advice and have been advised that the binary data as presented in a report should be divided by a 'design effect'. This is calculated using the mean number of participants per cluster (m) and the ICC [Design effect = 1+(m-1)*ICC] (Donner 2002). If the ICC was not reported it was assumed to be 0.1 (Ukoumunne 1999).

If, in future updates of this review cluster trials are identified, cluster studies will be appropriately analysed taking into account ICCs and relevant data documented in the report, synthesis with other studies would be 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 first 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 severe mental illness, if we encountered such trials, we planned only to use data of the first phase of cross-over studies.

3. Studies with multiple treatment groups

Where a study involves more than two treatment arms, if relevant, we presented the additional treatment arms in comparisons. If data were binary, we simply added these and combined them within the two-by-two table. If data were continuous, we combined data following the formula in section 7.7.3.8 (Combining groups) of the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011). Where the additional treatment arms were not relevant, we did not reproduce these data.

Dealing with missing data

1. Overall loss of credibility

At some degree of loss of follow-up, data must lose credibility (Xia 2009). Although high rates of premature discontinuation are a major problem in this field, we felt that it was unclear which degree of attrition leads to a high degree of bias. We, therefore, did not exclude outcomes on the basis of the percentage of participants completing them. However, we addressed the attrition problem in all parts of the review, including the abstract. For this purpose, we calculated, presented and commented on frequency statistics (overall rates of leaving the studies early in all studies and comparators pooled and their ranges). We assumed that the people who discontinued the studies for any reason did not show any response to the treatment.

2. Binary

We presented data on a 'once-randomised-always-analyse' basis (an intention-to-treat (ITT) analysis). We undertook a sensitivity analysis to test how prone the primary outcomes are to change when data only from people who complete the study to that point are compared with the ITTanalysis using the above assumptions.

3. Continuous
3.1 Attrition

In the case of continuous outcomes, we preferred to use ITT results, but if not available we used completer data.

3.2 Standard deviations

If SDs were not reported, we first tried to obtain the missing values from the authors. If not available, where there are missing measures of variance for continuous data, but an exact standard error (SE) and CIs available for group means, and either a P value or T value available for differences in mean, we can calculate them according to the rules described in the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011): When only the SE is reported, SDs are calculated by the formula SD = SE* square root (n). Chapters 7.7.3 and 16.1.3 of the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011) present detailed formulae for estimating SDs from P values, T or F values, CIs, ranges or other statistics. If these formulae do not apply, we would have calculated the SDs according to a validated imputation method, which is based on the SDs of the other included studies (Furukawa 2006). Although some of these imputation strategies can introduce error, the alternative would be to exclude a given study’s outcome and thus to lose information. We nevertheless would have examined the validity of the imputations in a sensitivity analysis excluding imputed values, had we imputed any values.

3.3 Last observation carried forward

We anticipated that in many studies the method of last observation carried forward (LOCF) would be employed within the study report. As with all methods of imputation to deal with missing data, LOCF introduces uncertainty about the reliability of the results (Leucht 2007). We nevertheless used LOCF data being aware that many results are the product of LOCF assumptions.

Assessment of heterogeneity

1. Clinical heterogeneity

We considered all included studies initially, without seeing comparison data, to judge clinical heterogeneity. We simply inspected all studies for clearly outlying people or situations which we had not predicted would arise. When such situations or participant groups arose, we discussed these fully.

2. Methodological heterogeneity

We considered all included studies initially, without seeing comparison data, to judge methodological heterogeneity. We simply inspected all studies for clearly outlying methods which we had not predicted would arise. When such methodological outliers arose, we discussed these fully.

3. Statistical heterogeneity
3.1 Visual inspection

We visually inspected graphs to investigate the possibility of statistical heterogeneity.

3.2 Employing the I2 statistic

We investigated heterogeneity between studies by considering the I2 method alongside the ChI2 P value. The I2 provides an estimate of the percentage of inconsistency thought to be due to chance (Higgins 2003). The importance of the observed value of I2 depends on i. magnitude and direction of effects and ii. strength of evidence for heterogeneity (e.g. P value from ChI2 test, or a confidence interval for I2). An I2 estimate greater than or equal to around 50% accompanied by a statistically significant ChI2 statistic was interpreted as evidence of substantial levels of heterogeneity (Higgins 2011). When substantial levels of heterogeneity were found in the primary outcome, we explored reasons for heterogeneity (Subgroup analysis and investigation of heterogeneity).

Assessment of reporting biases

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results (Egger 1997). These are described in Section 10 of the Handbook (Higgins 2011). We are aware that funnel plots may be useful in investigating reporting biases but are of limited power to detect small-study effects. We did not use funnel plots for outcomes where there were 10 or fewer studies, or where all studies were of similar sizes. In other cases, where funnel plots were possible, we sought statistical advice in their interpretation.

Data synthesis

We understand that there is no closed argument for preference for use of fixed-effect or random-effects models. The random-effects method incorporates an assumption that the different studies are estimating different, yet related, intervention effects. This often seems to be true to us and the random-effects model takes into account differences between studies even if there is no statistically significant heterogeneity. There is, however, a disadvantage to the random-effects model: it puts added weight onto small studies, which often are the most biased ones. Depending on the direction of effect, these studies can either inflate or deflate the effect size. Where possible, for both dichotomous and continuous data we used the random-effects model for data synthesis.

Subgroup analysis and investigation of heterogeneity

1. Subgroup analyses - only primary outcomes

We did not anticipate any subgroup analyses.

2. Investigation of heterogeneity

If inconsistency was high, we reported this. First, we investigated whether data had been entered correctly. Second, if data were correct, we visually inspected the graph and successively removed outlying studies to see if homogeneity was restored. For this review we decided that should this occur with data contributing to the summary finding of no more than around 10% of the total weighting, we would present data. If not, then we did not pool data and discussed relevant issues. We know of no supporting research for this 10% cut-off, but we used prediction intervals as an alternative to this unsatisfactory state.

When unanticipated clinical or methodological heterogeneity was obvious, we simply stated hypotheses regarding these for future reviews or versions of this review. We did not anticipate undertaking analyses relating to these.

Sensitivity analysis

1. Implication of randomisation

We aimed to include trials in a sensitivity analysis if they were described in some way so as to imply randomisation. For the primary outcomes, we included these studies and, if there was no substantive difference when the implied randomised studies were added to those with better description of randomisation, then we entered all data from these studies.

2. Assumptions for lost binary data

Where assumptions had to be made regarding people lost to follow-up (see Dealing with missing data), we compared the findings of the primary outcomes when we used our assumptions and when we used data only from people who completed the study to that point. If there was a substantial difference, we reported results and discussed them, but continued to employ our assumption.

Where assumptions had to be made regarding missing SDs data (see Dealing with missing data), we compared the findings of the primary outcomes when we used our assumptions and when we used data only from people who completed the study to that point. A sensitivity analysis was undertaken to test how prone results were to change when completer-only data only were compared to the imputed data using the above assumption. If there was a substantial difference, we reported results and discussed them, but continued to employ our assumption.

3. Risk of bias

We analysed the effects of excluding trials that were judged to be at high risk of bias across one or more of the domains of randomisation (implied as randomised with no further details available): allocation concealment, blinding and outcome reporting for the meta-analysis of the primary outcome. If the exclusion of trials at high risk of bias did not substantially alter the direction of effect or the precision of the effect estimates, then we included data from these trials in the analysis.

4. Imputed values

We planned to undertake a sensitivity analysis to assess the effects of including data from trials where we used imputed values for ICC in calculating the design effect in cluster randomised trials. However, no cluster-randomised trials were identified for this update.

In future updates, if cluster randomised trials are included we will undertake sensitivity analyses. If we note substantial differences in the direction or precision of effect estimates in any of the sensitivity analyses listed above, we will not pool data from the excluded trials with the other trials contributing to the outcome, but present them separately.

5. Skewed data

We planned sensitivity analyses a priori for examining the change in the robustness of the sensitivity to including studies with potentially skewed data.

6. Comparator dose

A recent report showed that some of the comparisons of atypical antipsychotics may have been biased by using inappropriate comparator doses (Heres 2006). We, therefore, also analysed whether the exclusion of studies with inappropriate comparator doses changed the results of the primary outcome and the general mental state.

Comparator doses were considered inappropriate where they exceeded BNF and Martindale recommended maximum doses (BNF 2013; Martindale 2013).

  • Aripiprazole: usual maintenance dose of 15 mg daily; range 10 to 15 mg once daily; maximum dose 30 mg daily.

  • Clozapine: usual dose 200 to 450 mg daily; maximum dose 900 mg daily.

  • Quetiapine: usual range 300 to 450 mg daily in two divided doses; maximum dose 750 mg daily.

  • Risperidone: usual dose 4 mg daily; maximum dose 50 mg every two weeks.

  • Ziprasidone: (oral) 20 mg twice daily, increased if necessary up to maximum 80 mg twice daily; usual maintenance dose 20 mg twice daily; (intramuscular (IM) for acute agitation) 10 to 20 mg as required; maximum dose 40 mg daily for three consecutive days (to switch to oral therapy as soon as possible).

  • Olanzapine: usual range 5 to 20 mg daily; maximum dose 20 mg daily.

Results

Description of studies

For a substantive description of studies please see Characteristics of included studies and Characteristics of excluded studies tables.

Results of the search

1. Original search (2005/2007)

The first search yielded 3620 reports of which 28 were closely inspected. After excluding 22 studies, six publications on four trials and two comparisons could be included: aripiprazole versus olanzapine (two) and aripiprazole versus risperidone (two) (Komossa 2009) (Figure 1).

2. Updated search (November 2011)

The search we undertook for the first update of the review (Khanna 2013) identified 618 further results and, after close inspection, we included eight more studies; making a total of 12 studies altogether. We excluded 38 trials, added 216 trials to 'Studies awaiting classification' (due to the need for translation or data extraction) and 16 trials to 'Ongoing studies' category (Khanna 2013) (Figure 2).

3. Updated search (November 2012)

The 2012 updated search for this current version of the review yielded 215 new citations; 209 full-text articles were assessed for eligibility, and ultimately 162 studies (from 167 references) were included. The total amount of included studies in this current review is 174 (Figure 3).

Included studies

The 174 included studies randomised 17,244 participants with the diagnosis of schizophrenia or schizoaffective disorder. All studies were described as randomised. We included both double blind and open label studies. Many were sponsored by pharmaceutical companies with some pecuniary interest in the result.

1. Length of studies

One trial was only five days long. The vast majority were short term with a duration of three to eight weeks. Seven medium-term studies ranged from 20 to 26 weeks, and long-term studies from 28 weeks to two years.

2. Setting

Studies reported inpatient and outpatient settings; the vast majority of studies were undertaken in China, where, it seems, aripiprazole is being heavily marketed.

3. Participants

Participants were diagnosed with varying diagnostic criteria; Diagnostic Statistical Manual version 4 (DSM-IV); clinical diagnosis (or no mention). The vast majority of participants in included studies were diagnosed using the Chinese Classification of Mental Disorders (CCMD-3). Participants were usually relatively chronically ill with mean ages in the late thirties.

4. Study size

The sample size varied from n = 40 (Zhang 2008b) to n = 1599 (Tandon 2006) people.

5. Interventions
5.1 Aripiprazole

Doses ranged between 2.5 to 30 mg/day.

5.2 Control drugs

Other atypical drugs, namely olanzapine, risperidone, ziprasidone and quetiapine were used as controls. As some studies did not elucidate doses it can only be presumed that therapeutic doses were employed.

6. Outcomes
6.1 Leaving the study early

Thirty-five studies reported on participants leaving the study early due to any reason.

6.2 Rating scales

Details of scales that provided usable data are shown below. Reasons for exclusion of data from other instruments are given under 'Outcomes' in the Characteristics of included studies.

6.2.1 Global state scales

6.2.1.1 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 used with low scores showing decreased severity and/or overall improvement.

6.2.1.2 Investigator's Assessment Questionnaire - IAQ (Tandon 2005)
The IAQ is a quantifiable clinical tool that can provide detailed information regarding common safety, efficacy and tolerability concerns that patients experience while taking antipsychotics. It has been shown to highly correlate with time to study discontinuation which is a common measure of effectiveness.

6.2.1.3 Arizona Sexual Experience Scale - ASEX (McGahuey 2000)
This is a brief scale for self-rating of sexual function. It has five items and is rated in five steps. Possible scores range from five to 30 with higher scores indicating more sexual dysfunction.

6.2.2 Mental state scales

6.2.2.1 Positive and Negative Syndrome Scale - PANSS (Kay 1986)
This schizophrenia scale has 30 items, each of which can be defined on a seven-point scoring system varying from one - absent to seven - extreme. It 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.

6.2.2.2 Positive and Negative Syndrome Scale-Excited Component - PANSS-EC (Chaichan 2008)
The PANSS-EC scale is derived as a sub scale of PANSS and is a simple scale used to measure the degree of agitation. The scale consists of five items (poor impulse control, tension, hostility, uncooperativeness, excitement), each being ranked from one to seven giving a potential maximum score of 35 points.

6.2.2.3 Brief Psychiatric Rating Scale – BPRS (Overall 1962)
This consists of 18 to 24 items (depending on the version) each rated on a scale from one (absent) to seven (extreme).

6.2.3 Adverse effects scales

6.2.3.1 Abnormal Involuntary Movement Scale - AIMS (Guy 1976)
This scale has been used to assess tardive dyskinesia, a long-term, drug-induced movement disorder and short-term movement disorders such as tremor.

6.2.3.2 Simpson Angus Scale - SAS (Simpson 1970)
This 10-item scale (with a scoring system of zero to four on each item) measures drug-induced parkinsonism, a short-term drug-induced movement disorder. A low score indicates low levels of parkinsonism.

6.2.3.3 Barnes Akathisia Scale - BAS (Barnes 1989)
The scale comprises items rating the observable, restless movements that characterise akathisia, a subjective awareness of restlessness, and any distress associated with the condition. These items are rated from zero (normal) to three (severe). In addition, there is an item for rating global severity (from zero (absent) to five (severe)). A low score indicates low levels of akathisia.

6.2.4 Quality of Life

6.2.4.1 Euro-QoL-5D - EQ-5D (Jelsma 2001)
The EuroQoL-5D is a generic preference based measure of health-related quality of life. It has five domains which are mobility, self-care, usual activities, pain/ discomfort and anxiety/ depression, each having three short questions. The EQ-5D Utility score assesses all five items on a scale of zero to one, where zero represents worst possible health and one represents perfect health. The EQ-5D Health Dimension Scale assesses each item on three possible scores where one is the best and three the worst score.

6.2.4.2 Quality of Life Scale – QLS (Heinrichs 1984)
Quality of Life Scale (QLS), a 21-item scale divided into four domains including Interpersonal relations, Instrumental role, Intrapsychic foundations and common objects/activities scored on a seven-point scale with lowest score indicating severe dysfunction.

6.2.4.3 Impact of Weight on Quality of Life - IwQOL-Lite (Kolotkin 2002)
This is a survey instrument that is used to quantitatively assess an individual's perception of how their weight affects their day-to-day life. This instrument is especially valuable to obesity researchers, clinicians, psychologists, medical device and/or pharmaceutical companies seeking to validate the effectiveness of their treatments for obesity using metrics that go beyond the physical measurements of weight loss.

6.2.4.4 World Health Organisation Quality of Life Scale (WHOQoL-Bref, O'Carroll 2000)
The WHOQoL-Bref is a 26-item self-report comprising satisfaction with health, psychological functioning, social relationships and environmental opportunities. Each item is scored on a five-point scale from one (poor) to five (worse). The Chinese version of the WHOQoL scale, the generic quality of life inventory (GQOLI-74), was also used in included Chinese studies.

6.2.1 Global state scales

6.2.1.1 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 used with low scores showing decreased severity and/or overall improvement.

6.2.1.2 Investigator's Assessment Questionnaire - IAQ (Tandon 2005)
The IAQ is a quantifiable clinical tool that can provide detailed information regarding common safety, efficacy and tolerability concerns that patients experience while taking antipsychotics. It has been shown to highly correlate with time to study discontinuation which is a common measure of effectiveness.

6.2.1.3 Arizona Sexual Experience Scale - ASEX (McGahuey 2000)
This is a brief scale for self-rating of sexual function. It has five items and is rated in five steps. Possible scores range from five to 30 with higher scores indicating more sexual dysfunction.

6.2.2 Mental state scales

6.2.2.1 Positive and Negative Syndrome Scale - PANSS (Kay 1986)
This schizophrenia scale has 30 items, each of which can be defined on a seven-point scoring system varying from one - absent to seven - extreme. It can be divided into three sub scale for measuring the severity of general psychopathology, positive symptoms (PANSS-P), and negative symptoms (PANSS-N). A low score indicates lesser severity.

6.2.2.2 Positive and Negative Syndrome Scale-Excited Component - PANSS-EC (Chaichan 2008)
The PANSS-EC scale is derived as a sub scale of PANSS and is a simple scale used to measure the degree of agitation. The scale consists of five items (poor impulse control, tension, hostility, uncooperativeness, excitement) each being ranked from one to seven giving a potential maximum score of 35 points.

6.2.2.3 Brief Psychiatric Rating Scale – BPRS (Overall 1962)
This consists of 18 to 24 items (depending on the version) each rated on a scale from one (absent) to seven (extreme).

6.2.3 Adverse effects scales

6.2.3.1 Abnormal Involuntary Movement Scale - AIMS (Guy 1976)
This scale has been used to assess tardive dyskinesia, a long-term, drug-induced movement disorder and short-term movement disorders such as tremor.

6.2.3.2 Simpson Angus Scale - SAS (Simpson 1970)
This 10-item scale (with a scoring system of zero to four on each item) measures drug-induced parkinsonism, a short-term drug-induced movement disorder. A low score indicates low levels of parkinsonism.

6.2.3.3 Barnes Akathisia Scale - BAS (Barnes 1989)
The scale comprises items rating the observable, restless movements that characterise akathisia, a subjective awareness of restlessness, and any distress associated with the condition. These items are rated from zero (normal) to three (severe). In addition, there is an item for rating global severity (from zero (absent) to five (severe)). A low score indicates low levels of akathisia.

6.2.4 Quality of Life

6.2.4.1 Euro-QoL-5D - EQ-5D (Jelsma 2001)
The EuroQoL-5D is a generic preference based measure of health-related quality of life. It has five domains which are mobility, self-care, usual activities, pain/ discomfort and anxiety/ depression, each having three short questions. The EQ-5D Utility score assesses all five items on a scale of zero to one, where zero represents worst possible health and one represents perfect health. The EQ-5D Health Dimension Scale assesses each item on three possible scores where one is the best and three the worst score.

6.2.4.2 Quality of Life Scale – QLS (Heinrichs 1984)
Quality of Life Scale (QLS), a 21-item scale divided into four domains including Interpersonal relations, Instrumental role, Intrapsychic foundations and common objects/activities scored on a seven-point scale with lowest score indicating severe dysfunction.

6.2.4.3 Impact of Wieght on Quality of Life - IwQOL-Lite (Kolotkin 2002)
This is a survey instrument that is used to quantitatively assess an individual's perception of how their weight affects their day-to-day life. This instrument is especially valuable to obesity researchers, clinicians, psychologists, medical device and/or pharmaceutical companies seeking to validate the effectiveness of their treatments for obesity using metrics that go beyond the physical measurements of weight loss.

6.2.4.4 World Health Organization Quality of Life Scale (WHOQoL-Bref, O'Carroll 2000)

The WHOQoL-Bref is a 26-item self-report comprising satisfaction with health, psychological functioning, social relationships and environmental opportunities. Each item is scored on a five-point scale from one (poor) to five (worse). The Chinese version of the WHOQoL scale, the generic quality of life inventory (GQOLI-74), was also used in included Chinese studies.

6.3 Adverse effects

Adverse effects were mainly recorded in open interviews. In addition, continuous data were provided for weight, QTc time and cholesterol levels.

6.4 Missing outcomes

No information was provided on the number of people hospitalised or global functioning. This can be an important and useful measure of the efficacy of medications being used. Also, not one study reported on functional outcomes, such as living skills, ability to live independently or employment. These trials clearly are more explanatory than pragmatic, focusing on whether in ideal circumstances aripiprazole has an effect rather than whether it would be useful in everyday routine care (Thorpe 2009).

Excluded studies

There are a total of 79 excluded studies in this 2012 update. The most common reason for exclusion was because of lack of randomisation (see Characteristics of excluded studies).

Awaiting classification

Four studies are awaiting assessment (Wang 2006f; Zhao 2006a; Zheng XR 2008; 陶建青, 2007). Three of these were because of inconsistent reporting of denominators. Since we were unable to get clarification from the authors, we decided to leave these trials in Studies awaiting classification until further information becomes available. Please refer to Characteristics of studies awaiting classification for further details.

Ongoing studies

There are 16 studies in this category (see Characteristics of ongoing studies). There appeared to be much ongoing research activity in 2005 but completed studies have not yet been identified. We have contacted authors for current information but have received no updates.

Risk of bias in included studies

For details please refer to the 'Risk of bias' table for each study and Figure 4 and Figure 5 for the graphic overview.

Figure 4.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 5.

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

Allocation

The vast majority of included studies were rated as an 'unclear' risk of bias. Eighteen trials were rated as a 'low' risk of bias and described randomisation methods in some detail (Figure 5). Three of these used computer-generated voice recognition systems. It remained unclear whether there was a risk of bias. Only one study described the method of allocation concealment - by means of a sealed envelope (Wei 2006).

Blinding

Only 11 included studies were described as double blind (Chen 2007a; Du 2006; Feng 2006; Fleischhacker 2008; Guo 2006; Kane 2009; Kinon 2004; McQuade 2004; Potkin 2003; Xu 2010; Zimbroff 2007). Chan 2007 and Potkin 2003 described using identical capsules for blinding. Zimbroff 2007 used double dummy administration of medication. The other studies did not provide any information on the blinding procedure. No study examined whether blinding was effective. Six studies were open label (Chen 2009; Kern 2006; Kerwin 2007; Tandon 2006; Wlodzmierz 2006; Wolf 2007), and two described single-blinding (Zhang 2009a; Zhu 2005). We found that the adverse effect profiles of examined compounds are quite different which may have made blinding difficult. We therefore conclude that the risk of bias for objective outcomes (e.g. death or laboratory values) was low but there was considerable risk of bias for subjective outcomes.

Incomplete outcome data

In two studies the rates of participants leaving the study early were higher than 30% (McQuade 2004; Potkin 2003); in McQuade 2004 it was as high as 72%. Overall attrition was about 35% to 40%. Last observation carried forward (LOCF) method to account for participants leaving the study early was used in studies that made clear attrition numbers, which we now know to be a far from ideal assumption (Leucht 2007). Only McQuade 2004, however, analysed the study completers in a secondary analysis assuming that a participant who left the study prematurely would not have had a change of condition if he/she had stayed in the study. This assumption can also be misleading. The majority of new data from Chinese studies states no incomplete data - therefore, this domain is largely rated across studies as a 'low' risk of bias. Twenty-eight studies did not mention or make explicit any participants lost through attrition, and so were rated as an 'unclear' risk of bias.

Selective reporting

In terms of selective reporting there was a high risk of bias in the majority of included studies. Overall, only 13 studies rated as a 'low' risk of bias, and only one rated as 'unclear', meaning that the remainder of the 174 included studies (160) were rated at a 'high' risk of bias with not all recorded outcomes reported. Six studies reported only adverse events that occurred in at least 5% to 10% of participants (Chan 2007; Fleischhacker 2008; Kane 2009; Potkin 2003; Zimbroff 2007). By this procedure rare, but important adverse events, can be missed. Kinon 2004 reported adverse effects that occurred in at least 1% of patients. McQuade 2004 did not report on the PANSS positive sub score despite having recorded it. See funnel plots for the primary outcome of no clinically significant response (Figure 6; Figure 7; Figure 8; Figure 9), where distrubution of studies is relatively symmetrical, except for comparison 5.1 (Figure 9), perhaps owing to less included studies.

Figure 6.

Funnel plot of comparison: 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, outcome: 1.1 Global state: 1. No clinically significant response (as defined by the original studies).

Figure 7.

Funnel plot of comparison: 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, outcome: 2.1 Global state: 1.No clinically significant response (as defined by original studies).

Figure 8.

Funnel plot of comparison: 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, outcome: 3.1 Global state: 1. No clinically significant response (as defined by the original studies).

Figure 9.

Funnel plot of comparison: 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, outcome: 5.1 Global state: 1.No clinically significant response (as defined by the original studies).

Other potential sources of bias

Many included studies were sponsored by the manufacturer of aripiprazole or the comparator drug. There is evidence that pharmaceutical companies may be selective in reporting the benefits and disadvantages of their own compounds (Heres 2006).

Effects of interventions

See: Summary of findings for the main comparison COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE for schizophrenia; Summary of findings 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE for schizophrenia; Summary of findings 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE for schizophrenia; Summary of findings 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE for schizophrenia; Summary of findings 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE for schizophrenia

We used risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data, with their respective 95% confidence intervals (CIs) throughout.

COMPARISON 1: ARIPIPRAZOLE versus CLOZAPINE

1.1 Global state: 1. No clinically significant response (as defined by the original studies)

Data demonstrate there was no difference between groups (29 RCTs, n = 2132, RR 1.05 CI 0.87 to 1.27, Analysis 1.1).

1.2 Mental state: 1. Specific - binary outcomes
1.2.1 Anxiety and agitation

In the short term, there was significant favour (P = 0.01) for clozapine with higher levels of anxiety seen in participants receiving aripiprazole (11 RCTs, n = 732, RR 2.62 CI 1.21 to 5.70), however, with a slight degree of heterogeneity (ChI2 = 13.34; df = 10; P = 0.21; I2 = 25%). Data demonstrate no difference between groups at medium term (1 RCT, n = 90). Data for levels of agitation at short term demonstrated no difference between groups (1 RCT, n = 60, Analysis 1.2).

1.3 Mental state: 2. Average endpoint scores of various scales (short term, up to 12 weeks, high = poor)

Data for all scales demonstrated no significant difference, including the BPRS (5 RCTs, n = 426); PANSS (23 RCTs, n = 1638), however with considerable heterogeneity present (ChI2 = 61.84; df = 22; P = 0.0; I2 = 64%); and SANS (1 RCT, n = 50, Analysis 1.3).

1.4 Mental state: 3. Average endpoint scores of various scales (medium term, 12 to 26 weeks, high = poor)

When using PANSS, data from 3 RCTs significantly favoured (P = 0.0004) aripiprazole (n = 236, MD -5.41 CI -8.42 to -2.41, Analysis 1.4).

1.5 Mental state: 4. Average endpoint scores of various scales (skewed)

All data for this outcome are skewed and are best inspected by viewing Analysis 1.5.

1.6 Mental state: 5. Specific - average endpoint positive score (PANSS, high = poor)

Overall, there was no difference between groups at both short and medium term (22 RCTs, n = 1523, Analysis 1.6), however there was considerable heterogeneity present (ChI2 = 74.67; df = 21; P = 0.00001; I2 = 72%).

By short term, data indicate no significant difference between groups (19 RCTs, n = 1287), however. considerable heterogeneity was present (ChI2 = 66.47; df = 18; P = 0.00001; I2 = 73%). Again, by the medium term, data indicate no significant difference between groups (3 RCTs, n = 236), however there was considerable heterogeneity present (ChI2 = 5.87; df = 2; P = 0.05; I2 = 66%).

1.7 Mental state: 6. Specific - average endpoint negative score (PANSS, high = poor)

Overall, there was no significant difference between aripiprazole between short term and medium term (23 RCTs, n = 1640), however considerable heterogeneity was present (ChI2 = 114.66; df = 22; P = 0.0001; I2 = 81%).

Short-term data indicate no significant difference between groups (20 RCTs, n = 1404), however there was considerable heterogeneity present (ChI2 = 51.61; df = 19; P = 0.0001; I2 = 63%). Medium-term data significantly favoured aripiprazole (3 RCTs, n = 236, MD -3.24 CI -5.82 to -0.67, Analysis 1.7), however with considerable heterogeneity (ChI2 = 15.99; df = 2; P = 0.0003; I2 = 87%)

1.8 Mental state: 7. Specific - average endpoint general psychopathological score (PANSS, high = poor )

Overall, data indicate no significant difference between groups (19 RCTs, n = 1330, Analysis 1.8). Data indicate a significant difference (P = 0.02) favouring aripiprazole at medium term (3 RCTs, n = 236 MD -1.89 CI -3.45 to -0.34).

1.9 Mental state: 8. Specific - average total score decreased rate (PANSS, low = poor)
1.9.1 By up to 12 weeks

Data in one small study indicate no significant difference between groups (1 RCT, n = 118, Analysis 1.9).

1.10 Mental state: 9. Specific - average positive score decreased rate (PANSS, low = poor)

Short-term data in one small study indicate no significant difference between groups (1 RCT, n = 118, Analysis 1.10).

1.11 Leaving the study early

Data demonstrate no significant difference between groups when leaving the study for any reasons (3 RCTs, n = 240, Analysis 1.11). This was also the case for adverse events (3 RCTs, n = 212) and due to 'economic issues' (1 RCT, n = 120).

1.12 Quality of life: 1a. Average scores (short term, up to 12 weeks, WHO-QOL-100, low = poor)

Data demonstrate statistical significance (P = 0.0001) in favour of aripiprazole in two small RCTs (n = 132, MD 2.59 CI 1.43 to 3.74, Analysis 1.12). On the physical health component, data demonstrate statistical significance (P = 0.01) in favour of aripiprazole in two small RCTs (n = 132, MD 7.73 CI 1.51 to 13.94), however with considerable heterogeneity present (ChI2 = 6.04; df = 1; P = 0.014; I2 = 83%). Again, mental health component data demonstrate statistical significance (P = 0.0001) in favour of aripiprazole in two small RCTs (n = 132, MD 9.21 CI 4.74 to 13.68), however there was considerable heterogeneity present (ChI2 = 2.31; df = 1; P = 0.13; I2 = 57%). Data from one small RCT demonstrate statistical significance (P = 0.00001) in favour of aripiprazole for the spiritual support component (1 RCT, n = 72, MD 6.61 CI 4.25 to 8.97), and for external environment (P = 0.0001) (3 RCTs, n = 248, MD 13.82 CI 8.69 to 18.94) again with considerable heterogeneity present (ChI2 = 7.63; df = 2; P = 0.02; I2 = 74%).
Data demonstrate no statistical significance for social function (2 RCTs, n = 132) again with considerable heterogeneity present (ChI2 = 23.23; df = 1; P = 0.00001; I2 = 96%) or independence (1 RCT, n = 72).

1.13 Quality of life: 1b. Average scores (medium term, 12 to 24 weeks, WHO-QOL-100, low = poor)

The endpoint score demonstrated statistical significance (P = 0.00001) in favour of aripiprazole (2 RCTs, n = 176, MD 2.75 CI 1.98 to 3.53, Analysis 1.13). Data demonstrate statistical significance in the physical health component (P = 0.04) in favour of aripiprazole (3 RCTs, n = 256, MD 4.89 CI 0.22 to 9.56), however with considerable heterogeneity present (ChI2 = 33.90; df = 2; P = 0.00001; I2 = 94%). Mental health data demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (3 RCTs, n = 256, MD 7.39 CI 5.26 to 9.53), again with considerable heterogeneity present (ChI2 = 2.6; df = 2; P = 0.27; I2 = 23%). This was also the case for social function with significant favour (P = 0.0008) of aripiprazole (3 RCTs, n = 256, MD 6.68 CI 2.79 to 10.56), again with considerable heterogeneity present (ChI2 = 13.19; df = 2; P = 0.001; I2 = 85%). Data in two small studies demonstrate statistical significance (P = 0.00001) in favour of aripiprazole for the independence component (2 RCTs, n = 176, MD 6.71 CI 4.76 to 8.66). Data demonstrate no significant difference between groups for material life (1 RCT, n = 80) and spiritual support (2 RCTs, n = 176).

1.14 Quality of life: 2. Average endpoint general quality of life score (GQOLI - 74, low = poor)

Physical health data from one small RCT demonstrate statistical significance (P = 0.01) in favour of aripiprazole ( n = 120, MD 7.70 CI 2.95 to 12.45, Analysis 1.14). Data for social function from one small RCT demonstrate statistical significance (P = 0.0002) in favour of aripiprazole (n = 120, MD 6.60 CI 3.15 to 10.05). Data from one small RCT demonstrate statistical significance (P = 0.0002) in favour of aripiprazole for environmental area (n = 90, MD 11.50 CI 5.55 to 17.45) and independence (P = 0.0003) in favour of aripiprazole (n = 90, MD 6.16 CI 2.84 to 9.48). No significant difference was found for: total GQOLI score (1 RCT, n = 114); mental health data (1 RCT, n = 120); and material life (1 RCT, n = 120)

1.15 Adverse effects:1. At least one adverse effect, non-specific

Data demonstrate statistical significance (P = 0.02) in favour of aripiprazole, with more people receiving clozapine experiencing at least one adverse effect (7 RCTs, n = 574, RR 0.67 CI 0.48 to 0.95, Analysis 1.15), however with considerable heterogeneity present (ChI2 = 18.17; df = 7; P = 0.01; I2 = 61%). There was no significant difference between groups in the short term for: epilepsy (1 RCT, n = 60); abnormal liver function (5 RCTs, n = 364); stuffy nose (3 RCTs, n = 258); sweating (1 RCT, n = 74); urinary retention (2 RCTs, n = 132); and urinary incontinence (2 RCTs, n = 120).

1.16 Adverse effects: 2. Cardiac effects

Overall, less cardiac effects were seen in people receiving aripiprazole compared with clozapine.

Significant results were found in the short term for abnormal ECG (P = 0.00001), with less occurrences found in people receiving aripiprazole (12 RCTs, n = 921, RR 0.38 CI 0.29 to 0.51, Analysis 1.16). Data were also significantly in favour of aripiprazole (P = 0.0003) for short-term general adverse cardiac events (1 RCT, n = 62, RR 0.32 CI 0.17 to 0.60). QTc prolongation was significantly in favour (P = 0.001) of aripiprazole in both the short (4 RCTs, n = 334, RR 0.16 CI 0.05 to 0.49) and medium (P = 0.03) term (1 RCT, n = 90, RR 0.05 CI 0.00 to 0.79), as well as tachycardia (P = 0.00001) in the short term (15 RCTs, n = 1104, RR 0.29 CI 0.22 to 0.38). There was no significant difference between groups for a short-term decrease in blood pressure (3 RCTs, n = 194); and medium-term tachycardia (1 RCT, n = 60).

1.17 Adverse effects: 3. Central/peripheral nervous system

Data showing a decrease in activity from one small RCT demonstrate statistical significance (P = 0.0002) in favour of aripiprazole at short term (n = 120, RR 0.21 CI 0.10 to 0.48, Analysis 1.17). This was also the case for blurred vision (P = 0.003) (6 RCTs, n = 472, RR 0.29 CI 0.12 to 0.66) with slight heterogeneity present (ChI2 = 9.11; df = 5; P = 0.105; I2 = 45%). Dizziness was also seen significantly more at short term (P = 0.05) in people receiving clozapine (9 RCTs, n = 698, RR 0.60 CI 0.36 to 1.00). Data from one small RCT for general vegetative nervous system adverse reaction demonstrate statistical significance (P = 0.01) in favour of aripiprazole (n = 62, RR 0.48 CI 0.27 to 0.84) by short term. Other short-term CNS adverse effects that were significantly in favour of aripiprazole include; hyper-salivation (P = 0.00001) (16 RCTs, n = 1074, RR 0.06 CI 0.03 to 0.10); memory decline (P = 0.04) (1 RCT n = 80, RR 0.13 CI 0.02 to 0.95); sedation (P = 0.02) (n = 80, RR 0.03 CI 0.00 to 0.52); and somnolence (P = 0.00001) (21 RCTs, n = 1492, RR 0.15 CI 0.09 to 0.24), with slight heterogeneity present (ChI2 = 35.6; df = 20; P = 0.02; I2 = 44%).

Data significantly favoured clozapine at medium term for: headache (P = 0.03) (16 RCTs, n = 1102, RR 2.28 CI 1.07 to 4.86), however with considerable heterogeneity present (ChI2 = 45.69; df = 15; P = 0.0001; I2 = 67%); and insomnia (P = 0.00001) (14 RCTs, n = 990, RR 5.62 CI 2.90 to 10.91).

There was no difference between groups in the short term for: increase in activity (1 RCT, n = 48); fatigue (4 RCTs, n = 300); general CNS adverse reaction (1 RCT, n = 62); irritability (2 RCTs, n = 120); as well as insomnia at medium term (1 RCT, n = 90); and headache at medium term (1 RCT, n = 90).

1.18 Adverse effects: 4. Extrapyramidal effects

No significant difference was found between groups at short term for the following outcomes: general EPS (8 RCTs, n = 520); tardive dyskinesia (1 RCT, n = 72). For medium-term outcomes, the following demonstrated no significant difference: akathisia (1 RCT, n = 80); dystonia (1 RCT, n = 80); spasmodic torticollis (1 RCT, n = 80); and tremor (1 RCT, n = 80, Analysis 1.18).

The only homogenous data that demonstrate statistical significance (P = 0.01) was in favour of clozapine for the outcome of dystonia at short term (5 RCTs, n = 374, RR 3.24 CI 1.29 to 8.12). All other data either presented no significant difference between groups, or no difference with varying degrees of heterogeneity. The latter include short-term data for akathisia, with no significant difference between groups (13 RCTs, n = 916, RR 1.21 CI 0.54 to 2.68) with considerable heterogeneity present (ChI2 = 25.43; df = 12; P = 0.01; I2 = 53%). Data for tremor at short term demonstrated no significant difference between groups (6 RCTs, n = 460, RR 1.99 CI 0.72 to 5.48) with slight heterogeneity present (ChI2 = 7.17; df = 5; P = 0.208; I2 = 30%). This was the same for use of antiparkinson medication in the short term (2 RCTs, n = 140, RR 2.84 CI 0.07 to 117.07) with considerable heterogeneity present (ChI2 = 6.94; df = 1; P = 0.008; I2 = 86%).

1.19 Adverse effects: 5. Gastrointestinal

No significant difference was found in the short term for: general gastrointestinal adverse reaction (2 RCTs, n = 130); and indigestion (1 RCT, n = 60). Data for dry mouth at short term also demonstrated no significant difference between groups (4 RCTs, n = 268, RR 0.64 CI 0.08 to 5.38) with substantial heterogeneity present (ChI2 = 13.3; df = 3; P = 0.004; I2 = 77%). This was also true for nausea/vomiting (10 RCTs, n = 790, RR 1.55 CI 0.71 to 3.38) again with heterogeneity present (ChI2 = 17.01; df = 9; P = 0.05; I2 = 47%, Analysis 1.20).

Data were significantly in favour of clozapine for abdominal discomfort or pain at short term (P = 0.03) (2 RCTs. n = 132, RR 10.21 CI 1.32 to 79.12). Short-term data for constipation demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (19 RCTs, n = 1390, RR 0.15 CI 0.08 to 0.31) with substantial heterogeneity present (ChI2 = 74.05; df = 18; P = 0.0; I2 = 76%). Remaing data for medium-term outcomes were in favour of aripiprazole, with significantly less instances of constipation (P = 0.007) (1 RCT, n = 90, RR 0.02 CI 0.00 to 0.36) and hyper-salivation (P = 0.005) (1 RCT, n = 90, RR 0.02 CI 0.00 to 0.29).

1.20 Adverse effects: 6. Haematological

All data for this outcome were homogenous and statistically significant in favour of aripiprazole, including abnormal blood routine in the short term (P = 0.007) (5 RCTs, n = 368, RR 0.16 CI 0.04 to 0.60, Analysis 1.19); and leucopenia in the short term (P = 0.002) (10 RCTs, n = 726, RR 0.21 CI 0.08 to 0.56). Abnormal blood routine in the medium term also demonstrates statistical significance (P = 0.008) in favour of aripiprazole (2 RCTs, n = 152, RR 0.32 CI 0.14 to 0.75).

1.21 Adverse effects: 7. Hormonal (short term, up to 12 weeks)

Data for lactation or menstrual changes demonstrate statistical significance (P = 0.003) in favour of aripiprazole (3 RCTs, n = 214, RR 0.11 CI 0.03 to 0.47, Analysis 1.21).

1.22 Adverse effects: 8a. Metabolic - binary measures
1.22.1 Blood glucose - increased (short term, up to 12 weeks)

Data demonstrate statistical significance (P = 0.0002) in favour of aripiprazole (5 RCTs, n = 410, RR 0.12 CI 0.04 to 0.37, Analysis 1.22).

1.22.2 C-peptide (short term, up to 12 weeks)

Data from one small RCT demonstrate statistical significance (P = 0.01) in favour of aripiprazole (1 RCT, n = 60, RR 0.03 CI 0.00 to 0.45).

1.22.3 Decrease appetite (short term, up to 12 weeks)

Data demonstrate statistical significance (P = 0.01) in favour of aripiprazole (2 RCTs, n = 130, RR 0.07 CI 0.01 to 0.54).

1.22.4 Postural hypotension (short term, up to 12 weeks)

Data demonstrate statistical significance (P = 0.001) in favour of aripiprazole (5 RCTs, n = 344, RR 0.16 CI 0.07 to 0.39).

1.22.5 PRL- increase (short term, up to 12 weeks)

Data from one small RCT demonstrate statistical significance (P = 0.04) in favour of aripiprazole (1 RCT, n = 48, RR 0.05 CI 0.00 to 0.82).

1.22.6 Weight gain (short term, up to 12 weeks)

Data demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (18 RCTs, n = 1318, RR 0.13 CI 0.08 to 0.22).

1.22.7 Blood glucose - increased (medium term, 12 to 24 weeks)

Data demonstrate no significant difference between groups (1 RCT, n = 90).

1.22.8 Decreased appetite (medium term, 12 to 24 weeks)

Data from one small RCT demonstrate statistical significance (P = 0.05) in favour of aripiprazole (n = 90, RR 0.06 CI 0.00 to 0.99).

1.22.9 Weight gain (medium term, 12 to 24 weeks)

Data from one small RCT demonstrate statistical significance (P = 0.009) in favour of aripiprazole (n = 90, RR 0.02 CI 0.00 to 0.39, Analysis 1.22).

1.23 Adverse effects: 8b. Metabolic - continuous measures
1.23.1 Blood glucose - FPG in HbA1c normal group (in mmol/L

Data demonstrate no significant difference between groups (1 RCT, n = 36).

1.23.2 Blood glucose - FPG in HbA1c abnormal group (in mmol/L)

Data demonstrate no significant difference between groups (1 RCT, n = 19).

1.23.3 Blood glucose - PBG in HbA1c normal group (in mmol/L)

Data demonstrate no significant difference between groups (1 RCT, n = 36).

1.23.4 Blood glucose - PBG in HbA1c abnormal group (in mmol/L)

Data from one small RCT demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (1 RCT, n = 19, MD -1.90 CI -2.63 to -1.17).

1.23.5 Blood glucose - FPG average endpoint (in mmol/L)

Data demonstrate statistical significance (P = 0.0009) in favour of aripiprazole (2 RCTs, n = 134, MD -0.52 CI -0.83 to -0.22).

1.23.6 Blood glucose - C-peptide average endpoint (in mg/dlmmol/L)

Data from one small RCT demonstrate statistical significance (P = 0.05) in favour of aripiprazole (1 RCT, n = 60, MD -0.72 CI -1.45 to 0.01).

1.23.7 Weight gain - average endpoint level (in kg)

Data demonstrate no significant difference between groups (1 RCT, n = 74, Analysis 1.23).

1.24 Cost-effectiveness analysis (skewed)

All data for this outcome are skewed and are best inspected by viewing Analysis 1.24.

COMPARISON 2: ARIPIPRAZOLE versus QUETIAPINE

2.1 Global state: 1. No clinically significant response (as defined by original studies)

Data demonstrate no significant difference between groups (12 RCTs, n = 991, Analysis 2.1).

2.2 Global state: 2 a. Average endpoint total score (short term, up to 12 weeks, high = poor)

Data for the CGI demonstrate no significant difference between groups (1 RCT, n = 80, Analysis 2.2). This was also the case for PANSS (10 RCTs, n = 831), however with considerable heterogeneity present (ChI2 = 21.14; df = 9; P = 0.012; I2 = 57%). Data from the BPRS from one small RCT demonstrate statistical significance (P = 0.007) in favour of aripiprazole (1 RCT, n = 80, MD -2.63 CI -4.55 to -0.71).

2.3 Global state: 2b. Average endpoint scale score (medium term, 12 to 24 weeks, high = poor)

Data for PANSS demonstrate no significant difference between groups (1 RCT, n = 100, Analysis 2.3).

2.4 Global state: 3. Average endpoint SI score (CGI, high = poor)
2.4.1 Up to 12 weeks - short term

Data demonstrate no significant difference between groups (1 RCT, n = 108, Analysis 2.4).

2.5 Mental state: 2a. Specific - binary outcomes

There was no significant difference between groups in the short term for: agitation (5 RCTs, n = 423); anxiety (2 RCTs, n = 168); and depression (1 RCT, n = 108, Analysis 2.5). This was also the case for agitation at medium term (1 RCT, n = 100).

2.6 Mental state: 3. Specific - average endpoint positive score (PANSS, high = poor)
2.6.1 By up to 12 weeks - short term

Short-term data demonstrate no significant difference between groups (7 RCTs, n = 583, Analysis 2.6) with substantial heterogeneity present (ChI2 = 20.25; df = 6; P = 0.002; I2 = 70%). Medium term data, again, demonstrate no significant difference between groups (1 RCT, n = 100).

2.7 Mental state: 4. Specific - average endpoint negative score (PANSS, high = poor)
2.7.1 Up to 12 weeks - short term

Short-term data demonstrate no significant difference between groups using PANSS negative score (6 RCTs, n = 443, Analysis 2.7); this is also the case for medium-term data (1 RCT, n = 100).

2.8 Mental state: 5. Specific - average endpoint general pathological score (PANSS, high = poor )
2.8.1 Up to 12 weeks - short term

Short-term data for PANSS pathological score demonstrate no significant difference between groups (10 RCTs, n = 831, Analysis 2.8) with substantial heterogeneity present (ChI2 = 83.29; df = 9; P = 0.00001; I2 = 89%). Medium-term data also demonstrate no significant difference between groups (1 RCT, n = 100).

2.9 Mental state: 6. Average scores of various scales (skewed)

All data for the various scales are skewed and are best inspected by viewing Analysis 2.9

2.10 Leaving the study early

All data for leaving the study early showed no significant difference between groups: any reason (2 RCTs, n = 168); because of no effect (1 RCT, n = 108); early discharge (1 RCT, n = 60); early treatment termination (2 RCTs, n = 168); violation of test scheme (1 RCT, n = 108); and withdrawal of informed consent (1 RCT, n = 108, Analysis 2.10).

2.11 Quality of life: Average score (medium term, 12 to 24 weeks, WHO-QOL-100, low = poor)

The majority of data from a single study are significantly in favour of aripiprazole for a better outcome using this scale, including; total score (P = 0.0001) (1 RCT, n = 100, MD 2.60 CI 1.31 to 3.89); physical health (P = 0.00001) (1 RCT, n = 100, MD 6.00 CI 4.38 to 7.62); mental health (P = 0.00001) (1 RCT, n = 100, MD 9.10 CI 5.92 to 12.28); social function (P = 0.00001) (1 RCT, n = 100, MD 5.60 CI 3.33 to 7.87); environmental area (P = 0.0001) (1 RCT, n = 100, MD 11.50 CI 5.86 to 17.14); and independence (P = 0.0001) (1 RCT, n = 100, MD 6.20 CI 3.05 to 9.35, Analysis 2.11). Data for spiritual pillar demonstrate no significant difference between groups (1 RCT, n = 100).

2.12 Adverse effects: 1. At least one adverse effect

For non-specific adverse effects, data demonstrate no significant difference between groups (3 RCTs, n = 258). All other data also demonstrated no significant difference, including: abnormal urinary test results (1 RCT, n = 108); abnormal liver function (8 RCTs, n = 658); stuffy nose (2 RCTs, n = 188); sweating (1 RCT, n = 70); urine routine abnormal (1 RCT, n = 80, Analysis 2.12).

2.13 Adverse effects: 2. Cardiac effects (short term, up to 12 weeks)

Data for tachycardia demonstrate statistical significance (P = 0.003) in favour of aripiprazole (8 RCTs, n = 643, RR 0.35 CI 0.18 to 0.69). All other data demonstrate no significant difference between groups: abnormal ECG (6 RCTs, n = 528); decrease in blood pressure (4 RCTs, n = 348); and QTc prolongation (3 RCTs, n = 225, Analysis 2.13).

2.14 Adverse effects: 3a. Central nervous system

No significant difference was found between groups in the short term for the following outcomes: blurred vision (6 RCTs, n = 521); dizziness (8 RCTs, n = 671); headache (5 RCTs, n = 436) with substantial heterogeneity present (ChI2 = 13.42; df = 4; P = 0.009; I2 = 70%); and insomnia (7 RCTs, n = 591). There was no difference at medium term for: dizziness (1 RCT, n = 100); insomnia (1 RCT, n = 100); or somnolence (1 RCT, n = 100, Analysis 2.14).

Data at short term for somnolence demonstrate statistical significance (P = 0.01) in favour of aripiprazole (9 RCTs, n = 731, RR 0.34 CI 0.15 to 0.77) with heterogeneity present (ChI2 = 18.37; df = 8; P = 0.019; I2 = 56%). Medium-term data for headache demonstrate statistical significance (P = 0.03) in favour of quetiapine (1 RCT, n = 100, RR 9.00 CI 1.18 to 48.42).

2.15 Adverse effects: 4. Various extrapyramidal symptoms (short term, up to 12 weeks)

All data demonstrated no significant difference between groups for akathisia (7 RCTs, n = 571, Analysis 2.15); dystonia (2 RCTs, n = 145); general EPS (4 RCTs, n = 348); and tremor (4 RCTs, n = 343).

2.16 Adverse effects: 5. Gastrointestinal

Data were significantly in favour of aripiprazole in the shot term from constipation (P = 0.005) (7 RCTs, n = 591, RR 0.38 CI 0.19 to 0.75, Analysis 2.16); dry mouth (P = 0.0007) (7 RCTs, n = 611, RR 0.23 CI 0.10 to 0.53); and in the medium term for dry mouth (P = 0.009) (1 RCT, n = 100, RR 0.11 CI 0.01 to 0.84). Data were significantly in favour of quetiapine in the short term for: nausea/ vomiting (P = 0.004) (7 RCTs, n = 611, RR 2.68 CI 1.36 to 5.26).There was no significant difference at medium term for nausea/vomiting (1 RCT, n = 100).

2.17 Adverse effects: 6. Haematological

Data demonstrate no significant difference in the short term for abnormal blood routine (1 RCT, n = 85, Analysis 2.17) and leucopenia (2 RCTs, n = 140).

2.18 Adverse effects: 7. Hormonal - binary measures
2.18.1 Menstrual disorder (short term, up to 12 weeks)

There was no significant difference between groups for menstrual disorder at both short term (6 RCTs, n = 518) and medium term (1 RCT, n = 100, Analysis 2.18).

2.19 Adverse effects: 8a. Metabolic - binary measures

At short term, there was no significant difference between groups for a decrease in appetite (4 RCTs, n = 328) and lactation (5 RCTs, n = 383). Medium data were also not significant for weight gain (1 RCT, n = 100). Data were significantly in favour of aripiprazole in the short term for weight gain (P = 0.01) (10 RCTs, n = 823, RR 0.45 CI 0.24 to 0.85) and at medium term for decreased appetite (P = 0.05) (1 RCT, n = 100, RR 0.13 CI 0.02 to 0.96, Analysis 2.19).

2.20 Adverse effects: 8b.Metabolic - continuous measure

Data from one small RCT demonstrate statistical significance (P = 0.03) in favour of aripiprazole for cholesterol TC average endpoint level (in mmol/L) (1 RCT, n = 180, MD -0.19 CI -0.36 to -0.02, Analysis 2.20). However, all other data demonstrated no significant difference between groups.

COMPARISON 3: ARIPIPRAZOLE versus RISPERIDONE

3.1 Global state: 1.No clinically significant response (as defined by the original studies)

Data are equivocal at short term, demonstrating no significant difference between groups (80 RCTs, n = 6381, RR 1.08 CI 0.96 to 1.21, Analysis 3.1).

3.2 Global state: 2. Average endpoint total score (short term, up to 12 weeks, CGI, high = poor)

Data demonstrate statistical significance (P = 0.006) in favour of risperidone (2 RCTs, n = 196, MD 0.35 CI 0.09 to 0.61, Analysis 3.2).

3.3 Global state: 3.Average CGI subscale scores (short term, up to 12 weeks, high = poor)

CGI-EI data demonstrate statistical significance (P = 0.006) in favour of risperidone (1 RCT, n = 120, MD 0.50 CI 0.14 to 0.86, Analysis 3.3), and CGI-SI data demonstrate statistical significance (P = 0.006) in favour of risperidone (1 RCT, n = 120, MD 0.40 CI 0.12 to 0.68).

3.4 Global state average endpoint of various scales (skewed)

All data are skewed and are best inspected by viewing Analysis 3.4.

3.5 Mental state: 1. Specific - binary outcomes (short term, up to 12 weeks)

Data for anxiety demonstrate statistical significance (P = 0.01) in favour of risperidone (9 RCTs, n = 744, RR 1.81 CI 1.12 to 2.94, Analysis 3.5); however all other data are equivocal, demonstrating no difference between groups, including for agitation/excitement (26 RCTs, n = 2038) and irritability (1 RCT, n = 100).

3.6 Mental state: 2a. Average endpoint scale score (short term, up to 12 weeks, high = poor)

Data at short term for BPRS demonstrate statistical significance (P = 0.004) in favour of aripiprazole (5 RCTs, n = 570, MD -1.33 CI -2.24 to -0.42, Analysis 3.6), as were data for PANSS short term which showed a risk reduction by 0.8 on the PANSS scale favouring aripiprazole group (77 RCTs, n = 5733, MD -0.80 95% CI -1.58 to -0.02, Analysis 3.6). However, all other data show no significant difference between groups: PANSS medium term (1 RCT, n = 50) and SANS medium term (1 RCT, n = 50).

3.7 Mental state: 3. Specific - average endpoint positive score (PANSS, high = poor)

Data are equivocal at both short and medium term, demonstrating no significant difference between groups (40 RCTs, n = 3205, MD 0.02 CI -0.37 to 0.41, Analysis 3.7).

3.8 Mental state: 4. Specific - average endpoint negative score (PANSS, high = poor)

Data demonstrate statistical significance (P = 0.001) in favour of aripiprazole at short term (37 RCTs, n = 2976, MD -0.64 CI -1.04 to -0.25, Analysis 3.8).

3.9 Mental state: 5. Specific - average endpoint general psychopathological score (PANSS, high = poor)

Data are equivocal at both short and medium term, demonstrating no significant difference between groups (58 RCTs, n = 4243, MD -0.25 CI -0.71 to 0.20, Analysis 3.9).

3.10 Mental state: 6. PANSS average score decreased rate (short term, up to 12 weeks, low = poor)

Data for total scale score decreased rate demonstrate statistical significance (P = 0.03) in favour of aripiprazole (3 RCTs, n = 219, MD 3.06 CI 0.24 to 5.87, Analysis 3.10). All other data demonstrate no significant difference between groups.

3.11 Mental state: 7. BPRS total score decreased rate (short term, up to 12 weeks, high = poor)

Data demonstrate no significant difference between groups (2 RCTs, n = 132, MD -2.97 CI -6.61 to 0.67, Analysis 3.11).

3.12 Mental state: 8. General - average total score (PANSS, high = poor)

Data from two RCTs demonstrate no significant difference between groups at short term (2 RCTs, n = 372, MD 1.50 CI -2.96 to 5.96, Analysis 3.12).

3.13 Mental state: 9. Average scores of various scale (skewed)

All data for this outcome are skewed, and are best inspected by viewing Analysis 3.13.

3.14 Leaving the study early

All data for leaving the study early demonstrate no significant difference between groups, including leaving for any reason (12 RCTs, n = 1239, Analysis 3.14); progressive disease (2 RCTs, n = 188); incomplete data (1 RCT, n = 180); adverse effects (9 RCTs, n = 1272); and no effect of study drug (5 RCTs, n = 681).

3.15 Adverse effects: 1. At least one adverse effect, non-specific

With more non-specific adverse effects seen with people receiving risperidone, data demonstrate statistical significance (P = 0.0002) in favour of aripiprazole (28 RCTs, n = 2361, RR 0.81 CI 0.73 to 0.91, Analysis 3.15). Generally, data demonstrated no significant difference between groups, including hyper-salivation (7 RCTs, n = 554), and sweating (4 RCTs, n = 278).

Data demonstrate statistical significance (P = 0.003) in favour of aripiprazole for abnormal liver function (29 RCTs, n = 2300, RR 0.63 CI 0.46 to 0.86) and sexual desire change (P = 0.0001) (8 RCTs, n = 614, RR 0.11 CI 0.04 to 0.30).

3.16 Adverse effects: 2a.Cardiac effects (short term, up to 12 weeks)

Data for tachycardia demonstrate statistical significance (P = 0.02) in favour of aripiprazole (49 RCTs, n = 3835, RR 0.76 CI 0.61 to 0.96, Analysis 3.16). All other data are equivocal, demonstrating no significant difference between groups.

3.17 Adverse effects: 2b. Cardiac - QTc change from baseline (in ms)

Data demonstrate statistical significance (P = 0.005) in favour of aripiprazole (2 RCTs, n = 383, MD -7.19 CI -12.19 to -2.19, Analysis 3.17).

3.18 Adverse effects: 3. Central nervous system (short term, up to 12 weeks)

The majority of data are equivocal, demonstrating no difference between groups. Data for headache demonstrate statistical significance (P = 0.01) in favour of risperidone (20 RCTs, n = 1505, RR 1.91 CI 1.31 to 2.78, Analysis 3.18). Data from one small RCT demonstrate statistical significance (P = 0.04) in favour of aripiprazole for decrease in memory, with higher instances seen in people receiving risperidone (1 RCT, n = 60, RR 0.22 CI 0.05 to 0.94).

3.19 Adverse effects: 3a. Endocrine - Prolactin - average change (ng/mL)

Data demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (2 RCTs, n = 383, MD -54.71 CI -60.06 to -49.36, Analysis 3.19).

3.20 Adverse effects: 3b. Endocrine - Prolactin - associated

Data from one small RCT demonstrate statistical significance (P = 0.00001) in favour of aripiprazole for abnormally high prolactin value (1 RCT, n = 301, RR 0.04 CI 0.02 to 0.08, Analysis 3.20). Data demonstrate no significant difference between groups for dysmenorrhoea (1 RCT, n = 91).

3.21 Adverse effects:4.Various extrapyramidal symptoms (short term, up to 12 weeks)
3.21.1 Akathisia

Data demonstrate statistical significance of aripiprazole for: akathisia (P = 0.00001) (42 RCTs, n = 3501, RR 0.60 CI 0.48 to 0.74, Analysis 3.21); tremor (P = 0.00001) (36 RCTs, n = 2799, RR 0.35 CI 0.27 to 0.45); dystonia (P = 0.00001) (32 RCTs, n = 2640, RR 0.35 CI 0.25 to 0.49); and EPS (P = 0.00001) (31 RCTs, n = 2605, RR 0.39 CI 0.31 to 0.50) with slight heterogeneity present (ChI2 = 53.91; df = 30; P = 0.005; I2 = 44%). All other data demonstrate no difference between groups for parkinsonism (1 RCT, n = 301); use of antiparkinson medication (1 RCT, n = 83); tremor (2 RCTs, n = 391).

3.22 Adverse effects: 4b. Extrapyramidal - average score
3.22.1 Abnormal Involuntary Movement Scale (high = poor)

Data demonstrate no significant difference between groups (2 RCTs, n = 383, MD -0.25 CI -1.24 to 0.75, Analysis 3.22) with considerable heterogeneity present (ChI2 = 3.09; df = 1; P = 0.079; I2 = 68%).

3.22.2 Barnes Akathisia Scale (high = poor)

Data demonstrate no significant difference between groups (2 RCTs, n = 383, MD -0.11 CI -0.49 to 0.27) with slight heterogeneity present (ChI2 = 1.98; df = 1; P = 0.16; I2 = 49%).

3.22.3 Simpson-Angus Scale (high = poor)

Data demonstrate no significant difference between groups (2 RCTs, n = 383, MD -0.70 CI -2.22 to 0.82) with substantial heterogeneity present (ChI2 = 5.11; df = 1; P = 0.024; I2 = 80%).

3.23 Adverse effects: 5. Gastrointestinal

Data for constipation (27 RCTs, n = 2067) and dry mouth (33 RCTs, n = 2658) are equivocal, demonstrating no significant difference between groups (Analysis 3.23). For nausea and vomiting data demonstrate statistical significance (P = 0.00001) in favour of risperidone (28 RCTs, n = 2180, RR 1.84 CI 1.31 to 2.56).

3.24 Adverse effects: 6. Haematological

All data demonstrate no difference between groups for abnormal blood routine (6 RCTs, n = 515, Analysis 3.24); leucopenia (1 RCT, n = 60) and abnormal blood lipids (1 RCT, n = 80).

3.25 Adverse effects: 7a. Metabolic - binary measures (short term, up to 12 weeks)
3.25.1 Appetite - decrease

Data demonstrate statistical significance (P = 0.05) in favour of aripiprazole (2 RCTs, n = 204, RR 0.26 CI 0.07 to 1.03, Analysis 3.25).

3.25.2 Blood glucose- increase

Data demonstrate statistical significance (P = 0.02) in favour of aripiprazole (5 RCTs, n = 358, RR 0.28 CI 0.09 to 0.82).

3.25.3 Endocrine disorder

Data demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (9 RCTs, n = 642, RR 0.07 CI 0.03 to 0.17).

3.25.4 Lactation

Data demonstrate statistical significance (P = 0.01) in favour of aripiprazole (3 RCTs, n = 216, RR 0.11 CI 0.02 to 0.60).

3.25.5 Menstrual disorder/lactation

Data demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (29 RCTs, n = 2278, RR 0.10 CI 0.06 to 0.16).

3.25.6 Menstrual disorder or sexual function change

Data demonstrate no significant difference between groups (1 RCT, n = 68).

3.25.7 Menstrual disorder

Data demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (9 RCTs, n = 655, RR 0.13 CI 0.06 to 0.27).

3.25.8 Skin symptoms

Data demonstrate statistical significance (P = 0.02) in favour of aripiprazole (9 RCTs, n = 778, RR 0.32 CI 0.12 to 0.86).

3.25.9 PRL-increase

Data demonstrate statistical significance (P = 0.002) in favour of aripiprazole (3 RCTs, n = 184, RR 0.07 CI 0.01 to 0.38).

3.25.10 Obesity

Data demonstrate no significant difference between groups (1 RCT, n = 72).

3.25.11 Vaginal bleeding

Data demonstrate no significant difference between groups (1 RCT, n = 72).

3.25.12 Weight gain

Data demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (58 RCTs, n = 4623, RR 0.22 CI 0.17 to 0.29).

3.25.13 Weight loss

Data demonstrate no significant difference between groups (1 RCT, n = 101)

3.26 Adverse effects: 7b. Metabolic - continuous measures
3.26.1 Endpoint average weight (in kg)

Data demonstrate statistical significance (P = 0.02) in favour of aripiprazole (5 RCTs, n = 465, MD -2.30 CI -4.17 to -0.44, Analysis 3.26), however with substantial heterogeneity present (ChI2 = 37.17; df = 4; P = 0.0; I2 = 89%).

3.26.2 Weight change from baseline (in kg)

Data from one small RCT demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (1 RCT, n = 100, MD -1.50 CI -1.84 to -1.16).

3.26.3 Average endpoint BMI of male participants (in kg/m2)

Data from one small RCT demonstrate statistical significance (P = 0.003) in favour of aripiprazole (1 RCT, n = 60, MD -2.46 CI -4.08 to -0.84).

3.26.4 Average endpoint BMI of female participants (in kg/m2)

Data demonstrate no significant difference between groups (2 RCTs, n = 124, MD -1.47 CI -3.55 to 0.60) with substantial heterogeneity between groups (ChI2 = 4.32; df = 1; P = 0.038; I2 = 77%).

3.26.5 Average endpoint blood glucose of female participants (in mmol/L)

Data demonstrate statistical significance (P = 0.00001) in favour of risperidone (1 RCT, n = 60).

3.26.6 Average endpoint blood glucose of male participants (in mmol/L)

Data demonstrate no significant difference between groups (1 RCT, n = 60).

3.26.7 Average endpoint blood glucose FBG (in mg/dL)

Data demonstrate no significant difference between groups (1 RCT, n = 60).

3.26.8 Average endpoint cholesterol - TC of female participants (in mmol/L)

Data from one small RCT demonstrate statistical significance (P = 0.03) in favour of aripiprazole (1 RCT, n = 60, MD -0.51 CI -0.96 to -0.06).

3.26.9 Average endpoint cholesterol - TC of male participants (in mmol/L)

Data from one small RCT demonstrate statistical significance (P = 0.05) in favour of aripiprazole (1 RCT, n = 60, MD -0.48 CI -0.96 to 0.00).

3.26.10 Average endpoint cholesterol - TC level (in mmol/L)

Data demonstrate no significant difference between groups (2 RCTs, n = 240).

3.26.11 Average endpoint cholesterol - TG level (in mmol/L)

Data demonstrate no significant difference between groups (1 RCT, n = 60).

3.26.12 Average endpoint cholesterol - LDL level (in mmol/L)

Data demonstrate no significant difference between groups (2 RCTs, n = 240).

3.26.13 Average endpoint waistline (in cm)

Data from one small RCT demonstrate statistical significance (P = 0.003) in favour of aripiprazole (1 RCT, n = 180, MD -3.30 CI -5.47 to -1.13).

3.27. Adverse effect: 7c. Metabolic - continuous measures

Data from one small RCT demonstrate statistical significance (P = 0.01) in favour of aripiprazole for change in cholesterol from baseline (1 RCT, n = 83, MD -22.30 CI -39.69 to -4.91, Analysis 3.27). Remaining data demonstrate no significant difference between groups.

3.28 Adverse effect: 8. required additional drug combination
3.28.1 Benzodiazepines

Data demonstrate no significant difference between groups (2 RCTs, n = 138, RR 1.07 CI 0.73 to 1.58, Analysis 3.28).

3.28.2 Benzhexol

Data from one small RCT demonstrate statistical significance (P = 0.04) in favour of aripiprazole (1 RCT, n = 69, RR 0.34 CI 0.12 to 0.93).

3.28.3 Benzhexol/propranolol

Data demonstrate no significant difference between groups (1 RCT, n = 69, RR 1.11 CI 0.45 to 2.72).

3.29 Adverse effects: 9.TESS score (short term, up to 12 weeks, high = poor)

Data demonstrate statistical significance (P = 0.006) in favour of aripiprazole (4 RCTs, n = 250, MD -1.34 CI -2.3 to -0.39, Analysis 3.29), however with substantial heterogeneity present (ChI2 = 48.54; df = 3; P = 0.00001; I2 = 94%).

3.30 Adverse effects: 10. TESS score (skewed)

All data for this outcome are skewed and are best inspected by viewing Analysis 3.30.

3.31 Adverse effects: 11. weight gain (skewed)

All data for this outcome are skewed and are best inspected by viewing Analysis 3.31.

3.32 Cognitive functioning: 1. Specific - average endpoint total score
3.32.1 Short term, up to 12 weeks, WMS, low = poor

Data demonstrate no significant difference between groups for both WMS (1 RCT, n = 72, Analysis 3.32) and WAIS-RC (1 RCT, n = 72).

3.33 Cost-effectiveness analysis (skewed)

All data for this outcome are skewed and are best viewed by inspecting Analysis 3.33.

COMPARISON 4: ARIPIPRAZOLE versus ZIPRASIDONE

4.1 Global state: 1. No clinically significant response (as defined by the original studies)

Short term data demonstrate no significant difference between groups (6 RCTs, n = 442, RR 0.97 CI 0.62 to 1.52, Analysis 4.1).

4.2 Global state: 2. Average endpoint CGI-GI score (short term, up to 12 weeks, high = poor)

Data from one small RCT demonstrate statistical significance (P = 0.001) in favour of aripiprazole (1 RCT, n = 86, MD -3.93 CI -6.32 to -1.54, Analysis 4.2).

4.3 Global state: 3. Average change score (CGI-S, decline = best)

Data demonstrate no significant difference between groups (1 RCT, n = 247, MD -0.03 CI -0.28 to 0.22, Analysis 4.3).

4.4 Mental state: 1. Average endpoint total score (short term, up to 12 weeks, high = poor)

PANSS data demonstrate no significant difference between groups (7 RCTs, n = 689, Analysis 4.4), neither do BPRS data (1 RCT, n = 247). However, SANS data demonstrate statistical significance (P = 0.02) in favour of aripiprazole (3 RCTs, n = 238, MD -1.39 CI -2.56 to -0.22).

4.5 Mental state: 2. Specific - binary outcomes (up to 12 weeks - short term)

There was no significant difference between groups for anxiety (1 RCT, n = 86) or agitation (2 RCTs, n = 150, Analysis 4.5).

4.6 Mental state: 3. Specific - average endpoint PANSS subscale scores (short term, high = poor)

There was no significant difference between groups for positive symptom score (2 RCTs, n = 146); negative symptom scores (4 RCTs, n = 272); and general pathology scores (5 RCTs, n = 382, Analysis 4.6.)

4.7 Mental state: 4. Average endpoint scores of various scales (skewed)

All data for this outcome are skewed and are best inspected by viewing Analysis 4.7.

4.8 Leaving the study early

All data for leaving study early were equivocal, demonstrating no significant difference between groups (Analysis 4.8).

4.9 Adverse effects:1.At least one adverse effect, non-specific

Data demonstrate statistical significance (P = 0.0001) in favour of ziprasidone for sexual function change (2 RCTs, n = 172, RR 8.00 CI 2.96 to 21.65, Analysis 4.9); all other data for adverse effects were equivocal.

4.10 Adverse effects: 2.Cardiac effects (short term, up to 12 weeks)

All data for cardiac effects are equivocal and demonstrate no difference between groups (Analysis 4.10).

4.11 Adverse effects: 3. Central/ peripheral nervous system

Data for dizziness demonstrate statistical significance (P = 0.002) in favour of ziprasidone (5 RCTs, n = 376, RR 3.24 CI 1.57 to 6.70, Analysis 4.11), as well as data for insomnia (P = 0.02) (5 RCTs, n = 382, RR 2.93 CI 1.17 to 7.30), however with slight heterogeneity present (ChI2 = 7.38; df = 4; P = 0.117; I2 = 46%). All other data are equivocal, demonstrating no significant difference between groups, including for headache (2 RCTs, n = 150); blurred vision (1 RCT, n = 84) and somnolence (4 RCTs, n = 296).

4.12 Adverse effects: 4. Various extrapyramidal symptoms (short term, up to 12 weeks)

All data were equivocal, demonstrating no difference between groups (Analysis 4.12), including dystonia (1 RCT, n = 84); tremor (2 RCTs, n = 152) and use of anti-Parkinson drugs (2 RCTs, n = 140) with substantial heterogeneity present (ChI2 = 6.94; df = 1; P = 0.008; I2 = 86%).

4.13 Adverse effects: 5. Gastrointestinal (short term, up to 12 weeks)

Again, all data were equivocal, demonstrating no difference between groups (Analysis 4.13), including: constipation (3 RCTs, n = 230); dry mouth (4 RCTs, n = 296); hyper-salivation (1 RCT, n = 86) and nausea/vomiting (6 RCTs, n = 442).

4.14 Adverse effects: 6. Haematological

Data for leucopenia demonstrate no significant difference between groups (2 RCTs, n = 140, Analysis 4.14).

4.15 Adverse effects: 7. Hormonal

Data for menstrual disorder demonstrate no significant difference between groups (6 RCTs, n = 538, Analysis 4.15).

4.16 Adverse effects: 8a. Metabolic - binary measures

All data were equivocal, demonstrating no difference between groups, including appetite decrease (2 RCTs, n = 152, Analysis 4.16)) with substantial heterogeneity present (ChI2 = 4.04; df = 1; P = 0.045; I2 = 75%); abnormal blood routine (1 RCT, n = 85); lactation (1 RCT, n = 66); and weight gain (3 RCTs, n = 232).

4.17 Adverse effects: 8b. Metabolic - continuous measures

Most data were equivocal, demonstrating no difference between groups; however, data for HDL demonstrate statistical significance (P = 0.04) in favour of aripiprazole (1 RCT, n = 180, MD 0.10 CI 0.01 to 0.19) and data for waistline average endpoint level (in cm) demonstrate statistical significance (P = 0.0004) in favour of aripiprazole (1 RCT, n = 180, MD -3.40 CI -5.29 to -1.51 Analysis 4.17).

COMPARISON 5: ARIPIPRAZOLE versus OLANZAPINE

5.1 Global state: 1. No clinically significant response (as defined by the original studies)

Data are equivocal at short term (10 RCTs, n = 1422) and medium term (1 RCT, n = 317), demonstrating no significant difference between groups (Analysis 5.1).

5.2 Global state: 2. Not responded (decline in PANSS of 30% or more)
5.2.1 By up to 12 weeks (short term)

Data from one small RCT demonstrate statistical significance (P = 0.04) in favour of olanzapine at short term (1 RCT, n = 566, RR 1.16 CI 1.01 to 1.34, Analysis 5.2) and long term (P = 0.05) (1 RCT, n = 566, RR 1.13 CI 1.0 to 1.27).

5.3 Global state: 3. Remission not achieved (as defined in the study)

Data demonstrate no significant difference between groups at short term (1 RCT, n = 566, Analysis 5.3). Data from one small RCT demonstrate statistical significance (P = 0.00001) in favour of olanzapine by long term (1 RCT, n = 566, RR 1.38 CI 1.23 to 1.56).

5.4 Global state: 4. Average endpoint EI score (CGI, high = poor)

Data demonstrate no significant difference between groups at short term (2 RCTs, n = 180, Analysis 5.4).

5.5 Global state: 5. Average endpoint CGI score decreased rate (short term, low = poor)

Data demonstrate no significant difference between groups (1 RCT, n = 60, Analysis 5.5).

5.6 Global state: 6. Average change score (CGI-S, decline = best)

Data demonstrate no significant difference between groups at long term (1 RCT, n = 566, Analysis 5.6).

5.7 Global state: 7. Improvement (CGI-I, high = poor)

Data demonstrate no significant difference between groups (1 RCT, n = 566, Analysis 5.7).

5.8 Mental state: 1. General - average total score (PANSS, high = poor)

Data are equivocal, demonstrating no significant difference between groups at short term (11 RCTs, n = 1500, Analysis 5.8) and medium term (2 RCTs, n = 139). Data from one small RCT demonstrate statistical significance (P = 0.04) in favour of olanzapine (1 RCT, n = 566, MD 4.20 CI 0.10 to 8.3) in the long term.

5.9 Mental state: 2. Average endpoint scale score (SANS, high = poor)

Data demonstrate no significant difference between groups at short term (1 RCT, n = 89, Analysis 5.9) and long term (1 RCT, n = 48).

5.10 Mental state: 3. average endpoint score (PANSS, skewed)

All data for this outcome are skewed and are best inspected by viewing Analysis 5.10.

5.11 Mental state: 4. Specific - average endpoint positive score (PANSS, high = poor)

Overall, data from all time frames demonstrate statistical significance (P = 0.01) in favour of olanzapine (7 RCTs, n = 1043, MD 0.71 CI 0.17 to 1.26, Analysis 5.11). Data are equivocal at short term, demonstrating no significant difference between groups (5 RCTs, n = 429) with slight heterogeneity between groups (ChI2 = 6.26; df = 4; P = 0.181; I2 = 36%). Data demonstrate no significant difference at medium term (1 RCT, n = 48) or long term (1 RCT, n = 566).

5.12 Mental state: 5. Specific - average endpoint negative subscale score (PANSS, high = poor)

At both short and medium term, data demonstrate no significant difference between group (6 RCTs, n = 967, Analysis 5.12).

5.13 Mental state: 6. Specific - average endpoint general pathological score (PANSS, high = poor)

At both short and medium term, data demonstrate no significant difference between groups (8 RCTs, n = 642, Analysis 5.13).

5.14 Mental state: 7. Specific - binary outcomes
5.14.1 Anxiety - labelled as" adverse effect"

Data demonstrate no significant difference between groups for anxiety (2 RCTs, n = 778, Analysis 5.14) or exacerbation of schizophrenia (2 RCTs, n = 778). Data from one small RCT demonstrate statistical significance (P = 0.04) in favour of aripiprazole for depression (1 RCT, n = 566, RR 0.27 CI 0.08 to 0.95).

5.15 Mental state: 8. Average various scale scores decreased rate (skewed)

All data for this outcome are skewed and are best inspected by viewing Analysis 5.15.

5.16 Adverse effects: 1. At least one adverse effect

For non-specific adverse effects, data demonstrate no significant difference between groups (1 RCT, n = 75, Analysis 5.16). For endocrine dyscrasia, data from one small RCT demonstrate statistical significance (P = 0.01) in favour of aripiprazole (1 RCT, n = 80, RR 0.08 CI 0.01 to 0.61); and for high prolactin level (P = 0.001) (1 RCT, n = 317, RR 0.27 CI 0.12 to 0.60). Remaining data are equivocal and demonstrate no difference between groups, including skin reaction (1 RCT, n = 89); and liver function abnormality  (5 RCTs, n = 348).

5.17 Adverse effects: 2. Cardiac effects

All data are equivocal and demonstrate no difference between groups for abnormal ECG (2 RCTs, n = 121); decrease in blood pressure (1 RCT, n = 89); QTc prolongation (3 RCTs, n = 618) and tachycardia (5 RCTs, n = 339).

5.18 Adverse effects: 3a. Cardiac - QTc change from baseline (in ms)

Data from one RCT demonstrate no significant difference between groups (1 RCT, n = 317, Analysis 5.18).

5.19 Adverse effects: 3b. Central/ peripheral nervous system

Data from two RCTs demonstrate statistical significance (P = 0.0001) in favour of aripiprazole for levels of sedation (2 RCTs, n = 883, RR 0.37 CI 0.23 to 0.60) and data from one small RCT demonstrate statistical significance (P = 0.05) in favour of aripiprazole for headache/dizziness (1 RCT, n = 89, RR 0.29 CI 0.09 to 1.00, Analysis 3.19). All other data are equivocal and demonstrate no difference between groups, including dizziness (6 RCTs, n = 1057); blurred vision (1 RCT, n = 75); fatigue (3 RCTs, n = 721) and insomnia (7 RCTs, n = 1141), however with considerable heterogeneity present (ChI2 = 13.87; df = 6; P = 0.031; I2 = 57%).

5.20 Adverse effects: 4. Endocrine - Prolactin - average increase

Data from one small RCT demonstrate statistical significance (P = 0.0001) in favour of aripiprazole (1 RCT, n = 566, MD -8.89 CI -12.96 to -4.82, Analysis 5.20).

5.21 Adverse effects: 5. Extrapyramidal - various

All data are equivocal and demonstrate no difference between groups, including: tremor (1 RCT, n = 61); EPS (4 RCTs, n = 667); and parkinsonism (3 RCTs, n = 618). Data for akathisia are equivocal, demonstrating no significant difference between groups (6 RCTs, n = 1320, Analysis 5.21), however with considerable heterogeneity present (ChI2 = 19.45; df = 6; P = 0.003; I2 = 69%).

5.22 Adverse effects: 6. Gastrointestinal

Data from one small RCT demonstrate statistical significance (P = 0.03) in favour of aripiprazole for abdominal pain (1 RCT, n = 566, RR 2.96 CI 1.09 to 8.03). All remaining data are equivocal and demonstrate no significant difference between groups, including: dry mouth (5 RCTs, n = 854); constipation (6 RCTs, n = 443) and nausea/vomiting (6 RCTs, n = 948, Analysis 5.22).

5.23 Adverse effects: 7. Hormonal
5.23.1 Menstrual changes

Data are equivocal and demonstrate no significant difference between groups (3 RCTs, n = 198, Analysis 5.23).

5.24 Adverse effects: 8a. Metabolic - binary measures

Data demonstrate statistical significance (P = 0.001) in favour of aripiprazole for blood glucose increase (3 RCTs, n = 227, RR 0.12 CI 0.03 to 0.44); for abnormally high cholesterol level (P = 0.0001) (1 RCT, n = 223, RR 0.32 CI 0.19 to 0.54, Analysis 5.24); and weight gain (P = 0.00001) (9 RCTs, n = 1538, RR 0.25 CI 0.15 to 0.43). All remaining data demonstrate no significant difference between groups for appetite increase (2 RCTs, n = 655); lactation (1 RCT, n = 60) and PRL increase (1 RCT, n = 89).

5.25 Adverse effects: 8b. Metabolic - continuous measures (high = poor)
5.25.1 Weight - average endpoint level (in kg)

Data demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (3 RCTs, n = 242, MD -7.43 CI -9.21 to -5.65, Analysis 5.25).

5.25.2 Weight gain - change from baseline (in kg)

Data demonstrate no significant difference between groups (2 RCTs, n = 656), however with substantial heterogeneity present (ChI2 = 6.31; df = 1; P = 0.012; I2 = 84%).

5.25.3 Cholesterol - change from baseline (in mg/dL)

Data demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (2 RCTs, n = 789, MD -15.37 CI -21.62 to -9.11).

5.25.4 Cholesterol - TC average endpoint level (in mmol/L)

Data demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (2 RCTs, n = 182, MD -1.00 CI -1.44 to -0.56).

5.25.5 Cholesterol - TG average endpoint level (in mmol/L

Data from one small RCT demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (1 RCT, n = 102, MD -1.00 CI -1.31 to -0.69).

5.25.6 Blood glucose - PBG average endpoint level (in mg/dL)

Data from one small RCT demonstrate statistical significance (P = 0.00001) in favour of aripiprazole (1 RCT, n = 60, MD -0.95 CI -1.27 to -0.63).

5.25.7 Glucose - change from baseline (in mg/dl)

Data demonstrate no significant difference between groups (2 RCTs, n = 883).

5.26 Adverse effects: average endpoint scale scores (TESS, skewed)

All data for this outcome are skewed and are best inspected by viewing Analysis 5.26.

5.27 Leaving the study early

Data for leaving for any reason from one small RCT demonstrate statistical significance (P = 0.002) in favour of olanzapine (9 RCTs, n = 2331, RR 1.15 CI 1.05 to 1.25, Analysis 5.27); statistical significance was also found in inefficacy (P = 0.003) in favour of olanzapine (4 RCTs, n = 1352, RR 1.81 CI 1.23 to 2.67). Remaining reasons for leaving the study early demonstrated no significant difference between groups, including adverse event (4 RCTs, n = 1352); early discharge (1 RCT, n = 60); medication non-compliance (1 RCT, n = 255); and death (1 RCT, n = 214).

5.28 Quality of life: 1. Average endpoint general quality of life score (GQOLI-74, low = poor)

All data are equivocal and demonstrate no difference between groups (Analysis 5.28).

COMPARISON 6: ARIPIPRAZOLE versus OLANZAPINE (acutely agitated people - all data by five days)

One study was included in this category.

6.1 Global state

An improvement was defined as reduction in the Brief Psychiatric Rating Scale (BPRS). There was no significant difference in the two groups (n = 471, MD -0.18, CI -0.79 to 0.43, Analysis 6.1).

6.2 Mental state

There was no significant difference reported in participants on aripiprazole and olanzapine in agitation level (defined as at least  40% reduction in PANSS-EC (n = 604, RR 0.92, CI 0.76 to 1.12). No significant difference was noted in agitation (n = 578, RR 0.25, CI 0.05 to 1.17); anxiety (n = 604, RR 0.93, CI 0.40 to 2.17) and exacerbation of schizophrenia (n = 604, RR 5.13, CI 0.25 to 106.49, Analysis 6.2). All such outcomes were labelled as “adverse effects” in the published report.

6.3 Leaving the study early

Both groups were similar in the number of participants leaving the study early due to adverse effects (n = 604, RR 0.68 CI 0.12 to 4.07, Analysis 6.3).

6.4 Adverse effects
6.4.1 Central nervous system

No significant difference was reported between administering aripiprazole or olanzapine in acutely agitated patients with regards to CNS side effects of dizziness (n = 578, RR 0.29, CI 0.06 to 1.36); sedation (n = 578, RR 0.71, CI 0.23 to 2.22); insomnia (n = 604, RR 1.60, CI 0.87 to 2.94) and somnolence (n = 578, RR 0.14, CI 0.02 to 1.15). Participants on aripiprazole reported more headaches (n = 578, RR 2.43, CI 1.02 to 5.77) and lethargy (n = 578, RR 1.33, CI 0.30 to 5.90, Analysis 6.4).

6.4.2 Endocrine system - increase in average levels of prolactin

People allocated aripiprazole reported significantly lower (P = 0.00001) prolactin level increase compared with participants given olanzapine (n = 604, MD -15.76, CI -19.18 to -12.34, Analysis 6.5).

6.4.3 Extrapyramidal side effects

Participants in both groups experienced similar rates of akathisia (n = 604, RR 1.43, CI 0.79 to 2.56) and parkinsonian symptoms (n = 604, 1 RCT, RR 1.71 CI 0.41 to 7.10, Analysis 6.6).

6.4.4 Extrapyramidal symptoms

Extrapyramidal symptoms were also reported by using scales where higher score represents a poor outcome. There was no significant difference between groups when assessed using Barnes Akathisia scale (n = 604, MD 0.07, CI -0.24 to 0.38) or Simpson Angus scale (n = 604, MD -0.05, CI -0.13 to 0.03, Analysis 6.7).

6.4.5 Gastrointestinal side effects

Both groups reported similar occurrence of dry mouth (n = 578, RR 1.00, CI 0.20 to 4.91) and twice the number of participants on olanzapine reported nausea/dyspepsia (n = 578, RR 0.50, CI 0.09 to 2.71, Analysis 6.8).

6.4.6 Metabolic side effects- increase in triglyceride levels

These results favoured patients on aripiprazole significantly (P = 0.00001) (n = 604, MD -35.62, CI -49.25 to -21.99, Analysis 6.9).

COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS

We used data from three studies for this comparison. In all three studies aripiprazole was compared with any one of several new generation antipsychotic drugs.

7.1 Global state: 1. No change as defined by the original study (measured by IAQ)

Kerwin 2007 showed an improvement in global state in energy (n = 523, 1 RCT, RR 0.69 CI 0.56 to 0.84); mood (n = 523, 1 RCT, RR 0.77 CI 0.65 to 0.92); negative symptoms (n = 523, 1 RCT, RR 0.82 CI 0.68 to 0.99); somnolence (n = 523, 1 RCT, RR 0.80 CI 0.69 to 0.93) and weight gain (n = 523, 1 RCT, RR 0.84 CI 0.76 to 0.94) when aripiprazole was used but no significant difference was noted in cognition (n = 523, 1 RCT, Analysis 7.1).

7.2 Global state: 2. Change in sexual dysfunction (measured by ASEX)

No significant difference was seen in the two groups (n = 85, 1 RCT, Analysis 7.2).

7.3 Mental state: 1. Binary outcomes

No significant difference was noted in anxiety (n = 1361, 2 RCTs); "schizophrenia" (n = 548, 1 RCT) and psychotic disorder (n = 2881, 3 RCTs). Participants on aripiprazole experienced slightly less agitation (n = 548, 1 RCT, RR 2.64 CI 0.96 to 7.23, Analysis 7.3).

7.4 Medication preference (study medication worse than or equal to previous medication)

People reported aripiprazole being better in the short term (n = 446, 1 RCT, RR 0.67 CI 0.49 to 0.91) and medium term (n = 330, 1 RCT, RR 0.39 CI 0.25 to 0.61). Carers, however, reported no difference in the two groups both in the short (n = 121, 1 RCT) and medium term (n = 80, 1 RCT, Analysis 7.4)

7.5 Quality of life: 1. Unsatisfactory response (Health dimension scale)

Fewer participants reported an unsatisfactory response on the health dimension scale when using aripiprazole (n = 329, 1 RCT, RR 0.29 CI 0.13 to 0.66, Analysis 7.5).

7.6 Quality of life: 2. Average change in Quality of Life score (high is better)

The results favoured other antipsychotics (n = 326, 1 RCT, MD 6.20 CI 3.08 to 9.32, Analysis 7.6).

7.7 Quality of life: 3. Average EQ-5D utility score (high is better)

No significant difference was noted in the two groups (n = 329, 1 RCT, Analysis 7.7).

7.8 Quality of life: 4a. Weight-related score - no meaningful change (measured by Impact of Weight on Quality of Life (IWQoL-Lite))

No significant difference was noted in the two groups when weight was measured in binary scale (n = 327, 1 RCT, Analysis 7.8).

7.9 Quality of life: 4b. Weight-related score (measured by Impact of Weight on Quality of Life (IWQoL-Lite))

No significant difference was noted in the two groups for average change in weight in the short term (n = 443, 1 RCT) and medium term (n = 328, 1 RCT, Analysis 7.9).

7.10 Leaving the study early

No significant difference was noted in the participants who left the study early in the three groups for any reason (n = 2908, 3 RCTs, RR 0.97 CI 0.78 to 1.19); administrative reasons (n = 833, 1 RCT, RR 0.80 CI 0.00 to 1.84); death (n = 555, 1 RCT, RR 0.48 CI 0.04 to 5.23); inefficacy (n = 2908, 3 RCTs, RR 0.94 CI 0.45 to 1.96); lost to follow-up (n = 1388, 2 RCTs, RR 0.85 CI 0.34 to 2.13); no longer meets criteria (n = 1388, 2 RCTs, RR 0.65 CI 0.16 to 2.63); other (n = 1388, 2 RCTs, RR 0.62 CI 0.10 to 3.80); compliance issues (n = 1388, 2 RCTs, RR 1.10 CI 0.53 to 2.32) and pregnancy (n = 555, 1 RCT, RR 0.95 CI 0.14 to 6.73). More participants in the aripiprazole group left due to adverse events (n = 2908, 3 RCTs, RR 1.40 CI 1.11 to 1.76). Fewer participants in the aripiprazole group withdrew from the study (n = 2908, 3 RCTs, RR 0.48 CI 0.36 to 0.66, Analysis 7.10).

7.11 Adverse effects - 1. At least one side effect

Participants taking other antipsychotics reported this slightly more (n = 2333, 2 RCTs, RR 1.14 CI 1.05 to 1.23, Analysis 7.11).

7.12 Adverse effects - 2. Central nervous system

No significant difference was noted in sleep disorder (n = 813, 1 RCT, RR 1.79 CI 0.78 to 4.10) and fatigue (n = 548, 1 RCT, RR 0.59 CI 0.27 to 1.28). A larger number of participants on aripiprazole reported insomnia (n = 2881, 3 RCTs, RR 2.09 CI 1.65 to 2.66) and headache (n = 2881, 3 RCTs, RR 1.47 CI 1.09 to 1.99). Fewer participants on aripiprazole reported somnolence (n = 2881, 3 RCTs, RR 0.52 CI 0.39 to 0.71, Analysis 7.12).

7.13 Adverse effects - 3a. Endocrine system - increase in prolactin level

Significantly fewer participants on aripiprazole reported an increased prolactin level (n = 548, 1 RCT, RR 0.31 CI 0.23 to 0.41, Analysis 7.13).

7.14 Adverse effects - 3b. Endocrine system - change in prolactin level from baseline

The results favoured aripiprazole (n = 94, 1 RCT, MD -8.60 CI -19.14 to 1.94, Analysis 7.14).

7.15 Adverse effects - 4. Extrapyramidal symptoms (EPS)

The results did not favour any of the comparison groups with a large confidence interval (n = 2881, 3 RCTs, RR 1.02 CI 0.09 to 11.09, Analysis 7.15) and prohibitively high heterogeneity (97%). It is unclear why Tandon 2006 causes this and removal of this study results in homogeneity being restored.

7.16 Adverse effects - 5. Gastrointestinal

A significantly larger number of people given aripiprazole reported symptoms of nausea (n = 2881, 3 RCTs, RR 3.13 CI 2.12 to 4.61, Analysis 7.16).

7.17 Adverse effects - 6a. Metabolic - binary measures

Significantly fewer people allocated aripiprazole reported 7% or more weight gain in the medium term (n = 330, 1 RCT, RR 0.35 CI 0.19 to 0.64); average weight gain (n = 548, 1 RCT, RR 0.11 CI 0.03 to 0.37); total cholesterol increase (n = 269, 1 RCT, RR 0.75 CI 0.62 to 0.91) and low-density lipoprotein (LDL) increase (n = 268, 1 RCT, RR 0.65 CI 0.51 to 0.84). We found no significant difference in either group in high-density lipoprotein (HDL) increase (n = 269, 1 RCT, RR 0.87 CI 0.61 to 1.22); triglyceride increase (n = 267, 1 RCT, RR O.80 CI 0.64 to 1.00) and increase in fasting glucose (n = 236, 1 RCT, RR 0.95 CI 0.62 to1.47). A greater number of people given aripiprazole reported 7% or more of weight loss in the medium term (n = 330, 1 RCT, RR 1.75 CI 0.97 to 3.19, Analysis 7.17).

7.18 Adverse effects - 6b. Metabolic - continuous measures

Aripiprazole was favoured for no risk of weight gain (n = 537, 1 RCT, MD -2.70 CI -3.68 to -1.72); weight change from baseline (n = 441, 1 RCT, MD short term -2.48 CI -3.30 to -1.66; n = 327, 1 RCT, MD medium term -3.74 CI -4.65 to -2.83); and change in fasting cholesterol (n = 262, 1 RCT, MD -9.70 CI -16.07 to -3.33). There was no difference reported in change in fasting glucose (n = 229, 1 RCT, MD -1.90 CI -5.78 to 1.98, Analysis 7.18).

8. SENSITIVITY ANALYSIS

We planned to undertake a sensitivity analysis for the primary outcomes of interest of (i) no clinically important response (as defined by each study); (ii) general functioning; and (iii) clinically important specific adverse effects. No study, however, reported data for the outcome of general functioning. For sensitivity analysis of 'comparator dose', we tested outcome of (i) no clinically important response (as defined by each study); and (ii) general mental state.

8.1 Implication of randomisation
8.1.1 Aripiprazole versus Clozapine
8.1.1.1 Global state: no clinically significant response (as defined by the individual studies)

There remained no significant differences between groups after removing studies from meta-analysis that only implied randomisation (n = 322, 4 RCTs, RR 1.04 CI 0.76 to 1.44).

8.1.1.2 Adverse effects - clinically important specific adverse effects

Few studies provided data at medium term for any clinically important adverse effects; for EPS effects, only one study (Li 2007) provided relevant data. This study only implied randomisation, therefore after removing this study from data and analysis, there were no data left to compare. However, at short term, there remained no significant differences between groups after removing studies from meta-analysis that only implied randomisation for the outcome of 'general EPS' (n = 60, 1 RCT, RR 1.50 CI 0.27 to 8.34). When implied randomised studies were removed from the outcome of akathisia, there was significantly greater instances (P = 0.002) in people receiving aripiprazole (n = 180, 2 RCTs, RR 4.99 CI 1.78 to 14.00).

8.1.2 Aripiprazole versus Quetiapine
8.1.2.1 Global state: no clinically significant response (as defined by the individual studies)

There remained no significant differences between groups after removing studies from meta-analysis that only implied randomisation (n = 108, 1 RCT, RR 1.00 CI 0.26 to 3.79).

8.1.2.2 Adverse effects - clinically important specific adverse effects

All adverse data reported are for the short term; there remained no significant differences between groups after removing studies from meta-analysis that only implied randomisation for the outcome of akathisia (n = 108, 1 RCT, RR 2.00 CI 0.19 to 21.41). This was also the case for tremor (n = 108, 1 RCT, RR 0.33 CI 0.01 to 8.01). Remaining studies in other outcomes of dystonia and general EPS were all implied as randomised; therefore, the removal of these studies left us with no data to compare.

8.1.3 Aripiprazole versus Risperidone
8.1.3.1 Global state: no clinically significant response (as defined by the individual studies)

There remained no significant differences between groups after removing studies from meta-analysis that only implied randomisation (n = 703, 7 RCTs, RR 1.29 CI 0.87 to 1.92).

8.1.3.2 Adverse effects - clinically important specific adverse effects

All adverse data reported are for the short term; data were no longer statistically significant in favour of aripiprazole for akathisia after removing studies from the meta-analysis that only implied randomisation (n = 293, 4 RCTs, RR 0.93 CI 0.45 to 1.90), this was also the case for tremor (n = 210, 3 RCTs, RR 0.61 CI 0.30 to 1.23). Data were still statistically significant (P = 0.003, albeit slightly lower in the level of significance) in favour of aripiprazole for the outcome of dystonia after the removal of implied randomised studies from meta-analysis (n = 210, 3 RCTs, RR 0.17 CI 0.05 to 0.56), as well as for general EPS (n = 367, 4 RCTs, RR 0.53 CI 0.35 to 0.80). All data for tremor and parkinsonism were from implied randomised studies, which left no data to compare after removal.

8.1.4 Aripiprazole versus Ziprasidone
8.1.4.1 Global state: no clinically important response (as defined by the individual studies)

All studies reporting this outcome were implied as randomised; therefore, there were no data left to compare once they were removed from the meta-analysis.

8.1.4.2 Adverse effects - clinically important specific adverse effects

All adverse data reported are for the short term; data remained equivocal for akathisia after removing implied randomised studies (n = 253, 1 RCT, RR 1.26 CI 0.48 to 3.27). Data for all other various EPS outcomes, including dystonia, tremor, use of antiparkinson medication and general EPS effects, were reported by implied randomised studies, leaving no data to compare once removed from analysis.

8.1.5 Aripiprazole versus Olanzapine
8.1.5.1 Global state: no clinically significant response (as defined by the individual studies)

There remained no significant differences between groups after removing studies from meta-analysis that only implied randomisation (n = 778, 2 RCTs, RR 1.00 CI 0.82 to 1.23).

8.1.5.2 Adverse effects - clinically important specific adverse effects

Data proved statistically significant (P = 0.05) in favour of olanzapine for akathisia after removing implied randomised studies from meta-analysis (n = 75, 1 RCT, RR 16.68 CI 1.01 to 276.65), while data for remaining extrapyramidal effects (tremor, EPS, parkinsonism) were from implied randomised studies, leaving no data to compare.

8.1.6 Aripiprazole versus Olanzapine (acutely agitated)

The one study included in this comparison only implied randomisation, therefore there were no data left to compare.

8.1.7 Aripiprazole versus Other antipsychotic drugs
8.1.7.1 Global state: no clinically significant response (as defined by the individual studies)

The one study included in this outcome only implied randomisation, therefore there were no data left to compare.

8.1.7.2 Adverse effects - clinically important specific adverse effects

For the outcome of akathisia, after removing the two studies that implied randomisation, only one study (with higher methodological quality) was left to compare (Tandon 2006), which eliminated the heterogeneity present and found statistical significance (P = 0.00001) in favour of aripiprazole over other antipsychotic drugs (n = 1520, 1 RCT, RR 0.17 CI 0.12 to 0.22).

8.2 Assumptions for lost binary data
8.2.1 Aripiprazole versus Clozapine

Only one study for this comparison did not report all data. Yu 2006 reported the loss of n = 5 participants; however it was not clear to which group these participants belonged.

8.2.2 Aripiprazole versus Quetiapine

No included studies reported losses for this comparison.

8.2.3 Aripiprazole versus Risperidone
8.2.3.1 Global state: no clinically significant response (as defined by the individual studies)

There remained no difference in the estimate of effect when completer-only data were pooled at short term (79 RCTs, n = 6245, RR 1.12 CI 0.98 to 1.28).

8.2.4 Aripiprazole versus Ziprasidone

No included studies reported losses for this comparison.

8.2.5 Aripiprazole versus Olanzapine
8.2.5.1 Global state: no clinically significant response (as defined by the individual studies

There remained no difference in the estimate of effect when completer-only data were pooled in the short and medium term combined (11 RCTs, n = 1558, RR 1.04 CI 0.93 to 1.16).

8.2.6 Aripiprazole versus Olanzapine (acutely agitated)

The one study included in this comparison did not report losses for this comparison.

8.2.7 Aripiprazole versus Other antipsychotic drugs

No included studies reported losses for this comparison.

8.3 Risk of bias
8.3.1 Aripiprazole versus Clozapine
8.3.1.1 Global state: no clinically significant response (as defined by the individual studies)

There remained no significant differences between groups after removing studies from meta-analysis that rated as a 'high' risk on one or more of the risk of bias domains (n = 90, 1 RCT, RR 0.91 CI 0.32 to 2.62).

8.3.1.2 General functioning: no clinically important change in general functioning

No included study reported this outcome.

8.3.1.3 Adverse effects - clinically important specific adverse effects

For extrapyramidal effects, all studies rated as a 'high' risk on one or more of the risk of bias domains, leaving no data to compare for this outcome.

8.3.2 Aripiprazole versus Quetiapine
8.3.2.1 Global state: no clinically significant response (as defined by the individual studies)

All studies rated as a 'high' risk on one or more of the risk of bias domains, leaving no data to compare for this outcome.

8.3.2.2 General functioning: no clinically important change in general functioning

No included study reported this outcome.

8.3.2.3 Adverse effects - clinically important specific adverse effects

All studies rated as a 'high' risk on one or more of the risk of bias domains, leaving no data to compare for this outcome.

8.3.3 Aripiprazole versus Risperidone
8.3.3.1 Global state: no clinically significant response (as defined by the individual studies)

There remained no significant differences between groups after removing studies from meta-analysis that rated as a 'high' risk on one or more of the risk of bias domains (n = 465, 6 RCTs, RR 1.27 CI 0.69 to 2.31).

8.3.3.2 General functioning: no clinically important change in general functioning

No included study reported this outcome.

8.3.3.3 Adverse effects - clinically important specific adverse effects

All adverse data reported are for the short term; data were no longer statistically significant in favour of aripiprazole for akathisia after removing studies that rated as a 'high' risk on one or more of the risk of bias domains (n = 161, 2 RCTs, RR 0.59 CI 0.14 to 2.55), this was also the case for tremor (n = 161, 2 RCTs, RR 0.20 CI 0.04 to 1.14), and dystonia (n = 161, 2 RCTs, RR 0.17 CI 0.59 to 4.21). However, data were still statistically significant (P = 0.0001) in favour of aripiprazole for general EPS (n = 284, 4 RCTs, RR 0.29 CI 0.16 to 0.51). All data for tremor and parkinsonism were rated as 'high' risk on one or more of the risk of bias domains, which left no data to compare after removal.

8.3.4 Aripiprazole versus Ziprasidone

All studies providing data for all primary outcomes rated as a 'high' risk on one or more of the risk of bias domains, leaving no data to compare for this outcome in a sensitivity analysis.

8.3.5 Aripiprazole versus Olanzapine

All studies providing data for all primary outcomes rated as a 'high' risk on one or more of the risk of bias domains, leaving no data to compare for this outcome in a sensitivity analysis.

8.3.6 Aripiprazole versus Olanzapine (acutely agitated)

The one study included in this comparison rated as a 'high' risk on one or more of the risk of bias domains, therefore there were no data left to compare.

8.3.7 Aripiprazole versus Other antipsychotic drugs

Again, all studies providing data for all primary outcomes rated as a 'high' risk on one or more of the risk of bias domains, leaving no data to compare for this outcome in a sensitivity analysis.

8.4 Imputed values

No values were imputed for intra-class correlation coefficients (ICC), since we included no cluster randomised trials in meta-analysis.

8.5 Skewed data

All skewed data have been presented separately in tables within data and analyses, therefore a sensitivity analysis was not possible via meta-analysis.

8.6 Comparator dose

Not all studies reported mean doses and standard deviations; therefore, this sensitivity analysis has been undertaken with the dose values made available, taking predominantly ranges into account.

8.6.1 Aripiprazole versus Clozapine
8.6.1.1 Global state: no clinically significant response (as defined by the individual studies)

There remained no significant difference between groups when removing two studies (Li 2007; Yu 2007) that compared doses of aripiprazole that exceeded BNF recommendations to lower doses of clozapine (27 RCTs, n = 1978, RR 1.08 CI 0.88 to 1.32).

8.6.1.2 General mental state (BPRS/ PANSS)

At short term, none of the five studies rating mental state using the BPRS (endpoint scores) used inappropriate comparator doses, therefore there were no differences between results. Using the PANSS at short term, after removing the two studies (Li 2007; Yu 2007) that compared doses of aripiprazole that exceeded BNF recommendations to lower doses of clozapine, there was still no significant difference between groups, (23 RCTs, n = 1484, MD 0.55 CI -0.53 to 1.63), however the degree of heterogeneity was reduced from I2 = 64% (P = 0.0001) to I2 = 44% (P = 0.02). At medium term, three studies provided data using PANSS used comparisons within the recommended doses.

8.6.2 Aripiprazole versus Quetiapine
8.6.2.1 Global state: no clinically significant response (as defined by the individual studies)

Three studies exceeded recommended doses of clozapine, each employing a maximum dose of 800 mg daily (Chen 2009; Li 2007b; Luo 2008). There was no difference in the estimate of the effect when these studies were excluded from meta-analysis (9 RCTs, n = 801, RR 0.91 CI 0.59 to 1.14)

8.6.2.2 General mental state (BPRS/ PANSS)

No studies provided data for general average endpoint scores using either the BPRS or PANSS.

8.6.3 Aripiprazole versus Risperidone

The majority of studies used a range with a maximum of 6 mg daily risperidone, which exceeds the 4 mg BNF recommendation.

8.6.3.1 Global state: no clinically significant response (as defined by the individual studies)

After excluding 70 studies with a range of 1 to 6 mg risperidone, there remained no difference between groups (9 RCTs, n = 727, RR 1.14 CI 0.76 to 1.71).

8.6.3.2 General mental state (BPRS/ PANSS)

For average endpoint mental state in the short term using BPRS, after excluding four of the five studies providing data, there was no longer significant favour for aripiprazole, instead showing no difference between groups (1 RCT, n = 68, MD 2.30 CI -1.17 to 5.77) and removing all heterogeneity. For PANSS in the short term, after removing 69 studies that used a higher than recommended dose of risperidone, results still demonstrated no difference (8 RCTs, n = 659, MD -0.50 CI -2.09 to 1.09s), however all heterogeneity was removed.

8.6.4 Aripiprazole versus Ziprasidone

None of the included studies for the outcomes of interest used inappropriate comparator doses; therefore, there were no studies to exclude.

8.6.5 Aripiprazole versus Olanzapine

None of the included studies for the outcomes of interest used inappropriate comparator doses; therefore, there were no studies to exclude.

8.6.6 Aripiprazole versus Olanzapine (acutely agitated)

The one study included in this comparison did not use any inappropriate comparator doses, therefore there was no difference in results.

8.6.7 Aripiprazole versus Other antipsychotic drugs

Of the three studies included in this outcome, Kerwin 2007 used higher than recommended doses of risperidone and quetiapine; however, this study did not provide data for the outcomes of interest, therefore there were no difference between results.

Discussion

Many trials were sponsored by the manufacturers of aripiprazole or the comparator agent manufacturers. In a blinded analysis of abstracts it has been shown that pharmaceutical companies emphasize positive aspects of their compounds (Heres 2006). Every result, without exception, therefore, must be viewed with this in mind.

Summary of main results

1. COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE

Thirty-nine studies fell into this category, please see Summary of findings for the main comparison. Data are generally of poor quality and we found no data on indices including service use or global functioning. Overall, inclusion of new Chinese studies gave us much more data for this comparison. Quality of life outcomes, more often than not, significantly favoured use of aripiprazole over clozapine. However, there was no difference between the use of either drug for the primary outcome of clinically significant response in global state. Largely, people were at significantly less risk of adverse effects when receiving aripiprazole (Analysis 1.15; Analysis 1.16), but greater risk of central nervous system (CNS) adverse effects such as headache and insomnia than people receiving clozapine (Analysis 1.17), Extrapyramidal effects (EPS) were largely equivocal between groups. Data were heterogeneous as regards EPS, which may well be attributable to the differing doses employed between studies - as some used low doses (between 5 to 20 mg aripiprazole versus 5 to 500 mg clozapine) of either drugs, and some used slightly higher (10 to 30 mg aripiprazole versus 50 to 270 mg clozapine). Evidence from 11 studies (n = 732) does suggest that people receiving aripiprazole had a greater risk of experiencing anxiety in the short term (Analysis 1.2).

2. COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE

Fifteen studies provided data for this comparison, please see Summary of findings 2; again, the inclusion of new Chinese studies gave us data for this comparison, which was lacking in the previous version of this review. The quality of the data were generally 'low' to 'very low', due to poor outcome reporting and methodological quality. There were, again, no data for service use; only one study reported data using any quality of life scale, which significantly favoured use of aripiprazole in six out of the seven components measured. Further larger scale, high-quality trials are needed in order to reach any confident conclusions for this outcome. The evidence from 12 included studies (n = 991) suggest no significant difference between the two drugs in terms of clinically significant response. Adverse effect data do suggest a greater risk of tachycardia in people receiving quetiapine (Analysis 2.13), as well as dry mouth, constipation (Analysis 2.16) and weight gain (Analysis 2.19). However, nausea and vomiting was more common in people receiving aripiprazole (Analysis 2.16).

3. COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE

Eighty studies (n = 6381) report data for the primary outcome of clinically significant response for this important comparison. Risperidone, now off-licence, is inexpensive and widely accessible; aripiprazole is not. Data are, again, of limited quality (randomisation and concealment methods being unclear, Summary of findings 3), however, this current update search has provided data that were lacking in the previous version of this review, including global functioning, and economic analyses; however, service use data are still missing. The majority of reported data are short term; adverse effects were selectively reported and studies were often sponsored by pharmaceutical companies.

For global outcomes there were no convincing differences between the two drugs (Analysis 3.1, Analysis 3.2, Analysis 3.3, Analysis 3.4). Binary mental state data were largely equivocal, with the exception of anxiety, which was significantly higher in people receiving aripiprazole (Analysis 3.5). Scale data for mental state favoured aripiprazole using the BPRS and PANSS average endpoint negative score (Analysis 3.6; Analysis 3.8). As regards adverse effects, the only convincing data were for tachycardia (Analysis 3.16) and abnormal liver function (Analysis 3.15) in risperidone. Risperidone also carried greater risk of metabolic adverse effects (Analysis 3.25) including weight gain, menstrual disorder and lactation. General EPS, akathisia, tremor and dystonia were all significantly higher in people receiving risperidone than aripiprazole (Analysis 3.21). Again, headache (Analysis 3.18), and nausea and vomiting were significantly more prominent in people receiving aripiprazole (Analysis 3.23). Both drugs may cause movement disorders and about one third of people allocated aripiprazole used antiparkinsonian drugs (Analysis 3.21).

4. COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE

The addition of new Chinese studies gave us an additional 15 studies to add to the previous one in this comparison. Ziprasidone is a major competitor of aripiprazole but data are of limited quality (Summary of findings 4), and there are still no data for service use. Data are all short term (four weeks).

There really does seem to be very little suggestion of differences in global state, attrition (about one third of people left in a matter of a few weeks) and mental state; however, there was greater improvement noted using SANS in people receiving aripiprazole in three RCTs (n = 238).

As regards adverse effects, there were largely no clear differences between groups; however, people receiving aripiprazole were significantly more likely to show signs of dizziness and insomnia (Analysis 4.11) as well as weight gain (Analysis 4.16). There is a need for better trials providing clear information for all interested in the care of people with schizophrenia who have access to these drugs.

5. COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE

Nineteen studies reported data for this comparison, see Summary of findings 5. Data are generally of poor quality and we found no data on indices including service use or global functioning. The inclusion of new Chinese studies gave data for quality of life outcomes (one RCT), which were lacking in the previous version of this review. The studies, although randomised and blinded, lack clarity on how both were carried out. Some studies were sponsored by pharmaceutical companies and adverse effects were seemingly selectively reported.

Even with the addition of new studies, global state outcomes show no clear differences between the drugs and the various measures of mental state did not clearly point to an advantage of one drug over another. The only significant findings from PANSS showed greater improvement in positive symptoms over each short, medium and long term combined (Analysis 5.11). Approaching 50% of people left these studies for any reason (Analysis 5.27) which may be a reflection of study design.

Regarding adverse effects, extrapyramidal side effects did not appear to be  a major problem. Weight gain appears to be olanzapine’s major shortcoming when compared with aripiprazole (Analysis 5.24). This is important as there were significantly smaller mean increase of cholesterol levels from baseline in the aripiprazole group than in people allocated olanzapine (Analysis 5.25). Few people like gain weight or to be exposed to risks resulting from higher cholesterol levels. Olanzapine seemed to have a higher sedative effect on people in two randomised trials (Analysis 5.19).

6. COMPARISON 6. ARIPIPRAZOLE versus OLANZAPINE (in acutely agitated patients)

These results were based on a single five-day trial but with nearly 500 participants. This comparison was included to comply with the protocol of this review but, in retrospect, we feel would be best in a separate review and are pleased to see that this is underway (Pagadala 2009). Overall, the results suggest that the two drugs may be of some use in the acute situation but data are few, not of high quality, undertaken by those with a pecuniary interest in the findings, and do not have a comparison group of other more widely used treatments for acute agitation thought due to serious mental illness.

Very few (0.83%) participants left the study early with numbers being similar in both groups. This very low figure may reflect the coercive nature of the treatment and that people were not free to leave. This is an observation and is not meant as criticism as this too may reflect real-world practice.

7. COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS

The studies were randomised but no concealment methods were clarified. We do think the comparison of aripiprazole with any one of several new generation antipsychotic drugs is practical and reflects real-world practice. One of the studies reported quality of life measures, which we feel gives a fresh dimension to the comparison. Although some attempts were made to incorporate clinically important issues, the overall quality of evidence remains low.

Many general measures did improve with aripiprazole although there was not any difference for sexual dysfunction. Several measures of mental state did not improve although evidence of limited quality did show some advantage of aripiprazole for negative symptoms. This latter finding is important and should be replicated in a study independent of industry conflicts of interest.

We are not sure why people with schizophrenia reported aripiprazole being preferred when their carers did not (Analysis 7.4). This could be a chance finding. Despite this expression of preference, about one third of participants left the trial early. Perhaps this is reflective of a vote of lack of confidence for the trial design rather than the drug itself.

It is good that quality of life is now recorded as a matter of routine in these studies but not good that it is measured by many scales that are problematic to interpret. Partly as a result of this, we are unsure of the effects of aripiprazole on quality of life compared with several of its competitors.

Aripiprazole is not free of adverse effects but there may be slightly less overall than with the other drugs. Nausea may be a problem (Analysis 7.16) but weight gain less problematic than other drugs.

Overall completeness and applicability of evidence

1. Completeness

Randomised evidence is available for only five out of eight possible comparisons of aripiprazole with other second generation antipsychotic drugs, although three studies compared aripiprazole with other atypical antipsychotics grouped together. Overall, evidence is incomplete. We do not have any good data on the implications of the use of aripiprazole on use of services from trials and we do think that 'admission' is a key outcome for people with schizophrenia. There are also very few economic data, which could be most important in this area.

2. Applicability

In terms of applicability, we highlight that most included studies were 'efficacy' studies. Large and simple, pragmatic, real-world effectiveness studies are not available, greatly limiting external validity (Thorpe 2009).

Quality of the evidence

All studies were randomised and double blind or open label, but details were rarely presented. It is therefore unclear whether randomisation and blinding, where mentioned, were really appropriately done. The high number of participants leaving studies early (between 30% to 40% overall) must call into question the credibility of the findings (Xia 2007) because, once a person is lost to follow-up outcomes become a matter of assumption. Three long-term studies were available but in a chronic, often life-long, disorder such as schizophrenia it is important that many more participants are followed up for longer. Overall, we considered the quality of evidence to be 'medium' at best with a moderate risk of bias.

Potential biases in the review process

It is possible that some important information may have been excluded during the review process due to human error or information not being available. New data from 162 Chinese studies that were previously awaiting assessment did not substantially change the findings of the first review, however they have given us more comparisons and increased precision whilst not clearly effecting overall quality of data.

Agreements and disagreements with other studies or reviews

An earlier Cochrane review compared aripiprazole with any other antipsychotic drugs (EL-Sayeh 2006). In this past review authors combined olanzapine and risperidone as one group of 'atypical antipsychotic' drugs. A subsequent review comparing aripiprazole with other atypical antipsychotics was also published (Komossa 2009) where the authors concluded that aripiprazole was not much different from other second generation antipsychotic drugs. This current update again concludes that aripiprazole was similar to other atypical antipsychotic drugs but we have found some evidence of it being better tolerated than its competitors.

Authors' conclusions

Implications for practice

1. For people with schizophrenia

For people with schizophrenia, it may be important to know that aripiprazole may be slightly less effective than olanzapine, but is less associated with adverse effects such as weight gain, cholesterol and prolactin increase and sedation. Aripiprazole's efficacy seems to be similar to that of risperidone, but certain movement disorders, cholesterol and prolactin increase may occur less frequently when taking aripiprazole. Aripiprazole may also be slightly better than ziprasidone with no clear differences apparent in adverse effects. When compared to other atypical antipsychotics as a group, people allocated to aripiprazole preferred its use. However, effects on quality of life were similar and carers found the two groups to be similar.

2. For clinicians

Clinicians should know that randomised evidence of the effects of aripiprazole compared with other second generation antipsychotic drugs is only available for a few drugs. Aripiprazole does not seem dogged by the problems of weight gain and raised prolactin. As with many antipsychotic drugs, it may, however, cause some extrapyramidal effects. More studies are needed to clarify the role of aripiprazole compared to other second generation antipsychotic drugs.

3. For managers/policy makers

Data that are relevant for policy makers such as service utilisation, functioning in society or costs are not available. We therefore find it difficult to make recommendations for decision makers.

Implications for research

1. General

Outcome reporting remains insufficient in antipsychotic drug trials. Strict adherence to the CONSORT statement (Moher 2001) would make such studies much more informative. Making all data available would set this compound far ahead of its competitors (ALLTRIALS). Increasingly healthcare sub-specialities are gaining universal agreement on core outcomes to be reported within all trials (COMET). This would greatly reduce disaggregation of data and add to the power of reviews such as this.

2. Specific

2.1 Reviews

Many interesting and potentially informative trials have had to be excluded as they are not of direct relevance to this review. Suggestions for their use within reviews are given in Table 1.

Table 1. Titles for reviews suggested by excluded studies
  1. * It is possible that these studies could also contribute to other titles not referenced in this column.

Suggested title/ongoing titleExcluded studyReference to relevant ongoing Cochrane title*
Alpha-receptor agonists for schizophrenia Bergman 2007  Currently no review.
Antidepressant augmentation of antipsychotic drugs for schizophrenia Fawzi 2009   Whitehead 2002
Aripiprazole augmentation of other antipsychotics for schizophrenia Bristol-Myers 2006, Shim 2006 Maayan 2011
Aripiprazole for people with metabolic syndrome Colombo 2008 Mukundan 2010
Aripiprazole versus first generation antipsychotics for schizophrenia Carson 2000, Mossner 2009, Talbott 2007, Taylor 2007 Bhattacharjee 2008
Aripiprazole versus placebo for schizophrenia Carson 2000, Henderson 2009, Mortimer 2004 Belgamwar 2011
Augmentation of clozapine for schizophrenia Fleischhacker 2008a, Kim 2006, Ma 2007, Millar 2008, Namey 2006, Remington 2009     Cipriani 2009
Psychosocial intervention for schizophrenia Anon 2008Unclear which of the many reviews would be relevant.
Switching from other antipsychotics to aripiprazole for schizophrenia Janssen 2005, Lan 2008, Pae 2009a, Schreiner 2009, Takeuchi 2008   Mukundan 2010
2.2 Trials

There is much room for further, better, randomised trials comparing aripiprazole with other second generation antipsychotic drugs. Comparisons with amisulpride, sertindole and zotepine are currently missing. We present a suggestion in Table 2 recognising that much goes into design and conduct of such a large study that cannot be captured in a table.

Table 2. Suggested design of future study
  1. * power calculation suggested 300/group would allow good chance of showing a 10% difference between groups for primary outcome.

    ** Primary outcome
    CGI: Clinical Global Impression Scale
    PANSS: Positive and Negative Syndrome Scale
    UKU: Udvalg for kliniske ndersogelser Side Effect Rating Scale -side effect rating scale

MethodsAllocation: randomised - clearly described generation of sequence and concealment of allocation.
Blindness: double - described and tested.
Duration: six months minimum.
ParticipantsDiagnosis: schizophrenia (operational criteria).
N = 2700.*
Age: any.
Gender: both.
History: any.
Interventions1. Aripiprazole: dose ˜ 10-30 mg/day. N = 300.
2. Amisulpride: dose ˜ 400-800 mg/day. N = 300.
3. Clozapine: dose ˜ 300-800 mg/day. N = 300.
4. Olanzapine: dose ˜ 10-20 mg/day. N = 300.
5. Quetiapine: dose ˜300-800 mg/day. N = 300.
6. Risperidone: dose ˜ 4-8 mg/day. N = 300.
7. Sertindole: dose ˜ 12-24 mg/day. N = 300.
8. Ziprasidone: dose ˜ 120-160 mg/day. N = 300.
9. Zotepine: dose ˜ 100-300 mg/day. N = 300.
OutcomesLeaving study early (any reason, adverse events, inefficacy).
Service outcomes: hospitalised, time in hospital, attending out patient clinics.
Global impression: CGI**, relapse.
Mental state: PANSS.
Adverse events/effects: UKU, major adverse event/effect.
Employment, living independently, family satisfaction, patient satisfaction.

Acknowledgements

We would like to thank all members of the Cochrane Schizophrenia Group editorial base for their editorial assistance, and Ben Gray for writing the plain language summary. The Cochrane Schizophrenia Group provides and maintains a standard template of text for the methods section of their reviews. We have used this and adapted it so it is relevant for this review.

We would like to acknowledge and thank Werner Kissling, Heike Hunger, Sandra Schwaz and Franziska Schmid for their contributions in previous versions of this review.

We thank Heather Maxwell for copy editing this review, her skill in this area is greatly appreciated.

Data and analyses

Download statistical data

Comparison 1. COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global state: 1. No clinically significant response (as defined by the original studies)292132Risk Ratio (M-H, Random, 95% CI)1.05 [0.87, 1.27]
2 Mental state: 1. Specific - binary outcomes11 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 anxiety (short term, up to 12 weeks)11732Risk Ratio (M-H, Random, 95% CI)2.62 [1.21, 5.70]
2.2 anxiety (medium term, 12 to 26 weeks)190Risk Ratio (M-H, Random, 95% CI)0.33 [0.04, 3.08]
2.3 agitation (short term, up to 12 weeks)160Risk Ratio (M-H, Random, 95% CI)1.87 [0.18, 19.55]
3 Mental state: 2. Average endpoint scores of various scales (short term, up to 12 weeks, high=poor)27 Mean Difference (IV, Random, 95% CI)Subtotals only
3.1 BPRS5426Mean Difference (IV, Random, 95% CI)-0.22 [-1.44, 1.00]
3.2 PANSS231638Mean Difference (IV, Random, 95% CI)-0.10 [-1.41, 1.22]
3.3 SANS150Mean Difference (IV, Random, 95% CI)-2.27 [-6.27, 1.73]
4 Mental state: 3. Average endpoint scores of various scales (medium term, 12 to 26 weeks, high=poor)3 Mean Difference (IV, Random, 95% CI)Subtotals only
4.1 PANSS3236Mean Difference (IV, Random, 95% CI)-5.41 [-8.42, -2.41]
5 Mental state: 4. Average endpoint scores of various scales (skewed data, high=poor)  Other dataNo numeric data
5.1 BPRS  Other dataNo numeric data
5.2 PANSS  Other dataNo numeric data
5.3 PANSS negative symptom subscale score  Other dataNo numeric data
6 Mental state: 5. Specific - average endpoint positive score (PANSS, high=poor)221523Mean Difference (IV, Random, 95% CI)0.27 [-0.48, 1.02]
6.1 by up to 12 weeks - short term191287Mean Difference (IV, Random, 95% CI)0.35 [-0.50, 1.20]
6.2 from 12-26 weeks - medium term3236Mean Difference (IV, Random, 95% CI)-0.23 [-1.79, 1.34]
7 Mental state: 6. Specific - average endpoint negative score (PANSS, high=poor)231640Mean Difference (IV, Random, 95% CI)-0.61 [-1.53, 0.30]
7.1 up to 12 weeks - short term201404Mean Difference (IV, Random, 95% CI)-0.04 [-0.79, 0.71]
7.2 from 12-26 weeks - medium term3236Mean Difference (IV, Random, 95% CI)-3.24 [-5.82, -0.67]
8 Mental state: 7. Specific - average endpoint general psychopathological score (PANSS, high=poor )191330Mean Difference (IV, Random, 95% CI)-0.27 [-0.78, 0.23]
8.1 up to 12 weeks - short term161094Mean Difference (IV, Random, 95% CI)-0.08 [-0.62, 0.45]
8.2 from 12-26 weeks - medium term3236Mean Difference (IV, Random, 95% CI)-1.89 [-3.45, -0.34]
9 Mental state: 8. Specific - average total score decreased rate (PANSS, low=poor)1 Mean Difference (IV, Random, 95% CI)Subtotals only
9.1 by up to 12 weeks1118Mean Difference (IV, Random, 95% CI)0.06 [-0.03, 0.15]
10 Mental state: 9. Specific - average positive score decreased rate (PANSS, low=poor)1 Mean Difference (IV, Random, 95% CI)Subtotals only
10.1 by up to 12 weeks - short term1118Mean Difference (IV, Random, 95% CI)-0.01 [-0.10, 0.08]
11 Leaving the study early4 Risk Ratio (M-H, Random, 95% CI)Subtotals only
11.1 Any reason3240Risk Ratio (M-H, Random, 95% CI)1.41 [0.46, 4.29]
11.2 Adverse events3212Risk Ratio (M-H, Random, 95% CI)0.76 [0.20, 2.92]
11.3 Economic issues1120Risk Ratio (M-H, Random, 95% CI)2.0 [0.38, 10.51]
12 Quality of life: 1a. Average scores (short term, up to 12 weeks, WHO-QOL-100, low=poor)4 Mean Difference (IV, Random, 95% CI)Subtotals only
12.1 endpoint scale score2132Mean Difference (IV, Random, 95% CI)2.59 [1.43, 3.74]
12.2 physical health2132Mean Difference (IV, Random, 95% CI)7.73 [1.51, 13.94]
12.3 mental health2132Mean Difference (IV, Random, 95% CI)9.21 [4.74, 13.68]
12.4 social function2132Mean Difference (IV, Random, 95% CI)7.78 [-0.98, 16.54]
12.5 external environmental3248Mean Difference (IV, Random, 95% CI)13.82 [8.69, 18.94]
12.6 independence172Mean Difference (IV, Random, 95% CI)0.08 [-1.62, 1.78]
12.7 spiritual support172Mean Difference (IV, Random, 95% CI)6.61 [4.25, 8.97]
13 Quality of life: 1b. Average scores (medium term, 12 to 24 weeks, WHO-QOL-100, low=poor)3 Mean Difference (IV, Random, 95% CI)Subtotals only
13.1 endpoint scale score2176Mean Difference (IV, Random, 95% CI)2.75 [1.98, 3.53]
13.2 physical health3256Mean Difference (IV, Random, 95% CI)4.89 [0.22, 9.56]
13.3 mental health3256Mean Difference (IV, Random, 95% CI)7.39 [5.26, 9.53]
13.4 social function3256Mean Difference (IV, Random, 95% CI)6.68 [2.79, 10.56]
13.5 material life180Mean Difference (IV, Random, 95% CI)-0.80 [-2.00, 2.40]
13.6 independence2176Mean Difference (IV, Random, 95% CI)6.71 [4.76, 8.66]
13.7 spiritual support2176Mean Difference (IV, Random, 95% CI)-0.31 [-1.37, 0.75]
14 Quality of life: 2. Average endpoint general quality of life score (GQOLI - 74, low=poor)2 Mean Difference (IV, Random, 95% CI)Subtotals only
14.1 Total score1114Mean Difference (IV, Random, 95% CI)0.5 [-3.40, 4.40]
14.2 Physical health1120Mean Difference (IV, Random, 95% CI)7.70 [2.95, 12.45]
14.3 Mental health1120Mean Difference (IV, Random, 95% CI)2.70 [-2.30, 7.70]
14.4 Social function1120Mean Difference (IV, Random, 95% CI)6.60 [3.15, 10.05]
14.5 Material life1120Mean Difference (IV, Random, 95% CI)0.10 [-5.30, 5.50]
14.6 Environmental area (medium term)190Mean Difference (IV, Random, 95% CI)11.5 [5.55, 17.45]
14.7 Independence (medium term)190Mean Difference (IV, Random, 95% CI)6.16 [2.84, 9.48]
15 Adverse effects: 1. At least one adverse effect151582Risk Ratio (M-H, Random, 95% CI)0.62 [0.47, 0.81]
15.1 Non-specific7574Risk Ratio (M-H, Random, 95% CI)0.67 [0.48, 0.95]
15.2 epilepsy160Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.87]
15.3 liver function abnormal5364Risk Ratio (M-H, Random, 95% CI)0.49 [0.16, 1.56]
15.4 stuffy nose3258Risk Ratio (M-H, Random, 95% CI)0.50 [0.21, 1.20]
15.5 sweating174Risk Ratio (M-H, Random, 95% CI)0.35 [0.04, 3.23]
15.6 urinary retention2132Risk Ratio (M-H, Random, 95% CI)1.00 [0.11, 9.39]
15.7 urinary incontinence2120Risk Ratio (M-H, Random, 95% CI)0.18 [0.02, 1.54]
16 Adverse effects: 2. Cardiac effects25 Risk Ratio (M-H, Random, 95% CI)Subtotals only
16.1 abnormal ECG (short term, up to 12 weeks)12921Risk Ratio (M-H, Random, 95% CI)0.38 [0.29, 0.51]
16.2 blood pressure- decrease (short term, up to 12 weeks)3194Risk Ratio (M-H, Random, 95% CI)0.57 [0.23, 1.43]
16.3 general adverse cardiac events (short term, up to 12 weeks)162Risk Ratio (M-H, Random, 95% CI)0.32 [0.17, 0.60]
16.4 QTc prolongation (short term, up to 12 weeks)4334Risk Ratio (M-H, Random, 95% CI)0.16 [0.05, 0.49]
16.5 tachycardia (short term, up to 12 weeks)151104Risk Ratio (M-H, Random, 95% CI)0.29 [0.22, 0.38]
16.6 QTc prolongation (medium term, 12 to 24 weeks)190Risk Ratio (M-H, Random, 95% CI)0.05 [0.00, 0.79]
16.7 tachycardia (medium term, 12 to 24 weeks)160Risk Ratio (M-H, Random, 95% CI)0.09 [0.01, 1.57]
17 Adverse effects: 3. Central / peripheral nervous system26 Risk Ratio (M-H, Random, 95% CI)Subtotals only
17.1 activity- decrease (short term, up to 12 weeks)1120Risk Ratio (M-H, Random, 95% CI)0.21 [0.10, 0.48]
17.2 activity- increase (short term, up to 12 weeks)148Risk Ratio (M-H, Random, 95% CI)4.26 [0.22, 84.28]
17.3 blurred vision (short term, up to 12 weeks)6472Risk Ratio (M-H, Random, 95% CI)0.29 [0.12, 0.66]
17.4 dizziness (short term, up to 12 weeks)9698Risk Ratio (M-H, Random, 95% CI)0.60 [0.36, 1.00]
17.5 fatigue (short term, up to 12 weeks)4300Risk Ratio (M-H, Random, 95% CI)0.57 [0.27, 1.23]
17.6 general central nervous system adverse reaction (short term, up to 12 weeks)162Risk Ratio (M-H, Random, 95% CI)2.0 [0.55, 7.29]
17.7 general vegetative nervous system adverse reaction (short term, up to 12 weeks)162Risk Ratio (M-H, Random, 95% CI)0.48 [0.27, 0.84]
17.8 headache (short term, up to 12 weeks)161102Risk Ratio (M-H, Random, 95% CI)2.28 [1.07, 4.86]
17.9 hyper-salivation (short term, up to 12 weeks)161074Risk Ratio (M-H, Random, 95% CI)0.06 [0.03, 0.10]
17.10 insomnia (short term, up to 12 weeks)14990Risk Ratio (M-H, Random, 95% CI)5.62 [2.90, 10.91]
17.11 irritability (short term, up to 12 weeks)2120Risk Ratio (M-H, Random, 95% CI)6.77 [0.82, 55.80]
17.12 memory decline (short term, up to 12 weeks)180Risk Ratio (M-H, Random, 95% CI)0.13 [0.02, 0.95]
17.13 sedation (short term, up to 12 weeks)180Risk Ratio (M-H, Random, 95% CI)0.03 [0.00, 0.52]
17.14 somnolence (short term, up to 12 weeks)211492Risk Ratio (M-H, Random, 95% CI)0.15 [0.09, 0.24]
17.15 insomnia (medium term, 12 to 24 weeks)190Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 71.74]
17.16 headache (medium term, 12 to 24 weeks)190Risk Ratio (M-H, Random, 95% CI)0.5 [0.10, 2.59]
18 Adverse effects: 4. Extrapyramidal effects21 Risk Ratio (M-H, Random, 95% CI)Subtotals only
18.1 akathisia (short term, up to 12 weeks)13916Risk Ratio (M-H, Random, 95% CI)1.21 [0.54, 2.68]
18.2 dystonia (short term, up to 12 weeks)5374Risk Ratio (M-H, Random, 95% CI)3.24 [1.29, 8.12]
18.3 general extrapyramidal symptoms (short term, up to 12 weeks)8520Risk Ratio (M-H, Random, 95% CI)1.91 [0.75, 4.85]
18.4 tardive dyskinesia (short term, up to 12 weeks)172Risk Ratio (M-H, Random, 95% CI)1.0 [0.15, 6.72]
18.5 tremor (short term, up to 12 weeks)6460Risk Ratio (M-H, Random, 95% CI)1.99 [0.72, 5.48]
18.6 use of antiparkinson medication (short term, up to 12 weeks)2140Risk Ratio (M-H, Random, 95% CI)2.84 [0.07, 117.07]
18.7 akathisia (medium term, 12 to 24 weeks)180Risk Ratio (M-H, Random, 95% CI)0.33 [0.04, 3.07]
18.8 dystonia (medium term, 12 to 24 weeks)180Risk Ratio (M-H, Random, 95% CI)0.5 [0.05, 5.30]
18.9 spasmodic torticollis (medium term, 12 to 24 weeks)180Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.95]
18.10 tremor (medium term, 12 to 24 weeks)180Risk Ratio (M-H, Random, 95% CI)1.0 [0.15, 6.76]
19 Adverse effects: 6. Haematological17 Risk Ratio (M-H, Random, 95% CI)Subtotals only
19.1 abnormal blood routine (short term, up to 12 weeks)5368Risk Ratio (M-H, Random, 95% CI)0.16 [0.04, 0.60]
19.2 leucopenia (short term, up to 12 weeks)10726Risk Ratio (M-H, Random, 95% CI)0.21 [0.08, 0.56]
19.3 abnormal blood routine (medium term, 12 to 24 weeks)2152Risk Ratio (M-H, Random, 95% CI)0.32 [0.14, 0.75]
20 Adverse effects: 5. Gastrointestinal22 Risk Ratio (M-H, Random, 95% CI)Subtotals only
20.1 abdominal discomfort / pain (short term, up to 12 weeks)2132Risk Ratio (M-H, Random, 95% CI)10.21 [1.32, 79.12]
20.2 constipation (short term, up to 12 weeks)191390Risk Ratio (M-H, Random, 95% CI)0.15 [0.08, 0.31]
20.3 dry mouth (short term, up to 12 weeks)4268Risk Ratio (M-H, Random, 95% CI)0.64 [0.08, 5.38]
20.4 general gastrointestinal aderse reaction (short term, up to 12 weeks)2130Risk Ratio (M-H, Random, 95% CI)1.17 [0.41, 3.39]
20.5 indigestion (short term, up to 12 weeks)160Risk Ratio (M-H, Random, 95% CI)0.47 [0.04, 4.89]
20.6 nausea / vomiting (short term, up to 12 weeks)10790Risk Ratio (M-H, Random, 95% CI)1.55 [0.71, 3.38]
20.7 constipation (medium term, 12 to 24 weeks)190Risk Ratio (M-H, Random, 95% CI)0.02 [0.00, 0.36]
20.8 hyper-salivation (medium term, 12 to 24 weeks)190Risk Ratio (M-H, Random, 95% CI)0.02 [0.00, 0.29]
21 Adverse effects: 7. Hormonal3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
21.1 lactation/menstrual changes (short term, up to 12 weeks)3214Risk Ratio (M-H, Random, 95% CI)0.11 [0.03, 0.47]
22 Adverse effects: 8a. Metabolic - binary measures20 Risk Ratio (M-H, Random, 95% CI)Subtotals only
22.1  blood glucose - increased (short term, up to 12 weeks)5410Risk Ratio (M-H, Random, 95% CI)0.12 [0.04, 0.37]
22.2  C-peptide (short term, up to 12 weeks)160Risk Ratio (M-H, Random, 95% CI)0.03 [0.00, 0.45]
22.3 decreased appetite (short term, up to 12 weeks)2130Risk Ratio (M-H, Random, 95% CI)0.07 [0.01, 0.54]
22.4 postural hypotension (short term, up to 12 weeks)5344Risk Ratio (M-H, Random, 95% CI)0.16 [0.07, 0.39]
22.5 PRL- increase (short term, up to 12 weeks)148Risk Ratio (M-H, Random, 95% CI)0.05 [0.00, 0.82]
22.6 weight gain (short term, up to 12 weeks)181318Risk Ratio (M-H, Random, 95% CI)0.13 [0.08, 0.22]
22.7 blood glucose - increased (medium term, 12 to 24 weeks)190Risk Ratio (M-H, Random, 95% CI)0.08 [0.00, 1.33]
22.8 decreased appetite (medium term, 12 to 24 weeks)190Risk Ratio (M-H, Random, 95% CI)0.06 [0.00, 0.99]
22.9 weight gain (medium term, 12 to 24 weeks)190Risk Ratio (M-H, Random, 95% CI)0.02 [0.00, 0.39]
23 Adverse effects: 8b. Metabolic - continuous measures (short term, up to 12 weeks, high=poor)3 Mean Difference (IV, Random, 95% CI)Subtotals only
23.1 blood glucose - FPG in HbA1c normal group (in mmol/l)136Mean Difference (IV, Random, 95% CI)0.0 [-0.39, 0.39]
23.2 blood glucose - FPG in HbA1c abnormal group (in mmol/l)119Mean Difference (IV, Random, 95% CI)0.0 [-0.61, 0.61]
23.3 blood glucose - PBG in HbA1c normal group (in mmol/l)136Mean Difference (IV, Random, 95% CI)-0.20 [-0.66, 0.26]
23.4 blood glucose - PBG in HbA1c abnormal group (in mmol/l)119Mean Difference (IV, Random, 95% CI)-1.90 [-2.63, -1.17]
23.5 blood glucose - FPG average endpoint (in mmol/l)2134Mean Difference (IV, Random, 95% CI)-0.52 [-0.83, -0.22]
23.6 blood glucose - C-peptide average endpoint (in mg/dlmmol/l)160Mean Difference (IV, Random, 95% CI)-0.72 [-1.45, 0.01]
23.7 weight gain - average endpoint level (in kg)174Mean Difference (IV, Random, 95% CI)-1.99 [-5.56, 1.58]
24 Cost effectiveness analysis (high=poor, data skewed)  Other dataNo numeric data
24.1 Cost of hospitalisation (in RMB)  Other dataNo numeric data
24.2 Cost of drug (in RMB)  Other dataNo numeric data
24.3 Length of hospitalisation (day)  Other dataNo numeric data
Analysis 1.1.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 1 Global state: 1. No clinically significant response (as defined by the original studies).

Analysis 1.2.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 2 Mental state: 1. Specific - binary outcomes.

Analysis 1.3.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 3 Mental state: 2. Average endpoint scores of various scales (short term, up to 12 weeks, high=poor).

Analysis 1.4.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 4 Mental state: 3. Average endpoint scores of various scales (medium term, 12 to 26 weeks, high=poor).

Analysis 1.5.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 5 Mental state: 4. Average endpoint scores of various scales (skewed data, high=poor).

Mental state: 4. Average endpoint scores of various scales (skewed data, high=poor)
StudyInterventionMeanSDNNotes
BPRS
Xiao 2007Aripiprazole15.337.9636 
Xiao 2007Clozapine15.9111.2236 
PANSS
Jiang 2009Aripiprazole53.213.940 
Jiang 2009Clozapine11.25.940 
PANSS negative symptom subscale score
Jiang 2009Aripiprazole16.46.540 
Jiang 2009Clozapine11.25.940 
Liu 2008Aripiprazole11.717.6031 
Liu 2008Clozapine11.826.7731 
Xiao 2007Aripiprazole6.315.2436 
Xiao 2007Clozapine13.375.1536 
Analysis 1.6.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 6 Mental state: 5. Specific - average endpoint positive score (PANSS, high=poor).

Analysis 1.7.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 7 Mental state: 6. Specific - average endpoint negative score (PANSS, high=poor).

Analysis 1.8.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 8 Mental state: 7. Specific - average endpoint general psychopathological score (PANSS, high=poor ).

Analysis 1.9.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 9 Mental state: 8. Specific - average total score decreased rate (PANSS, low=poor).

Analysis 1.10.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 10 Mental state: 9. Specific - average positive score decreased rate (PANSS, low=poor).

Analysis 1.11.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 11 Leaving the study early.

Analysis 1.12.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 12 Quality of life: 1a. Average scores (short term, up to 12 weeks, WHO-QOL-100, low=poor).

Analysis 1.13.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 13 Quality of life: 1b. Average scores (medium term, 12 to 24 weeks, WHO-QOL-100, low=poor).

Analysis 1.14.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 14 Quality of life: 2. Average endpoint general quality of life score (GQOLI - 74, low=poor).

Analysis 1.15.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 15 Adverse effects: 1. At least one adverse effect.

Analysis 1.16.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 16 Adverse effects: 2. Cardiac effects.

Analysis 1.17.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 17 Adverse effects: 3. Central / peripheral nervous system.

Analysis 1.18.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 18 Adverse effects: 4. Extrapyramidal effects.

Analysis 1.19.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 19 Adverse effects: 6. Haematological.

Analysis 1.20.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 20 Adverse effects: 5. Gastrointestinal.

Analysis 1.21.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 21 Adverse effects: 7. Hormonal.

Analysis 1.22.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 22 Adverse effects: 8a. Metabolic - binary measures.

Analysis 1.23.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 23 Adverse effects: 8b. Metabolic - continuous measures (short term, up to 12 weeks, high=poor).

Analysis 1.24.

Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 24 Cost effectiveness analysis (high=poor, data skewed).

Cost effectiveness analysis (high=poor, data skewed)
StudyInterventionMeanSDNNote
Cost of hospitalisation (in RMB)
Liu 2010Aripiprazole3413.661815.0530 
Liu 2010Clozapine4582.003372.4228 
Cost of drug (in RMB)
Liu 2010Aripiprazole418.13326.4330 
Liu 2010Clozapine210.39300.3228 
Length of hospitalisation (day)
Liu 2010Aripiprazole33.1916.7130 
Liu 2010Clozapine49.5030.8328 
Comparison 2. COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global state: 1.No clinically significant response (as defined by original studies)12991Risk Ratio (M-H, Random, 95% CI)0.92 [0.64, 1.32]
2 Global state: 2a. Average endpoint total score (short term, up to 12 weeks, high=poor)11991Mean Difference (IV, Random, 95% CI)-1.00 [-2.58, 0.57]
2.1 CGI180Mean Difference (IV, Random, 95% CI)0.10 [-0.49, 0.69]
2.2 PANSS10831Mean Difference (IV, Random, 95% CI)-0.88 [-3.15, 1.40]
2.3 BPRS180Mean Difference (IV, Random, 95% CI)-2.63 [-4.55, -0.71]
3 Global state: 2b. Average endpoint scale score (medium term, 12 to 24 weeks, high=poor)1 Mean Difference (IV, Random, 95% CI)Subtotals only
3.1 PANSS1100Mean Difference (IV, Random, 95% CI)-1.20 [-5.67, 3.27]
4 Global state: 3. Average endpoint SI score (CGI, high=poor)1 Mean Difference (IV, Random, 95% CI)Subtotals only
4.1 up to 12 weeks -short term1108Mean Difference (IV, Random, 95% CI)0.10 [-0.41, 0.61]
5 Mental state: 2a. Specific - binary outcomes8 Risk Ratio (M-H, Random, 95% CI)Subtotals only
5.1 agitation (short term, up to 12 weeks)5423Risk Ratio (M-H, Random, 95% CI)1.29 [0.27, 6.27]
5.2 anxiety (short term, up to 12 weeks)2168Risk Ratio (M-H, Random, 95% CI)2.18 [0.51, 9.35]
5.3 depression (short term, up to 12 weeks)1108Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.01]
5.4 agitation (medium term, 12 to 26 weeks)1100Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.99]
6 Mental state: 3. Specific - average endpoint positive score (PANSS, high=poor)8683Mean Difference (IV, Random, 95% CI)-0.83 [-1.99, 0.32]
6.1 by up to 12 weeks - short term7583Mean Difference (IV, Random, 95% CI)-0.97 [-2.34, 0.41]
6.2 from 12-26 weeks - medium term1100Mean Difference (IV, Random, 95% CI)-0.10 [-1.32, 1.12]
7 Mental state: 4. Specific - average endpoint negative score (PANSS, high=poor)7543Mean Difference (IV, Random, 95% CI)-0.48 [-1.17, 0.21]
7.1 up to 12 weeks - short term6443Mean Difference (IV, Random, 95% CI)-0.68 [-1.52, 0.17]
7.2 from 12-26 weeks - medium term1100Mean Difference (IV, Random, 95% CI)0.0 [-1.23, 1.23]
8 Mental state: 5. Specific - average endpoint general pathological score (PANSS, high=poor )11931Mean Difference (IV, Random, 95% CI)-1.69 [-3.81, 0.43]
8.1 up to 12 weeks - short term10831Mean Difference (IV, Random, 95% CI)-1.83 [-4.19, 0.54]
8.2 from 12-26 weeks - medium term1100Mean Difference (IV, Random, 95% CI)-0.40 [-2.52, 1.72]
9 Mental state: 6. average scores of various scales (high=poor, skewed data)  Other dataNo numeric data
9.1 BPRS endpoint scale score  Other dataNo numeric data
9.2 PANSS general pathology subscale score  Other dataNo numeric data
9.3 PANSS negative subscale score  Other dataNo numeric data
9.4 PANSS positive subscale score  Other dataNo numeric data
9.5 PANSS total endpoint scale score  Other dataNo numeric data
10 Leaving the study early2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
10.1 any reason2168Risk Ratio (M-H, Random, 95% CI)0.80 [0.22, 2.87]
10.2 no effect1108Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.01]
10.3 early discharge160Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 70.83]
10.4 early treatment termination2168Risk Ratio (M-H, Random, 95% CI)1.35 [0.09, 19.24]
10.5 violation of test scheme1108Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 101.77]
10.6 withdrew informed consent1108Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.01]
11 Quality of life: Average score (medium term, 12 to 24 weeks, WHO-QOL-100, low=poor)1 Mean Difference (IV, Random, 95% CI)Subtotals only
11.1 Total score1100Mean Difference (IV, Random, 95% CI)2.60 [1.31, 3.89]
11.2 Physical health1100Mean Difference (IV, Random, 95% CI)6.0 [4.38, 7.62]
11.3 Mental health1100Mean Difference (IV, Random, 95% CI)9.10 [5.92, 12.28]
11.4 Social function1100Mean Difference (IV, Random, 95% CI)5.60 [3.33, 7.87]
11.5 Spiritual pillar1100Mean Difference (IV, Random, 95% CI)0.10 [-1.49, 1.69]
11.6 Environmental area1100Mean Difference (IV, Random, 95% CI)11.5 [5.86, 17.14]
11.7 Independence1100Mean Difference (IV, Random, 95% CI)6.20 [3.05, 9.35]
12 Adverse effects:1. At least one adverse effect81362Risk Ratio (M-H, Random, 95% CI)0.89 [0.66, 1.20]
12.1 non-specific3258Risk Ratio (M-H, Random, 95% CI)0.98 [0.70, 1.37]
12.2 abnormal urinary test result1108Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.01]
12.3 liver function abnormal8658Risk Ratio (M-H, Random, 95% CI)0.54 [0.26, 1.13]
12.4 stuffy nose2188Risk Ratio (M-H, Random, 95% CI)3.0 [0.32, 28.32]
12.5 sweating170Risk Ratio (M-H, Random, 95% CI)1.0 [0.07, 15.36]
12.6 urine routine abnormal180Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.95]
13 Adverse effects: 2. Cardiac effects (short term, up to 12 weeks)9 Risk Ratio (M-H, Random, 95% CI)Subtotals only
13.1 abnormal ECG6528Risk Ratio (M-H, Random, 95% CI)0.95 [0.40, 2.26]
13.2 blood pressure- decrease4348Risk Ratio (M-H, Random, 95% CI)0.52 [0.20, 1.32]
13.3 QTc prolongation3225Risk Ratio (M-H, Random, 95% CI)0.34 [0.08, 1.39]
13.4 tachycardia8643Risk Ratio (M-H, Random, 95% CI)0.35 [0.18, 0.69]
14 Adverse effects: 3. Central / peripheral nervous system10 Risk Ratio (M-H, Random, 95% CI)Subtotals only
14.1 blurred vision (short term, up to 12 weeks)6521Risk Ratio (M-H, Random, 95% CI)0.88 [0.31, 2.49]
14.2 dizziness (short term, up to 12 weeks)8671Risk Ratio (M-H, Random, 95% CI)0.64 [0.34, 1.22]
14.3 headache (short term, up to 12 weeks)5436Risk Ratio (M-H, Random, 95% CI)3.15 [0.52, 18.94]
14.4 insomnia (short term, up to 12 weeks)7591Risk Ratio (M-H, Random, 95% CI)2.12 [0.88, 5.10]
14.5 somnolence (short term, up to 12 weeks)9731Risk Ratio (M-H, Random, 95% CI)0.34 [0.15, 0.77]
14.6 dizziness (medium term, 12 to 24 weeks)1100Risk Ratio (M-H, Random, 95% CI)0.86 [0.31, 2.37]
14.7 headache (medium term, 12 to 24 weeks)1100Risk Ratio (M-H, Random, 95% CI)9.00 [1.18, 68.42]
14.8 insomnia (medium term, 12 to 24 weeks)1100Risk Ratio (M-H, Random, 95% CI)2.0 [0.19, 21.36]
14.9 somnolence (medium term, 12 to 24 weeks)1100Risk Ratio (M-H, Random, 95% CI)0.8 [0.34, 1.86]
15 Adverse effects: 4. Extrapyramidal symptoms - various (short term, up to 12 weeks)10 Risk Ratio (M-H, Random, 95% CI)Subtotals only
15.1 akathisia7571Risk Ratio (M-H, Random, 95% CI)1.15 [0.49, 2.70]
15.2 dystonia2145Risk Ratio (M-H, Random, 95% CI)0.47 [0.06, 3.53]
15.3 general extrapyramidal symptoms4348Risk Ratio (M-H, Random, 95% CI)2.80 [0.64, 12.31]
15.4 tremor4343Risk Ratio (M-H, Random, 95% CI)0.44 [0.09, 2.07]
16 Adverse effects: 5. Gastrointestinal8 Risk Ratio (M-H, Random, 95% CI)Subtotals only
16.1 constipation (short term, up to 12 weeks)7591Risk Ratio (M-H, Random, 95% CI)0.38 [0.19, 0.75]
16.2 dry mouth (short term, up to 12 weeks)7611Risk Ratio (M-H, Random, 95% CI)0.23 [0.10, 0.53]
16.3 nausea / vomiting (short term, up to 12 weeks)7611Risk Ratio (M-H, Random, 95% CI)2.68 [1.36, 5.26]
16.4 dry mouth (medium term, 12 to 24 weeks)1100Risk Ratio (M-H, Random, 95% CI)0.11 [0.01, 0.84]
16.5 nausea / vomiting (medium term, 12 to 24 weeks)1100Risk Ratio (M-H, Random, 95% CI)7.00 [0.89, 54.83]
17 Adverse effects: 6. Haematological3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
17.1 blood routine abnormal (short term, up to 12 weeks)185Risk Ratio (M-H, Random, 95% CI)0.31 [0.01, 7.43]
17.2 leucopenia (short term, up to 12 weeks)2140Risk Ratio (M-H, Random, 95% CI)1.0 [0.07, 15.26]
18 Adverse events: 7. Hormonal7 Risk Ratio (M-H, Random, 95% CI)Subtotals only
18.1 menstrual disorder (short term, up to 12 weeks)6518Risk Ratio (M-H, Random, 95% CI)0.58 [0.20, 1.64]
18.2 menstrual disorder (medium term, 12 to 24 weeks)1100Risk Ratio (M-H, Random, 95% CI)0.5 [0.05, 5.34]
19 Adverse effects: 8a. Metabolic - binary measures11 Risk Ratio (M-H, Random, 95% CI)Subtotals only
19.1 decreased appetite (short term, up to 12 weeks)4328Risk Ratio (M-H, Random, 95% CI)0.28 [0.06, 1.39]
19.2 lactation (short term, up to 12 weeks)5383Risk Ratio (M-H, Random, 95% CI)0.57 [0.17, 1.92]
19.3 weight gain (short term, up to 12 weeks)10823Risk Ratio (M-H, Random, 95% CI)0.45 [0.24, 0.85]
19.4 decreased appetite (medium term, 12 to 24 weeks)1100Risk Ratio (M-H, Random, 95% CI)0.13 [0.02, 0.96]
19.5 lactation (medium term, 12 to 24 weeks)1100Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
19.6 weight gain (medium term, 12 to 24 weeks)1100Risk Ratio (M-H, Random, 95% CI)0.5 [0.05, 5.34]
20 Adverse effects: 8b. Metabolic - continuous measure1 Mean Difference (IV, Random, 95% CI)Subtotals only
20.1 cholesterol - TC average endpoint level (in mmol/L, high=poor)1180Mean Difference (IV, Random, 95% CI)-0.19 [-0.36, -0.02]
20.2 cholesterol-TG average endpoint level (in mmol/L, high=poor)1180Mean Difference (IV, Random, 95% CI)-0.04 [-0.21, 0.13]
20.3 cholesterol - LDL average endpoint level (in mmol/L, high=poor)1180Mean Difference (IV, Random, 95% CI)-0.12 [-0.26, 0.02]
20.4 waistline- average endpoint level (in cm, high=poor)1180Mean Difference (IV, Random, 95% CI)-1.80 [-3.88, 0.28]
20.5 weight- average endpoint level (in Kg, high=poor)1180Mean Difference (IV, Random, 95% CI)1.30 [-1.30, 3.90]
20.6 cholesterol - HDL average endpoint (in mmol/L, low=poor))1180Mean Difference (IV, Random, 95% CI)-0.02 [-0.11, 0.07]
Analysis 2.1.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 1 Global state: 1.No clinically significant response (as defined by original studies).

Analysis 2.2.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 2 Global state: 2a. Average endpoint total score (short term, up to 12 weeks, high=poor).

Analysis 2.3.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 3 Global state: 2b. Average endpoint scale score (medium term, 12 to 24 weeks, high=poor).

Analysis 2.4.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 4 Global state: 3. Average endpoint SI score (CGI, high=poor).

Analysis 2.5.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 5 Mental state: 2a. Specific - binary outcomes.

Analysis 2.6.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 6 Mental state: 3. Specific - average endpoint positive score (PANSS, high=poor).

Analysis 2.7.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 7 Mental state: 4. Specific - average endpoint negative score (PANSS, high=poor).

Analysis 2.8.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 8 Mental state: 5. Specific - average endpoint general pathological score (PANSS, high=poor ).

Analysis 2.9.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 9 Mental state: 6. average scores of various scales (high=poor, skewed data).

Mental state: 6. average scores of various scales (high=poor, skewed data)
StudyInterventionMeanSDNNote
BPRS endpoint scale score
Zhu 2008Aripiprazole23.814.329 
Zhu 2008Quetiapine23.913.729 
PANSS general pathology subscale score
Zhu 2008Aripiprazole19.411.729 
Zhu 2008Quetiapine19.511.329 
PANSS negative subscale score
Dai 2005Aripiprazole11.87.140 
Dai 2005Quetiapine11.77. 640 
Ge 2010Aripiprazole12.883.5440 
Ge 2010Quetiapine15.128.1540 
Wei 2006Aripiprazole11.97.254 
Wei 2006Quetiapine11.87.654 
Zhu 2008Aripiprazole10.98.129 
Zhu 2008Quetiapine11.47.429 
PANSS positive subscale score
Chen 2009Aripiprazole10.15.130 
Chen 2009Quetiapine10.76.230 
Dai 2005Aripiprazole12.36.940 
Dai 2005Quetiapine12.67.140 
Wei 2006Aripiprazole12 .46.954 
Wei 2006Quetiapine12.57.154 
Zhu 2008Aripiprazole12.88.329 
Zhu 2008Quetiapine14.37.929 
PANSS total endpoint scale score
Zhu 2008Aripiprazole44.223.629 
Zhu 2008Quetiapine4.3824.229 
Analysis 2.10.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 10 Leaving the study early.

Analysis 2.11.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 11 Quality of life: Average score (medium term, 12 to 24 weeks, WHO-QOL-100, low=poor).

Analysis 2.12.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 12 Adverse effects:1. At least one adverse effect.

Analysis 2.13.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 13 Adverse effects: 2. Cardiac effects (short term, up to 12 weeks).

Analysis 2.14.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 14 Adverse effects: 3. Central / peripheral nervous system.

Analysis 2.15.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 15 Adverse effects: 4. Extrapyramidal symptoms - various (short term, up to 12 weeks).

Analysis 2.16.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 16 Adverse effects: 5. Gastrointestinal.

Analysis 2.17.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 17 Adverse effects: 6. Haematological.

Analysis 2.18.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 18 Adverse events: 7. Hormonal.

Analysis 2.19.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 19 Adverse effects: 8a. Metabolic - binary measures.

Analysis 2.20.

Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 20 Adverse effects: 8b. Metabolic - continuous measure.

Comparison 3. COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global state: 1. No clinically significant response (as defined by the original studies)80 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 by up to 12 weeks -- short term806381Risk Ratio (M-H, Random, 95% CI)1.08 [0.96, 1.21]
2 Global state: 2. Average endpoint total score(short term, up to 12 weeks, CGI, high=poor)2196Mean Difference (IV, Random, 95% CI)0.35 [0.09, 0.61]
3 Global state: 3. Average CGI subscale scores (short term, up to 12 weeks, high=poor)1240Mean Difference (IV, Random, 95% CI)0.44 [0.22, 0.66]
3.1 CGI-EI1120Mean Difference (IV, Random, 95% CI)0.5 [0.14, 0.86]
3.2 CGI-SI1120Mean Difference (IV, Random, 95% CI)0.40 [0.12, 0.68]
4 Global state: 4. average endpoint data of various scales (high=poor, data skewed)  Other dataNo numeric data
4.1 CGI-GI  Other dataNo numeric data
4.2 CGI-SI  Other dataNo numeric data
4.3 CGI  Other dataNo numeric data
5 Mental state: 1. Specific - binary outcomes (short term, up to 12 weeks)34 Risk Ratio (M-H, Random, 95% CI)Subtotals only
5.1 anxiety9744Risk Ratio (M-H, Random, 95% CI)1.81 [1.12, 2.94]
5.2 agitation/excitement262038Risk Ratio (M-H, Random, 95% CI)1.26 [0.86, 1.84]
5.3 irritability1100Risk Ratio (M-H, Random, 95% CI)1.0 [0.06, 15.55]
6 Mental state: 2. Average endpoint scale score82 Mean Difference (IV, Random, 95% CI)Subtotals only
6.1 BPRS (short term, up to 12 weeks, high=poor)5570Mean Difference (IV, Random, 95% CI)-1.33 [-2.24, -0.42]
6.2 PANSS (short term, up to 12 weeks, high=poor)775733Mean Difference (IV, Random, 95% CI)-0.80 [-1.58, -0.02]
6.3 PANSS (medium term, 12 to 24 weeks, high=poor)150Mean Difference (IV, Random, 95% CI)-0.15 [-8.03, 7.73]
6.4 SANS (medium term, 12 to 24 weeks, high=poor)150Mean Difference (IV, Random, 95% CI)-0.55 [-3.72, 2.62]
7 Mental state: 3. Specific - average endpoint positive score (PANSS, high=poor)403205Mean Difference (IV, Random, 95% CI)0.02 [-0.37, 0.41]
7.1 short term (up to 12 weeks)393155Mean Difference (IV, Random, 95% CI)0.03 [-0.38, 0.43]
7.2 medium term (12-26 weeks)150Mean Difference (IV, Random, 95% CI)-0.21 [-2.38, 1.96]
8 Mental state: 4. Specific - average endpoint negative score (PANSS, high=poor)37 Mean Difference (IV, Random, 95% CI)Subtotals only
8.1 short term (up to 12 weeks)372976Mean Difference (IV, Random, 95% CI)-0.64 [-1.04, -0.25]
9 Mental state: 5. Specific - average endpoint general psychopathological score (PANSS, high=poor )584243Mean Difference (IV, Random, 95% CI)-0.25 [-0.71, 0.20]
9.1 by up to 12 weeks - short term574193Mean Difference (IV, Random, 95% CI)-0.27 [-0.74, 0.19]
9.2 12- 26 weeks - medium term150Mean Difference (IV, Random, 95% CI)1.52 [-2.66, 5.70]
10 Mental state: 6. PANSS average score decreased rate (short term, up to 12 weeks, low=poor)5 Mean Difference (IV, Random, 95% CI)Subtotals only
10.1 total scale score decreased rate3219Mean Difference (IV, Random, 95% CI)3.06 [0.24, 5.87]
10.2 negative symptom subscale score decreased rate3216Mean Difference (IV, Random, 95% CI)-0.02 [-0.11, 0.08]
10.3 positive symptom subscale score decreased rate3216Mean Difference (IV, Random, 95% CI)-0.01 [-0.10, 0.08]
10.4 general pathology subscale score decreased rate150Mean Difference (IV, Random, 95% CI)2.38 [-0.33, 5.09]
11 Mental state: 7. BPRS total score decreased rate (short term, up to 12 weeks, high=poor)2132Mean Difference (IV, Random, 95% CI)-2.97 [-6.61, 0.67]
12 Mental state: 8. General - average total score (PANSS, high=poor)2 Mean Difference (IV, Random, 95% CI)Subtotals only
12.1 up to 12 weeks (short-term)2372Mean Difference (IV, Random, 95% CI)1.5 [-2.96, 5.96]
13 Mental state: 9. average scores of various scale (high=poor, skewed data)  Other dataNo numeric data
13.1 SANS endpoint scale score  Other dataNo numeric data
13.2 PANSS general pathology subscale score  Other dataNo numeric data
13.3 PANSS negative symptom subscale score  Other dataNo numeric data
13.4 PANSS positive symptom subscale score  Other dataNo numeric data
14 Leaving the study early17 Risk Ratio (M-H, Random, 95% CI)Subtotals only
14.1 Any reason121239Risk Ratio (M-H, Random, 95% CI)1.02 [0.79, 1.32]
14.2 Progressive disease2188Risk Ratio (M-H, Random, 95% CI)0.86 [0.14, 5.09]
14.3 Not insisting follow up2146Risk Ratio (M-H, Random, 95% CI)1.48 [0.49, 4.44]
14.4 Termination treatment early1100Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 71.92]
14.5 Violation of study scheme2152Risk Ratio (M-H, Random, 95% CI)1.32 [0.30, 5.83]
14.6 Incomplete data1180Risk Ratio (M-H, Random, 95% CI)5.0 [0.24, 102.71]
14.7 Adverse effect91272Risk Ratio (M-H, Random, 95% CI)1.15 [0.64, 2.06]
14.8 Economic issue2160Risk Ratio (M-H, Random, 95% CI)1.02 [0.11, 9.60]
14.9 No effect5681Risk Ratio (M-H, Random, 95% CI)0.99 [0.49, 2.01]
15 Adverse effects: 1. At least one adverse effect, non-specific51 Risk Ratio (M-H, Random, 95% CI)Subtotals only
15.1 non-specific282361Risk Ratio (M-H, Random, 95% CI)0.81 [0.73, 0.91]
15.2 liver function abnormal292300Risk Ratio (M-H, Random, 95% CI)0.63 [0.46, 0.86]
15.3 hyper-salivation7554Risk Ratio (M-H, Random, 95% CI)0.63 [0.22, 1.80]
15.4 myalgia/ostealgia2100Risk Ratio (M-H, Random, 95% CI)1.95 [0.51, 7.46]
15.5 renal function abnormal1100Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
15.6 sexual desire change8614Risk Ratio (M-H, Random, 95% CI)0.11 [0.04, 0.30]
15.7 sweating- increase4278Risk Ratio (M-H, Random, 95% CI)0.65 [0.16, 2.59]
15.8 stuffy nose2165Risk Ratio (M-H, Random, 95% CI)3.90 [0.44, 34.47]
16 Adverse effects: 2a.Cardiac effects (short term, up to 12 weeks)61 Risk Ratio (M-H, Random, 95% CI)Subtotals only
16.1 abnormal ECG121032Risk Ratio (M-H, Random, 95% CI)0.66 [0.41, 1.05]
16.2 blood pressure decline or rise5363Risk Ratio (M-H, Random, 95% CI)1.54 [0.46, 5.15]
16.3 blood pressure- increase180Risk Ratio (M-H, Random, 95% CI)1.0 [0.06, 15.44]
16.4 blood pressure- decrease6504Risk Ratio (M-H, Random, 95% CI)1.15 [0.45, 2.90]
16.5 EEG abnormal1120Risk Ratio (M-H, Random, 95% CI)0.67 [0.12, 3.85]
16.6 postural hypotension6399Risk Ratio (M-H, Random, 95% CI)0.94 [0.46, 1.93]
16.7 QTc prolongation5649Risk Ratio (M-H, Random, 95% CI)0.37 [0.13, 1.09]
16.8 tachycardia493835Risk Ratio (M-H, Random, 95% CI)0.76 [0.61, 0.96]
17 Adverse effects: 2b. Cardiac - QTc change from baseline (in ms)2383Mean Difference (IV, Random, 95% CI)-7.19 [-12.19, -2.19]
18 Adverse effects: 3. Central / peripheral nervous system (short term, up to 12 weeks)63 Risk Ratio (M-H, Random, 95% CI)Subtotals only
18.1 acute onset of schizophrenia2120Risk Ratio (M-H, Random, 95% CI)1.33 [0.49, 3.64]
18.2 dizziness231896Risk Ratio (M-H, Random, 95% CI)1.06 [0.72, 1.54]
18.3 blurred vision393272Risk Ratio (M-H, Random, 95% CI)0.96 [0.70, 1.32]
18.4 fatigue5369Risk Ratio (M-H, Random, 95% CI)0.62 [0.29, 1.35]
18.5 headache201505Risk Ratio (M-H, Random, 95% CI)1.91 [1.31, 2.78]
18.6 headache/dizziness201486Risk Ratio (M-H, Random, 95% CI)1.29 [0.93, 1.79]
18.7 insomnia544209Risk Ratio (M-H, Random, 95% CI)1.17 [0.98, 1.39]
18.8 memory decrease160Risk Ratio (M-H, Random, 95% CI)0.22 [0.05, 0.94]
18.9 sedation2170Risk Ratio (M-H, Random, 95% CI)0.20 [0.04, 1.18]
18.10 sleep disorder2152Risk Ratio (M-H, Random, 95% CI)0.85 [0.39, 1.86]
18.11 somnolence352779Risk Ratio (M-H, Random, 95% CI)0.95 [0.74, 1.22]
19 Adverse effects: 3a. Endocrine - Prolactin - average change (ng/ml)2383Mean Difference (IV, Random, 95% CI)-54.71 [-60.06, -49.36]
20 Adverse effects: 3b. Endocrine - Prolactin-associated1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
20.1 abnormally high prolactin value1301Risk Ratio (M-H, Random, 95% CI)0.04 [0.02, 0.08]
20.2 dysmenorrhoea191Risk Ratio (M-H, Random, 95% CI)3.17 [0.17, 59.43]
21 Adverse effects: 4. Various extrapyramidal symptoms (short term, up to 12 weeks)64 Risk Ratio (M-H, Random, 95% CI)Subtotals only
21.1 akathisia423501Risk Ratio (M-H, Random, 95% CI)0.60 [0.48, 0.74]
21.2 tremor362799Risk Ratio (M-H, Random, 95% CI)0.35 [0.27, 0.45]
21.3 dystonia322640Risk Ratio (M-H, Random, 95% CI)0.35 [0.25, 0.49]
21.4 parkinsonism1301Risk Ratio (M-H, Random, 95% CI)7.39 [0.43, 128.08]
21.5 use of antiparkinson medication183Risk Ratio (M-H, Random, 95% CI)0.59 [0.32, 1.12]
21.6 extrapyramidal symptoms312605Risk Ratio (M-H, Random, 95% CI)0.39 [0.31, 0.50]
21.7 torsion spasm3200Risk Ratio (M-H, Random, 95% CI)0.52 [0.04, 7.18]
21.8 tremor2391Risk Ratio (M-H, Random, 95% CI)1.21 [0.07, 21.13]
21.9 increase activities164Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 100.20]
22 Adverse effects: 4b. Extrapyramidal - average score2 Mean Difference (IV, Random, 95% CI)Subtotals only
22.1 Abnormal Involuntary Movement Scale (high=poor)2383Mean Difference (IV, Random, 95% CI)-0.25 [-1.24, 0.75]
22.2 Barnes Akathisia Scale (high=poor)2383Mean Difference (IV, Random, 95% CI)-0.11 [-0.49, 0.27]
22.3 Simpson-Angus Scale (high=poor)2383Mean Difference (IV, Random, 95% CI)-0.70 [-2.22, 0.82]
23 Adverse effects: 5. Gastrointestinal46 Risk Ratio (M-H, Random, 95% CI)Subtotals only
23.1 constipation272067Risk Ratio (M-H, Random, 95% CI)0.75 [0.52, 1.08]
23.2 dry mouth332658Risk Ratio (M-H, Random, 95% CI)1.20 [0.86, 1.69]
23.3 gastrointestinal reaction3300Risk Ratio (M-H, Random, 95% CI)2.01 [0.76, 5.37]
23.4 nausea / vomiting282180Risk Ratio (M-H, Random, 95% CI)1.84 [1.31, 2.56]
24 Adverse effects: 6. Haematological8 Risk Ratio (M-H, Random, 95% CI)Subtotals only
24.1 blood routine abnormal6515Risk Ratio (M-H, Random, 95% CI)0.45 [0.20, 1.02]
24.2 leucopenia160Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.87]
24.3 blood lipid abnormal180Risk Ratio (M-H, Random, 95% CI)2.0 [0.19, 21.18]
25 Adverse effects: 7a. Metabolic - binary measures (short term, up to 12 weeks)62 Risk Ratio (M-H, Random, 95% CI)Subtotals only
25.1 appetite- decrease2204Risk Ratio (M-H, Random, 95% CI)0.26 [0.07, 1.03]
25.2 blood glucose- increase5358Risk Ratio (M-H, Random, 95% CI)0.28 [0.09, 0.82]
25.3 endocrine disorder9642Risk Ratio (M-H, Random, 95% CI)0.07 [0.03, 0.17]
25.4 lactation3216Risk Ratio (M-H, Random, 95% CI)0.11 [0.02, 0.60]
25.5 menstrual disorder/lactation292278Risk Ratio (M-H, Random, 95% CI)0.10 [0.06, 0.16]
25.6 menstrual disorder or sexual function change168Risk Ratio (M-H, Random, 95% CI)0.07 [0.00, 1.12]
25.7 menstrual disorder9655Risk Ratio (M-H, Random, 95% CI)0.13 [0.06, 0.27]
25.8 skin symptom9778Risk Ratio (M-H, Random, 95% CI)0.32 [0.12, 0.86]
25.9 PRL-increase3184Risk Ratio (M-H, Random, 95% CI)0.07 [0.01, 0.38]
25.10 obesity172Risk Ratio (M-H, Random, 95% CI)0.95 [0.14, 6.35]
25.11 vaginal bleeding172Risk Ratio (M-H, Random, 95% CI)2.84 [0.12, 67.53]
25.12 weight gain584623Risk Ratio (M-H, Random, 95% CI)0.22 [0.17, 0.29]
25.13 weight loss1101Risk Ratio (M-H, Random, 95% CI)2.94 [0.12, 70.56]
26 Adverse effects: 7b. Metabolic - continuous measures (high=poor )7 Mean Difference (IV, Random, 95% CI)Subtotals only
26.1 endpoint average weight (in kg)5465Mean Difference (IV, Random, 95% CI)-2.30 [-4.17, -0.44]
26.2 weight change from baseline (in kg)1100Mean Difference (IV, Random, 95% CI)-1.50 [-1.84, -1.16]
26.3 average endpoint BMI of male (in kg/m2)160Mean Difference (IV, Random, 95% CI)-2.46 [-4.08, -0.84]
26.4 average endpoint BMI of female (in kg/m2)2124Mean Difference (IV, Random, 95% CI)-1.47 [-3.55, 0.60]
26.5 average endpoint blood glucose of female (in mmol/L)160Mean Difference (IV, Random, 95% CI)4.29 [3.97, 4.61]
26.6 average endpoint blood glucose of male (in mmol/L)160Mean Difference (IV, Random, 95% CI)0.28 [-0.04, 0.60]
26.7 average endpoint blood glucose FBG (in mg/dl)160Mean Difference (IV, Random, 95% CI)-0.08 [-0.37, 0.21]
26.8 average endpoint cholesterol - TC of female (in mmol/L)160Mean Difference (IV, Random, 95% CI)-0.51 [-0.96, -0.06]
26.9 average endpoint cholesterol - TC of male (in mmol/L)160Mean Difference (IV, Random, 95% CI)-0.48 [-0.96, -0.00]
26.10 average endpoint cholesterol - TC level (in mmol/L)2240Mean Difference (IV, Random, 95% CI)-0.02 [-0.19, 0.14]
26.11 average endpoint cholesterol-TG level (in mmol/L)160Mean Difference (IV, Random, 95% CI)-0.07 [-0.21, 0.07]
26.12 average endpoint cholesterol - LDL level (in mmol/L)2240Mean Difference (IV, Random, 95% CI)0.07 [-0.11, 0.26]
26.13 average endpoint waistline (in cm)1180Mean Difference (IV, Random, 95% CI)-3.30 [-5.47, -1.13]
27 Adverse effect : 7c. Metabolic - continuous measures4789Mean Difference (IV, Random, 95% CI)-0.01 [-0.22, 0.21]
27.1 average endpoint cholesterol- HDL level (in mmol/L)2240Mean Difference (IV, Random, 95% CI)0.06 [-0.03, 0.14]
27.2 cholesterol - change from baseline (in mg/dl)183Mean Difference (IV, Random, 95% CI)-22.3 [-39.69, -4.91]
27.3 glucose - change from baseline (in mg/dl)183Mean Difference (IV, Random, 95% CI)6.8 [-6.10, 19.70]
27.4 weight gain - change from baseline (in kg)2383Mean Difference (IV, Random, 95% CI)-0.54 [-1.24, 0.15]
28 Adverse effect: 8. required additional drug combination2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
28.1 benzodiazepines2138Risk Ratio (M-H, Random, 95% CI)1.07 [0.73, 1.58]
28.2 benzhexol169Risk Ratio (M-H, Random, 95% CI)0.34 [0.12, 0.93]
28.3 benzhexol/propranolol169Risk Ratio (M-H, Random, 95% CI)1.11 [0.45, 2.72]
29 Adverse effects: 9. TESS score (short term, up to 12 weeks, high=poor)4250Mean Difference (IV, Random, 95% CI)-1.34 [-2.30, -0.39]
30 Adverse effects: 10. TESS score (short term, up to 12 weeks, high=poor, data skewed)  Other dataNo numeric data
31 Adverse effects: 11. weight gain (in KG, high=poor, data skewed)  Other dataNo numeric data
32 Cognitive functioning: 1. Specific - average endpoint total score1 Mean Difference (IV, Random, 95% CI)Subtotals only
32.1 (short term, up to 12 weeks, WMS, low= poor)172Mean Difference (IV, Random, 95% CI)-1.56 [-7.95, 4.83]
32.2 (short term, up to 12 weeks, WAIS-RC, low=poor)172Mean Difference (IV, Random, 95% CI)-1.57 [-8.92, 5.78]
33 Cost effectiveness analysis (high=poor, data skewed)  Other dataNo numeric data
33.1 Cost of hospitalisation (in RMB)  Other dataNo numeric data
33.2 Cost of drug (in RMB)  Other dataNo numeric data
33.3 Length of hospitalisation (day)  Other dataNo numeric data
Analysis 3.1.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 1 Global state: 1. No clinically significant response (as defined by the original studies).

Analysis 3.2.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 2 Global state: 2. Average endpoint total score(short term, up to 12 weeks, CGI, high=poor).

Analysis 3.3.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 3 Global state: 3. Average CGI subscale scores (short term, up to 12 weeks, high=poor).

Analysis 3.4.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 4 Global state: 4. average endpoint data of various scales (high=poor, data skewed).

Global state: 4. average endpoint data of various scales (high=poor, data skewed)
StudyInterventionMeanSDNNote
CGI-GI
Chen 2006Aripiprazole1.70.951 
Chen 2006Risperidone1.61.250 
CGI-SI
Chen 2006Aripiprazole2.51.451 
Chen 2006Risperidone2.31.250 
Yang 2008aAripiprazole2.221.2830 
Yang 2008aRisperidone2.351.1630 
CGI
Feng 2006 1.491.0535 
Feng 2006 1.441.234 
Zhang 2008Aripiprazole6.654.8830 
Zhang 2008Risperidone7.515.7630 
Analysis 3.5.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 5 Mental state: 1. Specific - binary outcomes (short term, up to 12 weeks).

Analysis 3.6.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 6 Mental state: 2. Average endpoint scale score.

Analysis 3.7.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 7 Mental state: 3. Specific - average endpoint positive score (PANSS, high=poor).

Analysis 3.8.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 8 Mental state: 4. Specific - average endpoint negative score (PANSS, high=poor).

Analysis 3.9.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 9 Mental state: 5. Specific - average endpoint general psychopathological score (PANSS, high=poor ).

Analysis 3.10.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 10 Mental state: 6. PANSS average score decreased rate (short term, up to 12 weeks, low=poor).

Analysis 3.11.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 11 Mental state: 7. BPRS total score decreased rate (short term, up to 12 weeks, high=poor).

Analysis 3.12.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 12 Mental state: 8. General - average total score (PANSS, high=poor).

Analysis 3.13.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 13 Mental state: 9. average scores of various scale (high=poor, skewed data).

Mental state: 9. average scores of various scale (high=poor, skewed data)
StudyInterventionMeanSDNNote
SANS endpoint scale score
Tong 2007Aripiprazole10. 614. 436 
Tong 2007Risperidone14. 220. 332 
PANSS general pathology subscale score
Chang 2007Aripiprazole18.6511.6450 
Chang 2007Risperidone19.1510.9550 
Xie 2008Aripiprazole19. 2412. 1842 
Xie 2008Risperidone19. 3610. 7142 
PANSS negative symptom subscale score
Chang 2007Aripiprazole12.046.4650 
Chang 2007Risperidone12.086.5650 
CuiMeng 2008Aripiprazole9. 28. 760 
CuiMeng 2008Ziprasidone12. 38. 260 
Deng 2008Aripiprazole14.893.8925 
Deng 2008Risperidone13.017.36225 
Guo 2006Aripiprazole12.43.918 
Guo 2006Risperidone15.89.220 
Ji 2007Aripiprazole12.714.5832 
Ji 2007Risperidone15.199.5732 
Li 2007dAripiprazole15.95.860 
Li 2007dRisperidone12.36.660 
Li 2009bAripiprazole11.16.230 
Li 2009bRisperidone11.16.130 
Li X 2007Aripiprazole12.27.236 
Li X 2007Risperidone12.58.435 
Liu 2006aAripiprazole11.37.445 
Liu 2006aRisperidone10.87.745 
Lv 2007Aripiprazole11. 53. 840 
Lv 2007Risperidone12. 56. 840 
Mai 2005Aripiprazole12. 97. 136 
Mai 2005Risperidone13. 96. 136 
Pan 2007Aripiprazole11.97.230 
Pan 2007Risperidone13.96.130 
Shan 2008Aripiprazole11.25.830 
Shan 2008Risperidone11.45.430 
Song 2009Aripiprazole11.76.530 
Song 2009Risperidone12.85.930 
Su 2007Aripiprazole11. 47. 639 
Su 2007Risperidone12. 66. 739 
Tang 2006Aripiprazole10.95.337 
Tang 2006Risperidone11.15.835 
Tang 2007Aripiprazole11.95.730 
Tang 2007Risperidone11.25.830 
Tu 2009Aripiprazole11.36.535 
Tu 2009Risperidone13.86.733 
Wen 2009aAripiprazole14.893.8840 
Wen 2009aRisperidone13.027.3440 
Xie 2008Aripiprazole11. 955. 6942 
Xie 2008Risperidone12. 326. 1742 
Xie 2010Aripiprazole10.764.5340 
Xie 2010Risperidone10.786.1140 
Yang 2008bAripiprazole12.16.945 
Yang 2008bRisperidone11.97.145 
Ye 2005aAripiprazole11. 84. 329 
Ye 2005aRisperidone12. 38. 229 
Zhang 2008bAripiprazole9.28.720 
Zhang 2008bRisperidone13.56.920 
Zhi 2005Aripiprazole10.76.540 
Zhi 2005Risperidone12.85.940 
Zhou 2008Aripiprazole10. 85. 570 
Zhou 2008Risperidone11. 25. 770 
Zhu 2010Aripiprazole10.406.5722 
Zhu 2010Risperidone11.674.3128 
PANSS positive symptom subscale score
Chang 2007Aripiprazole16.8211.6650 
Chang 2007Risperidone17.6411.7650 
Chen 2010Aripiprazole10.585.3332 
Chen 2010Risperidone11.315.3332 
Fan 2010Aripiprazole10.664.7130 
Fan 2010Risperidone8.964.9330 
Feng 2006Aripiprazole5.182.0430 
Feng 2006Risperidone4.913.1430 
Hu 2010Aripiprazole10.564.5225 
Hu 2010Risperidone11.166.2125 
Li 2007aAripiprazole10.396.0230 
Li 2007aRisperidone10.315.1130 
Li 2007dAripiprazole17.29.360 
Li 2007dRisperidone12.13.460 
Li X 2007Aripiprazole12836 
Li X 2007Risperidone13.27.335 
Lian 2008Aripiprazole8.94.143 
Lian 2008Risperidone11.55.943 
Liu 2006aAripiprazole12.47.245 
Liu 2006aRisperidone12.17.545 
Liu 2008cAripiprazole9. 593. 1737 
Liu 2008cRisperidone10. 295. 4735 
Mu 2008Aripiprazole10. 955. 0750 
Mu 2008Risperidone11. 506. 0250 
Song 2009Aripiprazole10.75.330 
Song 2009Risperidone11.35.930 
Su 2007Aripiprazole10. 87. 539 
Su 2007Risperidone12. 26. 839 
Tang 2006Aripiprazole10.65.137 
Tang 2006Risperidone11.26.035 
Tang 2007Aripiprazole10.15.330 
Tang 2007Risperidone8.66.530 
Tang 2010Aripiprazole10.24.138 
Tang 2010Risperidone10.65.840 
Wang 2007eAripiprazole9.75.830 
Wang 2007eRisperidone10.15.630 
Xie 2008Aripiprazole17. 2110. 9742 
Xie 2008Risperidone17. 3311. 8242 
Xie 2010Aripiprazole8.942.1340 
Xie 2010Risperidone9.414.7840 
Yang 2008bAripiprazole12.26.845 
Yang 2008bRisperidone12.37.145 
Yu 2008Aripiprazole9.75.5350 
Yu 2008Risperidone10.15.850 
Zhang 2007aAripiprazole8.02.425 
Zhang 2007aRisperidone9.315.1225 
Zhang 2008Aripiprazole9.776.7830 
Zhang 2008Risperidone11.175.7530 
Zhang 2008bAripiprazole13.18.620 
Zhang 2008bRisperidone9.17.620 
Zhi 2005Aripiprazole10.75.340 
Zhi 2005Risperidone11.35.940 
Analysis 3.14.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 14 Leaving the study early.

Analysis 3.15.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 15 Adverse effects: 1. At least one adverse effect, non-specific.

Analysis 3.16.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 16 Adverse effects: 2a.Cardiac effects (short term, up to 12 weeks).

Analysis 3.17.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 17 Adverse effects: 2b. Cardiac - QTc change from baseline (in ms).

Analysis 3.18.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 18 Adverse effects: 3. Central / peripheral nervous system (short term, up to 12 weeks).

Analysis 3.19.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 19 Adverse effects: 3a. Endocrine - Prolactin - average change (ng/ml).

Analysis 3.20.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 20 Adverse effects: 3b. Endocrine - Prolactin-associated.

Analysis 3.21.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 21 Adverse effects: 4. Various extrapyramidal symptoms (short term, up to 12 weeks).

Analysis 3.22.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 22 Adverse effects: 4b. Extrapyramidal - average score.

Analysis 3.23.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 23 Adverse effects: 5. Gastrointestinal.

Analysis 3.24.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 24 Adverse effects: 6. Haematological.

Analysis 3.25.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 25 Adverse effects: 7a. Metabolic - binary measures (short term, up to 12 weeks).

Analysis 3.26.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 26 Adverse effects: 7b. Metabolic - continuous measures (high=poor ).

Analysis 3.27.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 27 Adverse effect : 7c. Metabolic - continuous measures.

Analysis 3.28.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 28 Adverse effect: 8. required additional drug combination.

Analysis 3.29.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 29 Adverse effects: 9. TESS score (short term, up to 12 weeks, high=poor).

Analysis 3.30.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 30 Adverse effects: 10. TESS score (short term, up to 12 weeks, high=poor, data skewed).

Adverse effects: 10. TESS score (short term, up to 12 weeks, high=poor, data skewed)
StudyInterventionMeanSDNNote
Chen 2006Aripiprazole0.20.551 
Chen 2006Risperidone0.10.450 
CuiMeng 2008Aripiprazole5.354.2560 
CuiMeng 2008Risperidone7.955.1560 
Mu 2010Aripiprazole3.592.08129 
Mu 2010Risperidone3. 622.14129 
Qu 2009Aripiprazole5.354.230 
Qu 2009Risperidone7.955.130 
Yan 2010Aripiprazole3.422.3450 
Yan 2010Risperidone4.451.9250 
Zhang 2010aAripiprazole5.354.2550 
Zhang 2010aRisperidone7.955.1550 
Zhou 2007bAripiprazole5.354.2530 
Zhou 2007bRisperidone7.955.1530 

Analysis 3.31.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 31 Adverse effects: 11. weight gain (in KG, high=poor, data skewed).

Adverse effects: 11. weight gain (in KG, high=poor, data skewed)
StudyHeading 1Heading 2Heading 3Heading 4Heading 5
Chen 2006Aripiprazole1.11.551 
Chen 2006Risperidone1.81.450 
Tao 2008Aripiprazole2.062.6790 
Tao 2008Risperidone2.732.4390 
Wang 2007eAripiprazole0.31.9730 
Wang 2007eRisperidone1.03.130 
Analysis 3.32.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 32 Cognitive functioning: 1. Specific - average endpoint total score.

Analysis 3.33.

Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 33 Cost effectiveness analysis (high=poor, data skewed).

Cost effectiveness analysis (high=poor, data skewed)
StudyInterventionMeanSDNNote
Cost of hospitalisation (in RMB)
Liu 2010Aripiprazole3413.661815.0530 
Liu 2010Risperidone4551.413024.3854 
Cost of drug (in RMB)
Liu 2010Aripiprazole418.13326.4330 
Liu 2010Risperidone685.00493.0254 
Length of hospitalisation (day)
Liu 2010Aripiprazole33.1916.7130 
Liu 2010Risperidone50.8440.8528 
Comparison 4. COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global state: 1. No clinically significant response (as defined by the original studies)6 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 up to 12 weeks - short term6442Risk Ratio (M-H, Random, 95% CI)0.97 [0.62, 1.52]
2 Global state: 2. Average endpoint CGI-GI score (short term, up to 12 weeks, high=poor)1 Mean Difference (IV, Random, 95% CI)Subtotals only
3 Global state: 3. Average change score (CGI-S, decline=good)1 Mean Difference (IV, Random, 95% CI)Subtotals only
4 Mental state: 1. Average endpoint total score (short term, up to 12 weeks, high=poor)7 Mean Difference (IV, Random, 95% CI)Subtotals only
4.1 PANSS7689Mean Difference (IV, Random, 95% CI)-1.74 [-3.68, 0.20]
4.2 SANS3238Mean Difference (IV, Random, 95% CI)-1.39 [-2.56, -0.22]
4.3 BPRS1247Mean Difference (IV, Random, 95% CI)-2.20 [-4.97, 0.57]
5 Mental state: 2. Specific - binary outcomes (up to 12 weeks - short term)3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
5.1 anxiety - labelled as "adverse effect"186Risk Ratio (M-H, Random, 95% CI)3.0 [0.64, 14.04]
5.2 agitation - labelled as "adverse effect"2150Risk Ratio (M-H, Random, 95% CI)1.00 [0.11, 9.42]
6 Mental state: 3. Specific - average endpoint PANSS subscale scores (short term, high=poor)6 Mean Difference (IV, Random, 95% CI)Subtotals only
6.1 positive symptom scores2146Mean Difference (IV, Random, 95% CI)-0.16 [-1.36, 1.04]
6.2 negative symptom scores4272Mean Difference (IV, Random, 95% CI)-0.31 [-1.23, 0.61]
6.3 general pathology scores5382Mean Difference (IV, Random, 95% CI)-0.35 [-1.73, 1.04]
7 Mental state: endpoint scores of various scales (high=poor, data skewed)  Other dataNo numeric data
7.1 PANSS negative symptom subscale score  Other dataNo numeric data
7.2 PANSS positive symptom subscale score  Other dataNo numeric data
8 Leaving the study early2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
8.1 any reason2316Risk Ratio (M-H, Random, 95% CI)0.94 [0.66, 1.34]
8.2 adverse events1256Risk Ratio (M-H, Random, 95% CI)0.44 [0.14, 1.38]
8.3 defaulted1256Risk Ratio (M-H, Random, 95% CI)0.98 [0.58, 1.66]
8.4 inefficacy1256Risk Ratio (M-H, Random, 95% CI)1.48 [0.54, 4.03]
8.5 other/withdrew1256Risk Ratio (M-H, Random, 95% CI)0.98 [0.25, 3.85]
9 Adverse effects: 1. At least one adverse effect, non-specific8 Risk Ratio (M-H, Random, 95% CI)Subtotals only
9.1 non-specific2126Risk Ratio (M-H, Random, 95% CI)1.23 [0.85, 1.78]
9.2 endocrine disorder184Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
9.3 liver function abnormal184Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 71.61]
9.4 respiratory tract infection1253Risk Ratio (M-H, Random, 95% CI)0.33 [0.09, 1.17]
9.5 sexual function change2172Risk Ratio (M-H, Random, 95% CI)8.00 [2.96, 21.65]
9.6 skin rash160Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.87]
9.7 stuffy nose184Risk Ratio (M-H, Random, 95% CI)1.0 [0.06, 15.47]
9.8 sweating170Risk Ratio (M-H, Random, 95% CI)1.0 [0.07, 15.36]
9.9 urine routine abnormal180Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.95]
10 Adverse effects: 2. Cardiac effects (short term, up to 12 weeks)7 Risk Ratio (M-H, Random, 95% CI)Subtotals only
10.1 abnormal ECG4296Risk Ratio (M-H, Random, 95% CI)0.60 [0.22, 1.68]
10.2 QTc prolongation2145Risk Ratio (M-H, Random, 95% CI)0.42 [0.06, 2.79]
10.3 tachycardia3230Risk Ratio (M-H, Random, 95% CI)1.16 [0.43, 3.16]
10.4 blood pressure- decrease2144Risk Ratio (M-H, Random, 95% CI)3.92 [0.44, 34.66]
11 Adverse effects: 3. Central / peripheral nervous system (short term, up to 12 weeks)6 Risk Ratio (M-H, Random, 95% CI)Subtotals only
11.1 blurred vision184Risk Ratio (M-H, Random, 95% CI)7.0 [0.90, 54.44]
11.2 dizziness5376Risk Ratio (M-H, Random, 95% CI)3.24 [1.57, 6.70]
11.3 headache2150Risk Ratio (M-H, Random, 95% CI)4.92 [0.96, 25.27]
11.4 insomnia5382Risk Ratio (M-H, Random, 95% CI)2.93 [1.17, 7.30]
11.5 somnolence4296Risk Ratio (M-H, Random, 95% CI)1.45 [0.62, 3.39]
12 Adverse effects: 4. Various extrapyramidal symptoms (short term, up to 12 weeks)9 Risk Ratio (M-H, Random, 95% CI)Subtotals only
12.1 akathisia3423Risk Ratio (M-H, Random, 95% CI)0.80 [0.25, 2.61]
12.2 activity-decrease186Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 71.65]
12.3 dystonia184Risk Ratio (M-H, Random, 95% CI)0.07 [0.00, 1.13]
12.4 general extrapyramidal symptoms2120Risk Ratio (M-H, Random, 95% CI)0.77 [0.37, 1.62]
12.5 tremor2152Risk Ratio (M-H, Random, 95% CI)3.0 [0.32, 28.21]
12.6 spasmodic torticollis180Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.95]
12.7 use of antiparkinson medication2140Risk Ratio (M-H, Random, 95% CI)2.84 [0.07, 117.07]
13 Adverse effects: 5. Gastrointestinal (short term, up to 12 weeks)6 Risk Ratio (M-H, Random, 95% CI)Subtotals only
13.1 appetite-decrease186Risk Ratio (M-H, Random, 95% CI)2.0 [0.39, 10.35]
13.2 constipation3230Risk Ratio (M-H, Random, 95% CI)0.63 [0.13, 2.97]
13.3 dry mouth4296Risk Ratio (M-H, Random, 95% CI)0.54 [0.10, 2.80]
13.4 hyper-salivation186Risk Ratio (M-H, Random, 95% CI)2.0 [0.19, 21.24]
13.5 nausea / vomiting6442Risk Ratio (M-H, Random, 95% CI)2.53 [0.91, 7.09]
14 Adverse effects: 6. Haematological2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
14.1 leucopenia2140Risk Ratio (M-H, Random, 95% CI)1.0 [0.07, 15.26]
15 Adverse effects: 7. Hormonal6 Risk Ratio (M-H, Random, 95% CI)Subtotals only
15.1 menstrual disorder6538Risk Ratio (M-H, Random, 95% CI)0.74 [0.28, 1.93]
16 Adverse effects: 8a. Metabolic - binary measures5 Risk Ratio (M-H, Random, 95% CI)Subtotals only
16.1 appetite-decrease2152Risk Ratio (M-H, Random, 95% CI)0.57 [0.04, 7.93]
16.2 blood routine abnormal185Risk Ratio (M-H, Random, 95% CI)0.31 [0.01, 7.43]
16.3 lactation166Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 71.07]
16.4 weight gain3232Risk Ratio (M-H, Random, 95% CI)4.01 [1.10, 14.60]
17 Adverse effects: 8b. Metabolic - continuous measures1 Mean Difference (IV, Random, 95% CI)Subtotals only
17.1 cholesterol - TG average endpoint level (in mmol/L, high= poor)1180Mean Difference (IV, Random, 95% CI)-0.04 [-0.21, 0.13]
17.2 cholesterol - TC average endpoint level (in mmol/L, high= poor)1180Mean Difference (IV, Random, 95% CI)0.0 [-0.17, 0.17]
17.3 cholesterol - LDL average endpoint level (in mmol/L, high= poor)1180Mean Difference (IV, Random, 95% CI)0.13 [-0.04, 0.30]
17.4 HDL (low=poor)1180Mean Difference (IV, Random, 95% CI)0.10 [0.01, 0.19]
17.5 waistline- average endpoint level (in cm, high= poor)1180Mean Difference (IV, Random, 95% CI)-3.40 [-5.29, -1.51]
17.6 weight- average endpoint level (in kg, high= poor)1180Mean Difference (IV, Random, 95% CI)-2.5 [-5.06, 0.06]
Analysis 4.1.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 1 Global state: 1. No clinically significant response (as defined by the original studies).

Analysis 4.2.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 2 Global state: 2. Average endpoint CGI-GI score (short term, up to 12 weeks, high=poor).

Analysis 4.3.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 3 Global state: 3. Average change score (CGI-S, decline=good).

Analysis 4.4.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 4 Mental state: 1. Average endpoint total score (short term, up to 12 weeks, high=poor).

Analysis 4.5.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 5 Mental state: 2. Specific - binary outcomes (up to 12 weeks - short term).

Analysis 4.6.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 6 Mental state: 3. Specific - average endpoint PANSS subscale scores (short term, high=poor).

Analysis 4.7.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 7 Mental state: endpoint scores of various scales (high=poor, data skewed).

Mental state: endpoint scores of various scales (high=poor, data skewed)
StudyInterventionMeanSDNNote
PANSS negative symptom subscale score
Cheng 2009Aripiprazole14.569.5143 
Cheng 2009Ziprasidone13.125.1643 
PANSS positive symptom subscale score
Liu 2008aAripiprazole14.215.4533 
Liu 2008aZiprasidone12.968.4333 
Wang 2008cAripiprazole13.125.1643 
Wang 2008cZiprasidone14.569.5143 
Yang 2008Aripiprazole11.35.730 
Yang 2008Ziprasidone11.53.930 
Analysis 4.8.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 8 Leaving the study early.

Analysis 4.9.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 9 Adverse effects: 1. At least one adverse effect, non-specific.

Analysis 4.10.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 10 Adverse effects: 2. Cardiac effects (short term, up to 12 weeks).

Analysis 4.11.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 11 Adverse effects: 3. Central / peripheral nervous system (short term, up to 12 weeks).

Analysis 4.12.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 12 Adverse effects: 4. Various extrapyramidal symptoms (short term, up to 12 weeks).

Analysis 4.13.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 13 Adverse effects: 5. Gastrointestinal (short term, up to 12 weeks).

Analysis 4.14.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 14 Adverse effects: 6. Haematological.

Analysis 4.15.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 15 Adverse effects: 7. Hormonal.

Analysis 4.16.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 16 Adverse effects: 8a. Metabolic - binary measures.

Analysis 4.17.

Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 17 Adverse effects: 8b. Metabolic - continuous measures.

Comparison 5. COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global state: 1.No clinically significant response (as defined by the original studies)111739Risk Ratio (M-H, Random, 95% CI)1.06 [0.96, 1.17]
1.1 up to 12 weeks- short term101422Risk Ratio (M-H, Random, 95% CI)1.02 [0.86, 1.21]
1.2 from 12 to 26 weeks (medium-term)1317Risk Ratio (M-H, Random, 95% CI)1.08 [0.95, 1.22]
2 Global state: 2. Not responded (decline in PANSS of 30% or more)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 by up to 12 weeks (short-term)1566Risk Ratio (M-H, Random, 95% CI)1.16 [1.01, 1.34]
2.2 more than 26 weeks (long-term)1566Risk Ratio (M-H, Random, 95% CI)1.13 [1.00, 1.27]
3 Global state: 3. Remission not achieved (as defined in the study)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3.1 by up to 12 weeks (short-term)1566Risk Ratio (M-H, Random, 95% CI)1.01 [0.91, 1.13]
3.2 more than 26 weeks (long-term)1566Risk Ratio (M-H, Random, 95% CI)1.38 [1.23, 1.56]
4 Global state: 4. Average endpoint EI score (CGI, high=poor)2 Mean Difference (IV, Random, 95% CI)Subtotals only
4.1 up to 12 weeks - short term2180Mean Difference (IV, Random, 95% CI)0.0 [-0.16, 0.16]
5 Global state: 5. Average endpoint CGI score decreased rate (short term, low=poor)1 Mean Difference (IV, Random, 95% CI)Subtotals only
6 Global state: 6. Average change score (CGI-S, decline=best)1 Mean Difference (IV, Random, 95% CI)Subtotals only
6.1 more than 26 weeks (long-term)1566Mean Difference (IV, Random, 95% CI)0.10 [-0.12, 0.32]
7 Global state: 7. Improvement (CGI-I, high=poor)1566Mean Difference (IV, Random, 95% CI)0.10 [-0.12, 0.32]
8 Mental state: 1. Average endpoint scale score (PANSS, high=poor)13 Mean Difference (IV, Random, 95% CI)Subtotals only
8.1 up to 12 weeks - short term111500Mean Difference (IV, Random, 95% CI)0.61 [-0.23, 1.46]
8.2 12- 26 weeks - medium term2139Mean Difference (IV, Random, 95% CI)0.80 [-5.26, 6.87]
8.3 more than 26 weeks (long-term)1566Mean Difference (IV, Random, 95% CI)4.20 [0.10, 8.30]
9 Mental state: 2. Average endpoint scale score (SANS, high=poor)2137Mean Difference (IV, Random, 95% CI)-0.04 [-2.04, 1.97]
9.1 up to 12 weeks - short term189Mean Difference (IV, Random, 95% CI)-0.04 [-2.52, 2.44]
9.2 more than 26 weeks - long term148Mean Difference (IV, Random, 95% CI)-0.03 [-3.45, 3.39]
10 Mental state: 3. average endpoint score (PANSS, high=poor, data skewed)  Other dataNo numeric data
10.1 PANSS total  Other dataNo numeric data
10.2 PANSS negative symptom subscale score  Other dataNo numeric data
10.3 PANSS positive symptom subscale score  Other dataNo numeric data
11 Mental state: 4. Specific - average endpoint positive score (PANSS, high=poor)71043Mean Difference (IV, Random, 95% CI)0.71 [0.17, 1.26]
11.1 by up to 12 weeks - short term5429Mean Difference (IV, Random, 95% CI)0.77 [-0.16, 1.70]
11.2 12- 26 weeks - medium term148Mean Difference (IV, Random, 95% CI)0.66 [-1.54, 2.86]
11.3 more than 26 weeks1566Mean Difference (IV, Random, 95% CI)0.80 [-0.03, 1.63]
12 Mental state: 5. Specific - average endpoint negative subscale score (PANSS, high=poor)6967Mean Difference (IV, Random, 95% CI)0.42 [-0.25, 1.09]
12.1 up to 12 weeks - short term5401Mean Difference (IV, Random, 95% CI)0.16 [-0.59, 0.92]
12.2 more than 26 weeks1566Mean Difference (IV, Random, 95% CI)1.40 [-0.07, 2.87]
13 Mental state: 6. Specific - average endpoint general pathological score (PANSS, high=poor )8642Mean Difference (IV, Random, 95% CI)-0.80 [-2.24, 0.64]
13.1 up to 12 weeks - short term7594Mean Difference (IV, Random, 95% CI)-0.94 [-2.49, 0.60]
13.2 12- 26 weeks - medium term148Mean Difference (IV, Random, 95% CI)0.80 [-3.08, 4.68]
14 Mental state: 7. Specific - binary outcomes2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
14.1 anxiety - labelled as"adverse effect"2778Risk Ratio (M-H, Random, 95% CI)1.23 [0.79, 1.90]
14.2 depression - labelled as"adverse effect"1566Risk Ratio (M-H, Random, 95% CI)0.27 [0.08, 0.95]
14.3 exacerbation of schizophrenia - labelled as"adverse effect"2778Risk Ratio (M-H, Random, 95% CI)0.89 [0.50, 1.56]
15 Mental state: 8. Various scale scores decreased rate (low=poor, data skewed)  Other dataNo numeric data
15.1 PANSS positive symptom subscale  Other dataNo numeric data
15.2 PANSS negative symptom subscale  Other dataNo numeric data
15.3 PANSS general pathology subscale  Other dataNo numeric data
15.4 BPRS total  Other dataNo numeric data
15.5 PANSS total  Other dataNo numeric data
16 Adverse effects: 1. At least one adverse effect9 Risk Ratio (M-H, Random, 95% CI)Subtotals only
16.1 non-specific175Risk Ratio (M-H, Random, 95% CI)0.95 [0.69, 1.30]
16.2 endocrine dyscrasia180Risk Ratio (M-H, Random, 95% CI)0.08 [0.01, 0.61]
16.3 high prolactin level1317Risk Ratio (M-H, Random, 95% CI)0.27 [0.12, 0.60]
16.4 liver function abnormal5348Risk Ratio (M-H, Random, 95% CI)0.46 [0.20, 1.07]
16.5 skin adverse reaction189Risk Ratio (M-H, Random, 95% CI)1.63 [0.41, 6.41]
16.6 sweating- increase2138Risk Ratio (M-H, Random, 95% CI)3.0 [0.32, 28.16]
16.7 flu syndrome1212Risk Ratio (M-H, Random, 95% CI)0.49 [0.16, 1.54]
16.8 respiratory infection1212Risk Ratio (M-H, Random, 95% CI)1.54 [0.50, 4.69]
17 Adverse effects: 2. Cardiac effects8 Risk Ratio (M-H, Random, 95% CI)Subtotals only
17.1 abnormal ECG2121Risk Ratio (M-H, Random, 95% CI)0.96 [0.15, 6.29]
17.2 blood pressure- decrease189Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.80]
17.3 QTc prolongation3618Risk Ratio (M-H, Random, 95% CI)0.40 [0.11, 1.38]
17.4 tachycardia5339Risk Ratio (M-H, Random, 95% CI)0.91 [0.39, 2.08]
18 Adverse effects: 3a. Cardiac - QTc change from baseline (in ms)1317Mean Difference (IV, Random, 95% CI)-3.70 [-9.51, 2.11]
19 Adverse effects: 3b. Central / peripheral nervous system9 Risk Ratio (M-H, Random, 95% CI)Subtotals only
19.1 dizziness61057Risk Ratio (M-H, Random, 95% CI)0.98 [0.62, 1.53]
19.2 blurred vision175Risk Ratio (M-H, Random, 95% CI)0.13 [0.01, 2.35]
19.3 headache5991Risk Ratio (M-H, Random, 95% CI)2.03 [0.82, 5.07]
19.4 fatigue3721Risk Ratio (M-H, Random, 95% CI)0.58 [0.21, 1.62]
19.5 insomnia71141Risk Ratio (M-H, Random, 95% CI)1.81 [0.95, 3.45]
19.6 somnolence51003Risk Ratio (M-H, Random, 95% CI)0.65 [0.42, 1.01]
19.7 headache/dizziness189Risk Ratio (M-H, Random, 95% CI)0.29 [0.09, 1.00]
19.8 sedation2883Risk Ratio (M-H, Random, 95% CI)0.37 [0.23, 0.60]
19.9 nervousness1212Risk Ratio (M-H, Random, 95% CI)1.32 [0.42, 4.19]
19.10 CNS stimulation1212Risk Ratio (M-H, Random, 95% CI)0.73 [0.21, 2.52]
20 Adverse effects: 4. Endocrine - Prolactin - average increase1566Mean Difference (IV, Random, 95% CI)-8.89 [-12.96, -4.82]
21 Adverse effects: 5. Extrapyramidal - various8 Risk Ratio (M-H, Random, 95% CI)Subtotals only
21.1 Akathisia61320Risk Ratio (M-H, Random, 95% CI)1.56 [0.67, 3.60]
21.2 Tremor161Risk Ratio (M-H, Random, 95% CI)7.23 [0.95, 55.31]
21.3 Extrapyramidal symptoms4667Risk Ratio (M-H, Random, 95% CI)0.99 [0.62, 1.59]
21.4 Parkinsonism3618Risk Ratio (M-H, Random, 95% CI)0.80 [0.46, 1.38]
22 Adverse effects: 6. Gastrointestinal7 Risk Ratio (M-H, Random, 95% CI)Subtotals only
22.1 nausea / vomiting6948Risk Ratio (M-H, Random, 95% CI)1.34 [0.80, 2.26]
22.2 constipation6443Risk Ratio (M-H, Random, 95% CI)0.46 [0.21, 1.04]
22.3 dry mouth5854Risk Ratio (M-H, Random, 95% CI)0.67 [0.38, 1.19]
22.4 abdominal pain - upper1566Risk Ratio (M-H, Random, 95% CI)2.96 [1.09, 8.03]
23 Adverse effects: 7. Hormonal3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
23.1 menstrual changes3198Risk Ratio (M-H, Random, 95% CI)0.20 [0.04, 1.13]
24 Adverse effects: 8a. Metabolic - binary measures10 Risk Ratio (M-H, Random, 95% CI)Subtotals only
24.1 appetite- increase2655Risk Ratio (M-H, Random, 95% CI)0.33 [0.06, 2.00]
24.2  blood glucose - increase3227Risk Ratio (M-H, Random, 95% CI)0.12 [0.03, 0.44]
24.3 cholesterol - abnormally high cholesterol value1223Risk Ratio (M-H, Random, 95% CI)0.32 [0.19, 0.54]
24.4 lactation160Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.87]
24.5 PRL- increase189Risk Ratio (M-H, Random, 95% CI)0.09 [0.01, 1.56]
24.6 weight gain91538Risk Ratio (M-H, Random, 95% CI)0.25 [0.15, 0.43]
25 Adverse effects: 8b. Metabolic - continuous measures (high=poor)5 Mean Difference (IV, Random, 95% CI)Subtotals only
25.1 weight - average endpoint level (in kg)3242Mean Difference (IV, Random, 95% CI)-7.43 [-9.21, -5.65]
25.2 weight gain - change from baseline (in kg)2656Mean Difference (IV, Random, 95% CI)-3.03 [-7.35, 1.29]
25.3 cholesterol - change from baseline (in mg/dl)2789Mean Difference (IV, Random, 95% CI)-15.37 [-21.62, -9.11]
25.4 cholesterol - TC average endpoint level (in mmol/L)2182Mean Difference (IV, Random, 95% CI)-1.00 [-1.44, -0.56]
25.5 cholesterol - TG average endpoint level (in mmol/L)1102Mean Difference (IV, Random, 95% CI)-1.0 [-1.31, -0.69]
25.6 blood glucose - PBG average endpoint level (in mg/dl)160Mean Difference (IV, Random, 95% CI)-0.95 [-1.27, -0.63]
25.7 glucose - change from baseline (in mg/dl)2883Mean Difference (IV, Random, 95% CI)-3.39 [-7.98, 1.19]
26 Adverse effects: 9. Average endpoint scale score (TESS, high=poor, data skewed)  Other dataNo numeric data
27 Leaving the study early9 Risk Ratio (M-H, Random, 95% CI)Subtotals only
27.1 Any reason92331Risk Ratio (M-H, Random, 95% CI)1.15 [1.05, 1.25]
27.2 Economic issues180Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 71.51]
27.3 Early discharge160Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 70.83]
27.4 Refusing therapy160Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.87]
27.5 adverse events41352Risk Ratio (M-H, Random, 95% CI)1.20 [0.92, 1.59]
27.6 inefficacy41352Risk Ratio (M-H, Random, 95% CI)1.81 [1.23, 2.67]
27.7 lost to follow-up2821Risk Ratio (M-H, Random, 95% CI)0.74 [0.46, 1.17]
27.8 medication noncompliance1255Risk Ratio (M-H, Random, 95% CI)2.23 [0.71, 7.06]
27.9 others2780Risk Ratio (M-H, Random, 95% CI)2.21 [0.77, 6.34]
27.10 patient decision31035Risk Ratio (M-H, Random, 95% CI)1.04 [0.60, 1.81]
27.11 protocol entry or interim criteria not met1566Risk Ratio (M-H, Random, 95% CI)0.20 [0.02, 1.68]
27.12 protocol violation2821Risk Ratio (M-H, Random, 95% CI)0.80 [0.42, 1.53]
27.13 sponsor decision1566Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 8.03]
27.14 death1214Risk Ratio (M-H, Random, 95% CI)0.35 [0.01, 8.55]
28 Quality of life: 1. Average endpoint general quality of life score (GQOLI-74, low=poor)1 Mean Difference (IV, Random, 95% CI)Subtotals only
28.1 Total score168Mean Difference (IV, Random, 95% CI)-1.26 [-6.37, 3.85]
28.2 Physical health168Mean Difference (IV, Random, 95% CI)-0.19 [-4.72, 4.34]
28.3 Mental health168Mean Difference (IV, Random, 95% CI)-2.46 [-8.20, 3.28]
28.4 Social function168Mean Difference (IV, Random, 95% CI)1.21 [-3.41, 5.83]
28.5 Material life168Mean Difference (IV, Random, 95% CI)-0.77 [-4.62, 3.08]
Analysis 5.1.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 1 Global state: 1.No clinically significant response (as defined by the original studies).

Analysis 5.2.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 2 Global state: 2. Not responded (decline in PANSS of 30% or more).

Analysis 5.3.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 3 Global state: 3. Remission not achieved (as defined in the study).

Analysis 5.4.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 4 Global state: 4. Average endpoint EI score (CGI, high=poor).

Analysis 5.5.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 5 Global state: 5. Average endpoint CGI score decreased rate (short term, low=poor).

Analysis 5.6.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 6 Global state: 6. Average change score (CGI-S, decline=best).

Analysis 5.7.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 7 Global state: 7. Improvement (CGI-I, high=poor).

Analysis 5.8.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 8 Mental state: 1. Average endpoint scale score (PANSS, high=poor).

Analysis 5.9.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 9 Mental state: 2. Average endpoint scale score (SANS, high=poor).

Analysis 5.10.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 10 Mental state: 3. average endpoint score (PANSS, high=poor, data skewed).

Mental state: 3. average endpoint score (PANSS, high=poor, data skewed)
StudyInterventionMeanSDNNote
PANSS total
Bai 2007Aripiprazole11.265.0759 
Bai 2007Olanzapine10.245.8559 
PANSS negative symptom subscale score
Han 2007Aripiprazole12.73.830 
Han 2007Ziprasidone12.66.830 
PANSS positive symptom subscale score
Han 2007 11.34.330 
Han 2007 11.56.730 
Analysis 5.11.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 11 Mental state: 4. Specific - average endpoint positive score (PANSS, high=poor).

Analysis 5.12.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 12 Mental state: 5. Specific - average endpoint negative subscale score (PANSS, high=poor).

Analysis 5.13.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 13 Mental state: 6. Specific - average endpoint general pathological score (PANSS, high=poor ).

Analysis 5.14.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 14 Mental state: 7. Specific - binary outcomes.

Analysis 5.15.

Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 15 Mental state: 8. Various scale scores decreased rate (low=poor, data skewed).

Mental state: 8. Various scale scores decreased rate (low=poor, data skewed)
StudyHeading 1Heading 2Heading 3Heading 4Heading 5
PANSS positive symptom subscale
Ye 2005aAripiprazole12.88.434 
PANSS negative symptom subscale
Ye 2005aAripiprazole10.98.134 
PANSS general pathology subscale
Ye 2005aAripiprazole19.411.834 
BPRS total
Ye 2005aAripiprazole24.84.334 
PANSS total
Ye 2005aAripiprazole44.123.834