Critical Care

Melatonin and delirium in the intensive care units: a systematic review and meta-analysis of randomized controlled trials
Inès Lakbar, Daniele Poole, Louis Delamarre, Gérald Chanques, Joris Pensier, Clément Monet, Fouad Belafia, Mathieu Capdevila, Audrey De Jong, Samir Jaber

Abstract:

Background: Delirium is frequent in critically ill patients and is associated with increased mortality. Discrepancies were found in the results of recent randomized controlled trials (RCTs) regarding the effect of melatonin to prevent delirium onset in critically ill patients.

Methods: We searched MEDLINE, Embase, and Web of Science from inception to 5 July 2025 for RCTs evaluating melatonin in critically ill patients. The primary outcome was the incidence of delirium. The main secondary outcome was mortality. We generated pooled risk ratios (RR). To base our conclusions on the highest quality of evidence, our primary analysis was based only on the trials with low to moderate risk of bias for each outcome. A secondary analysis was conducted, including all the trials. The study was registered with PROSPERO (CRD420251041661).

Findings: Our primary analysis was based on six RCTs with 2209 patients and did not show any difference in the incidence of delirium attributable to the treatment with melatonin (RR 0.89, [95% confidence interval (CI) 0.73-1.09]). This result was consistent with the secondary analysis including thirteen RCTs with 2830 patients (RR 0.86, [95% CI 0.70-1.04]). No association was found between mortality and melatonin in the primary (seven RCTs, 2165 patients, RR 0.87, [95% CI 0.73-1.02]) and secondary (8 RCTs, 2396 patients, RR 0.92, [95% CI 0.79-1.06]) analyses.

Interpretation: The results suggest that compared to placebo, melatonin does not reduce delirium incidence in critically ill patients. Similarly, no effect was observed on mortality.

Keywords: Delirium; Melatonin; Meta-analysis; Sleep; Systematic review.

Annotation

The finding:  According to this systematic review and meta-analysis of methodologically robust RCTs,  melatonin did not reduce delirium incidence (low certainty) or confer mortality benefits (moderate certainty) in the critically ill population.

Strength and weaknesses: This primary analysis focused on methodologically rigorous studies and included the most recent well-designed RCT (Mekontso Dessap et al., 2025).  This analysis, however, did not evaluate the impact of melatonin on sleep quality or architecture.  Further, it could not address more granular issues, such as whether specific patient subgroups would benefit from individualized administration protocols.

Relevance:

Melatonin use is becoming ubiquitous in critical care settings, and a recent update to the PADIS guidelines (Lewis et al., 2025)–informed by a systematic review and meta-analysis by Tang et al. (2025)–suggested that melatonin may improve outcomes.   In contrast, the current meta-analysis based on a subset of trials, including the most recent high-quality RCT, did not identify a benefit for delirium prevention.  CL psychiatrists will continue watching as this area of inquiry evolves.  Further work is needed for a more nuanced approach, which may include targeting specific populations and tailoring melatonin administration strategies, in concert with sleep support protocols and ABCDEF bundles.  Melatonin may also have a different role in delirium prevention as opposed to management.

Lewis K, Balas MC, Stollings JL, et al. Executive Summary of a Focused Update to the Clinical Practice Guidelines for the Prevention and Management of Pain, Anxiety, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Critical Care Medicine. 2025;53(3):e701-e710. doi:10.1097/CCM.0000000000006573

Mekontso Dessap A, Ricard JD, Contou D, et al. Melatonin for prevention of delirium in patients receiving mechanical ventilation in the intensive care unit: a multiarm multistage adaptive randomized controlled clinical trial (DEMEL). Intensive Care Med. 2025;51(7):1292-1305. doi:10.1007/s00134-025-08002-z

Tang BHY, Manalo J, Chowdhury SR, et al. Melatonin Use in the ICU: A Systematic Review and Meta-Analysis. Critical Care Medicine. 2025;53(9):e1714-e1724. doi:10.1097/CCM.0000000000006767