Among the atypical antipsychotics, olanzapine has been studied more extensively. In an open trial of 79 hospitalized cancer patients with delirium, an oral formulation was used, with an initial dose range of 2.5 to 10 mg and a mean of 3 mg per dose in two daily doses. Seventy-six percent of patients had complete resolution of their delirium while taking olanzapine. No patients experienced EPS, but 30% experienced sedation, which was usually not severe enough to discontinue treatment. Predictors of a poor response included age older than 70 years, history of dementia, central nervous system involvement with cancer, hypoxia, hypoactive subtype, and delirium of severe intensity. Olanzapine is also reported to have antiemetic and possibly analgesic properties, although it is not used primarily for these indications.[Level of evidence: II]
Risperidone, another atypical antipsychotic, is also used extensively to treat delirium in clinical practice. In a single-blind randomized trial, the effectiveness of risperidone (n = 17) was compared with that of olanzapine (n = 15) for the treatment of delirium in patients with cancer. Both groups showed significant improvement in delirium as assessed by the Delirium Rating Scale. The response rates for improvement did not differ between the two groups. At the last observation, the mean dose of risperidone was 0.9 mg per day and that of olanzapine was 2.4 mg per day. Risperidone is available in oral tablet and liquid formulations; dosing begins at 0.5 to 1 mg per day in two divided daily doses that are titrated, if necessary, to a total daily dose of 4 to 6 mg per day.
Other atypical antipsychotics—specifically, quetiapine  and aripiprazole —have limited evidence in the treatment of delirium. The lack of an available parenteral formulation for any of the atypical antipsychotics is a disadvantage, especially in the context of agitated delirium.
Except for lorazepam and midazolam in selected situations, benzodiazepines are generally not recommended for the treatment of delirium. Lorazepam is a short-acting agent, and its use is largely reserved for the treatment of alcohol or benzodiazepine withdrawal. Lorazepam (0.5–1 mg orally or parenterally, every 1–2 hours) has also been used along with haloperidol in patients with delirium who are particularly sensitive to EPS. Another exception is midazolam, a very short-acting benzodiazepine, which is given by continuous subcutaneous or intravenous infusion in doses ranging from 30 to 100 mg over 24 hours. Midazolam is used to achieve deep sedation, especially in a terminal hyperactive or mixed delirium when agitation is refractory to other treatments, for example, doses of haloperidol in the region of 20 mg per day.
The decision to use a deep level of pharmacologically induced sedation in the treatment of agitated delirium often raises ethical concerns, fueled by the marked variability in the reported frequency (ranging from 10% to 52%) for this practice in patients dying from advanced cancer. Consistent with the goals of care, it is important that appropriate efforts are made to assess the reversibility of delirium, clarify the intent of sedation (the relief of refractory symptoms), and maintain clear communication with family members and health care team members regarding rationale and process.[2,4] (Refer to the Sedation for Refractory Delirium and Other Intractable Symptoms section of this summary for more information.)