Background       Although their use remains commonplace, there is not strong evidence to support the use of antipsychotics or benzodiazepines in the management of delirium (1-3). There are also barriers to the use of antipsychotics and/or benzodiazepines in long-term care facilities. While prevention remains key in reducing morbidity from delirium, and nonpharmacologic interventions are the first-line treatments for active delirium, some patients will have distressing and potentially harmful manifestations of delirium such as severe agitation. This Fast Fact will discuss the use of non-antipsychotics & non-benzodiazepines in the management of agitated delirium.  Much of the discussion is targeted to hospitalized adult patients, because what few data exist have all emerged from this population.  It is important to note that there is currently no consensus about the role of any drug to treat delirium (outside of patients near the end-of-life, when sedation is acceptable) including the drugs mentioned here. 

Valproate (VPA) 
Rationale: VPA was developed as an anticonvulsant. It is used in bipolar disease and acute mania (4). It affects dopamine, GABA, and glutamate neurotransmission, all of which are implicated in the pathogenesis of delirium (5).

Evidence: There is low-quality evidence, from case series and retrospective reviews, that VPA reduces agitation in delirious patients when added to conventional treatments (6-8). No studies compare VPA with placebo in the management of agitated delirium. 

Practical issues: The starting dose is between 500 mg to 1500 mg PO/IV a day in two to three doses. The dose is increased according to the patient’s response usually by 250-500 mg/day every 1-3 days. Median dose in an ICU cohort was 1500 mg/d (8). VPA can be administered intravenously or as oral sprinkles for patients with dysphagia. It does not prolong the QT interval or aggravate parkinsonian symptoms (5).

Melatonin Receptor Agonists (Melatonin and Ramelteon): see Fast Fact #306

Rationale: Melatonin regulates the sleep-wake cycle. Increasing levels of melatonin at dark facilitate sleep initiation and maintenance (9). Low levels of melatonin and/or lack of melatonin rhythmicity are associated with delirium (10). 

Evidence: There is low-quality evidence, from retrospective studies and case series, suggesting the efficacy of melatonin and ramelteon in the management of delirium (11-13). No randomized controlled trial (RCT) evaluates the use of melatonin and ramelteon with placebo in the management of delirium. Some authors support the use of melatonin receptor agonists to prevent delirium (9), however, systematic reviews and meta-analysis of RCTs have not shown consistent benefit nor side effects (10,14,15).

Practical issues: Although the supporting evidence is limited, melatonin receptor agonists can be considered in patients with delirium when there is a circadian rhythm disturbance (16). Melatonin 0.5, 2, 5, 6, or 10 mg at bedtime were prescribed in the cases reported (11,12,16). Ramelteon is a synthetic analog of melatonin that has a longer half-life and a higher affinity for melatonin receptors. The studied ramelteon dose is 8 mg at bedtime. 

Dexmedetomidine (DXM): see Fast Fact #280.

Rationale: DXM is an alpha(α)-2 adrenergic receptor agonist used as a sedative in ICU patients. It does not affect the respiratory drive or arousal state. DXM decreases the need for gamma-aminobutyric acid (GABA) agents, benzodiazepines, and opioids that are associated with delirium (17).

Evidence: Studies of delirium prevention in the ICU setting support this use of DXM (14). In one well-designed, randomized, double-blinded, placebo-controlled study (18), DXM demonstrated efficacy to treat delirium in intubated patients, reducing the time to extubation compared to placebo.  

Practical issues: Main side effects are hypotension and bradycardia which are severe enough often to restrict its use to the ICU. It has a modest analgesic effect. DXM is also quite expensive.

Clonidine and Guanfacine

Rationale: Both medications are also α-2 adrenergic receptor agonists. They have similar properties to DXM, but a lesser impact on systemic vascular resistance, blood pressure, and heart rate and therefore do not require ICU monitoring. Guanfacine is more specific for the α2A-subtype receptor than clonidine. Because of this, it is more sedating and has less analgesic effect compared to clonidine (25).  

Evidence: A pilot study suggested a clonidine infusion could reduce the severity of delirium after surgery for type A aortic dissection (19). A well-designed, double-blind RCT comparing enteral clonidine against placebo in delirious, hospitalized older patients did not demonstrate any benefit, although the trial failed to recruit adequate subjects and was under-powered (21). Unfortunately, there are no good, controlled data on guanfacine; however, case series and retrospective analyses suggest it is well-tolerated, affordable, and it may be effective at managing hyperactive delirium (26,27).

Practical issues: Clonidine is available in oral and transdermal routes. It has analgesic properties as well. Abrupt cessation of clonidine causes rebound hypertension (22). Guanfacine is only available orally. Experts recommend a dose range of 0.5 to 4 mg/day depending upon severity of symptoms.  It also is associated with a withdrawal syndrome, though likely less pronounced compared to DXM or clonidine.

Cholinesterase inhibitors: see Fast Fact #174

Rationale: A deficit of acetylcholine is associated with delirium. Cholinesterase inhibitors used in Alzheimer’s disease (e.g., donepezil, galantamine) increase the availability of acetylcholine (23). 

Evidence: Cholinergic agents such as physostigmine, galantamine, and donepezil are used to treat delirium from anticholinergic poisoning (23). A systematic review of seven RCTs that evaluated the role of cholinesterase inhibitors (rivastigmine and donepezil) in the treatment or prevention of delirium in older adults, did not find any meaningful benefit (24).

Practical issues: Nausea, vomiting, and diarrhea are common side effects for this medication class.

Summary     Of the above-mentioned drugs, only DXM has high quality evidence supporting its use, albeit in a narrow population (agitated patients on ventilators). Other drug classes need additional research before their clinical applicability is understood.   

References

1. Nikooie R, Neufeld KJ, Oh ES, et al. Antipsychotics for Treating Delirium in Hospitalized Adults: A Systematic Review. Annals of internal medicine. 2019.

2. Agar MR, Lawlor PG, Quinn S, et al. Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial. JAMA internal medicine. 2017;177(1):34-42.

3. Foy A, O’Connell D, Henry D, Kelly J, Cocking S, Halliday J. Benzodiazepine use as a cause of cognitive impairment in elderly hospital inpatients. The journals of gerontology Series A, Biological sciences and medical sciences. 1995;50(2):M99-106.

4. Haddad PM, Das A, Ashfaq M, Wieck A. A review of valproate in psychiatric practice. Expert opinion on drug metabolism & toxicology. 2009;5(5):539-551.

5. Sher Y, Miller Cramer AC, Ament A, Lolak S, Maldonado JR. Valproic Acid for Treatment of Hyperactive or Mixed Delirium: Rationale and Literature Review. Psychosomatics. 2015;56(6):615-625.

6. Bourgeois JA, Koike AK, Simmons JE, Telles S, Eggleston C. Adjunctive valproic acid for delirium and/or agitation on a consultation-liaison service: a report of six cases. The Journal of neuropsychiatry and clinical neurosciences. 2005;17(2):232-238.

7. Sher Y, Miller AC, Lolak S, Ament A, Maldonado JR. Adjunctive Valproic Acid in Management-Refractory Hyperactive Delirium: A Case Series and Rationale. The Journal of neuropsychiatry and clinical neurosciences. 2015;27(4):365-370.

8. Gagnon DJ, Fontaine GV, Smith KE, et al. Valproate for agitation in critically ill patients: A retrospective study. Journal of critical care. 2017;37:119-125.

9. 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):687-694.

10. Choy SW, Yeoh AC, Lee ZZ, Srikanth V, Moran C. Melatonin and the Prevention and Management of Delirium: A Scoping Study. Frontiers in medicine. 2017;4:242.

11. Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi journal of anaesthesia. 2010;4(3):169-173.

12. Kimura R, Mori K, Kumazaki H, Yanagida M, Taguchi S, Matsunaga H. Treatment of delirium with ramelteon: initial experience in three patients. General hospital psychiatry. 2011;33(4):407-409.

13. Furuya M, Miyaoka T, Yasuda H, et al. Marked improvement in delirium with ramelteon: five case reports. Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society. 2012;12(4):259-262.

14. Liu Y, Li XJ, Liang Y, Kang Y. Pharmacological Prevention of Postoperative Delirium: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Evidence-based complementary and alternative medicine : eCAM. 2019;2019:9607129.

15. Ng KT, Shubash CJ, Chong JS. The effect of dexmedetomidine on delirium and agitation in patients in intensive care: systematic review and meta-analysis with trial sequential analysis. Anaesthesia. 2019;74(3):380-392.

16. de Jonghe A, Korevaar JC, van Munster BC, de Rooij SE. Effectiveness of melatonin treatment on circadian rhythm disturbances in dementia. Are there implications for delirium? A systematic review. International journal of geriatric psychiatry. 2010;25(12):1201-1208.

17. Pavone KJ, Cacchione PZ, Polomano RC, Winner L, Compton P. Evaluating the use of dexmedetomidine for the reduction of delirium: An integrative review. Heart Lung. 2018;47(6):591-601.

18. Reade MC, Eastwood GM, Bellomo R, et al. Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial. Jama. 2016;315(14):1460-1468.

19. Rubino AS, Onorati F, Caroleo S, et al. Impact of clonidine administration on delirium and related respiratory weaning after surgical correction of acute type-A aortic dissection: results of a pilot study. Interact Cardiovasc Thorac Surg. 2010;10(1):58-62.

20. Gagnon DJ, Riker RR, Glisic EK, Kelner A, Perrey HM, Fraser GL. Transition from dexmedetomidine to enteral clonidine for ICU sedation: an observational pilot study. Pharmacotherapy. 2015;35(3):251-259.

21. Hov KR, Neerland BE, Undseth O, et al. The Oslo Study of Clonidine in Elderly Patients with Delirium; LUCID: a randomised placebo-controlled trial. International journal of geriatric psychiatry. 2019;34(7):974-981.

22. Gagnon DJ, Fontaine GV, Riker RR, Fraser GL. Repurposing Valproate, Enteral Clonidine, and Phenobarbital for Comfort in Adult ICU Patients: A Literature Review with Practical Considerations. Pharmacotherapy. 2017;37(10):1309-1321.

23. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium – theory, evidence and practice. Br J Clin Pharmacol. 2016;81(3):516-524.

24. Tampi RR, Tampi DJ, Ghori AK. Acetylcholinesterase Inhibitors for Delirium in Older Adults. Am J Alzheimers Dis Other Demen. 2016;31(4):305-310.

25.  Sabetkasaie M, Vala S, Khansefid N, Hosseini AR, Sadat Ladgevardi MA. Clonidine and guanfacine-induced antinociception in visceral pain: possible role of alpha 2/I2 binding sites. Eur J Pharmacol. 2004 Oct 6;501(1-3):95-101.

26.  Jiang S, Czuma R, Cohen-Oram A, Hartney K, Stern TA. Guanfacine for Hyperactive Delirium: A Case Series. Journal of the Academy of Consultation-Liaison Psychiatry. 2021;62(1):83-88.

27.   Jiang S, Hernandez M, Burke H, et al. A retrospective analysis of guanfacine for the pharmacological management of delirium. Cureus. 2023;15(1).

Authors’ Affiliations: Geisinger Medical Center, Danville, PA. 

Conflicts of Interest:  None disclosed

Version History:  first electronically published in May 2020; originally edited by Drew A Rosielle MD. Significant content update in March 2023 by Kevin Hopkins DO, Joshua B Borris PharmD MS, and Paul Noufi MD.