Benzodiazepines alone or in combination with antipsychotic drugs for acute psychosis

People with mental health problems may exhibit agitated, violent and aggressive behaviour which can be a danger to themselves or others. Usually, de-escalation techniques such as talking to the patient are used to calm down the situation. However, people’s behaviour may be too disturbed, violent or agitated. In these circumstances, rapid tranquillisation is given to achieve a state of calm. Three major classes of drugs are used to achieve rapid tranquillisation: typical antipsychotics; benzodiazepines; and more recently atypical antipsychotics. The review included 21 studies involving 1968 people. The aim was to explore the tranquillising effects of benzodiazepines (alone or in combination with antipsychotics; placebo; and antihistamines). Overall, there is insufficient information in these 21 studies to support or refute the use of benzodiazepines (alone or in combination with other drugs, where emergency drugs are needed). The majority of studies are too small, so that larger and more informative studies are required before definite conclusions can be drawn as to the effectiveness of benzodiazepines. However, there was good evidence to suggest that benzodiazepines are at least as effective as antipsychotics in reducing the agitation associated with mental illness. Side effects such as weight gain, shaking, tremors and slurred speech were significantly higher in people who received antipsychotics. Therefore, if antipsychotics are used for rapid tranquillisation, they should be given with other calming drugs (anticholinergic medication) which can prevent side effects. There was also some evidence that the combination of benzodiazepines with antipsychotics was superior to either drug alone and may also reduce side effects.

In summary, there is no strong information from these studies to support or refute the use of benzodiazepines (with or without antipsychotics or in combination with other drugs) if the situation has deteriorated to such an extent that emergency drugs are needed. However, the lower rates of side effects in people receiving benzodiazepines may be a reason to choose benzodiazepines over older antipsychotics. Lack of good quality evidence leaves managers, clinicians, psychiatrists and policy makers with difficult decisions to make. There is currently limited evidence to suggest that benzodiazepines (alone or in combination with antipsychotics) are clearly superior to antipsychotics (alone or in combination with antihistamines) in reducing acute psychotic behaviour, such as aggression or agitation.

This summary has been written by Benjamin Gray, Service User and Service User Expert, Rethink Mental Illness.

Authors' conclusions: 

The evidence from trials for the use of benzodiazepines alone is not good. There were relatively little good data and most trials are 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 needed in this area.

Read the full 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 estimate the effects of benzodiazepines, alone or in combination with antipsychotics, when compared with placebo or antipsychotics, alone or in combination with antihistamines, to control disturbed behaviour and reduce psychotic symptoms.

Search strategy: 

We searched the Cochrane Schizophrenia Group's register (January 2012), inspected reference lists of included and excluded studies and contacted authors of relevant studies.

Selection criteria: 

We included all randomised clinical 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 with acute psychotic illnesses.

Data collection and analysis: 

We reliably selected studies, quality assessed them and extracted data. For binary outcomes, we calculated standard estimates of relative risk (RR) and their 95% confidence intervals (CI) using a fixed-effect model. For continuous outcomes, we calculated the mean difference (MD) between groups. If heterogeneity was identified, this was explored using a random-effects model.

Main results: 

We included 21 trials with a total of n = 1968 participants. There was no significant difference for most outcomes in the one trial that compared benzodiazepines with placebo, although there was a higher risk of no improvement in people receiving placebo 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).

There was no difference in the number of participants who had not improved in the medium term when benzodiazepines were compared with antipsychotics (n = 308, 5 RCTs, RR 1.10, 95% CI 0.85 to 1.42, low quality evidence); however, people receiving benzodiazepines were less likely to experience extrapyramidal effects (EPS) in the medium term (n = 536, 8 RCTs, RR 0.15, 95% CI 0.06 to 0.39, moderate quality of evidence). Data comparing combined benzodiazepines and antipsychotics versus benzodiazepines alone did not yield any significant results.

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 = 155, 3 RCTs, RR 1.27, 95% CI 0.94 to 1.70, very 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). However, more participants receiving combined benzodiazepines and haloperidol had not improved by medium term when compared to participants receiving olanzapine (n = 60,1 RCT, RR 25.00, 95% CI 1.55 to 403.99, very low quality evidence) or ziprasidone (n = 60, 1 RCT, RR 4.00, 95% CI 1.25 to 12.75 very low quality evidence). When haloperidol and midazolam were compared with olanzapine, there was some evidence the combination was superior in terms of improvement, sedation and behaviour.

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