Haloperidol plus promethazine for psychosis‐induced aggression

Gisele Huf; Jacob Alexander; Pinky Gandhi; Michael H Allen

doi:10.1002/14651858.CD005146.pub3

Haloperidol más prometazina para la agresión inducida por psicosis

Appendices

Appendix 1. Previous searches

2.1 Search in 2004

We searched the Cochrane Schizophrenia Group's Register (July 2004) using the phrase'*Promethaz* in title, abstract or indexing terms of REFERENCE or *Promethaz* in interventions of STUDY

2.2 Search in 2008

We searched the Cochrane Schizophrenia Group's Register (January 2008) using the phrase

'*Promethaz* in title, abstract or indexing terms of REFERENCE or *Promethaz* in interventions of STUDY

Appendix 2. Methods ‐ as used in the 2009 version

1. Study selection
We (GH and JA) independently inspected the citations identified from the search. We identified potentially relevant abstracts and ordered full papers for reassessment for inclusion and methodological quality. We discussed and reported any disagreements and contacted study authors for further clarification where necessary.

2. Assessment of quality
Again working independently, we allocated trials to three quality categories, as described in the Cochrane Collaboration Handbook (Higgins 2005). Concealment of allocation remains the key aspect of methodology that predicts how susceptible results are to the inclusion of biases. Although adherence to blinding at outcome is also important, it is the ability of everyone involved to predict who will receive the next intervention that most substantially influences results. Category A studies in this review, where good concealment of allocation was made explicit, employed techniques that ensured that researchers and recipients could not have known the next intervention to be used. We considered these studies at low risk of bias. Any plausible biases were felt to be unlikely to seriously affect results. Category B studies assured the reader that studies were randomised but they did not make concealment of allocation explicit. We would have included these studies but these would have been at moderate risk of bias with some doubts about the results. We did not include Category C studies, where the process of allocation is neither described nor implied. These studies are at high risk of bias and the plausible bias seriously weakens confidence in the results.

If disputes had arisen as to which category a trial was to be allocated, again, resolution was to have been attempted by discussion. We included only trials in Category A or B in the review. Other dimensions of quality were not reasons for exclusion.

3. Data management
3.1 Data extraction
We (GH, JA) independently extracted data from included studies. Again, any disagreement was discussed, decisions documented and, if necessary, we contacted the authors of the studies for clarification. We documented justifications for excluding references from the review.

3.2 Intention to treat assumptions
For studies that did not specify the reasons for people leaving the study early, we assumed that these people had no change in clinical outcome variables. We excluded data from outcomes where attrition was greater than 50%.

5. Data analysis
5.1 Binary data
For binary outcomes we calculated a standard estimation of the fixed‐effect risk ratio (RR) and its 95% confidence interval (CI). Where binary results were statistically significant we calculated the number needed to treat/harm statistic (NNT/H), and its 95% confidence interval (CI) using Visual Rx (http://www.nntonline.net/) which takes account of the event rate in the control group.

5.2 Continuous data
5.2.1 Skewed data: continuous data on clinical and social outcomes are often not normally distributed. To avoid the pitfall of applying parametric tests to non‐parametric data, we applied the following standards to all data before inclusion: (a) standard deviations and means were reported in the paper or were obtainable from the authors; (b) when a scale started from the finite number zero, the standard deviation, when multiplied by two, was less than the mean (as otherwise the mean is unlikely to be an appropriate measure of the centre of the distribution, (Altman 1996); (c) if a scale started from a positive value (such as PANSS which can have values from 30 to 210) the calculation described above was modified to take the scale starting point into account. In these cases skew is present if 2SD>(S‐Smin), where S is the mean score and Smin is the minimum score. Endpoint scores on scales often have a finite start and end point and these rules can be applied. When continuous data are presented on a scale which includes a possibility of negative values (such as change data), it is difficult to tell whether data are skewed or not. Skewed data from studies of less than 200 participants would have been entered in additional tables rather than into an analysis. Skewed data pose less of a problem when looking at means if the sample size is large and would have been entered into a synthesis.

5.2.2 Summary statistic: for continuous outcomes we estimated a fixed‐effect weighted mean difference (WMD) between groups.

5.2.3 Valid scales: we included continuous data from rating scales only if the measuring instrument had been described in a peer‐reviewed journal (Marshall 2000) and the instrument was either a self‐report or completed by an independent rater or relative (not the therapist).

5.2.4 Endpoint versus change data: we find it preferable to use scale endpoint data, which typically cannot have negative values and is easier to interpret from a clinical point of view. Change data are often not ordinal and are very problematic to interpret. If endpoint data had not been available, we would have used change data.

5.2.5 Cluster trials: studies increasingly employ 'cluster randomisation' (such as randomisation by clinician or practice) but analysis and pooling of clustered data poses problems. Firstly, authors often fail to account for intraclass correlation in clustered studies, leading to a 'unit of analysis' error (Divine 1992) whereby p values are spuriously low, confidence intervals unduly narrow and statistical significance overestimated. This causes type I errors (Bland 1997, Gulliford 1999).

Where clustering was not accounted for in primary studies, we presented the data in a table, with a (*) symbol to indicate the presence of a probable unit of analysis error. In subsequent versions of this review we will seek to contact first authors of studies to obtain intraclass correlation coefficients of their clustered data and to adjust for this by using accepted methods (Gulliford 1999). Where clustering has been incorporated into the analysis of primary studies, we will also present these data as if from a non‐cluster randomised study, but adjusted for the clustering effect.

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

If cluster studies had been appropriately analysed taking into account intraclass correlation coefficients and relevant data documented in the report, synthesis with other studies would have been possible using the generic inverse variance technique.

6. Test for heterogeneity
Firstly, we considered all the included studies within any comparison to judge clinical heterogeneity. Then we visually inspected graphs to investigate the possibility of statistical heterogeneity. This was supplemented, primarily, by employing the I‐squared statistic. This provides an estimate of the percentage of inconsistency thought to be due to chance. Where the I‐squared estimate was greater than or equal to 75%, this was interpreted as evidence of high levels of heterogeneity (Higgins 2003). Data were then re‐analysed using a random‐effects model to see if this made a substantial difference. If it did, and results became more consistent, i.e. falling below 75% in the estimate, the studies were added to the main body of trials. If using the random‐effects model did not make a difference and inconsistency remained high, data were not summated, but were presented separately and reasons for heterogeneity investigated.

7. Addressing small study bias
We were to have entered data from all included studies into a funnel graph (trial effect against trial size) in an attempt to investigate the likelihood of overt publication bias (Egger 1997).

8. Sensitivity analyses
If necessary, we analysed the effect of including studies with high attrition rates in a sensitivity analysis. We also included trials in a sensitivity analysis if they were described as 'double blind' but only implied randomisation. If we found no substantive differences within primary outcomes when these high attrition and 'implied randomisation' studies were added to the overall results, we included them in the final analysis. However, if there was a substantive difference we only used clearly randomised trials, and those with attrition lower than 50%.

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

Figure 1

Haloperidol structure.

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Figure 2

Promethazine structure.

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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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Figure 5

Study flow diagram 2015 update.

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Analysis 1.1

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 1 Tranquil or asleep: 1. Not tranquil or asleep.

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Analysis 1.2

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 2 Tranquil or asleep: 2. Not asleep.

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Analysis 1.3

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 3 Tranquil or asleep: 3. Time until tranquil or asleep (RSS, high score=good).

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Analysis 1.4

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 4 Global state: 1. Needing restraints or seclusion.

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Analysis 1.5

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 5 Global state: 2. Various measures.

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Study	Intervention	Mean	SD	Total
Baldacara 2011	Haloperidol + Promethazine	1.10	1.03	30
Baldacara 2011	Haloperidol	1.53	1.19	30

Analysis 1.6

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 6 Global state: 3. Average value of additional medication ‐ after initial dose (skewed data).

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Analysis 1.7

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 7 Adverse effects: 1. General ‐ Any serious adverse effect.

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Analysis 1.8

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 8 Adverse effects: 2. Specific ‐ a. Cardiovascular ‐ hypotension.

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Analysis 1.9

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 9 Adverse effects: 2. Specific ‐ b. Central Nervous System.

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Analysis 1.10

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 10 Adverse effects: 2. Specific ‐ c. Extrapyramidal problems.

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Analysis 1.11

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 11 Service outcomes: Not discharged ‐ by 2 weeks.

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Analysis 1.12

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 12 Specific behaviour: 1. Aggression ‐ a. Other episode of agression.

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Analysis 1.13

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 13 Specific behaviour: 1. Aggression ‐ b. Average aggression score (OAS ,high score=bad).

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Analysis 1.14

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 14 Specific behaviour: 1. Aggression ‐ c. Average agitation score (OASS, high score=bad).

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Analysis 1.15

Comparison 1 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL, Outcome 15 Leaving the study early.

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Analysis 2.1

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 1 Tranquil or asleep: 1. Not tranquil or asleep.

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Analysis 2.2

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 2 Tranquil or asleep: 2. Not asleep.

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Analysis 2.3

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 3 Tranquil or asleep: 3. Never tranquil or asleep during first 4 hours.

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Analysis 2.4

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 4 Tranquil or asleep: 4. Average sedation score (RSS, high score=good).

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Study	Intervention	Mean (mins)	SD	N	Statistical test	p
time until tranquil or asleep
TREC‐Vellore‐II	Haloperidol + Promethazine	12.8	16.7	150	Mann‐Whitney U	0.4
TREC‐Vellore‐II	Olanzapine	20.5	34.5	150
time until asleep
TREC‐Vellore‐II	Haloperidol + Promethazine	26.2	32.2	150	Mann‐Whitney U	0.2
TREC‐Vellore‐II	Olanzapine	34.9	42.2	150

Analysis 2.5

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 5 Tranquil or asleep: 5. Time (skewed data).

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Study	Intervention	Mean	SD	N
at 30 minutes
Mantovani 2013	Haloperidol + Promethazine	10.9	6.7	27
Mantovani 2013	Olanzapine	10.1	6.4	25
at 60 minutes
Mantovani 2013	Haloperidol + Promethazine	11.1	7.6	27
Mantovani 2013	Olanzapine	8	3.8	25
at 90 minutes
Mantovani 2013	Haloperidol + Promethazine	10.7	6.7	27
Mantovani 2013	Olanzapine	9.2	5.3	25

Analysis 2.6

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 6 Tranquil or asleep: 6. Effect of tranquillisation (PANSS‐EC, high=bad) (skewed data).

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Study	Intervention	Mean	SD	Nl
at 30 minutes
Mantovani 2013	Haloperidol + Promethazine	5.2	8.1	27
Mantovani 2013	Olanzapine	5.5	7.5	25
at 90 minutes
Mantovani 2013	Haloperidol + Promethazine	5.0	10.8	27
Mantovani 2013	Olanzapine	5.8	10	25

Analysis 2.7

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 7 Tranquil or asleep: 7. Level of tranquillisation / agitation (ACES) (skewed data).

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Analysis 2.8

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 8 Global state: 1. No overall improvement.

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Analysis 2.9

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 9 Global state: 2. Needing restraints or seclusion.

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Analysis 2.10

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 10 Global state: 3. Various measures.

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Analysis 2.11

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 11 Global state: 4. Average improvement (CGI, high score=bad).

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Study	Intervention	Mean	SD	N
Baldacara 2011	Haloperidol + Promethazine	1.10	1.03	30
Baldacara 2011	Olanzapine	0.37	0.77	30

Analysis 2.12

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 12 Global state: 5. Average value of additional medication ‐ after initial dose (skewed data).

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Analysis 2.13

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 13 Adverse effects: 1. General ‐ Serious adverse effect.

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Analysis 2.14

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 14 Adverse effects: 2. Specific ‐ a. Cardiovascular ‐ hypotension.

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Analysis 2.15

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 15 Adverse effects: 2. Specific ‐ b. Central Nervous System ‐ sedation ‐ excessive.

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Analysis 2.16

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 16 Adverse effects: 2. Specific ‐ c. Extrapyramidal problems ‐ 0‐4 hours.

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Analysis 2.17

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 17 Specific behaviour: 1. Severe agitation.

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Analysis 2.18

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 18 Specific behaviour: 2. Average aggression score (OAS, high score=bad).

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Analysis 2.19

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 19 Specific behaviour: 3. Average agitation score (OASS, high score=bad).

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Analysis 2.20

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 20 Service outcomes.

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Analysis 2.21

Comparison 2 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE, Outcome 21 Leaving the study early.

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Analysis 3.1

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 1 Tranquil or asleep: 1. Average sedation score (RSS, high score=good).

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Study	Intervention	Mean	SD	N
at 30 minutes
Mantovani 2013	Haloperidol + Promethazine	10.9	6.7	27
Mantovani 2013	Ziprasidone	12.6	9.1	23
at 60 minutes
Mantovani 2013	Haloperidol + Promethazine	11.1	7.6	27
Mantovani 2013	Ziprasidone	10.5	8	23
at 90 minutes
Mantovani 2013	Haloperidol + Promethazine	10.7	9.2	27
Mantovani 2013	Ziprasidone	11.2	8.3	23

Analysis 3.2

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 2 Tranquil or asleep: 2. Effect of tranquilisation (PANSS‐EC, high=bad) (skewed data).

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Study	Intervention	Mean	SD	N
at 30 minutes
Mantovani 2013	Haloperidol + Promethazine	5.2	8.1	27
Mantovani 2013	Ziprasidone	4.8	4.6	23
at 90 minutes.
Mantovani 2013	Haloperidol + Promethazine	5.0	10.8	27
Mantovani 2013	Ziprasidone	5.1	6.9	23

Analysis 3.3

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 3 Tranquil or asleep: 3. Level of tranquilisation / agitation (ACES) (skewed data).

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Analysis 3.4

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 4 Global state: 1. Needing restraints or seclusion.

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Analysis 3.5

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 5 Global state: 2. Additional tranquillising drugs.

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Study	Intervention	Mean	SD	N
Baldacara 2011	Haloperidol + Promethazine	1.10	1.03	30
Baldacara 2011	Ziprasidone	0.77	0.98	30

Analysis 3.6

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 6 Global state: 3. Average value of additional medication ‐ after initial dose (skewed data).

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Analysis 3.7

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 7 Adverse effects: 1. Specific ‐ a. Cardiovascular ‐ hypotension.

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Analysis 3.8

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 8 Adverse effects: 1. Specific ‐ b. Central Nervous System ‐ excessive sedation.

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Analysis 3.9

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 9 Adverse effects: 1. Specific ‐ c. Extrapyramidal problems ‐ 0‐4 hours.

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Analysis 3.10

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 10 Specific behaviour: 1. Severe agitation.

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Analysis 3.11

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 11 Specific behaviour: 2. Average aggression score (OAS, high score=bad).

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Analysis 3.12

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 12 Specific behaviour: 3. Average agitation score (OASS, high score=bad).

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Analysis 3.13

Comparison 3 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE, Outcome 13 Leaving the study early.

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Analysis 4.1

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 1 Tranquil or asleep: 1. Average sedation score (RSS, high score=good).

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Study	Intervention	Mean	SD	N
at 30 minutes
Mantovani 2013	Haloperidol + Promethazine	10.9	6.7	27
Mantovani 2013	Haloperidol + Midazolam	8.7	4.1	25
at 60 minutes
Mantovani 2013	Haloperidol + Promethazine	11.1	7.6	27
Mantovani 2013	Haloperidol + Midazolam	8.8	6.1	25
at 90 minutes
Mantovani 2013	Haloperidol + Promethazine	10.7	9.2	27
Mantovani 2013	Haloperidol + Midazolam	9.4	9.4	25

Analysis 4.2

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 2 Tranquil or asleep: 2. Effect of tranquilisation (PANSS‐EC, high score=bad) (skewed data).

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Study	Intervention	Mean	SD	N
at 30 minutes
Mantovani 2013	Haloperidol + Promethazine	5.2	8.1	27
Mantovani 2013	Haloperidol + Midazolam	6	7.5	25
at 90 minutes
Mantovani 2013	Haloperidol + Promethazine	5.0	10.8	27
Mantovani 2013	Haloperidol + Midazolam	5.8	12.5	25

Analysis 4.3

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 3 Tranquil or asleep: 3. Level of tranquilisation / agitation (ACES) (skewed data).

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Analysis 4.4

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 4 Global state: 1. Needing restraints or seclusion.

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Analysis 4.5

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 5 Global state: 2. Additional tranquilising drugs.

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Study	Intervention	Mean	SD	N
Baldacara 2011	Haloperidol + Promethazine	1.10	1.03	30
Baldacara 2011	Haloperidol + Midazolam	1.73	0.87	30

Analysis 4.6

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 6 Global state: 3. Average value of additional medication ‐ after initial dose (skewed data).

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Analysis 4.7

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 7 Adverse effects: 1. Specific ‐ a. Cardiovascular ‐ hypotension.

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Analysis 4.8

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 8 Adverse effects: 1. Specific ‐ b. Central Nervous System ‐ excessive sedation.

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Analysis 4.9

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 9 Adverse effects: 1. Specific ‐ c. Extrapyramidal problems ‐ 0‐4 hours.

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Analysis 4.10

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 10 Specific behaviour: 1. Average aggression score (OAS, high score=bad).

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Analysis 4.11

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 11 Specific behaviour: 2. Average agitation score (OASS, high score=bad).

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Analysis 4.12

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 12 Specific behaviour: 3. Severe agitation.

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Analysis 4.13

Comparison 4 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM), Outcome 13 Leaving the study early.

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Analysis 5.1

Comparison 5 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM, Outcome 1 Tranquil or asleep: 1. Not tranquil or asleep.

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Analysis 5.2

Comparison 5 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM, Outcome 2 Tranquil or asleep: 2. Not asleep.

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Study	Intervention	Mean (mins)	SD	N	Statistical test	p
time until tranquil or asleep
TREC‐Vellore‐I	Haloperidol + Promethazine	29.7	35.6	100	Mann‐Whitney U 327.0	<0.001
TREC‐Vellore‐I	Lorazepam	47.8	46.7	100
time until asleep
TREC‐Vellore‐I	Haloperidol + Promethazine	37.4	42.9	100	Mann‐Whitney U 1893.5	<0.001
TREC‐Vellore‐I	Lorazepam	80.6	64.3	100

Analysis 5.3

Comparison 5 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM, Outcome 3 Tranquil or asleep: 3. Time (skewed data).

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Analysis 5.4

Comparison 5 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM, Outcome 4 Global state: 1. No overall improvement.

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Analysis 5.5

Comparison 5 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM, Outcome 5 Global state: 2. Needing restraints or seclusion.

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Analysis 5.6

Comparison 5 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM, Outcome 6 Global state: 3. Additional tranquillising drugs.

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Analysis 5.7

Comparison 5 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM, Outcome 7 Global state: 4. Various measures.

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Analysis 5.8

Comparison 5 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM, Outcome 8 Global state: 5. Average improvement (CGI, high score=bad) ).

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Analysis 5.9

Comparison 5 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM, Outcome 9 Adverse effects: 1. General ‐ serious adverse effect.

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Analysis 5.10

Comparison 5 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM, Outcome 10 Adverse effects: 2. Specific ‐ Extrapyramidal problems ‐ 0‐4 hours.

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Analysis 5.11

Comparison 5 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM, Outcome 11 Service outcomes: Not discharged.

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Analysis 5.12

Comparison 5 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM, Outcome 12 Leaving the study early.

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Analysis 6.1

Comparison 6 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ MIDAZOLAM, Outcome 1 Tranquil or asleep: 1. Not tranquil or asleep.

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Analysis 6.2

Comparison 6 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ MIDAZOLAM, Outcome 2 Tranquil or asleep: 2. Not asleep.

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Analysis 6.3

Comparison 6 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ MIDAZOLAM, Outcome 3 Global state: 1. Needing restraints or seclusion ‐ by 2hrs.

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Analysis 6.4

Comparison 6 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ MIDAZOLAM, Outcome 4 Global state: 2. Needing addition drugs during initial phase ‐ by 2hrs.

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Analysis 6.5

Comparison 6 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ MIDAZOLAM, Outcome 5 Global state: 3. Various measures.

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Analysis 6.6

Comparison 6 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ MIDAZOLAM, Outcome 6 Adverse effects: Serious adverse effect.

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Analysis 6.7

Comparison 6 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ MIDAZOLAM, Outcome 7 Service outcomes: Not discharged.

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Analysis 6.8

Comparison 6 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ MIDAZOLAM, Outcome 8 Specific Behaviours: 1. Aggression. a ‐ other episode of aggression ‐ by 24 hrs.

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Analysis 6.9

Comparison 6 HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ MIDAZOLAM, Outcome 9 Leaving the study early.

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Analysis 7.1

Comparison 7 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL ‐ additional 40 minutes data, Outcome 1 Tranquil or asleep: 1. Not tranquil or asleep.

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Analysis 7.2

Comparison 7 HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL ‐ additional 40 minutes data, Outcome 2 Tranquil or asleep: 2. Not asleep.

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Table 3. Included or excluded studies and Cochrane reviews

Study tag	Participants ‐ people with schizophrenia					Relevant Cochrane reviews
	+ additional problems	‐ not specifically aggressive/agitated		‐ aggressive/agitated
		Comparison		Comparison
		*Intervention #1*	*Intervention #2*	*Intervention #1*	*Intervention #2*
Baldacara 2011	+ none specified	Not applicable		Haloperidol	Haloperidol + midazolam	Gillies 2013; Powney 2012
					Olanzapine	Powney 2012
					Ziprasidone	Powney 2012
Hou 2011					Risperidone + lorazepam	Gillies 2013; Powney 2012
Baldacara 2011, Mantovani 2013				Haloperidol + midazolam	Olanzapine	Gillies 2013; Powney 2012
Baldacara 2011, Mantovani 2013				Haloperidol + midazolam	Ziprasidone	Gillies 2013; Powney 2012
Srinath 2010				Haloperidol + promethazine	Lorazepam	Gillies 2013; Powney 2012
Baldacara 2011, Mantovani 2013				Olanzapine	Ziprasidone	Belgamwar 2005
Levin 1959		Chlorpromazine	Phenobarbital	Not applicable		‐
			Placebo			Adams 2014
			Promethazine			‐
Bender 2003		Perazine	Trimipramine			‐
Levin 1959		Phenobarbital	Placebo			‐
		Promethazine	Phenobarbital			‐
		Promethazine	Placebo			‐
Merlo 2002		Risperidone (2 mg)	Risperidone (4 mg)			Li 2009
Brannen 1969		Trifluoperazine	Placebo			Koch 2014
St. Jean 1967	+ “mental deficiency" [? learning disability]	Chlorpromazine	Periciazine			‐
Yagi 1973	+ drug‐induced parkinsonism/EPS	Mazaticol hydrochloride	Promethazine			‐
Yagi 1973		Mazaticol hydrochloride	Trihexyphenidyl			‐
Otsuka 1978		Methixene	Promethazine			‐
Otsuka 1978		Methixene	Trihexyphenidyl			‐
Itoh 1972		Piroheptine	Promethazine			‐
Itoh 1972		Piroheptine	Trihexyphenidyl			‐
Perenyi 1989		Procyclidine	Promethazine			Essali 2013
St. Jean 1964		Promethazine	Placebo			‐
Otsuka 1978, Itoh 1972, Yagi 1973	+ drug‐induced parkinsonism/EPS	Promethazine	Trihexyphenidyl			‐
Claveria 1975	+ tardive dyskinesia	Pimozide	Placebo			Mothi 2013
Yang 1999	+ tardive dyskinesia	Promethazine	Placebo			‐
EPS: extrapyramidal symptoms

Table 3. Included or excluded studies and Cochrane reviews

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Table 4. Design of a future study

Methods	Allocation: randomised (clearly described). Blinding: single blind (outcomes assessor). Duration: up to 2 weeks. Design: parallel. Setting: emergency settings
Participants	Diagnosis: anyone whose aggressive behaviour is thought to be due to psychotic illness. N=300. Age: > 18 years. Sex: N/A. Inclusion criteria: other measures failed. Exclusion criteria: specific contra‐indication to evaluated treatments
Interventions	1. Drug intervention of choice. N=150. 2. Drug intervention of choice. N=150. Both drugs should be known to be effective, but the comparative effectiveness is unclear
Outcomes	Tranquil/asleep: binary outcomes, time. Behaviour: need for additional medication, additional aggressive episode. Adverse events. Acceptability of treatment. Costs: cost of services, cost of care. Service outcomes: days in hospital, discharged, transfer to secure unit

Table 4. Design of a future study

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Summary of findings for the main comparison. HALOPERIDOL + PROMETHAZINE compared to ANTIPSYCHOTIC ‐ HALOPERIDOL for psychosis‐induced aggression

HALOPERIDOL + PROMETHAZINE compared to ANTIPSYCHOTIC ‐ HALOPERIDOL for psychosis‐induced aggression
Patient or population: people with psychosis‐induced aggression Settings: Intervention: HALOPERIDOL + PROMETHAZINE Comparison: ANTIPSYCHOTIC ‐ HALOPERIDOL
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	ANTIPSYCHOTIC ‐ HALOPERIDOL	HALOPERIDOL + PROMETHAZINE
Tranquil or asleep: Not tranquil or asleep ‐ by 30 minutes	Moderate¹		RR 0.65 (0.49 to 0.87)	316 (1 study)	⊕⊕⊕⊕ high
	500 per 1000	325 per 1000 (245 to 435)
Global state: Needing restraints or seclusion by 12 hours	Moderate¹		RR 0.83 (0.28 to 2.44)	60 (1 study)	⊕⊕⊝⊝ low^2,3
	200 per 1000	166 per 1000 (56 to 488)
Adverse effects: Specific and serious adverse effects by 24 hours (not death) Central nervous system ‐ seizure	Moderate¹		RR 0.95 (0.06 to 15.01)	298 (1 study)	⊕⊕⊝⊝ low^4,5
	10 per 1000	9 per 1000 (1 to 150)
Adverse effect: Specific and serious ‐ Death	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome
Service outcomes: Not discharged ‐ by 2 weeks	Moderate¹		RR 0.83 (0.64 to 1.07)	310 (1 study)	⊕⊕⊕⊕ high
	500 per 1000	415 per 1000 (320 to 535)
Specific behaviours: Average aggression score ‐ by 12 hours Overt Aggression Scale		The mean specific behaviours: average aggression score in the intervention groups was 1.8 lower (1.93 to 1.67 lower)		60 (1 study)	⊕⊕⊝⊝ low^3,6
Economics: Costs of care	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: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Moderate control risk approximates to that of the included trial(s). ²Indirectness: rated 'serious' ‐ pre‐stated outcome was 'another episode of aggression' ‐ proxy outcome used. ³Imprecision: rated 'serious' ‐ sample size is small and confidence intervals wide. ⁴Indirectedness: rated 'serious' ‐ pre‐stated outcome was 'serious adverse event' ‐ proxy outcome used. ⁵Imprecision: rated 'serious' ‐ wide confidence intervals ‐ rare events. ⁶Indirectedness: rated 'serious' ‐ pre‐stated outcome was 'specific behaviours' ‐ proxy outcome used.

Summary of findings for the main comparison. HALOPERIDOL + PROMETHAZINE compared to ANTIPSYCHOTIC ‐ HALOPERIDOL for psychosis‐induced aggression

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Summary of findings 2. HALOPERIDOL + PROMETHAZINE compared to ANTIPSYCHOTIC ‐ OLANZAPINE for psychosis‐induced aggression

HALOPERIDOL + PROMETHAZINE compared to ANTIPSYCHOTIC ‐ OLANZAPINE for psychosis‐induced aggression
Patient or population: people with psychosis‐induced aggression Settings: Intervention: HALOPERIDOL + PROMETHAZINE Comparison: ANTIPSYCHOTIC ‐ OLANZAPINE
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	ANTIPSYCHOTIC ‐ OLANZAPINE	HALOPERIDOL + PROMETHAZINE
Tranquil or asleep: Not tranquil or asleep ‐ by 30 mins	Moderate¹		RR 0.60 (0.22 to 1.61)	300 (1 study)	⊕⊕⊕⊕ high
	100 per 1000	60 per 1000 (22 to 161)
Global state: Needing restraints or seclusion by 12 hours	Moderate		RR 5.00 (0.62 to 40.28)	60 (1 study)	⊕⊕⊝⊝ low^2,3
	50 per 1000¹	250 per 1000 (31 to 1000)
Adverse effects: Specific and serious adverse effects by 24 hours Central nervous system ‐ excessive sedation.	Moderate		RR 0.67 (0.12 to 3.84)	116 (2 studies)	⊕⊕⊝⊝ low^4,5
	100 per 1000¹	64 per 1000 (11 to 364)
Adverse effect: Specific ‐ Death	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome
Service outcomes: Not discharged ‐ by 4 hours	Moderate		RR 0.94 (0.77 to 1.16)	300 (1 study)	⊕⊕⊕⊕ high
	600 per 1000¹	564 per 1000 (462 to 696)
Specific behaviours: Average aggression score ‐ by 12 hours Overt Aggression Scale		The mean specific behaviours: average aggression score in the intervention groups was 2 lower (2.21 to 1.79 lower)		60 (1 study)	⊕⊕⊝⊝ low^5,6
Economics: Costs of care⁷	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: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Moderate control risk approximates to that of the included trial(s). ²Indirectness: rated 'serious' ‐ pre‐stated outcome was 'another episode of aggression' ‐ proxy outcome used. ³Imprecision: rated 'serious' as sample size too small and confidence interval too wide. ⁴Indirectness: rated 'serious' ‐ pre‐stated outcome was 'serious adverse effect' ‐ proxy outcome used. ⁵Imprecision: rated 'serious' ‐ sample size too small and confidence interval wide. ⁶Indirectness: rated 'serious' ‐ pre‐stated outcome was 'specific behaviours' ‐ proxy outcome used.

Summary of findings 2. HALOPERIDOL + PROMETHAZINE compared to ANTIPSYCHOTIC ‐ OLANZAPINE for psychosis‐induced aggression

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Summary of findings 3. HALOPERIDOL + PROMETHAZINE compared to ANTIPSYCHOTIC ‐ ZIPRASIDONE for psychosis‐induced aggression

HALOPERIDOL + PROMETHAZINE compared to ANTIPSYCHOTIC ‐ ZIPRASIDONE for psychosis‐induced aggression
Patient or population: people with psychosis‐induced aggression Settings: Intervention: HALOPERIDOL + PROMETHAZINE Comparison: ANTIPSYCHOTIC ‐ ZIPRASIDONE
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	ANTIPSYCHOTIC ‐ ZIPRASIDONE	HALOPERIDOL + PROMETHAZINE
Tranquil or asleep: Average sedation score ‐ by 30 minutes Ramsay Sedation Scale		The mean tranquil or asleep: average sedation score in the intervention groups was 0.1 lower (0.58 lower to 0.38 higher)		60 (1 study)	⊕⊕⊝⊝ low^1,2
Global state: Needing restraints or seclusion ‐ by 12 hours	Moderate		RR 0.5 (0.19 to 1.29)	60 (1 study)	⊕⊕⊕⊝ moderate⁴
	400 per 1000³	200 per 1000 (76 to 516)
Adverse effects: Specific and serious adverse effect ‐ by 24 hours Central nervous system ‐ excessive sedation.	Moderate		RR 0.30 (0.06 to 1.43)	111 (2 studies)	⊕⊕⊝⊝ low^2,5
	150 per 1000³	47 per 1000 (11 to 219)
Adverse effect: Specific ‐ Death	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome
Service outcomes: Not discharged ‐ by 2 weeks	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome
Specific behaviours: Average aggression score ‐ by 12 hours Overt Aggression Scale		The mean specific behaviours: average aggression score in the intervention groups was 1.6 lower (1.75 to 1.45 lower)		60 (1 study)	⊕⊕⊕⊝ moderate^2,4
Economics: Costs of care	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: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Indirectness: rated 'serious' ‐ pre‐stated outcome 'Tranquil or asleep' ‐ proxy outcome used. ²Imprecision: rated 'serious' ‐ sample size small. ³Moderate control risk approximates to that of the included trial. ⁴Indirectness: rated 'serious' ‐ pre‐stated outcome 'another episode of aggression' ‐ proxy outcome used. ⁵Indirectness: rated 'serious' ‐ pre‐stated outcome 'serious adverse effect' ‐ proxy outcome used.

Summary of findings 3. HALOPERIDOL + PROMETHAZINE compared to ANTIPSYCHOTIC ‐ ZIPRASIDONE for psychosis‐induced aggression

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Summary of findings 4. HALOPERIDOL + PROMETHAZINE compared to ANTIPSYCHOTIC & BENZODIAZEPINE ‐ HALOPERIDOL + MIDAZOLAM for psychosis‐induced aggression

HALOPERIDOL + PROMETHAZINE compared to ANTIPSYCHOTIC & BENZODIAZEPINE ‐ HALOPERIDOL + MIDAZOLAM for psychosis‐induced aggression
Patient or population: people with psychosis‐induced aggression Settings: Intervention: HALOPERIDOL + PROMETHAZINE Comparison: ANTIPSYCHOTIC & BENZODIAZEPINE ‐ HALOPERIDOL + MIDAZOLAM
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	ANTIPSYCHOTIC & BENZODIAZEPINE ‐ HALOPERIDOL + MIDAZOLAM	HALOPERIDOL + PROMETHAZINE
Tranquil or asleep: Average sedation score ‐ by 1 hour Ramsay Sedation Scale		The mean tranquil or asleep: average sedation score in the intervention groups was 0.6 lower (1.13 to 0.07 lower)		60 (1 study)	⊕⊕⊝⊝ low¹
Global state: Needing restraints or seclusion ‐ by 12 hours	Moderate		RR 0.24 (0.1 to 0.55)	60 (1 study)	See comment
	700 per 1000²	168 per 1000 (70 to 385)
Adverse effects: Specific and serious adverse effect ‐ by 24 hours Central nervous system ‐ excessive sedation	Moderate		RR 0.12 (0.03 to 0.49)	117 (2 studies)	⊕⊕⊝⊝ low^3,4
	300 per 1000²	33 per 1000 (9 to 141)
Adverse effect: Specific ‐ Death	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome
Service outcomes: Not discharged ‐ by 2 weeks	See comment	See comment	Not estimable	0 (0)	See comment	No study reported this outcome
Specific behaviours: Average aggression score ‐ by 12 hours Overt Aggression Scale		The mean specific behaviours: average aggression score in the intervention groups was 3.7 lower (4.39 to 3.01 lower)		60 (1 study)	See comment
Economics: Costs of care	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: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Indirectness: rated 'serious' ‐ pre‐stated outcome 'tranquil or asleep' ‐ proxy outcome used. ²Moderate control risk approximates to that of the included trial. ³Indirectness: rated 'serious' ‐ pre‐stated outcome was 'another episode of aggression' ‐ proxy outcome used. ⁴Imprecision: rated 'serious' ‐ sample size small.

Summary of findings 4. HALOPERIDOL + PROMETHAZINE compared to ANTIPSYCHOTIC & BENZODIAZEPINE ‐ HALOPERIDOL + MIDAZOLAM for psychosis‐induced aggression

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Summary of findings 5. HALOPERIDOL + PROMETHAZINE compared to BENZODIAZEPINES ‐ LORAZEPAM for psychosis‐induced aggression

HALOPERIDOL + PROMETHAZINE compared to BENZODIAZEPINES ‐ LORAZEPAM for psychosis‐induced aggression
Patient or population: people with psychosis‐induced aggression Settings: Intervention: HALOPERIDOL + PROMETHAZINE Comparison: BENZODIAZEPINES ‐ LORAZEPAM
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	BENZODIAZEPINES ‐ LORAZEPAM	HALOPERIDOL + PROMETHAZINE
Tranquil or asleep: Not tranquil or asleep ‐ by 30 mins Follow‐up: to 30 minutes	Moderate		RR 0.26 (0.1 to 0.68)	200 (1 study)	⊕⊕⊕⊕ high
	200 per 1000¹	52 per 1000 (20 to 136)
Global state: Needing restraints or seclusion ‐ by 12 hours	Moderate		RR 0.82 (0.35 to 1.89)	200 (1 study)	⊕⊕⊕⊝ moderate²
	150 per 1000¹	123 per 1000 (52 to 283)
Adverse effects: Specific and serious adverse effect ‐ by 24 hours Central nervous system ‐ excessive sedation	See comment		Not estimable	0 (0)	See comment	No study reported for this outcome
Adverse effect: Specific ‐ Death	See comment		Not estimable	0 (0)	See comment	No study reported for this outcome
Service outcomes: Not discharged ‐ by 4 hours	Moderate		RR 1.13 (0.85 to 1.5)	200 (1 study)	⊕⊕⊕⊕ high
	500 per 1000¹	565 per 1000 (425 to 750)
Specific behaviours: Average aggression score	See comment	See comment	Not estimable	0 (0)	See comment	No study reported for this outcome
Economics: Costs of care	See comment	See comment	Not estimable	0 (0)	See comment	No study reported for this outcome
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Moderate control risk approximates to that of the included trial. ²Indirectness: rated 'serious' ‐ pre‐stated outcome was 'another episode of aggression' ‐ proxy outcome used. ³Imprecision: rated 'serious' ‐ confidence interval is wide.

Summary of findings 5. HALOPERIDOL + PROMETHAZINE compared to BENZODIAZEPINES ‐ LORAZEPAM for psychosis‐induced aggression

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Summary of findings 6. HALOPERIDOL + PROMETHAZINE compared to BENZODIAZEPINES ‐ MIDAZOLAM for psychosis‐induced aggression

HALOPERIDOL + PROMETHAZINE compared to BENZODIAZEPINES ‐ MIDAZOLAM for psychosis‐induced aggression
Patient or population: people with psychosis‐induced aggression Settings: Intervention: HALOPERIDOL + PROMETHAZINE Comparison: BENZODIAZEPINES ‐ MIDAZOLAM
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	BENZODIAZEPINES ‐ MIDAZOLAM	HALOPERIDOL + PROMETHAZINE
Tranquil or asleep: Not tranquil or asleep Follow‐up: to 30 minutes	Moderate		RR 2.9 (1.75 to 4.8)	301 (1 study)	⊕⊕⊕⊕ high
	200 per 1000¹	580 per 1000 (350 to 960)
Global state: Needing restraints or seclusion‐ by 2 hours	Moderate		RR 1.22 (0.82 to 1.82)	301 (1 study)	⊕⊕⊕⊝ moderate²
	250 per 1000¹	305 per 1000 (205 to 455)
Adverse effect: Specific ‐ Death	See comment	See comment	Not estimable	0 (0)	See comment	No study reported for this outcome
Service outcomes: Not discharged ‐ Follow‐up: to 2 weeks	Moderate		RR 1.05 (0.84 to 1.29)	301 (1 study)	⊕⊕⊕⊕ high
	550 per 1000¹	577 per 1000 (462 to 709)
Specific behavioursAggression Follow‐up: to 12 hours	Moderate	RR 0.89 (0.62 to 1.29)	301 (1 study)	⊕⊕⊕⊝ moderate⁴
Economics: Costs of care	See comment	See comment	Not estimable	0 (0)	See comment	No study reported for this outcome
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Moderate control risk approximates to that of the included trial. ²Indirectness: rated 'serious' ‐ pre‐stated outcome was 'another episode of aggression' ‐ proxy outcome used. ³Imprecision: rated 'serious' ‐ confidence interval wide. ⁴Indirectness: rated 'serious' ‐ pre‐stated outcome was 'specific behaviours' ‐ proxy outcome used.

Summary of findings 6. HALOPERIDOL + PROMETHAZINE compared to BENZODIAZEPINES ‐ MIDAZOLAM for psychosis‐induced aggression

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Table 1. Survey of rapid tranquillisation in Rio de Janeiro 2002

Drug of choice	Frequency of use	mean mg (range)
Haloperidol + promethazine	61%	5 (2.5 to 10) + 50 (25 to 100)
Haloperidol + promethazine + diazepam	15%	5 (2.5 to 10) + 50 (25 to 100) + 10
Diazepam	9%	10
Haloperidol + promethazine + chlorpromazine	7%	5 + 50 + 25
Chlorpromazine + diazepam + promethazine	1%	25 + 10 + 50
Chlorpromazine + promethazine	1%	25 + 50
Chlorpromazine	1%	25
Diazepam + promethazine	1%	10 + 50
Haloperidol + diazepam	1%	5 + 10
Promethazine	1%	50

Table 1. Survey of rapid tranquillisation in Rio de Janeiro 2002

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Table 2. Other relevant Cochrane reviews

Focus of review	Reference
Completed and maintained reviews
'As required' medication regimens for seriously mentally ill people in hospital	Chakrabarti 2007
Benzodiazepines for psychosis‐induced aggression or agitation	Gillies 2005
Chlorpromazine for psychosis‐induced aggression or agitation	Ahmed 2010
Clotiapine for acute psychotic illnesses	Berk 2004
Containment strategies for people with serious mental illness	Muralidharan 2006
Droperidol for acute psychosis	Rathbone 2004
Haloperidol for psychosis‐induced aggression or agitation (rapid tranquillisation)	Powney 2012
Olanzapine IM or velotab for acutely disturbed/agitated people with suspected serious mental illnesses	Belgamwar 2005
Seclusion and restraint for serious mental illnesses	Sailas 2000
Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnesses	Gibson 2004
Reviews in the process of being completed
Risperidone for psychosis‐induced aggression or agitation	Ahmed 2011
Haloperidol for long‐term aggression in psychosis	Khushu 2012
Loxapine inhaler for psychosis‐induced aggression	Vangala 2012
Clozapine for people with schizophrenia and recurrent physical aggression	Toal 2012
Quetiapine for psychosis‐induced aggression or agitation	Wilkie 2012
De‐escalation techniques for psychosis‐induced aggression	Rao 2012

Table 2. Other relevant Cochrane reviews

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Comparison 1. HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tranquil or asleep: 1. Not tranquil or asleep Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 by 30 minutes	1	316	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.49, 0.87]
1.2 by 1 hour	1	316	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.46, 1.23]
1.3 by 2 hours	1	316	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.32, 0.96]
2 Tranquil or asleep: 2. Not asleep Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 by 30 minutes	1	316	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.82, 0.96]
2.2 by 1 hour	1	316	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.84, 1.28]
2.3 by 2 hours	1	316	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.77, 1.31]
3 Tranquil or asleep: 3. Time until tranquil or asleep (RSS, high score=good) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

3.1 by 1 hour	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.58, 0.38]
3.2 by 2 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.30, 0.50]
3.3 by 4 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.18, 0.78]
3.4 by 6 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.20 [‐0.08, 0.48]
3.5 by 12 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.28, 0.28]
4 Global state: 1. Needing restraints or seclusion Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 by 2 hours	1	311	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.54, 1.18]
4.2 by 12 hours	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.28, 2.44]
5 Global state: 2. Various measures Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 requiring additional drugs during initial phase ‐ by 2 hours	1	311	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.16, 1.25]
5.2 doctor called to see patient ‐ by 24 hours	1	298	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.44, 0.99]
5.3 refusing oral drugs ‐ at 24 hours	1	294	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.54, 1.97]
6 Global state: 3. Average value of additional medication ‐ after initial dose (skewed data) Show forest plot			Other data	No numeric data

7 Adverse effects: 1. General ‐ Any serious adverse effect Show forest plot	1	298	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.01, 0.66]

7.1 by 24 hours	1	298	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.01, 0.66]
8 Adverse effects: 2. Specific ‐ a. Cardiovascular ‐ hypotension Show forest plot	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	7.0 [0.38, 129.93]

9 Adverse effects: 2. Specific ‐ b. Central Nervous System Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 seizure ‐ by 24 hours	1	298	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.06, 15.01]
9.2 sedation ‐ excessive	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.04, 3.03]
10 Adverse effects: 2. Specific ‐ c. Extrapyramidal problems Show forest plot	2	358	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.14, 0.88]

10.1 acute dystonia ‐ by 24 hours	1	298	Risk Ratio (M‐H, Fixed, 95% CI)	0.05 [0.00, 0.76]
10.2 extrapyramidal problems (unspecified) ‐ 0‐4 hours	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.32, 3.10]
11 Service outcomes: Not discharged ‐ by 2 weeks Show forest plot	1	310	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.64, 1.07]

12 Specific behaviour: 1. Aggression ‐ a. Other episode of agression Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

12.1 other episode of aggression ‐ by 24 hours	1	298	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.68, 2.01]
13 Specific behaviour: 1. Aggression ‐ b. Average aggression score (OAS ,high score=bad) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

13.1 by 1 hour	1	60	Mean Difference (IV, Fixed, 95% CI)	4.50 [2.72, 6.28]
13.2 by 2 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.70 [‐0.49, 1.89]
13.3 by 4 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐0.71, ‐0.49]
13.4 by 6 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.1 [‐1.29, ‐0.91]
13.5 by 12 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.8 [‐1.93, ‐1.67]
14 Specific behaviour: 1. Aggression ‐ c. Average agitation score (OASS, high score=bad) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

14.1 by 1 hour	1	60	Mean Difference (IV, Fixed, 95% CI)	24.5 [21.68, 27.32]
14.2 by 2 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	9.40 [8.41, 10.39]
14.3 by 4 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	3.80 [3.27, 4.33]
14.4 by 6 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	2.6 [2.13, 3.07]
14.5 by 12 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.80 [0.55, 1.05]
15 Leaving the study early Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

15.1 before treatment	1	316	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.25, 8.63]
15.2 by 24 hours	2	376	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.41, 1.97]
15.3 by 2 weeks	1	316	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.20, 4.76]

Comparison 1. HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL

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Comparison 2. HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tranquil or asleep: 1. Not tranquil or asleep Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 by 30 minutes	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.6 [0.22, 1.61]
1.2 by 1 hour	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.01, 0.87]
1.3 by 2 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.14, 1.41]
1.4 by 4 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.26, 2.67]
2 Tranquil or asleep: 2. Not asleep Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 by 30 minutes	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.46, 0.93]
2.2 by 1 hour	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.40, 0.87]
2.3 by 2 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.14, 0.41]
2.4 by 4 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.44, 0.86]
3 Tranquil or asleep: 3. Never tranquil or asleep during first 4 hours Show forest plot	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.21]

4 Tranquil or asleep: 4. Average sedation score (RSS, high score=good) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.1 by 1 hour	1	60	Mean Difference (IV, Fixed, 95% CI)	0.20 [‐0.26, 0.66]
4.2 by 2 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.26, 0.46]
4.3 by 4 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.34, 0.54]
4.4 by 6 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.15, 0.35]
4.5 by 12 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.23, 0.23]
5 Tranquil or asleep: 5. Time (skewed data) Show forest plot			Other data	No numeric data

5.1 time until tranquil or asleep			Other data	No numeric data
5.2 time until asleep			Other data	No numeric data
6 Tranquil or asleep: 6. Effect of tranquillisation (PANSS‐EC, high=bad) (skewed data) Show forest plot			Other data	No numeric data

6.1 at 30 minutes			Other data	No numeric data
6.2 at 60 minutes			Other data	No numeric data
6.3 at 90 minutes			Other data	No numeric data
7 Tranquil or asleep: 7. Level of tranquillisation / agitation (ACES) (skewed data) Show forest plot			Other data	No numeric data

7.1 at 30 minutes			Other data	No numeric data
7.3 at 90 minutes			Other data	No numeric data
8 Global state: 1. No overall improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.1 by 30 minutes	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.36, 0.91]
8.2 by 1 hour	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.4 [0.21, 0.75]
8.3 by 2 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.24, 0.79]
8.4 by 4 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.22, 1.01]
9 Global state: 2. Needing restraints or seclusion Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 by 30 minutes	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.71, 1.47]
9.2 by 1 hour	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.66, 1.44]
9.3 by 2 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.51, 1.25]
9.4 by 4 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.34, 1.14]
9.5 by 12 hours	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.62, 40.28]
10 Global state: 3. Various measures Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.1 requiring additional drugs during initial phase ‐ by 4 hours	2	356	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.37, 0.74]
10.2 requiring further observation ‐ by 4 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.80, 1.71]
10.3 doctor called to see patient ‐ by 4 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.30, 0.73]
10.4 taking oral drugs ‐ at 2 weeks	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.89, 1.04]
11 Global state: 4. Average improvement (CGI, high score=bad) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

11.1 by 30 minutes	1	300	Mean Difference (IV, Fixed, 95% CI)	‐0.35 [‐0.58, ‐0.12]
11.2 by 1 hour	1	300	Mean Difference (IV, Fixed, 95% CI)	‐0.41 [‐0.60, ‐0.22]
11.3 by 2 hours	1	300	Mean Difference (IV, Fixed, 95% CI)	‐0.36 [‐0.56, ‐0.16]
11.4 by 4 hours	1	300	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.43, ‐0.11]
12 Global state: 5. Average value of additional medication ‐ after initial dose (skewed data) Show forest plot			Other data	No numeric data

13 Adverse effects: 1. General ‐ Serious adverse effect Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

13.1 by 4 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.04, 3.17]
13.2 at 2 weeks	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.12]
14 Adverse effects: 2. Specific ‐ a. Cardiovascular ‐ hypotension Show forest plot	2	116	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.49, 18.31]

15 Adverse effects: 2. Specific ‐ b. Central Nervous System ‐ sedation ‐ excessive Show forest plot	2	116	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.12, 3.84]

16 Adverse effects: 2. Specific ‐ c. Extrapyramidal problems ‐ 0‐4 hours Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

16.1 any change in scale‐rated extrapyramidal problems (Simpson & Angus Scale)	3	416	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [1.12, 2.77]
17 Specific behaviour: 1. Severe agitation Show forest plot	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	7.0 [0.38, 129.55]

18 Specific behaviour: 2. Average aggression score (OAS, high score=bad) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

18.1 by 1 hour	1	60	Mean Difference (IV, Fixed, 95% CI)	5.4 [3.72, 7.08]
18.2 by 2 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	1.20 [0.39, 2.01]
18.3 by 4 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.5 [‐0.68, ‐0.32]
18.4 by 6 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.20 [‐1.90, ‐0.50]
18.5 by 12 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐2.21, ‐1.79]
19 Specific behaviour: 3. Average agitation score (OASS, high score=bad) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

19.1 by 1 hour	1	60	Mean Difference (IV, Fixed, 95% CI)	26.5 [23.76, 29.24]
19.2 by 2 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	13.6 [12.64, 14.56]
19.3 by 4 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	4.0 [3.47, 4.53]
19.4 by 6 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	2.8 [2.31, 3.29]
19.5 by 12 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	1.70 [1.44, 1.96]
20 Service outcomes Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

20.1 admitted ‐ by 4 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.56, 1.16]
20.2 not discharged ‐ by 4 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.77, 1.16]
21 Leaving the study early Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

21.1 by 30 minutes	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.12]
21.2 by 2 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 2.74]
21.3 by 4 hours	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.01, 1.63]
21.4 by 24 hours	2	116	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.04, 3.01]
21.5 by 2 weeks	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.33, 1.56]

Comparison 2. HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ OLANZAPINE

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Comparison 3. HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tranquil or asleep: 1. Average sedation score (RSS, high score=good) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 by 1 hour	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.58, 0.38]
1.2 by 2 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.36, 0.56]
1.3 by 4 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.56, 0.36]
1.4 by 6 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.18, 0.38]
1.5 by 12 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.38, 0.18]
2 Tranquil or asleep: 2. Effect of tranquilisation (PANSS‐EC, high=bad) (skewed data) Show forest plot			Other data	No numeric data

2.1 at 30 minutes			Other data	No numeric data
2.2 at 60 minutes			Other data	No numeric data
2.3 at 90 minutes			Other data	No numeric data
3 Tranquil or asleep: 3. Level of tranquilisation / agitation (ACES) (skewed data) Show forest plot			Other data	No numeric data

3.1 at 30 minutes			Other data	No numeric data
3.2 at 90 minutes.			Other data	No numeric data
4 Global state: 1. Needing restraints or seclusion Show forest plot	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.19, 1.29]

5 Global state: 2. Additional tranquillising drugs Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.19, 1.36]

6 Global state: 3. Average value of additional medication ‐ after initial dose (skewed data) Show forest plot			Other data	No numeric data

7 Adverse effects: 1. Specific ‐ a. Cardiovascular ‐ hypotension Show forest plot	2	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.17, 1.75]

8 Adverse effects: 1. Specific ‐ b. Central Nervous System ‐ excessive sedation Show forest plot	2	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.30 [0.06, 1.43]

9 Adverse effects: 1. Specific ‐ c. Extrapyramidal problems ‐ 0‐4 hours Show forest plot	2	111	Risk Ratio (M‐H, Fixed, 95% CI)	1.72 [1.07, 2.76]

10 Specific behaviour: 1. Severe agitation Show forest plot	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.18, 3.69]

11 Specific behaviour: 2. Average aggression score (OAS, high score=bad) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

11.1 by 1 hour	1	60	Mean Difference (IV, Fixed, 95% CI)	4.50 [2.82, 6.18]
11.2 by 2 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	1.4 [0.55, 2.25]
11.3 by 4 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐0.62, 0.02]
11.4 by 6 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.40 [‐0.59, ‐0.21]
11.5 by 12 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.60 [‐1.75, ‐1.45]
12 Specific behaviour: 3. Average agitation score (OASS, high score=bad) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

12.1 by 1 hour	1	60	Mean Difference (IV, Fixed, 95% CI)	16.80 [13.68, 19.92]
12.2 by 2 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	5.5 [2.92, 8.08]
12.3 by 4 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐1.47, 0.27]
12.4 by 6 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐1.85, ‐0.15]
12.5 by 12 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.90 [‐2.34, ‐1.46]
13 Leaving the study early Show forest plot	2	111	Risk Ratio (M‐H, Fixed, 95% CI)	2.48 [0.11, 58.20]

13.1 by 24 hours	2	111	Risk Ratio (M‐H, Fixed, 95% CI)	2.48 [0.11, 58.20]

Comparison 3. HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ ZIPRASIDONE

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Comparison 4. HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tranquil or asleep: 1. Average sedation score (RSS, high score=good) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 by 1 hour	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐1.13, ‐0.07]
1.2 by 2 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.46, 0.46]
1.3 by 4 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.51, 0.51]
1.4 by 6 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.18, 0.38]
1.5 by 12 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.24, 0.44]
2 Tranquil or asleep: 2. Effect of tranquilisation (PANSS‐EC, high score=bad) (skewed data) Show forest plot			Other data	No numeric data

2.1 at 30 minutes			Other data	No numeric data
2.2 at 60 minutes			Other data	No numeric data
2.3 at 90 minutes			Other data	No numeric data
3 Tranquil or asleep: 3. Level of tranquilisation / agitation (ACES) (skewed data) Show forest plot			Other data	No numeric data

3.1 at 30 minutes			Other data	No numeric data
3.2 at 90 minutes			Other data	No numeric data
4 Global state: 1. Needing restraints or seclusion Show forest plot	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.10, 0.55]

5 Global state: 2. Additional tranquilising drugs Show forest plot	1	57	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.34, 3.19]

6 Global state: 3. Average value of additional medication ‐ after initial dose (skewed data) Show forest plot			Other data	No numeric data

7 Adverse effects: 1. Specific ‐ a. Cardiovascular ‐ hypotension Show forest plot	2	117	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.16, 1.58]

8 Adverse effects: 1. Specific ‐ b. Central Nervous System ‐ excessive sedation Show forest plot	2	117	Risk Ratio (M‐H, Fixed, 95% CI)	0.12 [0.03, 0.49]

9 Adverse effects: 1. Specific ‐ c. Extrapyramidal problems ‐ 0‐4 hours Show forest plot	2	117	Risk Ratio (M‐H, Fixed, 95% CI)	1.84 [1.12, 3.02]

10 Specific behaviour: 1. Average aggression score (OAS, high score=bad) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

10.1 by 1 hour	1	60	Mean Difference (IV, Fixed, 95% CI)	3.30 [1.35, 5.25]
10.2 by 2 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.70 [‐3.46, 0.06]
10.3 by 4 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.70 [‐1.27, ‐0.13]
10.4 by 6 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.70 [‐0.89, ‐0.51]
10.5 by 12 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐3.7 [‐4.39, ‐3.01]
11 Specific behaviour: 2. Average agitation score (OASS, high score=bad) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

11.1 by 1 hour	1	60	Mean Difference (IV, Fixed, 95% CI)	16.00 [13.02, 18.98]
11.2 by 2 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	2.70 [1.67, 3.73]
11.3 by 4 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.70 [‐2.79, ‐0.61]
11.4 by 6 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.10 [‐2.08, ‐0.12]
11.5 by 12 hours	1	60	Mean Difference (IV, Fixed, 95% CI)	‐10.40 [‐11.47, ‐9.33]
12 Specific behaviour: 3. Severe agitation Show forest plot	1	57	Risk Ratio (M‐H, Fixed, 95% CI)	1.55 [0.28, 8.61]

13 Leaving the study early Show forest plot	2	117	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.03, 2.18]

13.1 by 24 hours	2	117	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.03, 2.18]

Comparison 4. HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC + BENZODIAZEPINE (HALOPERIDOL + MIDAZOLAM)

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Comparison 5. HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tranquil or asleep: 1. Not tranquil or asleep Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 by 30 minutes	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.10, 0.68]
1.2 by 1 hour	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.2 [0.04, 0.89]
1.3 by 2 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.07, 0.86]
1.4 by 4 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.26, 3.89]
2 Tranquil or asleep: 2. Not asleep Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 by 30 minutes	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.40 [0.29, 0.54]
2.2 by 1 hour	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.36, 0.66]
2.3 by 2 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.36, 0.71]
2.4 by 4 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.30, 0.65]
3 Tranquil or asleep: 3. Time (skewed data) Show forest plot			Other data	No numeric data

3.1 time until tranquil or asleep			Other data	No numeric data
3.2 time until asleep			Other data	No numeric data
4 Global state: 1. No overall improvement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 by 30 minutes	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.40 [0.25, 0.66]
4.2 by 1 hour	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.32, 0.79]
4.3 by 2 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.25, 0.86]
4.4 by 4 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.46, 1.87]
5 Global state: 2. Needing restraints or seclusion Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 by 30 minutes	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.28, 1.09]
5.2 by 1 hour	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.27, 1.14]
5.3 by 2 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.35, 1.67]
5.4 by 4 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.35, 1.89]
6 Global state: 3. Additional tranquillising drugs Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 by 30 minutes	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.09]
6.2 by 1 hour	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.04, 3.15]
6.3 by 2 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.17, 3.27]
6.4 by 4 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.36, 2.21]
7 Global state: 4. Various measures Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 doctor called to see patient ‐ by 4 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.37, 1.39]
7.2 refusing oral medication ‐ by 2 weeks	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [0.70, 3.75]
8 Global state: 5. Average improvement (CGI, high score=bad) ) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

8.1 by 30 minutes	1	200	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐0.86, ‐0.34]
8.2 by 1 hour	1	200	Mean Difference (IV, Fixed, 95% CI)	‐0.33 [‐0.54, ‐0.12]
8.3 by 2 hours	1	200	Mean Difference (IV, Fixed, 95% CI)	‐0.23 [‐0.51, 0.05]
8.4 by 4 hours	1	200	Mean Difference (IV, Fixed, 95% CI)	‐0.09 [‐0.32, 0.14]
9 Adverse effects: 1. General ‐ serious adverse effect Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 by 30 minutes	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.09]
9.2 by 1 hour	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.3 by 2 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.4 by 4 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Adverse effects: 2. Specific ‐ Extrapyramidal problems ‐ 0‐4 hours Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.1 akathisia (Barnes Akathisia Scale)	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 any change in scale‐rated extrapyramidal problems (Simpson & Angus Scale)	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Service outcomes: Not discharged Show forest plot	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.85, 1.50]

11.1 by 4 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.85, 1.50]
12 Leaving the study early Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

12.1 by 4 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.12, 72.77]
12.2 by 2 weeks	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.51, 3.04]

Comparison 5. HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ LORAZEPAM

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Comparison 6. HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ MIDAZOLAM

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tranquil or asleep: 1. Not tranquil or asleep Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 by 30 minutes	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	2.90 [1.75, 4.80]
1.2 by 1 hour	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.91 [0.92, 3.98]
1.3 by 2 hours	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.73 [0.70, 4.26]
2 Tranquil or asleep: 2. Not asleep Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 by 30 minutes	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.86 [1.48, 2.33]
2.2 by 1 hour	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	2.18 [1.52, 3.12]
2.3 by 2 hours	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	2.13 [1.42, 3.20]
3 Global state: 1. Needing restraints or seclusion ‐ by 2hrs Show forest plot	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.82, 1.82]

4 Global state: 2. Needing addition drugs during initial phase ‐ by 2hrs Show forest plot	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	3.52 [0.74, 16.69]

5 Global state: 3. Various measures Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 doctor called to see patient ‐ by 24 hours	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.61, 1.19]
5.2 refusing oral drugs ‐ at 24 hours	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.33, 1.44]
6 Adverse effects: Serious adverse effect Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 by 30 minutes	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.06, 15.95]
6.2 by 1 hour	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.3 by 2 hours	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Service outcomes: Not discharged Show forest plot	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.84, 1.29]

7.1 by 15 days	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.84, 1.29]
8 Specific Behaviours: 1. Aggression. a ‐ other episode of aggression ‐ by 24 hrs Show forest plot	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.62, 1.29]

9 Leaving the study early Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 by 2 hours	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	2.01 [0.18, 21.97]
9.2 by 24 hours	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.36, 2.80]
9.3 by 2 weeks	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 2.76]

Comparison 6. HALOPERIDOL + PROMETHAZINE vs BENZODIAZEPINES ‐ MIDAZOLAM

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Comparison 7. HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL ‐ additional 40 minutes data

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tranquil or asleep: 1. Not tranquil or asleep Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 by 40 minutes	1	316	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.56, 1.24]
2 Tranquil or asleep: 2. Not asleep Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 by 40 minutes	1	316	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.85, 1.16]

Comparison 7. HALOPERIDOL + PROMETHAZINE vs ANTIPSYCHOTIC ‐ HALOPERIDOL ‐ additional 40 minutes data

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Haloperidol más prometazina para la agresión inducida por psicosis

Appendices

Appendix 1. Previous searches

2.1 Search in 2004

2.2 Search in 2008

Appendix 2. Methods ‐ as used in the 2009 version

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Appendices

Appendix 1. Previous searches

2.1 Search in 2004

2.2 Search in 2008

Appendix 2. Methods ‐ as used in the 2009 version

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Instituciones a las que se accedió previamente

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