Evidence-Based Reviews

Why off-label antipsychotics remain first-choice drugs for delirium

Current Psychiatry. 2007 October;6(10):49-63

References

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7. Trzepacz PT. Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin Clin Neuropsychiatry 2000;5(2):132-48.

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9. Diagnostic and statistical manual of mental disorders, 4th ed, text revision. Washington, DC: American Psychiatric Association; 2000.

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17. Kim JY, Jung IK, Han C, et al. Antipsychotics and dopamine transporter gene polymorphisms in delirium patients. Psychiatry Clin Neurosci. 2005;59(2):183-8.

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in the ICU, where close blood pressure monitoring was feasible
for severe agitation in terminally ill patients to decrease distress for the patient, family and staff.

Monitor chlorpromazine’s anticholinergic and hypotensive side effects, particularly in elderly patients. Its anticholinergic effects could worsen delirium, but we are not aware of any studies or case reports supporting that clinical outcome.

Atypical antipsychotics also may be used to treat delirium, as supported by the literature. Recommended dosing, available routes administration routes, and clinical comments are summarized in Table 3.²³

Table 3

Recommended antipsychotic dosing for delirium*

Antipsychotic	Dosage	Route^†	Comment
Typical agents
Haloperidol	Initial: 0.5 to 1 mg Range: 0.5 to 2 mg every 2 to 12 hours	Oral, IV, SC, IM	‘First choice’ for delirium when antipsychotic treatment is needed (per APA guidelines)
Chlorpromazine	Initial: 12.5 to 25 mg Range: 12.5 to 50 mg every 4 to 12 hours	Oral, IV, IM	Alternative to haloperidol plus lorazepam when increased sedation is needed
Atypical agents
Risperidone	Initial: 0.25 to 1 mg Range: 0.25 to 2 mg/d	Oral	Risk of sedation and orthostatic hypotension at higher doses
Olanzapine	Initial: 2.5 to 5 mg nightly Range: 2.5 to 10 mg/d	Oral	Sedation (a potential limiting factor) may be beneficial for hyperactive delirium
Quetiapine	Initial: 25 to 50 mg Range: 25 to 200 mg/d, usually divided into 2 daily doses	Oral	Sedation and orthostatic hypotension are dose-limiting factors
Ziprasidone	Initial: 20 mg bid Range: 20 to 160 mg/d, usually divided into 2 daily doses	Oral	Limited data in delirium because of concerns about QT interval prolongation in medically ill patients
Aripiprazole	Initial: 10 to 15 mg Range: 10 to 30 mg/d	Oral	‘Dopamine stabilizing’ effect might be preferable in hypoactive delirium
* For frail elderly patients, start with approximately one-half the suggested initial dose.
† Risperidone and aripiprazole are available in liquid formulations. Risperidone, olanzapine, and aripiprazole are available in orally disintegrating tablets.
APA: American Psychiatric Association; IM: intramuscular; IV: intravenous; SC: subcutaneous
Source: Reference 23

Managing adverse effects

Reassess patients frequently during a delirium episode to adjust the antipsychotic dose, search for underlying causes, and monitor for side effects (Table 4). In frail elderly patients, start with approximately one-half the recommended initial dose to reduce the side effect risk.

Antipsychotics may not be appropriate in certain populations with delirium, particularly in patients with:

dementia of Lewy body type or Parkinson’s disease dementia
stroke
history of adverse reactions to antipsychotics.

Clinical Point

In frail elderly patients, start with approximately one-half the usual recommended initial dose to reduce the risk of side effects

Mortality risk. All atypicals carry a “black-box” warning of increased risk of death when treating behavioral disturbances in elderly patients with dementia-related psychosis. The FDA advisory is based on a meta-analysis by Schneider et al² of 17 placebo-controlled trials totaling 3,353 patients with Alzheimer’s disease or dementia. Risk of death in the drug-treated patients was 1.6 to 1.7 times greater than in those who received placebo. Most deaths were associated with cardiovascular disease or infection (including pneumonia).

Although the FDA advisory did not apply to typical antipsychotics, Wang et al³—in a retrospective cohort of nearly 23,000 patients age >65—found statistically significant higher mortality rates with typical vs atypical antipsychotics. The increased mortality risk with the typical agents was seen whether or not patients had dementia. The greatest increases in risk occurred early in therapy and with relatively high dosages.

The mortality risk associated with short-term antipsychotic treatment in medically ill elderly patients is unknown. Untreated delirium may impose a greater risk of morbidity and mortality than the risk associated with antipsychotics, however. Until more evidence becomes available, we recommend that you try to use low antipsychotic doses, especially for the elderly.

EPS are more common with conventional antipsychotics but also can be associated with the atypicals—particularly with risperidone at doses higher than 4 to 6 mg/d. To minimize EPS risk, monitor delirium patients daily during antipsychotic treatment and identify populations at risk.

Clinical Point

Untreated delirium may pose a greater risk of morbidity and mortality than the risk associated with antipsychotics

Neuroleptic malignant syndrome. Watch for NMS while treating medically ill patients with delirium. Symptoms include severe rigidity, hyperthermia, altered mental status, and autonomic dysfunction.

QT interval prolongation. A prolonged QT interval increases the risk of ventricular arrhythmias—such as torsades de pointes and ventricular fibrillation—that can lead to syncope, cardiac arrest, or sudden cardiac death. Among the atypicals, ziprasidone has been associated with the highest rates of QT interval prolongation, followed by quetiapine, risperidone, and olanzapine.²⁴ Thioridazine carries the greatest risk among the typical agents.²⁵

When using antipsychotics for delirium, identify patients at risk for QT interval changes and monitor all patients during treatment. Risk factors include older age, female sex, preexisting heart disease, bradycardia, electrolyte abnormalities, and use of drugs that block potassium. APA guidelines recommend discontinuing antipsychotic therapy if QTc exceeds 450 msec or increases >25% from baseline.¹ Consult with a cardiologist when antipsychotic treatment is necessary despite QT prolongation.