Intervention Review

You have free access to this content

Benzodiazepines for psychosis-induced aggression or agitation

  1. Donna Gillies1,*,
  2. Stephanie Sampson2,
  3. Alison Beck3,
  4. John Rathbone4

Editorial Group: Cochrane Schizophrenia Group

Published Online: 30 APR 2013

Assessed as up-to-date: 1 JUN 2012

DOI: 10.1002/14651858.CD003079.pub3


How to Cite

Gillies D, Sampson S, Beck A, Rathbone J. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD003079. DOI: 10.1002/14651858.CD003079.pub3.

Author Information

  1. 1

    Western Sydney and Nepean Blue Mountains Local Health Districts - Mental Health, Parramatta, NSW, Australia

  2. 2

    The University of Nottingham, Cochrane Schizophrenia Group, Nottingham, UK

  3. 3

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

  4. 4

    The University of Sheffield, HEDS, ScHARR, Sheffield, UK

*Donna Gillies, Western Sydney and Nepean Blue Mountains Local Health Districts - Mental Health, Cumberland Hospital, Locked Bag 7118, Parramatta, NSW, 2150, Australia. Donna_Gillies@wsahs.nsw.gov.au.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 30 APR 2013

SEARCH

 

Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 
Summary of findings for the main comparison. BENZODIAZEPINES compared to PLACEBO for psychosis-induced aggression or agitation

BENZODIAZEPINES compared to PLACEBO for psychosis-induced aggression or agitation

Patient or population: patients with psychosis-induced aggression or agitation
Settings: hospitals (Romania & US)
Intervention: BENZODIAZEPINES
Comparison: PLACEBO

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PLACEBOBENZODIAZEPINES

Global impression - no improvement - medium term
As defined in each study
Follow-up: 24 hours
569 per 10001353 per 1000
(227 to 552)
RR 0.62
(0.4 to 0.97)
102
(1 study)
⊕⊝⊝⊝
very low2,3,4,5

Global impression - need for additional medication - medium term
Number of participants requiring additional medication
Follow-up: 24 hours
529 per 10001529 per 1000
(365 to 762)
RR 1
(0.69 to 1.44)
102
(1 study)
⊕⊝⊝⊝
very low2,3,4,5

Global impression - sedation - medium term
Number of participants sedated
Follow-up: 24 hours
59 per 1000198 per 1000
(25 to 389)
RR 1.67
(0.42 to 6.61)
102
(1 study)
⊕⊝⊝⊝
very low2,3,4,5

Adverse effects/events - extrapyramidal symptoms - medium term
Number of instances of extrapyramidal symptoms
Follow-up: 24 hours
59 per 1000119 per 1000
(2 to 182)
RR 0.33
(0.04 to 3.1)
102
(1 study)
⊕⊝⊝⊝
very low2,3,4,5

Satisfaction with treatment - generalSee commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.

Economic outcomes - cost-effectivenessSee commentSee commentNot estimable0
(0)
See commentNo study reported this outcome.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

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

 Summary of findings 2 BENZODIAZEPINES compared to ANTIPSYCHOTICS for psychosis-induced aggression or agitation

 Summary of findings 3 BENZODIAZEPINES + ANTIPSYCHOTICS compared to SAME BENZODIAZEPINES for psychosis-induced aggression or agitation

 Summary of findings 4 BENZODIAZEPINES + ANTIPSYCHOTICS compared to SAME ANTIPSYCHOTICS for psychosis-induced aggression or agitation

 Summary of findings 5 BENZODIAZEPINES + ANTIPSYCHOTICS compared to DIFFERENT ANTIPSYCHOTICS for psychosis-induced aggression or agitation

 Summary of findings 6 BENZODIAZEPINES + ANTIPSYCHOTICS compared to ANTIPSYCHOTICS + ANTIPSYCHOTICS for psychosis-induced aggression or agitation

 Summary of findings 7 BENZODIAZEPINES compared to ANTIHISTAMINES + ANTIPSYCHOTICS for psychosis-induced aggression or agitation

 Summary of findings 8 BENZODIAZEPINES + ANTIPSYCHOTICS compared to ANTIHISTAMINES + ANTIPSYCHOTICS for psychosis-induced aggression or agitation

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of the condition

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

 

Description of the intervention

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

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

 

How the intervention might work

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

 

Why it is important to do this review

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

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

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

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

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

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

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

 

Types of participants

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

 

Types of interventions

 

Benzodiazepines - given alone

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

Any dose, any means of administration.

Compared with the following.

 
1. Placebo

 
2. Other benzodiazepine - given alone

Any dose, any means of administration.

 
3. Antipsychotics

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

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

Any dose, any means of administration.

 
4. Other combinations of drugs

4.1 Benzodiazepines plus antipsychotics.

4.2 Antipsychotics plus antihistamine/anticholinergic drugs.

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

Any dose, any means of administration.

 
5. Non-pharmacological approaches

 

Benzodiazepines plus antipsychotics

Compared with the following.

 
1. Placebo

 
2. Any antipsychotics

Any dose, any means of administration.

 
3. Other combinations

3.1 Benzodiazepines plus antipsychotics.

3.2 Antipsychotics plus antihistamines.

 
4. Non-pharmacological approaches

 

Types of outcome measures

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

 

Primary outcomes

 
1.Global impression
 
1.1 Specific

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

 

Secondary outcomes

 
2. Global impression
 
2.1 General

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

 
2.2 Specific

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

 
3. Behaviour
 
3.1 General

3.1.1 No clinically important change in behaviour
3.1.2 Average behaviour score

 
4. Mental state
 
4.1 General

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

 
5. Adverse effects/events
 
5.1 General

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

 
5.2 Specific

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

 
6. Hospital and service outcomes
 
6.1 Hospitalisation

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

 
6.2 Seclusion

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

 
7. Satisfaction with treatment
 
7.1 Specific

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

 
8. Economic outcomes
 
8.1 Specific

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

 
9. Leaving the study early

 
10. 'Summary of findings' tables

We used the GRADE approach to interpret findings (Schünemann 2008) and used GRADE profiler (GRADEPRO) to import data from RevMan 5 (Review Manager) to create 'Summary of findings' tables. These tables provide outcome-specific information concerning the overall quality of evidence from each included study in the comparison, the magnitude of effect of the interventions examined, and the sum of available data on all outcomes we rated as important to patient care and decision making. We selected the following main outcomes for inclusion in the 'Summary of findings' table.

  1. Global impression: no improvement - medium term.
  2. Global impression: need for additional medication - medium term.
  3. Global impression: sedation - medium term.
  4. Adverse effects/events: EPS - medium term.
  5. Satisfaction with treatment: general.
  6. Economic outcomes: cost-effectiveness.

 

Search methods for identification of studies

 

Electronic searches

 

1. Cochrane Schizophrenia Group Trial Register (January 2012)

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

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

 

2. Previous electronic searches

For previous searches see (Appendix 1).

 

Searching other resources

 

1. Reference Searching

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

 

2. Handsearching

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

 

3. Requests for additional data

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

 

Data collection and analysis

 

Selection of studies

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

 

Data extraction and management

 

1. Extraction

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

 

2. Management

 
2.1 Forms

We extracted binary, continuous and other data onto standard, simple forms.

 
2.2 Scale-derived data

We included continuous data from rating scales only if:
a. the psychometric properties of the measuring instrument have been described in a peer-reviewed journal (Marshall 2000); and
b. the measuring instrument had not been written or modified by one of the trialists for that particular trial.
Ideally, the measuring instrument should either have been i. a self-report or ii. completed by an independent rater or relative (not the therapist). We realise that this is not often reported clearly; in (Description of studies) we noted if this is the case or not.

 
2.3 Endpoint versus change data

There are advantages of both endpoint and change data. Change data can remove a component of between-person variability from the analysis. On the other hand, calculation of change needs two assessments (baseline and endpoint) which can be difficult in unstable and difficult to measure conditions such as schizophrenia. We decided primarily to use endpoint data, and only use change data if the former were not available. Because endpoint and change data are combined in the analysis, we used mean differences (MD) rather than standardised mean differences (SMD) throughout (Higgins 2011).

 
2.4 Skewed data

Continuous data on clinical and social outcomes are often not normally distributed. To avoid the pitfall of applying parametric tests to non-parametric data, we aimed to apply the following standards to all data before inclusion:
a) standard deviations (SDs) and means are reported in the paper or obtainable from the authors;
b) when a scale starts from the finite number zero, the SD is more than the mean, this is considered strong evidence of skew (Higgins 2011);
c) if a scale started from a positive value (such as the Positive and Negative Syndrome Scale (PANSS) which can have values from 30 to 210), we modified the calculation described above to take the scale starting point into account. In these cases skew is present if SD > (S-S min), where S is the mean score and S min is the minimum score. Where skewed data were present, we presented results in a separate table.

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

When continuous data are presented on a scale that includes a possibility of negative values (such as change data), it is difficult to tell whether data are skewed or not; we entered change data from both large and small trials.

 
2.5 Common measure

To facilitate comparison between trials, we intended to convert variables that can be reported in different metrics, such as days in hospital (mean days per year, per week or per month) to a common metric (e.g. mean days per month) if necessary.

 
2.6 Direction of graphs

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

 

Assessment of risk of bias in included studies

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

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

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

 

Measures of treatment effect

 

1. Binary data

For binary outcomes we calculated a standard estimation of the risk ratio (RR) and its 95% confidence interval (CI). It has been shown that RR is more intuitive (Boissel 1999) than odds ratios and that odds ratios tend to be interpreted as RR by clinicians (Deeks 2000). If heterogeneity was identified (Assessment of heterogeneity), we used a random-effects model to explore whether this had an effect on findings. For statistically significant results, we used 'Summary of findings' tables to calculate the number needed to treat to provide benefit/to induce harm statistic and its 95% CI.

 

2. Continuous data

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

 

Unit of analysis issues

 

1. Cluster trials

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

None of the present included trials used cluster randomisation. for For the purposes of future updates of this review, where clustering is not accounted for in primary studies, we will present data in a table, with a (*) symbol to indicate the presence of a probable unit of analysis error. In subsequent versions of this review we will seek to contact first authors of trials to obtain intra-class correlation coefficients for their clustered data and to adjust for this by using accepted methods (Gulliford 1999). Where clustering may be incorporated into the analysis of primary studies, we will present these data as if from a non-cluster randomised study, but adjust for the clustering effect.

 

2. Cross-over trials

None of the present included trials employed a cross-over trial design; for the purposes of future updates of this review: a major concern of cross-over trials is the carry-over effect. It occurs if an effect (e.g. pharmacological, physiological or psychological) of the treatment in the first phase is carried over to the second phase. As a consequence, on entry to the second phase the participants can differ systematically from their initial state despite a wash-out phase. For the same reason cross-over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both effects are very likely in severe mental illness, we will only use data of the first phase of cross-over trials.

 

3. Studies with multiple treatment groups

Where a study involves more than two treatment arms, if two or more of the interventions were similar, data were pooled. If data were binary these have simply been added. If data were continuous, we combined data following the formula in section 7.7.3.8 (Combining groups) of the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011). Where the additional treatment arms were not relevant, we did not use these data.

 

Dealing with missing data

 

1. Overall loss of credibility

At some degree of loss of follow-up, data must lose credibility (Xia 2009). We chose that, for any particular outcome, should more than 50% of data be unaccounted for either group, we would not present these data or use them within analyses, (except for the outcome 'leaving the study early').

 

2. Binary

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

 

3. Continuous

 
3.1 Attrition

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

 
3.2 Standard deviations

If standard deviations (SDs) were not reported, we first tried to obtain the missing values from the authors. If not available, where there were missing measures of variance for continuous data, but an exact standard error (SE) and confidence intervals (CIs) available for group means, and either 'P' value or 't' value available for differences in mean, we could calculate them according to the rules described in the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011). When only the standard error (SE) was reported, SDs were calculated by the formula SD = SE * square root (n). Chapters 7.7.3 and 16.1.3 of the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011) present detailed formulae for estimating SDs from P values, t or F values, CIs, ranges or other statistics. If these formulae did not apply, we calculated the SDs according to a validated imputation method which is based on the SDs of the other included trials (Furukawa 2006). Although some of these imputation strategies can introduce error, the alternative would be to exclude a given study's outcome and thus to lose information. Where the only variance given was range (Diazepam 1979, IL), SDs were also estimated from the difference between the upper and lower value divided by four.

 
3.3 Last observation carried forward

We anticipated that in some trials the method of last observation carried forward (LOCF) would be employed within the study report. As with all methods of imputation to deal with missing data, LOCF introduces uncertainty about the reliability of the results (Leucht 2007). Therefore, where LOCF data were used in the trial, if less than 50% of the data had been assumed, we would have presented and used these data and indicated that they were the product of LOCF assumptions. Where LOCF were not used, data were analysed as they were presented in the original publications.

 

Assessment of heterogeneity

 

1. Clinical heterogeneity

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

 

2. Methodological heterogeneity

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

 

3. Statistical heterogeneity

 
3.1 Visual inspection

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

 
3.2 Employing the I2 statistic

Heterogeneity between trials was investigated by considering the I2 method alongside the Chi2 (P > 0.10). The I2 provides an estimate of the percentage of inconsistency thought to be due to chance (Higgins 2008). The importance of the observed value of I2 depends on i. magnitude and direction of effects and ii. strength of evidence for heterogeneity (e.g. 'P' value from Chi2  test, or a CI for I2). An I2 estimate greater than or equal to around 50% accompanied by a statistically significant Chi2 statistic, is interpreted as evidence of substantial levels of heterogeneity (Section 9.5.2 - Higgins 2011). When substantial levels of heterogeneity were found in the primary outcome, we explored reasons for heterogeneity (Subgroup analysis and investigation of heterogeneity).

 

Assessment of reporting biases

 

1. Protocol versus full study

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

 

2. Funnel plot

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results (Egger 1997). Again, these are described in Section 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We are aware that funnel plots may be useful in investigating reporting biases but are of limited power to detect small-study effects. We did not use funnel plots for outcomes where there were 10 or fewer trials, or where all trials were of similar sizes. In other cases, where funnel plots were possible, we sought statistical advice in their interpretation. Because there were more data available for the secondary outcome, sedation, a funnel plot analysis was completed using this outcome (Figure 1).

 FigureFigure 1. Funnel plot of comparison: 2. benzodiazepines vs antipsychotics, outcome: 2.3 Global impression - sedation.

 

Data synthesis

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

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

 

Subgroup analysis and investigation of heterogeneity

 

1. Subgroup analyses

Subgroup analyses were carried out for different antipsychotics.

 

2. Investigation of heterogeneity

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

 

Sensitivity analysis

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

 

1. Risk of bias

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

 

2. Fixed and random effects

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

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

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

 

Results of the search

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

 FigureFigure 2. Study flow diagram.

 

Included studies

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

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

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

 

1. Setting

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

 

2. Length of trials

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

 

3. Participants

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

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

 

4. Trial size

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

 

5. Interventions

 
1. Benzodiazepines versus placebo

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

 
2. Benzodiazepines versus antipsychotics

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

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

 
3. Combined benzodiazepines/antipsychotics versus same benzodiazepines alone

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

 
4. Combined benzodiazepines/antipsychotics versus same antipsychotics alone

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

 
5. Combined benzodiazepines/antipsychotics versus different antipsychotics alone

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

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

 
6. Benzodiazepines/antipsychotics versus antipsychotics/antipsychotics

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

 
7. Benzodiazepines versus combined antipsychotics/antihistamines

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

 
8. Combined benzodiazepines/antipsychotics versus combined antipsychotics/antihistamines

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

 

6. Outcomes scales

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

 
1. Global impression

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

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

 
2. Behaviour

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

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

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

 
3. Mental state

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

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

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

 

Excluded studies

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

 

Risk of bias in included studies

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

 FigureFigure 3. 'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
 FigureFigure 4. 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

 

Allocation

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

 

Blinding

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

 

Incomplete outcome data

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

 

Selective reporting

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

 

Other potential sources of bias

 
1. Funding

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

 
2. Rating scales

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

 

Effects of interventions

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

 

Comparison 1: BENZODIAZEPINES versus PLACEBO

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

 

1. Global impression

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

 

2. Behaviour

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

 

3. Mental state

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

 

4. Adverse events

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

 

5. Leaving study early

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

 

Comparison 2: BENZODIAZEPINES versus ANTIPSYCHOTICS

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

 

1. Global impression

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

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

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

 

2. Behaviour

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

 

3. Mental state

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

 

4. Adverse events

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

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

 

5. Leaving study early

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

 

Comparison 3: BENZODIAZEPINES + ANTIPSYCHOTICS versus SAME BENZODIAZEPINES

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

 

1. Global impression

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

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

 

2. Behaviour

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

 

3. Mental state

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

 

4. Adverse events

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

 

5. Leaving study early

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

 

Comparison 4: BENZODIAZEPINES + ANTIPSYCHOTICS versus SAME ANTIPSYCHOTICS

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

 

1. Global impression

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

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

 

2. Behaviour

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

 

3. Mental state

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

 

4. Adverse events

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

 

5. Hospital and service outcomes

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

 

Comparison 5: BENZODIAZEPINES + ANTIPSYCHOTICS versus DIFFERENT ANTIPSYCHOTICS

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

 

1. Global impression

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

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

 

2. Behaviour

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

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

 

3. Mental state

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

 

4. Adverse effects

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

 

Comparison 6: BENZODIAZEPINES + ANTIPSYCHOTICS versus ANTIPSYCHOTICS + ANTIPSYCHOTICS

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

 

1. Behaviour

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

 

2. Leaving the study early

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

 

Comparison 7: BENZODIAZEPINES versus ANTIPSYCHOTICS + ANTIHISTAMINES

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

 

1. Global impression

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

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

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

 

2. Adverse events

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

 

3. Leaving study early

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

 

4. Hospital and service outcomes

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

 

Comparison 8: BENZODIAZEPINES + ANTIPSYCHOTICS versus ANTIPSYCHOTICS + ANTIHISTAMINES

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

 

1. Global impression

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

 

2. Behaviour

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

 

3. Adverse events

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

 

SENSITIVITY ANALYSES

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

 

1. Randomised sequence generation

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

 

2. Allocation concealment

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

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

 

3. Blinded outcome measurement

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

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

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

 

4. Incomplete outcome data (attrition bias)

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

 

Publication bias

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

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Summary of main results

 

Comparison 1: BENZODIAZEPINES versus PLACEBO

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

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

 

Comparison 2: BENZODIAZEPINES versus ANTIPSYCHOTICS

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

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

 

Comparison 3: BENZODIAZEPINES + ANTIPSYCHOTICS versus SAME BENZODIAZEPINES

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

 

Comparison 4: BENZODIAZEPINES + ANTIPSYCHOTICS versus SAME ANTIPSYCHOTICS

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

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

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

 

Comparison 5: BENZODIAZEPINES + ANTIPSYCHOTICS versus DIFFERENT ANTIPSYCHOTICS

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

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

 

Comparison 6: BENZODIAZEPINES + ANTIPSYCHOTICS versus ANTIPSYCHOTICS + ANTIPSYCHOTICS

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

 

Comparison 7: BENZODIAZEPINES versus ANTIPSYCHOTICS + ANTIHISTAMINES

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

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

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

 

Comparison 8: BENZODIAZEPINES + ANTIPSYCHOTICS versus ANTIPSYCHOTICS + ANTIHISTAMINES

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

 

SENSITIVITY ANALYSIS

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

 

Overall completeness and applicability of evidence

 

1. Completeness

 

1.1 Power

 
1.1.1 Limited power

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

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

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

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

 
1.1.2 No power

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

 

1.2 Outcome measurement

 
1.2.1 Measures

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

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

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

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

 
1.2.2 Sedation

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

 

2. Applicability

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

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

 

Quality of the evidence

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

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

 

Potential biases in the review process

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

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

 

Agreements and disagreements with other studies or reviews

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

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 

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

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

2. For clinicians

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

3. For managers or policy-makers

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

 
Implications for research
1. General

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

2. Specific
2.1 Reviews

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

2.2 Research
 
2.2.1 Methods

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

 
2.2.2 Interventions

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

 
2.2.3 Outcomes

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

 
2.2.4 Suggested design of trial

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

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

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

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

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
Comparison 1. BENZODIAZEPINES vs PLACEBO

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global impression: 1. no improvement1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 short term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Global impression: 2. need for additional medication1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Global impression: 3. sedation1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Global impression: 4. average change score (CGI-S, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Behaviour: 1. average change score (ABS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Mental state: 1. average change score (PANSS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    6.1 medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Mental state: 2. average change score (PANSS-excited component, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    7.1 medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Adverse effects/events: 1. extrapyramidal symptoms1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    8.1 medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Adverse effects/events: 2. use of medication for EPS1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    9.1 medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 10 Adverse effects/events: 3. specific1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    10.1 dizziness - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    10.2 nausea - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    10.3 vomiting - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 11 Leaving the study early: 1. any reason1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    11.1 medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 2. BENZODIAZEPINES vs ANTIPSYCHOTICS

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global impression: 1. no improvement5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 vs olanzapine - short term
1150Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.95, 1.66]

    1.2 vs olanzapine - medium term
1150Risk Ratio (M-H, Fixed, 95% CI)1.84 [1.06, 3.18]

    1.3 vs haloperidol - medium term
4158Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.66, 1.17]

 2 Global impression: 2. need for additional medication3Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 vs droperidol - short term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 vs haloperidol - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.3 vs olanzapine - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Global impression: 3. sedation9Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 vs droperidol - short term
1153Risk Ratio (M-H, Fixed, 95% CI)2.71 [1.55, 4.73]

    3.2 vs haloperidol - short term
144Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.53, 2.59]

    3.3 vs haloperidol - medium term
8434Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.83, 1.54]

    3.4 vs olanzapine - medium term
1150Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.28, 1.98]

 4 Global impression: 4. average change/endpoint score (CGI-S, high = worse)3Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 vs haloperidol - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.4 vs olanzapine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Global impression: 6. average endpoint score (IMPS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Behaviour: 2. average change/endpoint score (ABS, high = worse)2Mean Difference (IV, Fixed, 95% CI)Totals not selected

    6.1 vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.2 vs olanzapine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Behaviour: 4. average change score (OAS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    7.1 vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Mental state: 1. average change/endpoint score (BPRS, high = worse)3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    8.1 vs haloperidol - short term
137Mean Difference (IV, Fixed, 95% CI)-3.26 [-10.65, 4.13]

    8.2 vs haloperidol - medium term
3123Mean Difference (IV, Fixed, 95% CI)1.67 [-1.84, 5.18]

 9 Mental state: 2. average endpoint score (BPRS psychosis subscale, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    9.1 vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 10 Mental state: 3. average change score (PANSS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    10.1 vs olanzapine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 11 Mental state: 4. average change score (PANSS-excited component, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    11.1 vs olanzapine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 12 Adverse effects/events: 1. extrapyramidal symptoms8536Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.06, 0.39]

    12.1 vs haloperidol - medium term
6233Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.04, 0.41]

    12.2 vs olanzapine - medium term
1150Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.03, 1.89]

    12.3 vs droperidol - medium term
1153Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.90]

 13 Adverse effects/events: 2. use of medication for EPS2216Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.15, 1.05]

    13.1 vs haloperidol - medium term
166Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.17, 1.47]

    13.2 vs olanzapine - medium term
1150Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.03, 1.89]

 14 Adverse effects/events: 3. specific4Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    14.1 vs droperidol - airway management - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.2 vs haloperidol - ataxia - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.3 vs droperidol - blood pressure - low - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.4 vs haloperidol - dizziness - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.5 vs olanzapine - dizziness - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.6 vs haloperidol - dry mouth - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.7 vs droperidol - heart rate - low - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.8 vs haloperidol - heart rate - high - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.9 vs droperidol - hypoxia - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.10 vs olanzapine - nausea - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.11 vs droperidol - seizure - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.12 vs haloperidol - speech disorder - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.13 vs haloperidol - tremor - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.14 vs droperidol - vomiting - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    14.15 vs olanzapine - vomiting - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 15 Leaving the study early: 1. any reason3339Risk Ratio (M-H, Fixed, 95% CI)1.48 [0.70, 3.13]

    15.1 vs droperidol - medium term
1173Risk Ratio (M-H, Fixed, 95% CI)1.51 [0.60, 3.79]

    15.2 vs haloperidol - medium term
116Risk Ratio (M-H, Fixed, 95% CI)0.2 [0.01, 3.61]

    15.3 vs olanzapine - medium term
1150Risk Ratio (M-H, Fixed, 95% CI)5.82 [0.62, 54.58]

 
Comparison 3. BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME BENZODIAZEPINES

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global impression: 1. no improvement3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 + haloperidol - short term
120Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 1.74]

    1.2 + haloperidol - medium term
283Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.69, 1.28]

    1.3 + risperidone - medium term
120Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.45, 1.64]

 2 Global impression: 2. need for additional medication3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 + haloperidol - medium term
3103Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.79, 1.32]

    2.2 + risperidone - medium term
120Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Global impression: 3. sedation2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 +haloperidol - short term
147Risk Ratio (M-H, Fixed, 95% CI)1.92 [1.10, 3.35]

    3.2 +haloperidol - medium term
2110Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.59, 1.19]

 4 Behaviour: 1. average endpoint score (ABS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 + haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Mental state: 1. average endpoint score (BPRS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 + risperidone - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 + risperidone - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Mental state: 1. average endpoint score (BPRS, high = worse, skew)Other dataNo numeric data

    6.1 +haloperidol - short term
Other dataNo numeric data

    6.2 +haloperidol - medium term
Other dataNo numeric data

 7 Mental state: 2. average endpoint score (BPRS psychosis subscale, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    7.1 + haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Mental state: 1. average endpoint score (PANSS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    8.1 + risperidone - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    8.2 + risperidone - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Mental state: 3. average endpoint score (PANSS, high = worse, skew)Other dataNo numeric data

    9.1 +haloperidol - short term
Other dataNo numeric data

    9.2 +haloperidol - medium term
Other dataNo numeric data

 10 Adverse effects/events: 1. extrapyramidal symptoms2Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    10.1 +haloperidol - medium term
2Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 11 Adverse effects/events: 2. use of medication for EPS1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    11.1 +haloperidol - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 12 Adverse effects/events: 3. specific1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    12.1 +haloperidol - ataxia - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    12.2 +haloperidol - dizziness - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    12.3 +haloperidol - dry mouth - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    12.4 +haloperidol - speech disorder - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 13 Leaving the study early: 1. any reason2Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    13.1 +haloperidol - medium term
2Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    13.2 +risperidone - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 4. BENZODIAZEPINES + ANTIPSYCHOTICS vs SAME ANTIPSYCHOTICS

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global impression: 1. no improvement3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 +/vs haloperidol - medium term
3155Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.94, 1.70]

 2 Global impression: 2. need for additional medication1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 +/vs haloperidol - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Global impression: 3. need for additional medication (mean dose, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    3.1 +/vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Global impression: 4. sedation3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 +/vs haloperidol - short term
145Risk Ratio (M-H, Fixed, 95% CI)2.25 [1.18, 4.30]

    4.2 +/vs haloperidol - medium term
3172Risk Ratio (M-H, Fixed, 95% CI)1.75 [1.14, 2.67]

 5 Global impression: 5. average change score (RSS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 +/vs haloperidol - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 +/vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Behaviour: 1. average endpoint score (ABS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    6.1 +/vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Behaviour: 2. average endpoint score (OAS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    7.1 +/vs haloperidol - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    7.2 +/vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Behaviour: 4. average endpoint score (OASS agitation scale, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    8.1 +/vs haloperidol - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    8.2 +/vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Mental state: 1. average endpoint score (BPRS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    9.1 +/vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 10 Mental state: 2. average endpoint score (BPRS psychosis subscale, high = worse)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    10.1 +/vs haloperidol - medium term
295Mean Difference (IV, Fixed, 95% CI)-1.19 [-4.60, 2.23]

 11 Adverse effects/events: 1. extrapyramidal symptoms2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 +/vs haloperidol - medium term
2127Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.16, 1.17]

 12 Adverse effects/events: 2. use of medication for EPS2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    12.1 +/vs haloperidol - medium term
295Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.27, 1.01]

 13 Adverse effects/events: 3. specific2Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    13.1 +/vs haloperidol - ataxia - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    13.2 +/vs haloperidol - dizziness - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    13.3 +/vs haloperidol - dry mouth - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    13.4 +/vs haloperidol - hypotension - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    13.5 +/vs haloperidol - speech disorder - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 14 Hospital and service outcomes: 1. changes in hospital status1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    14.1 +/vs haloperidol - not discharged - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 5. BENZODIAZEPINES + ANTIPSYCHOTICS vs DIFFERENT ANTIPSYCHOTICS

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global impression: 1. no improvement1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 +haloperidol vs olanzapine - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 +haloperidol vs ziprasidone - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Global impression: 2. need for additional medication (mean dose, high = worse, skew)Other dataNo numeric data

    2.1 +haloperidol vs olanzapine - medium term
Other dataNo numeric data

    2.2 +haloperidol vs ziprasidone - medium term
Other dataNo numeric data

 3 Global impression: 3. sedation1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 +haloperidol vs olanzapine - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 +haloperidol vs ziprasidone - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Global impression: 4. average endpoint score (RSS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 +haloperidol vs olanzapine - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 +haloperidol vs olanzapine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 +haloperidol vs ziprasidone - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.4 +haloperidol vs ziprasidone - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Behaviour: 1. average change score (OAS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 +haloperidol vs olanzapine - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 +haloperidol vs olanzapine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.3 +haloperidol vs ziprasidone - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.4 +haloperidol vs ziprasidone - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Behaviour: 2. average endpoint score (OASS agitation scale, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    6.1 +haloperidol vs olanzapine - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.2 +haloperidol vs olanzapine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.3 +haloperidol vs ziprasidone - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.4 +haloperidol vs ziprasidone - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Mental state: 1. average endpoint score (PANSS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    7.1 +risperidone vs clozapine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    7.2 +risperidone vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Mental state: 2. average endpoint score (PANSS-excited component, high = worse)2Mean Difference (IV, Fixed, 95% CI)Totals not selected

    8.1 +risperidone vs clozapine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    8.2 +risperidone vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    8.3 +olanzapine vs haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Adverse effects/ events: 1. side effects2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 +risperidone vs clozapine - medium term
276Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.02, 1.48]

    9.2 +risperidone vs haloperidol - medium term
140Risk Ratio (M-H, Fixed, 95% CI)0.05 [0.00, 0.85]

 10 Adverse effects/events: 2. extrapyramidal symptoms1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    10.1 +haloperidol vs olanzapine - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    10.2 +haloperidol vs ziprasidone - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 11 Adverse effects/events: 3. specific1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    11.1 +haloperidol vs olanzapine - hypotension - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    11.2 +haloperidol vs ziprasidone - hypotension - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 6. BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIPSYCHOTICS

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Behaviour: 3. average endpoint score (OAS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    1.1 + haloperidol vs clothiapine + haloperidol - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Leaving the study early: 1. any reason1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 +haloperidol vs clothiapine+haloperidol - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 7. BENZODIAZEPINES vs ANTIPSYCHOTICS + ANTIHISTAMINES

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global impression: 1. no improvement1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 vs haloperidol+promethazine - immediate term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 vs haloperidol+promethazine - short term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 vs haloperidol+promethazine - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Global impression: 2. need for additional medication1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    2.1 vs haloperidol+promethazine - immediate term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 vs haloperidol+promethazine - short term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.3 vs haloperidol+promethazine - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Global impression: 3. sedation2Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 vs haloperidol+promethazine - immediate term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 vs haloperidol+promethazine - short term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.3 vs haloperidol+promethazine - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.4 vs haloperidol+promethazine - short term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.5 vs haloperidol+promethazine - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Global impression: 4. average endpoint score (CGI, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 vs haloperidol+promethazine - immediate term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 vs haloperidol+promethazine - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 vs haloperidol+promethazine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Adverse effects/ events: 1. specific2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 vs haloperidol+promethazine - airway management - medium term
2501Risk Ratio (M-H, Fixed, 95% CI)2.99 [0.31, 28.54]

    5.2 vs haloperidol+promethazine - nausea - medium term
1200Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.12, 72.77]

    5.3 vs haloperidol+promethazine - seizure - medium term
1301Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 8.06]

 6 Leaving the study early: 1. any reason2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 vs haloperidol+promethazine - medium term
2501Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.06, 2.87]

 7 Hospital and service outcomes: 1. changes in hospital status1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    7.1 vs haloperidol+promethazine - not discharged - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 8. BENZODIAZEPINES + ANTIPSYCHOTICS vs ANTIPSYCHOTICS + ANTIHISTAMINES

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global impression: 1. no improvement1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 +haloperidol vs haloperidol+promethazine - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Global impression: 2. need for additional medication (mean dose, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    2.1 + haloperidol vs haloperidol + promethazine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Global impression: 3. sedation1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 +haloperidol vs haloperidol+promethazine - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Global impression: 4. average change score (RSS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    4.1 +haloperidol vs haloperidol+promethazine - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 +haloperidol vs haloperidol+promethazine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Behaviour: 1. average endpoint score (OAS, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    5.1 + haloperidol vs haloperidol + promethazine - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 + haloperidol vs haloperidol + promethazine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Behaviour: 2. average endpoint score (OASS agitation scale, high = worse)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    6.1 +haloperidol vs haloperidol+promethazine - short term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.2 +haloperidol vs haloperidol+promethazine - medium term
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 7 Adverse effects/events: 1. extrapyramidal symptoms1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    7.1 +haloperidol vs haloperidol+promethazine - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Adverse effects/events: 2. specific1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    8.1 +haloperidol vs haloperidol+promethazine - hypotension - medium term
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 9. SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 1. Random sequence generation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global impression: 1. no improvement5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 unknown risk of bias
3214Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.78, 1.63]

    1.2 low risk of bias
294Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.75, 1.49]

 2 Global impression: 2. sedation9Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 unknown risk of bias
6340Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.56, 1.26]

    2.2 low risk of bias
3247Risk Ratio (M-H, Fixed, 95% CI)2.22 [1.52, 3.25]

 3 Adverse effects/events: 1. extrapyramidal symptoms8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 unknown risk of bias
5285Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.05, 0.47]

    3.2 low risk of bias
3247Risk Ratio (M-H, Fixed, 95% CI)0.16 [0.03, 0.85]

 
Comparison 10. SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 2. Allocation concealment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global impression: 1. no improvement5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 unknown risk of bias
5308Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.85, 1.42]

 2 Global impression: 2. sedation9Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 high risk of bias
140Risk Ratio (M-H, Fixed, 95% CI)0.6 [0.27, 1.34]

    2.2 unknown risk of bias
7394Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.85, 1.70]

    2.3 low risk of bias
1153Risk Ratio (M-H, Fixed, 95% CI)2.71 [1.55, 4.73]

 3 Adverse effects/ events: 1. extrapyramidal symptoms8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 unknown risk of bias
7379Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.06, 0.41]

    3.2 low risk of bias
1153Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.90]

 
Comparison 11. SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 3. Blinded outcome measurement

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global impression: 1. no improvement5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 unknown risk of bias
2178Risk Ratio (M-H, Fixed, 95% CI)1.90 [1.11, 3.24]

    1.2 low risk of bias
3130Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.56, 0.96]

 2 Global impression: 2. sedation9Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 high risk of bias
2197Risk Ratio (M-H, Fixed, 95% CI)2.08 [1.35, 3.23]

    2.2 unknown risk of bias
4255Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.39, 1.20]

    2.3 low risk of bias
3135Risk Ratio (M-H, Fixed, 95% CI)1.56 [0.99, 2.46]

 3 Adverse effects/events: 1. extrapyramidal symptoms8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 high risk of bias
1153Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.90]

    3.2 unknown risk of bias
4257Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.03, 0.90]

    3.3 low risk of bias
3122Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.04, 0.48]

 
Comparison 12. SENSITIVITY ANALYSIS: BENZODIAZEPINES vs ANTIPSYCHOTICS - 4. Incomplete outcome data (attrition bias)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Global impression: 1. no improvement5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 high risk of bias
148Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.32, 0.97]

    1.2 unknown risk of bias
166Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.71, 1.38]

    1.3 low risk of bias
3194Risk Ratio (M-H, Fixed, 95% CI)1.85 [1.12, 3.06]

 2 Global impression: 2. sedation9Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 high risk of bias
3246Risk Ratio (M-H, Fixed, 95% CI)1.61 [1.10, 2.38]

    2.2 unknown risk of bias
3147Risk Ratio (M-H, Fixed, 95% CI)1.55 [1.01, 2.38]

    2.3 low risk of bias
3194Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.34, 1.58]

 3 Adverse effects/events: 1. extrapyramidal symptoms8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 high risk of bias
2193Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.02, 0.54]

    3.2 unknown risk of bias
3149Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.03, 0.70]

    3.3 low risk of bias
3190Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.05, 1.52]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. Previous search methods for identification of studies

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

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

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

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 1 June 2012.


DateEventDescription

18 March 2013New citation required and conclusions have changedMinor changes to conclusions after new data added to review.

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



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

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


DateEventDescription

22 October 2008AmendedConverted to new review format.

5 August 2005New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

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

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Internal sources

  • The Children's Hospital at Westmead, Sydney, Australia.
  • Central Wandsworth Community Mental Health Team, London, UK.
  • St George's Mental Health NHS Trust, London, UK.
  • Western Sydney Local Health District, Australia.

 

External sources

  • NHS National R&D Programme on Forensic Mental Health, UK.
  • National Institute for Health Research (NIHR), UK.
    Cochrane Collaboration Programme Grant 2011; Reference number: 10/4001/15

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

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

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Alprazolam 1992, USA {published data only}
  • Barbee JG, Mancuso DM, Freed CR, Todorov AA. Alprazolam as a neuroleptic adjunct in the emergency treatment of schizophrenia. American Journal of Psychiatry 1992;149:506-10.
Clonazepam 1993, CA {published data only}
  • Chouinard G, Annable L, Turnier L, Holobow N, Szkrumelak N. A double-blind randomized clinical trial of rapid tranquilization with I.M. clonazepam and I.M. haloperidol in agitated psychotic patients with manic symptoms [presented at the 143rd annual meeting of the American Psychiatric Association, NY, May 12-17, 1990, and at the 42nd annual meeting of the Canadian Psychiatric Association, Montreal, Quebec, September 17, 1992]. Canadian Journal of Psychiatry 1993;38:S114-S121.
Clonazepam 1999, CHN {published data only}
  • Qu HF, Zhang Z, Xu B. Comparison of the effects of clonazepam and haloperidol in the treatment of psychotic breakdown behavior. Health Psychology Journal 1999;7(2):134-5.
Clonazepam 2003, CHN {published data only}
  • Yang X, Wang Z, Ling Z. A randomly controlled comparison of risperidone added with intramuscular clonazepam in the treatment of excitement of schizophrenia. Shanghai Archives of Psychiatry 2003;15(2):98-9.
Clonazepam 2004, CHN {published data only}
  • Wang G, Cai ZJ, Wang LF. A multicenter study of risperidone treatment for acute agitation in patients with schizophrenia. Chinese Journal of Psychiatry 2004;37(2):88-91.
Clonazepam 2005, CHN {published data only}
  • Han Z, Wang L, Wang J. Efficacy of risperidone, clonazepam in the treatment of excitement state of schizophrenia. Ningxia Medical Journal 2005;27(9):631-2.
Clonazepam 2007, CHN {published data only}
  • Zhang HS. Study of olanzapine combined with clonazepam in treatment of schizophrenia with acute psychomotor excitation. Linchuang Jingshen Yixue Zazhi 2007;17(4):239-40.
Diazepam 1979, IL {published data only}
Flunitrazepam 1999, IL {published data only}
  • Dorevitch A, Katz N, Zemishlany Z, Aizenberg D, Weizman A. Intramuscular flunitrazepam versus intramuscular haloperidol in the emergency treatment of aggressive psychotic behavior. American Journal of Psychiatry 1999;156:142-4.
Lorazepam 1989, USA {published data only}
  • Garza-Trevino ES, Hollister LE, Overall JE, Alexander WF. Efficacy of combinations of intramuscular antipsychotics and sedative-hypnotics for control of psychotic agitation [presented in part at the 141st annual meeting of the American Psychiatric Association, Montreal, May 7-12, 1988, and at the 142nd annual meeting of the American Psychiatric Association, San Fransisco, May 6-11, 1989]. American Journal of Psychiatry 1989;146:1598-601.
Lorazepam 1991, USA {published data only}
  • Salzman C, Solomon D, Miyawaki E, Glassman R. Parenteral lorazepam versus parenteral haloperidol for the control of psychotic disruptive behavior. Journal of Clinical Psychiatry 1991;52(4):177-80.
  • Solomon DA, Miyawaki E, Salzman C. Benzodiazepine augmentation of the treatment of disruptive psychotic behaviour [Review]. Progress in Drug Research 1990;35:139-49.
Lorazepam 1997, USA {published data only}
  • Battaglia J, Moss S, Rush J, Kang J, Mendoza R, Leedom L. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. American Journal of Emergency Medicine 1997;15:335-40.
Lorazepam 1997a, USA {published data only}
  • Foster S, Kessel J, Berman ME, Simpson GM. Efficacy of lorazepam and haloperidol for rapid tranquilization in a psychiatric emergency room setting. International Clinical Psychopharmacology 1997;12:175-9.
Lorazepam 1998, SA {published data only}
  • Subramaney U, Brook S, Berk M. A prospective randomised double-blind controlled study of the efficacy of lorazepam versus clothiapine in the control of acutely behaviourally disturbed patients. South African Medical Journal 1998;88(3):307-10.
Lorazepam 1998, USA {published data only}
  • Bieniek SA, Ownby RL, Penalver A, Dominguez RA. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Pharmacotherapy 1998;18:57-62.
Lorazepam 2001, RO & USA {published data only}
  • Battaglia J, Lindborg SR, Alaka K, Meehan K, Wright P. Calming versus sedative effects of intramuscular olanzapine in agitated patients. American Journal of Emergency Medicine 2003;21(3):192-8.
  • Breier A, Meehan K, Birkett M, David S, Ferchland I, Sutton V, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Archives of General Psychiatry 2002;59(5):441-8. [DOI: 10.1001/archpsyc.59.5.441]
  • David SR, Battaglia J, Alaka K, Meehan K, Wright P. Calming versus sedative effects of IM olanzapine in agitated patients. 11th Association of European Psychiatrists Congress. Stockholm, Sweden, May 4-8, 2002; Vol. 17, issue Suppl 1:104s.
  • David SR, Jones B, Alaka K, Meehan K, Wright P, Taylor CC, et al. The efficacy of intramuscular olanzapine in acutely agitated patients. 155th Annual Meeting of the American Psychiatric Association. Philadelphia, PA, USA, May 18-23, 2002.
  • Meehan KZ. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. Journal of Clinical Psychopharmacology 2001;21(4):389-97.
Lorazepam 2004, IN {published data only}
  • Alexander J. Lorazepam versus a combination of haloperidol and promethazine in the acute management of agitation and aggression - a randomized controlled trial. MD Thesis. Vellore, India: Christian Medical College 2003.
  • Alexander J, John T, Tharyan P, Adams CE. TREC-India. A second arm of TREC. Schizophrenia Research 2002;53(3 Suppl. 1):236. [MEDLINE: 73085373; : PMID 4405388]
  • Alexander J, Tharyan P, Adams CE, John T, Mol C, Philip J. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting: a pragmatic randomised trial of intramuscular lorazepam versus haloperidol plus promethazine. British Journal of Psychiatry 2004;185:63-9.
Lorazepam 2006, USA {published data only}
  • Veser F, Zealburg J, Veser B, Zhu Y, Gharabawi G. Oral risperidone in the management of agitated behavior in emergency settings. Journal of the European College of Neuropsychopharmacology 2002;12(Suppl 3):S313.
  •  Veser FH, Veser BD, McMullan JT, Zealberg J, Currier GW. Risperidone versus haloperidol, in combination with lorazepam, in the treatment of acute agitation and psychosis: a pilot, Randomized, double-blind, placebo-controlled trial. Journal of Psychiatric Practice 2006;12(2):103-8.
Midazolam 2003, BZ {published data only}
  • Huf G, Coutinho ESF, Adams CE. The pharmacological management of agitated patients in emergency psychiatric hospitals in Rio de Janeiro, Brazil: the results of two pragmatic randomized clinical trials. 5th European Congress on Violence in Clinical Psychiatry.  Amsterdam, The Netherlands. 2007, 25-27 October 2007.
  • Huf G, Coutinho ESF, Adams CE. TREC III. The protocol and progress of TREC. Schizophrenia Research 2002;53(3 Suppl. 1):187. [MEDLINE: 73085373; : PMID 4405388]
  • Huf G, Coutinho ESF, Adams CE. TREC-Rio trial: a randomised controlled trial for rapid tranquillisation for agitated patients in emergency psychiatric rooms. BMC Psychiatry 2002;2(11):4. [: EMBASE 2002383527]
  • Huf G, Coutinho ESF, Fagundes HM Jr, Carvalho AL, Ramos FA, Keusen AL, et al. TREC II. Current practices in managing acutely disturbed patients at three hospitals in Rio de Janeiro, Brazil. Schizophrenia Research 2002;53(3):236-7. [MEDLINE: 73085373; : PMID 4405388]
  • TREC Collaborative Group. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. BMJ 2003;327(7417):708-13. [: EMBASE: 2003210869]
Midazolam 2006, AU {published data only}
  • Knott JC, Taylor D, Castle DJ. Randomized clinical trial comparing intravenous midazolam and droperidol for sedation of the acutely agitated patient in the emergency department. Annals of Emergency Medicine 2006;47(1):61-7.
Midazolam 2011, BZ {published data only}
  • Baldacara L, Sanches M, Cordeiro DC, Jackoswksi AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Revista Brasileire da Psiquiatria 2011;33(1):30-9.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Arana 1986 {published data only}
  • Arana GW, Ornsteen ML, Kanter F, Friedman HL, Greenblatt DJ, Shader RI. The use of benzodiazepines for psychotic disorders: a literature review and preliminary clinical findings. Psychopharmacology Bulletin 1986;22(1):77-87.
Davis 2008b {published data only}
  • Davis JM, Wang B, He Y, Jin H, Hu Q, Zhang M. The emergency treatment of acutely agitated psychotic schizophrenia patients. International Journal of Neuropsychopharmacology 2008;11(Supplement 1):163.
Guz 1972 {published data only}
  • Guz I, Moraes R, Sartoretto JN. The therapeutic effects of lorazepam in psychotic patients treated with haloperidol: a double blind study. Therapuetic Research Press 1972;14(12):767-74.
Hankoff 1962 {published data only}
  • Hankoff LD, Rudorfer L, Paley HM. A reference study of ataraxics: a two-week double blind outpatient evaluation. Journal of New Drugs 1962;2:173-8.
Hanlon 1970 {published data only}
  • Hanlon TE, Ota KY, Kurland AA. Comparative effects of fluphenazine, fluphenazine-chlordiazepoxide and fluphenazine-imipramine. Diseases of the Nervous System 1970;31(3):171-7.
Kang 2006 {published data only}
  • Kang MX. Clinical study on efficacy of quetiapine combined with clonazepam treated with acute agitation in schizophrenia patients. Linchuang Jingshen Yixue Zazhi 2006;16(4):221-2.
Lenox 1992 {published data only}
  • Lenox RH, Newhouse PA, Creelman WL, Whitaker TM. Adjunctive treatment of manic agitation with lorazepam versus haloperidol: a double-blind study. Journal of Clinical Psychiatry 1992;53(2):47-52.
Martel 2005 {published data only}
  • Martel M, Sterzinger A, Miner J, Clinton J, Biros M. Management of acute undifferentiated agitation in the emergency department: a randomized double-blind trial of droperidol, ziprasidone, and midazolam. Academic Emergency Medicine 2005;12(12):1167-72.
Mei 2006 {published data only}
  • Mei Y, Pan JPM. Clinical observation on acute excitation of schizophrenia treated with QIWEI combined with clonazepam. Chinese Nursing Research 2006;20(5):1176-7.
  • Wang DB, Xu SQ, Tang QP, Ying YF, Mei YT, He FX. Treatment of 80 cases of schizophrenia manifesting acute erethitic symptoms with quetiapine combined with clonazepam. Herald of Medicine 2005;24(8):687-8.
Nestoros 1982 {published data only}
Nobay 2004 {published data only}
  • Nobay F, Simon BC, Levitt MA, Dresden GM. A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients. Academic Emergency Medicine 2004;11(7):744-9.
Simpson 2003b {published data only}
  • Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. Journal of Clinial Psychiatry 2001;62(3):135-7.
  • Simpson GM, Morein JD, Reyes-Harde M, Gharabawi G. A pragmatic and convenient approach for the management or acute agitation: results from a series of clinical studies. Proceedings of the 16th European College of Neuropsychopharmacology Congress. Czech Republic, 2003; Vol. September:20-4.
Tang 2007 {published data only}
  • Tang Q, Yang L, Lai G, Zhand J. A clinical study of risperidone oral solution combined with clonazepam injection in the treatment of acute excitement phase schizophrenia patient. Shanghai Archives of Psychiatry 2007;19(3):153-5.
Wan Zhili 2005 {published data only}
  • Wan Z, Zhong Z. Curative effect of risperidone with BDZs in the treatment of excitement and agitation with schizophrenia in acute phase. Chinese Journal of Health Psychology 2005;13(1):23-4.
Wyant 1990 {published data only}
  • Wyant M, Diamond BI, O'Neal E, Sloan A, Borison RL. The use of midazolam in acutely agitated psychiatric patients. Psychopharmacology Bulletin 1990;26(1):126-9.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Ahmed 2010
Ahmed 2011
  • Ahmed U, Rehman F, Jones H, Adams CE. Risperidone for psychosis induced aggression or agitation. Cochrane Database of Systematic Reviews 2011, Issue 11. [DOI: 10.1002/14651858.CD009412]
Allen 2000
  • Allen MH. Managing the agitated psychotic patient: a reappraisal of the evidence. Journal of Clinical Psychiatry 2000;61(Suppl 14):11-20.
Allen 2005
  • Allen MH, Currier GW, Carpenter D, Ross RW Docherty JP. The expert consensus guideline series. Treatment of behavioural emergencies. Journal of Psyhciatric Practice 2005;11(suppl 1):5-108.
Battaglia 2005
Belgamwar 2005
Bland 1997
  • Bland JM. Statistics notes. Trials randomised in clusters. BMJ 1997;315:600.
Boissel 1999
  • Boissel JP, Cucherat M, Li W, Chatellier G, Gueyffier F, Buyse M, et al. The problem of therapeutic efficacy indices. 3. Comparison of the indices and their use [Apercu sur la problematique des indices d'efficacite therapeutique, 3: comparaison des indices et utilisation. Groupe d'Etude des Indices D'efficacite]. Therapie 1999;54(4):405-11.
Busner 2007
  • Busner JJ, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry 2007;4(7):28-37.
Cairns 1983
  • Cairns V, von Zerssen D, Stutte KH, Mombour W. The stability of the symptom groupings in the Inpatient Multidimensional Psychiatric Scale (IMPS). Journal of Psychiatric Research 1983;17(1):19-28.
Caplan 1999
  • Caplan B. Reliability of the Agitated Behaviour Scale. Journal of Head Trauma Rehabilitation 1999;14(1):91-6.
Chakrabarti 2007
Corrigan 1988
Deeks 2000
  • Deeks J. Issues in the selection for meta-analyses of binary data. Proceedings of the 8th International Cochrane Colloquium; 2000 Oct 25-28; Cape Town. Cape Town: The Cochrane Collaboration, 2000.
Divine 1992
Duggan 2005
Egger 1997
  • Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315(7109):629-34.
Elbourne 2002
  • Elbourne D, Altman DG, Higgins JPT, Curtina F, Worthingtond HV, Vaile A. Meta-analyses involving cross-over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140-9.
Essali 2009
Faustman 1989
  • Faustman W.O, Moses J.A, Csernansky J.G, White P.A. Correlations between the MMPI and the Brief Psychiatric Rating Scale in schizophrenic and schizoaffective patients. Psychiatry Research 1989;28:135-43.
Furukawa 2006
  • Furukawa TA, Barbui C, Cipriani A, Brambilla P, Watanabe N. Imputing missing standard deviations in meta-analyses can provide accurate results. Journal of Clinical Epidemiology 2006;59(7):7-10.
Gibson 2012
Goedhard 2006
  • Goedhard LE, Stolker JJ, Heerdink ER, Nijman HL, Olivier B, Egberts TC. Pharmacotherapy for the treatment of aggressive behavior in general adult psychiatry: A systematic review. Journal of Clinical Psychiatry 2006;67(7):1013-24.
Gulliford 1999
  • Gulliford MC. Components of variance and intraclass correlations for the design of community-based surveys and intervention studies: data from the Health Survey for England 1994. American Journal of Epidemiology 1999;149(9):876-83.
Guy 1970
  • Guy W, Bonato RR. Clinical global impressions. In: Guy W, Bonato RR editor(s). Manual for the ECDEU Assessment Battery. 2 Rev. National Institute of Mental Health, 1970:12-1-12-6.
Higgins 2008
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 [updated February 2008]. The Cochrane Collaboration, 2008.
Higgins 2011
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org..
Huf 2002
  • Huf G, da Silva Freire Coutinho E, Fagundes HM Jr, Oliveira ES, Lopez JR, Gewandszajder M, da Luz Carvalho A, Keusen A, Adams CE. Current practices in managing acutely disturbed patients at three hospitals in Rio de Janeiro-Brazil: a prevalence study. BMC Psychiatry 2002;2:4.
Huf 2009
James 2011
  • James BO. Rapid tranquillization agents for severe behavioural disturbance: a survey of African psychiatrists' prescription patterns. Tropical Doctor 2011;41(1):49-50.
Kay 1987
  • Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 1987;13(2):261-76.
Khushu 2012
  • Khushu A, Powney MJ, Adams CE. Haloperidol for long-term aggression in psychosis. Cochrane Database of Systematic Reviews 2012, Issue 5. [DOI: 10.1002/14651858.CD009830]
Larson 1994
  • Larson JS, Lunn JJ. Comparing drugs for short-term sedation. Contemporary Internal Medicine 1994;6(12):55-60.
Leucht 2007
  • Leucht S, Engel RR, Bauml J, Davis JM. Is the superior efficacy of new generation antipsychotics an artifact of LOCF?. Schizophrenia Bulletin 2007;33(1):183-91. [PUBMED: 16905632]
Lorr 1963
  • Lorr M, Klett CJ, McNair DM, Lasky JJ. Inpatient Multidimensional Psychiatric Scale. Palo Alto: Consulting Psychologists Press, 1963.
Marder 2006
  • Marder SR. A review of agitation in mental illness: treatment guidelines and current therapies. Journal of Clinical Psychiatry 2006;67(Suppl 10):13-21.
Marshall 2000
  • Marshall M, Lockwood A, Bradley C, Adams C, Joy C, Fenton M. Unpublished rating scales: a major source of bias in randomised controlled trials of treatments for schizophrenia. British Journal of Psychiatry 2000;176:249-52.
Mintzer 2006
  • Mintzer JE. Rapid tranquillization agents for severe behavioural disturbance: a survey of African psychiatrists' prescription patterns. Journal of Clinical Psychiatry 2006;67(Suppl 10):3-5.
Moher 2001
Muralidharan 2006
NICE 2005
  • The National Institute for Clinical Excellence. Violence: the short-term management of disturbed/violent behaviour in psychiatric in-patient settings and emergency departments. NICE Clinical Guideline 25 February 2005.
Overall 1967
  • Overall JE, Hollister LE, Pichot P. Major psychiatric disorders: a four dimensional model. Archives of General Psychiatry 1967;16(2):146-51.
Pagadala 2009
  • Pagadala B, Jayaram MB, Mitra L. Aripiprazole for psychosis-induced aggression or agitation. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/14651858.CD008074]
Powney 2011
  • Powney MJ, Adams CE, Jones H. Haloperidol (rapid tranquilisation) for psychosis induced aggression or agitation. Cochrane Database of Systematic Reviews 2011, Issue 10. [DOI: 10.1002/14651858.CD009377]
Ramsay 1974
  • Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. British Medical Journal 1974;2:656-9.
Rocca 2006
  • Rocca P, Villari V, Bogetto F. Managing the aggressive and violent patient in the psychiatric emergency. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2006;30(4):586-98.
Sailas 2000
  • Sailas EES, Fenton M. Seclusion and restraint for people with serious mental illnesses. Cochrane Database of Systematic Reviews 2000, Issue 1. [DOI: 10.1002/14651858.CD001163]
Schünemann 2008
  • Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, et al. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2008:359-83.
Shafer 2005
Silveira 2002
  • Silveira da Mota Neto JI, Soares B, Silva de Lima M. Amisulpride for schizophrenia. Cochrane Database of Systematic Reviews 2002, Issue 2. [DOI: 10.1002/14651858.CD001357]
TREC Vellore
  • Alexander J, Tharyan P, Adams CE, John T, Mol C, Philip J. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting: a pragmatic randomised trial of intramuscular lorazepam versus haloperidol plus promethazine. British Journal of Psychiatry 2004;185:63-9.
TREC-II Brazil
  • TREC Collaborative Group. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. BMJ 2003;327(7417):708-13. [EMBASE: 2003210869]
Vangala 2011
  • Vangala R, Ahmed U, Ahmed R. Loxapine inhaler for psychosis-induced aggression or agitation. Cochrane Database of Systematic Reviews 2012, Issue 11. [DOI: 10.1002/14651858.CD010190]
Volz 2007
Wilkie 2012
  • Wilkie F, Fenton M. Quetiapine for psychosis-induced aggression or agitation. Cochrane Database of Systematic Reviews 2012, Issue 4. [DOI: 10.1002/14651858.CD009801]
Xia 2009
  • Xia J, Adams CE, Bhagat N, Bhagat V, Bhoopathi P, El-Sayeh H, et al. Loss to outcomes stakeholder survey: the LOSS study. Psychiatric Bulletin 2009;33(7):254-7.
Yudofsky 1986
  • Yudofsky SC, Silver JM, Jackson W, Endicott J, Williams D. The Overt Aggression Scale for the objective rating of verbal and physical aggression. American Journal of Psychiatry 1986;143(1):35-9.
Yudofsky 1997
  • Yudofsky SC, Kopecky HJ, Kunik M, Silver JM, Endicott J. The Overt Agitation Severity Scale for the objective rating of agitation. Journal of Neuropsychiatry 1997;9(4):541-8.