Evidence-Based Reviews

Atypical antipsychotics for delirium: A reasonable alternative to haloperidol?

Current Psychiatry. 2011 January;10(1):37-46

References

1. Ely EW, Inouye SK, Bernard GR, et al. Delirium in the mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001;286:2703-2710.

2. Rudolph JL, Salow MJ, Angelini MC, et al. The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med. 2008;168(5):508-513.

3. Albers LJ, Hahn RK, Reist C. Handbook of psychiatric drugs 2008. Blue Jay, CA: Current Clinical Strategies Publishing; 2007.

4. Inouye SK. Delirium in older persons. N Engl J Med. 2006;354(11):1157-1165.

5. American Psychiatric Association. Practice guideline for the treatment of patients with delirium. Am J Psychiatry. 1999;156(suppl 5):1-20.

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

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

8. Lacasse H, Perreault MM, Williamson DR. Systematic review of antipsychotics for the treatment of hospital-associated delirium in medically or surgically ill patients. Ann Pharmacother. 2006;40(11):1966-1973.

9. Lonergan E, Britton AM, Luxenberg J, et al. Antipsychotics for delirium. Cochrane Database Syst Rev. 2007;(2):CD005594.-

10. Schwartz TL, Masand PS. The role of atypical antipsychotics in the treatment of delirium. Psychosomatics. 2002;43(3):171-174.

11. Sicouri S, Antzelevitch C. Sudden cardiac death secondary to antidepressant and antipsychotic drugs. Expert Opin Drug Saf. 2008;7(2):181-194.

12. Citrome L. Using oral ziprasidone effectively: the food effect and dose-response. Adv Ther. 2009;26(8):739-748.

13. Preskorn SH. Pharmacokinetics and therapeutics of acute intramuscular ziprasidone. Clin Pharmacokinet. 2005;44(11):1117-1133.

14. Girard TD, Pandharipande PP, Carson SS, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med. 2010;38(2):428-437.

15. Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107.

16. Horikawa N, Yamazaki T, Miyamoto K, et al. Treatment for delirium with risperidone: results of a prospective open trial with 10 patients. Gen Hosp Psychiatry. 2003;25(4):289-292.

17. Parellada E, Baeza I, de Pablo J, et al. Risperidone in the treatment of patients with delirium. J Clin Psychiatry. 2004;65(3):348-353.

18. Hans CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45(4):297-301.

19. Bourgeois JA, Hilty DM. Prolonged delirium managed with risperidone. Psychosomatics. 2005;46(1):90-91.

20. Naber D, Lambert M. The CATIE and CUtLASS studies in schizophrenia: results and implications for clinicians. CNS Drugs. 2009;23(8):649-659.

21. Zheng L, Mack WJ, Dagerman KS, et al. Metabolic changes associated with second-generation antipsychotic use in Alzheimer’s disease patients: the CATIE-AD study. Am J Psychiatry. 2009;166(5):583-590.

22. Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430.

23. Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics. 2002;43(3):175-182.

24. Hu H, Deng W, Yang H. A prospective random control study comparison of olanzapine and haloperidol in senile dementia. Chongqing Medical Journal. 2004;8:1234-1237.

25. Al-Samarrai S, Dunn J, Newmark T, et al. Quetiapine for treatment-resistant delirium. Psychosomatics. 2003;44(4):350-351.

26. Sasaki Y, Matsuyama T, Inoue S, et al. A prospective, open-label, flexible-dose study of quetiapine in the treatment of delirium. J Clin Psychiatry. 2003;64(11):1316-1321.

27. Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med. 2010;38(2):419-427.

28. Leso L, Schwartz TL. Ziprasidone treatment of delirium. Psychosomatics. 2002;43(1):61-62.

29. Young CC, Lujan E. Intravenous ziprasidone for treatment of delirium in the intensive care unit. Anesthesiology. 2004;101(3):794-795.

30. Alao AO, Moskowitz L. Aripiprazole and delirium. Ann Clin Psychiatry. 2006;18(4):267-269.

31. Straker DA, Shapiro PA, Muskin PR. Aripiprazole in the treatment of delirium. Psychosomatics. 2006;47(5):385-391.

32. Chew ML, Mulsant BH, Pollock BG, et al. Anticholinergic activity of 107 medications commonly used by older adults. J Am Geriatr Soc. 2008;56(7):1333-1341.

33. Chew ML, Mulsant BH, Pollock BG, et al. A model of anticholinergic activity of atypical antipsychotic medications. Schizophr Res. 2006;88(1-3):63-72.

34. Buckley NA, Sanders P. Cardiovascular adverse effects of antipsychotic drugs. Drug Saf. 2000;23:215-228.

35. Stöllberger C, Huber JO, Finsterer J. Antipsychotic drugs and QT prolongation. Int Clin Psychopharmacol. 2005;20(5):243-251.

36. Zemrak WR, Kenna GA. Association of antipsychotic and antidepressant drugs with Q-T interval prolongation. Am J Health Syst Pharm. 2008;65(11):1029-1038.

37. Alvarez PA, Pahissa J. QT alterations in psychopharmacology: proven candidates and suspects. Curr Drug Saf. 2010;5(1):97-104.

Table 2

Risperidone for delirium: What the evidence says

Study	Patients/dosage	Peak clinical response	Results/adverse effects (AEs)
Sipahimalani et al, 1997¹⁵	N=2 (age 14 and 60). Initial dose: 1 mg/d; maintenance dose: 2 mg/d	10 to 14 days	MMSE score increased. AEs: extrapyramidal symptoms (dystonia and cogwheeling)
Schwartz et al, 2002¹⁰	N=11 (age range 14 to 74). Mean dose: 1.59 ± 0.8 mg/d	5.1 ± 4.3 days	CGI score decreased. No reported AEs
Horikawa et al, 2003¹⁶	N=10 (mean age: 56.8; range: 22 to 81). Mean dose: 1.7 mg/d	7.1 days	DRS score decreased significantly in 80% of patients (P=.03) AEs: sleepiness (30%), mild drug-induced parkinsonism (10%)
Parellada et al, 2004¹⁷	N=64 (mean age: 67.3 ± 11.4 years). Mean dose: 2.6 ± 1.7 mg/d	3 to 7 days	Effective in 90.6% of patients with significant decreases in DRS, PANSS-P, and CGI and increase in MMSE (P < .001). AEs: drowsiness (3.1%), nausea (1.6%)
Hans et al, 2004¹⁸	N=12 (mean age: 65.6). Mean dose: 1.02 mg/d	4 to 7 days	MDAS scores decreased significantly (P < .05). No reported AEs
Bourgeois et al, 2005¹⁹	N=1 (age 57). Initial dose: 8 mg/d; maintenance dose: 2 mg/d	9 days	MMSE score increased. No reported AEs
CGI: Clinical Global Impressions scale; DRS: Delirium Rating Scale; MDAS: Memorial Delirium Assessment Scale; MMSE: Mini-Mental State Exam; PANSS-P: positive subscale of the Positive and Negative Syndrome Scale

Table 3

Olanzapine may have a role in treating delirium symptoms

Study	Patients/dosage	Peak clinical response	Results/adverse effects (AEs)
Sipahimalani et al, 1998²²	N=11 (mean age: 63.5 ± 23.2 years). Mean dose: 8.2 ± 3.4 mg/d	6.8 ± 3.5 days	Marked decrease (>50%) in DRS score for 5 patients. No reported AEs
Breitbart et al, 2002²³	N=79 (mean age: 60.6 ± 17.3 years; range: 19 to 89). Initial dose: 3 ± 0.14 mg/d; mean dose: 4.6 to 6.3 mg/d	2 to 7 days	MDAS decreased significantly (P < .001), with 76% of patients’ delirium reaching resolution (MDAS ≤10). AEs: sedation (30%)
Hu et al, 2004²⁴	N=74 (mean age: 74). Mean dose: 1.25 to 2 mg/d	2.78 ± 1.85 days	DRS score decreased significantly (P < .01) in 72.2% of patients. AEs: drowsiness (18.9%), dystonia (2.7%), dry mouth (2.7%)
DRS: Delirium Rating Scale; MDAS: Memorial Delirium Assessment Scale

Table 4

Evidence suggests quetiapine could reduce delirium symptoms

Study	Patients/dosage	Peak clinical response	Results/adverse effects (AEs)
Schwartz et al, 2002¹⁰	N=11 (age range: 19 to 91). Mean dose: 211.4 mg/d	6.5 days	Decrease in DRS score (>50% reduction in global delirium symptoms) for 10 patients. AEs: sedation
Al-Samarrai et al, 2003²⁵	N=2 (age 50 and 52). Mean dose: 200 to 400 mg/d	2 to 4 days	No specific rating scale used but clinical reduction in agitation and improvement in cognition were reported. AEs: drowsiness
Sasaki et al, 2003²⁶	N=12 (mean age: 67.3 ± 14.8 years). Mean dose: 44.9 ± 31.0 mg/d	4.8 ± 3.5 days	Decrease in DRS score and remission of delirium for all patients. Significant increase in MMSE (P=.0256). No reported AEs
Devlin et al, 2010²⁷	N=18 (adult ICU patients). Initial dose: 100 mg/d	36 to 87 hours	Significantly shorter time to first resolution of delirium and duration of delirium compared with placebo. AEs: somnolence
DRS: Delirium Rating Scale; ICU: intensive care unit; MMSE: Mini-Mental State Exam

Table 5

Limited data support ziprasidone and aripiprazole for treating delirium

Study	Patients/dosage	Peak clinical response	Results/adverse effects (AEs)
Ziprasidone
Leso et al, 2002²⁸	N=1 (age 34). Initial dose: 40 mg/d; maintenance dose: 100 mg/d	21 days	DRS score decreased from 26 to 14. AEs: 8.4% increase in QTc interval
Young et al, 2004²⁹	N=1 (age 47). Initial dose: 20 mg IV bolus, followed by an oral taper over 7 days.	7 days	No specific rating scale was used but dramatic improvement in patient’s restlessness was reported. No AEs reported
Aripiprazole
Alao et al, 2006³⁰	N=2 (age 62 and 37). Mean dose: 15 and 30 mg/d	2 to 7 days	Patient 1: DRS score decreased from 28 to 6 and MMSE score increased from 5 to 28. Patient 2: DRS score decreased from 18 to 6 and MMSE score increased from 7 to 27. No AEs reported
Straker et al, 2006³¹	N=14 (age range: 18 to 85). Mean dose: 8.9 mg/d	2 to 14 days	12 of 14 patients had a ≥50% decrease in DRS-R-98. AEs: 3 patients had prolonged QTc interval
DRS: Delirium Rating Scale; DRS-R-98: Delirium Rating Scale–Revised-98; MMSE: Mini-Mental State Exam

Anticholinergic activity

Clinical Point

A medication’s anticholinergic burden needs to be weighed against its potential nonanticholinergic adverse effects and other factors

Decreased acetylcholine activity (AA) is suspected in delirium pathogenesis.³² By extension of this theory, medications that block muscarinic receptors could worsen delirium. Haloperidol, risperidone, and ziprasidone have negligible or no AA, as reported in atropine equivalents. Quetiapine and olanzapine have mild (0.5 to 5 pmol/ mL) and moderate (5 to 15 pmol/mL) dose-related AA, respectively. For example, olanzapine, 5 mg/d, has roughly the same AA as quetiapine, 300 mg/d, whereas olanzapine, 10 mg/d, has about the same AA as quetiapine, 600 mg/d.^32,33