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Delirium in hospitalized patients: Risks and benefits of antipsychotics

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Atypical antipsychotics

Olanzapine, quetiapine, and risperidone are atypical antipsychotics that, like haloperidol, antagonize the dopamine D2 receptor, but also have antagonist action at serotonin, histamine, and alpha-2 receptors. This multireceptor antagonism reduces the risk of extrapyramidal symptoms but increases the risk of orthostatic hypotension.

Quetiapine, in particular, imposes an unacceptably high risk of orthostatic hypotension and so is not recommended for use in delirium in the emergency department.27 Additionally, quetiapine is anticholinergic, raising concerns about constipation and urinary retention.

Although the association between fall risk and antipsychotic use remains controversial,28,29 a study found that olanzapine conferred a lower fall risk than quetiapine and risperidone.30

Of these drugs, only olanzapine is available in an intramuscular dosage form. Both risperidone and olanzapine are available in dissolvable tablets; however, they are not sublingually absorbed.

Randomized controlled trials have shown that olanzapine is effective in managing cancer-related nausea, and therefore it may be useful in managing delirium in oncology patients.31,32

Patients with Parkinson disease are exquisitely sensitive to the antidopaminergic effects of antipsychotics but are also vulnerable to delirium, so they present a unique treatment challenge. The agent of choice in patients with Parkinson disease is quetiapine, as multiple trials have shown it has no effect on the motor symptoms of Parkinson disease (reviewed by Desmarais et al in a systematic meta-analysis33).

Aripiprazole is increasingly used to manage delirium. Its mechanism of action differs from that of the other atypical antipsychotics, as it is a partial dopamine agonist. It is available in oral, orally dissolvable, and intramuscular forms. It appears to be slightly less effective than the other atypical antipsychotics,34 but it may be useful for hypoactive delirium as it is less sedating than the other agents.35 Because its effect on the QT interval is negligible, it may also be favored in patients who have a high baseline QTc or other predisposing factors for torsades de pointes.

BALANCING THE RISKS

Antipsychotic drugs have been shown to be effective and generally safe. Antipsychotics do prolong the QT interval. However, other than with intravenous administration of haloperidol, the absolute effect is minimal. Although large meta-analyses have shown a higher rate of all-cause mortality in elderly outpatients with dementia who are prescribed atypical antipsychotics, an increase in death rates has not been borne out by prospective studies focusing on hospitalized patients who receive low doses of antipsychotics for a limited time.

There are no head-to-head randomized controlled trials comparing the efficacy of all of the 5 most commonly used antipsychotics. Therefore, we suggest considering the unique psychopharmacologic properties of each agent within the patient’s clinical setting, specifically taking into account the risk of cardiac arrhythmia, risk of orthostasis and falls, history of extrapyramidal symptoms, other comorbidities such as Parkinson disease and cancer, and the desired route of administration.

At the time the patient is discharged, we recommend a careful medication reconciliation and discontinuation of the antipsychotic drug once delirium has resolved. Studies show that at least 26% of antipsychotics initiated in the hospital are continued after discharge.36,37

Current delirium consensus statements recommend limiting the use of antipsychotics to target patient distress, impediment of care, or safety, because of the putative risks of antipsychotic use in the elderly. However, a growing body of evidence shows that low-dose, time-limited antipsychotic use is safe and effective in the treatment of delirium. In fact, González et al found that delirium is an independent risk factor for death, and each 48-hour increase in delirium is associated with an increased mortality risk of 11%, suggesting that delay in treating delirium may actually increase the risk of death.38

Therefore, we must balance the risks of prescribing antipsychotics in medically vulnerable patients against the increasing burden of evidence supporting the serious risks of morbidity and mortality of delirium, as well as the costs. Much remains to be studied to optimize antipsychotic use in delirium.

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