A.  ACUTE TREATMENT

Antipsychotics

Breitbart W, Marotta R, Platt MM, Weisman H, Derevenco M, Grau C, et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. The American Journal of Psychiatry 1996;153(2):231-7.

30 hospitalized patients with AIDS were randomly assigned (double-blind) to receive low-dose chlorpromazine, low-dose haloperidol or lorazepam if they developed a delirium.  The antipsychotics effectively treated the delirium while the benzodiazepine arm was terminated after it appeared to be ineffective while also causing side effects.

Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Medicine 2004;30(3):444-9.

In this randomized trial (N=73), olanzapine and haloperidol reduced delirium symptoms to a similar degree; olanzapine had less EPS.

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

Small randomized trial (double-blind) of 28 patients that found no clear differences between a 7-day course of risperidone or haloperidol in patients with delirium.

Lee KU, Won WY, Lee HK, Kweon YS, Lee CT, Pae CU, et al. Amisulpride versus quetiapine for the treatment of delirium: a randomized, open prospective study. International Clinical Psychopharmacology 2005;20(6):311-4.

Small randomized trial (N=40) comparing amisulpride with quetiapine for the treatment of delirium.  Both interventions were comparable with regards to side effects and reduction of delirium symptoms.

Devlin JW, Roberts RJ, Fong JJ, Skrobik Y, Riker RR, Hill NS, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study Critical Care Medicine 2010;38(2):419-27.

36 patients with delirium received ancillary quetiapine in this small RTC (double-blind, placebo-controlled).  All patients received as needed haloperidol.  The added quetiapine led to more sedation but also reduced the duration of delirium and agitation.

Girard TD, Pandharipande PP, Carson SS, Schmidt GA, Wright PE, Canonico AE, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Critical Care Medicine 2010;38(2):428-37.

In this double-blind, placebo-controlled RTC, 101 ventilated ICU patients received either haloperidol, ziprasidone or a placebo for 21 days.  There were no differences in side effects or “days spent alive without delirium or coma.”

Kim SW, Yoo JA, Lee SY, Kim SY, Bae KY, Yang SJ, et al. Risperidone versus olanzapine for the treatment of delirium. Human Psychopharmacology 2010;25(4):298-302.

Small randomized trial (N=32) that found no clear difference between risperidone and olanzapine in treating acute delirium.

Tahir TA, Eeles E, Karapareddy V, Muthuvelu P, Chapple S, Phillips B, et al. A randomized controlled trial of quetiapine versus placebo in the treatment of delirium. Journal of Psychosomatic Research 2010;69(5):485-90.

Small RTC (double-blind, placebo-controlled) of 42 patients that showed benefit from quetiapine for the treatment of delirium.  With treatment, it resolved faster.

Acetylcholinesterase Inhibitors

Overshott R, Vernon M, Morris J, Burns A. Rivastigmine in the treatment of delirium in older people: a pilot study. International Psychogeriatrics 2010;22(5):812-8.

Very small RTC (double-blind, placebo-controlled) trial in 15 patients who were treated for delirium with either rivastigmine or placebo.  The duration of delirium was comparable.

van Eijk MM, Roes KC, Honing ML, Kuiper MA, Karakus A, van der Jagt M, et al. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial. Lancet 2010;376(9755):1829-37.

Major multicenter RTC (double-blind, placebo-controlled) that examined if adding rivastigimine (12 mg TDD) to haloperidol in patients diagnosed with delirium would be helpful.  The approach has face validity as cholinergic load is often increased in delirium.  However, the intervention was not helpful.  Worse, rivastigmine prolonged the delirium and increased mortality (22% in treatment group vs. 8% on placebo; p=0.07).  The trial was prematurely terminated by the DSMB after 104 patients were enrolled because of the interim mortality findings.

B.  PROPHYLAXIS

Antipsychotics

Kalisvaart KJ, de Jonghe JF, Bogaards MJ, Vreeswijk R, Egberts TC, Burger BJ, et al. Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. Journal of the American Geriatrics Society. 2005;53(10):1658-66.

Large RTC (double-blind, placebo-controlled) of 430 patients over age 70 that examined if short-term, low-dose haloperidol (1.5 mg/day) treatment can prevent post-operative delirium following hip surgery.  The incidence of delirium was similar: 15.1% for the treatment group and 16.5% for the placebo group.  However, those patients who developed delirium had a less severe delirium of shorter duration if they had received prophylactic haloperidol.

Prakanrattana U, Prapaitrakool S. Efficacy of risperidone for prevention of postoperative delirium in cardiac surgery. Anaesth Intensive Care 2007;35(5):714-9.

120 patients received a one-time sublingual dose of 1 mg risperidone or placebo immediately following regaining consciousness after elective cardiac surgery.  The intervention reduced the risk of developing delirium (11.1% in the treatment group vs. 31.7% in the placebo group).

Larsen KA, Kelly SE, Stern TA, Bode RH, Jr., Price LL, Hunter DJ, et al. Administration of olanzapine to prevent postoperative delirium in elderly joint-replacement patients: a randomized, controlled trial. Psychosomatics 2010;51(5):409-18.

Large RTC (double-blind, placebo-controlled) of 400 patients that examined if peri-operatively administered olanzapine (5 mg before and after surgery) would reduce delirium in elderly patients admitted electively for joint replacement surgery.  While intervention reduced the incidence of delirium, the duration and severity of delirium was greater in the intervention group; nonetheless, dismissal to home rather than a rehabilitation facility was greater in the olanzapine-intervention group.

Acetylcholinesterase Inhibitors

Gamberini M, Bolliger D, Lurati Buse GA, Burkhart CS, Grapow M, Gagneux A, et al. Rivastigmine for the prevention of postoperative delirium in elderly patients undergoing elective cardiac surgery--a randomized controlled trial. Critical Care Medicine 2009;37(5):1762-8.

120 patients scheduled for elective cardiac received short-term, peri-operative rivastigmine (double-blind, placebo-controlled).  The incidence of post-operative delirium was 30% in the placebo group and 32% in the treatment group.

Melatonin

Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: A randomized, placebo-controlled trial. International Journal of Geriatric Psychiatry 2011;26(7):687-94

165 medically admitted patients age 65 or above received low-dose melatonin (0.5) at night to see if delirium was prevented.  The intervention effectively reduced the incident of delirium as determined by CAM (12% with melatonin vs. 31% with placebo).
(This was a double-blind, placebo-controlled RTC.)