Does Melatonin Decrease the Use of As-Needed Antipsychotics or Benzodiazepines in Noncritically Ill Hospitalized Patients? A Multicenter Retrospective Cohort Study

Abstract

Background:

Delirium is a common neuropsychiatric syndrome without an FDA-approved treatment. Commonly used modalities show little improvement in outcomes; therefore, prevention efforts are imperative. Abnormalities in the sleep/wake cycle have been linked to delirium, and melatonin has been proposed to replace the hypothesized low levels of endogenous melatonin and restore sleep/wake cycle synchronization.

Objectives:

The primary objective of this study was to evaluate the association between melatonin, benzodiazepines (BZDs) or zolpidem (ZLP), and the use of as-needed antipsychotics and BZDs for delirium in noncritically ill adult patients.

Methods:

This was a multicenter retrospective cohort study of noncritically ill adult patients admitted to two separate health systems from August 2012 to December 2018 receiving either melatonin or nonmelatonin medications (ZLP or BZDs) for sleep. The coprimary endpoint was the proportion of patients receiving a pro re nata (PRN) antipsychotic or BZD 5 days from the patient's first dose of melatonin, BZD, or ZLP. Secondary outcomes included evaluation of the coprimary outcome in patients 65 years of age or older, total number of PRN antipsychotic and BZD doses, and length of stay.

Results:

Two hundred and twenty-five patients were included in the final analysis. Administration of BZD or ZLP was associated with a higher risk of subsequent BZD administration as compared with melatonin (OR 2.78, 95% CI 1.2–1.87) and ZLP (OR 2.78, 95% CI 1.25–6.17). BZD or ZLP had no impact on PRN antipsychotic use compared with melatonin (OR 1.09, 95% CI 0.51–2.35) and ZLP (OR 1.16, 95% CI 0.56–2.4).

Conclusion:

Melatonin use was found to be associated with a significant decrease in PRN BZD use in noncritically ill patients hospitalized on general floors; however, there was no observed association with overall PRN antipsychotic use. These results suggest that using melatonin may help decrease utilization of medications commonly used to manage delirium.

Introduction

Delirium is a common neuropsychiatric syndrome characterized by fluctuating cognitive deficits, including visual impairment, disorientation, dysarthria, and overall brain dysfunction.¹ The prevalence of delirium in noncritically ill hospitalized patients has been reported as high as 74%, but varies significantly with regard to the patient's principle diagnosis.² Patients with older age, comorbid conditions (psychiatric, neurologic, cardiovascular, renal) and higher acuity of illness have a greater risk of experiencing delirium.² Modifiable risk factors include psychoactive medication use, electrolyte abnormalities, poor pain control, and sleep loss.³ Although its pathophysiological mechanisms are poorly understood, hospital-acquired delirium is an independent risk factor for increased hospital length of stay, long-term cognitive and functional decline, institutional placement, and death.^4
–6 These downstream consequences have been shown to increase health care cost 2.5-fold.⁷

Given the complex pathophysiology, treatment of delirium requires a multifaceted approach. Although there is no FDA-approved medication for the treatment of delirium, many pharmacological agents have been utilized such as antipsychotics, benzodiazepines (BZD), cholinesterase inhibitors, alpha-2 receptor agonists, and melatonin with little improvement in outcomes.^1,8 Despite the widespread use of antipsychotics to treat delirium, a meta-analysis from Neufeld et al. showed that antipsychotics had no significant effect on incidence, duration, or severity of delirium.⁹ Similar conclusions have been made regarding BZD use in delirium,¹⁰ and some studies even suggest BZDs may increase risk for delirium.^11,12 Due to lack of safe and effective pharmacologic treatment options for delirium, prevention efforts are necessary to mitigate this condition.¹³ Guidelines have identified sleep hygiene as an important prevention measure as a result of the association observed between sleep deprivation and the subsequent development of delirium.^8,14

Sleep deprivation can occur in hospitalized patients due to disruption of circadian rhythm and is associated with both lower melatonin concentrations and/or delayed secretion of melatonin. Furthermore, sleep deprivation is associated with an increased incidence of delirium, with up to 98% of delirious patients experiencing alterations of their sleep/wake cycle.^15,16 Several pharmacologic agents such as BZDs, antipsychotics, hypnotics, and antihistamines have been used to promote a healthy sleep/wake cycle among patients admitted to the hospital. However, these agents have many adverse effects, including extrapyramidal symptoms, QTc prolongation, complex sleep behaviors, oversedation, and fall risk. Other agents used to promote sleep include melatonin and ramelteon, which exert their pharmacologic action by replacing the hypothesized low levels of endogenous melatonin seen in many delirious patients.^15,17 These agents have demonstrated a favorable side effect profile with few adverse effects reported.^18,19 However, melatonin is a supplement not regulated by the FDA and thus has the potential to contain varying concentrations of active ingredient.

Several randomized control trials (RCTs) have validated the efficacy of melatonin and ramelteon for the prevention of delirium in the intensive care unit (ICU).^20

–23 A recent meta-analysis of RCTs from Yan et al. also shows that melatonin reduced the prevalence of ICU delirium (RR: 0.77; CI: 0.61–0.96), but this did not remain significant when RCTs without a low risk of bias were excluded and when trial sequential analysis was performed.¹⁹ Outside of the ICU, Al-Aama et al. examined the use of melatonin versus placebo for delirium prevention and found that melatonin was associated with an absolute risk reduction of 15.6% with a number needed to treat of 7.²⁴ Although these results are promising, a need exists for the comparison of melatonin and other commonly used sleep aids. Therefore, the purpose of this study is to evaluate the association between melatonin, BZDs or zolpidem (ZLP), and the use of as-needed antipsychotics and BZDs for prevention of delirium in noncritically ill adult patients.

Methods

This study was approved by the Institutional Review Board at all participating sites.

Study design

This study was a multicenter retrospective cohort study of noncritically ill adult patients admitted to two separate health systems from August 2012 to December 2018 receiving either melatonin or nonmelatonin medications for sleep (ZLP or BZDs). Study sites included community and large academic level I trauma centers. Patients were eligible for inclusion if they were 18 years or older, had an active order for pro re nata (PRN) antipsychotic or BZD, were admitted to a general (nonintensive care and nonsurgical) unit for 5 days or more, and received at least three nightly doses of melatonin, BZD, or ZLP out of the 5-day study period. Nightly, standing order doses of melatonin, BZDs, and ZLP were all indicated for sleep.

Patients were excluded if they were admitted to step-down units from an ICU, received antipsychotic or BZD for an indication other than sleep, received an antipsychotic at home or before administration of a study drug, had an active order for alcohol withdrawal with BZD per Clinical Institute Withdrawal Assessment for Alcohol protocol, or had a pre-existing diagnosis of encephalopathy, bipolar disorder, brain mass, meningitis, metastases, palliative care, schizophrenia, schizoaffective disorder, stroke, transient ischemic attack, traumatic brain injury, or dementia secondary to Alzheimer's/Lewy Body, Pick's, or Parkinson's Disease.

Outcomes

The coprimary endpoint was the proportion of patients receiving a PRN antipsychotic or BZD after 5 days from the patient's first dose of melatonin, BZD, or ZLP. Secondary outcomes included evaluation of the coprimary outcome in patients 65 years of age or older, total number of PRN antipsychotic and BZD doses, and length of stay.

Sample size

Sample size was based on a study conducted by Pinkhasov et al. that compared receipt of as-needed (PRN) antipsychotic medications between patients receiving ramelteon or no ramelteon. The ramelteon group had a lower incidence of subsequent PRN antipsychotic utilization (60%) compared with the group who did not receive ramelteon (86.2%).²⁵ Because a younger population was included in the present study, we initially powered the study to detect a smaller absolute difference of 15% (i.e., 80% vs. 65%), which was later changed to detect a difference of 20% (i.e., 80% vs. 60%). With 80% power and an alpha error rate of 0.05, 79 patients were needed per group for a total of 158 patients.

Statistical analysis

Descriptive statistics were used to characterize the study group and continuous variables were described as means with standard deviations or median with range or interquartile range. Categorical variables were described as frequency distributions and proportions. The association of demographic and clinical variables with each dependent variable was done using Student's t-test, analysis of variance, and chi-squared analysis as indicated by the data. Multiple logistic regression was performed using PRN antipsychotic or PRN BZD (yes/no) as the dependent variable. Variables were considered for inclusion into the model if there was a difference between study groups and were associated with the outcome (p < 0.2). All data were analyzed with SPSS v. 28.0 and a p-value of 0.05 or less was considered to indicate statistical significance.

Results

Baseline characteristics

A total of 1313 patients were screened from Ascension St. John Hospital, Ascension Macomb-Oakland Hospital, Ascension Providence Hospital, and Henry Ford Health System. Of these patients, 576 did not meet inclusion criteria due to admission to ICU (n = 430), admitted for less than 5 days (n = 130), and not receiving the study drug for at least 3 days (n = 16). Of the 737 patients identified for inclusion, 512 patients were excluded due to receipt of antipsychotic before study drug (n = 288), met a disease state exclusion (n = 160), were receiving BZD for alcohol withdrawal (n = 43), admitted to a step-down unit from the ICU (n = 18), or were admitted to palliative care (n = 3). A total of 225 patients were included in the final analysis. Of these, 130 patients received melatonin and 95 patients received BZDs or ZLP.

Baseline patient characteristics at the time of hospitalization in each group are reported in Table 1 and concomitant medications are reported in Table 2. Patients were predominantly older aged males. The mean (±SD) age was 69.6 ± 15.8 years in the melatonin group and 63.3 ± 16.5 years in the BZD or ZLP group. The presence of comorbid conditions was similar between groups, except for more patients in the melatonin group having liver disease (p = 0.02) and urinary incontinence (p = 0.04). Patients who received a scheduled nightly BZD received either clonazepam (median dose = 0.7 mg) or temazepam (median dose = 7.5 mg); median scheduled doses of melatonin and ZLP were 4 and 5 mg, respectively. Concomitant medication use was also similar between groups notwithstanding the greater proportion of subjects taking opioids in the BZD or ZLP group (p < 0.01) and the greater proportion of subjects using recreational marijuana in the melatonin group (p = 0.049).

Table 1.

Demographics and Baseline Comorbidities

	BZD+ZLP (n = 95)	Melatonin (n = 130)	p
Age (years)	63.9 ± 16.5	69.6 ± 15.8	<0.01
Female, n (%)	47 (49.5)	57 (43.8)	0.40
Height (inches)	66.4 ± 4.6	66.9 ± 4.8	0.44
Weight (kg)	77.5 ± 19.9	79.8 ± 22.2	0.43
COPD, n (%)	24 (25.3)	24 (18.5)	0.22
CKD, n (%)	21 (22.1)	23 (17.7)	0.41
CAD/PAD, n (%)	27 (28.4)	34 (26.2)	0.71
Diabetes, n (%)	26 (27.4)	46 (35.4)	0.20
CHF, n (%)	18 (18.9)	20 (15.4)	0.48
Hypothyroidism, n (%)	15 (15.8)	24 (18.5)	0.60
Liver disease, n (%)	0 (0)	8 (6.2)	0.02
Seizures, n (%)	6 (6.3)	15 (11.5)	0.18
Hemiplegia, n (%)	5 (5.3)	6 (4.6)	1
Incontinence, n (%)	4 (4.2)	16 (12.3)	0.04
Sensory impairment, n (%)	2 (2.1)	8 (6.2)	0.20
CCI, mean (SD)	3.4 (2.5)	3.9 (2.1)	0.12

Bold values indicate statistical significance.

BZD, benzodiazepine; CAD, coronary artery disease; CCI, Charlson comorbidity index; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; PAD, peripheral artery disease; SD, standard deviation; ZLP, zolpidem.

Table 2.

Medications During Study Period

	BZD+ZLP (n = 95)	Melatonin (n = 130)	p
Anticholinergics, n (%)	10 (10.5)	25 (19.2)	0.08
Antiepileptics, n (%)	11 (11.6)	19 (14.6)	0.51
Anti-Parkinsonian, n (%)	4 (4.2)	8 (6.2)	0.52
Beta-blockers, n (%)	40 (42.1)	61 (46.9)	0.47
H2RAs, n (%)	19 (20)	33 (25.4)	0.34
Lithium, n (%)	0 (0)	1 (0.8)	1
Tricyclic antidepressants, n (%)	6 (6.4)	4 (3.1)	0.33
Other antidepressants, n (%)	28 (29.5)	31 (23.8)	0.34
Dopamine antagonists, n (%)	8 (8.4)	17 (13.1)	0.27
1st gen antihistamines, n (%)	12 (12.8)	12 (9.3)	0.41
2nd gen antihistamines, n (%)	4 (4.2)	7 (5.4)	0.76
Fluoroquinolones, n (%)	9 (9.6)	6 (4.6)	0.14
Gabapentin or pregabalin, n (%)	14 (14.7)	17 (13.1)	0.72
Muscle relaxers, n (%)	10 (10.5)	12 (9.2)	0.75
Corticosteroids, n (%)	24 (25.3)	25 (19.2)	0.28
Opioids, n (%)	44 (46.3)	34 (26.2)	<0.01
Recreational marijuana, n (%)	3 (3.2)	13 (10)	0.049

Bold values indicate statistical significance.

BZD, benzodiazepine; ZLP, zolpidem; H2RA, H2 receptor antagonist.

Primary and secondary endpoints

At least one dose of PRN antipsychotic was administered in 56.8% of patients receiving BZDs or ZLP and in 50.8% of patients receiving melatonin (p = 0.37). Subsequent BZD administration occurred in 42.1% of patients receiving BZDs or ZLP and in 20.8% of patients receiving melatonin (p < 0.01). Subsequent BZD administration was consistent between BZD and ZLP groups (42.6% and 41.5%, respectively). After controlling for differences in baseline characteristics (age, liver disease, seizure disorder, incontinence, anticholinergic use, fluoroquinolone use, opioid use and recreational marijuana use), administration of BZD or ZLP was associated with a higher risk of subsequent BZD administration as compared with melatonin (OR 2.78, 95% CI 1.2–1.87) and ZLP (OR 2.78, 95% CI 1.25–6.17) (Table 3). BZD or ZLP had no impact on PRN antipsychotic use compared with melatonin (OR 1.09, 95% CI 0.51–2.35) and ZLP (OR 1.16, 95% CI 0.56–2.4) after controlling for differences in baseline characteristics. No missing data were present for any variable in both models.

Table 3.

Multivariate Analysis

	Odds ratio	95% CI	p
Primary outcome—BZD use
BZD compared with melatonin	2.78	1.20–1.87	0.02
ZLP compared with melatonin	2.78	1.25–6.17	0.01
Age	0.99	0.98–1	0.27
Liver disease	1.06	0.18–6.12	0.95
Seizures	3.13	1.08–9.07	0.04
Incontinence	0.33	0.07–1.58	0.17
Opioids	1.59	0.83–3.03	0.16
Recreational marijuana	1.01	0.28–3.64	0.98
Fluoroquinolones	0.51	0.13–2.05	0.34
Anticholinergics	1.49	0.62–3.57	0.37
Primary outcome—antipsychotic use
BZD compared with melatonin	1.09	0.51–2.35	0.83
ZLP compared with melatonin	1.16	0.56–2.4	0.7
Age	0.99	0.97–1.01	0.29
Liver disease	0.46	0.1–2.08	0.31
Seizures	1.24	0.46–3.38	0.67
Incontinence	1.92	0.67–5.54	0.23
Opioids	0.75	0.41–1.36	0.34
Recreational marijuana	0.15	0.04–0.6	0.01
Fluoroquinolones	1	0.31–3.19	0.99
Anticholinergics	1.39	0.64–3.03	0.4

Bold values indicate statistical significance.

BZD, benzodiazepine; ZLP, zolpidem.

We also explored the results of the primary outcome by study site institution. PRN BZD reduction was consistent across study sites with an absolute risk reduction of 17.2% (p = 0.01) and 27.1% (p = 0.01) at Henry Ford Health System and Ascension hospitals, respectively. Regarding PRN antipsychotic use, melatonin was associated with a significant absolute risk reduction of 21.6% (p = 0.05) at Ascension hospitals but was not different at Henry Ford Health System (2.6% increase, p = 0.76).

Similar results were seen with secondary outcomes. Patients receiving BZD or ZLP had more frequent administrations of BZD (1.81 vs. 0.38, p < 0.01) but not antipsychotics (1.33 vs. 1.52, p = 0.47). In addition to more frequent dosing, patients receiving BZD or ZLP also had a significantly higher average PRN BZD dose as compared with those receiving nightly melatonin (0.99 vs. 0.41 mg [lorazepam equivalents], p < 0.01). Results were also consistent in a subgroup of 130 patients at least 65 years or older. In this subgroup, at least one dose of a PRN antipsychotic was administered in patients receiving BZD or ZLP in 53.7% versus 55.1% (p = 0.88), respectively. Subsequent BZD administration occurred in 36.6% versus 18.0% of patients receiving BZD or ZLP versus melatonin, respectively (p < 0.01). There was no difference between the median length of stay between BZD or ZLP; 8 days (IQR 6–12.83) versus melatonin; 9 days (IQR 6–15.84) p = 0.29.

Discussion

The off-label use of melatonin and ramelteon for the prevention or treatment of delirium is common.¹⁹ Recent literature suggests that traditional agents used to treat delirium, such as antipsychotics and BZDs, are ineffective and may lead to poor outcomes.^{9,11,12,26
–28} These findings amplify the need for more robust data on alternative agents such as melatonin receptor agonists to prevent delirium. Although ramelteon and tasimelteon are highly selective melatonin receptor agonists with evidence suggesting superiority over melatonin,²⁹ high cost, and nonformulary status at participating sites during the study period precluded their use. Both institutions did have access to melatonin, which was able to significantly decrease receipt of subsequent BZDs but had no significant effect on antipsychotic administration. We suspect that the benefits arise from improvement in sleep quality, without enhancing the activity of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), as do both ZLP and BZDs. Downstream effects of GABA excitation are numerous and may preclude any benefits associated with these medications.

Frequency of PRN antipsychotic and BZD administration were chosen as surrogate markers for the development of delirium, as delirium screenings are not commonly performed on general medicine floors and these medications are frequently used to ease the symptoms of delirium.

Our findings are similar to Pinkhasov et al.'s findings that ramelteon supplementation decreased antipsychotic utilization in elderly patients with delirium as compared with no ramelteon (60% vs. 86.2%, p-value: 0.001).²⁵ Although we observed a nonsignificant decrease in overall PRN antipsychotic use, the risk difference seen with Ascension site-specific data (21.6%) is similar to the 26.2% risk difference that Pinkhasov et al. demonstrated. We hypothesize that differences in site-specific data may be a result of drug utilization variance among different institutions. Prescribing patterns and institutional policy may influence a medication's ability to represent as a surrogate outcome. Another important difference in our study is lack of delirium diagnosis and use of BZD or ZLP rather than a placebo control. Nevertheless, the results of the present study are important, as BZDs are deliriogenic medications that remain on the American Geriatrics Society Beers Criteria^® for Potentially Inappropriate Medication Use in Older Adults.^30,31

Few RCTs exist evaluating the use of melatonin for delirium prevention in a noncritically ill patient population and results are conflicting.^24,32 A subgroup meta-analysis of the two RCTs cited above found no difference in delirium prevention with melatonin receptor agonists compared with placebo (RR 0.88, 95% CI 0.15–5.31). However, the confidence intervals were broad and ranged from an 85% decrease in delirium to a greater than fivefold increase.²⁹ Another RCT from Hatta et al. shows that ramelteon is associated with an absolute risk reduction of 29% (p = 0.003), although roughly 36% of the patient population was admitted to the ICU and no subgroup analysis of non-ICU patients was performed.²⁰ Our study highlights the uncertainty of melatonin's role in the prevention of delirium by demonstrating a significant decrease in PRN BZD use without a significant overall decrease in PRN antipsychotic use. We also expand on what is currently known by including those <65 years of age, which the aforementioned studies excluded.

Several limitations were identified in this study. Data collection occurred by electronic medical record (EMR) review, which could introduce nondifferential misclassification bias; this may decrease the ability to detect a difference between groups. Additionally, any observational study has the risk of unmeasured confounding. Receipt of PRN antipsychotics or BZDs as a surrogate marker for delirium is also a limitation, as these agents show a lack of efficacy or even worsening of delirium. However, delirium is not documented consistently on the floor. The multicenter design of the study precluded gathering data such as sleep quality assessment, incidence/duration of delirium, and measures of agitation/sedation as these measures are inconsistently documented in the EMR outside of the ICU. Instead, data collection was standardized across sites to ensure validity. Additionally, if such outcomes were to have been collected in a standardized manner for the small percentage of those with adequate documentation, it is likely that data would only be available for patients with a higher acuity of illness, thus introducing a selection bias.³³

Exploratory analysis by institutional site suggests that an appropriate proxy for delirium may also vary by site. Lastly, melatonin was added to formulary at all sites in 2017, while alternative agents (BZD and ZLP) were available beforehand. This may have introduced selection bias because providers were not able to prescribe melatonin to study participants before 2017 (Supplementary Table S1 JICM_STROBE_checklist).

Conclusion

Melatonin was found to be associated with a statistically significant decrease in PRN BZD use in noncritically ill patients hospitalized on general floors. There was no observed association with overall PRN antipsychotic use. Our results suggest that using melatonin may help decrease the utilization of medications commonly used to manage delirium. Future trials could consider evaluation of outcomes associated with the development of delirium.

Footnotes

Authors' Contributions

P.D.: Writing—original draft, writing—review and editing, visualization, and validation. A.P.-S.: Writing—review and editing, investigation, and methodology. O.B.: Writing—review and editing, investigation, supervision, validation, and conceptualization. S.B.: Writing—review and editing, investigation, and methodology. C.G.: Conceptualization, software, formal analysis, data curation, supervision, and project administration.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Supplementary Material

Supplementary Table S1 JICM_STROBE_checklist

References

Thom

, Levy-Carrick

, Bui

, et al. Delirium. Am J Psychiatry, 2019; 176(10):785–793; doi: 10.1176/APPI.AJP.2018.18070893

Wilson

, Mart

, Cunningham

, et al. Delirium. Nat Rev Dis Primers 2020 6:1, 2020; 6(1):1–26; doi: 10.1038/s41572-020-00223-4

Inouye

, Westendorp

RGJ

, Saczynski

. Delirium in elderly people. Lancet, 2014; 383(9920):911–922; doi: 10.1016/S0140-6736(13)60688-1

Leslie

, Inouye

. The importance of delirium: Economic and societal costs. J Am Geriatr Soc, 2011; 59 Suppl 2(Suppl 2); doi: 10.1111/J.1532-5415.2011.03671.X

Goldberg

, Chen

, Wang

, et al. Association of delirium with long-term cognitive decline: A meta-analysis. JAMA Neurol, 2020; 77(11):1373–1381; doi: 10.1001/JAMANEUROL.2020.2273

Davis

DHJ

, Muniz Terrera

, Keage

, et al. Delirium is a strong risk factor for dementia in the oldest-old: A population-based cohort study. Brain, 2012; 135(Pt 9):2809–2816; doi: 10.1093/BRAIN/AWS190

Leslie

, Marcantonio

, Zhang

, et al. One-year health care costs associated with delirium in the elderly. Arch Intern Med, 2008; 168(1):27; doi: 10.1001/ARCHINTERNMED.2007.4

Grover

, Avasthi

. Clinical practice guidelines for management of delirium in elderly. Indian J Psychiatry, 2018; 60(Suppl 3):S329; doi: 10.4103/0019-5545.224473

Neufeld

, Yue

, Robinson

, et al. Antipsychotic medication for prevention and treatment of delirium in hospitalized adults: A systematic review and meta-analysis. J Am Geriatr Soc, 2016; 64(4):705–714; doi: 10.1111/JGS.14076

10.

, Ma

, Jin

, et al. Benzodiazepines for treatment of patients with delirium excluding those who are cared for in an intensive care unit. Cochrane Database Syst Rev, 2020; 2020(2); doi: 10.1002/14651858.CD012670.PUB2/MEDIA/CDSR/CD012670/IMAGE_N/NCD012670-CMP-003-03.PNG

11.

Hui

. Benzodiazepines for agitation in patients with delirium: Selecting the right patient, right time and right indication. Curr Opin Support Palliat Care, 2018; 12(4):489; doi: 10.1097/SPC.0000000000000395

12.

Lee

, Okoro

, Swanson

, et al. Opioid and benzodiazepine use in the emergency department and the recognition of delirium within the first 24 hours of hospitalization. J Psychosom Res, 2022; 153:110704; doi: 10.1016/J.JPSYCHORES.2021.110704

13.

Friedman

, Soleimani

, McGonigle

, et al. Pharmacological treatments of non-substance-withdrawal delirium: A systematic review of prospective trials. Am J Psychiatry, 2014; 171(2):151–159; doi: 10.1176/APPI.AJP.2013.13040458/SUPPL_FILE/151_DS001.PDF

14.

Farasat

, Dorsch

, Pearce

, et al. Sleep and delirium in older adults. Curr Sleep Med Rep, 2020; 6(3):136; doi: 10.1007/S40675-020-00174-Y

15.

Ángeles-Castellanos

, Ramírez-Gonzalez

, Ubaldo-Reyes

, et al. Loss of melatonin daily rhythmicity is asociated with delirium development in hospitalized older adults. Sleep Sci, 2016; 9(4):285–288; doi: 10.1016/j.slsci.2016.08.001

16.

Jabbar

, Leonard

, Meehan

, et al. Neuropsychiatric and cognitive profile of patients with DSM-IV delirium referred to an old age psychiatry consultation-liaison service. Int Psychogeriatr, 2011; 23(7):1167–1174; doi: 10.1017/S1041610210002383

17.

Shen

, Li

, Zhou

, et al. Relation of serum melatonin levels to postoperative delirium in older patients undergoing major abdominal surgery. J Int Med Res, 2020; 48(3):300060520910642; doi: 10.1177/0300060520910642

18.

Dang

, Mansukhani

, Wang

, et al. Prophylactic use of ramelteon for delirium in hospitalized patients: A systematic review and meta-analyses. J Acad Consult Liaison Psychiatry, 2023; 64(1):65–72; doi: 10.1016/j.jaclp.2022.06.002

19.

Yan

, Li

, Song

, et al. Prophylactic melatonin for delirium in critically ill patients: A systematic review and meta-analysis with trial sequential analysis. Medicine (Baltimore), 2022; 101(43):e31411; doi: 10.1097/MD.0000000000031411

20.

Hatta

, Kishi

, Wada

, et al. Preventive effects of ramelteon on delirium: A randomized placebo-controlled trial. JAMA Psychiatry, 2014; 71(4):397–403; doi: 10.1001/JAMAPSYCHIATRY.2013.3320

21.

Vijayakumar

, Ramya

, Duggappa

, et al. Effect of melatonin on duration of delirium in organophosphorus compound poisoning patients: A double-blind randomised placebo controlled trial. Indian J Anaesth, 2016; 60(11):814–820; doi: 10.4103/0019-5049.193664

22.

Shi

. Effects of melatonin on postoperative delirium after PCI in elderly patients: A randomized, single-center, double-blind, placebo-controlled trial. Heart Surg Forum, 2021; 24(5):E893–E897; doi: 10.1532/HSF.4049

23.

Nishikimi

, Numaguchi

, Takahashi

, et al. Effect of administration of ramelteon, a melatonin receptor agonist, on the duration of stay in the ICU: A single-center randomized placebo-controlled trial. Crit Care Med, 2018; 46(7):1099–1105; doi: 10.1097/CCM.0000000000003132

24.

Al-Aama

, Brymer

, Gutmanis

, et al. Melatonin decreases delirium in elderly patients: A randomized, placebo-controlled trial. Int J Geriatr Psychiatry, 2011; 26(7):687–694; doi: 10.1002/GPS.2582

25.

Pinkhasov

, James

, Fazzari

, et al. Role of ramelteon in reduction of as-needed antipsychotics in elderly patients with delirium in a general hospital setting. Clin Drug Investig, 2017; 37(12):1137–1141; doi: 10.1007/s40261-017-0573-5

26.

Mart

, Williams Roberson

, Salas

, et al. Prevention and management of delirium in the intensive care unit. Semin Respir Crit Care Med, 2021; 42(1):112; doi: 10.1055/S-0040-1710572

27.

Nikooie

, Neufeld

, Oh

, et al. Antipsychotics for treating delirium in hospitalized adults: A systematic review. Ann Intern Med, 2019; 171(7):485–494; doi: 10.7326/M19-1860

28.

Burry

, Hutton

, Williamson

, et al. Pharmacological interventions for the treatment of delirium in critically ill adults. Cochrane Database Syst Rev, 2019; 9(9):CD011749; doi: 10.1002/14651858.CD011749.PUB2

29.

Khaing

, Nair

. Melatonin for delirium prevention in hospitalized patients: A systematic review and meta-analysis. J Psychiatr Res, 2021; 133:181–190; doi: 10.1016/J.JPSYCHIRES.2020.12.020

30.

Fick

, Semla

, Steinman

, et al. American Geriatrics Society 2019 Updated AGS Beers Criteria^® for potentially inappropriate medication use in older adults. J Am Geriatr Soc, 2019; 67(4):674–694; doi: 10.1111/JGS.15767

31.

Zaal

, Devlin

, Hazelbag

, et al. Benzodiazepine-associated delirium in critically ill adults. Intensive Care Med, 2015; 41(12):2130–2137; doi: 10.1007/S00134-015-4063-Z/FIGURES/2

32.

Jaiswal

, McCarthy

, Wineinger

, et al. Melatonin and sleep in preventing hospitalized delirium: A randomized clinical trial. Am J Med, 2018; 131(9):1110–1117.e4; doi: 10.1016/J.AMJMED.2018.04.009

33.

Rusanov

, Weiskopf

, Wang

, et al. Hidden in plain sight: Bias towards sick patients when sampling patients with sufficient electronic health record data for research. BMC Med Inform Decis Mak, 2014; 14(1):51; doi: 10.1186/1472-6947-14-51

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.03 MB