Evidence-Based Reviews

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

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

References

1. American Psychiatric Association. Practice guidelines for the treatment of patients with delirium. Am J Psychiatry 1999;156:S1-S20.

2. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294(15):1934-43.

3. Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med 2005;353(22):2335-41.

4. Inouye SK. Delirium in older persons. N Engl J Med 2006;354(11):1157-65.

5. Casarett DJ, Inouye SK. Diagnosis and management of delirium near the end of life. Ann Intern Med 2001;135(1):32-40.

6. Trzepacz PT. Update on the neuropathogenesis of delirium. Dement Geriatr Cogn Disord 1999;10(5):330-4.

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.

8. Breitbart W, Gibson C, Tremblay A. The delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses. Psychosomatics 2002;43(3):183-94.

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

10. Seitz DP, Gill SS, van Zyl LT. Antipsychotics in the treatment of delirium: a systematic review. J Clin Psychiatry 2007;68(1):11-21.

11. Michaud L, Bula C, Berney A, et al. Delirium: guidelines for general hospitals. J Psychosom Res 2007;62(3):371-83.

12. Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996;153(2):231-7.

13. Horikawa N, Yamazaki T, Miyamoto K. Treatment for delirium with risperidone: results of a prospective open trial with 10 patients. Gen Hosp Psychiatry 2003;25:289-92.

14. Mittal D, Jimerson N, Neely E. Risperidone in the treatment of delirium: results from a prospective open-label trial. J Clin Psychiatry 2004;65:662-7.

15. Parellada E, Baeza I, de Pablo J. Risperidone in the treatment of patients with delirium. J Clin Psychiatry 2004;65:348-53.16.

16. Han C, Kim Y. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics 2004;45(4):297-301.

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.

18. Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics 2002;43(3):175-82.

19. Skrobik Y, Bergeron N, Dumont M. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med 2004;30:444-9.

20. Pae C, Lee S, Lee C. A pilot trial of quetiapine for the treatment of patients with delirium. Hum Psychopharmacol 2004;19:125-7.

21. Leso L, Schwartz T. Ziprasidone treatment of delirium. Psychosomatics 2002;43:61-2.

22. Straker DA, Shapiro PA, Muskin PR. Aripiprazole in the treatment of delirium. Psychosomatics. 2006;47(5):385-91.

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24. Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA 2003;289(16):2120-7.

25. Glassman AH, Bigger JT, Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry. 2001;158(11):1774-82.

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Clinical Point

Haloperidol is often the drug of choice for delirium because of its high potency, low sedative effect, and few anticholinergic side effects

An IV route can facilitate rapid onset of medication effects. Compared with oral haloperidol, IV administration is associated with a lower risk of extrapyramidal symptoms (EPS), which allows use of higher doses.

Any IV use of injectable haloperidol is off-label, however. If you choose the IV route, monitor patients carefully for cardiac arrhythmias. Haloperidol’s prescribing information carries a new warning of sudden death, QT prolongation, and torsades de pointes in patients given IV haloperidol.

Chlorpromazine. In a double-blind, randomized comparison trial of 30 hospitalized AIDS patients, our group¹² found oral and IM haloperidol (n=11) or chlorpromazine (n=13) highly effective in controlling delirium. Delirium symptoms improved significantly in both hypoactive and hyperactive subtypes with low doses of either antipsychotic (approximately 2 mg of haloperidol equivalent/day).

No patients developed dystonic or dyskinetic symptoms. Lorazepam, given to 6 patients, worsened delirium and cognitive impairment.

Table 1

Recognizing delirium: Diagnostic clinical features*

Altered level of alertness and arousal
Rapidly fluctuating course
Attention disturbance
Increased or decreased psychomotor activity
Disturbance of sleep-wake cycle
Affective symptoms
Altered perceptions
Disorganized thinking and incoherent speech
Disorientation and memory impairment
* Not all symptoms are present in every case.
Source: Reference 9

Table 2

Nonpharmacologic approaches to managing delirium

Search for and correct all causes of delirium, including underlying disease or a medication effect
Create a calm, comfortable environment
Provide orienting objects such as calendars and clocks
Have family members present
Limit room and staff changes
Allow patients uninterrupted rest at night to improve the sleep-wake cycle
Consider 1-to-1 nursing observation, as necessary
Source: Reference 4

Atypicals in delirium: Trial data

Risperidone. Three open-label studies of risperidone in patients with delirium reported minimal risk of sedation and EPS.^13-15

A 7-day, double-blind, flexible-dose trial of 24 patients with delirium¹⁶ found no significant difference between haloperidol (mean 1.71 mg/d) and risperidone (mean 1.02 mg/d) in clinical efficacy or response rate. The authors acknowledged, that they were unable to obtain identical-looking haloperidol and risperidone tablets for the trial.

Kim et al¹⁷ studied dopamine transporter gene polymorphism and use of haloperidol vs risperidone in 42 patients with delirium. Relatively low doses of both antipsychotics showed similar efficacy, and the authors concluded that dopamine transporter gene polymorphism did not influence delirium treatment.

Olanzapine. In an open trial of 79 inpatients with advanced cancer, olanzapine (mean 6.3 mg/d, range 2.5 to 20 mg/d) resolved delirium in 76% of patients, with no incidence of EPS.¹⁸ Age >70, history of dementia, hypoxia, cerebral metastasis, and hypoactive delirium were associated with poor response to olanzapine. This study is unique in assessing olanzapine’s efficacy in different delirium subtypes.

A prospective, randomized trial compared olanzapine (mean 4.5 mg/d, range 2.5 to 13.5 mg/d) with haloperidol (mean 6.5 mg/d, range 1 to 28 mg/d) in patients admitted with delirium to a critical care setting.¹⁹ Both treatment groups showed similar improvement over 5 days. No side effects were reported in the patients receiving olanzapine.

Clinical Point

Consider the patient’s risk of EPS, sedation, anticholinergic side effects, cardiac arrhythmias, and drug interactions

Quetiapine. A few authors have published their experience with quetiapine in treating delirium. An open-label, flexible-dose trial of 22 inpatients²⁰ showed significant improvement in delirium severity with the use of quetiapine. No patients experienced EPS; sedation was the most common side effect.

Ziprasidone. In the first case report in which ziprasidone was used to treat delirium,²¹ an HIV/AIDS patient was given 100 mg/d. Delirium symptoms improved, but treatment was discontinued because of side effects (hypokalemia, hypomagnesemia, premature ventricular contractions, and QT interval prolongation).

Aripiprazole. Straker et al²² reported 14 cases delirium treated with aripiprazole, which showed few side effects. Twelve patients had a ≥50% decrease in Delirium Rating Scale scores, and 13 showed improvement in Clinical Global Impression scale scores.

Clinical options

When choosing an antipsychotic to treat delirium, consider the individual patient’s risks of EPS, sedation, anticholinergic side effects, cardiac arrhythmias, and drug-drug interactions.

Haloperidol. When medication is necessary for delirium, American Psychiatric Association (APA) guidelines consider low-dose haloperidol as first-line treatment (see Related Resources). Recommended dosage is 1 to 2 mg (0.25 to 0.5 mg for the elderly) every 4 hours as needed.

Adding oral or IV lorazepam (0.5 to 1 mg every 1 to 2 hours) to haloperidol may help rapidly sedate the agitated delirious patient and minimize the risk of EPS associated with haloperidol.¹ Avoid benzodiazepine monotherapy unless delirium is related to alcohol or benzodiazepine withdrawal.

Chlorpromazine. We have successfully used oral or IV chlorpromazine (12.5 to 50 mg every 4 to 12 hours) instead of haloperidol plus lorazepam when increased sedation was required, especially: