A recent systematic literature review and meta-analysis by Dundar et al1 analyzed 17 randomized controlled trials (n=3841 patients) to compare the effectiveness of currently used pharmacotherapies for agitation in patients with psychosis (schizophrenia, schizophreniform disorder, schizoaffective disorder) and bipolar disorder.  The primary outcome was change in the Positive and Negative Syndrome Scale Excited Component (PANSS-EC) score. The researchers used a fixed effects model to combine the data at 60min and 120min. These time intervals were selected because they “are of key interest to clinicians.” They also examined the adverse events (AEs) of treatments, which included headache, dizziness, sleep problems, hypotension, sedation, and extrapyramidal symptoms.

Treatments included haloperidol, olanzapine, aripiprazole, risperidone, and lorazepam. In most of the trials, up to three doses of medication could be given throughout a 24-hour period, with at least two hours between any subsequent doses.

Study Findings


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Active treatments were found to be superior to placebo in all of the trials except for one, which compared haloperidol to placebo at 120min. The authors suggested that “appropriate use of de-escalation techniques may increase the placebo effect” and partly explain some of the non-significant differences in certain trials.

The more useful information for clinicians, the authors said, is whether one treatment is superior to another treatment. The pair-wise comparisons suggested that, after 60 minutes, no treatment was more effective than another with the exception of olanzapine, which proved to be superior to haloperidol. At 120 minutes, loxapine 10mg was found to be more effective than loxapine 5mg, and olanzapine was more effective than lorazepam.

The authors noted that at 60 minutes, olanzapine “had the greatest possibility” of being the most effective treatment, and at 120 minutes, the combination of risperidone plus clonazepam “had the greatest possibility” of being the most effective treatment.

The review noted a reduction in risk of AEs in favor of olanzapine, when compared with lorazepam, and a “substantial increase in risk” for haloperidol, when compared with clonazepam.

Table 1 contains a more detailed list of study findings.