Atypical antipsychotics, also called second-generation antipsychotics (SGA), were mostly developed in the 1990s and beyond. Several of these medications are commonly used in the acute setting. Olanzapine (Zyprexa), ziprasidone (Geodon), and aripiprazole (Abilify) come in both intramuscular and oral preparations. Risperidone (Risperdal) and quetiapine (Seroquel) are available in an oral formulation only.
As a class, these medications act as antagonists at the D2 receptor, as do FGAs, but also have comparable or stronger antagonism of other receptor subtypes, particularly serotonin-2A (5-HT2A) receptors. In addition, this class of medication has actions at other receptor types, such as histamine, norepinephrine, and α-2 receptors. Ziprasidone, for instance, has a high affinity for serotonin receptors compared to D2 receptors,28,29
while olanzapine and quetiapine have relatively higher affinities for the histamine receptor. In general, when compared with older drugs, SGAs have a reduced risk of near-term side effects such as dystonia or akathisia,30–32
with reported rates of less than 1%.30–32
This is lower than that reported with haloperidol alone23
and is some 10 times lower than even the combination of haloperidol + lorazepam.23,33
With the exception of risperidone, most randomized controlled trials of second-generation antipsychotics have been conducted in a psychiatric emergency department or inpatient ward, and not typical acute adult/pediatric emergency departments. Most of this research has generally indicated that most members of the class are effective in reducing agitation when compared to placebo, and are at least as calming as haloperidol.34–40
This is true of oral and oral rapid-dissolving formulations as well. In the limited number of studies that have compared oral antipsychotics, the combination of oral risperidone + lorazepam is as efficacious as intramuscular haloperidol + lorazepam, and oral risperidone alone is as efficacious as intramuscular haloperidol alone.37–40
Although there are no comparisons of oral olanzapine or oral ziprasidone with intramuscular haloperidol + lorazepam, oral olanzapine is as efficacious as oral risperidone alone.39
With the exception of risperidone, however, none of the SGAs have been compared against the more common regimen of haloperidol + lorazepam.37,38
Further, many of the published SGA investigations were industry-sponsored studies.
Although there have been no head-to-head trials of SGAs in the acute setting, published reviews have attempted to compare the effectiveness of different drugs in the class on a common scale, such as number-needed-to-treat.36
These reviews have generally indicated that most SGAs are equally effective at reducing agitation, with 3 possible exceptions. First, aripiprazole, the only partial D2 agonist approved for agitation, appears slightly less efficacious than other SGAs.36
Second, research on quetiapine has indicated that while this medication is useful in inpatient settings, it has an unacceptably high risk of orthostatic hypotension in the emergency department where patients are often volume depleted.41
Third, clozapine is only FDA approved for treatment-resistant schizophrenia and is not generally a first-line agent. Thus, although more study is needed, the use of aripiprazole, quetiapine, or clozapine cannot be recommended as first-line agents in the acute control of agitation. Other agents, such as lurasidone, iloperidone, and asenapine, are promising but have not yet been tested for acute agitation.
Most published studies of second-generation antipsychotics in agitated patients have not investigated their use either with benzodiazepines or in alcohol-intoxicated patients. Marder et al42
described a number of adverse events in patients who were administered the combination of olanzapine with benzodiazepines, and this combination is not currently recommended by the manufacturer. In 2 small retrospective studies, Wilson and colleagues43,44
noted that the combination of olanzapine + benzodiazepines did not cause vital sign abnormalities in patients who had not ingested alcohol. In some patients who had ingested alcohol, however, intramuscular olanzapine + benzodiazepines were associated with decreased oxygen saturations. These studies were too small, however, to provide conclusive evidence for the safety of olanzapine + benzodiazepines in nonintoxicated patients; thus, this combination should be avoided. Similarly, as little research has been conducted on other second-generation antipsychotics in alcohol-intoxicated patients, a first-generation antipsychotic may be a safer choice, especially if clinicians anticipate using a benzodiazepine as well.
A summary of dosing for medications recommended in the treatment of agitation is provided in the .
Medications recommended in the treatment of agitation.