Pharmacologic Management of Delirium: Update on Newer Agents

  • Earl Quijada MD
  • J Andrew Billings MD
  • Elizabeth A Bukowy DO

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Background    Delirium is common in those with serious medical illness. There may be underlying physiologic causes to delirium and it can be categorized as hyperactive, hypoactive, or mixed.  Common reversible etiologies include infections, constipation, urinary retention, medications, electrolyte abnormalities, and sleep deprivation. Initial management strategies should include identifying and treating the underlying cause, as well as non-pharmacological treatment.  However, when these strategies are not effective, pharmacological interventions may be necessary to ensure patient and staff safety.  This Fast Fact identifies pharmacologic pearls regarding the management of a reversible, hyperactive delirium. See Fast Fact #1 for more information on terminal delirium.

1st Generation Antipsychotics 

  • Haloperidol  (Haldol)  Although no medication has been FDA  approved for the treatment of delirium, haloperidol is most commonly used since it can be administered safely through oral, subcutaneous, and parenteral routes.  Starting doses are 0.5 – 1 mg PO/SC/IV.  Titration can occur by 2 – 5 mg every 1 hour as needed until a total daily requirement is established, which is then administered in daily or twice daily doses.  Recommended maximum dose is 100 mg/day.  IV or SC haloperidol may cause less extrapyramidal symptoms than oral but may cause more significant QTc prolongation.
  • Chlorpromazine  (Thorazine) has more sedative effects than haloperidol for patients in whom sedation is desired.  The starting dose is 25 – 50 mg PO or IV.  Titration can occur by 25 – 50 mg every 1 hour until a total daily requirement is established, which is then administered in daily or twice daily doses.  Slow titration is recommended for IV doing.  Maximum dose is 2000 mg/day.

2nd Generation Antipsychotics    Also known as atypical antipsychotics, no evidence currently exists for improved efficacy with 2nd generation antipsychotics, so they are not considered to be first-line treatment.  Still, these agents are associated with fewer extrapyramidal side effects than 1st generation antipsychotics, hence, in patients with a history of extrapyramidal reactions from 1st generation antipsychotics this class of agents may be preferred. For acutely agitated patients requiring onset of action within minutes, providers should know that these agents do not work as fast as conventional antipsychotics.

  • Olanzapine (Zyprexa) The starting daily dose is 2.5-5 mg PO. It is often given at night. After one week, the dose can be raised to 10 mg a day; then 20 mg a day.  Orally disintegrating tablets (Zydis) are available. It has shown effectiveness for chemotherapy-induced nausea (see Fast Fact #315).
  • Quetiapine (Seroquel) is initially given 25 mg PO once or twice a day which can be raised by 25 – 50 mg per dose every 2 – 3 days. Compared to the atypical neuroleptics, it has the least extrapyramidal side effects, but has more orthostasis and sedative potentials. It is the antipsychotic of choice for patient with Parkinson’s Disease or Lewy Body Dementia.
  • Risperidone  (Resperidal) is given 1 – 2 mg PO at night and is gradually raised 1 mg every 2 – 3 days until an effective dose (usually 4 – 6 mg PO) is reached.  It has minimal anticholinergic effects and does not cause orthostasis.  It is the least sedating of this class of antipsychotics
  • Aripiprazole (Abilify) initially 2 mg daily PO (tablet, solution, disintegrating), repeat dosing every 4-6 hours as needed to a maximum of 15 mg/day. Least likely to prolong QTc in retrospective studies. It has less sedation and extrapyramidal side effects but may cause orthostasis. It does not need dose adjustments in renal or hepatic failure. 

Risks    The FDA has issued a black-box warning about the increased risk of death and stroke when first- or second-generation antipsychotics are used to treat dementia-related psychosis in elderly patients. This warning is based on limited studies which have not been replicated and do not address the short-term use of antipsychotics to manage delirium especially in terminally ill patients.  Since, delirium is a poor prognostic marker, goals of care and values must be discussed and taken into account regarding the medical management of delirium.

Benzodiazepines  Benzodiazepines can make delirium worse and precipitate withdrawal syndromes. Hence, unless the patient is acutely dying, and sedation is preferred; the patient’s agitation is severe and uncontrolled; the patient is withdrawing from benzodiazepines or alcohol; or suffering from anticholinergic excess, benzodiazepines should be avoided for potentially reversible forms of delirium. 

Melatonin    This hormone is produced naturally in the pineal gland and can help regulate the sleep-wake rhythm cycle. Randomized placebo-controlled trials have validated the use of melatonin and a melatonin analog (ramelteon) in the prevention of delirium for at-risk, hospitalized patients.  See Fast Fact #306. 

Discharge Prior to discharge it is important to reconcile medications and discontinue antipsychotics once delirium has resolved. 


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Version History:  This Fast Fact was originally edited by David E Weissman MD.   2nd Edition published September 2006; 3rd Edition May 2015; 4th Edition March 2019.

Conflicts of Interest: None to report