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Applying various psychopharmacological combination and augmentation strategies in schizophrenia is common clinical practice. This meta-analysis evaluated the efficacy of benzodiazepines added to antipsychotics. The Cochrane Schizophrenia Group trial register (until February 2011) and PubMed/Medline (until July 2012) were searched for randomized controlled trials (RCTs) with a minimum duration of one week that compared benzodiazepine augmentation of antipsychotics with a control group receiving antipsychotic monotherapy in schizophrenia and schizophrenia-like psychoses. Study selection and data extraction were conducted independently by at least two authors. The primary outcome was response to treatment. Secondary outcomes were positive and negative schizophrenic symptoms, anxiety symptoms, and dropouts due to any reason, inefficacy of treatment, and adverse events. Pooled risk ratios (RRs) with the 95% confidence intervals (CIs) were calculated using a random-effects model, with number-needed-to-treat/harm (NNT/H) calculations where appropriate. Overall, 16 relevant RCTs with 1045 participants were identified. Benzodiazepine augmentation was not associated with statistically significantly more responders (N=6; n=511; RR 0.97, 95% CI 0.77-1.22). Adjunctive benzodiazepines were well accepted and tolerated according to dropout-rates and adverse effects apart from dizziness (N=3; n=190; RR 2.58, 95% CI 1.08-6.15) and somnolence (N=2; n=118; RR 3.30, 95% CI 1.04-10.40). There is no evidence for antipsychotic efficacy of additional benzodiazepine medication in schizophrenia. Therefore, benzodiazepines should be considered primarily for desired ultra short-term sedation of acutely agitated patients but not for augmentation of antipsychotics in the medium- and long-term pharmacotherapy of schizophrenia and related disorders., (Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.)

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 Methods: 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., 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.

Background: Because of the high number of people with schizophrenia not responding adequately to monotherapy with antipsychotic agents, the evidence regarding the efficacy and safety of additional medication was examined in a number of clinical trials. One approach to this research question was the use of benzodiazepines, as monotherapy as well as in combination with antipsychotics., Objectives: To determine the efficacy, acceptability, and tolerability of benzodiazepines in people with schizophrenia and schizophrenia-like psychoses., Search Methods: In February 2011, we updated the literature search of the previous version of this systematic review (last search March 2005). We searched the trial register of the Cochrane Schizophrenia Group (containing methodical searches of BIOSIS, CINAHL, Dissertation abstracts, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, RUSSMED, Sociofile, supplemented with hand searching of relevant journals and numerous conference proceedings). Additionally, we inspected references of all identified studies for further relevant studies and contacted authors of relevant publications in order to obtain missing data from existing trials. We applied no language restrictions., Selection Criteria: We included all randomised controlled trials comparing benzodiazepines (as monotherapy or as adjunctive agent) with antipsychotic drugs or placebo for the pharmacological management of schizophrenia and/or schizophrenia-like psychoses., Data Collection and Analysis: Review authors (MD and CL) analysed independently the new references of the update-search referring to the inclusion criteria. MD and CL extracted all data from the included trials. For dichotomous outcomes we calculated risk ratios (RR) and their 95% confidence intervals (CI). We analysed continuous data by using mean differences (MD) and their 95% CI. We assessed each pre-selected outcome from the included trials with the risk of bias tool., Main Results: The 2011 update search yielded three further randomised controlled trials. The review currently includes 34 studies with 2657 participants. Most studies were characterised by a small sample size, short duration, and incomplete outcome data reporting.Benzodiazepine monotherapy is compared with placebo in eight trials. The proportion of participants with no clinically important response did not significantly differ between those given benzodiazepines or placebo (N = 382, 6 RCTs, RR 0.67 CI 0.44 to 1.02). The results from the various rating scales applied to assess global and mental state were inconsistent.Fourteen studies examined benzodiazepine monotherapy in comparison with antipsychotic monotherapy. Clinically important treatment response assessment revealed no statistically significant difference between the study groups (30 minutes: N = 44, 1 RCT, RR 0.91 CI 0.58 to 1.43; 60 minutes: N = 44,1 RCT, RR 0.61 CI 0.20 to 1.86; 12 hours: N = 66, 1 RCT, RR 0.75 CI 0.44 to 1.30; pooled short-term studies: N = 112, 2 RCTs, RR 1.48 CI 0.64 to 3.46). Desired sedation occurred significantly more often among participants in the benzodiazepine group than in the antipsychotic group at 20 and 40 minutes. No significant between-group differences could be identified for global and mental state or occurrence of adverse effects.Twenty trials compared benzodiazepine augmentation of antipsychotics with antipsychotic monotherapy. Referring to clinically important response, statistically significant improvement could be demonstrated only for the first 30 minutes of augmentation treatment (30 minutes: 1 RCT, N = 45, RR 0.38 CI 0.18 to 0.80; 60 minutes: N = 45,1 RCT, RR 0.07 CI 0.00 to 1.13; 12 hour: N = 67,1 RCT, RR 0.85 CI 0.51 to 1.41; pooled short-term studies: N = 511, 6 RCTs, RR 0.87 CI 0.49 to 1.54). Analyses of the global and mental state yielded no between-group differences except for desired sedation at 30 as well as 60 minutes (30 minutes: N = 45, 1 RCT, RR 2.25 CI 1.18 to 4.30; 60 minutes: N = 45, 1 RCT, RR 1.39 CI 1.06 to 1.83)., Authors' Conclusions: There is currently no convincing evidence to confirm or refute the practise of administering benzodiazepines as monotherapy or in combination with antipsychotics for the pharmacological treatment of schizophrenia and schizophrenia-like psychosis. Low-quality evidence suggests that benzodiazepines are effective for very short-term sedation and could be considered for calming acutely agitated people with schizophrenia. Measured by the overall attrition rate, the acceptability of benzodiazepine treatment appears to be adequate. Adverse effects were generally poorly reported. High-quality future research projects with large sample sizes are required to clarify the evidence of benzodiazepine treatment in schizophrenia, especially regarding long-term augmentation strategies.

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 to placebo or antipsychotics, to control disturbed behaviour and reduce psychotic symptoms., Search Strategy: We searched the Cochrane Schizophrenia Group's register (October 2002 and April 2005), inspected reference lists of included and excluded studies and contacted authors of relevant studies., Selection Criteria: We included all randomised clinical trials comparing benzodiazepines, alone or in combination with antipsychotics, with placebo or sole use of antipsychotics, 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), and weighted number needed to treat or harm (NNT/NNH) statistics. For continuous outcomes we estimated a weighted mean difference between groups. If heterogeneity was found, we used a random effects model., Main Results: We included eleven studies with a total of 648 participants. When comparing benzodiazepines with placebo, sedation was equally prevalent (n=102, 1 RCT, RR 1.67 CI 0.4 to 6.6), however, fewer people allocated lorazepam remained excited at 24 hours (n=102, RR 0.62 CI 0.4 to 1.0, NNT 5 CI 3 to 59). The lorazepam and placebo group experienced similar non-significant, low levels of adverse effects. In the comparison of benzodiazepines versus use of antipsychotics without use of anticholinergics/antihistamines, people allocated benzodiazepines did not clearly need additional medication compared with those given antipsychotics (n=216, 2 RCTs, RR 1.28 CI 0.5 to 3.2). Numbers sedated were also equivocal between groups (n=324, 6 RCTs, RR 0.76 CI 0.5 to 1.2) as were mental state ratings. Extrapyramidal symptoms were significantly higher in the antipsychotic treatment group (n=391, 7 RCTs, RR 0.17 CI 0.1 to 0.4, NNT 6 CI 2 to 17). Two trials (total n=83) comparing lorazepam plus haloperidol with lorazepam alone found no clear difference for the need of additional medication (n=83, 2 RCTs, RR 1.02 CI 0.8 to 1.3) or 'not improved' at one hour (n=20, 1 RCT, RR 1.47 CI 0.66 to 3.25). There was no difference in the incidence of extrapyramidal symptoms (n=83, 2 RCTs, RR 1.94 CI 0.2 to 20.3). Finally when the benzodiazepine plus antipsychotic combination was compared with antipsychotics alone (2 RCTs, n=95) there was no difference between groups in the need for additional medications (n=67, 1 RCT, RR 0.95 CI 0.8 to 1.2) or for mental state measures. Extrapyramidal symptoms were significantly lower for people receiving both benzodiazepines and antipsychotics compared with those receiving antipsychotics alone (n=95, 2 RCTs, RR 0.45 CI 0.2 to 0.9, NNH 2 CI 1 to 5). There was no significant difference in the number of participants unfit for early discharge (n=28, 1 RCT, RR 0.90 CI 0.54 to 1.5)., Authors' Conclusions: There is insufficient data from these studies to support or refute the use of benzodiazepines with or without antipsychotics where emergency drugs are needed. The sole use of older antipsychotics unaccompanied by anticholinergic drugs may be problematic, but studies in this review are not large enough to identify any serious adverse effects of benzodiazepines such as respiratory depression. Larger, more informative studies are needed before definite conclusions can be drawn as to the efficacy of benzodiazapines.

The article focuses on the effectiveness of benzodiazepines in controlling psychosis-induced aggression and disturbed behavior as presented by D. Gillies and colleagues' study. Gillies and colleagues conducted a systematic review and meta-analysis of the register of the Cochrane Schizophrenia Group and concluded that benzodiazepines alone or in combination with other drugs are not effective in controlling such episodes. The author discusses the limitations and contribution of the study.