Effects of melatonin on the prevention of delirium in hospitalized older patients: systematic review and meta-analysis

Abstract

Objectives

Melatonin has been demonstrated to exert a preventive effect on delirium. This meta-analysis sought to investigate the preventive effects of melatonin and melatonin receptor agonists (ramelteon) on delirium in hospitalized elderly patients.

Methods

This systematic review and meta-analysis delineates the risk of delirium events in older hospitalized patients with melatonin/ramelteon compared with placebo, incorporating randomized controlled trials published up to 8 July 2024. The databases searched were PubMed, Embase and the Cochrane Library. The primary outcome measures were the incidence of delirium, while the secondary outcome measures were the length of hospital stay and mortality. The results are presented as odds ratios (OR) or mean differences (MD) with a 95% confidence interval. The review of publications was conducted in accordance with the guidelines set forth in the Cochrane Handbook and the Preferred Reporting Project for Systematic Review and Meta-Analysis (PRISMA). This study has been registered with INPLASY (number INPLASY202470044).

Results

A total of 2086 patients were included in 13 randomized controlled trials. The primary outcome of this meta-analysis demonstrated a statistically difference in the incidence of delirium between the melatonin and placebo groups in hospitalized elderly patients (OR = 0.59, 95% CI: 0.40–0.87, P < 0.01, I² = 60%), particularly in those who had undergone surgery (OR = 0.60, 95%CI: 0.40–0.89, P = 0.01, I² = 53%). No statistically differences were observed in terms of length of stay (MD=-0.07, 95%CI:-1.09-0.94, P = 0.89, I² = 72%) and mortality (OR = 0.79, 95%CI:0.58–1.06, P = 0.12, I² = 0%).

Conclusions

Melatonin has been demonstrated to exert a protective effect on delirium in elderly patients who are hospitalized, particularly in the context of perioperative care.

Introduction

Delirium is a psychiatric symptom-related syndrome that is estimated to occur in 20–30% of hospitalized elderly patients [1, 2]. However, incomplete knowledge among medical practitioners may result in an incomplete diagnosis of delirium. There is evidence to suggest that delirium exacerbates cognitive decline, prolongs hospitalization and increases mortality rates among elderly patients [3,4,5].

Patients with delirium may experience hallucinations and delusions, as well as other manifestations. Acute episodes of delirium can affect sleep patterns, and the course of the disease may fluctuate. There is evidence to suggest a potential mechanism relationship between delirium and sleep [6–7]. It is unfortunate that there is currently no effective treatment for delirium. Consequently, doctors often prescribe antipsychotic drugs to delirium patients. Nevertheless, research has demonstrated that antipsychotic aversion does not diminish the likelihood of delirium in patients, and the utilization of antipsychotic aversion is constrained by the occurrence of adverse drug reactions [8–9].

Melatonin is a naturally occurring hormone produced by the body that plays a role in regulating the body’s normal circadian rhythm. Given the abnormal secretion of melatonin observed in delirium patients, several studies have evaluated the potential role of melatonin (or melatonin receptor agonists, ramelteon) in preventing delirium in adults. However, the results of these studies have not been entirely consistent [10,11,12,13,14,15,16,17,18,19,20,21,22]. Previous meta-analyses have examined the impact of melatonin on delirium in hospitalized patients, yet the findings have been inconclusive. Khaing [23] analysis of 1712 hospitalized patients revealed that melatonin was effective in reducing delirium in surgical and critically ill patients. In contrast, You [24] included 18 randomized controlled trials that demonstrated the beneficial effects of melatonin in reducing delirium in medical patients. The present study aimed to analyze the preventive effect of melatonin (or melatonin receptor agonists, ramelteon) on the occurrence of delirium in a special group of elderly hospitalized patients. Additionally, the length of stay and mortality of elderly hospitalized patients were analyzed, with the objective of providing guidance for clinical practice.

Methods

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [25]. The pre-registration of our meta-analyses could be accessed via the International Platform of Registered Systematic Review and Meta-analysis Protocols database (Number: INPLASY202470044). The full text was available for download from inplasy.com (https://inplasy.com/inplasy-2024-7-0044). It should be noted that ethical approval was not required for this study.

Search strategy

A comprehensive electronic search of the literature was conducted by three researchers (Le Liu, Xin Ma and Zejun Song) for articles published in the field prior to 8 July 2024. A comprehensive search of the PubMed, Embase and Cochrane databases was conducted manually, with the objective of selecting relevant randomized controlled trials. For further details of the specific literature search strategies employed, please refer to the Appendix (Supplement Table S1).

Inclusion and exclusion

The document management process utilized the EndNote (X9) software, with two investigators independently assessing the eligibility of the project. The titles and abstracts were initially screened, and the resulting articles were then subjected to a full-text review. The studies included in the review were randomized controlled trials. The following inclusion criteria were met: (1) elderly patients who were hospitalized; (2) patients who were taking melatonin (or melatonin receptor agonists) or a placebo. The exclusion criteria include studies involving animals, studies conducted on subjects under the age of 60 years old for inclusion through the reading of studies, and studies with insufficient data extraction, including abstracts, reviews, pharmacological reports, and other literature. Should the necessity arise to obtain pertinent research data, the authors will be contacted in a timely manner. The primary outcome measures were the incidence of delirium, while the secondary outcome measures were the length of hospital stay and mortality (either during hospitalization or within 30 days of discharge).

Bias and quality assessment

Two researchers conducted independent evaluations, preliminary selections, and verifications of the literature in accordance with a unified and standardized method. The literature was included or excluded in accordance with the pre-established criteria, after which the data was collected. The quality of the selected articles was evaluated in accordance with the Cochrane Reviewer Handbook 5.1.0 [26]. The RoB tool was used to assess bias risk.

Data synthesis and analysis

The meta-analysis was conducted using RevMan 5.4. Data that met the criteria for homogeneity (P > 0.10 and I²≤50%) as determined by the heterogeneity test were subjected to meta-analysis using the fixed-effect model (M-H). In instances where the aforementioned homogeneity criteria were not met (P ≤ 0.10 or I² > 50%), and the presence of heterogeneity could not be discounted, the random-effect model was employed to consolidate the effects [27]. To compare the effects of melatonin/ramelteon with placebo, the odds ratios (OR) or mean differences (MD) with a 95% confidence interval (CI) were pooled according to the fixed and random effects model. A p-value of less than 0.05 was considered to be statistically significant.

Results

The flow chart (Fig. 1) provided a summary of the search and research selection process. A total of 857 literature sources were searched, 311 of which were excluded due to duplication. Additionally, 494 studies were excluded after a preliminary review of the title and abstract. The remaining 52 studies underwent a comprehensive evaluation based on a thorough reading of the full text. Of these, 13 randomized controlled trials assessed the efficacy of melatonin (or melatonin receptor agonists) in preventing delirium in hospitalized older patients.

Fig. 1

Selection process for studies included in the meta-analysis

The principal characteristics of the included trials were set forth in Table 1. A total of 2,086 patients were included in the analyses. All of the included studies were randomized controlled trials. The estimates are expressed as odds ratios (OR) or mean differences (MD) with a 95% confidence interval (CI). The primary outcome of this meta-analysis demonstrated a statistically difference in the incidence of delirium between the melatonin and placebo groups in hospitalized elderly patients (OR = 0.59, 95% CI: 0.40–0.87, P < 0.01, I² = 60%). A subsequent subgroup analysis demonstrated that the observed statistical difference was associated with older patients undergoing surgery (Fig. 2) (OR = 0.60, 95%CI: 0.40–0.89, P = 0.01, I2 = 53%), whereas no statistical difference was observed among patients hospitalised for medical reasons. The analysis of melatonin and melatonin receptor agonists across groups (Fig. 3) revealed a statistically difference in the risk of delirium with melatonin compared to placebo (OR = 0.65, 95%CI: 0.43–0.98, P = 0.04, I² = 66%), while no statistically difference was observed between melatonin receptor agonists and placebo (OR = 0.36, 95%CI: 0.12–1.09, P = 0.07, I² = 49%). With regard to secondary outcomes, no statistically differences were identified with respect to length of stay (MD = -0.07, 95% CI: -1.09 to -0.94, P = 0.89, I²=72%) (Fig. 4) and mortality (OR = 0.79, 95% CI: 0.58 to 1.06, P = 0.12, I²=0%) (Fig. 5).

Table 1 Design and outcomes of the studies included in the meta-analysis

Fig. 2

Incidence of delirium between melatonin and placebo (operation or not)

Fig. 3

Incidence of delirium between melatonin and placebo (melatonin or ramelteon)

Fig. 4

Comparisons of the 28-day mortality between melatonin and placebo

Fig. 5

Length of stay between melatonin and placebo

We use Revman to investigate the impact of a single study on the overall pooled estimate of each predefined outcome. The results of the bias risk assessment for these trials are summarized in the Supplementary. From the funnel plot, we can see the symmetric distribution of literature, and we can believe that there is no publication bias. In terms of quality evaluation, with eight of them achieving the maximum score, which serves to fully demonstrate the credibility of the research conclusions presented in this paper.

Discussion

Our meta-analysis clearly described the efficacy of melatonin in preventing delirium in elderly hospitalized patients. First of all, melatonin can reduce the risk of delirium in elderly hospitalized patients, especially postoperative elderly patients, while the incidence of delirium observed in medical patients was not statistically significant, providing certain clinical reference value. Second, the length of hospital stay and mortality of patients did not differ between the melatonin and control groups, suggesting the safety of its use. The distinction between this study and previous research is that our survey targeted older adults and classified them based on whether they had undergone surgical procedures [23–24]. The study population is more precisely defined, which lends credence to the notion that the results will be even more accurate. The findings of our study diverge from those of the aforementioned research [24] in that melatonin has been demonstrated to be a more efficacious intervention in reducing the incidence of delirium in surgical patients than in older patients receiving general medical care.

Patients undergoing surgical procedures are at risk of developing delirium due to the effects of the surgery itself on neurotransmitter levels in the body, which can directly damage the brain. The sedative effects of melatonin may prove beneficial for this group of patients, reducing the risk of delirium [28]. Furthermore, sleep disorders and sleep-wake cycle disorders have been identified as risk factors for postoperative delirium, and the sleep-inducing effects of melatonin have been identified as a potential mechanism of action [23]. Furthermore, delirium and surgical stress may induce the release of inflammatory mediators, and the anti-inflammatory and antioxidant effects of melatonin may also prove beneficial in this regard [29]. These effects may indicate a pivotal role for melatonin in mitigating the risk of delirium in elderly hospitalised patients.

The data indicate that melatonin may reduce the incidence of delirium, particularly in postoperative patients. However, further studies are required to validate these findings in this specific population. Furthermore, melatonin appears to be more effective than ramelteon in the prevention of delirium. However, this finding may be attributed to the limited sample size, and further experimental verification is necessary in the future. The principal advantage of this study is that the elderly were analysed as a group, and 13 randomised controlled trials were included in the meta-analysis, which is currently the largest sample size and may have a positive guiding effect on future clinical treatment.

It is important to note that the study is subject to several limitations. The relatively limited database searched, the language limited to English, and the absence of grey literature may have resulted in a reduction in the sample size of the study. The included randomised controlled trials employed disparate doses of melatonin and varying durations of intervention, in addition to discrepancies in the baseline characteristics of enrolled patients, clinical settings, and methods of measuring outcomes. These factors may have contributed to the heterogeneity of the studies. In the majority of randomized controlled trials, delirium was identified using the CAM or CAM-ICU. However, with a sensitivity of 94% and specificity of 89%, CAM is a screening tool and is not the gold standard for diagnosing delirium [30]. Future studies with larger sample sizes are needed to further confirm the value of melatonin in preventing delirium in elderly patients.

Conclusions

Melatonin has been demonstrated to have a preventative effect on delirium in elderly patients who are hospitalized. Furthermore, it has been shown not to increase the length of hospital stay or mortality, particularly in elderly patients who are hospitalized following surgery. Therefore, melatonin may be a beneficial intervention for the prevention of delirium.