CADTH Health Technology Review

Melatonin for the Treatment or Prevention of Delirium

Rapid Review

Authors: Sara D. Khangura, Danielle McDougall

Key Messages

• Variable findings were reported for clinical effectiveness of melatonin for the prevention or treatment of delirium compared with placebo in the literature that met the criteria for this review.

• No studies that met the criteria for this review were found on the clinical effectiveness of melatonin for the prevention and/or treatment of delirium versus antipsychotic drugs or cholinergic agents.

• There was limited evidence available on the clinical effectiveness of melatonin for the prevention and/or treatment of delirium versus dexmedetomidine.

• There were no statistically or clinically significant harms reported from the use of melatonin in the treatment of patients at risk from or experiencing delirium.

• Limited guidance was found that provided recommendations for the use of melatonin in the prevention and//or treatment of delirium for hospitalized inpatients.

Context and Policy Issues

Delirium is an acute condition that is characterized by confusion and altered consciousness, which commonly develops during hospitalization.¹ Delirium often affects older inpatients and those with comorbidities,^2-5 including visual and or cognitive impairment (e.g., dementia),^6,7 and has been characterized as the most common complication following surgery among older adults.⁴ In addition to patient characteristics, the risk for developing delirium has also been associated with health care factors, including poor nutrition, the need for use of restraints, and other iatrogenic events.⁶ Depending on the level of agitation and hyperactive behaviour, delirium may be more or less recognizable, making diagnosis a challenge in cases for which agitation is not apparent or is not severe enough to be noticed in a busy hospital or intensive care unit (ICU) setting.^5,6

Much of the published literature focuses on delirium in hospitalized older adults^,6 and/or those in the ICU; however, delirium can affect people of any age who are critically ill and in hospital,⁸ and often co-occurs with sleep disruption that is common when admitted to hospital and ICU environments.^3,6 Delirium can contribute to significant morbidity, including falls, longer stays in the ICU and/or hospital, higher rates of long-term care placement following discharge from hospital, hospital readmission, functional decline, and mortality.^3,4,6-8 The condition can have long-term effects for some patients, with a return to baseline cognition taking up to a year for some people; in others, the cognitive effects can be permanent.⁶ In addition to the deleterious effects that delirium can cause for patients, families, and health care providers, delirium has also been associated with higher costs of care. Its effective prevention and management is considered a health care quality indicator,^6,8 making it an important priority for individuals, communities, and health care systems.⁴

There are several approaches to managing delirium in the hospital setting, including both preventive and therapeutic interventions that may be either pharmacological and non-pharmaceutical.⁶ Non-pharmaceutical interventions aimed at the prevention of delirium focus on identifying and mitigating risk factors for developing delirium before its onset.⁶ Some research has investigated the use of medical interventions for the prevention of delirium (e.g., preoperative administration of antipsychotic medications); however, the evidence is inconclusive about the effectiveness of these preventive measures.⁶ Treatment of delirium may initially involve the use of non-pharmacological interventions (e.g., assistance with reorientation from a health care provider, family member, or other caregiver), or escalate to more intensive interventions, such as the use of physical restraints.⁶ Often the prevention and/or management of delirium requires the use of pharmacological intervention, including the use of antipsychotic medications or cholinesterase inhibitors; however, these are not thought to treat the underlying cause of delirium,⁹ are not supported by conclusive evidence of any preventive or therapeutic benefit,^5,8 and may cause harm.⁶

Melatonin has been suggested as a potentially useful intervention for the prevention and/or treatment of delirium in hospitalized patients^3,5 because it is a hormone, produced by the pineal gland, that supports healthy circadian rhythms and sleep patterns.¹⁰ Melatonin is also believed to have a favourable safety profile, with few side effects described in the literature to date.³ Because of the association between delirium and poor sleep,¹⁰ melatonin could potentially be a clinically effective intervention for the prevention and management of delirium in hospitalized inpatients.⁴ Nonetheless, currently available research describing the use of melatonin for the prevention and/or treatment of delirium has produced variable findings and has not supported consensus about its clinical effectiveness or utility.^3-5

Given the potential benefit that melatonin may offer to patients who are at risk for developing or experiencing delirium while hospitalized, this review aims to gather and summarize relevant evidence describing clinical effectiveness and evidence-based guidance.

Research Questions

1. What is the clinical effectiveness of melatonin versus no treatment or placebo for the treatment or prevention of delirium in adult patients in the hospital or intensive care unit?

2. What is the clinical effectiveness of melatonin versus antipsychotic drugs for the treatment or prevention of delirium in adult patients in the hospital or intensive care unit?

3. What is the clinical effectiveness of melatonin versus cholinergic agents for the treatment or prevention of delirium in adult patients in the hospital or intensive care unit?

4. What is the clinical effectiveness of melatonin versus dexmedetomidine for the treatment or prevention of delirium in adult patients in the hospital or intensive care unit?

5. What are the evidence-based guidelines regarding the use of melatonin for the treatment or prevention of delirium in adult patients in the hospital or intensive care unit?

Methods

Literature Search Methods

A limited literature search was conducted by an information specialist on key resources including MEDLINE, Embase, PsycINFO, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were melatonin and delirium. No filters were applied to limit the retrieval by study type. Conference abstracts were excluded. If possible, retrieval was limited to the human population. The search was completed on March 23, 2022, and was limited to English-language documents published since January 1, 2017.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed, and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, were duplicate publications, or were published before 2021. Systematic reviews (SRs) in which all relevant primary studies were captured in other more recent or more comprehensive SRs were excluded. SRs and primary studies retrieved by the search were excluded if they were captured in 1 or more included overviews of SRs or systematic reviews. Guidelines with unclear methodology were also excluded.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)¹¹ for overviews of SRs and systematic reviews, the Downs and Black checklist¹² for RCTs, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument¹³ for evidence-based guidelines. Summary scores were not calculated for the included studies and publications; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 213 citations were identified in the electronic literature search. Following screening of titles and abstracts, 178 citations were excluded and 35 potentially relevant reports from the electronic search were retrieved for full-text review. Two potentially relevant publications were retrieved from the grey literature search for full-text review. Of these 37 potentially relevant articles, 28 were excluded for various reasons, and 9 publications met the inclusion criteria and were included in this report. These comprised 1 overview of meta-analyses (with or without SRs), 1 SR, 6 randomized controlled trials (RCTs), and 1 evidence-based guideline. Appendix 1 presents the PRISMA¹⁴ flow chart outlining study selection.

Additional references of potential interest are provided in Appendix 5.

Summary of Study Characteristics

The overview and the SR in this report had broader inclusion criteria than this review.^15,16 Specifically, the authors evaluated the clinical effectiveness of melatonergic drugs (i.e., both melatonin and Ramelteon) for the prevention of delirium in hospitalized patients.^15,16 Similarly, the guideline included in this report was more broadly focused on sleep and circadian rhythm disorders (including those causing delirium);¹⁷ consequently, only the characteristics, results, and recommendations from the subset of studies and/or guidance that are relevant will be described in this report.

The overview was published in 2021 and sought meta-analyses (with or without SRs) published between January 2020 and August 2021.¹⁵ The overview included 3 meta-analyses of RCTs published between 2016 and 2020; however, none of the included studies were eligible for inclusion in this report. One study was a meta-analysis (conducted without an accompanying SR) that presented some data on melatonin separately; however, a meta-analysis without a SR was not an eligible study design for inclusion in this review. The other 2 were SRs with meta-analyses, with all data presented combining both melatonin and Ramelteon,¹⁵ which were not eligible for inclusion in this review because Ramelteon was not an eligible intervention. Thus, although the overview study itself met the eligibility criteria for this report, it was considered an empty overview because it contained no eligible studies (i.e., it was retained as an eligible study, but no data could be abstracted or summarized in this report).

Additional details regarding the characteristics of included publications are provided in Appendix 2.

Study Design

The SR was published in 2021.¹⁶ It included studies from the inception dates of the citation databases that were queried to May 2020 and included 9 RCTs, published between 2010 and 2020, that were eligible for inclusion in this report.¹⁶

Six RCTs were found to be eligible for this report, 2 of which were published in 2022^18,19 and 4 of which were published in 2021.^20-23 Five of these RCTs used a double-blind, placebo-controlled design,^18-21,23 and 1 did not specify whether participants, clinicians, and/or investigators were blinded to patient allocation to treatment.²² Four of the RCTs were conducted within a single centre,^19-21,23 whereas 1 RCT was conducted across 12 centres;¹⁸ another did not report information describing whether the study was single- or multi-centre.²² Although 5 of the 6 RCTs were designed as superiority trials,^18-20,22,23 1 was a feasibility study intended to assess the potential for conducting a large-scale RCT.²¹ Duration of follow-up ranged across 5 of the RCTs (and the outcomes measured) between 4 days and 90 days.^18-23 One RCT did not clearly report follow-up time.²⁰

The 1 guideline included in this report was published in 2021, and was developed by the Italian Society of Psychosomatic Medicine with several other organizations participating in and/or contributing to the development process: the Italian Association of Sleep Medicine, the Italian Association for the Fight Against Stigma, the Italian Society of Consultation-Liaison Psychiatry, the Italian Society of Neuropsychopharmacology, the Italian Society of Psychosomatic Medicine, the French Society for Sleep Research and Sleep Medicine, and the French Association of Biological Psychiatry and Neuropsychopharmacology.¹⁷ The guideline developers used a systematic literature review to identify and critically appraise relevant evidence. Following the synthesis of evidence, a modified Delphi technique was used to establish consensus on a set of recommendations between a panel of experts.¹⁷ The guideline developers did not report the use of a grading or rating system for the recommendations they published, and of the 9 recommendation statements included in the guideline, 1 recommendation addressed the use of melatonin for the treatment and prevention of delirium.¹⁷

Country of Origin

The SR was conducted by investigators based in Australia¹⁶ as were 2 of the RCTs included in this report.^18,21 Two of the other RCTs were conducted in China,^19,23 1 in Iran,²⁰ and another in Egypt.²² The guideline does not specify a context to which its recommendations apply; rather, it characterizes itself as an international guideline led by Italian and French experts.¹⁷

Patient Population

The SR included in this report described RCTs of adults who were 18 years of age or older and were hospitalized in medical or surgical wards or the ICU. It included 1,712 patients in total, 1,303 of whom contributed to data that were eligible for this report.¹⁶ The conditions, or reasons for hospitalization, were not provided in the overview study, although a reference to a high degree of heterogeneity was identified and quantified.¹⁵ Patients included in the eligible primary studies from the SR represented a broad range of conditions and/or reasons for hospitalization, including hip surgery, liver resection, organophosphate poisoning, and elective cardiac and pulmonary thromboendarterectomy (as well as several studies for which no specific condition or reason for hospitalization provided other than medical, surgical, emergency, and elective patients).¹⁶ Similarly, the SR noted a high degree of heterogeneity in the 9 studies investigating melatonin and specified patient characteristics as being 1 of several sources of this heterogeneity.¹⁶

The multi-centre RCT enrolled and randomized 847 adult patients, aged 18 years or older (841 of whom were included in the analyses), and admitted to the ICU for various reasons (i.e., medical, surgical, elective, and emergency) and diagnoses (including cardiovascular, gastrointestinal, sepsis-related, metabolic, trauma-related, neurologic, and respiratory).¹⁸ Similarly, the Australian feasibility RCT enrolled patients (29 randomized; 28 analyzed) with various reasons for admission (although limited to medical reasons only), including sepsis, trauma, and cardiovascular and metabolic reasons; however, this RCT also limited its population to older adults who were aged 70 years and older.²¹ The remaining 4 RCTs focused on patients who had a particular condition (i.e., acute heart failure)¹⁹ and/or underwent a particular surgical procedure (i.e., coronary artery bypass graft surgery^20,22 or percutaneous transluminal coronary intervention).²³ Three of these 4 RCTs limited their populations of interest to older adults who were at least 60 years of age or older,^19,22,23 whereas the fourth included patients as young as 30 years.²⁰ The 2 Chinese studies had larger sample sizes than the Iranian and Egyptian studies, with 497 patients randomized (and 480 with complete follow-up)¹⁹ and 297 patients randomized (285 analyzed).²³ Finally, the Iranian study randomized and analyzed 60 patients;²⁰ the Egyptian study randomized and analyzed 110 patients.²²

The guideline was developed to inform psychiatric clinicians about the preventive and therapeutic treatment of adult patients with neuropsychiatric disorders who suffer from sleep and circadian rhythm disturbances (including delirium).¹⁷ The recommendations specific to delirium are not particular to patients in a hospital and/or ICU setting; however, the evidence used to inform the recommendations was based on hospitalized patient data.¹⁷

Interventions and Comparators

The SR included studies that compared melatonin and/or Ramelteon (any dose) against placebo and/or usual care; studies eligible for this report described doses of melatonin between 0.5 mg/kg to 50 mg/kg.¹⁶ The SR described treatment durations ranging from 4 days to 14 days, and the daily doses for 8 of the 9 included RCTs eligible for this report, with a single preoperative dose administered in 1 of the RCTs.¹⁶

The 6 RCTs included in this report investigated melatonin at dosages ranging from 3 mg to 5 mg per day.^18-23 Five of the 6 RCTs investigated melatonin administered orally,^19-23 whereas 1 investigated the use of enterally administered melatonin.¹⁸ Five of the 6 RCTs included in this review compared melatonin against matching placebos,^18-21,23 with the sixth comparing melatonin plus dexmedetomidine against dexmedetomidine only.²² Patients who experienced severely agitated dementia in both arms of this latter trial also received haloperidol as needed.²²

The guideline provides recommendations for the use of melatonin at dosages ranging from 2 mg to 5 mg, depending on whether the dosage is immediate release versus prolonged release.¹⁷

Outcomes

The primary outcome for 7 of the 8 studies in this report that examined clinical effectiveness was the occurrence or presence of delirium,^{15,16,18-20,22,23} whereas 2 RCTs included severity of delirium in the primary outcome.^20,21 All studies that measured the presence of delirium reported use of the Confusion Assessment Method (CAM) and/or the CAM-ICU instrument(s),^{16,18-20,22,23} with severity of delirium measured using the Memorial Delirium Assessment Scale (MDAS)^20,21 and Confusion Assessment Method – Severity Scale (CAM-S).¹⁸ The CAM and CAM-ICU are diagnostic measures that detect the presence of delirium using an algorithm.²⁴ The MDAS and CAM-S instruments are measures of the severity of delirium, with higher scores indicating more severe delirium.^25,26 Additional measures of delirium were reported among some RCTs described in the SR, including the Abbreviated Mental Test and the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV).¹⁶

Secondary and other outcomes were measured without the use of standardized instruments, including those characterizing the prevention of delirium (i.e., time to onset of delirium)²² as well as those characterizing the management of delirium (i.e., duration of delirium)^16,22 and adjunct interventions (i.e., not melatonin) to manage delirium.^18,21,22 Additional outcomes measured included mortality,^16,18,19,23 length of stay (LOS) in hospital^{16,18,19,22,23} and/or the ICU,^16,18,20,22 as well as adverse events (AEs) and severe adverse events (SAEs).^16,18-21

The evidence-based guideline described the effectiveness of melatonin for the prevention and treatment of sleep disorders, including those associated with delirium.¹⁷

Summary of Critical Appraisal

Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.

Overview of Meta-Analyses With or Without Systematic Reviews

The overview demonstrated both strengths and limitations, such as the research objectives and eligibility criteria (i.e., population, intervention, comparator, and outcomes) were made clear and a protocol was produced a priori.¹⁵ The search strategy reported in the overview paper met the criteria of a comprehensive search,¹⁵ which is a component of a well-conducted review because it assures the reader that efforts have been made to identify the maximum amount of eligible information. The overview report also described the use of duplicate screening at the title and abstract phase (with insufficient information reported concerning full-text review) as well as duplicate data abstraction.¹⁵ The overview did not provide a list of excluded studies and the authors did not report the source(s) of funding for the included studies.¹⁵ These features are important to ensure transparency of the methods and reproducibility of the findings.^15,27

Systematic Review

The SR included in this review demonstrated both strengths and limitations, such as the research objectives and eligibility criteria were made clear,¹⁶ which is important for framing and establishing the aim and research question(s) of a review. The SR did not describe the production of a review protocol in advance of conducting the study, which is important to ensure transparency and reproducibility of the review and to mitigate the potential for introducing bias. Although the authors of the SR described a comprehensive search,¹⁶ neither duplicate screening nor duplicate data abstraction methods were reported.¹⁶ Screening by 2 independent reviewers is an important feature of a well-conducted SR because it helps ensure that all eligible studies are identified and included and reduces the potential for bias and error. Similarly, duplicate data abstraction is important for ensuring that data have been accurately and comprehensively identified. Risk of bias was assessed using the Cochrane risk of bias tool²⁸ and authors were careful to assess and describe significant clinical heterogeneity and publication bias as limiting factors of their review — which may cause any potential effect of an intervention to be less clearly apparent²⁹ — but also account for these limitations in their interpretation of findings.^16,29 Similar to the overview, the SR was limited in its description of excluded studies as well as the source(s) of funding for the included studies.^16,27 Other limitations included a lack of detail and interpretation describing the reported publication bias (e.g., the source or drivers), multiple typos and errors in the manuscript that interfered with the interpretation of findings for some outcomes, and failure to discuss the potential impact of risk of bias in the primary studies on the findings of the review.¹⁶

Randomized Controlled Trials

Similarly, the papers describing RCTs demonstrated strengths and limitations, with clear descriptions of several important features of the trial methods and findings.^18-23 Nonetheless, multiple typos and errors in 2 of the manuscripts were sufficient to interfere with the readability, comprehensibility, and interpretation of findings for some outcomes.^21,23 Furthermore, 3 of the papers were unclear about the outcomes and measures they described, which similarly rendered some of the findings unclear and challenging to interpret.^20-22 One of these RCTs also failed to provide any narrative summary of the results, providing only tabulated data in the results section of the paper.²² This unusual presentation of the study results made it particularly challenging to contextualize and interpret some of the findings.

Four RCTs^21,22 demonstrated sufficient external validity with apparently representative patient populations and hospital settings.^18-20,23 The other 2 RCTs did not include sufficient information with which to assess the representativeness of the study populations, health care received and health care settings.^21,22

Other strengths common to all RCTs included in this review and demonstrating internal validity were randomized assignment to treatment groups, adequate reporting of sufficient statistical testing methods, and no evidence of data dredging or post hoc analyses.^18-23 However, 1 of the RCTs was not clear about the methods used to randomize patients to the treatment groups,²² which is an important limitation rendering uncertainty about whether the randomization process was robust and/or free from any biases. Another strength common to 4 of the trials included in this review was double-blind administration of study treatments,^18,19,21,23 which is a methodological feature that helps to mitigate bias that could affect the measurement of treatment effects and contributes to confidence in the internal validity of these trials. Two of the RCTs did not report information about blinded allocation to treatment,^20,22 which is a limitation that could negatively impact the internal validity of the findings.

Four of the RCTs in this report described the use of power calculations that demonstrated sufficient power to detect any statistically significant differences between treatment groups;^18,19,22,23 however, 2 of the RCTs did not.^20,21 One of these RCTs was designed as a feasibility trial, which was intentionally limited in scope and was primarily interested in demonstrating whether a larger trial is feasible and how best to design it (i.e., the authors explicitly stated that they were not pursuing a power calculation in favour of demonstrating the standard deviation for the primary outcome as part of the primary objective of demonstrating feasibility).²¹ The research objective and small sample size (28 patients analyzed) in this RCT²¹ are important considerations when weighing the utility of its findings in this review. In addition, the other study in which no power calculation was described also used a small sample size (60 patients analyzed) and demonstrated other limitations that require consideration (e.g., no baseline assessments for psychological comorbidities, limited assessment of complications) when interpreting the findings in the context of this review.²⁰

Three of the RCTs had larger sample sizes (ranging from 285 to 841 patients analyzed) as well as robust methods for randomization and blinded allocation to treatment, which are strengths that warrant consideration about the value that their findings contribute to this review.^18,19,23 Nonetheless, some limitations were present in these studies as well, such as the authors of 2 of these larger RCTs explicitly acknowledged uncertainty about the dosages of melatonin used in their studies, and point out that this may have been a limiting factor affecting the findings because they describe the clinical effectiveness of melatonin for the prevention and/or treatment of delirium.^18,19 Finally, a limitation from the multicentre Australian study was clinical heterogeneity between patients included in the trial, including variability in the ages, diagnoses, and reasons for hospital admission.¹⁸ As in reviews of primary clinical studies, multiple differences in patient characteristics across a clinical study population can render variable findings that may lead to uncertainty in the potential effects of the intervention of interest.

Evidence-Based Guideline

The scope and purpose of the guideline included in this review was clear;¹⁷ however, because the scope is much broader than that of this report, there is limited information of relevance to the research question posed herein. Stakeholder involvement is a strength in terms of the multidisciplinary composition of the guideline developers, but there is no mention of patient or public involvement and the intended target users for the guideline are not made explicit.¹⁷ Rigour of development is strong regarding the use of an SR to identify evidence that is clearly linked to the relevant recommendations; however, there is no discussion of the quality of the evidence, how the evidence was used to develop the recommendations, nor the strength of the recommendations,¹⁷ which are key features of a robust evidence-based guideline.³⁰ There is also no description of a policy or plans for updating the guideline.¹⁷ Furthermore, the guideline is very limited in its clarity of presentation regarding delirium; that is, the recommendations are ambiguous and fail to provide clear and specific guidance.¹⁷ Similarly, the applicability of the recommendations regarding delirium are not clear, with no information about suggestions for implementing the guideline into clinical practice.¹⁷ Finally, funding and potential conflicts of interest were not described within the published report of the guideline,¹⁷ leaving uncertainty concerning the extent to which the guideline developers were able to maintain editorial independence. Nonetheless, given the context and subject matter of the recommendations specific to this report (i.e., melatonin is a generic supplement), it may be that editorial independence (e.g., from corporate or financial conflicts of interest) is less of a limiting factor of relevance to this report. Further, the guideline developers in this case are nonprofit groups with no obvious ties to financial or other potential conflicts of interest. Instead, the fact that authors of the guideline have published unclear and nonspecific guidance particular to delirium, neither advising in favour or against the use of melatonin (i.e., due to the uncertainty present in the relevant evidence base) is a more important limiting factor because it applies to the research question being posed by this report.

Summary of Findings

Clinical Effectiveness of Melatonin Versus No Treatment or Placebo for the Treatment or Prevention of Delirium

Treatment of Delirium

One SR and 3 RCTs included in this review presented results on the clinical effectiveness of melatonin compared with placebo or usual care (i.e., not otherwise described) by describing 3 outcomes relevant to the treatment of delirium: duration, severity, and adjunct interventions.^16,18,20,21

Duration of Delirium

The SR included 5 RCTs describing the duration of delirium. Note the findings of these were pooled in a meta-analysis of studies that included Ramelteon, which was not eligible for this report; therefore, the results for the quantitative synthesis were not eligible for inclusion in this report.¹⁶ These 5 RCTs had sample sizes ranging from 87 patients to 378 patients and mean ages ranging from 50 years to 84 years (as well as various diagnoses and reasons for admission) and dosages of melatonin ranging from 0.5 mg to 3 mg per day and follow-up durations between 5 days and 14 days. None reported a statistically significant difference between treatment groups in the duration of delirium.¹⁶

Severity of Delirium

Three RCTs included in this review reported on the severity of delirium, 2 of which used the MDAS measure^20,21 and 1 of which used the CAM-S measure.¹⁸ The studies ranged in sample size from 28 patients to 841 patients, with mean ages of treatment groups ranging from 60.26 (standard deviation [SD] = 9.50) years and 86.1 (SD = 4.40) years (as well as various diagnoses and reasons for admission), dosages of melatonin ranging from 3 mg to 5 mg per day (with 1 RCT using enteral administration of the study drugs¹⁸), and follow-up durations between 5 days and 14 days (with 1 RCT not reporting on follow-up duration²⁰).^18,20,21 Two of the RCTs reported no difference between the treatment groups in severity of delirium,^18,21 whereas the third reported a statistically significant difference between the treatment groups, but did not specify which intervention was favoured by the analysis, stating only that “The difference between the melatonin and control groups with regard to the severity of delirium and based on the MDAS was statistically significant (P=0.003) (p. 123).”²⁰

Adjunct Interventions for Delirium

Two of the RCTs included in this review reported on adjunct interventions required to manage delirium in patients (sample sizes ranging from 28 patients to 841 patients with various diagnoses and reasons for admission, and mean ages among treatment groups ranging from 61.9 years to 86.1 years) who received either melatonin (dosages ranging from 4 mg to 5 mg per day) or matching placebo for a range of 7 days to 14 days of follow-up.^18,21 One of the RCTs included enteral administration of the study drugs,¹⁸ and the other investigated orally administered study drugs.²¹ Both studies reported no statistically significant differences between treatment groups in the need for either rescue medications or restraints.^18,21

Prevention of Delirium

All 6 of the studies reporting on the clinical effectiveness of melatonin compared with placebo or usual care described 1 outcome relevant to the prevention of delirium (i.e., occurrence of delirium).^16,18-21,23

Occurrence of Delirium

Four of the 6 studies reporting on the occurrence of delirium showed no difference between the melatonin and placebo or usual care treatment groups,^16,18,20,21 including pooled results reported in the included SR combining data from 9 RCTs representing 1,285 patients, which generated a risk ratio (RR) of 0.67 (95% confidence interval [CI], 0.41 to 1.09).¹⁶ Among the individual RCTs included in the SR, 5 of 9 RCTs pooled in the MA investigating the occurrence of delirium showed no statistically significant difference between melatonin and placebo, with 4 of 9 RCTs finding a statistically significant difference favoured melatonin.¹⁶ A subgroup analysis focusing on only medical patients also did not demonstrate any statistically significant difference between the treatment groups (RR = 0.88; 95% CI, 0.15 to 5.31).¹⁶

The 2 studies that produced a statistically significant difference between treatment groups both indicated a benefit of melatonin compared with placebo.^19,23

Mortality

All-Cause Mortality

One SR and 3 RCTs presented data describing all-cause mortality in patients receiving melatonin versus placebo.^16,18,19,23 None of the RCTs (either those included in the SR or those included in this review) found a statistically significant difference between treatment groups in the number of deaths among study participants.^16,18,19,23

Health Care Utilization

One SR and 4 RCTs included in this review reported on the clinical effectiveness of melatonin compared with placebo or usual care by describing 2 outcomes relevant to the health care utilization (i.e., lengths of stay in hospital and/or ICU).^16,18-20,23

Length of Stay in Hospital

One SR and 3 RCTs investigated the effect of melatonin compared with placebo on the LOS in hospital. The 3 RCTs were clear about measuring this outcome in days,^18,19,23 the SR did not report the unit of measurement.¹⁶ Study sample sizes across the 5 eligible RCTs described in the SR and the 3 RCTs included in this review ranged from 87 patients to 841 patients with mean ages from 50 years to 84 years with various diagnoses and reasons for admission.^16,18,19,23 Dosages of melatonin ranged from 0.5 mg to 5 mg per day,^16,18,19,23 with 1 study investigating the use of study drugs administered enterally¹⁸ and the other 3 describing orally administered study medications.^16,19,23 Of the 5 RCTs included in the SR that reported on this outcome, none reported a statistically significant difference in length of hospital stay between the melatonin and placebo treatment groups.¹⁶ Of the 3 RCTs included in this review that reported data on mean number of days in hospital, 2 reported a statistically significant benefit for patients receiving melatonin (P = 0.01 in both studies, although the data were subject to an apparent error in 1 of these reports²³),^19,23 whereas the third found no significant difference in the median days hospitalized between the treatment groups (P = 0.816).¹⁸

Length of Stay in ICU

The SR and 2 RCTs included in this review reported on duration of stay in the ICU.^16,18,20 As with the outcome measuring LOS in hospital, the SR did not explicitly report the unit of measurement for this outcome,¹⁶ whereas the 2 RCTs were clear about reporting this outcome in mean number of days.^18,20 The SR also published what appeared to be a typographical error in the forest plot for this outcome, indicating that the intervention arm was “tryptophan”; however, there is no other mention of tryptophan in the article. One of the primary studies from the forest plot was retrieved to verify that the intervention was, in fact, melatonin.¹⁶ Study sample sizes across the 3 eligible RCTs described in the SR and the 2 RCTs included in this review ranged from 36 patients to 841 patients with mean ages between 50 years and 84 years and various diagnoses and reasons for admission.^16,18,20 Dosages of melatonin ranged from 0.5 mg to 5 mg per day,^16,18,20 with 1 study investigating the use of study drugs administered enterally¹⁸ and the other 2 describing orally administered study medications.^16,20 Of the 3 RCTs included in the SR that reported on this outcome, none reported a statistically significant difference in LOS in the ICU between the melatonin and placebo treatment groups.¹⁶ And of the 2 RCTs included in this review that reported data on number of days in hospital, 1 reported a statistically significant benefit for patients receiving melatonin (P = 0.04),²⁰ whereas the other found no significant difference in the median days hospitalized between the treatment groups (P = 0.135).¹⁸

Safety

One SR and 4 RCTs included in this review reported on the safety of melatonin compared with placebo or usual care by describing 2 relevant outcomes: AEs and SAEs.^16,18-20,23

Adverse Events

The SR and 3 RCTs reported on a variety of AEs, from measures of liver function,^16,18 gastrointestinal symptoms,^16,19 hallucinations and/or nightmares,¹⁶ falls, and new pressure areas.²¹ One RCT of 841 patients administered 4 mg per day for 14 days (or until ICU discharge) enterally to patients with a variety of diagnoses and reasons for admissions, and found no statistically significant differences in 3 measures of liver function: bilirubin, alanine transferase, and alkaline phosphatase.¹⁸ Another RCT including 497 patients measured mild liver dysfunction and found a statistically significant difference (P value not reported, i.e., reported narratively only) between the treatment groups that favoured placebo (melatonin group = 25 patients; as placebo group = 16 patients).¹⁹ The 2 studies reporting on diarrhea and gastrointestinal disorders were nonspecific in the description of their findings, with 1 RCT stating only that 2 patients in the melatonin group experienced diarrhea (and not reporting on the placebo group)¹⁹ and the SR describing gastrointestinal disorders as common in the melatonin group (with no information on the placebo group) from a narrative synthesis of 2 RCTs.¹⁶ Another RCT of 28 older adult patients with various diagnoses and reasons for hospital admission found no occurrences of new pressure areas, and reported 2 patients who experienced a fall in the melatonin group compared with no patients in the placebo group, but the difference was not statistically significant (P = 0.485).²¹

Severe Adverse Events

Two RCTs included in this review reported on the numbers of patients experiencing any SAE.^18,20 Both studies included patients with median ages in the early sixties and representing a variety of diagnoses and reasons for hospital admission, with 1 RCT reporting findings on 841 patients¹⁸ and the other on 60 patients.²⁰ Dosages of melatonin were 3 mg per day administered orally²⁰ and 4 mg per day administered enterally.¹⁸ No SAEs were reported in either the melatonin or placebo groups in the larger study,¹⁸ and no SAEs were reported in the melatonin group in the smaller study (with no data reported on the placebo group).²⁰

Clinical Effectiveness of Melatonin Versus Antipsychotic Drugs for the Treatment or Prevention of Delirium

No relevant evidence describing the clinical effectiveness of melatonin compared with antipsychotic drugs for the treatment or prevention of delirium was identified; therefore, no summary can be provided.

Clinical Effectiveness of Melatonin Versus Cholinergic Agents for the Treatment or Prevention of Delirium

No relevant evidence describing the clinical effectiveness of melatonin compared with cholinergic agents for the treatment or prevention of delirium was identified; therefore, no summary can be provided.

Clinical Effectiveness of Melatonin Versus Dexmedetomidine for the Treatment or Prevention of Delirium

Treatment of Delirium

The RCT describing the clinical effectiveness of melatonin (5 mg/day) plus dexmedetomidine as compared with dexmedetomidine only in older adults following coronary artery bypass graft surgery described outcomes relevant to the treatment of delirium (i.e., duration and adjunct interventions for the management of delirium).²²

Duration of Delirium

Mean hours of delirium were measured across 4 days of follow-up, although the unit of analysis in the tabulated-only results was unclear (e.g., per patient versus per episode of delirium, and so on) with a statistically significant mean difference between treatment groups reported in favour of the melatonin plus dexmedetomidine group (mean difference = –23.5; standard error [SE] = 6.2; 95% CI, −36.5 to −10.5; P = 0.001).²² This finding was corroborated by a Kaplan-Meier survival analysis of time to recovery from delirium, showing a statistically significant benefit of melatonin added to dexmedetomidine compared with dexmedetomidine alone (P < 0.001).²²

Adjunct Interventions for Delirium

The RCT also presented data on the need for haloperidol among the subset of patients in the study who experienced delirium (n = 21) and reported no statistically significant differences between melatonin plus dexmedetomidine versus dexmedetomidine alone (RR = 0.56; 95% CI, 0.17 to 1.85; P = 0.361).²²

Prevention of Delirium

This RCT also described outcomes relevant to the prevention of delirium (i.e., occurrence and time to onset of delirium).²²

Occurrence of Delirium

The study reported a statistically significant benefit of melatonin plus dexmedetomidine compared with dexmedetomidine alone in the proportion of patients who experienced delirium (RR = 0.40; 95% CI, 0.17 to 0.95; P = 0.029).²²

Time to Onset of Delirium

This RCT also reported a statistically significant benefit in favour of melatonin plus dexmedetomidine compared with dexmedetomidine alone in both the mean hours to onset of delirium (mean difference = 23.1; SE = 7.7; 95% CI, 7.0 to 39.2; P = 0.007) and the probability of not experiencing delirium across 96 hours of follow-up (P = 0.020).²²

Health Care Utilization

The RCT comparing melatonin plus dexmedetomidine to dexmedetomidine alone also described health care utilization outcomes, specifically, lengths of hospital and ICU stays.²²

Length of Stay in Hospital

Although results from this RCT showed fewer mean days in hospital in the group that received melatonin plus dexmedetomidine versus the group that received dexmedetomidine alone (mean = 11.9 [SE = 5.3] days versus mean = 13.8 [SE = 6.2] days, respectively), the difference between the treatment groups was not statistically significant (P = 0.096).²²

Length of Stay in ICU

The RCT also did not report a statistically significant difference in mean days admitted to the ICU between the group that received melatonin plus dexmedetomidine versus the group that received dexmedetomidine alone (mean difference = −0.5; SE = 0.3; 95% CI, −1.1 to 0.2; P = 0.160).²²

Guidelines

The international guideline included in this review published 2 recommendations addressing melatonin for the prevention and treatment of sleep and circadian rhythm disorders associated with delirium.¹⁷ The first recommendation indicates that dosages of between 2 mg and 5 mg (depending on whether the medication is immediate release compared with prolonged release) may be useful for the treatment of delirium, but that the evidence remains inadequate to support consensus among the expert panel to establish a recommendation that can be used in clinical practice.¹⁷ Similarly, the recommendation addressing prevention of delirium suggests that dosages between 2 mg and 5 mg (depending on whether the medication is immediate release or prolonged release) taken before bedtime may be useful for at-risk populations, but that the evidence remains inadequate to support consensus among the expert panel to establish a recommendation that can be used in clinical practice.¹⁷

The recommendations were based on evidence identified from a SR of the literature and included 3 SRs and 1 scoping review.¹⁷ There was no information provided describing the quality of these reviews, neither was there information provided concerning the strength of the recommendations.¹⁷

The data from the included studies by outcome are presented in Appendix 4.

Limitations

This review identified 7 studies describing the clinical effectiveness of melatonin compared with placebo for the treatment and/or prevention of delirium,^{15,16,18-21,23} but is limited to 1 study of 60 patients describing the clinical effectiveness of melatonin compared with another intervention (i.e., melatonin plus dexmedetomidine versus dexmedetomidine alone).²² No evidence was found comparing melatonin with either antipsychotic medications or cholinesterase inhibitors. Further, there is limited available guidance to inform the use of melatonin for the treatment and/or prevention of delirium with 1 evidence-based guideline identified that had a broader scope than the current review and contained limited relevant information.¹⁷

Clinical heterogeneity between the study populations of several RCTs (i.e., within-study heterogeneity) was a common feature in this review,^18,20,21 including various patient characteristics, such as age, diagnosis, and reason(s) for admission. This type of clinical heterogeneity can impact the treatment effect that is observed, either inflating or nullifying the effectiveness of an intervention.³¹ For this review, a variety of patients with a range of characteristics were examined within several of the included RCTs.^18,20,21 Although it is beyond the scope of this narrative synthesis review to investigate the extent to which these broadly variable patient populations may or may not have affected the effects or effect sizes that were observed within the included studies, it is a potential limitation worth considering when interpreting the findings of this report.

In addition, clinical heterogeneity was identified between the included RCTs in this review (i.e., between-study heterogeneity),^18-21,23 with significant statistical heterogeneity identified in the SR that included and/or reported on meta-analyses.¹⁶ Specifically, different patient groups across the studies (e.g., a variety of diagnoses, age groups, and types of reasons for admission to hospital), receiving different dosages of melatonin, using different modes of administration, across various durations of follow-up; and may be a contributing factor to the inconsistency in the findings observed across the trials included in this review.^18-21,23 Clinical heterogeneity can also contribute to statistical heterogeneity, the latter of which was identified as significant in both the overview and SR included in this review.¹⁶ Notably, this problematic degree of heterogeneity has been identified in other similar reviews that were not eligible for inclusion in the current report,^32,33 suggesting this may be a common current challenge within this body of evidence. Specific to this review, these fundamental differences between the studies examining the clinical effectiveness of melatonin for the treatment of delirium in hospitalized patients may be an important limiting factor when considering and interpreting the findings from the studies included in this review and the extent to which they can effectively answer the research questions posed herein.

In addition, authors of 2 of the RCTs included in this review made mention of the uncertainty about the optimal dosage of melatonin for the treatment or prevention of delirium.^18,19 The question about dosing of melatonin in the prevention and/or treatment of inpatient delirium appears elsewhere in the literature as well.³⁴ This suggests that there is uncertainty concerning this issue, which supports the need for additional research to help elucidate optimal dosing of melatonin for the treatment or prevention of delirium.

Clinical heterogeneity is also more broadly apparent as it concerns the evidence addressing the role of melatonin in the prevention and/or treatment of delirium, that is, the frequency with which melatonin receptor agonists are investigated in combination, particularly melatonin and Ramelteon,^35-39 (including the reviews included in this study^15,16). Currently, Ramelteon is not available in Canada,⁴⁰ making these combined data less relevant to the Canadian context; evidence that did not present data specific to melatonin only limited the ability to answer research questions specific to the clinical effectiveness of melatonin in a Canadian context.

Finally, because it concerns the evidence describing clinical effectiveness, small sample sizes and important methodological limitations observed in several of the included trials in this review and their reports of findings^20-22 limits the usefulness of these studies in answering the research questions and informing an understanding of the clinical effectiveness of melatonin for the prevention and/or treatment of delirium.

Conclusions and Implications for Decision- or Policy-Making

This review identified a large body of evidence addressing the use of melatonin for the prevention and/or treatment of delirium, but limited the eligible studies to those most recently published between 2021 and 2022. One overview of MAs, 1 SR, 6 RCTs and 1 evidence-based guideline were identified and summarized. As with other evidence syntheses and literature sources that have been published on this topic,^32,33,35,37 this review found variability in the findings and conclusions of included studies, making it difficult to establish any conclusive interpretations about the available evidence. This level of uncertainty seems to be a hallmark of the evidence in this area^3,4 and may be due to several factors, most notably clinical heterogeneity within and between studies, which also contributes to statistical heterogeneity in quantitative evidence syntheses.

The evidence is reasonably dichotomous (i.e., studies in this review generally report either no difference between melatonin and placebo¹⁸ or some benefit of melatonin).^19,23 This, combined with limited evidence of harms caused by melatonin and the limited evidence on the clinical effectiveness of melatonin compared with other interventions, supports continued research into the clinical effectiveness of this intervention.

In addition to the variability in clinical factors within and between studies that have been suggested in the limitations portion of this report, other sources of heterogeneity may be present and have been posited in the literature, such as there may be clinically important variability in the quality and potency of melatonin products given their non-pharmacological production and classification.³ This is only 1 possibility among many that may affect the clarity of the evidence in this area of research.

There have been multiple calls for more research investigating the clinical effectiveness of melatonin for the prevention and/or treatment of delirium in hospitalized patients.^4,35 The evidence identified in this review did share some important methodological components that may benefit future efforts to effectively synthesize quantitative data or the similar comparators across multiple studies (i.e., placebo or usual care) and frequently used outcome measures (e.g., the CAM, CAM-ICU, and MDAS). Future research investigating the role of melatonin in the prevention and/or treatment of delirium is likely to benefit from larger sample sizes and more homogeneous study patient populations.^4,41

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Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 2: Characteristics of Included Publications

Note that this appendix has not been copy-edited.

Table 2: Characteristics of Included Overview of Systematic Reviews

ICU = intensive care unit; MA = meta-analysis; NR = not reported; RCT = randomized controlled trial; SR = systematic review.

Table 3: Characteristics of Included Systematic Review

ICU = intensive care unit; RCT = randomized controlled trial.

Table 4: Characteristics of Included Primary Clinical Studies

CABG = coronary artery bypass; CAM = Confusion Assessment Method; CAM-ICU = Confusion Assessment Method for the Intensive Care Unit; EuroSCORE = European System for Cardiac Operative Risk Evaluation; h = hour(s); ICU = intensive care unit; ITT = intention-to-treat; LOS = length of stay; MDAS = Memorial Delirium Assessment Scale; min = minute(s); NR = not reported; PCI = percutaneous transluminal coronary intervention; Pro-MEDIC = prophylactic melatonin for delirium in intensive care; pt = patient(s); RCT = randomized controlled trial; SD = standard deviation

Table 5: Characteristics of Included Guideline

SR = systematic review.

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix has not been copy-edited.

Table 6: Strengths and Limitations of Overview of Systematic Reviews

AMSTAR-2 = A MeaSurement Tool to Assess systematic Reviews 2; MA = meta-analysis; PRISMA = Preferred Reporting Items of Systematic Reviews and Meta-Analyses; SR = systematic review.

Table 7: Strengths and Limitations of Systematic Review

Table 8: Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist¹²

RCT = randomized controlled trial.

Table 9: Strengths and Limitations of Guideline Using AGREE II¹³

AGREE II = Appraisal of Guidelines for Research and Evaluation II.

Appendix 4: Main Study Findings and Authors’ Conclusions

Note that this appendix has not been copy-edited.

Table 10: Summary of Findings for Clinical Effectiveness — Treatment of Delirium

CAM = Confusion Assessment Method; CAM-ICU = Confusion Assessment Method for the Intensive Care Unit; CI = confidence interval; ICU = intensive care unit; MDAS = Memorial Delirium Assessment Scale; NR = not reported; NS = not significant; RCT = randomized controlled trial; RR = relative risk; SD = standard deviation; SE = standard error; SR = systematic review.

^aThese data were reported for both the duration of delirium and days in hospital outcomes in this article;¹⁶ it is unclear whether this is an error.

^bThe study report was unclear as to whether the duration of delirium was per patient, per episode of delirium, or some other unit of analysis (i.e., NR)

Table 11: Summary of Findings for Clinical Effectiveness — Prevention of Delirium

CAM = Confusion Assessment Method; CI = confidence interval; ICU = intensive care unit; IQR = interquartile range; MA = meta-analysis; NR = not reported; NS = not significant; RCT = randomized controlled trial; RR = relative risk; SD = standard deviation; SE = standard error; SR = systematic review.

Table 12: Summary of Findings for Clinical Effectiveness — Mortality

CI = confidence interval; HR = hazard ratio; ICU = intensive care unit; NS = not significant; RCT = randomized controlled trial; RR = relative risk; SR = systematic review.

Table 13: Summary of Findings for Clinical Effectiveness — Health Care Utilization

CI = confidence interval; ICU = intensive care unit; IQR = interquartile range; LOS = length of stay; MA = meta-analysis; NR = not reported; NS = not significant; RCT = randomized controlled trial; RR = relative risk; SD = standard deviation; SE = standard error; SR = systematic review.

^aThese data were reported for both the duration of delirium and days in hospital outcomes in this article;¹⁶ it is unclear whether this is an error.

^bWhereas the figure from which these data were abstracted indicates the intervention arm as ‘Tryptophan,’ the remainder of the paper refers only to melatonin for these studies and outcomes and has been assumed to be a typo or error in the paper.

Table 14: Summary of Findings for Clinical Effectiveness — Safety

GI = gastrointestinal; IQR = interquartile range; NR = not reported; NS = not significant; RCT = randomized controlled trial; RR = relative risk; SR = systematic review.

Table 15: Summary of Recommendations in Included Guideline

IR = immediate release; NR = not reported; PR = prolonged release; SR = systematic review.

Appendix 5: References of Potential Interest

Note that this appendix has not been copy-edited.

Previous CADTH Reports

Melatonin for the treatment of insomnia: A review of clinical effectiveness, cost-effectiveness, and guidelines. (CADTH rapid response report: summary with critical appraisal). Ottawa (ON): CADTH; 2019 Feb. https://www.cadth.ca/melatonin-insomnia-review-clinical-effectiveness-cost-effectiveness-and-guidelines

Current practice analysis: interventions for insomnia disorder. (CADTH technology review: no.7). Ottawa (ON): CADTH; 2017 Jun. https://www.cadth.ca/current-practice-analysis-interventions-insomnia-disorder-optimal-use-project-june-2017

Sleep medications for the treatment or prevention of delirium: clinical effectiveness and guidelines. (CADTH rapid response report: summary of abstracts). Ottawa (ON): CADTH; 2016. https://www.cadth.ca/sleep-medications-treatment-or-prevention-delirium-clinical-effectiveness-and-guidelines

Articles Describing Ramelteon

Hamidi A, Roberts RJ, Weinhouse GL, et al. Characterization of nocturnal neuroactive medication use and related sleep documentation in critically ill adults. Crit Care Explor. 2021 Mar 15;3(3):e0367. PubMed

Oh ES, Leoutsakos JM, Rosenberg PB, et al. Effects of ramelteon on the prevention of postoperative delirium in older patients undergoing orthopedic surgery: the RECOVER randomized controlled trial. Am J Geriatr Psychiatry. 2021 Jan;29(1):90-100. PubMed

Hamblin SE, Burka AT. Ramelteon for ICU delirium prevention: is it time to melt away? Crit Care Med. 2019 Dec;47(12):1813-1815. PubMed

Hokuto D, Nomi T, Yoshikawa T, Matsuo Y, Kamitani N, Sho M. Preventative effects of ramelteon against postoperative delirium after elective liver resection. PLoS One. 2020 Nov 2;15(11):e0241673. PubMed

Jaiswal SJ, Vyas AD, Heisel AJ, et al. Ramelteon for prevention of postoperative delirium: a randomized controlled trial in patients undergoing elective pulmonary thromboendarterectomy. Crit Care Med. 2019 Dec;47(12):1751-1758. PubMed

Leon-Salas B, Trujillo-Martin MM, del Castillo LPM, et al. Pharmacologic interventions for prevention of delirium in hospitalized older people: A meta-analysis. Arch Gerontol Geriatr. Sep-Oct 2020;90:104171. PubMed

Lopez CN, Fuentes A, Dhala A, Balk J. Ramelteon for decreasing delirium in surgical intensive care unit patients. Clinical Medicine Insights: Psychiatry. January 2020.

Gupta PK, Verma R, Kohli M, Shukla N, Kannaujia S. The effect of ramelteon on postoperative delirium in elderly patients: A randomised double-blind study. J Clinical & Diagnostic Research. 2019 Dec;13(12):15-19.

Sanchez DL, Fusick AJ, Hudson WB, Schmitz JE, Catalano MC, Catalano G. Ramelteon in the treatment of delirium: New perspectives from reported findings and a case observation. Current Drug Therapy. 2019;14(3):184-191.

Thom R, Bui M, Rosner B, et al. Ramelteon is not associated with improved outcomes among critically ill delirious patients: a single-center retrospective cohort study. Psychosomatics. May-Jun 2019;60(3):289-297. PubMed

Wu YC, Tseng PT, Tu YK, et al. Association of delirium response and safety of pharmacological interventions for the management and prevention of delirium: a network meta-analysis. JAMA Psychiatry. 2019 May 1;76(5):526-535. PubMed

Nishikimi M, Numaguchi A, Takahashi K, 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 Jul;46(7):1099-1105. PubMed

Luther R, McLeod A. The effect of chronotherapy on delirium in critical care - a systematic review. Nurs Crit Care. 2018 Nov;23(6):283-290. PubMed

Pinkhasov A, James SA, Fazzari M, Singh D, Lam S. Role of ramelteon in reduction of as-needed antipsychotics in elderly patients with delirium in a general hospital setting. Clin Drug Investig. 2017 Dec;37(12):1137-1141. PubMed