Benzodiazepines for psychosis‐induced aggression or agitation

Hadar Zaman; Stephanie J Sampson; Alison LS Beck; Tarang Sharma; Fiona J Clay; Styliani Spyridi; Sai Zhao; Donna Gillies

doi:10.1002/14651858.CD003079.pub4

Cochrane Database of Systematic Reviews

Benzodiazepinas para la agresión o agitación inducida por la psicosis

Información

DOI:

https://doi.org/10.1002/14651858.CD003079.pub4 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

08 diciembre 2017see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Esquizofrenia

Copyright:

Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Contraer

Autores

Hadar Zaman

Correspondencia a: Bradford School of Pharmacy & Medical Sciences, Faculty of Life Sciences, University of Bradford, Bradford, UK

[email protected]
Stephanie J Sampson

Centre for Reviews and Dissemination, University of York, York, UK
Alison LS Beck

Trust HQ, South London and Maudsley NHS Foundation Trust, London, UK
Tarang Sharma

Nordic Cochrane Centre, Copenhagen, Denmark
Fiona J Clay

Department of Forensic Medicine, Monash University, Southbank, Australia
Styliani Spyridi

Department of Rehabilitation Sciences, Faculty of Health Sciences, Cyprus University of Technology, Lemesos, Cyprus
Sai Zhao

Systematic Review Solutions Ltd, The Ingenuity Centre, The University of Nottingham, Nottingham, UK
Donna Gillies

Sydney, Australia

Contributions of authors

HZ: data extraction, analysis, writing‐up, 2016 update.

SJS: data extraction, analysis, writing‐up, 2012 update.

AB: protocol development, data extraction, analysis, writing‐up for original version.

TS: study selection, data extraction, writing up, 2016 update.

FC: study selection, data extraction, writing up 2016 update.

SS: data extraction, analysis, writing‐up, 2016 update.

SZ: data extraction, analysis, writing‐up, 2016 update.

DG: protocol development, data extraction, analysis, writing‐up for original version, 2012 and 2016 update.

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
National Institute for Health Research (NIHR), UK

Cochrane Incentive Grant (2017 update)

Declarations of interest

HZ: received a grant for completion of the 2016 update

SJS: received a grant for completion of 2012 update.

AB: none known.

TS: none known.

FC: none known

SS: none known.

SZ: is employed by Review Solutions, a company that completes systematic reviews.

DG: none known.

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 review 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 and data extraction.

We would also like to acknowledge the contributions made by Annie McCloud and John Rathbone in previous versions of this review.

The searches for this review were developed and run by Farhad Shokraneh, the Trial Search Co‐ordinator of the Cochrane Schizophrenia Group.

This update was supported by a Cochrane Incentive Grant from the National Institute for Health Research (NIHR), the largest single funder of Cochrane Schizophrenia.

Note: the views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the NIHR, National Health Service or the Department of Health.

Version history

Published

Title

Stage

Authors

Version

2017 Dec 08

Benzodiazepines for psychosis‐induced aggression or agitation

Review

Hadar Zaman, Stephanie J Sampson, Alison LS Beck, Tarang Sharma, Fiona J Clay, Styliani Spyridi, Sai Zhao, Donna Gillies

https://doi.org/10.1002/14651858.CD003079.pub4

2013 Apr 30

Benzodiazepines for psychosis‐induced aggression or agitation

Review

Donna Gillies, Stephanie Sampson, Alison Beck, John Rathbone

https://doi.org/10.1002/14651858.CD003079.pub3

2005 Oct 19

Benzodiazepines for psychosis‐induced aggression or agitation

Review

Donna Gillies, Alison Beck, Annie McCloud, John Rathbone

https://doi.org/10.1002/14651858.CD003079.pub2

2001 Apr 23

Benzodiazepines alone or in combination with antipsychotic drugs for acute psychosis

Protocol

Donna Gillies, Alison Beck, Annie McCloud

https://doi.org/10.1002/14651858.CD003079

Differences between protocol and review

Minor

1. 'Risk of bias' tables for each included study have been extended to include random sequence generation (selection bias), allocation concealment, blinding (performance and detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias) and other bias.

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

Major

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 consider 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 review authors considered 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.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Funnel plot of comparison: 2 benzodiazepines versus antipsychotics, outcome: 2.1 Tranquillisation or asleep: 1. sedation.

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Figure 2

Study flow diagram.

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Figure 3

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

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Figure 4

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

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Analysis 1.1

Comparison 1: Benzodiazepines versus placebo, Outcome 1: Tranquillisation or asleep: 1. sedation

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Analysis 1.2

Comparison 1: Benzodiazepines versus placebo, Outcome 2: Behaviour: 1. mean change score (Agitated Behaviour Scale, high = worse)

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Analysis 1.3

Comparison 1: Benzodiazepines versus placebo, Outcome 3: Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC))

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Analysis 1.4

Comparison 1: Benzodiazepines versus placebo, Outcome 4: Global state: 2. need for additional medication

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Analysis 1.5

Comparison 1: Benzodiazepines versus placebo, Outcome 5: Global state: 3. mean change score (Clinical Global Impression Severity Scale, high = worse)

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Analysis 1.6

Comparison 1: Benzodiazepines versus placebo, Outcome 6: Mental state: 1. mean change score (Positive and Negative Syndrome Scale, high = worse)

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Analysis 1.7

Comparison 1: Benzodiazepines versus placebo, Outcome 7: Mental state: 2. mean change score (PANSS‐EC, high = worse)

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Analysis 1.8

Comparison 1: Benzodiazepines versus placebo, Outcome 8: Adverse effects/events: 1. extrapyramidal symptoms (EPS)

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Analysis 1.9

Comparison 1: Benzodiazepines versus placebo, Outcome 9: Adverse effects/events: 2. use of medication for EPS

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Analysis 1.10

Comparison 1: Benzodiazepines versus placebo, Outcome 10: Adverse effects/events: 3. specific

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Analysis 1.11

Comparison 1: Benzodiazepines versus placebo, Outcome 11: Leaving the study early: 1. any reason

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Analysis 2.1

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 1: Tranquillisation or asleep: 1. sedation

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Analysis 2.2

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 2: Behaviour: 2. mean change/endpoint score (Agitated Behaviour Scale, high = worse)

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Analysis 2.3

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 3: Behaviour: 4. mean change score (Overt Aggression Scale, high = worse)

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Analysis 2.4

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 4: Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC))

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Analysis 2.5

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 5: Global state: 2. need for additional medication

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Analysis 2.6

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 6: Global state: 3. mean change/endpoint score (Clinical Global Impression Severity Scale, high = worse)

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Analysis 2.7

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 7: Global state: 4. mean endpoint score (Inpatient Multidimensional Psychiatric Scale, high = worse)

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Analysis 2.8

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 8: Mental state: 1. no improvement (decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%)

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Analysis 2.9

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 9: Mental state: 2. mean change/endpoint score (BPRS, high = worse)

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Analysis 2.10

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 10: Mental state: 3. mean endpoint score (BPRS psychosis subscale, high = worse)

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Analysis 2.11

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 11: Mental state: 3a. mean endpoint score (BPRS positive subscale, high = worse)

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Analysis 2.12

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 12: Mental state: 4a. mean endpoint score (BPRS‐excited component, high = worse)

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Analysis 2.13

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 13: Mental state: 2a. mean change score (Positive and Negative Syndrome Scale, high = worse)

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Analysis 2.14

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 14: Mental state: 4. mean change score (PANSS‐EC, high = worse)

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Analysis 2.15

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 15: Adverse effects/events: 1. extrapyramidal symptoms (EPS)

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Analysis 2.16

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 16: Adverse effects/events: 2. use of medication for EPS

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Analysis 2.17

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 17: Adverse effects/events: 3. specific

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Analysis 2.18

Comparison 2: Benzodiazepines versus antipsychotics, Outcome 18: Leaving the study early: 1. any reason

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Analysis 3.1

Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 1: Tranquilisation or asleep: 1. sedation

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Analysis 3.2

Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 2: Global state: 1. no improvement (Clinical Global Impression (CGI) ‐ improvement scale dichotomised; much and very much improved)

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Analysis 3.3

Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 3: Global state: 2. need for additional medication

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Analysis 3.4

Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 4: Global state: 3. mean endpoint score (CGI, high = worse)

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Analysis 3.5

Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 5: Adverse effects/events: 1. specific

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Analysis 3.6

Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 6: Hospital and service outcomes: 1. changes in hospital status

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Analysis 3.7

Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 7: Leaving the study early: 1. any reason

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Analysis 4.1

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 1: Tranquillisation or asleep: 1. sedation

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Analysis 4.2

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 2: Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse)

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Analysis 4.3

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 3: Global state: 1. no improvement mean endpoint change in Clinical Global Impression score)

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Analysis 4.4

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 4: Global state: 2. need for additional medication

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Analysis 4.5

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 5: Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%)

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Analysis 4.6

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 6: Mental state: 2a. mean endpoint score (BPRS, high = worse)

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Study	Intervention	Mean	SD	N
Mental state: 2b. mean endpoint score (BPRS, high = worse, skew)
+ haloperidol ‐ short term
Lorazepam 2006, USA	Lorazepam	40.8	28.12	10
Lorazepam 2006, USA	Lorazepam+haloperidol	48.2	65.46	10
+ haloperidol ‐ medium term
Lorazepam 2006, USA	Lorazepam	35.5	25.61	10
Lorazepam 2006, USA	Lorazepam+haloperidol	40.1	51.23	10

Analysis 4.7

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 7: Mental state: 2b. mean endpoint score (BPRS, high = worse, skew)

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Analysis 4.8

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 8: Mental state: 2c. mean endpoint score (Positive and Negative Syndrome Scale (PANSS), high = worse)

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Study	Intervention	Mean	SD	N
Mental state: 2d. mean endpoint score (PANSS, high = worse, skew)
+ haloperidol ‐ short term
Lorazepam 2006, USA	Lorazepam	59.4	36.22	10
Lorazepam 2006, USA	Lorazepam+haloperidol	74.6	100.22	10
+ haloperidol ‐ medium term
Lorazepam 2006, USA	Lorazepam	53.9	35.53	10
Lorazepam 2006, USA	Lorazepam+haloperidol	65.8	100.4	10

Analysis 4.9

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 9: Mental state: 2d. mean endpoint score (PANSS, high = worse, skew)

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Analysis 4.10

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 10: Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse)

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Analysis 4.11

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 11: Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse)

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Analysis 4.12

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 12: Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse)

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Analysis 4.13

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 13: Adverse effects/events: 1. extrapyramidal symptoms (EPS)

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Analysis 4.14

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 14: Adverse effects/events: 2. use of medication for EPS

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Analysis 4.15

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 15: Adverse effects/events: 3. specific

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Analysis 4.16

Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 16: Leaving the study early: 1. any reason

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Analysis 5.1

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 1: Tranquillisation or asleep: 1. sedation

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Analysis 5.2

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 2: Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse)

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Analysis 5.3

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 3: Behaviour: 2. mean endpoint score (Overt Aggression Scale (OAS), high = worse)

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Analysis 5.4

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 4: Behaviour: 3. mean endpoint score (Overt Agitation Severity Scale, high = worse)

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Analysis 5.5

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 5: Global state: 1. no improvement

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Analysis 5.6

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 6: Global state: 2. need for additional medication

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Analysis 5.7

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 7: Global state: 3. need for additional medication (mean dose, high = worse)

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Analysis 5.8

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 8: Global state: 4. mean change score (Ramsey Sedation Scale, high = worse)

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Analysis 5.9

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 9: Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%)

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Analysis 5.10

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 10: Mental state: 2. mean endpoint score (BPRS, high = worse)

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Analysis 5.11

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 11: Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse)

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Analysis 5.12

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 12: Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse)

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Analysis 5.13

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 13: Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse)

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Analysis 5.14

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 14: Adverse effects/events: 1. extrapyramidal symptoms (EPS)

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Analysis 5.15

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 15: Adverse effects/events: 2. use of medication for EPS

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Analysis 5.16

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 16: Adverse effects/events: 3. specific

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Analysis 5.17

Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 17: Hospital and service outcomes: 1. changes in hospital status

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Analysis 6.1

Comparison 6: Benzodiazepines + antipsychotics versus antipsychotics plus antipsychotics, Outcome 1: Behaviour: 3. mean endpoint score (Overt Aggression Scale, high = worse)

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Analysis 6.2

Comparison 6: Benzodiazepines + antipsychotics versus antipsychotics plus antipsychotics, Outcome 2: Leaving the study early: 1. any reason

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Analysis 7.1

Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 1: Tranquilisation or asleep: 1. sedation

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Analysis 7.2

Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 2: Behaviour: 1. mean endpoint score (Overt Aggression Scale (OAS), high = worse)

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Analysis 7.3

Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 3: Behaviour: 2. mean endpoint score (Overt Agitation Severity Scale (OASS) agitation scale, high = worse)

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Analysis 7.4

Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 4: Global state: 1. no improvement (number of participants with < 10 points on the OAS and OASS after 12 hours)

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Analysis 7.5

Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 5: Global state: 2. need for additional medication (mean dose, high = worse)

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Analysis 7.6

Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 6: Global state: 3. mean change score (Ramsey Sedation Scale, high = worse)

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Analysis 7.7

Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 7: Adverse effects/events: 1. extrapyramidal symptoms

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Analysis 7.8

Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 8: Adverse effects/events: 2. specific

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Analysis 8.1

Comparison 8: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation, Outcome 1: Tranquilisation or asleep: 1. sedation

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Analysis 8.2

Comparison 8: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation, Outcome 2: Global state: 1. no improvement

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Analysis 8.3

Comparison 8: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation, Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms

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Analysis 9.1

Comparison 9: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment, Outcome 1: Tranquilisation or asleep: 1. sedation

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Analysis 9.2

Comparison 9: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment, Outcome 2: Global state: 1. no improvement

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Analysis 9.3

Comparison 9: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment, Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms

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Analysis 10.1

Comparison 10: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement, Outcome 1: Tranquilisation or asleep: 1. sedation

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Analysis 10.2

Comparison 10: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement, Outcome 2: Global state: 1. no improvement

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Analysis 10.3

Comparison 10: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement, Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms

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Analysis 11.1

Comparison 11: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias), Outcome 1: Tranquilisation or asleep: 1. sedation

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Analysis 11.2

Comparison 11: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias), Outcome 2: Global state: 1. no improvement

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Analysis 11.3

Comparison 11: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias), Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms

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Table 5. Suggested design of future reviews

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 to 1 hour); medium term (1‐48 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 or drug/alcohol use, or both. Age: adults, with age specified in trial. Sex: both.
Comparisons	a. Benzodiazepines ‐ given alone. Including: 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 or triazolam. Any dose, any means of administration. Compared with: 1. Other benzodiazepine ‐ given alone. Any dose, any means of administration. 2. 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 or zuclopenthixol. Second generation/atypical, including: amisulpride, aripiprazole, asenapine, clozapine, clothiapine, clotiapine, iloperidone, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone or zotepine. Any dose, any means of administration. 3. Other combinations of drugs. 3.1. Benzodiazepines + antipsychotics. 3.2. Antipsychotics + 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 or triprolidine. Any dose, any means of administration. 4. 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 1 measure of improvement was reported, then improvement in behaviour is used, followed by improvement in mental state, and then improvement in symptoms. 1.1.2. Tranquillisation (feeling of calmness or calm, non‐sedated behaviour (or both)). 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. Mean endpoint change in general functioning. 2.1.4. Mean 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. Mean change/endpoint scores. 3. Behaviour. 3.1. General. 3.1.1. No clinically important change in behaviour. 3.1.2. Mean behaviour score. 4. Mental state ‐ BPRS. 4.1. General. 4.1.1. No clinically important change in general mental state scores. 4.1.2. Mean 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. 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 (e.g. 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 carers. 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	‐
BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression; EPS: extrapyramidal symptoms.

Table 5. Suggested design of future reviews

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Table 6. Suggested design of future studies

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 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 or drug/alcohol use (or both) Number of participants > 400. Age: adults, with age specified in trial. Sex: both.
Interventions	1. Benzodiazepines ‐ given alone. Including: 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 or 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: chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, droperidol, flupentixol/flupenthixol, fluphenazine, haloperidol, levomepromazine, loxapine, mesoridazine, molindone, periciazine, perphenazine, pimozide, prochlorperazine, promazine, promethazine, thioridazine, thiothixene, trifluoperazine, triflupromazine or zuclopenthixol. Second generation/atypical, including: amisulpride, aripiprazole, asenapine, clozapine, clothiapine, clotiapine, iloperidone, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone or zotepine. Any dose, any means of administration. c. Other combinations of drugs. i. Benzodiazepines plus antipsychotics. ii. Antipsychotics plus antihistamine/anticholinergic drugs. Antihistamines including: 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 or triprolidine. Any dose, any means of administration. d. 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 1 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 adverse 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.
Notes	Any 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.
EPS: extrapyramidal symptoms.

Table 6. Suggested design of future studies

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Summary of findings 1. Benzodiazepines compared to placebo for psychosis‐induced aggression or agitation

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Benzodiazepines compared to placebo for psychosis‐induced aggression or agitation
Patient or population: people with psychosis‐induced aggression or agitation Settings: hospitals (Romania and US) Intervention: benzodiazepines Comparison: placebo
	Assumed risk	Corresponding risk
	Placebo	Benzodiazepines
Tranquillisation or asleep: sedation ‐ medium term Number of participants sedated Follow‐up: 24 hours	59 per 1000¹	98 per 1000 (25 to 389)	RR 1.67 (0.42 to 6.61)	102 (1 study)	⊕⊝⊝⊝ Very low^2,3,4	‐
Global state: no improvement ‐ medium term As defined in each study Follow‐up: 24 hours	569 per 1000¹	353 per 1000 (227 to 552)	RR 0.62 (0.40 to 0.97)	102 (1 study)	⊕⊝⊝⊝ Very low^2,3,4	‐
Global state: need for additional medication ‐ medium term Number of participants requiring additional medication Follow‐up: 24 hours	529 per 1000¹	529 per 1000 (365 to 762)	RR 1.00 (0.69 to 1.44)	102 (1 study)	⊕⊝⊝⊝ Very low^2,3,4	‐
Adverse effects/events: extrapyramidal symptoms ‐ medium term Number of instances of extrapyramidal symptoms Follow‐up: 24 hours	59 per 1000¹	19 per 1000 (2 to 182)	RR 0.33 (0.04 to 3.1)	102 (1 study)	⊕⊝⊝⊝ Very low^2,3,4	‐
Satisfaction with treatment: from the perspective of consumer, family and informal carers or professionals/carers at any point during the acute management stage	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Economic outcomes: cost‐effectiveness ‐ clinically important	See comment	See comment	Not estimable	0 (0)	See comment	No 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: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Assumed risk: mean baseline risk presented for single study. Equates with that of control group. ²Risk of bias: 'very serious' ‐ 90% of trial authors and coauthors were employed by trial sponsors at the time of the study ‐ downgraded by 1. ³Risk of bias: 'serious' ‐ randomisation poorly described ‐ downgraded by 1. ⁴Imprecision: 'serious' ‐ small sample size ‐ downgraded by 1.

Summary of findings 1. Benzodiazepines compared to placebo for psychosis‐induced aggression or agitation

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Summary of findings 2. Benzodiazepines compared to antipsychotics for psychosis‐induced aggression or agitation

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Benzodiazepines compared to antipsychotics for psychosis‐induced aggression or agitation
Patient or population: people with psychosis‐induced aggression or agitation Settings: hospitals (US, Canada, Israel, China, Australia) Intervention: benzodiazepines Comparison: antipsychotics
	Assumed risk	Corresponding risk
	Antipsychotics	Benzodiazepines
Tranquillisation or asleep: sedation ‐ medium term vs haloperidol Number of participants sedated Follow‐up: mean 16 hours	Low		RR 1.13 (0.83 to 1.54)	434 (8 studies)	⊕⊕⊝⊝ Low^1,2	‐
	100 per 1000	113 per 1000 (83 to 154)
	Moderate⁵
	227 per 1000	257 per 1000 (189 to 350)
	High
	500 per 1000	565 per 1000 (415 to 770)
Global state: no improvement ‐ vs haloperidol ‐ medium term As defined in each study Follow‐up: 24 hours	Low		RR 0.89 (0.71 to 1.11)	188 (5 studies)	⊕⊕⊝⊝ Low^1,2	‐
	77 per 1000	68 per 1000 (55 to 85)
	Moderate³
	619 per 1000	551 per 1000 (439 to 687)
	High
	933 per 1000	830 per 1000 (662 to 1000)
Global state: no improvement ‐ vs olanzapine ‐ medium term As defined in each study Follow‐up: 24 hours	192 per 1000	353 per 1000 (203 to 610)	RR 1.84 (1.06 to 3.18)	150 (1 study)	⊕⊝⊝⊝ Verylow^1,2,7	‐
Global state: need for additional medication ‐ medium term Number of participants requiring additional medication Follow‐up: 24 hours	See comment	See comment	Not estimable	216 (2 studies)	⊕⊝⊝⊝ Very low^1,2,4	High levels of heterogeneity between included studies (Chi² = 16.41; I² = 94%) ‐ data not pooled.⁴
Adverse effects/events: extrapyramidal symptoms ‐ vs haloperidol ‐ medium term Number of instances of extrapyramidal symptoms Follow‐up: 21 hours	Low		RR 0.13 (0.04 to 0.41)	233 (6 studies)	⊕⊕⊝⊝ Low^1,2	‐
	0 per 1000	0 per 1000 (0 to 0)
	Moderate⁶
	186 per 1000	24 per 1000 (7 to 76)
	High
	500 per 1000	65 per 1000 (20 to 205)
Satisfaction with treatment: from the perspective of consumer, family and informal care givers or professionals/carers at any point during the acute management stage	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Economic outcomes: cost‐effectiveness	See comment	See comment	Not estimable	0 (0)	See comment	No 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: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Risk of bias: 'serious' ‐ most trials received funding from a pharmaceutical institute and there was potential risk of selection bias. ²Imprecision: 'serious' ‐ confidence intervals for best estimate of effect included both 'no effect' and appreciable benefit/harm. ³Assumed risk: calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (61.9%). ⁴Inconsistency: 'serious' ‐ one study indicated significant favour of antipsychotics, while the other study indicated favour for benzodiazepines (non‐significant). ⁵Assumed risk: calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (22.7%). ⁶Assumed risk: calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (18.6%). ⁷Only one small study reporting data.

Summary of findings 2. Benzodiazepines compared to antipsychotics for psychosis‐induced aggression or agitation

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Summary of findings 3. Benzodiazepines compared to antihistamines plus antipsychotics for psychosis‐induced aggression or agitation

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Benzodiazepines compared to antihistamines + antipsychotics for psychosis‐induced aggression or agitation
Patient or population: people with psychosis‐induced aggression or agitation Settings: psychiatric hospitals (US, Canada, Israel, China, Australia) Intervention: benzodiazepines Comparison: antihistamines + antipsychotics
	Assumed risk	Corresponding risk
	Antihistaimes + antipsychotics	Benzodiazepines
Tranquillisation or asleep: sedation ‐ medium term ‐ lorazepam vs haloperidol + promethazine Number of participants sedated Follow‐up: 2 weeks	970 per 1000¹	883 per 1000 (815 to 951)	RR 0.91 (0.84 to 0.98)	200 (1 study)	⊕⊕⊝⊝ Low^2,3	‐
Tranquillisation or asleep: sedation ‐ medium term ‐ midazolam vs haloperidol + promethazine Number of participants sedated Follow‐up: 2 weeks	827 per 1000¹	934 per 1000 (860 to 1000)	RR 1.13 (1.04 to 1.23)	301 (1 study)	⊕⊕⊝⊝ Low^2,3	‐
Global state: no improvement ‐ medium term As defined in each study Follow‐up: 2 weeks	120 per 1000¹	260 per 1000 (139 to 486)	RR 2.17 (1.16 to 4.05)	200 (1 study)	⊕⊕⊝⊝ Low^2,3	‐
Global state: need for additional medication ‐ medium term Number of participants requiring additional medication Follow‐up: 2 weeks	30 per 1000¹	40 per 1000 (9 to 174)	RR 1.33 (0.31 to 5.81)	200 (1 study)	⊕⊕⊝⊝ Low^2,3	‐
Adverse effects/events: extrapyramidal symptoms ‐ medium term Number of instances of extrapyramidal symptoms	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Satisfaction with treatment: from the perspective of consumer, family and informal carers or professionals/carers at any point during the acute management stage	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Economic outcomes: cost‐effectiveness	See comment	See comment	Not estimable	0 (0)	See comment	No 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: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Assumed risk: mean baseline risk presented for single study. Equates with that of control group. ²Risk of bias: 'serious' ‐ non‐blind, open‐label study. ³Imprecision: 'serious' ‐ small sample size.

Summary of findings 3. Benzodiazepines compared to antihistamines plus antipsychotics for psychosis‐induced aggression or agitation

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Summary of findings 4. Benzodiazepines + antipsychotics compared to same enzodiazepines for psychosis‐induced aggression or agitation

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Benzodiazepines + antipsychotics compared to same benzodiazepinesfor psychosis‐induced aggression or agitation
Patient or population: people with psychosis‐induced aggression or agitation Settings: hospitals (USA, China) Intervention: benzodiazepines + antipsychotics Comparison: same benzodiazepines
	Assumed risk	Corresponding risk
	Same benzodiazepines	Benzodiazepines+ antipsychotics
Tranquillisation or asleep: sedation ‐ medium term‐ + haloperidol ‐ medium term Number of participants sedated Follow‐up: 24 hours	Moderate⁵		RR 0.84 (0.59 to 1.19)	110 (2 studies)	⊕⊕⊝⊝ Low^1,2	‐
	556 per 1000	467 per 1000 (328 to 661)	RR 0.84 (0.59 to 1.19)	110 (2 studies)	⊕⊕⊝⊝ Low^1,2	‐
Global state: no improvement ‐ + haloperidol ‐ medium term As defined in each study Follow‐up: 24 hours	Low		RR 0.96 (0.76 to 1.20)	113 (3 studies)	⊕⊕⊝⊝ Low^1,2	‐
	677 per 1000	650 per 1000 (515 to 812)
	Modertate³
	732 per 1000	703 per 1000 (556 to 879)
	High
	867 per 1000	832 per 1000 (659 to 1000)
Global state: no improvement ‐ lorazepam + risperidone vs lorazepam ‐ medium term As defined in each study Follow‐up: 12 hours	700 per 1000	602 per 1000 (315 to 1000)	RR 0.86 (0.45 to 1.64)	20 (1 study)	⊕⊕⊝⊝ Low^1,2	‐
Global state: need for additional medication ‐ + haloperidol ‐ medium term Number of participants requiring additional medication Follow‐up: 24 hours	Low		RR 1.02 (0.79 to 1.32)	103 (3 studies)	⊕⊕⊝⊝ Low^1,2	‐
	0 per 1000	0 per 1000 (0 to 0)
	Moderate⁴
	500 per 1000	510 per 1000 (395 to 660)
	High
	774 per 1000	789 per 1000 (611 to 1000)
Adverse effects/events: extrapyramidal symptoms ‐ + haloperidol ‐ medium term Number of instances of extrapyramidal symptoms Follow‐up: 24 hours	24 per 1000⁶	46 per 1000 (4 to 483)	RR 1.94 (0.18 to 20.30)	83 (2 studies)	⊕⊕⊝⊝ Low^1,2	‐
Satisfaction with treatment: from the perspective of consumer, family and informal carers or professionals/carers at any point during the acute management stage	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Economic outcomes: cost‐effectiveness	See comment	See comment	Not estimable	0 (0)	See comment	No 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: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Risk of bias: 'serious' ‐ most trials received funding from a pharmaceutical institute and there was potential risk of selection bias. ²Imprecision: 'serious' ‐ confidence intervals for best estimate of effect included both 'no effect' and appreciable benefit/harm. ³Assumed risk: calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (73.2%). ⁴Assumed risk: calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (50%). ⁵Calculated from the included studies ‐ 'moderate' risk equates with that of control group (55.6%). ⁶Calculated from the included studies ‐ 'moderate' risk equates with that of control group (2.4%).

Summary of findings 4. Benzodiazepines + antipsychotics compared to same enzodiazepines for psychosis‐induced aggression or agitation

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Summary of findings 5. Benzodiazepines + antipsychotics compared to same antipsychotics for psychosis‐induced aggression or agitation

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Benzodiazepines + antipsychotics compared to same antipsychotics for psychosis‐induced aggression or agitation
Patient or population: people with psychosis‐induced aggression or agitation Settings: hospitals (US, China, Brazil) Intervention: benzodiazepines + antipsychotics Comparison: same antipsychotics
	Assumed risk	Corresponding risk
	Same antipsychotics	Benzodiazepines+ antipsychotics
Tranquillisation or asleep: sedation ‐ medium term ‐ +/vs haloperidol Number of participants sedated Follow‐up: 12 hours	Moderate⁵		RR 1.75 (1.14 to 2.67)	172 (3 studies)	⊕⊝⊝⊝ Very low^1,2,3	‐
	256 per 1000	448 per 1000 (292 to 683)
	Low
	100 per 1000	175 per 1000 (114 to 267)
	High
	380 per 1000	665 per 1000 (433 to 1000)
Global state: no improvement ‐ +/vs haloperidol ‐ medium term As defined in each study Follow‐up: 36 hours	Moderate⁴		RR 1.17 (0.93 to 1.46)	185 (4 studies)	⊕⊕⊝⊝ Low^1,2	‐
	521 per 1000	610 per 1000 (485 to 761)
	Low
	33 per 1000	39 per 1000 (31 to 48)
	High
	933 per 1000	1000 per 1000 (868 to 1000)
Global state: need for additional medication Number of participants requiring additional medication Follow‐up: 12 hours	See comment	See comment	Not estimable	67 (1 study)	⊕⊕⊝⊝ Low^2,3	‐
Adverse effects/events: extrapyramidal symptoms ‐ +/vs haloperidol ‐ medium term Number of instances of extrapyramidal symptoms Follow‐up: 18 hours	Moderate⁶		RR 0.44 (0.16 to 1.17)	127 (2 studies)	⊕⊕⊝⊝ Low²	‐
	185 per 1000	81 per 1000 (30 to 216)	RR 0.44 (0.16 to 1.17)	127 (2 studies)	⊕⊕⊝⊝ Low²	‐
Satisfaction with treatment: from the perspective of consumer, family and informal carers or professionals/carers at any point during the acute management stage	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Economic outcomes: cost‐effectiveness	See comment	See comment	Not estimable	0 (0)	See comment	No 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). +/vs: with or versus; CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Inconsistency: 'serious' ‐ high levels of heterogeneity. ²Imprecision: 'serious' ‐ confidence intervals for best estimate of effect included both 'no effect' and appreciable benefit/harm. ³Risk of bias: 'serious' ‐ funded by pharmaceutical institutes. ⁴Calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (52.1%). ⁵Calculated from the included studies ‐ presented three risks based on the control group risks ‐ 'moderate' risk equates with that of control group (25.6%). ⁶Calculated from the included studies ‐ 'moderate' risk equates with that of control group (18.5%).

Summary of findings 5. Benzodiazepines + antipsychotics compared to same antipsychotics for psychosis‐induced aggression or agitation

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Summary of findings 6. Benzodiazepines plus antipsychotics compared to antipsychotics plus antipsychotics for psychosis‐induced aggression or agitation

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Benzodiazepines + antipsychotics compared to antipsychotics + antipsychotics for psychosis‐induced aggression or agitation
Patient or population: people with psychosis‐induced aggression or agitation Settings: n/a Intervention: benzodiazepines + antipsychotics Comparison: antipsychotics + antipsychotics
	Assumed risk	Corresponding risk
	Antipsychotics+ antipsychotics	Benzodiazepines+ antipsychotics
Tranquillisation or asleep: sedation ‐ medium term	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Global state: no improvement ‐ medium term	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Global state: need for additional medication ‐ medium term	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Adverse effects/events: extrapyramidal symptoms ‐ medium term	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Satisfaction with treatment: from the perspective of consumer, family and informal carers or professionals/carers at any point during the acute management stage	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Economic outcomes: cost‐effectiveness	See comment	See comment	Not estimable	0 (0)	See comment	No 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: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Summary of findings 6. Benzodiazepines plus antipsychotics compared to antipsychotics plus antipsychotics for psychosis‐induced aggression or agitation

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Summary of findings 7. Benzodiazepines plus antipsychotics compared to antihistamines plus antipsychotics for psychosis‐induced aggression or agitation

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Benzodiazepines + antipsychotics compared to antihistamines + antipsychotics for psychosis‐induced aggression or agitation
Patient or population: people with psychosis‐induced aggression or agitation Settings: psychiatric emergency department (Brazil) Intervention: benzodiazepines + antipsychotics Comparison: antihistamines + antipsychotics
	Assumed risk	Corresponding risk
	Antihistamine + antipsychotics	Benzodiazepines+ antipsychotics
Tranquillisation or asleep: sedation ‐ medium term Number of participants sedated Follow‐up: 12 hours	33 per 1000⁵	400 per 1000 (55 to 1000)	RR 12.00 (1.66 to 86.59)	60 (1 study)	⊕⊝⊝⊝ Very low^3,4	‐
Global state: no improvement ‐ medium term As defined in each study Follow‐up: 12 hours	0 per 1000¹	0 per 1000 (0 to 0)²	RR 25.00 (1.55 to 403.99)	60 (1 study)	⊕⊝⊝⊝ Very low^3,4	‐
Global state: 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^3,4	Skewed data ‐ see 'data and analysis'.
Adverse effects/events: extrapyramidal symptoms ‐ medium term Number of instances of extrapyramidal symptoms Follow‐up: 12 hours	167 per 1000⁵	100 per 1000 (27 to 382)	RR 0.60 (0.16 to 2.29)	60 (1 study)	⊕⊝⊝⊝ Very low^3,4	‐
Satisfaction with treatment: from the perspective of consumer, family and informal carers or professionals/carers at any point during the acute management stage	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome.
Economic outcomes: cost‐effectiveness	See comment	See comment	Not estimable	0 (0)	See comment	No 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: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Assumed risk: mean baseline risk ‐ only one trial reported with 0 events in the control group and 12 events in the intervention group. ²Corresponding risk: one trial reported 12 events in the intervention group (40%). ³Risk of bias: 'serious' ‐ study funded by pharmaceutical institutes, potential risk of selection bias, performance bias and attrition bias. ⁴Imprecision: 'very serious' ‐ only one study reported data for this outcome, data were skew. ⁵Assumed risk: mean baseline risk presented for single study. Equates with that of control group.

Summary of findings 7. Benzodiazepines plus antipsychotics compared to antihistamines plus antipsychotics for psychosis‐induced aggression or agitation

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Table 1. The benzodiazepine family

Name	Code	Chemical name
Benzodiazepines
Bromazepam	Ro 5‐3350	7‐bromo‐1, 3‐dihydro‐5‐(2‐pyridyl)‐2H‐1, 4‐benzodiazepin‐2‐one
Camazepam	SB 5833	7‐chloro‐1, 3‐dihydro‐3‐hydroxy‐1‐methyl‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one dimethylcarbamate
Chlordiazepoxide	Ro 5‐0690	7‐chloro‐2‐methylamino‐5‐phenyl‐3H‐1, 4‐benzodiazepin‐4‐oxide
Cinolazepam	OX 373	7‐chloro‐5‐(o‐fluorophenyl)‐2, 3‐dihydro‐3‐hydroxy‐2‐oxo‐1H‐1, 4‐benzodiazepine‐1‐ propionitrile
Clobaza	HR 376 H 4723 LM 2717	7‐chloro‐1‐methyl‐5‐phenyl‐1H‐1, 5‐benzodiazepine‐2, 4‐(3H, 5H)‐dione
Clonazepam	Ro 5‐4023	5‐(o‐chlorophenyl)‐1, 3‐dihydro‐7‐nitro‐2H‐1, 4‐benzodiazepin‐2‐one
Clorazepate	4306CB A35.616	dipotassium 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
Cyprazepam	W 3623	7‐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
Diazepam	Ro 5‐2807 WY 3467 LA III	7‐chloro‐1, 3‐dihydro‐1‐methyl‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Doxefazepam	SAS 643	7‐chloro‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐3‐hydroxy‐1‐(2‐hydroxyethyl)‐2H‐1, 4‐benzodiazepin‐2‐one
Elfazepam	SKF 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 loflazepate	CM 6912	ethyl 7‐chloro‐5‐(o‐fluorophenyl)‐2, 3‐dihydro‐2‐oxo‐1H‐1, 4‐ benzodiazepine‐3‐carboxylate
Fletazepam	SCH 15.698	7‐chloro‐5‐(o‐fluorophenyl)‐2, 3‐dihydro‐1‐(2, 2, 2‐trifluoroethyl)‐1H‐1, 4‐benzodiazepine
Fludiazepam	ID 540	7‐chloro‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐1 methyl‐2H‐1, 4‐benzodiazepine‐2‐0
Flunitrazepam	Ro 5‐4200	5‐(o‐fluorophenyl)‐1, 3‐dihydro‐1‐methyl‐7‐nitro‐2H‐1, 4‐ benzodiazepin‐2‐one
Flurazepam	Ro 5‐6901	7‐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
Flutoprazepam	KB 509 ID 1937	7‐chloro‐1‐(cyclopropylmethyl)‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐2H‐1, 4‐benzodiazepin‐2‐one
Fosazepam	HR 930	7‐chloro‐1‐[(dimethylphosphinyl)methyl]‐1, 3‐dihydro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Girisopam	GYKI 51.189 EGIS 5810	1‐(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
Halazepam	SCH 12.041	7‐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
Lorazepam	WY 4036	7‐chloro‐5‐(o‐chlorophenyl)‐1, 3‐dihydro‐3‐hydroxy‐2‐1, 4‐benzodiazepin‐2‐one
Lormetazepam	WY 4082	7‐chloro‐5‐(o‐chlorophenyl)‐1, 3‐dihydro‐3‐hydroxy‐1‐methyl‐2H‐1, 4‐benzodiazepin‐2‐one
M ORF8063	WE 352	1‐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
Medazepam	Ro 5‐4556	7‐chloro‐2, 3‐dihydro‐1‐methyl‐5‐phenyl‐1H‐1, 4‐benzodiazepine
Menitrazepam	CB 4857	5‐(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
Nimetazepam	S 1530	1, 3‐dihydro‐1‐methyl‐7‐nitro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Nitrazepam	Ro 4‐5360 Ro 5‐3059 CB 4395 (potassium salt)	1, 3‐dihydro‐7‐nitro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Nordazepam	Ro 5‐2180 A 101	7‐chloro‐1, 3‐dihydro‐3‐hydroxy‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Normetrazepam	CB 4260	7‐chloro‐5‐(1‐cyclohexen‐1‐yl)‐1, 3‐dilhydro‐2H‐1, 4‐benzodiazepin‐2‐one
Oxazepam	WY 3498 8092 CB Ro 5‐6789	7‐chloro‐1, 3‐dihydro‐3‐hydroxy‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Oxazepam hemisuccinate	SAS 538	7‐chloro‐2, 3‐dihydro‐3‐hydroxy‐2‐(1H)‐oxo‐5‐phenyl‐1, 4‐benzodiazepin‐3‐yl hydrogen succinate
Pinazepam	Z 905	7‐chloro‐1, 3‐dihydro‐5‐phenyl‐1‐(2‐propynyl)‐2H‐1, 4‐benzodiazepin‐2‐one
Potassium nitrazepate	CB 4335	2, 3‐dihydro‐7‐nitro‐2‐oxo‐5‐phenyl‐1H‐1, 4‐benzodiazepin‐3‐carboxylic acid monopotassium salt
Prazepam	W 4020	7‐chloro‐1‐(cyclopropylmethyl)‐1, 3‐dihydro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Quazepam	SCH 16.134	7‐chloro‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐1‐(2, 2, 2‐trifluoroethyl)‐2H‐1, 4‐benzodiazepine‐2‐thione
Reclazepam	SC 33.963	2‐[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
Sulazepam	W3676	7‐chloro‐1, 3‐ dihydro‐1‐methyl‐5‐phenyl‐ 2H‐1, 4‐ benzodiazepin‐ 2‐thione
Temazepam	ER 115 Ro 5‐5345 WY 3917	7‐chloro‐1, 3‐dihydro‐3‐hydroxy‐1‐methyl‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Tetrazepam	CB 4261	7‐chloro‐5‐(cyclohexen‐1‐yl)‐1, 3‐dihydro‐1‐methyl‐2H‐1, 4‐benzodiazepin‐2‐one
Tofisopam	EGYT 341	5‐ethyl‐7‐8‐dimethoxy‐1‐(3, 4‐dimethoxyphenyl)‐4‐methyl‐5H‐2, 3‐benzodiazepine
Uldazepam	U 31.920	2‐[(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
Adinazolam	U 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)
Alprazolam	U 31.889	8‐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
Cloxazolam	CS 370 MT 14‐411	10‐chloro‐11b‐(o‐chlorophenyl)‐2, 3, 7, 11b‐tetrahydro‐oxazolo[3, 2‐d][1, 4]benzodiazepin‐6 (5H)‐one
Estazolam noralprazolam	D 40 TA Lu 7426 Abbott 47631	8‐chloro‐6‐phenyl‐4H‐s‐triazolo[4, 3‐a][1, 4] benzodiazepine
Flutazolam	MS 4101	10‐chloro‐11b‐(2‐flurophenyl)‐2, 3, 7, 11b‐tetrahydro‐7‐(2‐hydroxyethyl‐oxazolo[ 3, 2‐d] [1, 4] benzodiazepin‐6(5H)‐one
Gp 55.129	U 40125	8‐chloro‐6‐phenyl‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine‐1‐methanol
Haloxazolam	CS 430	10‐bromo‐11b‐(o‐fluorophenyl)‐2, 3, 7, 11b‐tetrahydrooxazolo[3, 2‐d][1, 4]benzodiazepin‐6(5H)‐one
Ketazolam	U 28.774	11‐chloro‐8, 12b‐dihydro‐2, 8‐dimethyl‐12b‐phenyl‐4H‐[1, 3]oxazino[3, 2‐d][1, 4]benzodiazepine‐4, 7(6H)‐ dione
Loprazolam	RU 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
Mexazolam	CS 386	10‐chloro‐11b‐(o‐chlorophenyl)‐2, 3, 7, 11b‐tetrahydro‐3‐methyl‐oxazolo[3, 2‐d][1, 4]benzodiazepin‐6(5)‐one
Midazolam	Ro 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)
Noradinazolam	U 42.352	8‐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)
Triazolam	U 33.030	8‐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
Devazepide	L 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 52.322	EGIS 6775	1‐(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
Tifluadom	KC 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 941	2‐bromo‐4‐(o‐chlorophenyl)‐9‐methyl‐6H‐thieno [3, 2‐f]‐s‐triazolo[4, 3‐a][1, 4]diazepine
Ciclotizolam	We 973‐BS	2‐bromo‐4‐(o‐chlorophenyl)‐9‐cyclohexyl‐6H‐thieno[3, 2‐f]‐s‐triazolo[4, 3‐a][1, 4]diazepine
Clotiazepam	Y 6047	5‐(o‐chlorophenyl)‐7‐ethyl‐1, 3‐dihydro‐1‐methyl‐2H‐thieno[2, 3‐e][1, 4]diazepin‐2‐one
Etizolam	AHR 3219 Y 7131	4‐(o‐chlorophenyl)‐2‐ethyl‐9‐methyl‐6H‐thieno [3, 2‐f]‐s‐triazolo[4, 3‐a][1, 4]diazepine
Lopirazepam	D 12524	7‐chloro‐5‐(o‐chlorophenyl)‐1, 2‐dihydro‐3‐hydroxy‐3H‐pyrido[3, 2‐ e][1, 4]diazepin‐2‐one
Premazepam	MDL 181	3, 7‐dihydro‐6, 7‐dimethyl‐5‐phenylpyrrolo[3, 4‐e][1, 4]diazepin‐2(1H)‐one
Razobazam	Hoe 175	4, 8‐dihydro‐3, 8‐dimethyl‐4‐phenylpyrazolo[3, 4‐b][1, 4]diazepine‐5, 7(1H, 6H)‐dione
Ripazepam	CI 683	1‐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
Thiadipone	CI 718 bentazepam QM 6008	1, 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
Zometapine	CI 781	7, 8‐dihydro‐1, 3‐dimethyl‐4‐phenyl‐6H‐pyrazolo[3, 4‐e][1, 4] diazepine

Table 1. The benzodiazepine family

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Table 2. Half lives of some benzodiazepines

Benzodiazepine	Half‐life
1. Long
Chlordiazepoxide	5‐30 hours
Clobazam	16‐60 hours
Clorazepate	1‐2 hours
Diazepam	20‐40 hours
Flurazepam	1‐2 hours
Ketazolam	~30 hours
Metaclazepam	7‐23 hours
Oxazolam	~30 hours
2. Medium/short
Alprazolam	10‐15 hours
Bromazepam	10‐20 hours
Brotizolam	4‐7 hours
Clotiazepam	3‐15 hours
Loprazolam	6‐8 hours
Lorazepam	8‐24 hours
Lormetazepam	8‐14 hours
Nitrazepam	15‐30 hours
Oxazepam	4‐15 hours
Temazepam	5‐14 hours
3. Extremely short
Midazolam	1‐7 hours
Triazolam	1.5‐5 hours

Table 2. Half lives of some benzodiazepines

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Table 3. Reviews focusing on similar participant groups

Focus of review	Reference
Aripiprazole for psychosis‐induced agitation/aggression	Pagadala 2009
Benzodiazepines for schizophrenia	Volz 2007
Containment strategies for people with serious mental illness	Muralidharan 2006
Chlorpromazine for psychosis‐induced agitation/aggression	Ahmed 2010
Haloperidol (rapid tranquillisation) for psychosis‐induced agitation/aggression	Powney 2011
Haloperidol for long‐term aggression in psychosis	Khushu 2012
Haloperidol plus promethazine for psychosis‐induced agitation/aggression	Huf 2009
Loxapine for schizophrenia	Chakrabarti 2007
Loxapine inhaler for psychosis‐induced aggression or agitation	Vangala 2012
Olanzapine IM or velotab for acutely disturbed/agitated people with suspected serious mental illnesses	Belgamwar 2005
Quetiapine for psychosis‐induced aggression or agitation	Wilkie 2012
Risperidone for psychosis‐induced agitation/aggression	Ahmed 2011
Seclusion and restraint for people with serious mental illnesses	Sailas 2000
Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnesses	Gibson 2012

Table 3. Reviews focusing on similar participant groups

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Table 4. High and low attrition studies

Attrition	Study	% loss	Duration	Notes
High	Alprazolam 1992, USA	31	72 hours	‐
	Clonazepam 1993, CA	12	2 hours	‐
	Midazolam 2006, AU	10	100 minutes	‐
	Diazepam 1979, IL	50	24 hours	‐
	Lorazepam 1991, USA	33	48 hours	33% participants lost to follow‐up for EPS outcome and 12% loss for 'sedation'
	Lorazepam 2006, USA	10	90 minutes	‐
Low	Lorazepam 1998, USA	0	7 days	‐
	Flunitrazepam 1999, IL	0	2 hours	‐
	Lorazepam 2001, RO and USA	4	24 hours	‐
	Lorazepam 1998, SA	0	7 days	‐
	Midazolam 2003, BZ	1	2 weeks	‐
	Lorazepam 2004, IN	0.5	4 hours	‐
	Clonazepam 1999, CHN	0	24 hours	‐
	Clonazepam 2007a, CHN	0	24 hours	‐
	Lorazepam 1989, USA	0	60 minutes	‐
	Lorazepam 1997a, USA	0	24 hours	‐
	Lorazepam 1997b, USA	0	4 hours	‐
	Midazolam 2011, BZ	0	12 hours	‐
Unclear	Lorazepam 2009, SK	Unclear	120 minutes	Only abstract available.
Unclear	Lorazepam 2010, IN	Unclear	24 hours	Only abstract available.
Trials were considered to have a high attrition rates if it was more than 5% within the first two hours or 25% to 50% overall. EPS: extrapyramidal symptoms.

Table 4. High and low attrition studies

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Comparison 1. Benzodiazepines versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Tranquillisation or asleep: 1. sedation Show forest plot	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.42, 6.61]

1.1.1 medium term	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.42, 6.61]
1.2 Behaviour: 1. mean change score (Agitated Behaviour Scale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.2.1 medium term	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.3 Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC)) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.3.1 short term	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.69, 1.16]
1.3.2 medium term	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.40, 0.97]
1.4 Global state: 2. need for additional medication Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.4.1 medium term	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.5 Global state: 3. mean change score (Clinical Global Impression Severity Scale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.5.1 medium term	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.6 Mental state: 1. mean change score (Positive and Negative Syndrome Scale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.6.1 medium term	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.7 Mental state: 2. mean change score (PANSS‐EC, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.7.1 medium term	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.8 Adverse effects/events: 1. extrapyramidal symptoms (EPS) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.8.1 medium term	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.9 Adverse effects/events: 2. use of medication for EPS Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.9.1 medium term	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.10 Adverse effects/events: 3. specific Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.10.1 dizziness ‐ medium term	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.10.2 nausea ‐ medium term	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.10.3 vomiting ‐ medium term	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.11 Leaving the study early: 1. any reason Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.11.1 medium term	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 1. Benzodiazepines versus placebo

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Comparison 2. Benzodiazepines versus antipsychotics

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Tranquillisation or asleep: 1. sedation Show forest plot	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1.1 vs droperidol ‐ short term	1	153	Risk Ratio (M‐H, Fixed, 95% CI)	2.71 [1.55, 4.73]
2.1.2 vs haloperidol ‐ short term	1	44	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.53, 2.59]
2.1.3 vs haloperidol ‐ medium term	8	434	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.83, 1.54]
2.1.4 vs olanzapine ‐ medium term	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.28, 1.98]
2.2 Behaviour: 2. mean change/endpoint score (Agitated Behaviour Scale, high = worse) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.2.1 vs haloperidol ‐ medium term	1	66	Mean Difference (IV, Fixed, 95% CI)	1.80 [‐2.39, 5.99]
2.2.2 vs olanzapine ‐ medium term	1	149	Mean Difference (IV, Fixed, 95% CI)	2.91 [0.80, 5.02]
2.3 Behaviour: 4. mean change score (Overt Aggression Scale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.3.1 vs haloperidol ‐ medium term	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.4 Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC)) Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.4.1 vs olanzapine ‐ short term	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.95, 1.66]
2.4.2 vs olanzapine ‐ medium term	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	1.84 [1.06, 3.18]
2.4.3 vs haloperidol ‐ medium term	5	188	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.71, 1.11]
2.5 Global state: 2. need for additional medication Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.5.1 vs droperidol ‐ short term	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.5.2 vs haloperidol ‐ medium term	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.5.3 vs olanzapine ‐ medium term	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.6 Global state: 3. mean change/endpoint score (Clinical Global Impression Severity Scale, high = worse) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.6.1 vs haloperidol ‐ short term	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.6.2 vs haloperidol ‐ medium term	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.6.3 vs haloperidol ‐ medium term	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.6.4 vs olanzapine ‐ medium term	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.7 Global state: 4. mean endpoint score (Inpatient Multidimensional Psychiatric Scale, high = worse) Show forest plot	1	16	Mean Difference (IV, Fixed, 95% CI)	2.60 [‐3.04, 8.24]

2.7.1 vs haloperidol ‐ medium term	1	16	Mean Difference (IV, Fixed, 95% CI)	2.60 [‐3.04, 8.24]
2.8 Mental state: 1. no improvement (decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%) Show forest plot	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.73, 1.18]

2.8.1 vs haloperidol ‐ medium term	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.73, 1.18]
2.9 Mental state: 2. mean change/endpoint score (BPRS, high = worse) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.9.1 vs haloperidol ‐ short term	1	37	Mean Difference (IV, Fixed, 95% CI)	‐3.26 [‐10.65, 4.13]
2.9.2 vs haloperidol ‐ medium term	3	123	Mean Difference (IV, Fixed, 95% CI)	1.67 [‐1.84, 5.18]
2.10 Mental state: 3. mean endpoint score (BPRS psychosis subscale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.10.1 vs haloperidol ‐ medium term	1	66	Mean Difference (IV, Fixed, 95% CI)	0.70 [‐7.20, 8.60]
2.11 Mental state: 3a. mean endpoint score (BPRS positive subscale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.11.1 vs haloperidol ‐ medium term	1	30	Mean Difference (IV, Fixed, 95% CI)	0.80 [‐1.83, 3.43]
2.12 Mental state: 4a. mean endpoint score (BPRS‐excited component, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.12.1 vs haloperidol ‐ medium term	1	30	Mean Difference (IV, Fixed, 95% CI)	1.27 [‐0.49, 3.03]
2.13 Mental state: 2a. mean change score (Positive and Negative Syndrome Scale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.13.1 vs olanzapine ‐ medium term	1	146	Mean Difference (IV, Fixed, 95% CI)	5.64 [2.20, 9.08]
2.14 Mental state: 4. mean change score (PANSS‐EC, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.14.1 vs olanzapine ‐ medium term	1	149	Mean Difference (IV, Fixed, 95% CI)	2.85 [1.14, 4.56]
2.15 Adverse effects/events: 1. extrapyramidal symptoms (EPS) Show forest plot	8	536	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.06, 0.39]

2.15.1 vs haloperidol ‐ medium term	6	233	Risk Ratio (M‐H, Fixed, 95% CI)	0.13 [0.04, 0.41]
2.15.2 vs olanzapine ‐ medium term	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.03, 1.89]
2.15.3 vs droperidol ‐ medium term	1	153	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.90]
2.16 Adverse effects/events: 2. use of medication for EPS Show forest plot	2	216	Risk Ratio (M‐H, Fixed, 95% CI)	0.40 [0.15, 1.05]

2.16.1 vs haloperidol ‐ medium term	1	66	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.17, 1.47]
2.16.2 vs olanzapine ‐ medium term	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.03, 1.89]
2.17 Adverse effects/events: 3. specific Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.17.1 vs haloperidol ‐ akathisia ‐ medium term	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.58]
2.17.2 vs droperidol ‐ airway management ‐ medium term	1	153	Risk Ratio (M‐H, Fixed, 95% CI)	7.47 [0.39, 142.14]
2.17.3 vs haloperidol ‐ ataxia ‐ medium term	1	66	Risk Ratio (M‐H, Fixed, 95% CI)	2.26 [0.22, 23.71]
2.17.4 vs droperidol ‐ low blood pressure ‐ medium term	1	153	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.33, 6.15]
2.17.5 vs haloperidol ‐ dizziness ‐ medium term	1	66	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.25, 5.19]
2.17.6 vs olanzapine ‐ dizziness ‐ medium term	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	1.51 [0.60, 3.82]
2.17.7 vs haloperidol ‐ drowsiness ‐ medium term	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.07, 14.55]
2.17.8 vs haloperidol ‐ dry mouth ‐ medium term	1	66	Risk Ratio (M‐H, Fixed, 95% CI)	1.88 [0.49, 7.24]
2.17.9 vs droperidol ‐ low heart rate ‐ medium term	1	153	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.01, 8.59]
2.17.10 vs haloperidol ‐ high heart rate ‐ medium term	1	46	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.01, 4.29]
2.17.11 vs droperidol ‐ hypoxia ‐ medium term	1	153	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.33, 6.15]
2.17.12 vs olanzapine ‐ nausea ‐ medium term	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	7.76 [0.89, 67.67]
2.17.13 vs droperidol ‐ seizure ‐ medium term	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.17.14 vs haloperidol ‐ speech disorder ‐ medium term	1	66	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.11, 2.87]
2.17.15 vs haloperidol ‐ tremor ‐ medium term	1	46	Risk Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 1.69]
2.17.16 vs droperidol ‐ vomiting ‐ medium term	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.17.17 vs olanzapine ‐ vomiting ‐ medium term	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	13.46 [0.71, 255.70]
2.18 Leaving the study early: 1. any reason Show forest plot	3	339	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.70, 3.13]

2.18.1 vs droperidol ‐ medium term	1	173	Risk Ratio (M‐H, Fixed, 95% CI)	1.51 [0.60, 3.79]
2.18.2 vs haloperidol ‐ medium term	1	16	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 3.61]
2.18.3 vs olanzapine ‐ medium term	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	5.82 [0.62, 54.58]

Comparison 2. Benzodiazepines versus antipsychotics

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Comparison 3. Benzodiazepines versus antipsychotics plus antihistamines

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Tranquilisation or asleep: 1. sedation Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1.1 vs haloperidol + promethazine ‐ immediate term	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.77, 0.99]
3.1.2 vs haloperidol + promethazine ‐ short term	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.77, 0.95]
3.1.3 vs haloperidol + promethazine ‐ medium term	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.84, 0.98]
3.1.4 vs haloperidol + promethazine ‐ short term	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [1.16, 1.49]
3.1.5 vs haloperidol + promethazine ‐ medium term	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [1.04, 1.23]
3.2 Global state: 1. no improvement (Clinical Global Impression (CGI) ‐ improvement scale dichotomised; much and very much improved) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.2.1 vs haloperidol + promethazine ‐ immediate term	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.79 [1.36, 2.37]
3.2.2 vs haloperidol + promethazine ‐ short term	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	2.47 [1.51, 4.03]
3.2.3 vs haloperidol + promethazine ‐ medium term	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	2.17 [1.16, 4.05]
3.3 Global state: 2. need for additional medication Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.3.1 vs haloperidol + promethazine ‐ immediate term	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3.2 vs haloperidol + promethazine ‐ short term	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.12, 72.77]
3.3.3 vs haloperidol + promethazine ‐ medium term	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.31, 5.81]
3.4 Global state: 3. mean endpoint score (CGI, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

3.4.1 vs haloperidol + promethazine ‐ immediate term	1	200	Mean Difference (IV, Fixed, 95% CI)	0.49 [0.23, 0.75]
3.4.2 vs haloperidol + promethazine ‐ short term	1	200	Mean Difference (IV, Fixed, 95% CI)	0.60 [0.34, 0.86]
3.4.3 vs haloperidol + promethazine ‐ medium term	1	200	Mean Difference (IV, Fixed, 95% CI)	0.23 [‐0.05, 0.51]
3.5 Adverse effects/events: 1. specific Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.5.1 vs haloperidol + promethazine ‐ airway management ‐ medium term	2	501	Risk Ratio (M‐H, Fixed, 95% CI)	2.99 [0.31, 28.54]
3.5.2 vs haloperidol + promethazine ‐ nausea ‐ medium term	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.12, 72.77]
3.5.3 vs haloperidol + promethazine ‐ seizure ‐ medium term	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.06]
3.6 Hospital and service outcomes: 1. changes in hospital status Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.6.1 vs haloperidol + promethazine ‐ not discharged ‐ medium term	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.86, 1.48]
3.7 Leaving the study early: 1. any reason Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.7.1 vs haloperidol + promethazine ‐ medium term	2	501	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.06, 2.87]

Comparison 3. Benzodiazepines versus antipsychotics plus antihistamines

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Comparison 4. Benzodiazepines plus antipsychotics vs same benzodiazepines

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Tranquillisation or asleep: 1. sedation Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1.1 + haloperidol ‐ short term	1	47	Risk Ratio (M‐H, Fixed, 95% CI)	1.92 [1.10, 3.35]
4.1.2 + haloperidol ‐ medium term	2	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.59, 1.19]
4.2 Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.2.1 + haloperidol ‐ medium term	1	63	Mean Difference (IV, Fixed, 95% CI)	‐1.60 [‐5.94, 2.74]
4.3 Global state: 1. no improvement mean endpoint change in Clinical Global Impression score) Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.3.1 + haloperidol ‐ short term	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.01, 1.74]
4.3.2 + haloperidol ‐ medium term	3	113	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.76, 1.20]
4.3.3 + risperidone ‐ medium term	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.45, 1.64]
4.4 Global state: 2. need for additional medication Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.4.1 + haloperidol ‐ medium term	3	103	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.79, 1.32]
4.4.2 + risperidone ‐ medium term	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.5 Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.5.1 + haloperidol ‐ medium term	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.76, 1.32]
4.6 Mental state: 2a. mean endpoint score (BPRS, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.6.1 + risperidone ‐ short term	1	20	Mean Difference (IV, Fixed, 95% CI)	1.10 [‐23.17, 25.37]
4.6.2 + risperidone ‐ medium term	1	20	Mean Difference (IV, Fixed, 95% CI)	‐1.70 [‐24.26, 20.86]
4.7 Mental state: 2b. mean endpoint score (BPRS, high = worse, skew) Show forest plot	1		Other data	No numeric data

4.7.1 + haloperidol ‐ short term	1		Other data	No numeric data
4.7.2 + haloperidol ‐ medium term	1		Other data	No numeric data
4.8 Mental state: 2c. mean endpoint score (Positive and Negative Syndrome Scale (PANSS), high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.8.1 + risperidone ‐ short term	1	20	Mean Difference (IV, Fixed, 95% CI)	6.40 [‐36.50, 49.30]
4.8.2 + risperidone ‐ medium term	1	20	Mean Difference (IV, Fixed, 95% CI)	3.20 [‐29.41, 35.81]
4.9 Mental state: 2d. mean endpoint score (PANSS, high = worse, skew) Show forest plot	1		Other data	No numeric data

4.9.1 + haloperidol ‐ short term	1		Other data	No numeric data
4.9.2 + haloperidol ‐ medium term	1		Other data	No numeric data
4.10 Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.10.1 + haloperidol ‐ medium term	1	63	Mean Difference (IV, Fixed, 95% CI)	1.20 [‐6.28, 8.68]
4.11 Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.11.1 vs haloperidol ‐ medium term	1	30	Mean Difference (IV, Fixed, 95% CI)	0.06 [‐2.73, 2.85]
4.12 Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.12.1 vs haloperidol ‐ medium term	1	30	Mean Difference (IV, Fixed, 95% CI)	‐0.80 [‐2.41, 0.81]
4.13 Adverse effects/events: 1. extrapyramidal symptoms (EPS) Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.13.1 + haloperidol ‐ medium term	2	83	Risk Ratio (M‐H, Fixed, 95% CI)	1.94 [0.18, 20.30]
4.14 Adverse effects/events: 2. use of medication for EPS Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.14.1 + haloperidol ‐ medium term	1	63	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.18, 2.99]
4.15 Adverse effects/events: 3. specific Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.15.1 + haloperidol ‐ akathisia ‐ medium term	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.15.2 + haloperidol ‐ ataxia ‐ medium term	1	63	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [0.26, 8.11]
4.15.3 + haloperidol ‐ dizziness ‐ medium term	1	63	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.12, 3.61]
4.15.4 + haloperidol ‐ drowsiness ‐ medium term	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.07, 14.55]
4.15.5 + haloperidol ‐ dry mouth ‐ medium term	1	63	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.15, 2.23]
4.15.6 + haloperidol ‐ speech disorder ‐ medium term	1	63	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [0.26, 8.11]
4.16 Leaving the study early: 1. any reason Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.16.1 + haloperidol ‐ medium term	2	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.34, 1.50]
4.16.2 + risperidone ‐ medium term	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.45, 1.64]

Comparison 4. Benzodiazepines plus antipsychotics vs same benzodiazepines

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Comparison 5. Benzodiazepines plus antipsychotics versus same antipsychotics

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Tranquillisation or asleep: 1. sedation Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1.1 +/vs haloperidol ‐ short term	1	45	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [1.18, 4.30]
5.1.2 +/vs haloperidol ‐ medium term	3	172	Risk Ratio (M‐H, Fixed, 95% CI)	1.75 [1.14, 2.67]
5.2 Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.2.1 +/vs haloperidol ‐ medium term	1	67	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐5.05, 4.65]
5.3 Behaviour: 2. mean endpoint score (Overt Aggression Scale (OAS), high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.3.1 +/vs haloperidol ‐ short term	1	60	Mean Difference (IV, Fixed, 95% CI)	1.20 [‐0.04, 2.44]
5.3.2 +/vs haloperidol ‐ medium term	1	60	Mean Difference (IV, Fixed, 95% CI)	2.40 [0.59, 4.21]
5.4 Behaviour: 3. mean endpoint score (Overt Agitation Severity Scale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.4.1 +/vs haloperidol ‐ short term	1	60	Mean Difference (IV, Fixed, 95% CI)	8.50 [7.07, 9.93]
5.4.2 +/vs haloperidol ‐ medium term	1	60	Mean Difference (IV, Fixed, 95% CI)	6.70 [5.94, 7.46]
5.5 Global state: 1. no improvement Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.5.1 +/vs haloperidol ‐ medium term	4	185	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.93, 1.46]
5.6 Global state: 2. need for additional medication Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.6.1 +/vs haloperidol ‐ medium term	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.79, 1.15]
5.7 Global state: 3. need for additional medication (mean dose, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.7.1 +/vs haloperidol ‐ medium term	1	60	Mean Difference (IV, Fixed, 95% CI)	0.20 [‐0.33, 0.73]
5.8 Global state: 4. mean change score (Ramsey Sedation Scale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.8.1 +/vs haloperidol ‐ short term	1	60	Mean Difference (IV, Fixed, 95% CI)	0.50 [‐0.01, 1.01]
5.8.2 +/vs haloperidol ‐ medium term	1	60	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.36, 0.56]
5.9 Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.9.1 +/vs haloperidol ‐ medium term	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.73, 1.18]
5.10 Mental state: 2. mean endpoint score (BPRS, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.10.1 +/vs haloperidol ‐ medium term	1	28	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐7.26, 7.28]
5.11 Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.11.1 +/vs haloperidol ‐ medium term	2	95	Mean Difference (IV, Fixed, 95% CI)	‐1.19 [‐4.60, 2.23]
5.12 Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.12.1 vs haloperidol ‐ medium term	1	30	Mean Difference (IV, Fixed, 95% CI)	0.86 [‐1.62, 3.34]
5.13 Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.13.1 vs hoperidol ‐ medium term	1	30	Mean Difference (IV, Fixed, 95% CI)	0.47 [‐1.32, 2.26]
5.14 Adverse effects/events: 1. extrapyramidal symptoms (EPS) Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.14.1 +/vs haloperidol ‐ medium term	2	127	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.16, 1.17]
5.15 Adverse effects/events: 2. use of medication for EPS Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.15.1 +/vs haloperidol ‐ medium term	2	95	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.27, 1.01]
5.16 Adverse effects/events: 3. specific Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.16.1 +/vs haloperidol ‐ akathisia ‐ medium term	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.58]
5.16.2 +/vs haloperidol ‐ ataxia ‐ medium term	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	3.28 [0.36, 29.97]
5.16.3 +/vs haloperidol ‐ dizziness ‐ medium term	2	92	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.12, 2.32]
5.16.4 +/vs haloperidol ‐ drowsiness ‐ medium term	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.07, 14.55]
5.16.5 +/vs haloperidol ‐ dry mouth ‐ medium term	2	92	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.32, 4.92]
5.16.6 +/vs haloperidol ‐ hypotension ‐ medium term	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	11.00 [0.64, 190.53]
5.16.7 +/vs haloperidol ‐ speech disorder ‐ medium term	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.20, 3.39]
5.17 Hospital and service outcomes: 1. changes in hospital status Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.17.1 +/vs haloperidol ‐ not discharged ‐ medium term	1	28	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.54, 1.50]

Comparison 5. Benzodiazepines plus antipsychotics versus same antipsychotics

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Comparison 6. Benzodiazepines + antipsychotics versus antipsychotics plus antipsychotics

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Behaviour: 3. mean endpoint score (Overt Aggression Scale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1.1 + haloperidol vs clothiapine + haloperidol ‐ medium term	1	60	Mean Difference (IV, Fixed, 95% CI)	‐5.83 [‐27.60, 15.94]
6.2 Leaving the study early: 1. any reason Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.2.1 + haloperidol vs clothiapine + haloperidol ‐ medium term	1	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

Comparison 6. Benzodiazepines + antipsychotics versus antipsychotics plus antipsychotics

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Comparison 7. Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Tranquilisation or asleep: 1. sedation Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1.1 + haloperidol vs haloperidol + promethazine ‐ medium term	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	12.00 [1.66, 86.59]
7.2 Behaviour: 1. mean endpoint score (Overt Aggression Scale (OAS), high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

7.2.1 + haloperidol vs haloperidol + promethazine ‐ short term	1	60	Mean Difference (IV, Fixed, 95% CI)	‐3.30 [‐5.25, ‐1.35]
7.2.2 + haloperidol vs haloperidol + promethazine ‐ medium term	1	60	Mean Difference (IV, Fixed, 95% CI)	1.70 [‐0.06, 3.46]
7.3 Behaviour: 2. mean endpoint score (Overt Agitation Severity Scale (OASS) agitation scale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

7.3.1 + haloperidol vs haloperidol + promethazine ‐ short term	1	60	Mean Difference (IV, Fixed, 95% CI)	‐16.00 [‐18.98, ‐13.02]
7.3.2 + haloperidol vs haloperidol + promethazine ‐ medium term	1	60	Mean Difference (IV, Fixed, 95% CI)	‐2.70 [‐3.73, ‐1.67]
7.4 Global state: 1. no improvement (number of participants with < 10 points on the OAS and OASS after 12 hours) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.4.1 + haloperidol vs haloperidol + promethazine ‐ medium term	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	25.00 [1.55, 403.99]
7.5 Global state: 2. need for additional medication (mean dose, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

7.5.1 + haloperidol vs haloperidol + promethazine ‐ medium term	1	60	Mean Difference (IV, Fixed, 95% CI)	0.63 [0.15, 1.11]
7.6 Global state: 3. mean change score (Ramsey Sedation Scale, high = worse) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

7.6.1 + haloperidol vs haloperidol + promethazine ‐ short term	1	60	Mean Difference (IV, Fixed, 95% CI)	0.60 [0.07, 1.13]
7.6.2 + haloperidol vs haloperidol + promethazine ‐ medium term	1	60	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.46, 0.46]
7.7 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.7.1 + haloperidol vs haloperidol + promethazine ‐ medium term	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.16, 2.29]
7.8 Adverse effects/events: 2. specific Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.8.1 + haloperidol vs haloperidol + promethazine ‐ hypotension ‐ medium term	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.44, 6.36]

Comparison 7. Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines

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Comparison 8. Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Tranquilisation or asleep: 1. sedation Show forest plot	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.1.1 unclear risk of bias	6	340	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.56, 1.26]
8.1.2 low risk of bias	3	247	Risk Ratio (M‐H, Fixed, 95% CI)	2.22 [1.52, 3.25]
8.2 Global state: 1. no improvement Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.2.1 unclear risk of bias	3	214	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.78, 1.63]
8.2.2 low risk of bias	3	124	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.80, 1.28]
8.3 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.3.1 unclear risk of bias	5	285	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.05, 0.47]
8.3.2 low risk of bias	3	247	Risk Ratio (M‐H, Fixed, 95% CI)	0.16 [0.03, 0.85]

Comparison 8. Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation

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Comparison 9. Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Tranquilisation or asleep: 1. sedation Show forest plot	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1.1 unclear risk of bias	8	434	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.79, 1.48]
9.1.2 low risk of bias	1	153	Risk Ratio (M‐H, Fixed, 95% CI)	2.71 [1.55, 4.73]
9.2 Global state: 1. no improvement Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.2.1 unclear risk of bias	6	338	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.86, 1.32]
9.3 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.3.1 unclear risk of bias	7	379	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.06, 0.41]
9.3.2 low risk of bias	1	153	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.90]

Comparison 9. Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment

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Comparison 10. Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Tranquilisation or asleep: 1. sedation Show forest plot	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.1.1 high risk of bias	1	44	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.56, 2.34]
10.1.2 unclear risk of bias	6	424	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [0.93, 1.94]
10.1.3 low risk of bias	2	119	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [1.05, 2.64]
10.2 Global state: 1. no improvement Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.2.1 unclear risk of bias	4	224	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.88, 1.59]
10.2.2 low risk of bias	2	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.60, 1.07]
10.3 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.3.1 unclear risk of bias	6	426	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.05, 0.68]
10.3.2 low risk of bias	2	106	Risk Ratio (M‐H, Fixed, 95% CI)	0.12 [0.03, 0.48]

Comparison 10. Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement

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Comparison 11. Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Tranquilisation or asleep: 1. sedation Show forest plot	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

11.1.1 high risk of bias	2	193	Risk Ratio (M‐H, Fixed, 95% CI)	1.78 [1.15, 2.75]
11.1.2 unclear risk of bias	3	134	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.62, 1.83]
11.1.3 low risk of bias	4	260	Risk Ratio (M‐H, Fixed, 95% CI)	1.30 [0.83, 2.03]
11.2 Global state: 1. no improvement Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

11.2.1 unclear risk of bias	1	48	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.32, 0.97]
11.2.2 low risk of bias	5	290	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.98, 1.56]
11.3 Adverse effects/events: 1. extrapyramidal symptoms Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

11.3.1 high risk of bias	1	153	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.90]
11.3.2 unclear risk of bias	2	77	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.01, 0.65]
11.3.3 low risk of bias	5	302	Risk Ratio (M‐H, Fixed, 95% CI)	0.18 [0.06, 0.60]

Comparison 11. Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias)

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