Olanzapine (Zyprexa®) IM has shown superior effect for patients with acute agitation related to psychosis, bipolar mania, and Alzheimer’s dementia when compared to haloperidol.³ IM olanzapine enjoyed faster onset, greater efficacy, and reduced adverse event rate when compared in head to head prospective trials with either haloperidol, lorazepam, or combination therapy.^{3 12,13,14,15} Specifically, IM olanzapine exhibits less dystonia and akathisia in addition to a distinct calming effect as opposed to frank sedation.^1,3 Unfortunately, olanzapine IM has been shown to be synergistic with other CNS depressants; for this reason it should not be used with severely intoxicated patients, those taking benzodiazepines or those under other drug induced states. Eight case studies reported fatalities with olanzapine combination treatment (benzodiazepines or other antipsychotics), and no randomized controlled trials have examined olanzapine safety in those with significant co-morbidities that would lead to CNS depression.⁴ In addition, olanzapine portends mild hypotension and significant anticholinergic effects.¹⁴ For example, the drug would be contraindicated in a patient taking diphenhydramine or jimson weed, as it could exacerbate an anticholinergic delirium.¹³ Though most of the data surrounding olanzapine use remains in the psychiatric literature, two studies have shown beneficial results in the undifferentiated ED population.^1,12

Ziprasidone (Geodon®) IM also has significant advantages over haloperidol. Ziprasidone exhibits faster onset of action, lack of over-sedation, superior efficacy, reduced EPS, an easier transition to oral ziprasidone, reduced adverse effects and improved medication tolerance.^1,3 As with olanzapine, most of the positive data stems from psychiatric literature. However, one study conducted in a psychiatric emergency department compared IM ziprasidone to lorazepam / haloperidol combination therapy, and showed a similar side effect profile.¹⁶ In addition, one prospective, randomized, double blinded study comparing use of droperidol vs. ziprasidone in undifferentiated ED patients did show a 40% reduced restraint time.¹⁷ Conversely, ziprasidone has been shown to increase the QTc more than any other atypical antipsychotic, with increases similar to those seen in haloperidol. The data varies, with most studies showing QTc increases 16-28 from baseline, and none with QTc’s increasing more than 500.¹⁸ Though ziprasidone has been studied in a wide variety of patients, it currently holds FDA approval only for use in those with schizophrenia or bipolar mania.

Aripiprazole® is a dopamine / serotonin / alpha 1 / H1 agonist with recent conversion to IM formulation. This drug has been well studied only in those with severe agitation for bipolar mania or schizophrenia. When compared with haloperidol, the 10 mg IM formulation showed less EPS and reduced over-sedation.^19,20,21 No studies have been performed in the undifferentiated ED population.