Benzodiazepines for psychosis-induced aggression or agitation

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

Acute psychotic illness, especially when associated with agitated or violent behaviour, can require urgent pharmacological tranquillisation or sedation. In several countries, clinicians often use benzodiazepines (either alone or in combination with antipsychotics) for this outcome.

Objectives

To estimate the effects of benzodiazepines, alone or in combination with antipsychotics, when compared with placebo or antipsychotics, alone or in combination with antihistamines, to control disturbed behaviour and reduce psychotic symptoms.

Search methods

We searched the Cochrane Schizophrenia Group's register (January 2012), inspected reference lists of included and excluded studies and contacted authors of relevant studies.

Selection criteria

We included all randomised clinical trials (RCTs) comparing benzodiazepines alone or in combination with any antipsychotics, versus antipsychotics alone or in combination with any other antipsychotics, benzodiazepines or antihistamines, for people with acute psychotic illnesses.

Data collection and analysis

We reliably selected studies, quality assessed them and extracted data. For binary outcomes, we calculated standard estimates of relative risk (RR) and their 95% confidence intervals (CI) using a fixed-effect model. For continuous outcomes, we calculated the mean difference (MD) between groups. If heterogeneity was identified, this was explored using a random-effects model.

Main results

We included 21 trials with a total of n = 1968 participants. There was no significant difference for most outcomes in the one trial that compared benzodiazepines with placebo, although there was a higher risk of no improvement in people receiving placebo in the medium term (one to 48 hours) (n = 102, 1 RCT, RR 0.62, 95% CI 0.40 to 0.97, very low quality evidence).

There was no difference in the number of participants who had not improved in the medium term when benzodiazepines were compared with antipsychotics (n = 308, 5 RCTs, RR 1.10, 95% CI 0.85 to 1.42, low quality evidence); however, people receiving benzodiazepines were less likely to experience extrapyramidal effects (EPS) in the medium term (n = 536, 8 RCTs, RR 0.15, 95% CI 0.06 to 0.39, moderate quality of evidence). Data comparing combined benzodiazepines and antipsychotics versus benzodiazepines alone did not yield any significant results.

When comparing combined benzodiazepines/antipsychotics (all studies compared haloperidol) with the same antipsychotics alone (haloperidol), there was no difference between groups in improvement in the medium term (n = 155, 3 RCTs, RR 1.27, 95% CI 0.94 to 1.70, very low quality evidence) but sedation was more likely in people who received the combination therapy (n = 172, 3 RCTs, RR 1.75, 95% CI 1.14 to 2.67, very low quality evidence). However, more participants receiving combined benzodiazepines and haloperidol had not improved by medium term when compared to participants receiving olanzapine (n = 60,1 RCT, RR 25.00, 95% CI 1.55 to 403.99, very low quality evidence) or ziprasidone (n = 60, 1 RCT, RR 4.00, 95% CI 1.25 to 12.75 very low quality evidence). When haloperidol and midazolam were compared with olanzapine, there was some evidence the combination was superior in terms of improvement, sedation and behaviour.

Authors' conclusions

The evidence from trials for the use of benzodiazepines alone is not good. There were relatively little good data and most trials are too small to highlight differences in either positive or negative effects. Adding a benzodiazepine to other drugs does not seem to confer clear advantage and has potential for adding unnecessary adverse effects. Sole use of older antipsychotics unaccompanied by anticholinergic drugs seems difficult to justify. Much more high quality research is needed in this area.

Résumé scientifique

Benzodiazépines dans l'agressivité ou l'agitation occasionnée par une psychose

Contexte

Les troubles psychotiques aigus, en particulier lorsqu'ils sont associés à des comportements agités ou violents, peuvent requérir urgemment une tranquillisation ou une sédation médicamenteuse. Dans plusieurs pays, les cliniciens utilisent souvent des benzodiazépines (seules ou en combinaison avec des antipsychotiques) pour ce résultat.

Objectifs

Estimer les effets des benzodiazépines, seules ou en combinaison avec des antipsychotiques, par rapport à un placebo ou des antipsychotiques, seuls ou en combinaison avec des antihistaminiques, pour contrôler les comportements perturbés et réduire les symptômes psychotiques.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre du groupe Cochrane sur la schizophrénie (janvier 2012), examiné les références bibliographiques des études incluses et exclues et contacté les auteurs des études pertinentes.

Critères de sélection

Nous avons inclus tous les essais cliniques randomisés (ECR) comparant des benzodiazépines seules ou en combinaison avec des antipsychotiques, par rapport à des antipsychotiques seuls ou en combinaison avec d'autres antipsychotiques, les benzodiazépines ou anti-histaminiques, pour les personnes atteintes de troubles psychotiques aigus.

Recueil et analyse des données

Nous avons sélectionné les études, évalué leur qualité et extrait les données de manière fiable. Pour les résultats binaires, nous avons calculé les estimations standard du risque relatif (RR) et leurs intervalles de confiance (IC) à 95% à l'aide d'un modèle à effets fixes. Pour les résultats continus, nous avons calculé la différence moyenne (DM) entre les groupes. Si l'hétérogénéité a été identifiée, elle a été explorée en utilisant un modèle à effets aléatoires.

Résultats principaux

Nous avons inclus 21 essais portant sur un total de n =1968 participants. Il n'y avait aucune différence significative pour la plupart des critères de jugement dans le seul essai qui comparait les benzodiazépines à un placebo, bien qu'il y avait un risque plus élevé d'absence d'amélioration chez les personnes recevant un placebo à moyen terme (une à 48 heures) (n =102, 1 ECR, RR de 0,62, IC à 95 % 0,40 à 0,97, Des preuves de qualité très médiocre ).

Il n'y avait aucune différence dans le nombre de participants qui n'étaient pas améliorés à moyen terme lorsque les benzodiazépines ont été comparées avec des antipsychotiques (n =308, 5 ECR, RR de 1,10, IC à 95 % 0,85 à 1,42 ; Des preuves de faible qualité ) ; cependant, les patients sous benzodiazépines étaient moins susceptibles de présenter des effets extrapyramidaux (SEP) à moyen terme (n =536, 8 ECR, RR 0,15, IC à 95 % 0,06 à 0,39 , des preuves de qualité moyenne .) des données comparant des benzodiazépines combinées à des antipsychotiques par rapport aux benzodiazépines seules n'a pas permis d'identifier des résultats significatifs.

En comparant les combinaisons benzodiazepines/antipsychotics (toutes les études comparaient l'halopéridol) avec le même antipsychotique seul (l'halopéridol), il n'y avait aucune différence entre les groupes dans l'amélioration à moyen terme (n =155, 3 ECR, RR de 1,27, IC à 95 % 0,94 à 1,70, Des preuves de qualité très médiocre ), mais la sédation était plus probable chez les personnes ayant reçu le traitement combiné (n =172, 3 ECR, RR 1,75, IC à 95 % 1,14 à 2,67 , des preuves de qualité très médiocre ). Cependant, davantage de participants recevant un traitement combiné de benzodiazépine et d'halopéridol n'avaient pas été améliorés à moyen terme par rapport aux participants recevant de l'olanzapine (n =60, 1 ECR, RR de 25,00, IC à 95 % 1,55 à 403.99 , des preuves de qualité très médiocre ) ou de la ziprasidone (n =60, 1 ECR, RR 4,00, IC à 95 % 1,25 à 12.75 Des preuves de qualité très médiocre ). Lorsque l'halopéridol et le midazolam ont été comparés à l'olanzapine, il y avait certaines preuves que cette combinaison était supérieure en termes d'amélioration, de sédation et de comportement.

Conclusions des auteurs

Les preuves issues d'essais pour l'utilisation des benzodiazépines seules ne sont pas bonnes. Il n'y avait relativement que peu de données de bonne qualité et la plupart des essais sont trop petits pour mettre en évidence des différences dans les effets positifs ou négatifs. L'ajout d'une benzodiazépine à d'autres médicaments ne semble pas conférer de bénéfice clair et présente un potentiel pour l'ajout d'inutiles effets indésirables. l'utilisation d'antipsychotiques plus anciens seuls sans anticholinergiques semble difficile à justifier. davantage de recherches de haute qualité sont nécessaires dans ce domaine.

Plain language summary

Benzodiazepines alone or in combination with antipsychotic drugs for acute psychosis

People with mental health problems may exhibit agitated, violent and aggressive behaviour which can be a danger to themselves or others. Usually, de-escalation techniques such as talking to the patient are used to calm down the situation. However, people’s behaviour may be too disturbed, violent or agitated. In these circumstances, rapid tranquillisation is given to achieve a state of calm. Three major classes of drugs are used to achieve rapid tranquillisation: typical antipsychotics; benzodiazepines; and more recently atypical antipsychotics. The review included 21 studies involving 1968 people. The aim was to explore the tranquillising effects of benzodiazepines (alone or in combination with antipsychotics; placebo; and antihistamines). Overall, there is insufficient information in these 21 studies to support or refute the use of benzodiazepines (alone or in combination with other drugs, where emergency drugs are needed). The majority of studies are too small, so that larger and more informative studies are required before definite conclusions can be drawn as to the effectiveness of benzodiazepines. However, there was good evidence to suggest that benzodiazepines are at least as effective as antipsychotics in reducing the agitation associated with mental illness. Side effects such as weight gain, shaking, tremors and slurred speech were significantly higher in people who received antipsychotics. Therefore, if antipsychotics are used for rapid tranquillisation, they should be given with other calming drugs (anticholinergic medication) which can prevent side effects. There was also some evidence that the combination of benzodiazepines with antipsychotics was superior to either drug alone and may also reduce side effects.

In summary, there is no strong information from these studies to support or refute the use of benzodiazepines (with or without antipsychotics or in combination with other drugs) if the situation has deteriorated to such an extent that emergency drugs are needed. However, the lower rates of side effects in people receiving benzodiazepines may be a reason to choose benzodiazepines over older antipsychotics. Lack of good quality evidence leaves managers, clinicians, psychiatrists and policy makers with difficult decisions to make. There is currently limited evidence to suggest that benzodiazepines (alone or in combination with antipsychotics) are clearly superior to antipsychotics (alone or in combination with antihistamines) in reducing acute psychotic behaviour, such as aggression or agitation.

This summary has been written by Benjamin Gray, Service User and Service User Expert, Rethink Mental Illness.

Résumé simplifié

Benzodiazépines seules ou en combinaison avec des médicaments antipsychotiques dans la psychose aiguë

Les personnes souffrant de problèmes de santé mentale peuvent présenter un comportement agité, agressif et violent, qui peut être un danger pour eux-mêmes ou pour autrui. habituellement, des techniques d'apaisement telles que le fait de parler au patient sont utilisés pour calmer la situation. Cependant, le comportement des patients peut être trop perturbé, violent. ou agité . dans ces circonstances, une tranquillisation rapide est administrée pour atteindre un état de calme. trois principales classes de médicaments sont utilisées pour obtenir une tranquillisation rapide : les Antipsychotiques typiques, les benzodiazépines et, plus récemment, les antipsychotiques atypiques. La revue a inclus 21 études impliquant 1968 personnes. l'objectif était d'étudier les effets tranquillisants des benzodiazépines (seule ou en combinaison avec des antipsychotiques ; un placebo ; et des anti-histaminiques). Globalement, il n'existe pas suffisamment d'informations dans ces 21 études pour étayer ou réfuter l'utilisation des benzodiazépines (seule ou en combinaison avec d'autres médicaments, quand un traitement d'urgence est nécessaire). la majorité des études sont trop petites, de sorte que des études de plus grande taille et plus informatives sont nécessaires avant de tirer des conclusions définitives concernant l'efficacité des benzodiazépines. Cependant, il y avait des preuves solides suggérant que les benzodiazépines sont au moins aussi efficaces que les antipsychotiques dans la réduction de l'agitation associée à une maladie mentale. des effets secondaires tels que prise de poids, tremblements, trépidation et des troubles de l'élocution étaient significativement plus élevés chez les personnes qui recevaient des antipsychotiques. Par conséquent, si les neuroleptiques sont utilisés pour une tranquillisation rapide, ils devraient être administrés avec d'autres médicaments calmant (médicaments anticholinergiques) qui peuvent prévenir les effets secondaires. Il 'y avait également des preuves que la combinaison des benzodiazépines à des antipsychotiques était supérieure à chacun des médicaments seul, et peut également réduire les effets secondaires.

En résumé, il n'existe aucune information solide de ces études pour étayer ou réfuter l'utilisation des benzodiazépines (avec ou sans antipsychotiques ou en combinaison avec d'autres médicaments) si la situation s'est détériorée à un tel point qu'un traitement d'urgence est nécessaire. Cependant, le plus bas taux d'effets secondaires chez les patients sous benzodiazépines pourrait être une raison de choisir les benzodiazépines par rapport aux antipsychotiques plus anciens. le manque de preuves de bonne qualité laisse les gestionnaires, les cliniciens, les psychiatres et les décideurs politiques avec des décisions difficiles à prendre. Il existe actuellement des preuves limitées suggérant que les benzodiazépines (seules ou en combinaison avec des antipsychotiques) sont clairement supérieures à des antipsychotiques ( seuls ou en combinaison avec des antihistaminiques) dans la réduction des comportements psychotiques aigus, tels que l'agressivité ou l'agitation.

Ce résumé a été rédigé par Benjamin Gray, Bénéficiaire du service et Expert auprès des bénéficiaires du service, Rethink Mental Illness.

Notes de traduction

Traduit par: French Cochrane Centre 5th November, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Laički sažetak

Benzodiazepini sami ili u kombinaciji s antipsihoticima u terapiji akutne psihoze

Osobe s mentalnim bolestima mogu se ponašati uznemireno, nasilno ili agresivno, što može predstavljati opasnost za njih same ili za druge. Obično se za smirivanje situacije koriste tehnike smirivanja poput razgovora s pacijentom. Međutim ponašanje osobe može biti previše poremećeno, nasilno ili uznemireno. U takvim okolnostima se za smirivanje pacijenta koriste brzodjelujući lijekovi za smirenje. Tri glavne skupine lijekova koji djeluju kao brzodjelujući lijekovi za smirenje su tipični antipsihotici, benzodiazepini i, odnedavno, atipični antipsihotici. Ovaj Cochrane sustavni pregled uključio je 21 studiju s ukupno 1968 ispitanika. Cilj je bilo istražiti umirujuće efekte lijekova iz skupine benzodiazepina (samih ili u kombinaciji s lijekovima antipsihoticima, placebom i antihistaminicima). Zaključak je zbirne analize pronađenih dokaza da u uključenih 21 studija ne postoji dovoljna količina informacija koje bi podržale ili pobile upotrebu benzodiazepina (samih ili u kombinaciji s drugim lijekovima, kada su hitno potrebni lijekovi) za smirenje psihotičnih pacijenata koji su agresivni i uznemireni. Većina studija je uključila premali broj ispitanika, tako da su potrebne veće i informativnije studije prije nego što se mogu donijeti konačni zaključci o učinkovitosti benzodiazepina za to stanje. Međutim, postoji mnogo dokaza koji upućuju da su benzodiazepini barem jednako učinkoviti kao antipsihotici u smanjenju uznemirenosti povezane s mentalnom bolešću. Nuspojave poput povećanja tjelesne mase, tresavice i nerazgovjetnog govora bile su značajno češće kod osoba koje su primale antipsihotike. Ako se antipsihotici koriste za brzo smirenje bolesnika , trebali bi se davati s drugim lijekovima za smirenje (antikolinergicima) koji mogu spriječiti nuspojave. Postoje i određeni dokazi da je kombinacija benzodiazepina i antipsihotika bila bolja nego bilo koji od zasebnih lijekova te da može smanjiti nuspojave.

Ukratko, ne postoje dovoljno snažni dokaziiz tih studija koji bi podržali ili odbacili upotrebu benzodiazepina (sa ili bez antipsihotika ili u kombinaciji s drugim lijekovima) ako se situacija toliko pogoršala da je potrebna hitna upotreba lijekova. Međutim, manje nuspojava zabilježeno je kod osoba koje su primale benzodiazepine što bi mogao biti razlog da odaberu ti lijekovi umjesto starijih antipsihotika. Zbog nedostatka dokaza dobre kvalitete će zdravstveni radnici, uključujući upravitelje, kliničare, psihijatre i osobe koje izrađuju smjernice, i dalje trebati donositi teške odluke po tom pitanju. Trenutačno postoje ograničeni dokazi koji pokazuju da su benzodiazepini (sami ili u kombinaciji s antipsihoticima) očito bolji u odonosu na antipsihotike (same ili u kombinaciji s antihistaminicima) u smirivanju akutnog psihotičnog ponašanja, poput agresije ili uznemirenosti.

Ovaj laički sažetak Cochrane sustavnog pregleda je napisao Benjamin Gray iz udruge Rethink Mental Illness.

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

Summary of findings(Explanation)

Summary of findings for the main comparison. BENZODIAZEPINES compared to PLACEBO for psychosis-induced aggression or agitation
  1. 1 Assumed risk: mean baseline risk presented for single study. Equates with that of control group.
    2 Risk of bias: 'very serious' - 90% of trial authors and co-authors were employed by trial sponsors at the time of the study.
    3 Risk of bias: 'serious' - randomisation poorly described.
    4 Indirectness: 'serious' - only one study reported results on this outcome. There was an additional treatment arm, therefore the total amount of participants in the study are not accounted for.
    5 Imprecision: 'serious' - only one study reported data for this outcome.

BENZODIAZEPINES compared to PLACEBO for psychosis-induced aggression or agitation
Patient or population: patients with psychosis-induced aggression or agitation
Settings: hospitals (Romania & US)
Intervention: BENZODIAZEPINES
Comparison: PLACEBO
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
PLACEBOBENZODIAZEPINES
Global impression - no improvement - medium term
As defined in each study
Follow-up: 24 hours
569 per 1000 1353 per 1000
(227 to 552)
RR 0.62
(0.4 to 0.97)
102
(1 study)
⊕⊝⊝⊝
very low 2,3,4,5
 
Global impression - need for additional medication - medium term
Number of participants requiring additional medication
Follow-up: 24 hours
529 per 1000 1529 per 1000
(365 to 762)
RR 1
(0.69 to 1.44)
102
(1 study)
⊕⊝⊝⊝
very low 2,3,4,5
 
Global impression - sedation - medium term
Number of participants sedated
Follow-up: 24 hours
59 per 1000 198 per 1000
(25 to 389)
RR 1.67
(0.42 to 6.61)
102
(1 study)
⊕⊝⊝⊝
very low 2,3,4,5
 
Adverse effects/events - extrapyramidal symptoms - medium term
Number of instances of extrapyramidal symptoms
Follow-up: 24 hours
59 per 1000 119 per 1000
(2 to 182)
RR 0.33
(0.04 to 3.1)
102
(1 study)
⊕⊝⊝⊝
very low 2,3,4,5
 
Satisfaction with treatment - generalSee commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.
Economic outcomes - cost-effectivenessSee commentSee commentNot estimable0
(0)
See commentNo study 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 BENZODIAZEPINES compared to ANTIPSYCHOTICS for psychosis-induced aggression or agitation

Summary of findings 2. BENZODIAZEPINES compared to ANTIPSYCHOTICS for psychosis-induced aggression or agitation
  1. 1 Assumed risk: calculated from the included studies - presents 3 risks based on the control group risks - 'moderate' risk equates with that of control group (35.9%).
    2 Indirectness: 'serious' - 40% studies had more than one treatment arm; 60% of included studies used different types of antipsychotics/benzodiazepines and dosages.
    3 Imprecision: 'serious' - confidence intervals for best estimate of effect include both 'no effect' and appreciable benefit/harm.
    4 Risk or bias: 'serious' - randomisation poorly described in 50% of included studies.
    5 Imprecision: 'serious' - total number of events is less than 300; confidence intervals for best estimate of effect include both 'no effect' and appreciable benefit/harm.
    6 One study indicated significant favour of antipsychotics, while the other study indicated favour for benzodiazepines (non-significant).
    7 Assumed risk: calculated from the included studies - presents 3 risks based on the control group risks - 'moderate' risk equates with that of control group (22.7%).
    8 Assumed risk: calculated from the included studies - presents 3 risks based on the control group risks - 'moderate' risk equates with that of control group (12.5%).

BENZODIAZEPINES compared to ANTIPSYCHOTICS for psychosis-induced aggression or agitation
Patient or population: patients with psychosis-induced aggression or agitation
Settings: hospitals (US, Canada, Israel, China, Australia)
Intervention: BENZODIAZEPINES
Comparison: ANTIPSYCHOTICS
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ANTIPSYCHOTICSBENZODIAZEPINES
Global impression - no improvement - medium term
As defined in each study
Follow-up: mean 30 hours
Low1RR 1.10
(0.85 to 1.42)
308
(5 studies)
⊕⊕⊝⊝
low 2,3
 
200 per 1000220 per 1000
(170 to 284)
Moderate1
400 per 1000440 per 1000
(340 to 568)
High1
800 per 1000880 per 1000
(680 to 1000)
Global impression - need for additional medication - medium term
Number of participants requiring additional medication
Follow-up: mean 24 hours
See commentSee commentNot estimable216
(2 studies)
⊕⊝⊝⊝
very low 4,5
High levels of heterogeneity between included studies (Chi² = 16.41; I² = 94%) - data not pooled.6
Global impression - sedation - medium term
Number of participants sedated
Follow-up: mean 16 hours
Low1,7RR 1.13
(0.83 to 1.54)
434
(8 studies)
⊕⊕⊕⊝
moderate 3
 
100 per 1000113 per 1000
(83 to 154)
Moderate1,7
250 per 1000282 per 1000
(207 to 385)
High1,7
500 per 1000565 per 1000
(415 to 770)
Adverse effects/events - extrapyramidal symptoms - medium term
Number of instances of extrapyramidal symptoms
Follow-up: mean 21 hours
Low9RR 0.15
(0.06 to 0.39)
471
(6 studies)
⊕⊕⊕⊝
moderate 3
 
0 per 10000 per 1000
(0 to 0)
Moderate9
200 per 100030 per 1000
(12 to 78)
High9
500 per 100075 per 1000
(30 to 195)
Satisfaction with treatment - generalSee commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.
Economic outcomes - cost-effectivenessSee commentSee commentNot estimable0
(0)
See commentNo study 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 BENZODIAZEPINES + ANTIPSYCHOTICS compared to SAME BENZODIAZEPINES for psychosis-induced aggression or agitation

Summary of findings 3. BENZODIAZEPINES + ANTIPSYCHOTICS compared to SAME BENZODIAZEPINES for psychosis-induced aggression or agitation
  1. 1 Assumed risk: median control group risk from the included studies due to little variation in the baseline risks.
    2 Indirectness: 'serious' - multiple treatment arms were employed in each study.
    3 Imprecision: 'serious' - confidence intervals for best estimate of effect include both 'no effect' and appreciable benefit/harm.
    4 Assumed risk: mean baseline risk presented for single study. Equates with that of control group.
    5 Imprecision: 'very serious' - only three small studies reported data for this outcome.
    6 Risk of bias: 'serious' - inadequate description of randomisation.
    7 Imprecision: 'very serious' - only one small study with few participants reported data for this outcome.
    8 Not pooled - no events were seen in either group.
    9 Imprecision: 'very serious' - only two small studies with few participants reported data for this outcome.
    10 Assumed risk: median control group risk from the included studies due to little variation in the baseline risks. One study reported zero events in both groups.

BENZODIAZEPINES + ANTIPSYCHOTICS compared to BENZODIAZEPINES for psychosis-induced aggression or agitation
Patient or population: patients with psychosis-induced aggression or agitation
Settings: hospitals (US)
Intervention: BENZODIAZEPINES + ANTIPSYCHOTICS
Comparison: BENZODIAZEPINES
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
BENZODIAZEPINESBENZODIAZEPINES + ANTIPSYCHOTICS
Global impression - no improvement - lorazepam+haloperidol vs lorazepam - medium term
As defined in each study
Follow-up: mean 12 hours
Moderate1RR 0.94
(0.69 to 1.28)
83
(2 studies)
⊕⊕⊝⊝
low 2,3
 
689 per 1000648 per 1000
(475 to 882)
Global impression - no improvement - lorazepam+risperidone vs lorazepam - medium term
As defined in each study
Follow-up: 12 hours
700 per 1000 4602 per 1000
(315 to 1000)
RR 0.86
(0.45 to 1.64)
20
(1 study)
⊕⊕⊝⊝
low 2,3
 
Global impression - need for additional medication - lorazepam+haloperidol vs lorazepam - medium term
Number of participants requiring additional medication
Follow-up: mean 64 hours
Moderate1RR 1.02
(0.79 to 1.32)
103
(3 studies)
⊕⊕⊝⊝
low 2,5
 
182 per 1000186 per 1000
(144 to 240)
Global impression - need for additional medication - lorazepam+risperidone vs lorazepam - medium term
Number of participants requiring additional medication
Follow-up: 90 minutes
ModerateNot estimable20
(1 study)
⊕⊝⊝⊝
very low 6,7
Not pooled.8
0 per 10000 per 1000
(0 to 0)
Global impression - sedation - lorazepam+haloperidol vs lorazepam - medium term
Number of participants sedated
Follow-up: mean 13 hours
Moderate1RR 0.84
(0.59 to 1.19)
110
(2 studies)
⊕⊝⊝⊝
very low 2,3,9
 
540 per 1000454 per 1000
(319 to 643)
Adverse effects/events - extrapyramidal symptoms - lorazepam+haloperidol vs lorazepam - medium term
Number of instances of extrapyramidal symptoms
Follow-up: mean 48 hours
Moderate10RR 1.94
(0.18 to 20.3)
83
(2 studies)
⊕⊝⊝⊝
very low 2,6,9
 
16 per 100031 per 1000
(3 to 325)
Satisfaction with treatment - generalSee commentSee commentNot estimable0
(0)
See commentNo study 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 BENZODIAZEPINES + ANTIPSYCHOTICS compared to SAME ANTIPSYCHOTICS for psychosis-induced aggression or agitation

Summary of findings 4. BENZODIAZEPINES + ANTIPSYCHOTICS compared to SAME ANTIPSYCHOTICS for psychosis-induced aggression or agitation
  1. 1 Inconsistency: 'serious' - high levels of heterogeneity in the three studies (Chi² = 9.33; I² = 79%).
    2 Indirectness: 'serious' - 66% of included studies had multiple treatment arms, including different benzodiazepines and antipsychotics.
    3 Imprecision: 'serious' - confidence intervals for best estimate of effect include both 'no effect' and appreciable benefit/harm.
    4 Two studies indicated slight favour of antipsychotics, while the other study indicated significant favour for benzodiazepines.
    5 Indirectness: 'serious' - multiple treatment arms were employed in the single study.
    6 Imprecision: 'very serious' - only one study reported data for this outcome.
    7 Indirectness: 'serious' - all included studies had multiple treatment arms, including different benzodiazepines and antipsychotics.
    8 Two studies indicated significant favour of antipsychotics, while the other study indicated favour for benzodiazepines combined with antipsychotics (non-significant).
    9 Assumed risk: calculated from the included studies - presents 3 risks based on the control group risks - 'moderate' risk equates with that of control group (18.5%).
    10 Imprecision: 'very serious' - only two small studies reported data for this outcome.

BENZODIAZEPINES + ANTIPSYCHOTICS compared to SAME ANTIPSYCHOTICS for psychosis-induced aggression or agitation
Patient or population: patients with psychosis-induced aggression or agitation
Settings: hospitals (US, Brazil)
Intervention: BENZODIAZEPINES + ANTIPSYCHOTICS
Comparison: SAME ANTIPSYCHOTICS
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
SAME ANTIPSYCHOTICSBENZODIAZEPINES + ANTIPSYCHOTICS
Global impression - no improvement - +/vs haloperidol - medium term
As defined in each study
Follow-up: mean 36 hours
See commentSee commentNot estimable155
(3 studies)
⊕⊝⊝⊝
very low 1,2,3
High levels of heterogeneity between included studies (Chi² = 9.33; I² = 79%) - data not pooled.4
Global impression - need for additional medication - medium term
Number of participants requiring additional medication
Follow-up: 12 hours
 The mean global impression - need for additional medication - medium term in the intervention groups was
0 higher
(0 to 0 higher)
 60
(1 study)
⊕⊝⊝⊝
very low 5,6
Skewed data - see 'data and analysis'.
Global impression - sedation - +/vs haloperidol - medium term
Number of participants sedated
Follow-up: mean 12 hours
See commentSee commentNot estimable172
(3 studies)
⊕⊝⊝⊝
very low 3,7
High levels of heterogeneity between included studies (Chi² = 6.90; I² = 71%) - data not pooled.8
Adverse effects/events - extrapyramidal symptoms - +/vs haloperidol - medium term
Number of instances of extrapyramidal symptoms
Follow-up: mean 18 hours
Low9RR 0.44
(0.16 to 1.17)
127
(2 studies)
⊕⊕⊝⊝
low 7,10
 
50 per 100022 per 1000
(8 to 58)
Moderate9
150 per 100066 per 1000
(24 to 175)
High9
300 per 1000132 per 1000
(48 to 351)
Satisfaction with treatment - generalSee commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.
Economic outcomes - cost-effectivenessSee commentSee commentNot estimable0
(0)
See commentNo study 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 BENZODIAZEPINES + ANTIPSYCHOTICS compared to DIFFERENT ANTIPSYCHOTICS for psychosis-induced aggression or agitation

Summary of findings 5. BENZODIAZEPINES + ANTIPSYCHOTICS compared to DIFFERENT ANTIPSYCHOTICS for psychosis-induced aggression or agitation
  1. 1 Corresponding risk: one trial reported 12 events in the intervention group (40%).
    2 Indirectness: 'serious' - multiple treatment arms were employed in the single study.
    3 Imprecision: 'very serious' - only one study reported data for this outcome.
    4 Assumed risk: mean baseline risk presented for single study. Equates with that of control group.
    5 Assumed risk: mean baseline risk - only one trial reported with 0 events in the control group and 3 events in the intervention group.

BENZODIAZEPINES + ANTIPSYCHOTICS compared to DIFFERENT ANTIPSYCHOTICS for psychosis-induced aggression or agitation
Patient or population: patients with psychosis-induced aggression or agitation
Settings: hospital (Brazil)
Intervention: BENZODIAZEPINES + ANTIPSYCHOTICS
Comparison: DIFFERENT ANTIPSYCHOTICS
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
DIFFERENT ANTIPSYCHOTICSBENZODIAZEPINES + ANTIPSYCHOTICS
Global impression - no improvement - +haloperidol vs olanzapine - medium term
As defined in each study
Follow-up: 12 hours
0 per 1000 10 per 1000
(0 to 0)
RR 25
(1.55 to 403.99)
60
(1 study)
⊕⊝⊝⊝
very low 2,3
 
Global impression - no improvement - +haloperidol vs ziprasidone - medium term
Number of participants requiring additional medication
Follow-up: 12 hours
100 per 1000 4400 per 1000
(125 to 1000)
RR 4
(1.25 to 12.75)
60
(1 study)
⊕⊝⊝⊝
very low 3
 
Global impression - need for additional medication - medium term (Copy)
Number of participants requiring additional medication
See commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.
Global impression - sedation - +haloperidol vs olanzapine - medium term
Number of participants sedated
Follow-up: 12 hours
33 per 1000 4400 per 1000
(55 to 1000)
RR 12
(1.66 to 86.59)
60
(1 study)
⊕⊝⊝⊝
very low 2,3
 
Global impression - sedation - +haloperidol vs ziprasidone - medium term
Number of participants sedated
Follow-up: 12 hours
100 per 1000 4400 per 1000
(125 to 1000)
RR 4
(1.25 to 12.75)
60
(1 study)
⊕⊝⊝⊝
very low 2,3
 
Adverse effects/events - extrapyramidal symptoms - +haloperidol vs olanzapine - medium term
Number of instances of extrapyramidal symptoms
Follow-up: 12 hours
0 per 1000 50 per 1000
(0 to 0)
RR 7
(0.38 to 129.93)
60
(1 study)
⊕⊝⊝⊝
very low 2,3
 
Adverse effects/events - extrapyramidal symptoms - +haloperidol vs ziprasidone - medium term
Number of instances of extrapyramidal symptoms
Follow-up: 12 hours
0 per 1000 50 per 1000
(0 to 0)
RR 7
(0.38 to 129.93)
60
(1 study)
⊕⊝⊝⊝
very low 2,3
 
*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 6 BENZODIAZEPINES + ANTIPSYCHOTICS compared to ANTIPSYCHOTICS + ANTIPSYCHOTICS for psychosis-induced aggression or agitation

Summary of findings 6. BENZODIAZEPINES + ANTIPSYCHOTICS compared to ANTIPSYCHOTICS + ANTIPSYCHOTICS for psychosis-induced aggression or agitation
BENZODIAZEPINES + ANTIPSYCHOTICS compared to ANTIPSYCHOTICS + ANTIPSYCHOTICS for psychosis-induced aggression or agitation
Patient or population: patients with psychosis-induced aggression or agitation
Settings: n/a
Intervention: BENZODIAZEPINES + ANTIPSYCHOTICS
Comparison: ANTIPSYCHOTICS + ANTIPSYCHOTICS
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ANTIPSYCHOTICS + ANTIPSYCHOTICSBENZODIAZEPINES + ANTIPSYCHOTICS
Global impression - no improvement - medium termSee commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.
Global impression - need for additional medication - medium termSee commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.
Global impression - sedation - medium termSee commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.
Adverse effects/events - extrapyramidal symptoms - medium termSee commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.
Satisfaction with treatment - generalSee commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.
Economic outcomes - cost-effectivenessSee commentSee commentNot estimable0
(0)
See commentNo study 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;
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 7 BENZODIAZEPINES compared to ANTIHISTAMINES + ANTIPSYCHOTICS for psychosis-induced aggression or agitation

Summary of findings 7. BENZODIAZEPINES compared to ANTIHISTAMINES + ANTIPSYCHOTICS for psychosis-induced aggression or agitation
  1. 1 Assumed risk: mean baseline risk presented for single study. Equates with that of control group.
    2 Risk of bias: 'serious' - non-blind, open label study.
    3 Imprecision: 'very serious' - only one study reported data for this outcome.

BENZODIAZEPINES compared to ANTIHISTAMINES + ANTIPSYCHOTICS for psychosis-induced aggression or agitation
Patient or population: patients with psychosis-induced aggression or agitation
Settings: psychiatric hospitals (US, Canada, Israel, China, Australia)
Intervention: BENZODIAZEPINES
Comparison: ANTIHISTAMINES + ANTIPSYCHOTICS
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ANTIHISTAMINES + ANTIPSYCHOTICSBENZODIAZEPINES
Global impression - no improvement - medium term
As defined in each study
Follow-up: 2 weeks
120 per 1000 1260 per 1000
(139 to 486)
RR 2.17
(1.16 to 4.05)
200
(1 study)
⊕⊝⊝⊝
very low 2,3
 
Global impression - need for additional medication - medium term
Number of participants requiring additional medication
Follow-up: 2 weeks
30 per 1000 140 per 1000
(9 to 174)
RR 1.33
(0.31 to 5.81)
200
(1 study)
⊕⊝⊝⊝
very low 2,3
 
Global impression - sedation - lorazepam vs haloperidol+promethazine - medium term
Number of participants sedated
Follow-up: 2 weeks
970 per 1000 1883 per 1000
(815 to 951)
RR 0.91
(0.84 to 0.98)
200
(1 study)
⊕⊝⊝⊝
very low 2,3
 
Global impression - sedation - midazolam vs haloperidol+promethazine - medium term
Number of participants sedated
Follow-up: 2 weeks
827 per 1000 1934 per 1000
(860 to 1000)
RR 1.13
(1.04 to 1.23)
301
(1 study)
⊕⊝⊝⊝
very low 2,3
 
Adverse effects/events - extrapyramidal symptoms - medium term
Number of instances of extrapyramidal symptoms
See commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.
Satisfaction with treatment - generalSee commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.
Economic outcomes - cost-effectivenessSee commentSee commentNot estimable0
(0)
See commentNo study 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 8 BENZODIAZEPINES + ANTIPSYCHOTICS compared to ANTIHISTAMINES + ANTIPSYCHOTICS for psychosis-induced aggression or agitation

Summary of findings 8. BENZODIAZEPINES + ANTIPSYCHOTICS compared to ANTIHISTAMINES + ANTIPSYCHOTICS for psychosis-induced aggression or agitation
  1. 1 Assumed risk: mean baseline risk - only one trial reported with 0 events in the control group and 12 events in the intervention group.
    2 Corresponding risk: one trial reported 12 events in the intervention group (40%).
    3 Indirectness: 'serious' - multiple treatment arms were employed in the single study.
    4 Imprecision: 'serious' - only one study reported data for this outcome.
    5 Imprecision: 'very serious' - only one study reported data for this outcome, data were skew.
    6 Assumed risk: mean baseline risk presented for single study. Equates with that of control group.

BENZODIAZEPINES + ANTIPSYCHOTICS compared to ANTIHISTAMINES + ANTIPSYCHOTICS for psychosis-induced aggression or agitation
Patient or population: patients with psychosis-induced aggression or agitation
Settings: psychiatric emergency room (Brazil)
Intervention: BENZODIAZEPINES + ANTIPSYCHOTICS
Comparison: ANTIHISTAMINES + ANTIPSYCHOTICS
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ANTIHISTAMINES + ANTIPSYCHOTICSBENZODIAZEPINES + ANTIPSYCHOTICS
Global impression - no improvement - medium term
As defined in each study
Follow-up: 12 hours
0 per 1000 10 per 1000
(0 to 0)2
RR 25
(1.55 to 403.99)
60
(1 study)
⊕⊕⊝⊝
low 3,4
 
Global impression - need for additional medication - medium term
Number of participants requiring additional medication
Follow-up: 12 hours
 The mean global impression - need for additional medication - medium term in the intervention groups was
0 higher
(0 to 0 higher)
 60
(1 study)
⊕⊕⊝⊝
low 3,5
Skewed data - see 'data and analysis'.
Global impression - sedation - medium term
Number of participants sedated
Follow-up: 12 hours
33 per 1000 6400 per 1000
(55 to 1000)
RR 12
(1.66 to 86.59)
60
(1 study)
⊕⊕⊝⊝
low 3,4
 
Adverse effects/events - extrapyramidal symptoms - medium term
Number of instances of extrapyramidal symptoms
Follow-up: 12 hours
167 per 1000 6100 per 1000
(27 to 382)
RR 0.6
(0.16 to 2.29)
60
(1 study)
⊕⊝⊝⊝
very low 3,4
 
Satisfaction with treatment - generalSee commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.
Economic outcomes - cost-effectivenessSee commentSee commentNot estimable0
(0)
See commentNo study 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

Acutely psychotic people may exhibit agitated and aggressive behaviour which can present a danger to themselves or others. In order to ensure a safe and therapeutic environment, de-escalation techniques should be used to calm the patient (NICE 2005; Rocca 2006). Frequently, however, the behaviour may be too disturbed or agitated for these methods to be effective, and it might prove imperative that further action in the form of rapid tranquillisation is given (NICE 2005; Rocca 2006). The aim of rapid tranquillisation is to achieve a state of calm which is sufficient to minimise risk of harm to the agitated person themselves, or to others around them, and allow treatment of the underlying condition (Battaglia 2005; NICE 2005). Rapid tranquillisation may serve as primary therapy in such instances but may also be used in conjunction with other de-escalation methods (Marder 2006; NICE 2005).

Description of the intervention

Rapid tranquillisation is commonly used in emergency settings in general and psychiatric hospitals around the world (Goedhard 2006; Marder 2006). Three major classes of drugs are used to achieve rapid tranquillisation: the typical antipsychotics; benzodiazepines; and more recently, atypical antipsychotics (Marder 2006). Intramuscular injections of typical antipsychotics and benzodiazepines, alone or in combination, have been the treatment of choice for several decades. In a review of the research literature (Battaglia 2005), the typical antipsychotic, haloperidol, and the benzodiazepine, lorazepam, were reported as the most widely used drugs. However, the drugs used for rapid tranquillisation may vary widely in different countries. A survey in Rio de Janeiro, Brazil, showed that a haloperidol-promethazine mixture was commonly used (Huf 2002) while a survey of African psychiatrists found that chlorpromazine and diazepam were most commonly prescribed, although the choice of drug tended to be governed by availability rather than preference (James 2011). With the introduction of parenteral forms of the atypical antipsychotics, these are also gaining in popularity as the first-line treatment for agitation in the psychiatric emergency setting (Marder 2006; Mintzer 2006).

The benzodiazepine family is large (Table 1) and with different characteristics of metabolism (Table 2).

Table 1. The Benzodiazepine family
NameCodeChemical name
Benzodiazepines
BromazepamRo 5-33507-bromo-1, 3-dihydro-5-(2-pyridyl)-2H-1, 4-benzodiazepin-2-one
CamazepamSB 58337-chloro-1, 3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one dimethylcarbamate
ChlordiazepoxideRo 5-06907-chloro-2-methylamino-5-phenyl-3H-1, 4-benzodiazepin-4-oxide
CinolazepamOX 3737-chloro-5-(o-fluorophenyl)-2, 3-dihydro-3-hydroxy-2-oxo-1H-1, 4-benzodiazepine-1- propionitrile
ClobazaHR 376 H 4723 LM 27177-chloro-1-methyl-5-phenyl-1H-1, 5-benzodiazepine-2, 4-(3H, 5H)-dione
ClonazepamRo 5-40235-(o-chlorophenyl)-1, 3-dihydro-7-nitro-2H-1, 4-benzodiazepin-2-one
Clorazepate Chlorazepate4306CB A35.616dipotassium 7-chloro-2, 3-dihydro-2, 2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3-carboxylate
Cp 1414 S 2-amino-7-nitro-5-phenyl-3H-1, 5-benzodiazepin-4-one
CyprazepamW 36237-chloro-2-[(cyclopropylmethyl)amino]-5-phenyl-3H-1, 4-benzodiazepin-4-oxide
Delorazepam Chlordemethyldiazepam 7-chloro-5-(o-chlorophenyl)-1, 3-dihydro-2H-1, 4-benzodiazepin-2-one
DiazepamRo 5-2807 WY 3467 LA III7-chloro-1, 3-dihydro-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one
DoxefazepamSAS 6437-chloro-5-(o-fluorophenyl)-1, 3-dihydro-3-hydroxy-1-(2-hydroxyethyl)-2H-1, 4-benzodiazepin-2-one
ElfazepamSKF 72.517)7-chloro-1-[2-(ethylsulfonyl)ethyl]-5-(o-fluorophenyl)-1, 3-dihydro-2H-1, 4-benzodiazepin-2-one
Ethyl Carfluzepate ethyl ester of 7-chloro-5-(o-fluorophenyl)-2, 3-dihydro-1- (methylcarbamoyl)-2-oxo-1H-1, 4-benzodiazepine-3-carboxylic acid
Ethyl Dirazepate ethyl 7-chloro-5-(o-chlorophenyl)-2, 3-dihydro-2-oxo-1H-1, 4-benzodiazepine-3-carboxylate
Ethyl LoflazepateCM 6912ethyl 7-chloro-5-(o-fluorophenyl)-2, 3-dihydro-2-oxo-1H-1, 4- benzodiazepine-3-carboxylate
FletazepamSCH 15.6987-chloro-5-(o-fluorophenyl)-2, 3-dihydro-1-(2, 2, 2-trifluoroethyl)-1H-1, 4-benzodiazepine
FludiazepamID 5407-chloro-5-(o-fluorophenyl)-1, 3-dihydro-1 methyl-2H-1, 4-benzodiazepine-2-0
FlunitrazepamRo 5-42005-(o-fluorophenyl)-1, 3-dihydro-1-methyl-7-nitro-2H-1, 4- benzodiazepin-2-one
FlurazepamRo 5-69017-chloro-1-[2-(diethylamino)ethyl]-5-(o-fluorophenyl)-1, 3-dihydro-2H-1, 4-benzodiazepin-2-one . dihydrochloride
Flutemazepam 7-chloro-5-(o-fluorophenyl)-1, 3-dihydro-3-hydroxy-1-methyl-2H-1, 4-benzodiazepine-2-one
FlutoprazepamKB 509 ID 19377-chloro-1-(cyclopropylmethyl)-5-(o-fluorophenyl)-1, 3-dihydro-2H-1, 4-benzodiazepin-2-one
FosazepamHR 9307-chloro-1-[(dimethylphosphinyl)methyl]-1, 3-dihydro-5-phenyl-2H-1, 4-benzodiazepin-2-one
GirisopamGYKI 51.189 EGIS 58101-(3-chlorophenyl)-4-methyl-7, 8-dimethoxy-5H-2, 3-benzodiazepine
Gv 150013 (R)-N-[(adamantane-1-methyl)-2, 4-dioxo-5-phenyl-2, 3, 4, 5-tetrahydro-1H-1, 5-benzodiazepin-3-yl]-N-phenylurea
HalazepamSCH 12.0417-chloro-1, 3-dihydro-5-phenyl-1-(2, 2, 2-trifluoroethyl)-2H-1, 4-benzodiazepin-2-one
Iclazepam Clazepam (Formerly) 7-chloro-1-[2-(cyclopropylmethoxy)ethyl]-1, 3-dihydro-5-phenyl-2H-1, 4-benzodiazepin-2-one
LorazepamWY 40367-chloro-5-(o-chlorophenyl)-1, 3-dihydro-3-hydroxy-2-1, 4-benzodiazepin-2-one
LormetazepamWY 40827-chloro-5-(o-chlorophenyl)-1, 3-dihydro-3-hydroxy-1-methyl-2H-1, 4-benzodiazepin-2-one
M ORF8063WE 3521-methyl-5-phenyl-7-(trifluoromethyl)-1H-1, 5-benzodiazepine-2, 4(3H, 5H)dione
Meclonazepam(3-methylclonazepam) Ro 11-3128 (meclonazepam, Roche) Ro 11-3624 (steric antipode of meclonazepam)(+)-(S)-5-(o-chlorophenyl)-1, 3-dihydro-3-methyl-7-nitro-2H-1, 4-benzodiazepin-2-one
MedazepamRo 5-45567-chloro-2, 3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepine
MenitrazepamCB 48575-(1-cyclohexen-1-yl)-1, 3-dihydro-1-methyl-7-nitro-2H-1, 4-benzodiazepin-2-one
Metaclazepam (Formerly: Brometazepam)KC 2547 KC 3755 (normetaclazepam (active metabolite)7-bromo-5-(o-chlorophenyl)-2, 3-dihydro-2-(methoxymethyl)-1-methyl-1H-1, 4-benzodiazepine
NimetazepamS 15301, 3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1, 4-benzodiazepin-2-one
NitrazepamRo 4-5360 Ro 5-3059 CB 4395 (potassium salt)1, 3-dihydro-7-nitro-5-phenyl-2H-1, 4-benzodiazepin-2-one
NordazepamRo 5-2180 A 1017-chloro-1, 3-dihydro-3-hydroxy-5-phenyl-2H-1, 4-benzodiazepin-2-one
NormetrazepamCB 42607-chloro-5-(1-cyclohexen-1-yl)-1, 3-dilhydro-2H-1, 4-benzodiazepin-2-one
OxazepamWY 3498 8092 CB Ro 5-67897-chloro-1, 3-dihydro-3-hydroxy-5-phenyl-2H-1, 4-benzodiazepin-2-one
Oxazepam HemisuccinateSAS 5387-chloro-2, 3-dihydro-3-hydroxy-2-(1H)-oxo-5-phenyl-1, 4-benzodiazepin-3-yl hydrogen succinate
PinazepamZ 9057-chloro-1, 3-dihydro-5-phenyl-1-(2-propynyl)-2H-1, 4-benzodiazepin-2-one
Potassium NitrazepateCB 43352, 3-dihydro-7-nitro-2-oxo-5-phenyl-1H-1, 4-benzodiazepin-3-carboxylic acid monopotassium salt
PrazepamW 40207-chloro-1-(cyclopropylmethyl)-1, 3-dihydro-5-phenyl-2H-1, 4-benzodiazepin-2-one
QuazepamSCH 16.1347-chloro-5-(o-fluorophenyl)-1, 3-dihydro-1-(2, 2, 2-trifluoroethyl)-2H-1, 4-benzodiazepine-2-thione
ReclazepamSC 33.9632-[7-chloro-5-(o-chlorophenyl)-2, 3-dihydro-1H-1, 4-benzodiazepin-1-yl]-2-oxazolin-4-one
Sc 32.855 7-chloro-5-(o-chlorophenyl)-1- (4, 5-dihydro-2-oxazolyl)-2, 3-dihydro-1H-1, 4-benzodiazepine
SulazepamW36767-chloro-1, 3- dihydro-1-methyl-5-phenyl- 2H-1, 4- benzodiazepin- 2-thione
TemazepamER 115 Ro 5-5345 WY 39177-chloro-1, 3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one
TetrazepamCB 42617-chloro-5-(cyclohexen-1-yl)-1, 3-dihydro-1-methyl-2H-1, 4-benzodiazepin-2-one
TofisopamEGYT 3415-ethyl-7-8-dimethoxy-1-(3, 4-dimethoxyphenyl)-4-methyl-5H-2, 3-benzodiazepine
UldazepamU 31.9202-[(allyloxy)amino]-7-chloro-5-(o-chlorophenyl)-3H-1, 4-benzodiazepine
Tricyclic benzodiazepines
1-Hydroxytriazolam 8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4, 3-a][1, 4]benzodiazepine-1-methanol
AdinazolamU 41.123 F (mesylate) U 41.123 (base)8-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4, 3-a][1, 4]benzodiazepine (mesylate)
AlprazolamU 31.8898-chloro-1-methyl-6-phenyl-4H-s-triazolo[4, 3-a][1, 4]benzodiazepine
Climazolam 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-imidazo[1, 5-a][1, 4]benzodiazepine
CloxazolamCS 370 MT 14-41110-chloro-11b-(o-chlorophenyl)-2, 3, 7, 11b-tetrahydro-oxazolo[3, 2-d][1, 4]benzodiazepin-6 (5H)-one
Estazolam NoralprazolamD 40 TA Lu 7426 Abbott 476318-chloro-6-phenyl-4H-s-triazolo[4, 3-a][1, 4] benzodiazepine
FlutazolamMS 410110-chloro-11b-(2-flurophenyl)-2, 3, 7, 11b-tetrahydro-7-(2-hydroxyethyl-oxazolo[ 3, 2-d] [1, 4] benzodiazepin-6(5H)-one
Gp 55.129U 401258-chloro-6-phenyl-4H-s-triazolo[4, 3-a][1, 4]benzodiazepine-1-methanol
HaloxazolamCS 43010-bromo-11b-(o-fluorophenyl)-2, 3, 7, 11b-tetrahydrooxazolo[3, 2-d][1, 4]benzodiazepin-6(5H)-one
KetazolamU 28.77411-chloro-8, 12b-dihydro-2, 8-dimethyl-12b-phenyl-4H-[1, 3]oxazino[3, 2-d][1, 4]benzodiazepine-4, 7(6H)- dione
LoprazolamRU 31.158 HR 158(Z)-6-(o-chlorophenyl)-2, 4-dihydro-2-[(4-methylpiperazin-1-yl)methylene]-8-nitro-1H- imidazo[1, 2-a][1,˜ 4]benzodiazepin-1-one
MexazolamCS 38610-chloro-11b-(o-chlorophenyl)-2, 3, 7, 11b-tetrahydro-3-methyl-oxazolo[3, 2-d][1, 4]benzodiazepin-6(5)-one
MidazolamRo 21-3981 (maleate) Ro 21-3981/003 (HCl)8-chloro-6-(o-fluorophenyl)-1-methyl-4H-imidazo [1, 5-a][1, 4]benzodiazepine maleate (1: 1)
NoradinazolamU 42.3528-chloro-1-(methylamino)methyl]-6-phenyl-4H-s-triazolo[4, 3-a][1, 4]benzodiazepine
Oxazolam 10-chloro-2, 3, 7, 11b-tetrahydro-2-methyl-11b-phenyloxazolo[3, 2-d][1, 4]benzodiazepin- 6(5H)-one
Ru 31.124 8-chloro-6-(o-chlorophenyl)-2-(4-ethylpiperazin-1-yl)methyl]-2, 4-dihydro-1H-imidazo[1, 2-a][1, 4]benzodiazepin -1-one (methyl bridge or methylene group uncertain)
TriazolamU 33.0308-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4, 3-a][1, 4]benzodiazepine
Benzodiazepines with atypical mode of action
Arfendazam ethyl 7-chloro-2, 3, 4, 5-tetrahydro-4-oxo-5-phenyl-1H-1, 5-benzodiazepine-1-carboxylate
DevazepideL 364.718 (former designation) MK 329 (Merck and Co., USA) L 365.031(Merck)(S)-N-(2, 3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4- benzodiazepin-3-yl)-indole-2-carboxamideL 365031 N-(2, 3- dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepin-3-yl)-1H-p-bromobenzamide
Gyki 52.322EGIS 67751-(4-aminophenyl)-4-methyl-7, 8-dimethoxy-5H-2, 3-benzodiazepine 2, 3-
L 365260 (R)-N-(2, 3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepin-3-yl)-N’-(3-methylphenyl)-urea
Ro 15-4513 ethyl 8-azido-5, 6-dihydro-6-oxo-4H-imidazo[1, 5-a][1, 4]benzodiazepine-3-carboxylate
Ro 5-4864 7-chloro-5-(p-chlorophenyl)-1, 3-dihydro-1-methyl-2H-1, 4-benzodiazepin-2-one
TifluadomKC 5103 (+)-tifluadom KC 6128 (Sandoz/Kali- Chemie, BRD) (-)-tifluadom KC5911(+/-)-N-[[5-(o-fluorophenyl)-2, 3-dihydro-1-methyl-1H-1, 4-benzodiazepin-2-yl]methyl]-3-thiophenecarboxamide
Fused benzodiazepines
Brotizolam Ladormin (Provisional Name)We 9412-bromo-4-(o-chlorophenyl)-9-methyl-6H-thieno [3, 2-f]-s-triazolo[4, 3-a][1, 4]diazepine
CiclotizolamWe 973-BS2-bromo-4-(o-chlorophenyl)-9-cyclohexyl-6H-thieno[3, 2-f]-s-triazolo[4, 3-a][1, 4]diazepine
ClotiazepamY 60475-(o-chlorophenyl)-7-ethyl-1, 3-dihydro-1-methyl-2H-thieno[2, 3-e][1, 4]diazepin-2-one
EtizolamAHR 3219 Y 71314-(o-chlorophenyl)-2-ethyl-9-methyl-6H-thieno [3, 2-f]-s-triazolo[4, 3-a][1, 4]diazepine
LopirazepamD 125247-chloro-5-(o-chlorophenyl)-1, 2-dihydro-3-hydroxy-3H-pyrido[3, 2- e][1, 4]diazepin-2-one
PremazepamMDL 1813, 7-dihydro-6, 7-dimethyl-5-phenylpyrrolo[3, 4-e][1, 4]diazepin-2(1H)-one
RazobazamHoe 1754, 8-dihydro-3, 8-dimethyl-4-phenylpyrazolo[3, 4-b][1, 4]diazepine-5, 7(1H, 6H)-dione
RipazepamCI 6831-ethyl-4, 6-dihydro-3-methyl-8-phenylpyrazolo[4, 3-e][1, 4]diazepin-5(1H)-one
Ro 11-7800 9-aminomethyl-2-chloro-4-(o-chlorophenyl)-6H-thieno[3, 2-f]-s-triazolo[4, 3-a][1, 4] diazepine
ThiadiponeCI 718 bentazepam QM 60081, 3, 6, 7, 8, 9-hexahydro-5-phenyl-2H-[1]benzothieno[2, 3-e][1, 4]diazepin-2-one
Zapizolam 8-chloro-6-(o-chlorophenyl)-4H-pyrido[2, 3-f]-s-triazolo[4, 3-a][1, 4]diazepine
Zomebazam 4, 8-dihydro-1, 3, 8-trimethyl-4-phenylpyrazolo [3, 4-b][1, 4]diazepine-5, 7(1H, 6H)-dione
ZometapineCI 7817, 8-dihydro-1, 3-dimethyl-4-phenyl-6H-pyrazolo[3, 4-e][1, 4] diazepine
Table 2. Half lives of some benzodiazepines
 Half life
1. LONG
Chlordiazepoxide5-30 hours
Clobazam16-60 hours
Chlorazepate1-2 hours
Diazepam20-40 hours
Flurazepam1-2 hours
Ketazolam+/-30 hours
Metaclazepam7-23 hours
Oxazolam+/-30 hours
2. MEDIUM/SHORT
Alprazolam10-15 hours
Bromazepam10-20 hours
Brotizolam4-7 hours
Clotiazepam3-15 hours
Loprazolam6-8 hours
Lorazepam8-24 hours
Lormetazepam8-14 hours
Nitrazepam15-30 hours
Oxazepam4-15 hours
Temazepam5-14 hours
3. EXTREMELY SHORT
Midazolam1-7 hours
Triazolam1 1/2-5 hours

How the intervention might work

Among other actions, benzodiazepines enhance the effect of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which results in sleep inducing, sedative, anti-anxiety, muscle relaxant and amnesic effects. First discovered in 1955, through long experience, it is clear that these drugs are effective for managing aggression, but it is not clear just how effective and, if they are better or worse than other compounds or combinations of compounds.

Why it is important to do this review

Guidance suggests benzodiazepines are at least as effective as antipsychotics in controlling severely agitated behaviour (Allen 2000; NICE 2005; Rocca 2006,) and indeed this was the finding of the original Cochrane review (Gillies 2005). Some authors suggest that the combination of antipsychotics with benzodiazepines may be more advantageous than either drug alone (NICE 2005; Rocca 2006) but there was inadequate evidence of this in the original Cochrane review (Gillies 2005). This update includes all new trials comparing benzodiazepines (alone or combined with antipsychotics) with antipsychotics (alone or in combination with benzodiazepines). In addition, in this update, we included trials that compared benzodiazepines alone or in combination with antipsychotics, compared to other antipsychotics, benzodiazepines or antihistamines.

While there is evidence that both benzodiazepines and antipsychotics are effective in decreasing agitation, both can cause undesirable adverse effects. Acute phase treatment with the typical antipsychotic drugs may result in debilitating extrapyramidal symptoms (EPS) including Parkinson's-like symptoms, hypotension, lowering of the seizure threshold, cardiac arrhythmia, and neuroleptic malignant syndrome (Battaglia 2005; NICE 2005; Rocca 2006). Benzodiazepines produce EPS less frequently, but can cause respiratory depression, ataxia, excessive sedation, memory impairment and paradoxical disinhibition (Battaglia 2005; Marder 2006; Rocca 2006). The adverse effect profile of combined therapy with benzodiazepines and antipsychotics is as yet unclear (Gillies 2005) although it has been suggested that the combination therapy may decrease the incidence of side effects (Battaglia 2005). It is also thought that the broader activity profile of atypical antipsychotics may mean they are less likely to produce the EPS side effects of the typical antipsychotics (Duggan 2005; Essali 2009; Silveira 2002) but there have been reports of severe adverse events associated with the intramuscular administration of these drugs (Battaglia 2005).

This is one of a series of similar reviews (Table 3).

Table 3. Reviews focusing on similar participant groups
Focus of ReviewReference
Aripiprazole for psychosis-induced agitation/aggressionPagadala 2009
Benzodiazepines for schizophreniaVolz 2007
Containment strategies for people with serious mental illnessMuralidharan 2006
Chlorpromazine for psychosis-induced agitation/aggressionAhmed 2010
Haloperidol (rapid tranquillisation) for psychosis-induced agitation/aggressionPowney 2011
Haloperidol for long-term aggression in psychosisKhushu 2012
Haloperidol + promethazine for psychosis-induced agitation/aggressionHuf 2009
Loxapine for schizophreniaChakrabarti 2007
Loxapine inhaler for psychosis-induced aggression or agitationVangala 2011
Olanzapine IM or velotab for acutely disturbed/agitated people with suspected serious mental illnessesBelgamwar 2005
Quetiapine for psychosis-induced aggression or agitationWilkie 2012
Risperidone for psychosis-induced agitation/aggressionAhmed 2011
Seclusion and restraint for people with serious mental illnessesSailas 2000
Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnessesGibson 2012

Objectives

To estimate the effects of benzodiazepines used alone or in combination with antipsychotic drugs for acutely disturbed people with psychosis-induced aggression or agitation.

Methods

Criteria for considering studies for this review

Types of studies

We included all relevant randomised controlled trials. We excluded quasi-randomised trials, such as those allocating by days of the week.

Types of participants

Any people presenting to the adult services with acutely disturbed/aggressive/agitated behaviour believed to be secondary to psychotic illnesses such as schizophrenia, schizoaffective disorder, mixed affective disorders, manic phase of bipolar disorder or brief psychotic episode. For the purposes of this review, we have defined 'acute' as where authors of trials state or imply that the behavioural disturbance is of sudden onset and/or extreme in nature. Where trials included people with organic illnesses or people abusing substances, we only included these trials if over 60% of participants were exhibiting disturbed behaviour resulting from a psychotic episode.

Types of interventions

Benzodiazepines - given alone

Benzodiazepines include: alprazolam, bretazenil, bromazepam, chlordiazepoxide, cinolazepam, clonazepam, clorazepate, clotiazepam, cloxazolam, delorazepam, diazepam, estazolam, flunitrazepam, halazepam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, quazepam, temazepam, tetrazepam, triazolam (Table 1).

Any dose, any means of administration.

Compared with the following.

1. Placebo
2. Other benzodiazepine - given alone

Any dose, any means of administration.

3. Antipsychotics

First generation/ typical, including: chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, droperidol, flupentixol/flupenthixol, fluphenazine, haloperidol, levomepromazine, loxapine, mesoridazine, molindone, periciazine, perphenazine, pimozide, prochlorperazine, promazine, promethazine, thioridazine, thiothixene, trifluoperazine, triflupromazine, zuclopenthixol.

Second generation/ atypical, including: amisulpride, aripiprazole, asenapine, clozapine, clothiapine, clotiapin, iloperidone, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone, zotepine.

Any dose, any means of administration.

4. Other combinations of drugs

4.1 Benzodiazepines plus antipsychotics.

4.2 Antipsychotics plus antihistamine/anticholinergic drugs.

Antihistamines include: azelastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, deschlorpheniramine, dexchlorpheniramine, dimenhydrinate, dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, levocetirizine, loratadine, meclozine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, rupatadine, tripelennamine, triprolidine.

Any dose, any means of administration.

5. Non-pharmacological approaches
Benzodiazepines plus antipsychotics

Compared with the following.

1. Placebo
2. Any antipsychotics

Any dose, any means of administration.

3. Other combinations

3.1 Benzodiazepines plus antipsychotics.

3.2 Antipsychotics plus antihistamines.

4. Non-pharmacological approaches

Types of outcome measures

As this was a review of the effects on acute psychosis, we only included those outcomes up to and including 48 hours after the initial dose of medication was given. Outcomes were divided into immediate term (zero to 15 minutes), short term (15 minutes to one hour) and medium term (one hour to 48 hours).

Primary outcomes
1.Global impression
1.1 Specific

1.1.1 No improvement: as defined by each study. If more than one measure of improvement was reported, then improvement in behaviour was used, followed by improvement in mental state, and then improvement in symptoms.

Secondary outcomes
2. Global impression
2.1 General

2.1.1 No clinically important change in general functioning
2.1.2 No change in general functioning
2.1.3 Average endpoint change in general functioning
2.1.4 Average change in general functioning

2.2 Specific

2.2.1 Tranquillisation (feeling of calmness and/or calm, non-sedated behaviour)
2.2.2 Aggression
2.2.3 Self-harm, including suicide
2.2.4 Injury to others
2.2.5 Improvement in self-care or degree of improvement in self-care
2.2.6 Sedation (sleepiness and drowsiness)
2.2.7 Compulsory administrations of treatment
2.2.8 Need for additional medication
2.2.9 Decrease in medication
2.2.10 No change in medication dosage
2.2.11 Average change/endpoint scores

3. Behaviour
3.1 General

3.1.1 No clinically important change in behaviour
3.1.2 Average behaviour score

4. Mental state
4.1 General

4.1.1 No clinically important change in general mental state scores
4.1.2 Average endpoint general mental state score

5. Adverse effects/events
5.1 General

5.1.1 Incidence of side effects, general or specific
5.1.2 Severity of symptoms
5.1.3 Measured acceptance of treatment
5.1.4 Sudden or unexpected death

5.2 Specific

5.2.1 Extrapyramidal symptoms (EPS)
5.2.2 Use of medication for EPS

6. Hospital and service outcomes
6.1 Hospitalisation

6.1.1 Time to hospitalisation
6.1.2 Hospitalisation of people in the community
6.1.3 Duration of hospital stay
6.1.4 Changes in services provided by community teams

6.2 Seclusion

6.2.1 Time in seclusion
6.2.2 Changes in hospital status (for example, changes from voluntary to involuntary care, changes in level of observation, use of seclusion)

7. Satisfaction with treatment
7.1 Specific

7.1.1 Consumers
7.1.2 Family and informal care givers
7.1.3 Professionals/carers

8. Economic outcomes
8.1 Specific

8.1.1 Direct costs  - as defined by trial authors
8.1.2 Indirect costs - as defined by trial authors
8.1.3 Cost-effectiveness - as defined by trial authors

9. Leaving the study early
10. 'Summary of findings' tables

We used the GRADE approach to interpret findings (Schünemann 2008) and used GRADE profiler (GRADEPRO) to import data from RevMan 5 (Review Manager) 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' table.

  1. Global impression: no improvement - medium term.

  2. Global impression: need for additional medication - medium term.

  3. Global impression: sedation - medium term.

  4. Adverse effects/events: EPS - medium term.

  5. Satisfaction with treatment: general.

  6. Economic outcomes: cost-effectiveness.

Search methods for identification of studies

Electronic searches

1. Cochrane Schizophrenia Group Trial Register (January 2012)

We searched the Cochrane Schizophrenia Group's register (Jan 2012), which is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO, using the following search strategy.

(*azepam* OR *zolam* OR *diazep* or *Anthramycin* OR *clorazepat* OR *Devazepid* OR *Flumazenil* OR *Pirenzepine* OR *clobazam* OR *flutazoram* or *girisopam* or *nerisopam* or *pinasepam* or *tofisopam* or *triflubazam*) and (*agitat* OR *aggress* OR *violen* OR *disturb* or *acute* or *behave* or *tranquil* or *sedat* or *restrain*) in title, abstract, or index terms.

2. Previous electronic searches

For previous searches see (Appendix 1).

Searching other resources

1. Reference Searching

We inspected references of all included studies for further relevant studies.

2. Handsearching

We sought additional relevant trials by handsearching reference lists of included and excluded trials.

3. Requests for additional data

We attempted to contact authors of relevant trials to inquire about other sources of relevant information.

Data collection and analysis

Selection of studies

Material downloaded from electronic sources included details of author, institution or journal of publication. Review author DG inspected all reports, which were then re-inspected by review authors AB, AM, JR or SS in order to ensure reliable selection. We resolved any disagreement by discussion, and where there was still doubt, we acquired the full article for further inspection. Once the full articles were obtained, we decided whether the studies met the review criteria. If disagreement could not be resolved by discussion, we sought further information and added these trials to the list of those awaiting assessment.

Data extraction and management

1. Extraction

Review authors AB, DG, JR and SS extracted data from all included studies. In addition, to ensure reliability, Clive Adams (CEA) independently extracted data from a random sample of these studies, comprising 10% of the total. Again, any disagreement was discussed, decisions documented and, if necessary, authors of studies were contacted for clarification. With remaining problems, CEA helped clarify issues and these final decisions were documented. Data presented only in graphs and figures were extracted whenever possible, but included only if two review authors independently had the same result. We attempted to contact authors through an open-ended request in order to obtain missing information or for clarification whenever necessary. If studies were multi-centre, where possible, we extracted data relevant to each component centre separately.

2. Management
2.1 Forms

We extracted binary, continuous and other 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 had not been written or modified by one of the trialists for that particular trial.
Ideally, the measuring instrument should either have been i. a self-report or ii. completed by an independent rater or relative (not the therapist). We realise that this is not often reported clearly; in (Description of studies) we noted if this is the case or not.

2.3 Endpoint versus change data

There are advantages of both endpoint and change data. Change data can remove a component of between-person variability from the analysis. On the other hand, calculation of change needs two assessments (baseline and endpoint) which can be difficult in 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. Because endpoint and change data are combined in the analysis, we used mean differences (MD) rather than standardised mean differences (SMD) throughout (Higgins 2011).

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 is more than the mean, this is considered strong evidence of skew (Higgins 2011);
c) if a scale started from a positive value (such as the Positive and Negative Syndrome Scale (PANSS) 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 SD > (S-S min), where S is the mean score and S min is the minimum score. Where skewed data were present, we presented results in a separate table.

Skewed endpoint data from trials of less than 200 participants were entered in additional tables rather than into an analysis. Skewed endpoint data pose less of a problem when looking at means if the sample size is large (over 200 participants) and were entered 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 change data from both large and small trials.

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) if necessary.

2.6 Direction of graphs

We entered data in such a way that the area to the left of the line of no effect indicates a favourable outcome for benzodiazepines alone, or (in the absence of a benzodiazepine alone) benzodiazepines in combination with antipsychotics.

Assessment of risk of bias in included studies

Review authors DG and SS worked independently to assess risk of bias by using criteria described in the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011) to assess trial quality. This set of criteria is based on evidence of associations between overestimate of effect and high risk of bias of the article such as sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting.

Where the raters disagreed, the final rating was made by consensus, with the involvement of another member of the review group. Where inadequate details of randomisation and other characteristics of trials were provided, we contacted authors of the trials in order to obtain further information. Non-concurrence in quality assessment was reported, but where disputes arose as to which category a trial was to be allocated, again, we resolved by discussion.

The level of risk of bias is noted in both the text of the review and in the 'Summary of findings' tables.

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). If heterogeneity was identified (Assessment of heterogeneity), we used a random-effects model to explore whether this had an effect on findings. For statistically significant results, we used 'Summary of findings' tables to calculate the number needed to treat to provide benefit/to induce harm statistic and its 95% CI.

2. Continuous data

For continuous outcomes, estimated mean difference (MD) between groups were used as change and endpoint data were combined. If scales of considerable similarity had been used, we would have presumed there was a small difference in measurement, calculated effect size and transformed the effect back to the units of one or more of the specific instruments. However, data of this type were not identified.

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. Firstly, authors often fail to account for intra-class correlation in clustered trials, leading to a 'unit of analysis' error (Divine 1992) whereby P values are spuriously low, confidence intervals unduly narrow and statistically significant difference overestimated. This causes type I errors (Bland 1997; Gulliford 1999).

None of the present included trials used cluster randomisation. for For the purposes of future updates of this review, 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 trials to obtain intra-class correlation coefficients for their clustered data and to adjust for this by using accepted methods (Gulliford 1999). Where clustering may be 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.

2. Cross-over trials

None of the present included trials employed a cross-over trial design; for the purposes of future updates of this review: 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, we will only use data of the first phase of cross-over trials.

3. Studies with multiple treatment groups

Where a study involves more than two treatment arms, if two or more of the interventions were similar, data were pooled. If data were binary these have simply been added. 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 use 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). We chose that, for any particular outcome, should more than 50% of data be unaccounted for either group, we would not present these data or use them within analyses, (except for the outcome 'leaving the study early').

2. Binary

Where attrition for a binary outcome was between 0% and 50%, we presented data on a 'once-randomised-always-analyse' basis (an intention-to-treat analysis) by including those leaving the study early in the denominator.

3. Continuous
3.1 Attrition

Where attrition for a continuous outcome was between 0% and 50%, and data only from people who completed the study to that point were reported, we presented and used these data.

3.2 Standard deviations

If standard deviations (SDs) were not reported, we first tried to obtain the missing values from the authors. If not available, where there were missing measures of variance for continuous data, but an exact standard error (SE) and confidence intervals (CIs) available for group means, and either 'P' value or 't' value available for differences in mean, we could calculate them according to the rules described in the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011). When only the standard error (SE) was reported, SDs were 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 did not apply, we calculated the SDs according to a validated imputation method which is based on the SDs of the other included trials (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. Where the only variance given was range (Diazepam 1979, IL), SDs were also estimated from the difference between the upper and lower value divided by four.

3.3 Last observation carried forward

We anticipated that in some trials 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). Therefore, where LOCF data were used in the trial, if less than 50% of the data had been assumed, we would have presented and used these data and indicated that they were the product of LOCF assumptions. Where LOCF were not used, data were analysed as they were presented in the original publications.

Assessment of heterogeneity

1. Clinical heterogeneity

We considered all included trials initially, without seeing comparison data, to judge clinical heterogeneity. We simply inspected all trials for clearly outlying people or situations which we had not predicted would arise. When such situations or participant groups arose, these implications are covered in the Discussion.

2. Methodological heterogeneity

We considered all included trials initially, without seeing comparison data, to judge methodological heterogeneity. We simply inspected all trials for clearly outlying methods which we had not predicted would arise. When such methodological differences arose, these have been considered in the Discussion.

3. Statistical heterogeneity
3.1 Visual inspection

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

3.2 Employing the I2 statistic

Heterogeneity between trials was investigated by considering the I2 method alongside the Chi2 (P > 0.10). The I2 provides an estimate of the percentage of inconsistency thought to be due to chance (Higgins 2008). 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 CI for I2). An I2 estimate greater than or equal to around 50% accompanied by a statistically significant Chi2 statistic, is interpreted as evidence of substantial levels of heterogeneity (Section 9.5.2 - 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

1. Protocol versus full study

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results. These are described in section 10.1 of the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011). We attempted to locate protocols of included randomised trials. If the protocol was available, outcomes in the protocol and in the published report were compared. If the protocol was not available, outcomes listed in the methods section of the trial report were compared with actually reported results.

2. Funnel plot

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results (Egger 1997). Again, these are described in Section 10 of the Cochrane Handbook for Systematic Reviews of Interventions (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 trials, or where all trials were of similar sizes. In other cases, where funnel plots were possible, we sought statistical advice in their interpretation. Because there were more data available for the secondary outcome, sedation, a funnel plot analysis was completed using this outcome (Figure 1).

Figure 1.

Funnel plot of comparison: 2. benzodiazepines vs antipsychotics, outcome: 2.3 Global impression - sedation.

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 trials 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 trials even if there is no statistically significant heterogeneity. There is, however, a disadvantage to the random-effects model. It puts added weight onto small trials which often are the most biased ones. Depending on the direction of effect, these trials can either inflate or deflate the effect size. We chose a fixed-effect model for all analyses, and if heterogeneity was identified we used a random-effects model.

As this is a review of the effects on acute psychosis, we included only those outcomes up to and including 48 hours after the initial dose of medication. Where data were for more than one time interval within the immediate (nought to 15 minutes), short term (15 minutes to one hour) and medium term (one hour to 48 hours) categories, the earlier data were used for the review. The only exception to this were the data from (Diazepam 1979, IL); this trial reported CGI data at four and 24 hours (medium term) but because the loss to follow-up was more than 50% for one group at four hours and complete at 24 hours, we used the latter data.

Subgroup analysis and investigation of heterogeneity

1. Subgroup analyses

Subgroup analyses were carried out for different antipsychotics.

2. Investigation of heterogeneity

If inconsistency was high, this was reported. First, we investigated whether data had been entered correctly. Second, if data were correct, we visually inspected the graph and if the results of trials were clearly different, these data were not pooled (Analysis 2.4). Where there was evidence of substantial statistical heterogeneity data (Analysis 2.8; Analysis 4.1; Analysis 4.4), these were also analysed using a random-effects model and any differences in the results of fixed-effect and random-effects models covered in the Discussion. Possible reasons for identified heterogeneity are also considered in the Discussion.

Sensitivity analysis

Sensitivity analyses based on the quality criteria reported in this review: randomised sequence generation; allocation concealment; blinding of outcome measurement; incomplete reporting of outcome data; and loss to follow-up were carried out to investigate whether there may have been any possible biases in the estimate of effects.

1. Risk of bias

We analysed the effects of excluding trials that were judged to be at high risk of bias across the domains of allocation concealment, blinding and outcome reporting for the binary outcomes improvement, sedation and EPS.

2. Fixed and random effects

All data were synthesised using a fixed-effect model, however, we also synthesised data for the primary outcomes using a random-effects model to evaluate whether this altered the significance of the results.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

For this update we used a modified search, based on the search strategy from the original review (see Appendix 1), which identified 494 references. An additional 19 potentially relevant references were identified from the reference lists of published trials and reviews (see Figure 2).

Figure 2.

Study flow diagram.

Included studies

Please see Characteristics of included studies for descriptions of each study. This review update had adopted a different means of presenting included studies. We decided to present included studies in such a way as to describe the type of benzodiazepine employed in the study, as well as the year and country in which the study was undertaken. For example, in the study that was referenced in the previous review as 'Qu 1999', participants received either 2 mg clonazepam or 10 mg haloperidol and the study was undertaken in China in 1999, therefore, it is now presented as Clonazepam 1999, CHN. We felt that this method - although unconventional - would be most suitable in order to present the findings in a logical and concise manner, as results are clustered in graphs for ease of understanding.

Twenty-one trials are included. This is the total of the 11 trials from the first review and a further 10 after the recent search. In this 2012 update, the inclusion criteria were changed to include the comparison of antihistamines in combination with antipsychotics, as we felt that a review of the effect of benzodiazepines for psychosis-induced aggression should take into account the potential use of antihistamines for the treatment of psychosis-induced aggression due to its potential sedative and anticholinergenic properties and the widespread use of this combination. The inclusion criteria were clarified to specify the inclusion of benzodiazepines either alone or in combination with any other antipsychotic drug, versus either placebo, benzodiazepines or antipsychotics alone or combined with any other antipsychotic, antihistamine or benzodiazepine. This had the result of permitting the inclusion of previously excluded studies, which were excluded for not fitting the initial review criteria (Clonazepam 2003, CHN; Clonazepam 2004, CHN; Clonazepam 2007, CHN; Lorazepam 2004, IN; Lorazepam 2006, USA; Midazolam 2003, BZ). Midazolam 2011, BZ and Clonazepam 2005, CHN were also identified in our new trial search.

In this update, we agreed that one of the original 12 trials was a duplicate (Solomon 1990) of another included study (Lorazepam 1991, USA). Therefore, the analysis of EPS has been corrected to avoid double counting. One trial compared benzodiazepines with placebo (Lorazepam 2001, RO & USA), 11 compared benzodiazepines with antipsychotics (Clonazepam 1993, CA; Clonazepam 1999, CHN; Diazepam 1979, IL; Flunitrazepam 1999, IL; Lorazepam 1989, USA; Lorazepam 1991, USA; Lorazepam 1997, USA; Lorazepam 1997a, USA; Lorazepam 1998, SA; Lorazepam 2001, RO & USA; Midazolam 2006, AU), two trials compared benzodiazepines with antihistamines combined with antipsychotics (Lorazepam 2004, IN; Midazolam 2003, BZ), one trial compared benzodiazepines combined with antipsychotics with antihistamines combined with antipsychotics (Midazolam 2011, BZ), eight trials compared benzodiazepines combined with antipsychotics with antipsychotics alone (Alprazolam 1992, USA; Clonazepam 2003, CHN; Clonazepam 2004, CHN; Clonazepam 2005, CHN; Clonazepam 2007, CHN; Lorazepam 1989, USA; Lorazepam 1997, USA; Midazolam 2011, BZ) and four trials compared benzodiazepines combined with antipsychotics with benzodiazepines alone (Lorazepam 1997, USA; Lorazepam 1998, USA; Lorazepam 1989, USA; Lorazepam 2006, USA).

1. Setting

The trials by Lorazepam 1997, USA Clonazepam 1993, CA, Midazolam 2006, AU and Lorazepam 2006, USA took place in general emergency departments; five trials were set in psychiatric hospitals (Diazepam 1979, IL; Lorazepam 1989, USA; Lorazepam 1998, SA; Lorazepam 2004, IN; Midazolam 2003, BZ); one was implied as having taken place in a psychiatric hospital (Flunitrazepam 1999, IL) and one within a general hospital (Lorazepam 2001, RO & USA). Five trials were conducted in psychiatric emergency departments (Alprazolam 1992, USA; Clonazepam 1993, CA; Lorazepam 1997a, USA; Lorazepam 1998, USA; Midazolam 2011, BZ); one trial took place in a locked intensive care unit (Lorazepam 1991, USA) and five trials were implied as having taken place in a Chinese hospital (Clonazepam 2005, CHN; Clonazepam 1999, CHN; Clonazepam 2004, CHN; Clonazepam 2003, CHN; Clonazepam 2007, CHN). The majority of these trials took place in the Americas, followed by China, Israel, Canada, Australia, Romania, South Africa and India.

2. Length of trials

The duration of included trials varied from one hour (Lorazepam 1989, USA), seven days (Clonazepam 2004, CHN; Clonazepam 2007, CHN; Lorazepam 1998, SA; Lorazepam 1998, USA), two weeks (Clonazepam 2003, CHN; Lorazepam 2004, IN; Midazolam 2003, BZ) and 28 days (Clonazepam 2005, CHN), although only data up to 48 hours were included for this review.

3. Participants

Participants in nine of the included trials appear to have been inpatients (Clonazepam 1999, CHN; Clonazepam 2003, CHN; Clonazepam 2004, CHN; Clonazepam 2005, CHN; Clonazepam 2007, CHN; Flunitrazepam 1999, IL; Lorazepam 1989, USA; Lorazepam 1991, USA; Lorazepam 2001, RO & USA) while in 11 trials, participants appear to have been newly admitted (Alprazolam 1992, USA; Diazepam 1979, IL; Lorazepam 1997, USA; Lorazepam 1997a, USA; Lorazepam 1998, SA; Lorazepam 1998, USA; Lorazepam 2004, IN; Lorazepam 2006, USA; Midazolam 2003, BZ; Midazolam 2006, AU; Midazolam 2011, BZ) and in one trial, patients were a mixture of inpatients and new admissions (Clonazepam 1993, CA).

In most trials, participants were of mixed diagnoses (Clonazepam 1993, CA; Clonazepam 1999, CHN; Diazepam 1979, IL; Flunitrazepam 1999, IL; Lorazepam 1989, USA; Lorazepam 1991, USA; Lorazepam 1997, USA; Lorazepam 1997a, USA; Lorazepam 1998, SA; Lorazepam 1998, USA; Lorazepam 2001, RO & USA; Lorazepam 2004, IN; Lorazepam 2006, USA; Midazolam 2003, BZ; Midazolam 2011, BZ). Participants in Alprazolam 1992, USA, Clonazepam 2004, CHN, Clonazepam 2003, CHN and Clonazepam 2007, CHN were diagnosed as having schizophrenia and in Clonazepam 2005, CHN schizophrenia with agitation/aggression. In Midazolam 2006, AU, diagnosis was not explicit but was described as a 'mental illness diagnosis'.

4. Trial size

The overall sample size in all the included trials was generally small. The total number of participants in each trial ranged from n = 16 (Clonazepam 1993, CA) to n = 301 (Midazolam 2003, BZ).

5. Interventions
1. Benzodiazepines versus placebo

We were able to include one trial comparing benzodiazepines with placebo (Lorazepam 2001, RO & USA). This trial compared one to three intramuscular (IM) injections of lorazepam (2-5 mg) with IM placebo.

2. Benzodiazepines versus antipsychotics

Eleven trials were included comparing benzodiazepines with antipsychotics; five trials compared lorazepam with haloperidol. Three trials compared 2 mg of lorazepam versus 5 mg of haloperidol (Lorazepam 1997, USA; Lorazepam 1997a, USA; Lorazepam 1991, USA, ) and one compared 4 mg of lorazepam to 5 mg of haloperidol (Lorazepam 1989, USA). In all of these trials, both interventions were given as an IM injection, although in the trial by Lorazepam 1997a, USA, participants were able to receive the administered dose as an oral concentrate. Medications were given as a single injection in the trials by Lorazepam 1989, USA and Lorazepam 1991, USA. In the trial by Lorazepam 1997a, USA, doses were administered every 30 minutes for four hours or until the patient was sedated. Additional doses could be given in the trial by Lorazepam 1991, USA, where the mean number of doses of lorazepam was 1.13 and haloperidol was 1.10. Participants in Lorazepam 1997, USA could be given up to six doses over eight hours although the majority (71% of patients receiving haloperidol and 74% receiving lorazepam) received less than three doses. Lorazepam 2001, RO & USA compared 2-5 mg IM lorazepam with 10-25 mg IM olanzapine. In this trial, participants received 1-3 doses based on the clinical judgment of 'the investigator'.

In the remaining trials that compared benzodiazepines with antipsychotics, four compared IM benzodiazepine with IM haloperidol. Clonazepam 1993, CA compared 1-2 mg of clonazepam with 5-10 mg of haloperidol at 0, 0.5 and one hour. Flunitrazepam 1999, IL compared single doses of 1 mg flunitrazepam with 5 mg haloperidol. The trial by Diazepam 1979, IL compared diazepam (mean dose of 35 mg/3h) with high-dose haloperidol (35 mg over three hours) and low-dose haloperidol (20 mg over three hours) and Clonazepam 1999, CHN compared 2 mg IM clonazepam with 10 mg IM of haloperidol. Midazolam 2006, AU compared 5 mg midazolam with 10 mg droperidol, both of which were given intravenously, with repeat doses given until sedation was achieved.

3. Combined benzodiazepines/antipsychotics versus same benzodiazepines alone

Four trials compared a combination of lorazepam with haloperidol versus lorazepam alone. Lorazepam 1997, USA and Lorazepam 1998, USA compared a combination of 2 mg lorazepam and 5 mg haloperidol with 2 mg lorazepam alone while Lorazepam 1989, USA compared 4 mg lorazepam combined with 5 mg haloperidol with 4 mg lorazepam. All were given as an IM injection. Lorazepam 2006, USA compared 2 mg IM lorazepam plus 2 mg of oral risperidone, or 2 mg IM lorazepam plus 5 mg oral haloperidol with 2 mg IM lorazepam (plus oral placebo). In Lorazepam 1989, USA and Lorazepam 2006, USA single doses were given. Participants in Lorazepam 1998, USA could receive a second dose within the first hour, and in Lorazepam 1997, USA participants could be given up to six doses over eight hours. The majority of participants, however, received less than three doses (91% of patients receiving both drugs and 74% of patients receiving lorazepam alone).

4. Combined benzodiazepines/antipsychotics versus same antipsychotics alone

Four trials comparing combined benzodiazepines/antipsychotics with the same antipsychotics alone were identified - in each study, benzodiazepines were combined with and compared with 5 mg doses of haloperidol; Alprazolam 1992, USA compared 1 mg alprazolam plus 5 mg of haloperidol with 5 mg of haloperidol plus placebo; Lorazepam 1997, USA compared 2 mg of lorazepam plus 5 mg of haloperidol with 5 mg of haloperidol alone; and Lorazepam 1989, USA compared 4 mg lorazepam plus 5 mg haloperidol with 5 mg haloperidol. All drugs were administered as an IM injection. In the trials by Lorazepam 1989, USA single doses were given; in Alprazolam 1992, USA medications were administered as a daily oral dose although additional doses could be given if the psychosis scores were high; and in Lorazepam 1997, USA, 9% of the patients receiving both drugs and 29% of the patients receiving haloperidol were given three or more doses. Midazolam 2011, BZ compared combined 15 mg midazolam with haloperidol 5 mg IM versus 5 mg haloperidol 5 mg IM (see below: 6: Combined benzodiazepines/antipsychotics versus different antipsychotics alone).

5. Combined benzodiazepines/antipsychotics versus different antipsychotics alone

Five trials comparing combined benzodiazepines/antipsychotics with different antipsychotics alone were identified; Clonazepam 2003, CHN; Clonazepam 2004, CHN; Clonazepam 2005, CHN; Clonazepam 2007, CHN; Midazolam 2011, BZ.

Clonazepam 2005, CHN compared the effects of clonazepam (2-6 mg IM initially, then orally at 4-6 mg after one week) combined with risperidone 4-6 mg IM versus 200-400 mg clozapine IM. Clonazepam 2004, CHN compared 2-4 mg clonazepam combined with 2-4 mg risperidone with either 50-200 mg clozapine or 10-20 mg haloperidol, and Clonazepam 2003, CHN compared 2-6 mg clonazepam IM plus 2-6 mg risperidone IM to 25-125 mg clozapine IM and 5-20 mg haloperidol IM. Combined clonazepam (mean dose 3.5 mg IM) and olanzapine 5-30 mg (orally - mean dose 14.8 mg) versus 5-20 mg haloperidol IM (mean dose 12.8 mg) was compared in Clonazepam 2007, CHN - participants in this study were administered trihexyphenidyl at 0.3 mg where serious EPS occurred. Midazolam 2011, BZ compared combined 15 mg midazolam with haloperidol 5 mg IM with either 10 mg olanzapine or 20 mg ziprasidone IM.

6. Benzodiazepines/antipsychotics versus antipsychotics/antipsychotics

Lorazepam 1998, SA compared 4 mg IM lorazepam with 40 mg IM clotiapine given at six hourly intervals 'if warranted'. Both groups also received 10 mg of IM haloperidol at the same time.

7. Benzodiazepines versus combined antipsychotics/antihistamines

Two trials were identified for this comparison; both were large, higher quality trials that compared the effects of benzodiazepines versus combined haloperidol with promethazine. In Midazolam 2003, BZ, 15 mg IM midazolam (with flumazenil made available for use in the event of midazolam toxicity) was compared with haloperidol 5-10 mg IM (n = 77 received 5 mg, n = 71 received 10 mg) combined with promethazine 25-50 mg IM (n = 147 received 50 mg, n = 1 received 25 mg). Similarly, Lorazepam 2004, IN compared lorazepam 4 mg IM with haloperidol 10 mg IM combine with promethazine 25-50 mg IM (n = 96 received 50 mg, n = 4 received 25 mg) - all doses were given at the discretion of the treating physician.

8. Combined benzodiazepines/antipsychotics versus combined antipsychotics/antihistamines

One trial was identified for this comparison (Midazolam 2011, BZ), which compared combined 15 mg midazolam and 5 mg haloperidol (each administered IM) with combined 50 mg promethazine and 5 mg haloperidol (also administered IM). After the initial dose, only additional doses of the haloperidol/promethazine combination could be used, according to clinical judgement. If a participant needed another intervention, he or she were immediately removed from the study.

6. Outcomes scales

The following outcome scales were used in the trials included in this review.

1. Global impression

i. Clinical Global Impression (CGI, Busner 2007; Guy 1970) (high = worse)
The CGI was designed to quantify severity of illness and overall clinical improvement in people with a psychiatric disorder. A seven-point scoring system is usually used for severity and improvement with low scores indicating decreased severity and/or greater recovery. The CGI scale was used by Alprazolam 1992, USA; Lorazepam 1997a, USA; Diazepam 1979, IL and Lorazepam 2001, RO & USA. Lorazepam 1998, USA dichotomised scores by defining a reduction of at least 3 points on the CGI as improvement. Lorazepam 2004, IN dichotomised the outcomes of this scale to present outcomes of those clinically improved.

ii. Ramsay Sedation Scale (RSS, Ramsay 1974)
The RSS is a six-item rating scale used to assess levels of sedation by selecting the most appropriate level of response. A rating of one indicates an agitated, anxious state, and a rating of six indicates an unresponsive state. Midazolam 2011, BZ is the only trial that reported data using this scale.

2. Behaviour

i. Agitated Behaviour Scale (ABS, Corrigan 1988) (high = worse)
The ABS was originally developed in response to the need to make serial assessments of agitation during the acute period following traumatic brain injury (Caplan 1999). It originally consisted of 39 items, but was subsequently reduced to 14 items following validation and includes a range of agitated behaviour, such as short attention span; impulsiveness; violence/threatening violence; uncooperativeness; restlessness and repetitive behaviour. The 14-item ratings range on a scale of one to four, with one indicating the absence of agitated behaviour, and four indicating the extreme presence of agitated behaviour. This scale was used by Lorazepam 2001, RO & USA. Lorazepam 1997, USA also used this scale, but presented skewed data (see Data and analyses).

ii. Overt Aggression Scale (OAS, Yudofsky 1986) (high = worse)
The OAS is designed to assess observable aggressive or violent behaviour and consists of four categories: verbal aggression; physical aggression against objects; physical aggression against self; and physical aggression against other people. Within each category, four types of aggressive behaviour are listed. The OAS was used by Clonazepam 1999, CHN; Midazolam 2011, BZ and Lorazepam 1998, SA. Improvement was defined as reduction of at least 4 points on the OAS by Flunitrazepam 1999, IL and as a decrease of 50% or more by Lorazepam 1998, USA. Lorazepam 1991, USA also used this scale, defining improvement as a 'greater than mean decrease' in scores at two hours.

iii. Overt Agitation Severity Scale (OASS, Yudofsky 1997) (high = worse)
The OASS is designed to define and objectively rate the severity of agitated behaviour and confines its rating exclusively to observable behavioural manifestations of agitation. This comprises three categories - vocalisations and oral/facial movements; upper torso and upper extremity movements; and lower extremity movements - each with four types of agitated behaviour listed. These types of behaviour are rated on a 0-4 point scale, with 0 = not present and 4 = always present. Midazolam 2011, BZ is the only trial that reported data using this scale.

3. Mental state

i. Brief Psychiatric Rating Scale (BPRS, Overall 1967; Shafer 2005) (high = worse)
The BPRS lists a range of psychiatric symptoms generally associated with the domains of anxiety and depression, hostility and suspiciousness, thought disturbance, and withdrawal/motor retardation. The original scale has 16 items, but a revised 18-item scale is commonly used. Each item is rated on a seven-point scale varying from 'not present' to 'extremely severe'. Alprazolam 1992, USA; Lorazepam 1997a, USA and Clonazepam 1999, CHN reported data from this scale. Alprazolam 1992, USA and Lorazepam 1997, USA also reported data using the 11 psychosis-anxiety items from the BPRS, classified as the BPRS-psychosis subscale (Faustman 1989). Lorazepam 2006, USA reported skew data from this scale.

ii. Inpatient Multidimensional Psychiatric Scale (IMPS, Cairns 1983; Lorr 1963)
The IMPS measures psychotic symptom scales in psychiatric inpatients. It originally consisted of 75 items and 10 domains. The addition of another 15 items resulted in 12 domains: excitement, hostile belligerence; grandiose expansiveness; paranoid projection; perceptual distortions; anxious depression; retardation and apathy; conceptual disorganisation; motor disturbances; disoriented behaviour; impaired functioning; and obsessive-phobic. The IMPS was used by Clonazepam 1993, CA who reported a reduction of at least 50% as improvement.

iii. Positive and Negative Symptom Scale (PANSS, Kay 1987) (high = worse)
PANSS was developed from the BPRS and the Psychopathology Rating Scale. It is used to evaluate positive, negative and other symptom dimensions in schizophrenia. The scale has 30 items, each measured on a seven-point scoring system varying from one (absent) to seven (extreme). Clonazepam 2003, CHN reported data from this scale - as did Lorazepam 2006, USA, however, data were skewed for the latter. Lorazepam 2001, RO & USA; Clonazepam 2004, CHN and Clonazepam 2007, CHN each reported data from the PANNS-Excited Component subscale (PANSS-EC); Lorazepam 2001, RO & USA defined a reduction of 40% or more on the PANSS-EC as a measure of improvement.

Excluded studies

We excluded 15 studies. All did not fit the inclusion criteria. Arana 1986 and Simpson 2003b did not appear to be randomised. Lenox 1992, Nestoros 1982 and Nobay 2004 were excluded because participants were not acutely psychotic. Wyant 1990 was excluded because the psychometric properties of the Clinical Global rating scale were not available - and there were no other outcomes. Martel 2005 was excluded because agitation appeared to be due to alcohol intoxication in 93% of participants. We excluded Davis 2008b because there were no useable data. Guz 1972, Hankoff 1962, Hanlon 1970, Kang 2006, Mei 2006, Tang 2007 and Wan Zhili 2005 were all excluded because there were no usable data before 48 hours.

Risk of bias in included studies

For a summary of the overall risk of bias in included trials please see Figure 3 and Figure 4.

Figure 3.

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

Figure 4.

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

Allocation

All 21 included trials were described as randomised but overall the description of allocation and concealment was poor. Only Midazolam 2011, BZ, Midazolam 2006, AU, Midazolam 2003, BZ and Lorazepam 2004, IN adequately described the process used for randomisation and the concealment of allocation. In five trials it was stated that a table of random numbers was used to allocate patients (Lorazepam 1997, USA; Lorazepam 1998, USA, Flunitrazepam 1999, IL; Clonazepam 2004, CHN; Clonazepam 2007, CHN) with no further detail. Diazepam 1979, IL was described as a randomised trial but also referred to alternate allocation. There was no description of the method of allocation and concealment in the remaining trials.

Blinding

Ten of the included trials were described as double-blinded, however the method of blinding was not clear (Clonazepam 1999, CHN; Clonazepam 2003, CHN; Clonazepam 2005, CHN; Clonazepam 2007, CHN; Flunitrazepam 1999, IL; Lorazepam 1997a, USA; Lorazepam 1998, SA; Lorazepam 2001, RO & USA; Lorazepam 2006, USA; Midazolam 2006, AU), with only five trials explaining blinding methods (Alprazolam 1992, USA; Clonazepam 1993, CA; Lorazepam 1997, USA; Lorazepam 1998, USA; Midazolam 2011, BZ). Two trials were single/observer blinded (Diazepam 1979, IL; Lorazepam 1991, USA) and Lorazepam 1989, USA and Clonazepam 2004, CHN were not blinded. Midazolam 2003, BZ and Lorazepam 2004, IN were blind up until point of treatment assignment.

Incomplete outcome data

High loss to follow-up was defined as where the number of participants lost to follow-up was more than 5% in the first two hours or between 25% and 50% overall. In nine of the trials, the follow-up rate was unclear (Clonazepam 1999, CHN; Clonazepam 2003, CHN; Clonazepam 2004, CHN; Clonazepam 2005, CHN; Clonazepam 2007, CHN; Lorazepam 1989, USA; Lorazepam 1997, USA; Lorazepam 1997a, USA; Midazolam 2011, BZ), six had a high loss to follow-up rate (Alprazolam 1992, USA; Clonazepam 1993, CA; Diazepam 1979, IL; Lorazepam 1991, USA; Lorazepam 2006, USA; Midazolam 2006, AU) and six had a low loss to follow-up (Flunitrazepam 1999, IL; Lorazepam 1998, SA; Lorazepam 1998, USA; Lorazepam 2001, RO & USA; Lorazepam 2004, IN; Midazolam 2003, BZ, see Table 4).

Table 4. High and low attrition studies
  1. Trials were considered to have a high attrition rates if it was more than 5% within the first 2 hours or 25-50% overall.

    EPS - extrapyramidal symptoms

AttritionStudy% lossDurationNotes
HighAlprazolam 1992, USA3172 hours 
 Clonazepam 1993, CA122 hours 
 Midazolam 2006, AU10100 minutes 
 Diazepam 1979, IL5024 hours 
 Lorazepam 1991, USA3348 hours- for EPS outcome; 12% loss for 'sedation'
 Lorazepam 2006, USA6090 minutes 
LowLorazepam 1998, USA07 days 
 Flunitrazepam 1999, IL02 hours 
 Lorazepam 2001, RO & USA424 hours 
 Lorazepam 1998, SA07 days 
 Midazolam 2003, BZ12 weeks 
 Lorazepam 2004, IN12 weeks 

Selective reporting

Lorazepam 1997, USA had an unclear risk; sample numbers were not clear as the authors stated that data were only collected if the participant was awake. In Lorazepam 1998, USA, a higher risk of bias was noted, as the trial authors changed the criteria for 'improvement' (using the VAS) post-study, after analysis had taken place. Similarly, in Midazolam 2006, AU, the original inclusion criteria of 18-65 year-olds was subsequently changed to 15-76 year-olds in order to include the data from 11 additional participants who were either above or below the original threshold. The trial also reported the loss of trial packs and study information, however, it is not made clear exactly how many study packs were lost. Furthermore, it is acknowledged in Lorazepam 2001, RO & USA that the number of participants who reported outcomes from rating scales at baseline and endpoint differ to the total number of participants randomised into each treatment arm. It is stated that not all participants completed both a baseline and post-baseline rating scale.

Other potential sources of bias

1. Funding

Several trials were funded by pharmaceutical companies: Alprazolam 1992, USA was supported in part by a grant from The Upjohn Company (now Pfizer); Lorazepam 1997, USA was supported in part by a grant from Wyeth-Ayerst Research (now also part of Pfizer); Lorazepam 2001, RO & USA was funded by Lilly Resesarch Laboratories, Indiana, and developed a rating scale for use in the study (which was excluded from analysis); 90% of the trial authors of this study were also employed by the same pharmaceutical company. Lorazepam 1991, USA was supported in part by Wyeth Laboratories, and Lorazepam 2006, USA was funded by a grant from Janssen Pharmaceutica. Other sources of funding include support from the National Alliance for Research on Schizophrenia and Depression (Lorazepam 1997a, USA); a postgraduate scholarship from the National Health and Medicine Research Council and a research grant from the Australasian College for Emergency Medicine (Morson Taylor Award, Midazolam 2006, AU); a grant from the Gralnick Foundation, High Point Hospital, Port Chester, NY (Diazepam 1979, IL); funding from Fundação Oswaldo Cruz, the British Council, CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and FAPERJ (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro, Midazolam 2003, BZ); funding by intramural research grants from Fluid Research Fund (Christian Medical College, Vellore), and the Cochrane Schizophrenia Group general fund (Lorazepam 2004, IN).

2. Rating scales

In the trials that used rating scales, seven did not specify who administered the scales or whether they were conducted by independent raters (Clonazepam 1999, CHN; Lorazepam 1989, USA; Lorazepam 1991, USA; Lorazepam 1997a, USA; Lorazepam 1998, SA; Lorazepam 1998, USA; Midazolam 2011, BZ). Raters were not stated as independent in Alprazolam 1992, USA, Clonazepam 1993, CA, Flunitrazepam 1999, IL or Lorazepam 2001, RO & USA.

Effects of interventions

See: Summary of findings for the main comparison BENZODIAZEPINES compared to PLACEBO for psychosis-induced aggression or agitation; Summary of findings 2 BENZODIAZEPINES compared to ANTIPSYCHOTICS for psychosis-induced aggression or agitation; Summary of findings 3 BENZODIAZEPINES + ANTIPSYCHOTICS compared to SAME BENZODIAZEPINES for psychosis-induced aggression or agitation; Summary of findings 4 BENZODIAZEPINES + ANTIPSYCHOTICS compared to SAME ANTIPSYCHOTICS for psychosis-induced aggression or agitation; Summary of findings 5 BENZODIAZEPINES + ANTIPSYCHOTICS compared to DIFFERENT ANTIPSYCHOTICS for psychosis-induced aggression or agitation; Summary of findings 6 BENZODIAZEPINES + ANTIPSYCHOTICS compared to ANTIPSYCHOTICS + ANTIPSYCHOTICS for psychosis-induced aggression or agitation; Summary of findings 7 BENZODIAZEPINES compared to ANTIHISTAMINES + ANTIPSYCHOTICS for psychosis-induced aggression or agitation; Summary of findings 8 BENZODIAZEPINES + ANTIPSYCHOTICS compared to ANTIHISTAMINES + ANTIPSYCHOTICS for psychosis-induced aggression or agitation

Comparison 1: BENZODIAZEPINES versus PLACEBO

All data for this comparison came from (Lorazepam 2001, RO & USA, n = 102).

1. Global impression

There was no difference in the number of people who had not improved in the short term (n = 102, risk ratio (RR) 0.89, 95% confidence interval (CI) 0.69 to 1.16) but fewer people receiving benzodiazepines were rated as not improved in the medium term (n = 102, RR 0.62, 95% CI 0.40 to 0.97, Analysis 1.1). There was no difference between the benzodiazepine and placebo groups in the number of people who needed additional medication (n = 102, RR 1.00, 95% CI 0.69 to 1.44, Analysis 1.2) or were sedated (n = 102, RR 1.67, 95% CI 0.42 to 6.61, Analysis 1.3). The average change in CGI scores were also not different (n = 76, mean difference (MD) 0.07, 95% CI -0.46 to 0.60, Analysis 1.4).

2. Behaviour

ABS scores were significantly better in the benzodiazepines group (n = 101, MD -3.61, 95% CI -5.92 to -1.30, Analysis 1.5).

3. Mental state

There were no differences between groups in the change in PANSS (n = 99, MD -2.57, 95% CI -6.23 to 1.09, Analysis 1.6) or PANSS excited component scores (n = 101, MD -1.91, 95% CI -3.83 to 0.01, Analysis 1.7).

4. Adverse events

There were no differences between the benzodiazepine and placebo groups in EPS (n = 102, RR 0.33, 95% CI 0.04 to 3.10, Analysis 1.8) or receiving medication for EPS (n = 102, RR 0.33, 95% CI 0.04 to 3.10, Analysis 1.9) There was no difference in the adverse effects: dizziness, nausea and vomiting (Analysis 1.10).

5. Leaving study early

There was no difference in leaving the study early for any reason in the one study that compared benzodiazepines with placebo (n = 102, RR 0.60, 95% CI 0.15 to 2.38, Analysis 1.11).

Comparison 2: BENZODIAZEPINES versus ANTIPSYCHOTICS

We included 10 trials (n = 224) comparing benzodiazepines with antipsychotics (Clonazepam 1993, CA; Clonazepam 1999, CHN; Diazepam 1979, IL; Flunitrazepam 1999, IL; Lorazepam 1989, USA; Lorazepam 1991, USA; Lorazepam 1997, USA; Lorazepam 1997a, USA; Lorazepam 2001, RO & USA; Midazolam 2006, AU).

1. Global impression

More people in the benzodiazepines group were likely to be rated as not improved in the medium term (n = 150, 1 RCT, RR 1.84, 95% CI 1.06 to 3.18) when compared with olanzapine but there was no difference in the short term (n = 150, 1 RCT, RR 1.26, 95% CI 0.95 to 1.66) or when benzodiazepines were compared with haloperidol in the medium term (n = 158, 4 RCTs, RR 0.88, 95% CI 0.66 to 1.17). These differences between subgroups were significant (Chi2= 6.53, P = 0.04, I2 = 69%, Analysis 2.1).
People receiving benzodiazepines were no more likely to need additional medication compared with those receiving droperidol in the short term (n = 153, 1 RCT, RR 1.87, 95% CI 0.83 to 4.19) or haloperidol in the medium term (n = 66, 1 RCT, RR 0.87, 95% CI 0.70 to 1.09, Analysis 2.2). However, participants receiving lorazepam were more likely to require additional medication than those receiving olanzapine in the medium term (n = 150, 1 RCT, RR 2.02, 95% CI 1.33 to 3.07).

There was no difference in the number of people sedated when benzodiazepines were compared with haloperidol in the short term (n = 44, 1 RCT, RR 1.17, 95% CI 0.53 to 2.59) or medium term (n = 434, 8 RCTs, RR 1.13, 95% CI 0.83 to 1.54) or olanzapine in the medium term (n = 150, 1 RCT, RR 0.75, 95% CI 0.28 to 1.98). However, people receiving benzodiazepines were more likely to be sedated in the short term when compared with people receiving droperidol (n = 153, 1 RCT, RR 2.71, 95% CI 1.55 to 4.73). The differences between subgroups were significant (Chi2 = 8.77, P = 0.03, I2 = 66% Analysis 2.3).

CGI change/endpoint scores for the short term favoured lorazepam when compared with haloperidol (n = 37, 1 RCT, MD -0.67, 95% CI -1.09 to -0.25). Because of the marked heterogeneity of medium-term data, these were not pooled. Results significantly favoured lorazepam compared with haloperidol (n = 37, 1 RCT, MD -0.81, 95% CI -1.37 to -0.25). There was no difference when diazepam was compared with haloperidol (n = 40, 1 RCT, MD 0.60, 95% CI -0.17 to 1.37) nor when olanzapine was compared with lorazepam (n = 147, 1 RCT, MD 0.14, 95% CI -0.15 to 0.43, Analysis 2.4). There was also no difference in IMPS scores in the medium term when clonazepam was compared with haloperidol (n = 16, 1 RCT, MD 2.60, 95% CI -3.04 to 8.24, Analysis 2.5).

2. Behaviour

People receiving olanzapine scored significantly lower on the Agitated Behaviour Scale (ABS) in the medium term (n = 149,1 RCT, MD 2.91, 95% CI 0.80 to 5.02) but there was no difference when haloperidol was compared with lorazepam (n = 66,1 RCT, MD 1.80, 95% CI -2.39 to 5.99, Analysis 2.6). There was no significant difference in OAS scores at medium term when clonazepam was compared with haloperidol (n = 46, 1 RCT, MD 0.20, 95% CI -0.57 to 0.97, Analysis 2.7).

3. Mental state

There was no difference in BPRS scores in the short term (n = 37, 1 RCT, MD -3.26, 95% CI -10.65 to 4.13) or medium term (n = 123, 3 RCTs, MD 1.67, 95% CI -1.84 to 5.18, Analysis 2.8). As the medium-term data were heterogenous (Chi2 = 4.43, P = 0.11, I2 = 55%) a random-effects model was also used but these results were also equivocal (n = 123, 3 RCTs, MD 1.18, 95% CI -4.18 to 6.53). In the medium term there was no difference between people receiving lorazepam or haloperidol in BPRS psychosis subscale scores (n = 66, 1 RCT, MD = 0.70, -7.20 to 8.60, Analysis 2.9). For people receiving antipsychotics, the change in PANSS (n = 146, 1 RCT, MD 5.64, 95% CI 2.20 to 9.08, Analysis 2.10) and PANSS excited component scores were significantly better for people receiving olanzapine compared to those receiving lorazepam (n = 149, 1 RCT, MD 2.85, 95% CI 1.14 to 4.56, Analysis 2.11).

4. Adverse events

EPS were significantly lower in the group receiving benzodiazepines compared with those receiving haloperidol (n = 233, 6 RCTs, RR 0.13, 95% CI 0.04 to 0.41) and overall (n = 536, 8 RCTs, RR 0.15, 95% CI 0.06 to 0.39) but there was no difference in the single trials where lorazepam was compared with olanzapine (n = 150, 1 RCT, RR 0.24, 95% CI 0.03 to 1.89) and midazolam was compared with droperidol (n = 153, 1 RCT, RR 0.15, 95% CI 0.01 to 2.90, Analysis 2.12). People receiving antipsychotics were no more likely to require medication for EPS overall (n = 216, 2 RCT, RR 0.40, 95% CI 0.15 to 1.05) or the single trials which compared lorazepam with haloperidol (n = 66, 1 RCT, RR 0.50, 95% CI 0.17 to 1.47) or olanzapine (n = 150, 1 RCT, RR 0.24, 95% CI 0.03 to 1.89, Analysis 2.13).

There were no difference in the number of people experiencing the specific adverse effects: airway management, ataxia, problems, low blood pressure, dizziness, dry mouth, hypoxia, high or low heart rates, nausea or vomiting, seizures, speech disorder or tremor when compared with people receiving antipsychotics. However, these results all came from single trials (Analysis 2.14).

5. Leaving study early

There was no significant difference between groups in leaving the study early (n = 339, 3 RCTs, RR 1.48, 95% CI 0.70 to 3.13, Analysis 2.15).

Comparison 3: BENZODIAZEPINES + ANTIPSYCHOTICS versus SAME BENZODIAZEPINES

Four trials reported data for this comparison, including Lorazepam 1997, USA; Lorazepam 1998, USA; Lorazepam 1989, USA and Lorazepam 2006, USA, n = 216.

1. Global impression

There was no difference in improvement when people who received combined lorazepam/haloperidol were compared to people receiving lorazepam in the short term (n = 20, 1 RCT, RR 0.11, 95% CI 0.01 to 1.74) or medium term (n = 83, 2 RCTs, RR 0.94, 95% CI 0.69 to 1.28) or compared to people receiving combined lorazepam/risperidone in the medium term (n = 20, 1 RCT, RR 0.86, 95% CI 0.45 to 1.64, Analysis 3.1). There was no difference in the number of participants requiring additional medication when lorazepam was compared with lorazepam/haloperidol (n = 103, 2 RCTs, RR 1.02, 95% CI 0.79 to 1.32), with no instances reported when comparing combined lorazepam/risperidone with lorazepam alone (Analysis 3.2).

Sedation was significantly higher in the lorazepam/haloperidol combination group than the lorazepam only group in the short term (n = 47, 1 RCT, RR 1.92, 95% CI 1.10 to 3.35) although there was no difference in the medium term (n = 110, 2 RCTs, RR 0.84, 95% CI 0.59 to 1.19, Analysis 3.3).

2. Behaviour

Medium term ABS scores for people receiving lorazepam were not different from those receiving the combined lorazepam/haloperidol treatment (n = 63, 1 RCT, RR -1.60, 95% CI -5.94 to 2.74, Analysis 3.4).

3. Mental state

For the BPRS (short term: n = 20, 1 RCT, MD 1.10, 95% CI -23.17 to 25.37; medium term: n = 20, 1 RCT, MD -1.70, 95% CI -24.26 to 20.86, Analysis 3.5), BPRS psychosis subscale (n = 63, 1 RCT, MD 1.20, 95% CI -6.28 to 8.68, Analysis 3.7) and PANSS (short term: n = 20, 1 RCT, MD 6.40, 95% CI -36.50 to 49.30; medium term: n = 20, 1 RCT, MD 3.20, 95% CI -29.41 to 35.81, Analysis 3.8) there was no difference between people who received combined lorazepam/antipsychotics compared with those who received lorazepam alone. Data from Lorazepam 2006, USA could not be added to the meta-analysis for BPRS (Analysis 3.6) and PANSS scores (Analysis 3.9) because data appeared to be skewed .

4. Adverse events

There was no difference in EPS when comparing combined lorazepam/haloperidol with lorazepam alone (n = 83, 2 RCTs, RR 1.94, 95% CI 0.18 to 20.30, Analysis 3.10), but Lorazepam 1998, USA reported no instances of EPS in their study. There was also no difference in the need for medication for EPS (n = 63, 1 RCT, RR 0.73, 95% CI 0.18 to 2.99, Analysis 3.11), nor was there any difference in the specific adverse events; ataxia, dizziness, dry mouth or speech disorder, Analysis 3.12).

5. Leaving study early

There was no difference in the number of people leaving the study early when lorazepam was compared with lorazepam/haloperidol (n = 40, 2 RCTs, RR 0.71, 95% CI 0.34 to 1.50) or lorazepam/risperidone (n = 20, 1 RCT, RR 0.86, 95% CI 0.45 to 1.64, Analysis 3.13).

Comparison 4: BENZODIAZEPINES + ANTIPSYCHOTICS versus SAME ANTIPSYCHOTICS

All data for this comparison came from four trials (total n = 759, Alprazolam 1992, USA; Lorazepam 1997, USA; Lorazepam 1989, USA; Midazolam 2011, BZ). All trials compared a benzodiazepines/haloperidol mix with haloperidol alone.

1. Global impression

In the medium term, people who received combined benzodiazepines/haloperidol were no more likely to improve than those receiving haloperidol alone (n = 155, 3 RCTs, RR 1.27, 95% CI 0.94 to 1.70, Analysis 4.1). These results were heterogeneous (Chi2 = 9.33, P = 0.01, I2 = 79%) but this was due to one small study contributing only 2.9% of weight to the analysis. The findings using a random-effects model were very similar (n = 155, 3 RCTs, RR 1.28 CI 0.57 to 2.84). In the medium term, people receiving haloperidol alone were no more likely to require additional medication than those receiving combined lorazepam/haloperidol (n = 67, 1 RCT, RR 0.95, 95% CI 0.79 to 1.15, Analysis 4.2). There was also no difference in mean doses of additional medication when midazolam plus haloperidol was compared with midazolam (n = 60, 1 RCT, MD 0.20, 95% CI -0.33 to 0.73, Analysis 4.3. Sedation was significantly more likely in the combined benzodiazepines/haloperidol group compared with haloperidol in the short term (n = 45, 1 RCT, RR 2.25, 95% CI 1.18 to 4.30) and medium term (n = 172, 3 RCTs, RR 1.75, 95% CI 1.14 to 2.67, Analysis 4.4) when using a fixed-effect model. However, the medium-term results were highly heterogeneous (Chi2 = 6.90, P = 0.03, I2 = 71%) and no longer significant when a random-effects model was used (n = 172, 3 RCTs, RR 1.67, 95% CI 0.67 to 4.12).

Sedation scores using the RSS were significantly higher in the combined midazolam/haloperidol group when compared with haloperidol in the short term (n = 60, 1 RCT, MD 0.50, 95% CI -0.01 to 1.01) although this was not different in the medium term (n = 60, 1 RCT, MD 0.10, 95% CI -0.36 to 0.56 (Analysis 4.5).

2. Behaviour

There was no difference in ABS agitation scores (n = 67, 1 RCT, MD -0.20, 95% CI -5.05 to 4.65, Analysis 4.6) when lorazepam plus haloperidol was compared with haloperidol. OAS aggression scores were also not different in the short term (n = 60, 1 RCT, MD 1.20, 95% CI -0.04 to 2.44, Analysis 4.7) when midazolam/haloperidol was compared with haloperidol but in the medium term favoured the haloperidol only group (n = 60, 1 RCT, MD 2.40, 95% CI 0.59 to 4.21, Analysis 4.7). Agitation scores using the OASS were significantly higher in the midazolam/haloperidol group compared with haloperidol in the short term (n = 60, 1 RCT, MD 8.50, 95% CI 7.07 to 9.93) and medium term (n = 60, 1 RCT, MD 6.70, 95% CI 5.94 to 7.46, Analysis 4.8).

3. Mental state

Alprazolam 1992, USA reported medium term BPRS scale data, with no significant difference between the two groups (n = 28, MD 0.01, 95% CI -7.26 to 7.28, Analysis 4.9). Medium term BPRS psychosis subscale scores were not different between groups receiving the combination treatment compared to benzodiazepine alone (n = 95, 2 RCTs, MD -1.19, 95% CI -4.60 to 2.23, Analysis 4.10).

4. Adverse events

There was no difference in the rate of EPS (n = 127, 2 RCTs, RR 0.44, 95% CI 0.16 to 1.17, Analysis 4.11) or medication for EPS (n = 95, 2 RCTs, RR 0.52, 95% CI 0.27 to 1.01, Analysis 4.12) when people receiving combined benzodiazepines/haloperidol were compared with those receiving haloperidol alone. There was no difference between groups when assessing specific adverse events (Analysis 4.13).

5. Hospital and service outcomes

In Alprazolam 1992, USA, there no difference in participants who had not been discharged in the medium term (n = 28, 1 RCT, RR 0.90, 95% CI 0.54 to 1.50, Analysis 4.14).

Comparison 5: BENZODIAZEPINES + ANTIPSYCHOTICS versus DIFFERENT ANTIPSYCHOTICS

Data for this comparison came from five trials (total n = 565, Clonazepam 2003, CHN; Clonazepam 2004, CHN; Clonazepam 2005, CHN; Clonazepam 2007, CHN; Midazolam 2011, BZ).

1. Global impression

More people in the combined midazolam/haloperidol treatment group had not improved in the medium term compared to the olanzapine group (n = 60, 1 RCT, RR 25.00, 95% CI 1.55 to 403.99) and ziprasidone (n = 60, 1 RCT, RR 4.00, 95% CI 1.25 to 12.75, Analysis 5.1). Mean doses of additional medication were skewed, but results suggest that people receiving the midazolam/haloperidol mix were more likely to require additional medication than people receiving either olanzapine or ziprasidone (Analysis 5.2).
People were significantly more likely to be sedated in the combined midazolam/haloperidol group in the medium term when compared with olanzapine (n = 60, 1 RCT, RR 12.00, 95% CI 1.66 to 86.59) or ziprasidone (n = 60, 1 RCT, RR 4.00, 95% CI 1.25 to 12.75, Analysis 5.3).

The change in RSS sedation scores also favoured olanzapine (n = 60, 1 RCT, MD 0.80, 95% CI 0.31 to 1.29) in the short term, however there was no difference between groups in the medium term (n = 60, 1 RCT, MD 0.10, 95% CI -0.32 to 0.52); or compared to ziprasidone in the short (n = 60, 1 RCT, MD 0.50, 95% CI -0.01 to 1.01) or medium term (n = 60, 1 RCT, MD 0.10, 95% CI -0.41 to 0.61, Analysis 5.4).

2. Behaviour

Aggression scores using the OAS were significantly higher in the combined midazolam/haloperidol group compared with the olanzapine and ziprasidone groups in the short term (olanzapine: n = 60, 1 RCT, MD 2.10, 95% CI 1.00 to 3.20; ziprasidone n = 60, 1 RCT, MD 1.20, 95% CI 0.10 to 2.30) and medium term (olanzapine: n = 60, 1 RCT, MD 2.90, 95% CI 1.32 to 4.48; ziprasidone: n = 60, 1 RCT, MD 3.10, 95% CI 1.49 to 4.71, Analysis 5.5).

OASS agitation scores were also higher in people receiving combined midazolam/haloperidol compared to people receiving olanzapine in the short term (n = 60, 1 RCT, MD 10.50, 95% CI 9.24 to 11.76) and medium term (n = 60, 1 RCT, MD 10.90, 95% CI 10.18 to 11.62); and compared to those receiving ziprasidone in the medium term (n = 60, 1 RCT, MD 2.80, 95% CI 0.30 to 5.30) but not the short term (n = 60, 1 RCT, MD 0.80, 95% CI -1.16 to 2.76, Analysis 5.6).

3. Mental state

In the medium term, mean PANSS scores were significantly higher when clonazepam/risperidone was compared with clozapine (n = 38, 1 RCT, MD 2.50, 95% CI 0.32 to 4.68) but not when the combination was compared with haloperidol (n = 38, 1 RCT, MD 0.50, 95% CI -2.15 to 3.15, Analysis 5.7). There was no difference in PANSS excited component scores in the medium term when clonazepam/risperidone was compared with clozapine (n = 172, 1 RCT, MD -0.10, 95% CI -1.04 to 0.84) and haloperidol (n = 172, 1 RCT, MD 0.30, 95% CI -0.64 to 1.24) or when clonazepam/olanzapine was compared with haloperidol (n = 65, 1 RCT, MD 0.30, 95% CI -1.40 to 2.00, Analysis 5.8).

4. Adverse effects

General side effects were not different when clonazepam plus risperidone was compared with clozapine (n = 76, 1 RCT, RR 0.18, 95% CI 0.02 to 1.48), although adverse effects were significantly lower in the group receiving the clonazepam/risperidone combination compared with haloperidol (n = 40, 2 RCT, RR 0.05, 95% CI 0.00 to 0.85, Analysis 5.9). There was no difference in the rate of EPS in the combined midazolam/haloperidol group when compared with olanzapine (n = 60, 1 RCT, RR 7.00, 95% CI 0.38 to 129.93) or ziprasidone (n = 60, 1 RCT, RR 7.00, 95% CI 0.38 to 129.93, Analysis 5.10). Incidences of hypotension were equivocal when midazolam/haloperidol was compared with olanzapine (n = 60, 1 RCT, RR 5.00, 95% CI 0.62 to 40.28) and ziprasidone (n = 60, 1 RCT, RR 0.83, 95% CI 0.28 to 2.44, Analysis 5.11).

Comparison 6: BENZODIAZEPINES + ANTIPSYCHOTICS versus ANTIPSYCHOTICS + ANTIPSYCHOTICS

One study reported data for this comparison (Lorazepam 1998, SA, n = 60).

1. Behaviour

There was no difference in medium term OAS scores when a combination of lorazepam plus haloperidol was compared with clothiapine plus haloperidol (n = 60, 1 RCT, MD -5.83, 95% CI -27.60 to 15.94, Analysis 6.1).

2. Leaving the study early

No participants were reported leaving the study early in the one study that reported this comparison (Analysis 6.2).

Comparison 7: BENZODIAZEPINES versus ANTIPSYCHOTICS + ANTIHISTAMINES

Two trials provided the data for this comparison (Lorazepam 2004, IN; Midazolam 2003, BZ).

1. Global impression

One study reported the majority of these outcomes (Lorazepam 2004, IN). Significantly more people receiving lorazepam had not improved compared to those receiving haloperidol plus promethazine - in the immediate term (n = 200, 1 RCT, RR 1.79, 95% CI 1.36 to 2.37), short term (n = 200, 1 RCT, RR 2.47, 95% CI 1.51 to 4.03), and medium term (n = 200, 1 RCT, RR 2.17, 95% CI 1.16 to 4.05, Analysis 7.1). Neither group required additional medication in the immediate term and there was no difference between groups in the short term (n = 200, RR 3.00, 95% CI 0.12 to 72.77) and medium term (n = 200, RR 1.33, 95% CI 0.31 to 5.81, Analysis 7.2).

The two trials presented conflicting results for sedation (Midazolam 2003, BZ; Lorazepam 2004, IN). People receiving lorazepam were less likely to be sedated compared with haloperidol and promethazine in the immediate term (n = 200, 1 RCT, RR 0.88, 95% CI 0.77 to 0.99), short term (n = 200, 1 RCT, RR 0.85, 95% CI 0.77 to 0.95) and medium term (n = 200, 1 RCT, RR 0.91, 95% CI 0.84 to 0.98) while people receiving midazolam were more likely to be sedated in the short term (n = 301, 1 RCT, RR 1.32, 95% CI 1.16 to 1.49) and medium term (n = 301, 1 RCT, RR 1.13, 95% CI 1.04 to 1.23, Analysis 7.3) compared to those receiving the haloperidol/ promethazine mix. Because of the high degree of heterogeneity (short term: Chi² = 30.06; I² = 97%; medium term: Chi² = 14.31; I² = 93%), data from these trials were not pooled (see Summary of main results).

Average CGI scores (Lorazepam 2004, IN) significantly favoured those receiving the haloperidol and promethazine mix in the immediate term (n = 200, 1 RCT, MD 0.49, 95% CI 0.23 to 0.75) and short term (n = 200, 1 RCT, MD 0.60, 95% CI 0.34 to 0.86) but not the medium term (n = 200, 1 RCT, MD 0.23, 95% CI -0.05 to 0.51, Analysis 7.4).

2. Adverse events

There were no differences in the specific adverse events: airway management (n = 501, 2 RCTs, RR 2.99, 95% CI 0.31 to 28.54, nausea (n = 200, 1 RCT, (RR 3.00; 95% CI 0.12 to 72.77) or seizure (n = 301, 1 RCT, RR 0.33, 95% CI 0.01 to 8.06, Analysis 7.5) when midazolam or lorazepam were compared with combined haloperidol/promethazine.

3. Leaving study early

There was no difference in people lost to follow-up when midazolam and lorazepam were compared with combined haloperidol/promethazine (n = 501, 2 RCTs, RR 0.43, 95% CI 0.06 to 2.87, Analysis 7.6).

4. Hospital and service outcomes

There was no significant difference in the number of people 'not discharged' in each treatment group (n = 200, medium term RR 1.13, 95% CI 0.86 to 1.48, Analysis 7.7).

Comparison 8: BENZODIAZEPINES + ANTIPSYCHOTICS versus ANTIPSYCHOTICS + ANTIHISTAMINES

One study reported data for this comparison (Midazolam 2011, BZ, total n = 150).

1. Global impression

In the medium term, more people receiving midazolam and haloperidol had not improved (n = 60, 1 RCT, RR 25.00, 95% CI 1.55 to 403.99, Analysis 8.1) and were given a higher dose of additional medication compared with the promethazine/haloperidol group (n = 60, 1 RCT, MD 0.63, 95% CI 0.15 to 1.11, Analysis 8.2). Medium-term sedation (n = 60, 1 RCT, RR 12.00, 95% CI 1.66 to 86.59, Analysis 8.3) and short-term RSS sedation scores (n = 60, 1 RCT, MD short term 0.60, 95% CI 0.07 to 1.13) were also higher in the midazolam/haloperidol group although there was no difference in medium-term RSS scores (n = 60, 1 RCT, MD 0.00, 95% CI -0.46 to 0.46, Analysis 8.4).

2. Behaviour

OAS aggression scores in people receiving midazolam/haloperidol were significantly lower than scores in the promethazine/haloperidol group in the short term (n = 60, 1 RCT, MD -3.30, 95% CI -5.25 to -1.35) but there was no difference in the medium term (n = 60, 1 RCT, MD 1.70, 95% CI -0.06 to 3.46, Analysis 8.5). Those who received midazolam/haloperidol scored significantly lower on the OASS agitation scale in the short term (n = 60, 1 RCT, MD -16.00, 95% CI -18.98 to -13.02) and medium term (n = 60, 1 RCT, MD -2.70, 95% CI -3.73 to -1.67, Analysis 8.6).

3. Adverse events

There was no difference between groups in the medium-term incidence of EPS (n = 60, 1 RCT, RR 0.60, 95% CI 0.16 to 2.29, Analysis 8.7) or hypotension (n = 60, 1 RCT, RR 1.67, 95% CI 0.44 to 6.36, Analysis 8.8).

SENSITIVITY ANALYSES

We conducted sensitivity analyses for the Comparison 2 (BENZODIAZEPINES versus ANTIPSYCHOTICS) for the primary outcome of 'improvement' as well as the secondary outcomes of 'sedation' and 'extrapyramidal symptoms' as these analyses had the most available data.

1. Randomised sequence generation

In trials rated as low risk of bias, there was no difference between groups in the numbers who had not improved (n = 94, 2 RCTs, RR 1.06, 95% CI 0.75 to 1.49, Analysis 9.1), nor was there any difference between groups in trials where the method of sequence generation was unclear (n = 94, 2 RCTs, RR 1.13, 95% CI 0.78 to 1.63), however heterogeneity was high (Chi² = 9.34, P =.009, I² = 79%). The test for differences between subgroups was not significant (Chi² = 0.06, P = 0.81, I² = 0%). In trials rated as low risk of bias, people receiving benzodiazepines were significantly more likely to be sedated compared with people receiving antipsychotics (n = 247, 3 RCTs, RR 2.22, 95% CI 1.52 to 3.25) with slight heterogeneity (Chi² = 2.26, P = 0.32, I² = 11%); there was no difference between groups in trials where the method of sequence generation was unclear (n = 340, 6 RCTs, RR 0.84, 95% CI 0.56 to 1.26, Analysis 9.2). The test for differences between subgroups was significant and demonstrated high heterogeneity (Chi2 = 11.86, P = 0.0006, I² = 91.6%). The estimates of EPS were similar in trials with a low risk of bias (n = 247, 3 RCTs, RR 0.16, 95% CI 0.03 to 0.85) and for those that were unclear (n = 285, 5 RCTs, RR 0.15, 95% CI 0.05 to 0.47); both groups demonstrating statistically significant difference (Analysis 9.3). There was no significant difference between subgroups (Chi2 = 0.00, P = 0.95, I2 = 0%).

2. Allocation concealment

All trials reporting improvement/no improvement were rated as having an unknown risk of bias. There was no difference in 'no improvement' (n = 308, 5 RCTs, RR 1.10, 95% CI 0.85 to 1.42), however, results displayed high heterogeneity (Chi² = 10.28, P = 0.04, I² = 61%, Analysis 10.1). People receiving benzodiazepines were significantly more likely to be sedated in the one trial rated as a low risk of bias for allocation concealment (n = 153, RR 2.71, 95% CI 1.55 to 4.73) although there was no difference between groups for those trials rated as unknown (n = 394, 7 RCTs, RR 1.20, 95% CI 0.85 to 1.70) or high risk of bias (n = 40, 1 RCT, RR 0.60, 95% CI 0.27 to 1.34, Analysis 10.2). The difference between subgroups was significant and demonstrated high heterogeneity (Chi2 = 10.37, P = 0.006, I2 = 80.7%).

The risk of EPS was slightly reduced in the benzodiazepine group in one study at a low risk of bias (n = 153, RR 0.15, 95% CI 0.01 to 2.90) and significantly reduced in the seven trials with an unknown risk of allocation bias (n = 379, RR 0.15, 95% CI 0.06 to 0.41, Analysis 10.3). There was no significant difference between subgroups (Chi2 = 0.00, P = 1.00, I2 = 0%).

3. Blinded outcome measurement

In trials rated as having an unknown risk of bias, people receiving benzodiazepines were significantly more likely to demonstrate no improvement than people receiving antipsychotics (n = 178, 2 RCTs, RR 1.90, 95% CI 1.11 to 3.24) and in trials rated as low risk of bias, there was no difference in improvement between groups (n = 130, 3 RCTs, RR 0.73, 95% CI 0.56 to 0.96), but heterogeneity was high (Chi² = 10.28, P = 0.04, I² = 61%); differences between subgroups were significant with high heterogeneity (Chi² = 9.65, P = 0.002, I² = 89.6%, Analysis 11.1).

There was no difference in the amount of people who were sedated in those trials that were rated as a low (n = 135, 3 RCTs, RR 1.56, 95% CI 0.99 to 2.46) or unknown risk (n = 255, 4 RCTs, RR 0.69, 95% CI 0.39 to 1.20) of bias for blinded outcome measurement. There was also no change in trials exhibiting a high risk (n = 197, 2 RCTs, RR 2.08, 95% CI 1.35 to 3.23), however, heterogeneity was high (Analysis 11.2). This difference between subgroups was significant with high heterogeneity (Chi² = 9.56, df = 2(P = 0.08), I² = 79.1%).

There was a similar significant decreased risk of EPS in people receiving benzodiazepines, irrespective of whether trials were rated as low (n = 122, 3 RCTs, RR 0.14, 95% CI 0.04 to 0.48) or unknown risk of bias (n = 257, 4 RCTs, RR 0.18, 95% CI 0.03 to 0.90) for blinded outcome measurement (Analysis 11.3). For the single trial where risk of bias was high, there was no difference in levels of EPS (n = 153, 1 RCT, RR 0.15, 95% CI 0.01 to 2.90). There was no significant difference between subgroups (Chi² = 0.06, P = 0.97, I² = 0%).

4. Incomplete outcome data (attrition bias)

Trials rated as a low risk of attrition bias were more likely to find significantly higher rates of no improvement in people receiving benzodiazepines compared with people receiving antipsychotics (n = 194, 3 RCTs, RR 1.85, 95% CI 1.12 to 3.06), whereas, there was no difference in the one trial rated as an unknown risk of bias (n = 66, RR 0.99, 95 % CI 0.71 to 1.38) and the single trial rated as a high risk of bias favoured people receiving benzodiazepines (n = 48, RR 0.56, 95% CI 0.32 to 0.97, Analysis 12.1). There was a statistically significant difference between these subgroups (Chi² = 9.90, P = 0.007, I² = 79.8%). There was no difference in sedation whether trials were rated as a low (n = 194, 3 RCTs, RR 0.73, 95% CI 0.34 to 1.58) or an unknown risk of bias (n = 147, 3 RCTs, RR 1.55, 95% CI 1.01 to 2.38). Where risk of bias was high, there was a difference in favour of antipsychotics, but heterogeneity between trials was high (n = 246, 3 RCTs, RR 1.61, 95% CI 1.10 to 2.38, Analysis 12.2). Apparent differences between subgroups were not significant (Chi² = 3.41, P = 0.18, I² = 41.3%). The finding that EPS were lower in people receiving benzodiazepines was not significant in low risk of bias trials (n = 190, 2 RCTs, RR 0.27, 95% CI 0.05 to 1.52) but was significant in unknown (n = 149, 3 RCTs, RR 0.13, 95% CI 0.03 to 0.70) and high risk of bias trials (n = 193, 3 RCTs, RR 0.11, 95% CI 0.02 to 0.54, Analysis 12.3). However, this apparent difference between subgroups was not significant (Chi² = 0.65, P = 0.72, I² = 0%).

Publication bias

Sedation data from the comparison of benzodiazepines versus antipsychotics were used to investigate whether there was evidence of systematic small trial bias in a funnel plot analysis. There was a small number of trials and it is difficult to be sure of any asymmetry Figure 1. We think it inadvisable to read too much into this exploratory, low-powered technique of investigation. What is needed are more trials with a wide spread of findings.

Discussion

Summary of main results

Comparison 1: BENZODIAZEPINES versus PLACEBO

Please see Summary of findings for the main comparison. There was some evidence that lorazepam was superior to placebo in terms of improvement and behaviour although these data comes from a single small study and are therefore graded as very low quality evidence.

It is understandable that placebo-controlled trials in this area are uncommon as withholding treatment from people in such a distressed state can be considered unethical. Therefore, evidence from randomised controlled trials (RCTs) that benzodiazepines are superior to placebo is weak.

Comparison 2: BENZODIAZEPINES versus ANTIPSYCHOTICS

Please see Summary of findings 2. Overall, there was low to moderate quality evidence of no difference between benzodiazepines and antipsychotics in terms of global impression. However, evidence of moderate quality showed that EPS were considerably lower in people receiving benzodiazepines. There was some evidence that atypical antipsychotics were more favourable in terms of improvement, global impression and mental state but these data were from single small trials with high heterogeneity. There were not enough data to compare the effects of different types and doses of benzodiazepine

Because EPS were significantly higher in people receiving antipsychotics, this must be an important factor in choosing the correct treatment to give in an emergency situation. In clinical practice, antipsychotics are often accompanied by anticholinergic treatment that may substantially decrease the incidence of EPS. Therefore, the use of atypical antipsychotics such as haloperidol without accompanying anticholinergics does not seem acceptable and is consistent with outcomes of other relevant reviews (Huf 2009).

Comparison 3: BENZODIAZEPINES + ANTIPSYCHOTICS versus SAME BENZODIAZEPINES

Please see Summary of findings 3. There was little difference between combined benzodiazepines and antipsychotics compared with benzodiazepines alone but the quality of these data were low to very low. The only significant difference was that sedation was more likely in those receiving the combination in the short term although these data were from one small trial. Ratings of global impression, mental state, behaviour and adverse effects were all equivocal between groups - as could be expected in such low power. A real and important difference could exist, but larger trials are needed before any confident conclusions can be drawn.

Comparison 4: BENZODIAZEPINES + ANTIPSYCHOTICS versus SAME ANTIPSYCHOTICS

Please see Summary of findings 4. There were no apparent advantages in using a combination of benzodiazepines and antipsychotics compared with benzodiazepines alone in terms of our primary outcome of no improvement but there were relatively few data with considerable heterogeneity. Also, as each of the included trials defined ‘improvement’ differently, it is difficult to interpret how meaningful these data are.

Sedation rates were significantly higher in the combined benzodiazepines/haloperidol group compared with haloperidol in the short and medium term although the medium-term data were heterogeneous. There were no differences between groups in the incidence of EPS or other adverse effects but these were rated as low quality evidence.

Behaviour scores did seem to favour haloperidol when compared with midazolam plus haloperidol but these data came from one small trial.

Comparison 5: BENZODIAZEPINES + ANTIPSYCHOTICS versus DIFFERENT ANTIPSYCHOTICS

Please see Summary of findings 5. The majority of data for this comparison came from one trial with multiple treatment arms (Midazolam 2011, BZ). There was some evidence from this relatively small trial that the atypical antipsychotics olanzapine and ziprasidone were superior to a combination of midazolam and haloperidol in regards to Clinical Global Impression and behaviour. In the one trial that reported 'side effects', these were not different when people receiving a clonazepam/risperidone mix were compared to people receiving clonazepam but side effects were higher in people receiving haloperidol compared with the combination.

Because the quality of evidence for these comparisons was considered very low, no valuable conclusions can be made from these data.

Comparison 6: BENZODIAZEPINES + ANTIPSYCHOTICS versus ANTIPSYCHOTICS + ANTIPSYCHOTICS

Please see Summary of findings 6. The only trial to report data for this comparison provided scarce data (Lorazepam 1998, SA), with no documented instances of people leaving the study early, and no difference in aggression ratings. It is therefore difficult to draw any meaningful conclusions from this comparison; larger, more informative trials with clearly defined outcomes are needed before any conclusions can be made.

Comparison 7: BENZODIAZEPINES versus ANTIPSYCHOTICS + ANTIHISTAMINES

Please see Summary of findings 7. This comparison included Midazolam 2003, BZ and Lorazepam 2004, IN which were large, high-quality trials. Results for improvement and global impression scores favoured the use of combined haloperidol/promethazine over lorazepam in both the immediate and short term but all of these data came from Lorazepam 2004, IN; however, sedation was more likely in people receiving the combination treatment. Sedation was also reported in Midazolam 2003, BZ but data could not be pooled because of substantial heterogeneity between the two trials. People receiving midazolam were more likely to become sedated compared with haloperidol/promethazine in Midazolam 2003, BZ, unlike Lorazepam 2004, IN where people receiving haloperidol/promethazine were more likely to become sedated. Possible reasons for this dramatic heterogeneity has been discussed in depth in another review (Huf 2009) but the most likely is because midazolam is a faster-acting and more potent benzodiazepine than lorazepam (Larson 1994).

Lorazepam 2004, IN also reported the use of physical restraints. Throughout the course of the trial, people receiving lorazepam alone were more likely to be mechanically restrained than those who received haloperidol plus promethazine. Although restraint was not a stated outcome in our protocol and may be of more relevance to clinicians in countries where the use of mechanical restraints is employed, we feel that it is an important outcome and should be considered in future reviews and trials.

In these larger and better-reported trials, the adverse effects were infrequent but important, and included respiratory depression and nausea. Respiratory depression is a very serious potential adverse effect of all benzodiazepines, and occurred in both trials; although, the participant in Midazolam 2003, BZ was admitted with cocaine-induced aggression, a potential mitigating factor. Nevertheless, the potential for respiratory depression is a major cause for concern. Although it can be controlled with flumazenil, caution should be observed when using any benzodiazepine (particularly midazolam), to ensure a clinical team has the necessary equipment and ability to manage such an event.

Comparison 8: BENZODIAZEPINES + ANTIPSYCHOTICS versus ANTIPSYCHOTICS + ANTIHISTAMINES

Only one trial (Midazolam 2011, BZ) reported two relevant arms (total n = 60), so power is very limited. Please see Summary of findings 8. There was some evidence from this trial that the haloperidol/promethazine combination was significantly better than the midazolam/haloperidol combination in terms of improvement, need for additional medication, sedation, and behaviour. However, as the sample size was small, larger, higher-quality trials need to confirm any potential positive or negative effects of this comparison.

SENSITIVITY ANALYSIS

Although sensitivity analyses were conducted for the 'Risk of bias' criteria, sequence generation, allocation concealment, blinded outcome measurement and incomplete data, there were few differences between trials at high, low and unknown risk of bias. Trials at low risk of bias for sequence generation, allocation concealment, and blinded outcome measurement were more likely to favour antipsychotics over benzodiazepines in terms of sedation. However, these findings were based on relatively few data and should at this stage be interpreted with caution.

Overall completeness and applicability of evidence

1. Completeness

1.1 Power
1.1.1 Limited power

We only found one trial (n = 102) comparing benzodiazepines with placebo. Although data are incomplete, we know enough to suggest that randomisation of benzodiazepine versus placebo to be ethical only in the most constrained services of such limited supply that anything but randomisation would be inequitable.

Benzodiazepines were compared directly with antipsychotics in 11 trials averaging 26 participants per trial. When a benzodiazepine was compared with the combination of benzodiazepine plus antipsychotic, the four trials averaged 50 participants. Even if the outcome reporting had been comprehensive - taking into account views of clinicians and participants as well as researchers - the depth and strength of evidence in this area is very far from complete. Despite an increasing trend to consider atypical antipsychotics as more suitable for rapid tranquillisation than the older antipsychotics, there were inadequate data to compare atypical antipsychotics with benzodiazepines. Such promotion of the antipsychotics is based more on well-meaning faith combined with an understandable lack of resistance from industry rather than good evidence.

The two TREC trials that compared benzodiazepines with combined haloperidol/promethazine were large (n = 200 and 301), high-powered trials, recognised for high methodological quality in this area of research (NICE 2005). These trials do not have an emphasis on recording scale-derived data but do provide useful binary outcomes.

The comparison for combined benzodiazepines/haloperidol versus combined haloperidol/promethazine was very limited (1 RCT, n = 60) with little data from a single trial with multiple treatment arms. All outcomes need to be interpreted with great caution.

1.1.2 No power

The trial search did not identify trials that compared specific benzodiazepines at a high versus low dose; oral versus intramuscular/intravenous; or low frequency versus high frequency (as defined by each study). Future research could examine these comparisons in order to bring to light any potential benefits/efficacy of specifically named benzodiazepines in the management of psychosis-induced aggression/agitation.

1.2 Outcome measurement
1.2.1 Measures

A major difficulty in synthesising data from trials in this review is the considerable variability in what and how outcomes were measured. A number of trials reported outcomes that were not valid and therefore could not be used.

Of the 21 trials included in this update, only 10 reported our primary outcome of interest (improved/not improved). This outcome should be reported in future trials but definitions of improvement should be based on validated criteria and defined prior to data collection.

Given the potential for adverse events with benzodiazepines and antipsychotics, future trials should also ensure that these data are collected and reported. Also, as most trials allow for 'as-needed' repeat doses of these drugs, the number of additional doses or mean dosage is also an important outcome in these trials.

In addition, because a range of modified versions of validated measures or domain scores were used, these data could not be synthesised in this review. If scales are to be used it is important that they, and the individual subscales, are validated. Consistent use of measures of agreed importance is important.

1.2.2 Sedation

More recently, the need to achieve behavioural control without sedation has been recognised (Rocca 2006). This perspective is reflected by sedation being reported as a positive outcome in earlier trials but as negative in more recent trials. Sedation, however, remains important and should be recorded and value judgements can be made by those who wish to use the evidence. In future trials, other outcomes such as improvement should be reported, as consensus guidelines have emphasised that calming an agitated/aggressive person is the key goal in an acute setting as opposed to rapid tranquillisation (Allen 2005).

2. Applicability

Despite a relatively broad range of inclusion criteria in regard to participants and settings, results were quite homogenous. Largely, participants, interventions and situations of administration were familiar to the average clinical setting and what data there are, do seem to be applicable. Benzodiazepines and antipsychotics were used quite consistently across trials. The majority used lorazepam or haloperidol in consistent clinically applicable doses. Only six trials used atypical antipsychotics. The IM administration route was also extremely consistent across trials except Midazolam 2006, AU which administered medications intravenously.

The major sources of heterogeneity were CGI scores when lorazepam and diazepam were compared with haloperidol (Analysis 2.4), OASS scores when midazolam plus haloperidol was compared with olanzapine and ziprasidone (Analysis 5.6), and sedation when lorazepam and midazolam were compared with haloperidol plus promethazine (Analysis 7.3). There were several potential reasons for this heterogeneity. The most identifiable of these were differences in the types and doses of benzodiazepines and antipsychotics that were used.

Quality of the evidence

Overall, most quality criteria were poorly reported in the trials included in this review. Large, well-designed, clinically relevant and clearly reported trials are clearly possible (Lorazepam 2004, IN; Midazolam 2003, BZ) but these are very much the exceptions to the rule. Better reporting of the methods used to ensure trials of high quality as outlined in the CONSORT statement (Moher 2001) could have resulted in this review being more conclusive.

Because dosages could be adjusted on an as-needed basis in the majority (17) of trials, it is difficult to make conclusions about what doses of which drugs are most suitable for managing psychosis-induced aggression or agitation. As the ability to adjust doses would seem to be the only ethical option in longer-term trials, these data also need to be reported in future trials.

Potential biases in the review process

It is entirely possible that we have failed to identify small negative trials and would be most interested if readers know of these.

The highest quality trials in this review (Lorazepam 2004, IN; Midazolam 2003, BZ) include one author known to the review team and therefore, our highlighting of them could be misjudged. We hope we have made reasons for this explicit and leave the readers to judge.

Agreements and disagreements with other studies or reviews

The findings of this review agree with other narrative syntheses of the literature that have concluded that benzodiazepines are at least as effective as antipsychotics in controlling severely agitated behaviour (Allen 2000; NICE 2005; Rocca 2006); however, because benzodiazepines have the potential to cause respiratory depression, their use should be carefully monitored in an environment suited to manage such cases. The findings are also consistent with other similar and overlapping reviews (please see Implications for practice - 3. for managers and policy-makers).

Authors' conclusions

Implications for practice

1. For people with agitation/aggression due to schizophrenia or schizophrenia-like illnesses

Being in a situation where others feel that rapid tranquillisation is needed is frightening and distressing, and can be dangerous. Treatments that bring the fear, distress and danger to an end quickly and safely are needed. Benzodiazepines are a viable option for care in acute aggression thought secondary to psychotic illness but much of the data on which practice is based are poor - although there are exceptions. Many recommendations for treatment are based on clinicians experience rather than good data from trials or well-considered consumer feedback. We think that the situation is changing but certainly more well-designed, conducted and reported trials are needed.

2. For clinicians

Benzodiazepines appear to be as effective as antipsychotics alone but data are limited and not of high quality. Using a combination of benzodiazepine plus antipsychotic does not seem to confer any advantage over use of either single drug. The use of older antipsychotics without additional medication to offset movement disorders seems hard to justify. There is some evidence that newer antipsychotics may be more beneficial than benzodiazepines but data are very limited at this stage.

3. For managers or policy-makers

Lack of good quality data leaves managers and policy makers with difficult decisions to make. There is currently insufficient clinical evidence to suggest that the benzodiazepine group of drugs (alone or in combination with antipsychotics) is clearly superior to antipsychotics in reducing acute psychotic behaviour.

Implications for research

1. General

Adherence to the CONSORT statement (Moher 2001), would probably have resulted in this review being more conclusive. Clear descriptions of randomisation would have reassured users of these trials that selection bias had been minimised and well-described and blinded outcome measurement could have encouraged greater confidence in the control of performance and detection bias. The use of validated binary outcomes should take preference over continuous results because they are easier to interpret and better reporting of validated rating scales would have provided more usable data. The reporting of outcomes with their means and standard deviations, again, would have provided more usable data and facilitated synthesis of findings. When presenting data in a graph, the exact numbers and standard deviations should also be reported.

2. Specific

2.1 Reviews

Although our original protocol specified a focus on rapid tranquillisation for acute psychosis, but by restricting our analyses up to 48 hours, other potential serious adverse effects may have been overlooked. For further reviews on this topic, or the update of this review, we recommend a less rigid time restriction on long-term effects of benzodiazepines to attain a more accurate consideration of the outcomes and other adverse effects (see Table 5).

Table 5. Suggested design for future reviews
  1. BPRS - Brief Psychiatric Rating Scale.
    CGI - Clinical Global Impression.
    EPS - extrapyramidal symptoms.

Methods

Allocation: randomised, fully described in terms of methods of randomisation and allocation concealment.

Blinding: double/single blind, with methods of maintenance of blinding fully described.

Setting: psychiatric emergency settings/hospital.

Duration: Immediate term (0-15 minutes); short term (15 minutes-one hour); medium term (one hour-48 hours); long term (48 hours ≥).

Participants

Diagnosis: primary diagnosis of schizophrenia or related disorders, including schizophreniform disorder, schizoaffective disorder and delusional disorder with psychosis-induced aggression or agitation.

Subgroups: dual diagnoses and/or drug/alcohol use.

Age: adults, with age specified in trial.

Sex: both.

Comparisons

a. Benzodiazepines - given alone.

Including either: alprazolam, bretazenil, bromazepam, chlordiazepoxide, cinolazepam, clonazepam, clorazepate, clotiazepam, cloxazolam, delorazepam, diazepam, estazolam, flunitrazepam, halazepam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, quazepam, temazepam, tetrazepam, triazolam.

Any dose, any means of administration.

Compared with:

2. Other benzodiazepine - given alone.

Any dose, any means of administration.

3. Antipsychotics.

First generation/typical, including either: chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, droperidol, flupentixol/flupenthixol, fluphenazine, haloperidol, levomepromazine, loxapine, mesoridazine, molindone, periciazine, perphenazine, pimozide, prochlorperazine, promazine, promethazine, thioridazine, thiothixene, trifluoperazine, triflupromazine, zuclopenthixol.

Second generation/atypical, including either: amisulpride, aripiprazole, asenapine, clozapine, clothiapine, clotiapin, iloperidone, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone, zotepine.

Any dose, any means of administration.

4. Other combinations of drugs.

4.1 Benzodiazepines plus antipsychotics.

4.2 Antipsychotics plus antihistamine/anticholinergic drugs.

Antihistamines include: azelastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, deschlorpheniramine, dexchlorpheniramine, dimenhydrinate, dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, levocetirizine, loratadine, meclozine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, rupatadine, tripelennamine, triprolidine.

Any dose, any means of administration.

5. Non-pharmacological approaches.

b. Benzodiazepines plus antipsychotics.

Compared with:

1. Placebo.

2. Antipsychotics.

Any dose, any means of administration.

3. Other combinations.

3.1 Benzodiazepines plus antipsychotics.

3.2 Antipsychotics plus antihistamines.

4. Non-pharmacological approaches.

c. Benzodiazepines (specific named drug) - given alone.

1. High dose (as defined by each study).

2. Low or standard dose (as defined by each study).

d. Benzodiazepines (specific named drug) - given alone.

1. Oral.

2. Intramuscular or intravenous.

e. Benzodiazepines (specific named drug) - given alone.

1. Low frequency (as defined by each study).

2. High frequency (as defined by each study).

Outcomes measures

Primary outcomes.

1.Global impression.

1.1 Specific.

1.1.1 No improvement: as defined by each study. If more than one measure of improvement was reported, then improvement in behaviour was used, followed by improvement in mental state, and then improvement in symptoms.

1.1.2 Tranquillisation (feeling of calmness and/or calm, non-sedated behaviour).

Secondary outcomes.

2. Global impression - CGI.

2.1 General.

2.1.1 No clinically important change in general functioning.
2.1.2 No change in general functioning.
2.1.3 Average endpoint change in general functioning.
2.1.4 Average change in general functioning.

2.2 Specific.

2.2.1 Aggression.
2.2.2 Self-harm, including suicide.
2.2.3 Injury to others.
2.2.4 Improvement in self-care or degree of improvement in self-care.
2.2.5 Sedation (sleepiness and drowsiness).
2.2.6 Compulsory administrations of treatment.
2.2.7 Need for additional medication.
2.2.8 Decrease in medication.
2.2.9 No change in medication dosage.
2.2.10 Average change/endpoint scores.

3. Behaviour.

3.1 General.

3.1.1 No clinically important change in behaviour.
3.1.2 Average behaviour score.

4. Mental state - BPRS.

4.1 General.

4.1.1 No clinically important change in general mental state scores.
4.1.2 Average endpoint general mental state score.

5. Adverse effects/events.

5.1 General.

5.1.1 Incidence of side effects, general or specific.
5.1.2 Severity of symptoms.
5.1.3 Measured acceptance of treatment.
5.1.4 Sudden or unexpected death.

5.2 Specific.

5.2.1 Extrapyramidal symptoms (EPS).
5.2.2 Use of medication for EPS.

6. Hospital and service outcomes.

6.1 Hospitalisation.

6.1.1 Time to hospitalisation.
6.1.2 Hospitalisation of people in the community.
6.1.3 Duration of hospital stay.
6.1.4 Changes in services provided by community teams.

6.2 Seclusion.

6.2.1 Time in seclusion.
6.2.2 Changes in hospital status (for example, changes from voluntary to involuntary care, changes in level of observation, use of seclusion).

7. Satisfaction with treatment.

7.1 Specific.

7.1.1 Consumers.
7.1.2 Family and informal care givers.
7.1.3 Professionals/carers.

8. Economic outcomes.

8.1 Cost-effectiveness.

8.2 Direct costs.

8.3 Indirect costs.

9. Leaving the study early.

9.1 For any reason.

9.2. For reasons treatment related.

9.3 For reasons unrelated to treatment.

9.4 Due to relapse.

9.5 Due to adverse effects.

Notes 
2.2 Research
2.2.1 Methods

There is a need for better evidence regarding the relative effectiveness of benzodiazepines and antipsychotics, particularly regarding the reporting of both short-term and long-term adverse effects. We did identify large, well-designed and clearly reported trials in this area (TREC Vellore; TREC-II Brazil).

2.2.2 Interventions

More trials comparing the atypical antipsychotics, such as intramuscular clozapine or olanzapine, with benzodiazepines are needed. Additional trials that compare combined benzodiazepines and antipsychotics with either drug alone are still needed, particularly where the newer antipsychotics are used.

2.2.3 Outcomes

Standardised, validated scales that are acceptable to recipients of this care, clinicians working in the field, researchers and those working with regulatory authorities are needed to measure outcomes in future trials. This will mean selective reporting biases are more likely to be eliminated and better-quality meta-analyses possible. One way to address this fundamental issue would be to develop and employ a standardised set of outcome measurements - or ‘core outcome sets’. This may be achieved through the COMET (Core Outcome Measures in Effectiveness Trials http://www.comet-initiative.org/) Initiative that seeks to identify a standardised set of outcomes, with consensus on how these are to be defined and measured.

2.2.4 Suggested design of trial

We realise that design of suitable trials takes time and a great deal of care but we have spent some considerable period studying the relevant existing trials and therefore, suggest an outline of a suitable trial design (Table 6).

Table 6. Suggested design of future studies
  1. EPS - extrapyramidal symptoms

Methods

Allocation: randomised, fully described in terms of methods of randomisation and allocation concealment.

Blinding: Double/single blind, with methods of maintenance of blinding fully described.

Setting: psychiatric emergency settings/hospital.

Duration: follow-up of 72 hours.

Participants

Diagnosis: primary diagnosis of schizophrenia or related disorders, including schizophreniform disorder; schizoaffective disorder and delusional disorder with psychosis-induced aggression or agitation.

Subgroups: dual diagnoses and/or drug/alcohol use.

N > 400.

Age: adults, with age specified in trial.

Sex: both.

Interventions

1. Benzodiazepines - given alone.

Including either: alprazolam, bretazenil, bromazepam, chlordiazepoxide, cinolazepam, clonazepam, clorazepate, clotiazepam, cloxazolam, delorazepam, diazepam, estazolam, flunitrazepam, halazepam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, quazepam, temazepam, tetrazepam, triazolam.

Any dose, any means of administration.

Compared with:

a. Other benzodiazepine - given alone.

Any dose, any means of administration.

b. Antipsychotics.

First generation/typical, including either: chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, droperidol, flupentixol/flupenthixol, fluphenazine, haloperidol, levomepromazine, loxapine, mesoridazine, molindone, periciazine, perphenazine, pimozide, prochlorperazine, promazine, promethazine, thioridazine, thiothixene, trifluoperazine, triflupromazine, zuclopenthixol.

Second generation/atypical, including either: amisulpride, aripiprazole, asenapine, clozapine, clothiapine, clotiapin, iloperidone, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone, zotepine.

Any dose, any means of administration.

c. Other combinations of drugs.

(i) Benzodiazepines plus antipsychotics.

(ii) Antipsychotics plus antihistamine/anticholinergic drugs.

Antihistamines include: azelastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, deschlorpheniramine, dexchlorpheniramine, dimenhydrinate, dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, levocetirizine, loratadine, meclozine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, rupatadine, tripelennamine, triprolidine.

Any dose, any means of administration.

5. Non-pharmacological approaches.

2. Benzodiazepines plus antipsychotics.

Compared with:

a. Placebo.

b. Antipsychotics.

Any dose, any means of administration.

c. Other combinations.

(i) Benzodiazepines plus antipsychotics.

(ii) Antipsychotics plus antihistamines.

d. Non-pharmacological approaches.

Outcomes

1. Global impression - no improvement (as defined by each study. If more than one measure of improvement was reported, then improvement in behaviour was used, followed by improvement in mental state, and then improvement in symptoms).

2. Global impression - general/specific (including tranquillisation/sedation/need for additional medication/decrease in medication/injury to others/self-harm/aggression or agitation/compulsory administration of treatment).

3. Behaviour - no clinically important change in behaviour.

4. Mental state - no clinically important change in general mental state scores.

5. Adverse effects/events (including incidence of specific side effects/severity of symptoms/death/EPS/use of medication for EPS).

6. Hospital and service outcomes (including time to hospitalisation/duration of hospital stay/seclusion/time in seclusion/changes in hospital status/use of mechanical restraints).

7. Satisfaction with treatment.

8. Economic outcomes.

9. Leaving the study early.

NotesAny outcomes measured using scale-derived data should be interpreted in such a way as to make clear the real-life relevance of changes in scale score

Acknowledgements

The Cochrane Schizophrenia Group produces and maintains a template for the methods section of their reviews. We have used this and adapted it for this update. The authors would like to thank Mark Fenton (Cochrane Schizophrenia Group) for his assistance in the early stages of the original review, and Jun Xia for her help with translating Chinese studies.

The searches for this review have been developed and run by the Trial Search Co-ordinator of the Cochrane Schizophrenia Group, Samantha Roberts.

Data and analyses

Download statistical data

Comparison 1. BENZODIAZEPINES vs PLACEBO
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global impression: 1. no improvement1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
1.1 short term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Global impression: 2. need for additional medication1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Global impression: 3. sedation1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Global impression: 4. average change score (CGI-S, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Behaviour: 1. average change score (ABS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Mental state: 1. average change score (PANSS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mental state: 2. average change score (PANSS-excited component, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Adverse effects/events: 1. extrapyramidal symptoms1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
8.1 medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Adverse effects/events: 2. use of medication for EPS1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
9.1 medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Adverse effects/events: 3. specific1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
10.1 dizziness - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10.2 nausea - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10.3 vomiting - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
11 Leaving the study early: 1. any reason1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
11.1 medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 BENZODIAZEPINES vs PLACEBO, Outcome 1 Global impression: 1. no improvement.

Analysis 1.2.

Comparison 1 BENZODIAZEPINES vs PLACEBO, Outcome 2 Global impression: 2. need for additional medication.

Analysis 1.3.

Comparison 1 BENZODIAZEPINES vs PLACEBO, Outcome 3 Global impression: 3. sedation.

Analysis 1.4.

Comparison 1 BENZODIAZEPINES vs PLACEBO, Outcome 4 Global impression: 4. average change score (CGI-S, high = worse).

Analysis 1.5.

Comparison 1 BENZODIAZEPINES vs PLACEBO, Outcome 5 Behaviour: 1. average change score (ABS, high = worse).

Analysis 1.6.

Comparison 1 BENZODIAZEPINES vs PLACEBO, Outcome 6 Mental state: 1. average change score (PANSS, high = worse).

Analysis 1.7.

Comparison 1 BENZODIAZEPINES vs PLACEBO, Outcome 7 Mental state: 2. average change score (PANSS-excited component, high = worse).

Analysis 1.8.

Comparison 1 BENZODIAZEPINES vs PLACEBO, Outcome 8 Adverse effects/events: 1. extrapyramidal symptoms.

Analysis 1.9.

Comparison 1 BENZODIAZEPINES vs PLACEBO, Outcome 9 Adverse effects/events: 2. use of medication for EPS.

Analysis 1.10.

Comparison 1 BENZODIAZEPINES vs PLACEBO, Outcome 10 Adverse effects/events: 3. specific.

Analysis 1.11.

Comparison 1 BENZODIAZEPINES vs PLACEBO, Outcome 11 Leaving the study early: 1. any reason.

Comparison 2. BENZODIAZEPINES vs ANTIPSYCHOTICS
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global impression: 1. no improvement5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 vs olanzapine - short term1150Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.95, 1.66]
1.2 vs olanzapine - medium term1150Risk Ratio (M-H, Fixed, 95% CI)1.84 [1.06, 3.18]
1.3 vs haloperidol - medium term4158Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.66, 1.17]
2 Global impression: 2. need for additional medication3 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 vs droperidol - short term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 vs haloperidol - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.3 vs olanzapine - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Global impression: 3. sedation9 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 vs droperidol - short term1153Risk Ratio (M-H, Fixed, 95% CI)2.71 [1.55, 4.73]
3.2 vs haloperidol - short term144Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.53, 2.59]
3.3 vs haloperidol - medium term8434Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.83, 1.54]
3.4 vs olanzapine - medium term1150Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.28, 1.98]
4 Global impression: 4. average change/endpoint score (CGI-S, high = worse)3 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 vs haloperidol - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.4 vs olanzapine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Global impression: 6. average endpoint score (IMPS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Behaviour: 2. average change/endpoint score (ABS, high = worse)2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 vs olanzapine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Behaviour: 4. average change score (OAS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mental state: 1. average change/endpoint score (BPRS, high = worse)3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
8.1 vs haloperidol - short term137Mean Difference (IV, Fixed, 95% CI)-3.26 [-10.65, 4.13]
8.2 vs haloperidol - medium term3123Mean Difference (IV, Fixed, 95% CI)1.67 [-1.84, 5.18]
9 Mental state: 2. average endpoint score (BPRS psychosis subscale, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
9.1 vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Mental state: 3. average change score (PANSS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
10.1 vs olanzapine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
11 Mental state: 4. average change score (PANSS-excited component, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
11.1 vs olanzapine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
12 Adverse effects/events: 1. extrapyramidal symptoms8536Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.06, 0.39]
12.1 vs haloperidol - medium term6233Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.04, 0.41]
12.2 vs olanzapine - medium term1150Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.03, 1.89]
12.3 vs droperidol - medium term1153Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.90]
13 Adverse effects/events: 2. use of medication for EPS2216Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.15, 1.05]
13.1 vs haloperidol - medium term166Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.17, 1.47]
13.2 vs olanzapine - medium term1150Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.03, 1.89]
14 Adverse effects/events: 3. specific4 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
14.1 vs droperidol - airway management - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.2 vs haloperidol - ataxia - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.3 vs droperidol - blood pressure - low - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.4 vs haloperidol - dizziness - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.5 vs olanzapine - dizziness - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.6 vs haloperidol - dry mouth - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.7 vs droperidol - heart rate - low - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.8 vs haloperidol - heart rate - high - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.9 vs droperidol - hypoxia - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.10 vs olanzapine - nausea - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.11 vs droperidol - seizure - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.12 vs haloperidol - speech disorder - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.13 vs haloperidol - tremor - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.14 vs droperidol - vomiting - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14.15 vs olanzapine - vomiting - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
15 Leaving the study early: 1. any reason3339Risk Ratio (M-H, Fixed, 95% CI)1.48 [0.70, 3.13]
15.1 vs droperidol - medium term1173Risk Ratio (M-H, Fixed, 95% CI)1.51 [0.60, 3.79]
15.2 vs haloperidol - medium term116Risk Ratio (M-H, Fixed, 95% CI)0.2 [0.01, 3.61]
15.3 vs olanzapine - medium term1150Risk Ratio (M-H, Fixed, 95% CI)5.82 [0.62, 54.58]
Analysis 2.1.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 1 Global impression: 1. no improvement.

Analysis 2.2.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 2 Global impression: 2. need for additional medication.

Analysis 2.3.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 3 Global impression: 3. sedation.

Analysis 2.4.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 4 Global impression: 4. average change/endpoint score (CGI-S, high = worse).

Analysis 2.5.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 5 Global impression: 6. average endpoint score (IMPS, high = worse).

Analysis 2.6.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 6 Behaviour: 2. average change/endpoint score (ABS, high = worse).

Analysis 2.7.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 7 Behaviour: 4. average change score (OAS, high = worse).

Analysis 2.8.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 8 Mental state: 1. average change/endpoint score (BPRS, high = worse).

Analysis 2.9.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 9 Mental state: 2. average endpoint score (BPRS psychosis subscale, high = worse).

Analysis 2.10.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 10 Mental state: 3. average change score (PANSS, high = worse).

Analysis 2.11.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 11 Mental state: 4. average change score (PANSS-excited component, high = worse).

Analysis 2.12.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 12 Adverse effects/events: 1. extrapyramidal symptoms.

Analysis 2.13.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 13 Adverse effects/events: 2. use of medication for EPS.

Analysis 2.14.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 14 Adverse effects/events: 3. specific.

Analysis 2.15.

Comparison 2 BENZODIAZEPINES vs ANTIPSYCHOTICS, Outcome 15 Leaving the study early: 1. any reason.

Comparison 3. BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global impression: 1. no improvement3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 + haloperidol - short term120Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 1.74]
1.2 + haloperidol - medium term283Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.69, 1.28]
1.3 + risperidone - medium term120Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.45, 1.64]
2 Global impression: 2. need for additional medication3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 + haloperidol - medium term3103Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.79, 1.32]
2.2 + risperidone - medium term120Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Global impression: 3. sedation2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 +haloperidol - short term147Risk Ratio (M-H, Fixed, 95% CI)1.92 [1.10, 3.35]
3.2 +haloperidol - medium term2110Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.59, 1.19]
4 Behaviour: 1. average endpoint score (ABS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 + haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Mental state: 1. average endpoint score (BPRS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 + risperidone - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 + risperidone - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Mental state: 1. average endpoint score (BPRS, high = worse, skew)  Other dataNo numeric data
6.1 +haloperidol - short term  Other dataNo numeric data
6.2 +haloperidol - medium term  Other dataNo numeric data
7 Mental state: 2. average endpoint score (BPRS psychosis subscale, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 + haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mental state: 1. average endpoint score (PANSS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 + risperidone - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8.2 + risperidone - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Mental state: 3. average endpoint score (PANSS, high = worse, skew)  Other dataNo numeric data
9.1 +haloperidol - short term  Other dataNo numeric data
9.2 +haloperidol - medium term  Other dataNo numeric data
10 Adverse effects/events: 1. extrapyramidal symptoms2 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
10.1 +haloperidol - medium term2 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
11 Adverse effects/events: 2. use of medication for EPS1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
11.1 +haloperidol - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
12 Adverse effects/events: 3. specific1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
12.1 +haloperidol - ataxia - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
12.2 +haloperidol - dizziness - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
12.3 +haloperidol - dry mouth - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
12.4 +haloperidol - speech disorder - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
13 Leaving the study early: 1. any reason2 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
13.1 +haloperidol - medium term2 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
13.2 +risperidone - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 1 Global impression: 1. no improvement.

Analysis 3.2.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 2 Global impression: 2. need for additional medication.

Analysis 3.3.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 3 Global impression: 3. sedation.

Analysis 3.4.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 4 Behaviour: 1. average endpoint score (ABS, high = worse).

Analysis 3.5.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 5 Mental state: 1. average endpoint score (BPRS, high = worse).

Analysis 3.6.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 6 Mental state: 1. average endpoint score (BPRS, high = worse, skew).

Mental state: 1. average endpoint score (BPRS, high = worse, skew)
StudyInterventionMeanSDN
+haloperidol - short term
Lorazepam 2006, USALorazepam40.828.1210
Lorazepam 2006, USALorazepam+haloperidol48.265.4610
+haloperidol - medium term
Lorazepam 2006, USALorazepam35.525.6110
Lorazepam 2006, USALorazepam+haloperidol40.151.2310
Analysis 3.7.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 7 Mental state: 2. average endpoint score (BPRS psychosis subscale, high = worse).

Analysis 3.8.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 8 Mental state: 1. average endpoint score (PANSS, high = worse).

Analysis 3.9.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 9 Mental state: 3. average endpoint score (PANSS, high = worse, skew).

Mental state: 3. average endpoint score (PANSS, high = worse, skew)
StudyInterventionMeanSDN
+haloperidol - short term
Lorazepam 2006, USALorazepam59.436.2210
Lorazepam 2006, USALorazepam+haloperidol74.6100.2210
+haloperidol - medium term
Lorazepam 2006, USALorazepam53.935.5310
Lorazepam 2006, USALorazepam+haloperidol65.8100.410
Analysis 3.10.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 10 Adverse effects/events: 1. extrapyramidal symptoms.

Analysis 3.11.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 11 Adverse effects/events: 2. use of medication for EPS.

Analysis 3.12.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 12 Adverse effects/events: 3. specific.

Analysis 3.13.

Comparison 3 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES, Outcome 13 Leaving the study early: 1. any reason.

Comparison 4. BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global impression: 1. no improvement3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 +/vs haloperidol - medium term3155Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.94, 1.70]
2 Global impression: 2. need for additional medication1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 +/vs haloperidol - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Global impression: 3. need for additional medication (mean dose, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 +/vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Global impression: 4. sedation3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 +/vs haloperidol - short term145Risk Ratio (M-H, Fixed, 95% CI)2.25 [1.18, 4.30]
4.2 +/vs haloperidol - medium term3172Risk Ratio (M-H, Fixed, 95% CI)1.75 [1.14, 2.67]
5 Global impression: 5. average change score (RSS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 +/vs haloperidol - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 +/vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Behaviour: 1. average endpoint score (ABS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 +/vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Behaviour: 2. average endpoint score (OAS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 +/vs haloperidol - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7.2 +/vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Behaviour: 4. average endpoint score (OASS agitation scale, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 +/vs haloperidol - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8.2 +/vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Mental state: 1. average endpoint score (BPRS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
9.1 +/vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Mental state: 2. average endpoint score (BPRS psychosis subscale, high = worse)2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
10.1 +/vs haloperidol - medium term295Mean Difference (IV, Fixed, 95% CI)-1.19 [-4.60, 2.23]
11 Adverse effects/events: 1. extrapyramidal symptoms2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
11.1 +/vs haloperidol - medium term2127Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.16, 1.17]
12 Adverse effects/events: 2. use of medication for EPS2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
12.1 +/vs haloperidol - medium term295Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.27, 1.01]
13 Adverse effects/events: 3. specific2 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
13.1 +/vs haloperidol - ataxia - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
13.2 +/vs haloperidol - dizziness - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
13.3 +/vs haloperidol - dry mouth - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
13.4 +/vs haloperidol - hypotension - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
13.5 +/vs haloperidol - speech disorder - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14 Hospital and service outcomes: 1. changes in hospital status1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
14.1 +/vs haloperidol - not discharged - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 4.1.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 1 Global impression: 1. no improvement.

Analysis 4.2.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 2 Global impression: 2. need for additional medication.

Analysis 4.3.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 3 Global impression: 3. need for additional medication (mean dose, high = worse).

Analysis 4.4.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 4 Global impression: 4. sedation.

Analysis 4.5.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 5 Global impression: 5. average change score (RSS, high = worse).

Analysis 4.6.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 6 Behaviour: 1. average endpoint score (ABS, high = worse).

Analysis 4.7.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 7 Behaviour: 2. average endpoint score (OAS, high = worse).

Analysis 4.8.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 8 Behaviour: 4. average endpoint score (OASS agitation scale, high = worse).

Analysis 4.9.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 9 Mental state: 1. average endpoint score (BPRS, high = worse).

Analysis 4.10.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 10 Mental state: 2. average endpoint score (BPRS psychosis subscale, high = worse).

Analysis 4.11.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 11 Adverse effects/events: 1. extrapyramidal symptoms.

Analysis 4.12.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 12 Adverse effects/events: 2. use of medication for EPS.

Analysis 4.13.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 13 Adverse effects/events: 3. specific.

Analysis 4.14.

Comparison 4 BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS, Outcome 14 Hospital and service outcomes: 1. changes in hospital status.

Comparison 5. BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global impression: 1. no improvement1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
1.1 +haloperidol vs olanzapine - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 +haloperidol vs ziprasidone - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Global impression: 2. need for additional medication (mean dose, high = worse, skew)  Other dataNo numeric data
2.1 +haloperidol vs olanzapine - medium term  Other dataNo numeric data
2.2 +haloperidol vs ziprasidone - medium term  Other dataNo numeric data
3 Global impression: 3. sedation1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 +haloperidol vs olanzapine - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 +haloperidol vs ziprasidone - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Global impression: 4. average endpoint score (RSS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 +haloperidol vs olanzapine - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 +haloperidol vs olanzapine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 +haloperidol vs ziprasidone - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.4 +haloperidol vs ziprasidone - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Behaviour: 1. average change score (OAS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 +haloperidol vs olanzapine - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 +haloperidol vs olanzapine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.3 +haloperidol vs ziprasidone - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.4 +haloperidol vs ziprasidone - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Behaviour: 2. average endpoint score (OASS agitation scale, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 +haloperidol vs olanzapine - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 +haloperidol vs olanzapine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 +haloperidol vs ziprasidone - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.4 +haloperidol vs ziprasidone - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Mental state: 1. average endpoint score (PANSS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7.1 +risperidone vs clozapine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7.2 +risperidone vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Mental state: 2. average endpoint score (PANSS-excited component, high = worse)2 Mean Difference (IV, Fixed, 95% CI)Totals not selected
8.1 +risperidone vs clozapine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8.2 +risperidone vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
8.3 +olanzapine vs haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Adverse effects/ events: 1. side effects2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
9.1 +risperidone vs clozapine - medium term276Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.02, 1.48]
9.2 +risperidone vs haloperidol - medium term140Risk Ratio (M-H, Fixed, 95% CI)0.05 [0.00, 0.85]
10 Adverse effects/events: 2. extrapyramidal symptoms1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
10.1 +haloperidol vs olanzapine - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10.2 +haloperidol vs ziprasidone - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
11 Adverse effects/events: 3. specific1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
11.1 +haloperidol vs olanzapine - hypotension - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
11.2 +haloperidol vs ziprasidone - hypotension - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 5.1.

Comparison 5 BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS, Outcome 1 Global impression: 1. no improvement.

Analysis 5.2.

Comparison 5 BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS, Outcome 2 Global impression: 2. need for additional medication (mean dose, high = worse, skew).

Global impression: 2. need for additional medication (mean dose, high = worse, skew)
StudyInterventionMeanSDN
+haloperidol vs olanzapine - medium term
Midazolam 2011, BZMidazolam+haloperidol1.730.8730
Midazolam 2011, BZOlanzapine0.370.7730
+haloperidol vs ziprasidone - medium term
Midazolam 2011, BZMidazolam+haloperidol1.730.8730
Midazolam 2011, BZZiprasidone0.770.9830
Analysis 5.3.

Comparison 5 BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS, Outcome 3 Global impression: 3. sedation.

Analysis 5.4.

Comparison 5 BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS, Outcome 4 Global impression: 4. average endpoint score (RSS, high = worse).

Analysis 5.5.

Comparison 5 BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS, Outcome 5 Behaviour: 1. average change score (OAS, high = worse).

Analysis 5.6.

Comparison 5 BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS, Outcome 6 Behaviour: 2. average endpoint score (OASS agitation scale, high = worse).

Analysis 5.7.

Comparison 5 BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS, Outcome 7 Mental state: 1. average endpoint score (PANSS, high = worse).

Analysis 5.8.

Comparison 5 BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS, Outcome 8 Mental state: 2. average endpoint score (PANSS-excited component, high = worse).

Analysis 5.9.

Comparison 5 BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS, Outcome 9 Adverse effects/ events: 1. side effects.

Analysis 5.10.

Comparison 5 BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS, Outcome 10 Adverse effects/events: 2. extrapyramidal symptoms.

Analysis 5.11.

Comparison 5 BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS, Outcome 11 Adverse effects/events: 3. specific.

Comparison 6. BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIPSYCHOTICS
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Behaviour: 3. average endpoint score (OAS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 + haloperidol vs clothiapine + haloperidol - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Leaving the study early: 1. any reason1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 +haloperidol vs clothiapine+haloperidol - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 6.1.

Comparison 6 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIPSYCHOTICS, Outcome 1 Behaviour: 3. average endpoint score (OAS, high = worse).

Analysis 6.2.

Comparison 6 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIPSYCHOTICS, Outcome 2 Leaving the study early: 1. any reason.

Comparison 7. BENZODIAZEPINES vs ANTIPSYCHOTICS + ANTIHISTAMINES
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global impression: 1. no improvement1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
1.1 vs haloperidol+promethazine - immediate term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 vs haloperidol+promethazine - short term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 vs haloperidol+promethazine - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Global impression: 2. need for additional medication1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 vs haloperidol+promethazine - immediate term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 vs haloperidol+promethazine - short term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.3 vs haloperidol+promethazine - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Global impression: 3. sedation2 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 vs haloperidol+promethazine - immediate term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 vs haloperidol+promethazine - short term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 vs haloperidol+promethazine - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.4 vs haloperidol+promethazine - short term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.5 vs haloperidol+promethazine - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Global impression: 4. average endpoint score (CGI, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 vs haloperidol+promethazine - immediate term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 vs haloperidol+promethazine - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 vs haloperidol+promethazine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Adverse effects/ events: 1. specific2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 vs haloperidol+promethazine - airway management - medium term2501Risk Ratio (M-H, Fixed, 95% CI)2.99 [0.31, 28.54]
5.2 vs haloperidol+promethazine - nausea - medium term1200Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.12, 72.77]
5.3 vs haloperidol+promethazine - seizure - medium term1301Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 8.06]
6 Leaving the study early: 1. any reason2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 vs haloperidol+promethazine - medium term2501Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.06, 2.87]
7 Hospital and service outcomes: 1. changes in hospital status1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
7.1 vs haloperidol+promethazine - not discharged - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 7.1.

Comparison 7 BENZODIAZEPINES vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 1 Global impression: 1. no improvement.

Analysis 7.2.

Comparison 7 BENZODIAZEPINES vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 2 Global impression: 2. need for additional medication.

Analysis 7.3.

Comparison 7 BENZODIAZEPINES vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 3 Global impression: 3. sedation.

Analysis 7.4.

Comparison 7 BENZODIAZEPINES vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 4 Global impression: 4. average endpoint score (CGI, high = worse).

Analysis 7.5.

Comparison 7 BENZODIAZEPINES vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 5 Adverse effects/ events: 1. specific.

Analysis 7.6.

Comparison 7 BENZODIAZEPINES vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 6 Leaving the study early: 1. any reason.

Analysis 7.7.

Comparison 7 BENZODIAZEPINES vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 7 Hospital and service outcomes: 1. changes in hospital status.

Comparison 8. BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIHISTAMINES
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global impression: 1. no improvement1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
1.1 +haloperidol vs haloperidol+promethazine - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Global impression: 2. need for additional medication (mean dose, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 + haloperidol vs haloperidol + promethazine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Global impression: 3. sedation1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 +haloperidol vs haloperidol+promethazine - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Global impression: 4. average change score (RSS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 +haloperidol vs haloperidol+promethazine - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 +haloperidol vs haloperidol+promethazine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Behaviour: 1. average endpoint score (OAS, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 + haloperidol vs haloperidol + promethazine - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 + haloperidol vs haloperidol + promethazine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Behaviour: 2. average endpoint score (OASS agitation scale, high = worse)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 +haloperidol vs haloperidol+promethazine - short term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 +haloperidol vs haloperidol+promethazine - medium term1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Adverse effects/events: 1. extrapyramidal symptoms1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
7.1 +haloperidol vs haloperidol+promethazine - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Adverse effects/events: 2. specific1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
8.1 +haloperidol vs haloperidol+promethazine - hypotension - medium term1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 8.1.

Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 1 Global impression: 1. no improvement.

Analysis 8.2.

Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 2 Global impression: 2. need for additional medication (mean dose, high = worse).

Analysis 8.3.

Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 3 Global impression: 3. sedation.

Analysis 8.4.

Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 4 Global impression: 4. average change score (RSS, high = worse).

Analysis 8.5.

Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 5 Behaviour: 1. average endpoint score (OAS, high = worse).

Analysis 8.6.

Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 6 Behaviour: 2. average endpoint score (OASS agitation scale, high = worse).

Analysis 8.7.

Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 7 Adverse effects/events: 1. extrapyramidal symptoms.

Analysis 8.8.

Comparison 8 BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIHISTAMINES, Outcome 8 Adverse effects/events: 2. specific.

Comparison 9. SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 1. Random sequence generation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global impression: 1. no improvement5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 unknown risk of bias3214Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.78, 1.63]
1.2 low risk of bias294Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.75, 1.49]
2 Global impression: 2. sedation9 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 unknown risk of bias6340Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.56, 1.26]
2.2 low risk of bias3247Risk Ratio (M-H, Fixed, 95% CI)2.22 [1.52, 3.25]
3 Adverse effects/events: 1. extrapyramidal symptoms8 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 unknown risk of bias5285Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.05, 0.47]
3.2 low risk of bias3247Risk Ratio (M-H, Fixed, 95% CI)0.16 [0.03, 0.85]
Analysis 9.1.

Comparison 9 SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 1. Random sequence generation, Outcome 1 Global impression: 1. no improvement.

Analysis 9.2.

Comparison 9 SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 1. Random sequence generation, Outcome 2 Global impression: 2. sedation.

Analysis 9.3.

Comparison 9 SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 1. Random sequence generation, Outcome 3 Adverse effects/events: 1. extrapyramidal symptoms.

Comparison 10. SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 2. Allocation concealment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global impression: 1. no improvement5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 unknown risk of bias5308Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.85, 1.42]
2 Global impression: 2. sedation9 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 high risk of bias140Risk Ratio (M-H, Fixed, 95% CI)0.6 [0.27, 1.34]
2.2 unknown risk of bias7394Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.85, 1.70]
2.3 low risk of bias1153Risk Ratio (M-H, Fixed, 95% CI)2.71 [1.55, 4.73]
3 Adverse effects/ events: 1. extrapyramidal symptoms8 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 unknown risk of bias7379Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.06, 0.41]
3.2 low risk of bias1153Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.90]
Analysis 10.1.

Comparison 10 SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 2. Allocation concealment, Outcome 1 Global impression: 1. no improvement.

Analysis 10.2.

Comparison 10 SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 2. Allocation concealment, Outcome 2 Global impression: 2. sedation.

Analysis 10.3.

Comparison 10 SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 2. Allocation concealment, Outcome 3 Adverse effects/ events: 1. extrapyramidal symptoms.

Comparison 11. SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 3. Blinded outcome measurement
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global impression: 1. no improvement5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 unknown risk of bias2178Risk Ratio (M-H, Fixed, 95% CI)1.90 [1.11, 3.24]
1.2 low risk of bias3130Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.56, 0.96]
2 Global impression: 2. sedation9 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 high risk of bias2197Risk Ratio (M-H, Fixed, 95% CI)2.08 [1.35, 3.23]
2.2 unknown risk of bias4255Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.39, 1.20]
2.3 low risk of bias3135Risk Ratio (M-H, Fixed, 95% CI)1.56 [0.99, 2.46]
3 Adverse effects/events: 1. extrapyramidal symptoms8 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 high risk of bias1153Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.90]
3.2 unknown risk of bias4257Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.03, 0.90]
3.3 low risk of bias3122Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.04, 0.48]
Analysis 11.1.

Comparison 11 SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 3. Blinded outcome measurement, Outcome 1 Global impression: 1. no improvement.

Analysis 11.2.

Comparison 11 SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 3. Blinded outcome measurement, Outcome 2 Global impression: 2. sedation.

Analysis 11.3.

Comparison 11 SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 3. Blinded outcome measurement, Outcome 3 Adverse effects/events: 1. extrapyramidal symptoms.

Comparison 12. SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 4. Incomplete outcome data (attrition bias)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Global impression: 1. no improvement5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 high risk of bias148Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.32, 0.97]
1.2 unknown risk of bias166Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.71, 1.38]
1.3 low risk of bias3194Risk Ratio (M-H, Fixed, 95% CI)1.85 [1.12, 3.06]
2 Global impression: 2. sedation9 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 high risk of bias3246Risk Ratio (M-H, Fixed, 95% CI)1.61 [1.10, 2.38]
2.2 unknown risk of bias3147Risk Ratio (M-H, Fixed, 95% CI)1.55 [1.01, 2.38]
2.3 low risk of bias3194Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.34, 1.58]
3 Adverse effects/events: 1. extrapyramidal symptoms8 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 high risk of bias2193Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.02, 0.54]
3.2 unknown risk of bias3149Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.03, 0.70]
3.3 low risk of bias3190Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.05, 1.52]
Analysis 12.1.

Comparison 12 SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 4. Incomplete outcome data (attrition bias), Outcome 1 Global impression: 1. no improvement.

Analysis 12.2.

Comparison 12 SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 4. Incomplete outcome data (attrition bias), Outcome 2 Global impression: 2. sedation.

Analysis 12.3.

Comparison 12 SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 4. Incomplete outcome data (attrition bias), Outcome 3 Adverse effects/events: 1. extrapyramidal symptoms.

Appendices

Appendix 1. Previous search methods for identification of studies

We identified relevant randomised controlled trials by searching the Cochrane Schizophrenia Group's register (October 2002) using the following search strategy which was designed to identify references relevant to benzodiazepines.

[benzodiazepine* or adinazolam or alprazolam or anthramycin or bentazepam or bromazepam or chlordiazepoxide or cinolazepam or clobazam or clonazepam or "clorazepam clorazepate" or clotiazepam or cloxazolam or cyprazepam or diazepam or doxefazepam or estazolam or etizolam or flunitrazepam or flurazepam or flutazoram or fosazepam or girisopam or halazepam or haloxazepam or ketazolam or loprazolam or lorazepam or lormetazepam or meclonazepam or medazepam or metaclazepam or mexazolam or midazolam or midazepam or nerisopam or nitrazepam or nordazepam or oxazepam or oxazolam or pinasepam or prazepam or temazepam or tetrazepam or tofisopam or triazolam or triflubazam]

Prior to publication of the review a further update of the Cochrane Schizophrenia Group's Trials Register was searched (April 2005) using the phrase:
[(*azepam* OR *zolam* OR *diazep* or *Anthramycin* OR *clorazepat* OR *Devazepid* OR *Flumazenil* OR *Pirenzepine* OR *clobazam* OR * flutazoram* or *girisopam* or *nerisopam* or *pinasepam* or *tofisopam* or *triflubazam*)in REFERENCE Ti/Ab/In and (*azepam* OR *zolam* OR *diazep* or *Anthramycin* OR *clorazepat* OR *Devazepid* OR *Flumazenil* OR *Pirenzepine* OR *clobazam*) in STUDY Intervention].

What's new

DateEventDescription
18 March 2013New citation required and conclusions have changedMinor changes to conclusions after new data added to review.
1 March 2013New search has been performedResults of update search added. Ten new trials included bringing the total number of included studies in the review to 21, new comparisons and outcomes added with new data resulting in minor changes to conclusions.

History

Protocol first published: Issue 2, 2001
Review first published: Issue 4, 2005

DateEventDescription
22 October 2008AmendedConverted to new review format.
5 August 2005New citation required and conclusions have changedSubstantive amendment

Contributions of authors

Alison Beck - protocol development, data extraction, analysis, writing-up.
Donna Gillies - protocol development, data extraction, analysis, writing-up.
Annie McCloud - protocol development, data extraction, analysis, writing-up of the original review.
John Rathbone - data extraction, analysis, writing-up.
Stephanie Sampson - data extraction, analysis, writing-up, 2012 update.

Declarations of interest

None known.

Sources of support

Internal sources

  • The Children's Hospital at Westmead, Sydney, Australia.

  • Central Wandsworth Community Mental Health Team, London, UK.

  • St George's Mental Health NHS Trust, London, UK.

  • Western Sydney Local Health District, Australia.

External sources

  • NHS National R&D Programme on Forensic Mental Health, UK.

  • National Institute for Health Research (NIHR), UK.

    Cochrane Collaboration Programme Grant 2011; Reference number: 10/4001/15

Differences between protocol and review

See Table 7 to review differences between protocol and review that have been classified as either 'minor' or 'major'.

Table 7. Differences between protocol and review
MinorMajor

1. In the protocol, it was proposed that for outcome data from a continuous scale to be included: '(a) the psychometric properties of the instrument should have been described in a peer-reviewed journal; (b) the instrument should either be a self-report, or completed by an independent rater or relative (not the therapist); and (c) the instrument should be a global assessment of an area of functioning'. As this previous definition was less clear in defining the scope of inclusion, this has now been rephrased as: '(a) the psychometric properties of the instrument had been described in a peer-reviewed journal; and (b) it should be a self-report measure or completed by a blinded independent rater. If it was not clear whether these criteria were met, this should be recorded under potential biases.'

2. 'Risk of bias' tables for each included study have been extended to include (i) random sequence generation (sedation bias), (ii) allocation concealment (iii) blinding (performance and detection bias), (iv) incomplete outcome data (attrition bias), (v) selective reporting (reporting bias) and (vi) other bias.

3. 'Summary of findings' tables have been added to include a summary of the main outcomes of interest for each comparison.

1. In this update, there have been additions to the Types of interventions section, to include recent important research comparing benzodiazepines (alone or in combination with antipsychotics) with combined antipsychotics/antihistamines. The authors feel that this is an area of research of fundamental value that merits inclusion in this systematic review, as benzodiazepines were employed and so should not have been overlooked.

2. Types of outcome measures have been modified/clarified from the original protocol - this decision was not influenced by any outcomes. Where the protocol did not define the primary outcome of interest, this update specified 'no improvement' as the primary outcome. This was to be defined by each trial author, as the authors felt that numbers of people who did not improve by use of a particular intervention was of fundamental importance to both service users and care providers.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Alprazolam 1992, USA

Methods

Allocation: randomised.

Blinding: double blind.

Design: not stated.

Duration: 72 hours.

Setting: hospital - psychiatric emergency service, United States.

Participants

Diagnosis: all participants fulfilled DSM-III-R criteria for schizophrenia.
n = 28.

Age: mean 33 years.
Gender: 11 male, 17 female.

Racial origin: Black (n = 23).
Consent: gave informed consent.

History: not stated.

Inclusion: 18-60 years old, actively psychotic with a minimum score of 12 on the abbreviated BPRS.

Exclusion: co-existing major axis disorder, significant medical illness, pregnancy, use of non-prescription psychoactive drug or alcohol in previous 72 hours.

Interventions

Benzodiazepines plus antipsychotics versus same antipsychotics:

1. Alprazolam 1 mg oral tablet + haloperidol 5 mg oral concentrate, mean 3.2 doses (n = 14).

2. Haloperidol 5 mg oral concentrate + placebo tablet, mean 2.1 doses (n = 14).

Repeat dose given within first 24 hours if psychotic subscale was at least 11. Total dose administered on day 1 was repeated days 2 and 3. Each patient received a minimum of 2 doses.

Outcomes

Global impression: no improvement*.

Mental state: average endpoint score (BPRS and BPRS-psychosis subscale).

Adverse effects/events: use of medication for EPS.

Hospital and service outcomes: discharged.

Unable to use -

Global impression: level of positive psychiatric symptoms (SAPS); level of negative psychiatric symptoms (SANS) (no data within 48 hours).

Adverse effects/events: EPS (no useable data).

Notes*'Improvement' - undefined; this result included the number of participants who demonstrated lower mean baseline scores on the SAPS and BPRS subscale and were subsequently discharged before the completion of the study.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised - participants were 'randomly allocated', however no further description of randomisation is provided.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind - the investigators who administered the scales were blind to each other's ratings, and DMM was blind to the dose and schedule of treatment. Both investigators were blind to drug assignment.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Follow-up: 69%.

Participants that were permitted to leave the study early did so for 'humanitarian reasons', as they had sufficiently improved to allow for early discharge. In this case, a final set of ratings were administered before discharge, and the results were included in the analyses.

Last observation carried forward used for the analysis.

Selective reporting (reporting bias)Unclear riskUse of Simpson-Angus Side Effects Profile and 'another side effects rating scale' was mentioned, but no data were reported.
Other biasHigh risk

Funding: supported in part by a grant from The Upjohn Company (now Pfizer).

Rating scales: trial author JGB administered the BPRS-psychosis subscale, SANS, SAPS and trial author DMM administered the full-scale version of the BPRS - ratings were not a self-report or completed by an independent rater.

Clonazepam 1993, CA

Methods

Allocation: randomised.

Blinding: double blind.

Design: parallel.

Duration: 2 hours.

Setting: psychiatric emergency services, Canada.

Participants

Diagnosis: bipolar (n = 7), chronic schizophrenia (n = 5), schizoaffective disorder (n = 3), brief reactive psychosis (n = 1).
n = 16 (14 were psychiatric inpatients at l'Hôpital Louis-H. Lafontaine, Montreal; 2 were recruited from the emergency room of the Royal Victoria Hosptial, Montreal, Canada).

Age: 18-60 years (mean 35 years).
Gender: 10 male, 6 female.

Racial origin: not stated.

Consent: participants gave voluntary, informed, written consent; in addition, signatures from two staff psychiatrists were required.

History: not stated.

Inclusion criteria: 18-60 year olds with a DSM-III diagnosis of bipolar affective illness (manic phase, schizoaffective disorder, schizophrenia, schizophreniform disorder, brief reactive psychosis or atypical psychosis) and have a score of at least 4 on one of 4 items - hyperactivity, agitation, intrusiveness and impulsive behaviour on the Target Manic Behaviour Scale.

Exclusion criteria: symptoms of organic brain syndromes, drug or alcohol abuse, epileptic disorders or ECT within the past six months.

Interventions

Benzodiazepines versus antipsychotics:

1. Clonazepam 1-2 mg IM, mean dose 5.4 mg + procyclidine placebo, mean dose 15.9 mg (n = 8).

2. Haloperidol 5-10 mg IM, mean dose 19.4 mg + procyclidine, mean dose 12.5 mg (n = 8).

Given at 0, 0.5 and 1-hour intervals.

Dosage adjusted by blinded psychiatrist; procyclidine given to haloperidol group and procyclidine placebo given to clonazepam group. No other psychotropic medication was used during the course of the study.

Outcomes

Global impression: no improvement*; sedation; average score (IMPS).
Adverse effects/events: EPS.

Leaving the study early**.

Unable to use -
Global impression: using a modified 9-point CGI Severity Scale (not validated).

Behaviour: Target Manic Behaviour Symptom Scale (not validated).

Mental state: NOSIE (only selected items, which were not validated, were reported).

Notes

*'Improvement' - defined as a reduction of at least 50% on the baseline IMPS score.

**Both participants who left the study early were included in the statistical analysis by using the endpoint score at time of exclusion.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, however no further description of randomisation is provided.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind - the evaluating psychiatrist was blind to treatment allocations and determined the exact dose of medication. The haloperidol group also received procyclidine with each dose - in order to maintain double blind conditions, the clonazepam group received procyclidine placebo with each dose.
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up: 88%* - last observation carried forward.
Selective reporting (reporting bias)Unclear riskNone detected.
Other biasHigh risk

The 9-point CGI-S scale used in the study was modified from the original, validated 7-point scale.

Rating scales: completed by a study psychiatrist, not an independent rater.

Clonazepam 1999, CHN

Methods

Allocation: randomised.

Blinding: double blind.

Design: not stated.

Duration: 24 hours.

Setting: inpatients, Chinese hospital.

Participants

Diagnosis: schizophrenia (n = 19), mood disorder (n = 19), schizoaffective psychosis (n = 6), epileptic mental disorder (n = 1), alcohol induced psychosis (n = 1) from Chinese Classification of Mental Disorders (CCMD-2-R).

n = 46.

Age: mean 32 years.
Gender: 32 male, 14 female.

Racial origin: not stated.

Consent: not stated.

History: not stated.

Inclusion criteria: aggressive patients with mental illness.

Exclusion criteria: not stated.

Interventions

Benzodiazepines versus antipsychotics:

1. Clonazepam 2 mg IM (n = 22).

2. Haloperidol 10 mg IM (n = 24).

Outcomes

Behaviour: average endpoint (OAS).

Mental state: average endpoint score (BPRS).
Adverse effects/events: EPS; tremor; high heart rate.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised - no further description.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: not clear.
Selective reporting (reporting bias)Unclear riskUnclear.
Other biasUnclear risk

Funding: not stated.

Rating scales: it is unclear who administered the rating scales used.

Clonazepam 2003, CHN

Methods

Allocation: randomised.

Blinding: not stated.

Design: not stated.

Duration: 2 weeks.

Setting: inpatients, Chinese hospital.

Participants

Diagnosis: schizophrenia or schizophreniform disorder (ICD-10).

n = 58.

Age: 18-50 years.
Gender: 23 male, 35 female.

Racial origin: not stated.
Consent: not stated.

History: mean length of illness 7.8 years.

Inclusion criteria: ICD-10 diagnosis for schizophrenia/ schizophreniform disorder; score of >60 PANSS.

Exclusion criteria: not stated.

Interventions

Benzodiazepines plus antipsychotics versus different antipsychotics:

1. Clonazepam 2-6 mg IM + risperidone 2-6 mg IM (n = 20).

2. Clozapine 25-125 mg IM (n = 18).

3. Haloperidol 5-20 mg IM (or 4-8 mg oral tablet after eight days, n = 20).

Outcomes

Mental state: average score (PANSS).

Adverse effects/events: side effects.

Unable to use -

Specific/ general adverse effects/events (no data within 48 hours).

Leaving the study early (no data within 48 hours).

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised - using random numbers.
Allocation concealment (selection bias)Unclear riskAllocation concealment was not mentioned.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskBlinding was not mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data.
Selective reporting (reporting bias)High riskAlthough the study protocol is not available, the published report appears to have reported all the pre-specified outcomes.
Other biasUnclear risk

Funding: not stated.

Rating scales: it is unclear who administered the rating scales used.

Clonazepam 2004, CHN

Methods

Allocation: randomised.

Blinding: none - open label.

Design: not stated.

Duration: 7 days.

Setting: inpatients, Chinese hospital.

Participants

Diagnosis: schizophrenia (CCMD-II-R).

n = 254.

Age: 18-50 years.
Gender: 143 male and 111 female.

Racial origin: not stated.
Consent: not stated.

History: mean length of illness 79 months.

Inclusion criteria: schizophrenia (CCMD-II-R).

Exclusion criteria: serious physical illness; substance dependence; taken experimental drugs within 4 weeks prior to trial.

Interventions

Benzodiazepines plus antipsychotics versus different antipsychotics:

1. Clonazepam 2-4 mg + risperidone 2-4 mg (n = 88).

2. Clozapine 50-200 mg (n = 84).

3. Haloperidol 10-20 mg (n = 84).

Outcomes

Mental state: average score (PANSS-EC).

Unable to use -

Behaviour: agitation score (no data within 48 hours).

Adverse effects/ events: specific (no data within 48 hours).

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised - according to ‘random number and hospital admission order’. No further description on how these numbers were used to ensure randomisation.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskNon-blind - open label.
Incomplete outcome data (attrition bias)
All outcomes
High risk

Follow-up: not clear.

Total of 11 participants dropped-out of the study (one from the combination group; one from the clozapine group and nine from the haloperidol group) - reasons not addressed/ reported.

Selective reporting (reporting bias)Low riskAll measured outcomes were reported.
Other biasUnclear risk

Funding: not stated.

Rating scales: it is unclear who administered the rating scales used.

Clonazepam 2005, CHN

Methods

Allocation: randomised.

Blinding: not stated.

Design: not stated.

Duration: 28 days.

Setting: inpatients, Chinese hospital.

Participants

Diagnosis: schizophrenia with agitation/ aggression (CMD-III).

n = 38.

Age: 17-52.
Gender: 15 male, 23 female.

Racial origin: not stated.

Consent: not stated.

History: average length of illness 0.25-10 years.

Inclusion criteria: schizophrenia with agitation/ aggression (CMD-III).

Exclusion criteria: not stated.

Interventions

Benzodiazepines plus antipsychotics versus different antipsychotics:

1. Clonazepam (2-6 mg IM, then orally at 4-6 mg after one week) + risperidone 4-6 mg (n = 20).

2. Clozapine 200-400 mg (n = 18).

Outcomes

Adverse effects/ events: side effects.

Unable to use -

Mental state: average score (PANSS-EC) (no data before 48 hours).

Adverse effects/ events: EPS (no data within 48 hours); specific (no data within 48 hours).

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised - no further description.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: not clear.
Selective reporting (reporting bias)High riskTESS scale was used, but assessment score was not reported.
Other biasUnclear risk

Funding: not stated.

Rating scales: not stated who administered rating scales.

Clonazepam 2007, CHN

Methods

Allocation: randomised.

Blinding: not stated.

Design: not stated.

Duration: 7 days.

Setting: inpatients, Chinese hospital.

Participants

Diagnosis: schizophrenia (CCMD-III).

n = 65.

Age: 18-65 years.
Gender: 35 male and 31 female*.

Racial origin: not stated.
Consent: not stated.

History: mean length of illness for intervention group 63 months, mean length of illness for control group 58 months.

Inclusion criteria: schizophrenia (CCMD-III).

Exclusion criteria: serious physical illness, substance dependence, pregnancy.

Interventions

Benzodiazepines plus antipsychotics versus different antipsychotics:

1. Clonazepam IM (mean dose 3.5 mg) + olanzapine 5-30 mg oral (mean dose 14.8 mg, n = 34).

2. Haloperidol 5-20 mg IM (mean dose 12.8 mg, n = 31).

Participants were administered trihexyphenidyl 0.3 mg where serious EPS occurred.

Outcomes

Mental state: average score (PANSS-EC).

Unable to use -

Adverse effects/ events (no data within 48 hours).

Notes*One drop-out after randomisation as family refused to continue treatment.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised - using random numbers.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: unclear.
Selective reporting (reporting bias)High riskTESS scale was used, but assessment score was not reported.
Other biasUnclear risk

Funding: not stated.

Rating scales: it is unclear who administered the rating scales used.

Diazepam 1979, IL

Methods

Allocation: randomised.

Blinding: double blind.

Design: not stated.

Duration: 24 hours.

Setting: Eitanim Psychiatric Hospital, Israel.

Participants

Diagnosis: paranoid schizophrenia (n = 9), schizoaffective schizophrenia (n = 9), schizophrenia subtypes (n = 5), paranoid states (n = 2), mania (n = 5), no diagnosis (n = 10).

n = 40.

Age: 20-49 years old (mean 33 years).
Gender: 27 male, 13 female.

Racial origin: not stated.

Consent: not stated.

History: previous hospitalisation (mean 3 instances).

Inclusion criteria: newly admitted psychotic patients of 20 to 50 years after two days of drug-free observation.

Exclusion criteria: physical illness.

Interventions

Benzodiazepines versus antipsychotics:

1. Diazepam 30-40 mg IV (n = 20).

2. Haloperidol 20-35 mg IV (n = 20).

In the haloperidol group, ten participants received high-dose haloperidol and ten participants received moderately high-dose haloperidol - these scores were analysed together.

Doses were given over a 3-hour period.

All patients were free from neuroleptics for 48 hours before the study began.

OutcomesGlobal impression: sedation; average score (CGI).
Mental state: average score (BPRS).
NotesNote: assumptions were made regarding missing SDs data - standard deviations for the CGI-S and BPRS average scores were estimated from the range.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised - no further description.
Allocation concealment (selection bias)High riskAlternation between medications (high-dose and moderately high-dose haloperidol).
Blinding (performance bias and detection bias)
All outcomes
Unclear riskObserver blind - it is not made clear how trial authors remained blinded to alternation and decrease of haloperidol dosage.
Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 50%*.
Selective reporting (reporting bias)Unclear riskNone detected.
Other biasUnclear risk

Funding: supported by a grant from the Gralnick Foundation, High Point Hospital, Port Chester, NY.

Rating scales: BPRS and CGI were performed by consensus of two physicians (trial authors EL and YL), who were 'unaware of the treatment administered'.

Flunitrazepam 1999, IL

Methods

Allocation: randomised.

Blinding: double blind.

Design: not stated.

Duration: 2 hours.

Setting: psychiatric hospital, Israel.

Participants

Diagnosis: schizophrenia (n = 19), schizoaffective disorder (n = 7), bipolar (n = 2, DSM-IV, Axis I Structured Clinical Interview).
n = 28.

Age: 20-60 years (mean 36.8 years).
Gender: 13 male, 15 female.

Racial origin: not stated.

Consent: need for informed consent waived.

History: not stated.

Inclusion criteria: active psychosis, disruptive or aggressive behaviour, pronounced psychomotor agitation or violent outbursts, and hospitalisation in an acute ward.

Exclusion criteria: not stated.

Interventions

Benzodiazepines versus antipsychotics:

1. Flunitrazepam 1 mg IM, single dose (n = 15).

2. Haloperidol 5 mg IM, single dose (n = 13).

Patients were monitored for 120 minutes. Patients on routine psychotropic treatment.

Outcomes

Global impression: no improvement*; sedation.
Adverse effects/events: EPS.

Unable to use -

Behaviour: OAS scores (variance not reported).

Notes

*'Improvement' - defined as reduction of at least 50% in the OAS score at 90 minutes.

Participants in each group were taking additional medications leading up to the study, including the following in the haloperidol group -

haloperidol 5-10 mg/day (n = 4); perphenazine 5-20 mg/day (n = 5); levomepromazine 50-200 mg/day (n = 2); zuclopenthixol 25 mg/day (n = 2).

The following in the flunitrazepam group -

perphenazine 5-20 mg/day (n = 4); haloperidol 5-15 mg/day (n = 6); levomepromazine 75 mg/day (n = 1); zuclopenthixol 25-50 mg/day (n = 4).

Four patients (two from each group) were also taking mood stabilisers (carbamazepine and valproic acid) and lorazepam.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised - assigned using a table of random numbers.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskAll ratings were compiled by author NK, who was blind to the study medications - it is unclear whether dose adjustment was blind.
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up: 100%.
Selective reporting (reporting bias)Unclear riskNone detected.
Other biasHigh risk

Funding: not stated.

Rating scales: trial co-author administered rating scales used for the study, not an independent rater.

Lorazepam 1989, USA

Methods

Allocation: randomised.

Blinding: non-blind.

Design: not stated.

Duration: 'more than 60 minutes'.

Setting: metropolitan psychiatric hospital, US.

Participants

Diagnosis: manic (n = 22), schizophrenia (n = 16), atypical psychotics (n = 16), miscellaneous diagnoses (n = 14).
n = 68.

Age: not stated.
Gender: 41 male, 27 female.

Racial origin: not stated.

Consent: not stated.

History: not stated.

Inclusion criteria: patients were judged to require immediate treatment for agitated or assaultive behaviour and had to score more than > 50 mm on a 100 mm Visual Analogue Scale (VAS) for agitation. All had failed to respond to non-pharmacological interventions to control agitation.

Exclusion criteria: not stated.

Interventions

Benzodiazepines plus antipsychotics versus same benzodiazepine versus same antipsychotic.

1. Lorazepam + haloperidol: haloperidol 5 mg IM + lorazepam 4 mg IM (n = 24).

2. Lorazepam 4 mg IM (n = 23).

3. Haloperidol 5 mg IM (n = 21).

All given as a single dose.

OutcomesGlobal impression: sedation.
NotesThe balance of male/females differed between treatment groups.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, however no further description of randomisation is provided.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskNon-blind, the authors state 'we considered that the degree of tranquillisation desired when treating agitated patients is easily ascertained, and thus we did not use control subjects and a blind design'.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: not clear.
Selective reporting (reporting bias)Unclear riskNone detected.
Other biasUnclear risk

Funding: not stated.

Rating scales: it is unclear who administered the rating scales used to determine baseline agitation ratings.

Lorazepam 1991, USA

Methods

Allocation: randomised.

Blinding: single blind.

Design: prospective.

Duration: 48 hours - intervention in an emergency situation; patients in both groups usually required only one parenteral injection for behavioural control during the study period (mean number of injections for the lorazepam group=1.13; mean number of injections for the haloperidol group=1.10).

Setting: Locked intensive care unit at the Massachusetts Mental Health Center, Boston (US).

Participants

Diagnosis: schizophrenia (n = 16), bipolar (n = 11), schizoaffective disorder (n = 4), organic mental disorder (n = 6), other (n = 13).
n = 60*.

Age: mean 34 years.
Gender: not stated.

Racial origin: not stated.
Consent: not required.

History: not stated.

Inclusion: Psychotic patients on a locked intensive care unit who required the use of parenteral medication to control aggressive, assaultive or disruptive behaviour.

Exclusion: known substance abuse documented by positive toxicology screen on admission.

Interventions

Benzodiazepines versus antipsychotics:

1. Lorazepam 2 mg IM, mean 1.13 injections (n = 30).

2. Haloperidol 5 mg IM, mean 1.10 injections (n = 30).

It is not clear when additional doses were given.

Outcomes

Global impression: no improvement*.

Global impression: sedation.
Adverse effects/ events: EPS.

Unable to use -
Global impression: CGI (no standard deviation available).
Behaviour: OAS (no standard deviation available).
Mental state: BPRS (no standard deviation available).

Notes

*'Improvement' - defined as a greater than mean decrease in OAS scores at 2 hours.

'More bipolar participants received haloperidol by chance'.

*At the time of entering the study:

- n = 4 in the lorazepam group and n = 6 from in the haloperidol group were receiving lithium carbonate.

During the study period:

- n = 3 in the lorazepam group and n = 3 from in the haloperidol group also received anticonvulsants.

- n = 3 in the lorazepam group and n = 3 from in the haloperidol group also received BETA-blocking agents.

- n = 7 in the lorazepam group and n = 3 from in the haloperidol group also received benzodiazepines.

(Separate data analyses were conducted for patients receiving these additional psychotropic medications, but results did not differ).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised - no further description.
Allocation concealment (selection bias)Unclear riskNot stated how participants were allocated - 'potential patients for this study were identified when emergency parenteral medication for behavioural control was required'.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskSingle - parenteral medication was prepared in advance by a member of the research staff who had no direct clinical responsibility for the patient; raters were blind to the treatment condition received by the patient.
Incomplete outcome data (attrition bias)
All outcomes
High risk

Follow-up: sedation 88%; EPS 67%.

ITT: not stated.

Many participants were unavailable for all ratings - 'the number of patients available for rating after baseline declined in both treatment groups because some were discharged or transferred from the locked intensive care unit'.

Selective reporting (reporting bias)Unclear riskComplete data not available - standard deviations not available for most reported outcomes.
Other biasUnclear risk

Funding: supported in part by Wyeth Laboratories.

Rating scales: OAS ratings were obtained by staff nurses at time of parenteral injection at baseline and then at 2 and 24 hours. BPRS ratings were obtained by 'trained study psychiatrists' at the time of baseline and at 24 and 48 hours. Side effects and sedation were assessed at baseline, 1 hour and 24 hours by clinicians who did not participate in evaluating therapeutic results. It is unclear the extent to which rating scales were administered by an independent rater.

Lorazepam 1997, USA

Methods

Allocation: randomised.

Blinding: double blind.

Design: prospective, parallel, multi-centre.

Duration: 24 hours.

Setting: emergency departments in five university/ general hospitals, United States: i. University of Texas Southwestern Medical Center, Dallas; ii. Harbor-UCLA Medical Centre, Los Angeles; iii. University of Nebraska Medical Center, Omaha; iv. Albert Einstein Medical Centre, Philadelphia; v. Harborview Medical Center, Seattle.

Participants

Diagnosis: schizophrenia (n = 47), psychosis (n = 27), psychoactive substance abuse (n = 16), mania (n = 13), schizophreniform disorder (n = 1).
n = 98.

Age: mean 34 years.
Gender: 73 male, 25 female.

Racial origin: not stated.

Consent: informed consent wherever possible.

History: all participants exhibited psychosis and behavioural dyscontrol (agitated, aggressive, destructive, assaultive or restless behaviour).

Inclusion: Patients presented to the emergency department with psychosis and behavioural dyscontrol to the extent they were capable of harming themselves or others.  A score of at least 5 on three or more psychosis/anxiety items from the BPRS.

Exclusion: obvious alcohol intoxication, Central Nervous System (CNS) depression, allergic hypersensitivity, delirium, neuroleptic malignant syndrome, airway obstruction, severe hypo or hypertension, acute narrow angle glaucoma, benzodiazepine or antipsychotic in previous 24 hours, fluphenazine decanoate in previous 2 weeks, haloperidol decanoate in previous 4 weeks, pregnancy.

Interventions

Benzodiazepine plus antipsychotic versus benzodiazepine versus same antipsychotic:

1. Lorazepam 2 mg IM + haloperidol 5 mg IM, maximum 6 doses (n = 32).

2. Lorazepam 2 mg IM, maximum 6 doses (n = 31).

3. Haloperidol 5 mg IM, maximum 6 doses (n = 35).

Administered over 12 hours with a total of no more than 6 doses. First three injections at least 1 hour apart and remainder 2 hours apart. Need for subsequent doses made by blinded evaluator. Most patients had less than 3 doses (lorazepam: 74%; haloperidol: 71%; combination: 91%).

Outcomes

Global impression: no improvement*; need for additional medication; sedation.

Behaviour: average behaviour score (ABS).

Mental state: average endpoint score (BPRS psychosis subscale).
Adverse effects/events: EPS; use of medication for EPS; ataxia, dizziness, dry mouth, speech disorder.

Unable to use -
Global impression: CGI (no useable data).

Notes

*'Improvement' - defined as a decrease of one from baseline or two or more from baseline on the CGI (at 3 hours).

Sample numbers were not made clear, as the authors stated that data were only collected if the patient was awake.

Note: assumptions were made regarding missing SDs data - .

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised - eligible participants were sequentially assigned using a computer-generated table of random numbers to receive one of three therapies.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind - 'the emergency department psychiatrist who treated and rated the patient remained blinded to the identity of the patient's medication throughout treatment.'
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Follow-up: not clear.

The data from two participants were excluded from the efficacy analysis, as it was later determined that they had both received proscribed antipsychotic medication shortly before entering the study. It is unclear which group(s) these two participants were excluded from.

Selective reporting (reporting bias)Unclear riskSample numbers were not clear as the authors stated that data were only collected if the patient was awake.
Other biasUnclear risk

Funding: supported in part by a grant from Wyeth-Ayerst Research (now Pfizer).

Rating scales: administered by the emergency department psychiatrist, who also treated the patient, but 'remained blinded to the identity of the patient's medication throughout'.

Lorazepam 1997a, USA

Methods

Allocation: randomised.

Blinding: double blind.

Design: not stated.

Duration: 4 hours.

Setting: Psychiatric Emergency Service, Eastern Pennsylvania Psychiatric Institute, US.

Participants

Diagnosis: schizophrenia (n = 13), bipolar (n = 13), schizoaffective (n = 4), psychotic disorder not otherwise specified (n = 7).
n = 37.

Age: 18-61 years.
Gender: 26 male, 11 female.

Racial origin: White (n = 21), African-American (n = 14), Hispanic (n = 2).

Consent: need for informed consent waived.

History: drug abuse or dependence n = 10.

Inclusion criteria: highly agitated patients exhibiting psychotic symptoms, judged by emergency room staff to be an imminent danger to themselves, required restraint, scored 5 or more on at least three BPRS items and at least 4 on the CGI.

Exclusion criteria: not stated.

Interventions

Benzodiazepines versus antipsychotics:

1. Lorazepam 2 mg oral or IM (n = 17).

2. Haloperidol 5 mg oral or IM (n = 20).

Medication was administered every 30 minutes for 4 hours 'as needed' until the patient was sedated or no longer posed a danger to themselves or staff.

Outcomes

Global impression: sedation; average endpoint score (CGI-S).

Mental state: average endpoint score (BPRS).
Adverse effects/events: EPS.

NotesMore bipolar patients received lorazepam (n = 10) than haloperidol (n = 3).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, however no further description of randomisation is provided.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind, however no further description of blinding is provided.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: not clear.
Selective reporting (reporting bias)Unclear riskNone detected.
Other biasUnclear risk

Funding: supported in part by a grant from the National Alliance for Research on Schizophrenia and Depression.

Rating scales: symptom ratings were conducted by one of four raters (psychiatry residents or psychiatric nursing staff). Raters were trained by trial author SF.

Lorazepam 1998, SA

Methods

Allocation: randomised.

Blinding: double blind.

Design: not stated.

Duration: 7 days.

Setting: Sterkfontein psychiatric hospital, South Africa.

Participants

Diagnosis: (DSM-III-R) organic (psycho-active substance) hallucinosis or delusional disorder (n = 24) schizophrenia (n = 16) bipolar disorder (n = 14) no diagnosis (n = 6).
n = 60.

Age: 18-45 years.
Gender: 46 male, 14 female.

Racial origin: not stated.
Consent: signed informed consent obtained - when consent was difficult to obtain, relatives were called upon to provide consent.

History: not stated.

Inclusion criteria: all patients, aged 18 to 45 years, with aggressive and disorganised behaviour.

Exclusion criteria: physical illness, pregnancy, abnormal routine blood tests.

Interventions

Benzodiazepines plus antipsychotics versus antipsychotics plus antipsychotics:

1. Lorazepam 4 mg IM + haloperidol 10 mg oral (n = 30).

2. Clothiapine 40 mg IM + haloperidol 10 mg oral (n = 30).

Dose repeated 6 hourly 'if warranted'.

Outcomes

Behaviour: average aggression score (OAS).

Leaving the study early.

Unable to use -
Mental state: average score (BPRS) (no data within 48 hours).

Extrapyramdial side effects (SAS) (no data within 48 hours).

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised - no further description.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind - no further description.
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up: 100%.
Selective reporting (reporting bias)Unclear riskNone detected.
Other biasUnclear risk

Funding: not stated.

Rating scales: it is unclear who administered the rating scales used.

Lorazepam 1998, USA

Methods

Allocation: randomised.

Blinding: double blind.

Design: not stated.

Duration: 3 hours.

Setting:psychiatric emergency service, US hospital.

Participants

Diagnosis: bipolar (n = 9); psychosis (n = 4); paranoid schizophrenia (n = 3); brief reactive psychosis (n = 1); undifferentiated schizophrenia (n = 1); substance-induced (n = 2).
n = 20.

Age: mean 36 years.
Gender: 13 male, 7 female.

Racial origin: not stated.

Consent: waiver of informed consent obtained.

History: not stated.

Inclusion criteria: 18-50 year olds presenting to the psychiatry emergency service with acutely agitated behaviour which met clinical criteria for chemical restraint, defined by a minimum score of 4, with a score of 2 or more on at least one OAS item, and a minimum rating of 50 on a 100 point Visual Analogue Scale (VAS) reflecting agitation and hostility (n = 20).

Exclusion criteria: pregnancy; HIV positive; history of seizures; severe head trauma; psychopathology due to suspected general medical condition or those whose symptoms related to drug or alcohol abuse.

Interventions

Benzodiazepine plus antipsychotic versus same benzodiazepine:

1. Lorazepam 2 mg IM + haloperidol 5 mg IM (n = 9).

2. Lorazepam 2 mg IM (n = 11).

(Repeated once at 60 minutes if patients were still severely agitated).

Outcomes

Global impression: no improvement*; need for additional medication.
Adverse effects/events: EPS.

Leaving the study early.

Unable to use -

Global impression: CGI (variance was not reported).

Behaviour: average aggression score (VAS) (variance was not reported); OAS scores (variance was not reported).

Notes*'Improvement' - defined as participants who demonstrated a decrease in four or more points on the OAS scale.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised - 'Participants were assigned to treatment according to computer-generated forced randomisation blocks of four.'
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind - 'a member of nursing staff, independent of patient assessment or treatment, prepared and coded each injection of equal volume'.
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up: 100%.
Selective reporting (reporting bias)High riskAuthors changed criteria for 'improvement' on the Visual Analogue Scale post-study, after analysis had taken place. Full data not reported (i.e. continuous data for rating scales). Ratings for CGI; VAS and OAS taken at 30, 60, 120 and 180 minutes - but no data were reported.
Other biasUnclear risk

Funding: not stated.

Rating scales: administered by an investigator - it is unclear whether this investigator was an independent rater.

Lorazepam 2001, RO & USA

Methods

Allocation: randomised.

Blinding: double blind.

Design: not stated.

Duration: 24 hours.

Setting: hospitals in Romania and US.

Participants

Diagnosis: manic, mixed with psychotic features (52.3%; n = 105/201) mood congruent (87.5%; n = 176/201) rapid cycling (52.2%; n = 105/201).

n = 201.

Age: mean 40 years.
Gender: 107 male, 94 female.

Racial origin: White (n = 146), Black (n = 32), other (n = 23).

Consent: written informed consent.

History: age of onset mania or hypomania (mean 23.8) depression (mean 22.6) mixed episode (mean 24.7).

Inclusion criteria: At least 18 years old with DSM-IV bipolar disorder (manic or mixed), deemed by a physician to have agitation severe enough to receive injections, a minimum total PANSS-EC score of 14, and at least one individual item score of at least 4.

Exclusion criteria: not stated.

Interventions

Benzodiazepines versus antipsychotics versus placebo:

1. Lorazepam 2-5 mg IM (n = 51).

2. Olanzapine 10-25 mg IM (n = 99).

3. Placebo (first and second injections were placebo, the third injection was olanzapine 10 mg - participants requiring the third injection were excluded from 24 hour analysis, n = 21, n = 51).

Patients received 1-3 doses over 3-20 hours based on the clinical judgement of the investigator.

Outcomes

Global impression: no improvement*; sedation; need for additional medication; average change (CGI-S).

Behaviour: average behaviour score (ABS).

Mental state: average change (PANSS and PANSS-excited component).

Adverse effects/events: EPS; use of medication for EPS; dizziness; vomiting; nausea.

Leaving the study early.

Unable to use -
Agitation-Calmness Evaluation Scale (ACES) (not validated - developed by trial sponsors).

Notes*'Improvement' - defined as a reduction of 40% or more on the excited component (PANSS-EC) subscale.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised - no further description.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind - no further description.
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Follow-up: 96%.

ITT analysis used (last observation carried forward).

Selective reporting (reporting bias)Unclear riskThe number of participants who reported outcomes from rating scales at baseline and post-baseline differ to total number of participants randomised into each treatment arm. It is stated that not all participants completed both a baseline and post-baseline rating scale.
Other biasHigh risk

Funding: study sponsored by Eli Lilly and Company - Lilly Resesarch Laboratories, Lilly Corporate Center, Indianapolis, Indiana.

Lead trial author KM and co-authors FZ, SD, MT, KK, RR, DW, PT and AB were each employed by trial sponsors Eli Lilly and Company at the time of the study.

Rating scales: Agitation-Calmness Evaluation Scale (ACES) - single-item 9-point scale, developed by trial sponsors Eli Lilly and Company (results not included). It is unclear who administered the rating scales used.

Lorazepam 2004, IN

Methods

Allocation: randomised.

Blinding: open.

Design: parallel.

Duration: 2 weeks.

Setting: Department of Psychiatry, Christian Medial College, Vellore, Tamil Nadu, India.

Participants

Diagnosis: schizophrenia (n = 37) acute psychosis (n = 22) mania (n = 97) depression (n = 19) substance misuse (n = 10) other (n = 15).
n = 200.

Age: mean 32.2 (lorazepam group); mean 30.9 (combination group).
Gender: 119 male, 81 female.

Racial origin: not stated.
Consent: consent was obtained from a responsible relative if patients refused, or lacked capacity to consent to treatment by virtue of severe mental illness. Relatives were fully informed and written consent obtained.

History:

Inclusion criteria: where treating clinician felt that participants needed acute intramuscular sedation due to agitation and dangerous behaviour; where treating physician did not feel that either intervention would pose an addition risk to the participant.

Exclusion criteria: participants without a responsible relative were excluded.

Interventions

Benzodiazpeines versus antipsychotics plus antihistamines:

1. Lorazepam 4 mg IM (n = 100).

2. Haloperidol 10 mg IM + promethazine 25/50 mg IM (n = 96 received 50 mg; n = 4 received 25 mg, drawn into the same syringe, n = 100).

All doses were given at the discretion of the treating physician.

Outcomes

Global impression: clinical improvement*; need for additional medication; sedation; average score (CGI).

Adverse effects/events: airway management; nausea.

Hospital and service outcomes: discharged.

Leaving the study early: loss to follow-up.

Unable to use -

Use of physical restraints (not in remit of review).

Leaving the study early (no data within 48 hours).

Notes

*'Improvement' - defined as 'clinically improved' under the CGI - improvement scale dichotomised; much and very much improved.

Participants in each group were receiving other medications at the time of entering the study:

Anticonvulsants (n = 15) anticholinergics (n = 14) antidepressants (n = 17) antipsychotics (n = 53) benzodiazepines (n = 23) beta-blockers (n = 1) lithium (n = 14).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised - 'pragmatic' - computer-generated random numbers list in varying sized blocks of less than 10.
Allocation concealment (selection bias)Low riskA table of allocation sequence independent of block size was produced. Tables were then sent to a colleague independent of the TREC team who ensured that the correct drug was in the consecutively numbered local pack before it was sealed. These packs were constructed of cardboard, were identical, and were sealed firmly with tape, across which the consecutive number was written.
Blinding (performance bias and detection bias)
All outcomes
High riskNon-blinded - open label: blind until point of treatment assignment, which minimised selection bias.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Follow-up: 100% in lorazepam group at 4 hours; 99% in combination group at 4 hours.

Missing data were reported at each level of assessment (total n = 12).

Selective reporting (reporting bias)Low riskAll measured outcomes were reported.
Other biasUnclear risk

Funding: funded by intramural research grants from Fluid Research Fund (Christian Medical College, Vellore), and Cochrane Schizophrenia Group general fund.

Rating scales: study coordinators, who were blind to interventions given, undertook ratings.

Lorazepam 2006, USA

Methods

Allocation: randomised.

Blinding: double blind.

Design: prospective.

Duration: 90 minutes.

Setting: university affiliated emergency department, US.

Participants

Diagnosis: schizophrenia (n = 13), substance abuse (n = 8), bipolar (n = 4), personality disorder (n = 2), schizoaffective (n = 1), not stated (n = 2).
n = 30.

Age: mean 40 years.
Gender: 23 male, 7 female.

Racial origin: not stated.
Consent: informed consent required.

History: not stated.

Inclusion criteria: 18-65 years of age, agitated and/or acutely psychotic patients who required immediate treatment for symptom reduction.

Exclusion criteria: medically unstable conditions, inability to provide informed consent; known allergy or adverse reaction to study drugs; pregnancy; administration of sedatives or antipsychotics in the emergency department prior to enrolment.

Interventions

Benzodiazepines plus antipsychotics versus same benzodiazepines:

1. Lorazepam 2 mg IM + placebo oral (n = 10).

2. Lorazepam 2 mg IM + risperidone 2 mg oral (n = 10).

3. Lorazepam 2 mg IM + haloperidol 5 mg oral (n = 10).

Outcomes

Global impression: no improvement*; need for additional medication.

Mental state: average score (BPRS) (skew); average score (PANSS) (skew).

Leaving the study early.

Notes

*'Improvement' - defined as number of participants who returned for the 24-hour follow-up visit and demonstrated a marked improvement on both BPRS and PANSS.

30% of participants tested positive on the urine screen for marijuana or cocaine; 33% of participants had positive blood alcohol levels.

Pilot study.

Standard deviations calculated using the mean and confidence intervals.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised - no further description.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble blind - no further description.
Incomplete outcome data (attrition bias)
All outcomes
High riskFollow-up: 94%.
Selective reporting (reporting bias)Unclear riskNone detected.
Other biasUnclear risk

Funding: study funded by a grant from Janssen Pharmaceutica.

Rating scales: administered by trained study evaluators, with inter-rater reliability assessed by independent evaluation of a video-taped model.

Midazolam 2003, BZ

Methods

Allocation: randomised.

Blinding: open.

Design: parallel.

Duration: 2 weeks.

Setting: three public psychiatric hospitals, Rio de Janeiro, Brazil.

Participants

Diagnosis: psychosis (n = 219) substance misuse (n = 51) not stated (n = 30)*.
n = 301.

Age: mean 38 years.
Gender: 146 male, 155 female.

Racial origin: not stated.
Consent: not required from participant in the emergency setting; if relatives were present they were fully informed and consent was requested.

History: 9% of participants included had no previous psychiatric attendance.

Inclusion criteria: where treating clinician was uncertain of which treatment to implement where participants needed acute intramuscular sedation due to agitation and dangerous behaviour.

Exclusion criteria: where treating clinician believed one treatment represented an additional risk for the participant.

Interventions

Benzodiazpeines versus antipsychotics plus antihistamines:

1. Midazolam 15 mg IM (n = 150).

2. Haloperidol 5-10 mg IM (n = 77 received 5 mg; n = 71 received 10 mg) + promethazine 50 mg IM (n = 147 received 50 mg; n = 1 received 25 mg, drawn into the same syringe, n = 148).

The benzodiazepine antagonist flumazenil was made available at each centre for use in the event of midazolam toxicity.

Outcomes

Global impression: sedation**.

Adverse effects/ events: seizure; airway management.

Leaving the study early.

Unable to use -

Global impression: sedation (no data within 48 hours).

Hospital and service outcomes: discharged (no data within 48 hours).

Notes

*One participant unaccounted for in diagnosis.

**The primary interest of this trial was defined as 'tranquillised or asleep by 20 minutes' - participants were considered tranquillised when they were calm and peaceful - i.e. neither agitated or restless, and not showing threatening verbal behaviour or physical aggression against objects, other people or themselves.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised - 'pragmatic' - Microsoft Excel used to generate even random numbers less than 10 - blocks were then applied to a table of random numbers.
Allocation concealment (selection bias)Low riskA table of allocation sequence independent of block size was produced. Tables were then sent to a colleague independent of the TREC team who ensured that the correct drug was in the consecutively numbered local pack before it was sealed. These packs were constructed of cardboard, were identical, and were sealed firmly with tape, across which the consecutive number was written.
Blinding (performance bias and detection bias)
All outcomes
High riskNon-blinded - open label: blind until point of treatment assignment, which minimised selection bias.
Incomplete outcome data (attrition bias)
All outcomes
Low riskFollow-up: 99%
Selective reporting (reporting bias)Low riskAll measured outcomes were reported.
Other biasLow risk

Funding: jointly funded by Fundação Oswaldo Cruz, the Cochrane Schizophrenia Group, the British Council, CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and FAPERJ (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro).

Rating scales: raters were nurses/ doctors not involved in the management of the emergency - unknown to treating clinicians.

Midazolam 2006, AU

Methods

Allocation: randomised.

Blinding: double blind.

Design: not stated.

Duration: 100 minutes.

Setting: emergency department of a large metropolitan Australian university hospital.

Participants

Diagnosis: mental illness (ICD-10 codes F09 - F69 and F99, n = 100), no diagnosis (n = 53).

n = 170.

Age: 15-67 years (median 34 years).
Gender: 98 male, 55 female*.

Racial origin: not stated.

Consent: not required.

History: not stated.

Inclusion criteria: adults, 18 to 65 years, who were acutely agitated because of mental illness and required chemical restraint.

Exclusion criteria: hypersensitivity to either drug, pregnancy, readily reversible causes for agitation, agitation believed to be due to acute alcohol withdrawal.

Interventions

Benzodiazepines versus antipsychotics:

1. Midazolam 4 mg + saline solution 1 mg IV (n = 74).

2. Droperidol 4 mg + saline solution 1 mg IV (n = 79).

Patients were given the 5 mg doses every 5 minutes until adequate sedation was achieved.  For patients less than 50 kg the dose was 2.5 mg.  Physicians were free to choose subsequent therapy if adequate sedation was not achieved with the full 20 mg dose.

Outcomes

Global impression: sedation; need for additional medication.

Adverse effects/events: low blood pressure; airway management; vomiting; seizure; hypoxia; low heart rate; EPS.

Leaving the study early.

Notes*Numbers for gender for the 170 originally randomised participants are not given, only numbers from 153 available for analysis are given.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number tables and serially numbered study packs.
Allocation concealment (selection bias)Low riskCodes from study packs remained with the pharmacy until the study was complete.
Blinding (performance bias and detection bias)
All outcomes
High risk

Double blind - blinding was maintained by returning sealed envelopes contained in the study pack. It is stated, however, that 'if necessary for patient treatment, unblinding of the drug could be achieved by opening [the sealed envelope]'; it is unclear whether this was done or not.

A blinded explicit review of the patient's medical record was performed after discharge.

Two participants from each treatment group (n = 4) were treated on an 'unblinded' basis - no further details are given.

Incomplete outcome data (attrition bias)
All outcomes
High risk

Follow-up: 90%.

The data from 17 study packs were lost, so only data from the remaining 153 participants were used.

Selective reporting (reporting bias)High risk

Original inclusion criteria of 18-65 year-olds was subsequently changed to 15-76 year-olds, in order to include the data from 11 additional participants who were either above or below the original threshold. It is stated that these additional participants were sedated before their full details became available.

It is not made clear how 17 of the study packs were lost.

Other biasUnclear risk

Funding: supported by a postgraduate scholarship from the National Health and Medicine Research Council and a research grant from the Australasian College for Emergency Medicine (Morson Taylor Award).

Rating scale: not stated who administered rating scales.

The patient's medical records were reviewed to identify adverse effects.

Midazolam 2011, BZ

  1. a

    General:

    EPS - extrapyramidal symptoms.
    IM - intramuscular.
    IV - intravenous.
    ITT - intention-to-treat.

    Diagnostic tools:

    DSM - Diagnostic and Statistical Manual of Mental Disorders.
    CCMD - Chinese Classification of Mental Disorders.
    ICD-10 - The International Statistical Classification of Diseases and Related Health Problems, 10th Revision.

    Rating Scales:

    Behaviour
    ABS - Agitated Behaviour Scale.
    OAS - Overt Agression Scale.
    OASS -  Overt AgitationSeverity Scale.
    VAS - Visual Analogue Scale.

    Global state
    CGI - Clinical Global Impression.
    CGI-S - Clinical Global Impression Severity Scale.
    RSS - Ramsey Sedation Scale.

    Mental state
    BPRS - Brief Psychiatric Rating Scale.
    IMPS - Inpatient Multidimensional Psychiatric Scale.
    NOSIE - Nurses' Observation Scale for Inpatient Evaluation.
    PANSS - Positive and Negative syndrome Scale.
    PANSS-EC - Positive and Negative syndrome Scale-Excited Component.
    SANS - Scale for the Assessment of Negative Symptoms.
    SAPS - Scale for the Assessment of Positive Symptoms.
    TESS - Treatment Emergent Symptom Scale.

    Side effects
    SAS - Simpson-Angus Scale.

Methods

Allocation: randomised.

Blinding: double.

Design: not stated.

Duration: 12 hours.

Setting: psychiatric emergency room of Santa Casa de Sao Paulo, Brazil.

Participants

Diagnosis: bipolar (n = 62) psychotic disorder (n = 88).
n = 150.

Age: 18-50 years, mean 32.1 years.
Gender: 91 male, 59 female.

Racial origin: not stated.
Consent: informed written consent - before and after participation in the study, which was reviewed and approved by the institutional review board. Written consent was obtained before admission to the emergency unit by a legal guardian and after 12 hours by the patient (when he/she was able to understand the information) or by the guardian.

History: agitation caused by psychotic or bipolar disorder.

Inclusion: signs of agitation; aged between 18-50 years; bipolar (manic or mixed episode) or psychotic disorder diagnosis (DSM-IV-TR criteria); Overt Agitation Severity Scale (OASS) total score equal or greater than 20; and an Overt Aggression Scale (OAS) with four or more positive items.

Exclusion: disorders due to drug abuse; organic disorder; anxiety or personality disorder (DSM-IV-TR criteria); failure to agree to participate in the study; incapability of completing all steps of the study; and unstable clinical disease.

Interventions

Benzodiazpeines plus antipsychotics versus antihistamines plus antipsychotics versus same antipsychotics versus different antipsychotics:

1. Midazolam 15 mg IM + haloperidol 5 mg IM (n = 30).

2. Promethazine 50 mg IM + haloperidol 5 mg IM (n = 30).

3. Olanzapine 10 mg IM (n = 30).

4. Ziprasidone 20 mg IM (n = 30).

5. Haloperidol 5 mg IM (n = 30).

After the initial dose, only additional doses of the combination of haloperidol + promethazine could be used according to clinical judgement. If a participant needed another intervention, he or she was immediately removed from the study.

Outcomes

Global impression: no improvement*; need for additional medication mean dose (skew); numbers sedated; sedation (RSS change scores).

Behaviour: average aggression change (OAS); average behaviour change (OASS agitation scale).

Adverse effects/events: hypotension; EPS.

Notes*'Improvement' - defined as the number of participants with <10 points on the OAS and OASS after 12 hours.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised - allocation by 'permuted blocks - each drug regimen was assigned to blocks of five patients and distributed in this order: olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. This assignment was repeated until the total number of subjects (150) was reached.'
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind - study medications were packaged in identical colour-coded boxes.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up: unclear - 'participants were withdrawn from the trial if they requested discontinuation; if the physician suggested withdrawal due to an adverse event; if the treatment showed lack of efficacy; or if the participants were uncooperative.' It is not stated whether this occurred in the study.
Selective reporting (reporting bias)Unclear riskAdverse effects/events - unclear whether participants in treatment arms olanzapine and ziprasidone experienced adverse effects/ events.
Other biasUnclear riskRating scales were repeatedly administered by two raters - it is unclear whether these were independent raters.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Arana 1986Allocation: not randomised - controlled design.
Davis 2008b

Allocation: randomised.

Participants: acutely agitated people with schizophrenia.

Intervention: haloperidol versus clonazepam versus haloperidol + clonazepam.

Outcomes: no useable data.

Guz 1972

Allocation: randomised.

Participants: acutely agitated people with schizophrenia.

Intervention: haloperidol + lorazepam versus haloperidol + placebo.

Outcomes: no useable data - all exceed 48 hours.

Hankoff 1962

Allocation: randomised.

Participants: acutely agitated people with and without schizophrenia.

Intervention: chlorpromazine versus chlordiazepoxide versus meprobamate versus placebo.

Outcomes: no useable data - all exceed 48 hours.

Hanlon 1970

Allocation: randomised.

Participants: acutely disturbed psychiatric patients.

Intervention: fluphenazine + chlordiazepoxide versus fluphenazine + imipramine.

Outcomes: no useable data - all exceed 48 hours.

Kang 2006

Allocation: randomised.

Participants: schizophrenia.

Interventions: quetiapine + clonazepam versus chlorpromazine versus clozapine.

Outcomes: no usable data - all exceed 48 hours.

Lenox 1992

Allocation: randomised.

Participants: bipolar illness, manic type - not acutely psychotic.

Martel 2005

Allocation: randomised.

Participants: emergency department patients requiring emergent sedation - aggression was not psychosis-induced (agitation was ascribed to alcohol intoxication in 94% of participants).

Mei 2006

Allocation: randomised.

Participants: people with schizophrenia.

Interventions: quetiapine + clonazepam versus haloperidol + scopolamine.

Outcomes: no usable data - all exceed 48 hours.

Nestoros 1982

Allocation: randomised.

Participants: people with schizophrenia - not acutely psychotic.

Nobay 2004

Allocation: randomised.

Participants: aggression was not psychosis-induced (violent and severely agitated patients).

Simpson 2003bAllocation: not randomised - a prospective, naturalistic study.
Tang 2007

Allocation: randomised.

Participants: people with schizophrenia.

Interventions: risperidone + clonazepam versus haloperidol + scopolamine.

Outcomes: no usable data - all exceed 48 hours.

Wan Zhili 2005

Allocation: randomised.

Participants: agitated/ aggressive people with schizophrenia.

Interventions: risperidone + clonazepam versus haloperidol versus chlorpromazine.

Outcomes: no usable data - all exceed 48 hours.

Wyant 1990

Allocation: randomised.

Participants: people with schizophrenia.

Interventions: midazolam versus haloperidol.

Outcomes: no usable data.