Benzodiazepines for psychosis‐induced aggression or agitation

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

doi:10.1002/14651858.CD003079.pub4

Benzodiazepinas para la agresión o agitación inducida por la psicosis

Declaraciones de intereses de los autores

Versión publicada: 08 diciembre 2017 Historial de versiones

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

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Antecedentes

La enfermedad psicótica aguda, en especial cuando está asociada con conducta agitada o violenta, puede requerir tranquilización o sedación farmacológica urgente. En numerosos países, los médicos a menudo utilizan benzodiazepinas, ya sea solas o en combinación con antipsicóticos, para lograrla.

Objetivos

Examinar si las benzodiacepinas, solas o en combinación con otros agentes farmacológicos, son un tratamiento eficaz para la agresión o la agitación inducidas por la psicosis en comparación con el placebo, otros agentes farmacológicos (solos o en combinación) o los enfoques no farmacológicos.

Métodos de búsqueda

Se realizaron búsquedas en el registro del Grupo Cochrane de Esquizofrenia (Cochrane Schizophrenia Group) (enero de 2012, 20 de agosto de 2015 y 3 de agosto de 2016), se inspeccionaron las listas de referencias de los estudios incluidos y excluidos y se estableció contacto con los autores de los estudios pertinentes.

Criterios de selección

Se incluyeron todos los ensayos controlados aleatorizados (ECA) que compararan benzodiazepinas solas o en combinación con cualquier antipsicótico versus un antipsicótico solo o en combinación con otros antipsicóticos, benzodiazepinas o antihistamínicos, en los pacientes agresivos o agitados por la psicosis.

Obtención y análisis de los datos

Se seleccionaron los estudios, se evaluó su calidad y se extrajeron los datos de manera fiable. Para los resultados binarios, se calcularon las estimaciones estándar del riesgo relativo (RR) y los intervalos de confianza (IC) del 95% mediante un modelo de efectos fijos. Para los resultados continuos, se calculó la diferencia de medias (DM) entre los grupos. En caso de heterogeneidad, se exploró mediante un modelo de efectos aleatorios. Se evaluó el riesgo de sesgo y se creó una tabla "Resumen de los hallazgos" con la metodología GRADE.

Resultados principales

Ahora se incluyen 20 ensayos con 695 participantes en la revisión. Los ensayos compararon las benzodiacepinas o las benzodiacepinas más un antipsicótico con el placebo, los antipsicóticos, los antihistamínicos o una combinación de estos. La calidad de la evidencia para los resultados principales fue baja o muy baja debido al tamaño muy pequeño de la muestra de los estudios incluidos y al grave riesgo de sesgo (la asignación al azar, la ocultación de la asignación y el cegamiento no se realizaron bien en los ensayos incluidos, el 30% de los ensayos (seis de 20) fueron apoyados por institutos farmacéuticos). No se observaron efectos claros para la mayoría de resultados.

Benzodiacepinas versus placebo

Un ensay comparó benzodiazepinas con placebo. No hubo diferencia en la cantidad de participantes sedados a las 24 horas (evidencia de calidad muy baja). No obstante, para el resultado de estado general, hubo claramente más gente que recibió placebo que no mostró mejoría a medio plazo (1 a 48 horas) (n = 102, 1 ECA, RR 0,62; IC del 95%: 0,40 a 0,97; evidencia de muy baja calidad).
Benzodiacepinas versus antipsicóticos

En comparación con el haloperidol, no se observó ningún efecto de las benzodiacepinas para la sedación a las 16 horas (n = 434, 8 ECA, RR 1,13, IC del 95%: 0,83 a 1,54, evidencia de baja calidad). No hubo diferencias en el número de participantes que no habían mejorado a medio plazo (n = 188, 5 ECA, RR 0,89; IC del 95%: 0,71 a 1,11; evidencia de baja calidad). Sin embargo, un estudio pequeño encontró que menos participantes mejoraron cuando recibieron benzodiazepinas en comparación con la olanzapina (n = 150, 1 ECA, RR 1,84, IC del 95%: 1,06 a 3,18, evidencia de muy baja calidad). Fue menos probable que los pacientes que recibieron benzodiazepinas presentaran efectos extrapiramidales a medio plazo comparado con aquellos que recibieron haloperidol (n = 233, 6 ECA, RR 0,13; IC del 95%: 0,04 a 0,41 evidencia de calidad moderada).

Benzodiazepinas versus combinado de antipsicóticos/antihistamínicos

Cuando se compararon las benzodiacepinas con antipsicóticos/antihistamínicos combinados (haloperidol más prometazina), hubo un mayor riesgo de que no hubiera mejoras en las personas que recibían benzodiacepinas a medio plazo (n = 200, 1 ECA, RR 2,17, IC del 95%: 1,16 a 4,05, evidencia de calidad baja). Sin embargo, en el caso de la sedación, los resultados fueron polémicos entre dos grupos: el lorazepam puede conllevar un menor riesgo de sedación que los antipsicóticos/antihistamínicos combinados (n = 200, 1 ECA, RR 0,91, IC del 95%: 0,84 a 0,98, evidencia de baja calidad); mientras que el midazolam puede conllevar un mayor riesgo de sedación que los antipsicóticos/antihistamínicos combinados (n = 200, 1 ECA, RR 1,13, IC del 95%: 1,04 a 1,23, evidencia de baja calidad).

Otras combinaciones

Los datos que compararon benzodiazepinas más antipsicóticos versus benzodiazepinas solas no produjeron ningún resultado con diferencias claras; todos fueron de calidad muy baja. Cuando se compararon benzodiazepinas/antipsicóticos combinados (todos los estudios compararon haloperidol) con el mismo antipsicótico solo (haloperidol), no hubo diferencias entre los grupos en la mejoría a medio plazo (n = 185, 4 ECA, RR 1,17; IC del 95%: 0,93 a 1,46; evidencia de muy baja calidad) pero la sedación fue más probable en los pacientes que recibieron tratamiento combinado (n = 172, 3 ECA, RR 1,75; IC del 95%: 1,14 a 2,67; evidencia de muy baja calidad). Solo un estudio comparó la combinación de benzodiazepinas y antipsicóticos con antipsicóticos solos; sin embargo, no informó los resultados principales de esta revisión. Un estudio pequeño comparó la combinación de benzodiazepinas y antipsicóticos versus antipsicóticos y antihistamínicos combinados. Los resultados mostraron un mayor riesgo de ausencia de mejoría clínica (n = 60, 1 ECA, RR 25,00, IC del 95%: 1,55 a 403,99, evidencia de muy baja calidad) y de estado de sedación (n = 60, 1 ECA, RR 12,00, IC del 95%: 1,66 a 86,59, evidencia de muy baja calidad) en el grupo combinado de benzodiacepinas/antipsicóticos.

Conclusiones de los autores

La evidencia de los ensayos para el uso de benzodiazepinas solas no es buena. Hubo relativamente pocos datos de calidad. En su mayoría, los ensayos fueron demasiado pequeños para destacar diferencias en los efectos positivos o negativos. Añadir una benzodiazepina a otros fármacos no parece conferir una ventaja clara y es posible que se agreguen efectos adversos innecesarios. El uso único de antipsicóticos más antiguos sin acompañarlos de fármacos anticolinérgicos parece difícil de justificar. Continúa necesitándose mucha más investigación de alta calidad en esta área.

PICO

Population

Intervention

Comparison

Outcome

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

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

Resumen en términos sencillos

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Benzodiazepinas solas o en combinación con antipsicóticos para la psicosis aguda

Pregunta de la revisión

El objetivo de esta revisión fue comparar los efectos tranquilizantes (calmantes) o sedantes (somnolencia) de las benzodiacepinas, administradas solas o combinadas con otros fármacos, en comparación con el efecto del placebo (un tratamiento simulado), otros fármacos o tratamientos no farmacológicos para las personas agresivas o agitadas por padecer psicosis.

Antecedentes

La psicosis aguda es un rápido empeoramiento del estado mental de una persona en el que a menudo se pierde el contacto con la realidad. Las personas pueden experimentar delirios o alucinaciones aterradoras que son angustiosas y pueden causar un comportamiento agitado o agresivo. En casos urgentes, esta agitación o agresión puede causar daño a la persona que experimenta la psicosis o a otros a su alrededor. Para evitar ese daño, puede ser necesaria una rápida tranquilización o sedación con medicamentos. Los medicamentos más ampliamente utilizados para lograr un estado de calma o sedación son las benzodiacepinas, que pueden administrarse solas o en combinación con antipsicóticos.

Búsqueda

La búsqueda original de esta revisión se realizó en enero de 2012 y posteriormente se realizaron otras dos búsquedas de actualización en agosto de 2015 y agosto de 2016. En total, estas búsquedas encontraron 2497 registros, que los autores de la revisión comprobaron para su inclusión o exclusión de la revisión. Los autores incluyeron los registros sólo si se trataba de ensayos aleatorizados (estudios clínicos en los que las personas son asignadas al azar a uno de dos o más grupos de tratamiento) que asignaban a las personas con psicosis aguda que presentaban un comportamiento agitado, violento o agresivo (o una combinación de estos) a recibir benzodiacepinas, ya sea administradas solas o combinadas con cualquier antipsicótico, frente a placebo, antipsicóticos solos o en combinación con otros antipsicóticos/benzodiacepinas/antihistamínicos o tratamientos no farmacológicos.

Evidencia encontrada

En total, se incluyeron 20 ensayos. En general la calidad de la evidencia fue baja o muy baja debido al importante riesgo de sesgo y al pequeño tamaño de los ensayos incluidos. No hubo una diferencia clara en la mejora entre las benzodiacepinas y el placebo, las benzodiacepinas y los antipsicóticos o las benzodiacepinas más los antipsicóticos y las benzodiacepinas solas o los antipsicóticos solos. Cuando se compararon las benzodiacepinas con antipsicóticos/antihistamínicos combinados, hubo un mayor riesgo de que no hubiera mejoras en las personas que recibían benzodiacepinas solas, pero la evidencia era de baja calidad. Solo un estudio mostró un menor efecto de la combinación de benzodiazepinas y antipsicóticos versus antipsicóticos y antihistamínicos combinados. Sin embargo, la evidencia era de muy baja calidad. En lo que respecta a los efectos secundarios, las personas que recibieron benzodiacepinas, en comparación con los antipsicóticos, tuvieron un riesgo menor de presentar síntomas como temblores, sacudidas y dificultad para hablar, mientras que los resultados de la sedación causada no estuvieron claros.

Conclusiones

Los ensayos existentes no son lo suficientemente informativos como para apoyar o refutar el uso de las benzodiacepinas por sí solas o como complemento de otros medicamentos cuando se requiere una urgente tranquilización o sedación con medicamentos. Aunque las benzodiacepinas solas pueden causar menos efectos secundarios en comparación con los antipsicóticos más antiguos, añadirlas a otros medicamentos puede provocar efectos secundarios innecesarios. Se necesitan más estudios para proporcionar evidencia de buena calidad con conclusiones sólidas que sirvan de base a la práctica clínica y las políticas en torno a la rápida tranquilización de las personas con psicosis que están agresivas o agitadas.

Authors' conclusions

Implications for practice

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

The intervention selected must be a reasonable and proportionate response to the risk posed by the person at that particular time. The aim of rapid tranquillisation is to achieve a state of calm sufficient to minimise the risk posed to patients or others. To achieve this state of calmness, various interventions can be used ranging from de‐escalation to pharmacological. Benzodiazepines are a viable option for care in acute aggression though 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 clinician's experience, expert consensus or local prescribing practice rather than data from high‐quality 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

The data suggest that there is no difference between benzodiazepines and antipsychotics in particular relation to sedation but data are limited and not of high quality. Moreover, low‐quality evidence of differences between benzodiazepine and olanzapine exists even if not for every outcome. Using a combined benzodiazepine/antipsychotic does not seem to confer any advantage over use of either drug alone. There is some evidence that newer antipsychotics may be more beneficial than benzodiazepines but data are very limited.

3. For managers or policy‐makers

Lack of high‐quality evidence 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 would probably have resulted in this review being more conclusive (Moher 2001). 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 in the future, 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 IM clozapine or olanzapine, with benzodiazepines are needed. Additional trials that compare combined benzodiazepines/antipsychotics with either drug alone are still needed, particularly where the newer antipsychotics are used. Because dosages could be adjusted on an as‐needed basis in the majority 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.

2.2.3. Outcomes

Standardised, validated scales that are acceptable to recipients of this care, clinicians working in the field, researchers and people working with regulatory authorities are needed to measure outcomes in future trials. Possible outcome measures should include measures of violence, degree of sedation, acceptability of the medication and adverse effects, all recorded over a suitable timescale to match the pharmacokinetic properties of the drugs. 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; 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).

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Table 5. Suggested design of future reviews

Methods	Allocation: randomised, fully described in terms of methods of randomisation and allocation concealment. Blinding: double/single blind, with methods of maintenance of blinding fully described. Setting: psychiatric emergency settings/hospital. Duration: immediate term (0‐15 minutes); short term (15 minutes to 1 hour); medium term (1‐48 hours); long term (≥ 48 hours).
Participants	Diagnosis: primary diagnosis of schizophrenia or related disorders, including schizophreniform disorder, schizoaffective disorder and delusional disorder with psychosis‐induced aggression or agitation. Subgroups: dual diagnoses or drug/alcohol use, or both. Age: adults, with age specified in trial. Sex: both.
Comparisons	a. Benzodiazepines ‐ given alone. Including: alprazolam, bretazenil, bromazepam, chlordiazepoxide, cinolazepam, clonazepam, clorazepate, clotiazepam, cloxazolam, delorazepam, diazepam, estazolam, flunitrazepam, halazepam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, quazepam, temazepam, tetrazepam or triazolam. Any dose, any means of administration. Compared with: 1. Other benzodiazepine ‐ given alone. Any dose, any means of administration. 2. Antipsychotics. First generation/typical, including: chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, droperidol, flupentixol/flupenthixol, fluphenazine, haloperidol, levomepromazine, loxapine, mesoridazine, molindone, periciazine, perphenazine, pimozide, prochlorperazine, promazine, promethazine, thioridazine, thiothixene, trifluoperazine, triflupromazine or zuclopenthixol. Second generation/atypical, including: amisulpride, aripiprazole, asenapine, clozapine, clothiapine, clotiapine, iloperidone, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone or zotepine. Any dose, any means of administration. 3. Other combinations of drugs. 3.1. Benzodiazepines + antipsychotics. 3.2. Antipsychotics + antihistamine/anticholinergic drugs. Antihistamines include: azelastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, deschlorpheniramine, dexchlorpheniramine, dimenhydrinate, dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, levocetirizine, loratadine, meclozine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, rupatadine, tripelennamine or triprolidine. Any dose, any means of administration. 4. Non‐pharmacological approaches. b. Benzodiazepines plus antipsychotics. Compared with: 1. Placebo. 2. Antipsychotics. Any dose, any means of administration. 3. Other combinations. 3.1. Benzodiazepines plus antipsychotics. 3.2. Antipsychotics plus antihistamines. 4. Non‐pharmacological approaches. c. Benzodiazepines (specific named drug) ‐ given alone. 1. High dose (as defined by each study). 2. Low or standard dose (as defined by each study). d. Benzodiazepines (specific named drug) ‐ given alone. 1. Oral. 2. Intramuscular or intravenous. e. Benzodiazepines (specific named drug) ‐ given alone. 1. Low frequency (as defined by each study). 2. High frequency (as defined by each study).
Outcomes measures	Primary outcomes. 1. Global impression. 1.1. Specific. 1.1.1. No improvement: as defined by each study. If more than 1 measure of improvement was reported, then improvement in behaviour is used, followed by improvement in mental state, and then improvement in symptoms. 1.1.2. Tranquillisation (feeling of calmness or calm, non‐sedated behaviour (or both)). Secondary outcomes. 2. Global impression ‐ CGI. 2.1. General. 2.1.1. No clinically important change in general functioning. 2.1.2. No change in general functioning. 2.1.3. Mean endpoint change in general functioning. 2.1.4. Mean change in general functioning. 2.2. Specific. 2.2.1. Aggression. 2.2.2. Self‐harm, including suicide. 2.2.3. Injury to others. 2.2.4. Improvement in self‐care or degree of improvement in self‐care. 2.2.5. Sedation (sleepiness and drowsiness). 2.2.6. Compulsory administrations of treatment. 2.2.7. Need for additional medication. 2.2.8. Decrease in medication. 2.2.9. No change in medication dosage. 2.2.10. Mean change/endpoint scores. 3. Behaviour. 3.1. General. 3.1.1. No clinically important change in behaviour. 3.1.2. Mean behaviour score. 4. Mental state ‐ BPRS. 4.1. General. 4.1.1. No clinically important change in general mental state scores. 4.1.2. Mean endpoint general mental state score. 5. Adverse effects/events. 5.1. General. 5.1.1. Incidence of side effects, general or specific. 5.1.2. Severity of symptoms. 5.1.3. Measured acceptance of treatment. 5.1.4. Sudden or unexpected death. 5.2. Specific. 5.2.1. EPS. 5.2.2. Use of medication for EPS. 6. Hospital and service outcomes. 6.1. Hospitalisation. 6.1.1. Time to hospitalisation. 6.1.2. Hospitalisation of people in the community. 6.1.3. Duration of hospital stay. 6.1.4. Changes in services provided by community teams. 6.2. Seclusion. 6.2.1. Time in seclusion. 6.2.2. Changes in hospital status (e.g. changes from voluntary to involuntary care, changes in level of observation, use of seclusion). 7. Satisfaction with treatment. 7.1. Specific. 7.1.1. Consumers. 7.1.2. Family and informal carers. 7.1.3. Professionals/carers. 8. Economic outcomes. 8.1. Cost‐effectiveness. 8.2. Direct costs. 8.3. Indirect costs. 9. Leaving the study early. 9.1. For any reason. 9.2. For reasons treatment related. 9.3. For reasons unrelated to treatment. 9.4. Due to relapse. 9.5. Due to adverse effects.
Notes	‐

BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression; EPS: extrapyramidal symptoms.

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Table 6. Suggested design of future studies

Methods	Allocation: randomised, fully described in terms of methods of randomisation and allocation concealment. Blinding: double/single blind, with methods of maintenance of blinding fully described. Setting: psychiatric emergency settings/hospital. Duration: follow‐up 72 hours.
Participants	Diagnosis: primary diagnosis of schizophrenia or related disorders, including schizophreniform disorder, schizoaffective disorder and delusional disorder with psychosis‐induced aggression or agitation. Subgroups: dual diagnoses or drug/alcohol use (or both) Number of participants > 400. Age: adults, with age specified in trial. Sex: both.
Interventions	1. Benzodiazepines ‐ given alone. Including: alprazolam, bretazenil, bromazepam, chlordiazepoxide, cinolazepam, clonazepam, clorazepate, clotiazepam, cloxazolam, delorazepam, diazepam, estazolam, flunitrazepam, halazepam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, quazepam, temazepam, tetrazepam or triazolam. Any dose, any means of administration. Compared with: a. Other benzodiazepine ‐ given alone. Any dose, any means of administration. b. Antipsychotics. First generation/typical, including: chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, droperidol, flupentixol/flupenthixol, fluphenazine, haloperidol, levomepromazine, loxapine, mesoridazine, molindone, periciazine, perphenazine, pimozide, prochlorperazine, promazine, promethazine, thioridazine, thiothixene, trifluoperazine, triflupromazine or zuclopenthixol. Second generation/atypical, including: amisulpride, aripiprazole, asenapine, clozapine, clothiapine, clotiapine, iloperidone, lurasidone, mosapramine, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, ziprasidone or zotepine. Any dose, any means of administration. c. Other combinations of drugs. i. Benzodiazepines plus antipsychotics. ii. Antipsychotics plus antihistamine/anticholinergic drugs. Antihistamines including: azelastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, deschlorpheniramine, dexchlorpheniramine, dimenhydrinate, dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, levocetirizine, loratadine, meclozine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, rupatadine, tripelennamine or triprolidine. Any dose, any means of administration. d. Non‐pharmacological approaches. 2. Benzodiazepines plus antipsychotics. Compared with: a. Placebo. b. Antipsychotics. Any dose, any means of administration. c. Other combinations. i. Benzodiazepines plus antipsychotics. ii. Antipsychotics plus antihistamines. d. Non‐pharmacological approaches.
Outcomes	1. Global impression: no improvement (as defined by each study. If more than 1 measure of improvement was reported, then improvement in behaviour was used, followed by improvement in mental state, and then improvement in symptoms). 2. Global impression; general/specific (including tranquillisation/sedation/need for additional medication/decrease in medication/injury to others/self‐harm/aggression or agitation/compulsory administration of treatment). 3. Behaviour: no clinically important change in behaviour. 4. Mental state: no clinically important change in general mental state scores. 5. Adverse effects/events (including incidence of specific adverse effects/severity of symptoms/death/EPS/use of medication for EPS). 6. Hospital and service outcomes (including time to hospitalisation/duration of hospital stay/seclusion/time in seclusion/changes in hospital status/use of mechanical restraints). 7. Satisfaction with treatment. 8. Economic outcomes. 9. Leaving the study early.
Notes	Any outcomes measured using scale‐derived data should be interpreted in such a way as to make clear the real‐life relevance of changes in scale score.

EPS: extrapyramidal symptoms.

Summary of findings

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Background

Description of the condition

Acutely psychotic people may exhibit agitated and aggressive behaviour that can present a danger to themselves or others. To ensure a safe and therapeutic environment where the patients have their dignity and privacy respected, de‐escalation techniques should be used to calm the patient (NICE 2015; 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 usually as a last resort because the risk to the person or other people is too high (NICE 2015; Rocca 2006). The aim of rapid tranquillisation is to achieve a state of calm that 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 2015). 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 2015).

Description of the intervention

Rapid tranquillisation is commonly used in emergency settings in general and psychiatric hospitals worldwide (Goedhard 2006; Marder 2006). Three major classes of drugs are used to achieve rapid tranquillisation: typical antipsychotics, benzodiazepines and, more recently, atypical antipsychotics (Marder 2006). Intramuscular (IM) injections of typical antipsychotics and benzodiazepines, alone or in combination, have been the treatment of choice for several decades. One review of the research literature reported that the typical antipsychotic, haloperidol, and the benzodiazepine, lorazepam, were the most widely used drugs (Battaglia 2005). However, the drugs used for rapid tranquillisation may vary widely in different countries. One survey in Rio de Janeiro, Brazil, showed that a haloperidol/promethazine mixture was commonly used (Huf 2002), while one 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).

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Table 1. The benzodiazepine family

Name	Code	Chemical name
Benzodiazepines
Bromazepam	Ro 5‐3350	7‐bromo‐1, 3‐dihydro‐5‐(2‐pyridyl)‐2H‐1, 4‐benzodiazepin‐2‐one
Camazepam	SB 5833	7‐chloro‐1, 3‐dihydro‐3‐hydroxy‐1‐methyl‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one dimethylcarbamate
Chlordiazepoxide	Ro 5‐0690	7‐chloro‐2‐methylamino‐5‐phenyl‐3H‐1, 4‐benzodiazepin‐4‐oxide
Cinolazepam	OX 373	7‐chloro‐5‐(o‐fluorophenyl)‐2, 3‐dihydro‐3‐hydroxy‐2‐oxo‐1H‐1, 4‐benzodiazepine‐1‐ propionitrile
Clobaza	HR 376 H 4723 LM 2717	7‐chloro‐1‐methyl‐5‐phenyl‐1H‐1, 5‐benzodiazepine‐2, 4‐(3H, 5H)‐dione
Clonazepam	Ro 5‐4023	5‐(o‐chlorophenyl)‐1, 3‐dihydro‐7‐nitro‐2H‐1, 4‐benzodiazepin‐2‐one
Clorazepate	4306CB A35.616	dipotassium 7‐chloro‐2, 3‐dihydro‐2, 2‐oxo‐5‐phenyl‐1H‐1, 4‐benzodiazepine‐3‐carboxylate
Cp 1414 S	‐	2‐amino‐7‐nitro‐5‐phenyl‐3H‐1, 5‐benzodiazepin‐4‐one
Cyprazepam	W 3623	7‐chloro‐2‐[(cyclopropylmethyl)amino]‐5‐phenyl‐3H‐1, 4‐benzodiazepin‐4‐oxide
Delorazepam chlordemethyldiazepam	‐	7‐chloro‐5‐(o‐chlorophenyl)‐1, 3‐dihydro‐2H‐1, 4‐benzodiazepin‐2‐one
Diazepam	Ro 5‐2807 WY 3467 LA III	7‐chloro‐1, 3‐dihydro‐1‐methyl‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Doxefazepam	SAS 643	7‐chloro‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐3‐hydroxy‐1‐(2‐hydroxyethyl)‐2H‐1, 4‐benzodiazepin‐2‐one
Elfazepam	SKF 72.517)	7‐chloro‐1‐[2‐(ethylsulfonyl)ethyl]‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐2H‐1, 4‐benzodiazepin‐2‐one
Ethyl carfluzepate	‐	ethyl ester of 7‐chloro‐5‐(o‐fluorophenyl)‐2, 3‐dihydro‐1‐ (methylcarbamoyl)‐2‐oxo‐1H‐1, 4‐benzodiazepine‐3‐carboxylic acid
Ethyl dirazepate	‐	ethyl 7‐chloro‐5‐(o‐chlorophenyl)‐2, 3‐dihydro‐2‐oxo‐1H‐1, 4‐benzodiazepine‐3‐carboxylate
Ethyl loflazepate	CM 6912	ethyl 7‐chloro‐5‐(o‐fluorophenyl)‐2, 3‐dihydro‐2‐oxo‐1H‐1, 4‐ benzodiazepine‐3‐carboxylate
Fletazepam	SCH 15.698	7‐chloro‐5‐(o‐fluorophenyl)‐2, 3‐dihydro‐1‐(2, 2, 2‐trifluoroethyl)‐1H‐1, 4‐benzodiazepine
Fludiazepam	ID 540	7‐chloro‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐1 methyl‐2H‐1, 4‐benzodiazepine‐2‐0
Flunitrazepam	Ro 5‐4200	5‐(o‐fluorophenyl)‐1, 3‐dihydro‐1‐methyl‐7‐nitro‐2H‐1, 4‐ benzodiazepin‐2‐one
Flurazepam	Ro 5‐6901	7‐chloro‐1‐[2‐(diethylamino)ethyl]‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐2H‐1, 4‐benzodiazepin‐2‐one. dihydrochloride
Flutemazepam	‐	7‐chloro‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐3‐hydroxy‐1‐methyl‐2H‐1, 4‐benzodiazepine‐2‐one
Flutoprazepam	KB 509 ID 1937	7‐chloro‐1‐(cyclopropylmethyl)‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐2H‐1, 4‐benzodiazepin‐2‐one
Fosazepam	HR 930	7‐chloro‐1‐[(dimethylphosphinyl)methyl]‐1, 3‐dihydro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Girisopam	GYKI 51.189 EGIS 5810	1‐(3‐chlorophenyl)‐4‐methyl‐7, 8‐dimethoxy‐5H‐2, 3‐benzodiazepine
Gv 150013	‐	(R)‐N‐[(adamantane‐1‐methyl)‐2, 4‐dioxo‐5‐phenyl‐2, 3, 4, 5‐tetrahydro‐1H‐1, 5‐benzodiazepin‐3‐yl]‐N‐phenylurea
Halazepam	SCH 12.041	7‐chloro‐1, 3‐dihydro‐5‐phenyl‐1‐(2, 2, 2‐trifluoroethyl)‐2H‐1, 4‐benzodiazepin‐2‐one
Iclazepam clazepam (formerly)	‐	7‐chloro‐1‐[2‐(cyclopropylmethoxy)ethyl]‐1, 3‐dihydro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Lorazepam	WY 4036	7‐chloro‐5‐(o‐chlorophenyl)‐1, 3‐dihydro‐3‐hydroxy‐2‐1, 4‐benzodiazepin‐2‐one
Lormetazepam	WY 4082	7‐chloro‐5‐(o‐chlorophenyl)‐1, 3‐dihydro‐3‐hydroxy‐1‐methyl‐2H‐1, 4‐benzodiazepin‐2‐one
M ORF8063	WE 352	1‐methyl‐5‐phenyl‐7‐(trifluoromethyl)‐1H‐1, 5‐benzodiazepine‐2, 4(3H, 5H)dione
Meclonazepam	(3‐methylclonazepam) Ro 11‐3128 (meclonazepam, Roche) Ro 11‐3624 (steric antipode of meclonazepam)	(+)‐(S)‐5‐(o‐chlorophenyl)‐1, 3‐dihydro‐3‐methyl‐7‐nitro‐2H‐1, 4‐benzodiazepin‐2‐one
Medazepam	Ro 5‐4556	7‐chloro‐2, 3‐dihydro‐1‐methyl‐5‐phenyl‐1H‐1, 4‐benzodiazepine
Menitrazepam	CB 4857	5‐(1‐cyclohexen‐1‐yl)‐1, 3‐dihydro‐1‐methyl‐7‐nitro‐2H‐1, 4‐benzodiazepin‐2‐one
Metaclazepam (formerly: Brometazepam)	KC 2547 KC 3755 (normetaclazepam (active metabolite)	7‐bromo‐5‐(o‐chlorophenyl)‐2, 3‐dihydro‐2‐(methoxymethyl)‐1‐methyl‐1H‐1, 4‐benzodiazepine
Nimetazepam	S 1530	1, 3‐dihydro‐1‐methyl‐7‐nitro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Nitrazepam	Ro 4‐5360 Ro 5‐3059 CB 4395 (potassium salt)	1, 3‐dihydro‐7‐nitro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Nordazepam	Ro 5‐2180 A 101	7‐chloro‐1, 3‐dihydro‐3‐hydroxy‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Normetrazepam	CB 4260	7‐chloro‐5‐(1‐cyclohexen‐1‐yl)‐1, 3‐dilhydro‐2H‐1, 4‐benzodiazepin‐2‐one
Oxazepam	WY 3498 8092 CB Ro 5‐6789	7‐chloro‐1, 3‐dihydro‐3‐hydroxy‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Oxazepam hemisuccinate	SAS 538	7‐chloro‐2, 3‐dihydro‐3‐hydroxy‐2‐(1H)‐oxo‐5‐phenyl‐1, 4‐benzodiazepin‐3‐yl hydrogen succinate
Pinazepam	Z 905	7‐chloro‐1, 3‐dihydro‐5‐phenyl‐1‐(2‐propynyl)‐2H‐1, 4‐benzodiazepin‐2‐one
Potassium nitrazepate	CB 4335	2, 3‐dihydro‐7‐nitro‐2‐oxo‐5‐phenyl‐1H‐1, 4‐benzodiazepin‐3‐carboxylic acid monopotassium salt
Prazepam	W 4020	7‐chloro‐1‐(cyclopropylmethyl)‐1, 3‐dihydro‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Quazepam	SCH 16.134	7‐chloro‐5‐(o‐fluorophenyl)‐1, 3‐dihydro‐1‐(2, 2, 2‐trifluoroethyl)‐2H‐1, 4‐benzodiazepine‐2‐thione
Reclazepam	SC 33.963	2‐[7‐chloro‐5‐(o‐chlorophenyl)‐2, 3‐dihydro‐1H‐1, 4‐benzodiazepin‐1‐yl]‐2‐oxazolin‐4‐one
Sc 32.855	‐	7‐chloro‐5‐(o‐chlorophenyl)‐1‐ (4, 5‐dihydro‐2‐oxazolyl)‐2, 3‐dihydro‐1H‐1, 4‐benzodiazepine
Sulazepam	W3676	7‐chloro‐1, 3‐ dihydro‐1‐methyl‐5‐phenyl‐ 2H‐1, 4‐ benzodiazepin‐ 2‐thione
Temazepam	ER 115 Ro 5‐5345 WY 3917	7‐chloro‐1, 3‐dihydro‐3‐hydroxy‐1‐methyl‐5‐phenyl‐2H‐1, 4‐benzodiazepin‐2‐one
Tetrazepam	CB 4261	7‐chloro‐5‐(cyclohexen‐1‐yl)‐1, 3‐dihydro‐1‐methyl‐2H‐1, 4‐benzodiazepin‐2‐one
Tofisopam	EGYT 341	5‐ethyl‐7‐8‐dimethoxy‐1‐(3, 4‐dimethoxyphenyl)‐4‐methyl‐5H‐2, 3‐benzodiazepine
Uldazepam	U 31.920	2‐[(allyloxy)amino]‐7‐chloro‐5‐(o‐chlorophenyl)‐3H‐1, 4‐benzodiazepine
Tricyclic benzodiazepines
1‐Hydroxytriazolam	‐	8‐chloro‐6‐(o‐chlorophenyl)‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine‐1‐methanol
Adinazolam	U 41.123 F (mesylate) U 41.123 (base)	8‐chloro‐1‐[(dimethylamino)methyl]‐6‐phenyl‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine (mesylate)
Alprazolam	U 31.889	8‐chloro‐1‐methyl‐6‐phenyl‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine
Climazolam	‐	8‐chloro‐6‐(o‐chlorophenyl)‐1‐methyl‐4H‐imidazo[1, 5‐a][1, 4]benzodiazepine
Cloxazolam	CS 370 MT 14‐411	10‐chloro‐11b‐(o‐chlorophenyl)‐2, 3, 7, 11b‐tetrahydro‐oxazolo[3, 2‐d][1, 4]benzodiazepin‐6 (5H)‐one
Estazolam noralprazolam	D 40 TA Lu 7426 Abbott 47631	8‐chloro‐6‐phenyl‐4H‐s‐triazolo[4, 3‐a][1, 4] benzodiazepine
Flutazolam	MS 4101	10‐chloro‐11b‐(2‐flurophenyl)‐2, 3, 7, 11b‐tetrahydro‐7‐(2‐hydroxyethyl‐oxazolo[ 3, 2‐d] [1, 4] benzodiazepin‐6(5H)‐one
Gp 55.129	U 40125	8‐chloro‐6‐phenyl‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine‐1‐methanol
Haloxazolam	CS 430	10‐bromo‐11b‐(o‐fluorophenyl)‐2, 3, 7, 11b‐tetrahydrooxazolo[3, 2‐d][1, 4]benzodiazepin‐6(5H)‐one
Ketazolam	U 28.774	11‐chloro‐8, 12b‐dihydro‐2, 8‐dimethyl‐12b‐phenyl‐4H‐[1, 3]oxazino[3, 2‐d][1, 4]benzodiazepine‐4, 7(6H)‐ dione
Loprazolam	RU 31.158 HR 158	(Z)‐6‐(o‐chlorophenyl)‐2, 4‐dihydro‐2‐[(4‐methylpiperazin‐1‐yl)methylene]‐8‐nitro‐1H‐ imidazo[1, 2‐a][1,~ 4]benzodiazepin‐1‐one
Mexazolam	CS 386	10‐chloro‐11b‐(o‐chlorophenyl)‐2, 3, 7, 11b‐tetrahydro‐3‐methyl‐oxazolo[3, 2‐d][1, 4]benzodiazepin‐6(5)‐one
Midazolam	Ro 21‐3981 (maleate) Ro 21‐3981/003 (HCl)	8‐chloro‐6‐(o‐fluorophenyl)‐1‐methyl‐4H‐imidazo [1, 5‐a][1, 4]benzodiazepine maleate (1: 1)
Noradinazolam	U 42.352	8‐chloro‐1‐(methylamino)methyl]‐6‐phenyl‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine
Oxazolam	‐	10‐chloro‐2, 3, 7, 11b‐tetrahydro‐2‐methyl‐11b‐phenyloxazolo[3, 2‐d][1, 4]benzodiazepin‐ 6(5H)‐one
Ru 31.124	‐	8‐chloro‐6‐(o‐chlorophenyl)‐2‐(4‐ethylpiperazin‐1‐yl)methyl]‐2, 4‐dihydro‐1H‐imidazo[1, 2‐a][1, 4]benzodiazepin‐1‐one (methyl bridge or methylene group uncertain)
Triazolam	U 33.030	8‐chloro‐6‐(o‐chlorophenyl)‐1‐methyl‐4H‐s‐triazolo[4, 3‐a][1, 4]benzodiazepine
Benzodiazepines with atypical mode of action
Arfendazam	‐	ethyl 7‐chloro‐2, 3, 4, 5‐tetrahydro‐4‐oxo‐5‐phenyl‐1H‐1, 5‐benzodiazepine‐1‐carboxylate
Devazepide	L 364.718 (former designation) MK 329 (Merck and Co., USA) L 365.031(Merck)	(S)‐N‐(2, 3‐dihydro‐1‐methyl‐2‐oxo‐5‐phenyl‐1H‐1, 4‐ benzodiazepin‐3‐yl)‐indole‐2‐carboxamideL 365031 N‐(2, 3‐ dihydro‐1‐methyl‐2‐oxo‐5‐phenyl‐1H‐1, 4‐benzodiazepin‐3‐yl)‐1H‐p‐bromobenzamide
Gyki 52.322	EGIS 6775	1‐(4‐aminophenyl)‐4‐methyl‐7, 8‐dimethoxy‐5H‐2, 3‐benzodiazepine 2, 3‐
L 365260	‐	(R)‐N‐(2, 3‐dihydro‐1‐methyl‐2‐oxo‐5‐phenyl‐1H‐1, 4‐benzodiazepin‐3‐yl)‐N’‐(3‐methylphenyl)‐urea
Ro 15‐4513	‐	ethyl 8‐azido‐5, 6‐dihydro‐6‐oxo‐4H‐imidazo[1, 5‐a][1, 4]benzodiazepine‐3‐carboxylate
Ro 5‐4864	‐	7‐chloro‐5‐(p‐chlorophenyl)‐1, 3‐dihydro‐1‐methyl‐2H‐1, 4‐benzodiazepin‐2‐one
Tifluadom	KC 5103 (+)‐tifluadom KC 6128 (Sandoz/Kali‐ Chemie, BRD) (‐)‐tifluadom KC5911	(+/‐)‐N‐[[5‐(o‐fluorophenyl)‐2, 3‐dihydro‐1‐methyl‐1H‐1, 4‐benzodiazepin‐2‐yl]methyl]‐3‐thiophenecarboxamide
Fused benzodiazepines
Brotizolam Ladormin (provisional name)	We 941	2‐bromo‐4‐(o‐chlorophenyl)‐9‐methyl‐6H‐thieno [3, 2‐f]‐s‐triazolo[4, 3‐a][1, 4]diazepine
Ciclotizolam	We 973‐BS	2‐bromo‐4‐(o‐chlorophenyl)‐9‐cyclohexyl‐6H‐thieno[3, 2‐f]‐s‐triazolo[4, 3‐a][1, 4]diazepine
Clotiazepam	Y 6047	5‐(o‐chlorophenyl)‐7‐ethyl‐1, 3‐dihydro‐1‐methyl‐2H‐thieno[2, 3‐e][1, 4]diazepin‐2‐one
Etizolam	AHR 3219 Y 7131	4‐(o‐chlorophenyl)‐2‐ethyl‐9‐methyl‐6H‐thieno [3, 2‐f]‐s‐triazolo[4, 3‐a][1, 4]diazepine
Lopirazepam	D 12524	7‐chloro‐5‐(o‐chlorophenyl)‐1, 2‐dihydro‐3‐hydroxy‐3H‐pyrido[3, 2‐ e][1, 4]diazepin‐2‐one
Premazepam	MDL 181	3, 7‐dihydro‐6, 7‐dimethyl‐5‐phenylpyrrolo[3, 4‐e][1, 4]diazepin‐2(1H)‐one
Razobazam	Hoe 175	4, 8‐dihydro‐3, 8‐dimethyl‐4‐phenylpyrazolo[3, 4‐b][1, 4]diazepine‐5, 7(1H, 6H)‐dione
Ripazepam	CI 683	1‐ethyl‐4, 6‐dihydro‐3‐methyl‐8‐phenylpyrazolo[4, 3‐e][1, 4]diazepin‐5(1H)‐one
Ro 11‐7800	‐	9‐aminomethyl‐2‐chloro‐4‐(o‐chlorophenyl)‐6H‐thieno[3, 2‐f]‐s‐triazolo[4, 3‐a][1, 4] diazepine
Thiadipone	CI 718 bentazepam QM 6008	1, 3, 6, 7, 8, 9‐hexahydro‐5‐phenyl‐2H‐[1]benzothieno[2, 3‐e][1, 4]diazepin‐2‐one
Zapizolam	‐	8‐chloro‐6‐(o‐chlorophenyl)‐4H‐pyrido[2, 3‐f]‐s‐triazolo[4, 3‐a][1, 4]diazepine
Zomebazam	‐	4, 8‐dihydro‐1, 3, 8‐trimethyl‐4‐phenylpyrazolo [3, 4‐b][1, 4]diazepine‐5, 7(1H, 6H)‐dione
Zometapine	CI 781	7, 8‐dihydro‐1, 3‐dimethyl‐4‐phenyl‐6H‐pyrazolo[3, 4‐e][1, 4] diazepine

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Table 2. Half lives of some benzodiazepines

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

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, antianxiety, 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 unclear 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 2015; 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 (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 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 2015; 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 combination therapy may decrease the incidence of adverse 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 adverse effects of the typical antipsychotics (Duggan 2005; Essali 2009; Silveira da Mota Neto 2002), but there have been reports of severe adverse events associated with the IM administration of these drugs (Battaglia 2005).

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

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Table 3. Reviews focusing on similar participant groups

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

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.

Methods

Criteria for considering studies for this review

Types of studies

We included all relevant randomised controlled trials (RCTs). We excluded quasi‐randomised trials, such as those allocating by days of the week. If a trial was described as 'double blind' but implied randomisation, we included such trials in a sensitivity analysis (see Sensitivity analysis). If their inclusion did not result in a substantive difference, they remained in the analyses. If their inclusion resulted in a clear effect, we did not add the data from these lower‐quality studies to the results of the better‐designed trials, but presented such data within a subcategory.

Types of participants

Any people presenting to the adult services with acutely disturbed/aggressive/agitated behaviour thought 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 defined 'acute' as where authors of trials stated or implied that the behavioural disturbance was of sudden onset or extreme in nature, or both. 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 included: 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).