Review question
The aim of this review was to compare the tranquillising (calming) or sedative (sleepiness) effects of benzodiazepines, given alone or combined with other drugs compared with the effect of placebo (a pretend treatment), other drugs or non-drug treatments for people who are aggressive or agitated because they are experiencing psychoses.
Background
Acute psychosis is a rapid worsening of a person’s mental state where touch with reality is often lost. People may experience frightening delusions or hallucinations which are distressing and may cause agitated or aggressive behaviour. In urgent cases, this agitation or aggression may cause harm to the person experiencing the psychoses or others around them. To avoid such harm, rapid tranquillisation or sedation with medicines may be required. The most common medicines used to achieve a state of calmness or sedation are benzodiazepines and these can be given either alone or in combination with antipsychotics.
Searching
The original search for this review was carried out in January 2012 and subsequently two further update searches were run in August 2015 and August 2016. In total, these searches found 2497 records, which the review authors checked for inclusion or exclusion from the review. Authors included records only if they were randomised trials (clinical studies where people are randomly put into one of two or more treatment groups) that allocated people with acute psychosis who presented with agitation, violence aggressive behaviour (or a combination of these) to receive benzodiazepines either given alone or combined with any antipsychotics, versus placebo, antipsychotics alone or in combination with other antipsychotics/benzodiazepines/antihistamines or non-drug treatments.
Evidence found
In total, 20 trials were included. Overall, the quality of evidence was low or very low due to serious risk of bias and very small size of included trials. There was no clear difference in improvement between benzodiazepines and placebo, benzodiazepines and antipsychotics or benzodiazepines plus antipsychotics and benzodiazepines alone or antipsychotic alone. When benzodiazepines were compared with combined antipsychotics/antihistamines, there was a higher risk of no improvement in people receiving benzodiazepine alone but the evidence was of low quality. Only one study showed lower effect of combined benzodiazepines/antipsychotics versus combined antihistamines/antipsychotics. However, the evidence was of very low quality. In terms of side effects, people receiving benzodiazepines compared to antipsychotics had lower risk of presenting with symptoms such as shaking, tremors and slurred speech whereas the results for the sedation caused were unclear.
Conclusions
The existing trials are not informative enough to support or refute the use of benzodiazepines alone or in additional to other medicines when urgent tranquillisation or sedation with medicines is required. Although benzodiazepines alone may cause fewer side effects compared to older antipsychotics, when they are added on to other medicines this may lead to unnecessary side effects. Further studies are needed to provide good-quality evidence with robust conclusions to inform clinical practice and policies around rapid tranquillisation for people with psychoses who are aggressive or agitated.
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.
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.
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.
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.
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.
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.
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 placebo
One 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 antipsychotics
For the outcome of sedation by 16 hours, there was no difference between haloperidol and benzodiazepine (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/antihistamines
When 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 combinations
Data 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.