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Review
. 2017 Dec 8;12(12):CD003079.
doi: 10.1002/14651858.CD003079.pub4.

Benzodiazepines for psychosis-induced aggression or agitation

Hadar Zaman  1 , Stephanie J Sampson, Alison Ls Beck, Tarang Sharma, Fiona J Clay, Styliani Spyridi, Sai Zhao, Donna Gillies
Affiliations
Review

Benzodiazepines for psychosis-induced aggression or agitation

Hadar Zaman et al. Cochrane Database Syst Rev. .

Abstract

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

Objectives: To examine whether benzodiazepines, alone or in combination with other pharmacological agents, is an effective treatment for psychosis-induced aggression or agitation when compared with placebo, other pharmacological agents (alone or in combination) or non-pharmacological approaches.

Search methods: We searched the Cochrane Schizophrenia Group's register (January 2012, 20 August 2015 and 3 August 2016), inspected reference lists of included and excluded studies, and contacted authors of relevant studies.

Selection criteria: We included all randomised controlled trials (RCTs) comparing benzodiazepines alone or in combination with any antipsychotics, versus antipsychotics alone or in combination with any other antipsychotics, benzodiazepines or antihistamines, for people who were aggressive or agitated due to psychosis.

Data collection and analysis: We reliably selected studies, quality assessed them and extracted data. For binary outcomes, we calculated standard estimates of risk ratio (RR) and their 95% confidence intervals (CI) using a fixed-effect model. For continuous outcomes, we calculated the mean difference (MD) between groups. If there was heterogeneity, this was explored using a random-effects model. We assessed risk of bias and created a 'Summary of findings' table using GRADE.

Main results: Twenty trials including 695 participants are now included in the review. The trials compared benzodiazepines or benzodiazepines plus an antipsychotic with placebo, antipsychotics, antihistamines, or a combination of these. The quality of evidence for the main outcomes was low or very low due to very small sample size of included studies and serious risk of bias (randomisation, allocation concealment and blinding were not well conducted in the included trials, 30% of trials (six out of 20) were supported by pharmaceutical institutes). There was no clear effect for most outcomes.Benzodiazepines versus placeboOne trial compared benzodiazepines with placebo. There was no difference in the number of participants sedated at 24 hours (very low quality evidence). However, for the outcome of global state, clearly more people receiving placebo showed no improvement in the medium term (one to 48 hours) (n = 102, 1 RCT, RR 0.62, 95% CI 0.40 to 0.97, very low quality evidence). Benzodiazepines versus antipsychoticsWhen compared with haloperidol, there was no observed effect for benzodiazepines for sedation by 16 hours (n = 434, 8 RCTs, RR 1.13, 95% CI 0.83 to 1.54, low quality evidence). There was no difference in the number of participants who had not improved in the medium term (n = 188, 5 RCTs, RR 0.89, 95% CI 0.71 to 1.11, low quality evidence). However, one small study found fewer participants improved when receiving benzodiazepines compared with olanzapine (n = 150, 1 RCT, RR 1.84, 95% CI 1.06 to 3.18, very low quality evidence). People receiving benzodiazepines were less likely to experience extrapyramidal effects in the medium term compared to people receiving haloperidol (n = 233, 6 RCTs, RR 0.13, 95% CI 0.04 to 0.41, low quality evidence).Benzodiazepines versus combined antipsychotics/antihistaminesWhen benzodiazepine was compared with combined antipsychotics/antihistamines (haloperidol plus promethazine), there was a higher risk of no improvement in people receiving benzodiazepines in the medium term (n = 200, 1 RCT, RR 2.17, 95% CI 1.16 to 4.05, low quality evidence). However, for sedation, the results were controversial between two groups: lorazepam may lead to lower risk of sedation than combined antipsychotics/antihistamines (n = 200, 1 RCT, RR 0.91, 95% CI 0.84 to 0.98, low quality evidence); while, midazolam may lead to higher risk of sedation than combined antipsychotics/antihistamines (n = 200, 1 RCT, RR 1.13, 95% CI 1.04 to 1.23, low quality evidence).Other combinationsData comparing benzodiazepines plus antipsychotics versus benzodiazepines alone did not yield any results with clear differences; all were very low quality evidence. When comparing combined benzodiazepines/antipsychotics (all studies compared haloperidol) with the same antipsychotics alone (haloperidol), there was no difference between groups in improvement in the medium term (n = 185, 4 RCTs, RR 1.17, 95% CI 0.93 to 1.46, low quality evidence), but sedation was more likely in people who received the combination therapy (n = 172, 3 RCTs, RR 1.75, 95% CI 1.14 to 2.67,very low quality evidence). Only one study compared combined benzodiazepine/antipsychotics with antipsychotics; however, this study did not report our primary outcomes. One small study compared combined benzodiazepines/antipsychotics with combined antihistamines/antipsychotics. Results showed a higher risk of no clinical improvement (n = 60, 1 RCT, RR 25.00, 95% CI 1.55 to 403.99, very low quality evidence) and sedation status (n = 60, 1 RCT, RR 12.00, 95% CI 1.66 to 86.59, very low quality evidence) in the combined benzodiazepines/antipsychotics group.

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

PubMed Disclaimer

Conflict of interest statement

HZ: received a grant for completion of the 2016 update

SJS: received a grant for completion of 2012 update.

AB: none known.

TS: none known.

FC: none known

SS: none known.

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

DG: none known.

Figures

1
1
Funnel plot of comparison: 2 benzodiazepines versus antipsychotics, outcome: 2.1 Tranquillisation or asleep: 1. sedation.
2
2
Study flow diagram.
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
4
4
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1: Benzodiazepines versus placebo, Outcome 1: Tranquillisation or asleep: 1. sedation
1.2
1.2. Analysis
Comparison 1: Benzodiazepines versus placebo, Outcome 2: Behaviour: 1. mean change score (Agitated Behaviour Scale, high = worse)
1.3
1.3. Analysis
Comparison 1: Benzodiazepines versus placebo, Outcome 3: Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC))
1.4
1.4. Analysis
Comparison 1: Benzodiazepines versus placebo, Outcome 4: Global state: 2. need for additional medication
1.5
1.5. Analysis
Comparison 1: Benzodiazepines versus placebo, Outcome 5: Global state: 3. mean change score (Clinical Global Impression Severity Scale, high = worse)
1.6
1.6. Analysis
Comparison 1: Benzodiazepines versus placebo, Outcome 6: Mental state: 1. mean change score (Positive and Negative Syndrome Scale, high = worse)
1.7
1.7. Analysis
Comparison 1: Benzodiazepines versus placebo, Outcome 7: Mental state: 2. mean change score (PANSS‐EC, high = worse)
1.8
1.8. Analysis
Comparison 1: Benzodiazepines versus placebo, Outcome 8: Adverse effects/events: 1. extrapyramidal symptoms (EPS)
1.9
1.9. Analysis
Comparison 1: Benzodiazepines versus placebo, Outcome 9: Adverse effects/events: 2. use of medication for EPS
1.10
1.10. Analysis
Comparison 1: Benzodiazepines versus placebo, Outcome 10: Adverse effects/events: 3. specific
1.11
1.11. Analysis
Comparison 1: Benzodiazepines versus placebo, Outcome 11: Leaving the study early: 1. any reason
2.1
2.1. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 1: Tranquillisation or asleep: 1. sedation
2.2
2.2. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 2: Behaviour: 2. mean change/endpoint score (Agitated Behaviour Scale, high = worse)
2.3
2.3. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 3: Behaviour: 4. mean change score (Overt Aggression Scale, high = worse)
2.4
2.4. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 4: Global state: 1. no improvement (> 40% reduction Positive and Negative Syndrome Scale‐Excited Component (PANSS‐EC))
2.5
2.5. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 5: Global state: 2. need for additional medication
2.6
2.6. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 6: Global state: 3. mean change/endpoint score (Clinical Global Impression Severity Scale, high = worse)
2.7
2.7. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 7: Global state: 4. mean endpoint score (Inpatient Multidimensional Psychiatric Scale, high = worse)
2.8
2.8. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 8: Mental state: 1. no improvement (decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%)
2.9
2.9. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 9: Mental state: 2. mean change/endpoint score (BPRS, high = worse)
2.10
2.10. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 10: Mental state: 3. mean endpoint score (BPRS psychosis subscale, high = worse)
2.11
2.11. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 11: Mental state: 3a. mean endpoint score (BPRS positive subscale, high = worse)
2.12
2.12. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 12: Mental state: 4a. mean endpoint score (BPRS‐excited component, high = worse)
2.13
2.13. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 13: Mental state: 2a. mean change score (Positive and Negative Syndrome Scale, high = worse)
2.14
2.14. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 14: Mental state: 4. mean change score (PANSS‐EC, high = worse)
2.15
2.15. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 15: Adverse effects/events: 1. extrapyramidal symptoms (EPS)
2.16
2.16. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 16: Adverse effects/events: 2. use of medication for EPS
2.17
2.17. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 17: Adverse effects/events: 3. specific
2.18
2.18. Analysis
Comparison 2: Benzodiazepines versus antipsychotics, Outcome 18: Leaving the study early: 1. any reason
3.1
3.1. Analysis
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 1: Tranquilisation or asleep: 1. sedation
3.2
3.2. Analysis
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 2: Global state: 1. no improvement (Clinical Global Impression (CGI) ‐ improvement scale dichotomised; much and very much improved)
3.3
3.3. Analysis
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 3: Global state: 2. need for additional medication
3.4
3.4. Analysis
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 4: Global state: 3. mean endpoint score (CGI, high = worse)
3.5
3.5. Analysis
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 5: Adverse effects/events: 1. specific
3.6
3.6. Analysis
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 6: Hospital and service outcomes: 1. changes in hospital status
3.7
3.7. Analysis
Comparison 3: Benzodiazepines versus antipsychotics plus antihistamines, Outcome 7: Leaving the study early: 1. any reason
4.1
4.1. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 1: Tranquillisation or asleep: 1. sedation
4.2
4.2. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 2: Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse)
4.3
4.3. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 3: Global state: 1. no improvement mean endpoint change in Clinical Global Impression score)
4.4
4.4. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 4: Global state: 2. need for additional medication
4.5
4.5. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 5: Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%)
4.6
4.6. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 6: Mental state: 2a. mean endpoint score (BPRS, high = worse)
4.8
4.8. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 8: Mental state: 2c. mean endpoint score (Positive and Negative Syndrome Scale (PANSS), high = worse)
4.10
4.10. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 10: Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse)
4.11
4.11. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 11: Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse)
4.12
4.12. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 12: Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse)
4.13
4.13. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 13: Adverse effects/events: 1. extrapyramidal symptoms (EPS)
4.14
4.14. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 14: Adverse effects/events: 2. use of medication for EPS
4.15
4.15. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 15: Adverse effects/events: 3. specific
4.16
4.16. Analysis
Comparison 4: Benzodiazepines plus antipsychotics vs same benzodiazepines, Outcome 16: Leaving the study early: 1. any reason
5.1
5.1. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 1: Tranquillisation or asleep: 1. sedation
5.2
5.2. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 2: Behaviour: 1. mean endpoint score (Agitated Behaviour Scale, high = worse)
5.3
5.3. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 3: Behaviour: 2. mean endpoint score (Overt Aggression Scale (OAS), high = worse)
5.4
5.4. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 4: Behaviour: 3. mean endpoint score (Overt Agitation Severity Scale, high = worse)
5.5
5.5. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 5: Global state: 1. no improvement
5.6
5.6. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 6: Global state: 2. need for additional medication
5.7
5.7. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 7: Global state: 3. need for additional medication (mean dose, high = worse)
5.8
5.8. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 8: Global state: 4. mean change score (Ramsey Sedation Scale, high = worse)
5.9
5.9. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 9: Mental state: 1. no improvement (the decrease rate of Brief Psychiatric Rating Scale (BPRS) score < 30%)
5.10
5.10. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 10: Mental state: 2. mean endpoint score (BPRS, high = worse)
5.11
5.11. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 11: Mental state: 3a. mean endpoint score (BPRS psychosis subscale, high = worse)
5.12
5.12. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 12: Mental state: 3b. mean endpoint score (BPRS positive subscale, high = worse)
5.13
5.13. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 13: Mental state: 4. mean endpoint score (BPRS‐excited component, high = worse)
5.14
5.14. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 14: Adverse effects/events: 1. extrapyramidal symptoms (EPS)
5.15
5.15. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 15: Adverse effects/events: 2. use of medication for EPS
5.16
5.16. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 16: Adverse effects/events: 3. specific
5.17
5.17. Analysis
Comparison 5: Benzodiazepines plus antipsychotics versus same antipsychotics, Outcome 17: Hospital and service outcomes: 1. changes in hospital status
6.1
6.1. Analysis
Comparison 6: Benzodiazepines + antipsychotics versus antipsychotics plus antipsychotics, Outcome 1: Behaviour: 3. mean endpoint score (Overt Aggression Scale, high = worse)
6.2
6.2. Analysis
Comparison 6: Benzodiazepines + antipsychotics versus antipsychotics plus antipsychotics, Outcome 2: Leaving the study early: 1. any reason
7.1
7.1. Analysis
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 1: Tranquilisation or asleep: 1. sedation
7.2
7.2. Analysis
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 2: Behaviour: 1. mean endpoint score (Overt Aggression Scale (OAS), high = worse)
7.3
7.3. Analysis
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 3: Behaviour: 2. mean endpoint score (Overt Agitation Severity Scale (OASS) agitation scale, high = worse)
7.4
7.4. Analysis
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 4: Global state: 1. no improvement (number of participants with < 10 points on the OAS and OASS after 12 hours)
7.5
7.5. Analysis
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 5: Global state: 2. need for additional medication (mean dose, high = worse)
7.6
7.6. Analysis
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 6: Global state: 3. mean change score (Ramsey Sedation Scale, high = worse)
7.7
7.7. Analysis
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 7: Adverse effects/events: 1. extrapyramidal symptoms
7.8
7.8. Analysis
Comparison 7: Benzodiazepines plus antipsychotics versus antipsychotics plus antihistamines, Outcome 8: Adverse effects/events: 2. specific
8.1
8.1. Analysis
Comparison 8: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation, Outcome 1: Tranquilisation or asleep: 1. sedation
8.2
8.2. Analysis
Comparison 8: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation, Outcome 2: Global state: 1. no improvement
8.3
8.3. Analysis
Comparison 8: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 1. Random sequence generation, Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms
9.1
9.1. Analysis
Comparison 9: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment, Outcome 1: Tranquilisation or asleep: 1. sedation
9.2
9.2. Analysis
Comparison 9: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment, Outcome 2: Global state: 1. no improvement
9.3
9.3. Analysis
Comparison 9: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 2. Allocation concealment, Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms
10.1
10.1. Analysis
Comparison 10: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement, Outcome 1: Tranquilisation or asleep: 1. sedation
10.2
10.2. Analysis
Comparison 10: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement, Outcome 2: Global state: 1. no improvement
10.3
10.3. Analysis
Comparison 10: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 3. Blinded outcome measurement, Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms
11.1
11.1. Analysis
Comparison 11: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias), Outcome 1: Tranquilisation or asleep: 1. sedation
11.2
11.2. Analysis
Comparison 11: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias), Outcome 2: Global state: 1. no improvement
11.3
11.3. Analysis
Comparison 11: Sensitivity analysis: benzodiazepines versus antipsychotics ‐ 4. Incomplete outcome data (attrition bias), Outcome 3: Adverse effects/events: 1. extrapyramidal symptoms
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Update of

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    1. 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. [CSZG: Ref9090]
    1. 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. [CSZG: Ref13125] - PubMed
Lorazepam 2009, SK {published data only}Std19990
    1. Kong BG, Shim JC, Lee SK. Comparison of the effects of intramuscular antipsychotics injection in the treatment of acute agitation in psychosis. European Neuropsychopharmacology 2009;19:S525-6. [CSZG: Ref24883]
Lorazepam 2010, IN {published data only}Std16448
    1. Srinath G, Shailaja B, Sai PG, Reddy KA. A comparative study of injection haloperidol and promethazine vs. injection lorazepam in controlling acute psychotic agitation. Indian Journal of Psychiatry 2010;52:S21. [CSZG: Ref20833]
Midazolam 2003, BZ {published data only}Std10285
    1. Huf G, Coutinho ESF, Adams CE. TREC III. The protocol and progress of TREC. Schizophrenia Research 2002;53(3 (Suppl 1)):187. [CSZG: Ref8077] [MEDLINE: ] [PMID 4405388]
    1. 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. [CSZG: Ref8765] [EMBASE 2002383527] - PMC - PubMed
    1. 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. In: 5th European Congress on Violence in Clinical Psychiatry; 2007 Oct 25-27; Amsterdam, The Netherlands. . [CSZG: Ref16746]
    1. 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. [CSZG: Ref8075] [MEDLINE: ] [PMID 4405388] - PMC - PubMed
    1. Huf G. Haloperidol plus promethazine versus haloperidol for psychosis induced aggression. Data on file 2004. [CSZG: Ref16747] [MEDLINE: ]
Midazolam 2006, AU {published data only}Std9969
    1. 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. [CSZG: Ref13930] - PubMed
Midazolam 2011, BZ {published data only}Std18200
    1. 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. [CSZG: Ref22900] - PubMed

References to studies excluded from this review

Arana 1986 {published data only}
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Chen 2012 {published data only}
    1. 陈琦, 薄奇静, 迟勇, 赵幸福, 李晓驷, 谭云龙, et al. 齐拉西酮合并氯硝西泮治疗急性期伴激越精神分裂症患者的对照研究. 临床精神医学杂志 2012;4:217-9.
Currier 2000 {published data only}
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Currier 2004 {published data only}
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Davis 2008 {published data only}
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Deng 2004 {published data only}
    1. 邓云峰, 刘重阳, 刘峥嵘, 张威. The combination of risperidone clonazepam therapy of acute schizophrenia excited state efficacy [利培酮合用氯硝西泮治疗精神分裂症急性期兴奋状态疗效观察]. Chinese Journal of Practical Internal Medicine 2004;24(8):496-7.
Esmailian 2015 {published data only}
    1. Esmailian M, Ahmadi O, Taheri M, Zamani M. Comparison of haloperidol and midazolam in restless management of patients referred to the emergency department: a double-blinded, randomized clinical trial. Journal of Research in Medical Sciences 2015;20(9):844-9. - PMC - PubMed
Ge 2004 {published data only}
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Gharabawi 2003 {published data only}
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Guz 1972 {published data only}
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Han 2005 {published data only}
    1. 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.
Hankoff 1962 {published data only}
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Hanlon 1970 {published data only}
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He 2011 {published data only}
    1. 何震, 吴延海, 翟长平. The clonazepam intramuscular combination of aripiprazole treatment of men with acute schizophrenia excited control study [氯硝西泮肌注合用阿立哌唑治疗男性精神分裂症急性兴奋的对照研究]. Medical Journal of Chinese Civil Administration [中国民康医学] 2011;23(13):1588-9. [MEDLINE: ]
Hou 2011 {published data only}
    1. 侯春兰, 侯凌峰, 张东升, 董继雪. Risperidone oral solution with lorazepam treatment of schizophrenia excited state [利培酮口服液合并劳拉西泮治疗精神分裂症兴奋状态]. China Journal of Health Psychology [中国健康心理学杂志] 2011;19(7):787-9. [MEDLINE: ]
Huf 2007 {published data only}
    1. Huf G, Coutinho ESF, Adams CE. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine. BMJ 2007;335(7625):869-72. [MEDLINE: ] - PMC - PubMed
Hwang 2012 {published data only}
    1. Hwang TJ, Chen YH, Huang LC, Huang GH, Hwu HG. Intramuscular olanzapine versus intramuscular haloperidol plus lorazepam in the treatment of acute agitation in schizophrenia. European Neuropsychopharmacology 2012;22(Suppl 2):S333-S4. - PubMed
Isbister 2010 {published data only}
    1. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Annals of Emergency Medicine 2010;56(4):392-401. - PubMed
Kang 2006 {published data only}
    1. 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.
Kinon 2002 {published data only}
    1. Kinon B, Rotelli MD, Gilmore JA. Efficacy of olanzapine and adjunctive lorazepam to control agitation in schizophrenia. International Journal of Neuropsychopharmacology 2002;5(Suppl 1):S128.
Kinon 2004 {published data only}
    1. Kinon BJ, Ahl J, Rotelli MD, McMullen E. Efficacy of accelerated dose titration of olanzapine with adjunctive lorazepam to treat acute agitation in schizophrenia. American Journal of Emergency Medicine 2004;22(3):181-6. [MEDLINE: ] - PubMed
Lenox 1992 {published data only}
    1. 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. - PubMed
Liang 2003 {published data only}
    1. 梁芝国, 罗维肖. Clonazepam and haloperidol on patients with acute agitation control study [氯硝西泮和氟哌啶醇联用治疗急性激越的对照研究]. Medical Journal of Chinese Civil Administration 2003;15(5):293-4.
Martel 2005 {published data only}
    1. 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. - PubMed
Mei 2006 {published data only}
    1. 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.
    1. 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.
NCT00797277 {published data only}
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NCT00859872 {published data only}
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Nestoros 1982 {published data only}
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Nobay 2004 {published data only}
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Richards 1998 {published data only}
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Simpson 2003 {published data only}
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Stevens 1992 {published data only}
    1. Stevens A, Stevens I, Mahal A, Gaertner HJ. Haloperidol and lorazepam combined: clinical effects and drug plasma levels in the treatment of acute schizophrenic psychosis. Pharmacopsychiatry 1992;25(6):273-7. [MEDLINE: ] - PubMed
Tang 2007 {published data only}
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Veraksa 2016 {published data only}
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Wan 2005 {published data only}
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Wang 2004 {published data only}
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Wetzel 1997 {published data only}
    1. Wetzel H, Klawe CJ, Muller MJ, Wiesner J, Benkert O. Lorazepam for stupor and mutism: a double-blind placebo-controlled cross-over study. 10th European College of Neuropsychopharmacology Congress; 1997 Sept 13-17; Vienna, Austria. [MEDLINE: ]
Wu 2006 {published data only}
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Wyant 1990 {published data only}
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Yang 2003 {published data only}
    1. 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.
Yang 2006 {published data only}
    1. Yang S. Quetiapine combination clonazepam diazepam treatment of acute schizophrenia clinical studies of excitement [奎硫平合用氯硝西泮治疗精神分裂症急性期兴奋的临床研究]. Journal of Qiqihar Medical College [Qiqihar Yixueyuan xuebao][齊齊哈爾醫學院學報] 2006;27(9):1034-5.
Yu 2006 {published data only}
    1. Yu J. Risperidone combined clonazepam controlled study of the treatment of acute schizophrenia [利培酮合并氯硝西泮治疗急性期精神分裂症的对照研究]. Nervous Diseases and Mental Hygiene 2006;6(2):129-30.
Zhang 2007 {published data only}
    1. 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.
Zhang 2008 {published data only}
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Zhong 2006 {published data only}
    1. Zhong Y. Risperidone combining clonazepam and haloperidol in the treatment of first episode of acute schizophrenia clinical control study [利培酮合并氯硝西泮与氟哌啶醇治疗首发精神分裂症急性期的临床对照研究]. 中国医药导报 2006;3(32):69-70.
Zhou 2012 {published data only}
    1. 周德祥, 蒋幸衍, 徐清, 方馨怡, 夏鸣华, 陆雅娜. 利培酮口服液合并氯硝西泮治疗精神分裂症兴奋激越症状的随机对照研究. 中国健康心理学杂志 2012;8:1123-4.
Zhou 2014 {published data only}
    1. 周升宝, 孙晓丹, 庞琦, 李志梅, 赵继舒, 张峰. 齐拉西酮联合氯硝西泮治疗精神分裂症急性期兴奋激越症状对照研究. 长治医学院学报 2014;20(2):17-20.
Zhu 2005 {published data only}
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