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.

23. Boettger S, Breitbart W. Atypical antipsychotics in the management of delirium: a review of the empirical literature. Palliat Support Care 2005;3(3):227-37.

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.

26. Nasrallah HA, Newcomer JW. Atypical antipsychotics and metabolic dysregulation: evaluating the risk/benefit equation and improving the standard of care. J Clin Psychopharmacol 2004;24(5 suppl 1):S7-S14.

Metabolic syndrome. Long-term use of atypical antipsychotics—particularly olanzapine—has been associated with metabolic dysregulation and increased risk of obesity and diabetes. In the absence of data on the atypicals’ short-term effects on metabolism, we recommend careful monitoring for metabolic syndrome when using these agents, especially in patients with preexisting metabolic disturbances.²⁶

Table 4

Monitoring for antipsychotic side effects during delirium treatment

Side effects	How to monitor
EPS (parkinsonism, akathisia, dystonia)	Neurologic examination
Neuroleptic malignant syndrome	Neurologic examination, serum creatinine phosphokinase, serum prolactin
QT interval prolongation, torsades de pointes	ECG, serum potassium and magnesium, family history of QT prolongation
Metabolic syndrome (hyperglycemia, hyperlipidemia, weight gain)	Fasting blood glucose, lipid profile, weight, hemoglobin A1c
Anticholinergic symptoms (dry mouth, constipation)	History and physical examination
EPS: extrapyramidal symptoms

Discontinuing antipsychotics

No evidence-based or expert consensus guidelines have addressed when or how to discontinue antipsychotic treatment of delirium. Several studies—including a randomized, controlled trial by our group¹²—used protocols that reflect expert clinician practice.

Antipsychotic therapy is initiated to control delirium’s symptoms and is presumed to be needed until the causes have been identified or have resolved. Thus, antipsychotics are typically given in 3 phases:

Clinical Point

Antipsychotic therapy is presumed to be needed for delirium symptoms until the causes have been identified or have resolved

Initial phase. Start antipsychotic therapy to control delirium symptoms, usually by dose titration over the first 24 to 48 hours.

Maintenance. Continue the antipsychotic 7 to 10 days—typically at two-thirds to one-half the initial-phase dosage—to allow delirium causes to be identified and resolve.

Tapering/discontinuation. If delirium symptoms resolve, taper and discontinue the antipsychotic relatively slowly over 3 to 5 days to allow for rapid control should delirium symptoms reemerge. Re-emergence suggests that new or unrecognized causes of delirium are present or identified causes have not resolved.

Related Resources

American Psychiatric Association. Treating delirium: a quick reference guide. www.psych.org/psych_pract/treatg/quick_ref_guide/DeliriumQRG_4-15-05.pdf.
American Psychiatric Association. Guideline watch: practice guideline for the treatment of patients with delirium. www.psych.org/psych_pract/treatg/pg/Delirium.watch.pdf.
American Psychosocial Oncology Society. Multidisciplinary training in psycho-oncology: delirium. www.apos-society.org/professionals/meetings-ed/webcasts/webcasts-multidisciplinary.aspx.

Drug brand names

Aripiprazole • Abilify
Chlorpromazine • various
Haloperidol • various
Lorazepam • Ativan
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

Disclosures

Dr. Breitbart is a consultant to Cephalon and a speaker for Cephalon, Janssen Pharmaceutica, Purdue Pharma, Eli Lilly and Company, and Bristol-Myers Squibb.

Dr. Alici-Evcimen reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.