# Melatonin for ICU delirium: a promising molecule, a broken path

Inès Lakbar, Timothy Girard, Samir Jaber

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Inès Lakbar, Timothy Girard, Samir Jaber. Melatonin for ICU delirium: a promising molecule, a broken path. Intensive Care Medicine, 2025, 10.1007/s00134-025-08236-x. hal-05406021

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# Melatonin for ICU delirium: a promising molecule, a broken path

Inès Lakbar<sup>1 2</sup>, Timothy D Girard<sup>3</sup>, Samir Jaber<sup>4</sup>

**\*Correspondence:**

ines.lakbar@chu-montpellier.fr

3 Département d'Anesthésie-Réanimation B (DAR B), Montpellier, France

<footnote n="1"><sup>1</sup> Department of Anesthesia and Intensive Care Unit, Regional University Hospital of Montpellier, St-Eloi Hospital, University of Montpellier, PhyMedExp, INSERM U1046, CNRS UMR, Montpellier, France. ines.lakbar@chu-montpellier.fr.</footnote>

<footnote n="2"><sup>2</sup> Département d'Anesthésie-Réanimation B (DAR B), Montpellier, France. ines.lakbar@chu-montpellier.fr.</footnote>

<footnote n="3"><sup>3</sup> Center for Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) in the Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, USA.</footnote>

<footnote n="4"><sup>4</sup> Department of Anesthesia and Intensive Care Unit, Regional University Hospital of Montpellier, St-Eloi Hospital, University of Montpellier, PhyMedExp, INSERM U1046, CNRS UMR, Montpellier, France.</footnote>
Delirium is a frequent and serious manifestation of acute brain dysfunction in critically ill patients. It affects up to 80% of patients receiving mechanical ventilation and is associated with increased mortality, longer durations of mechanical ventilation, and persistent cognitive impairment after discharge [1, 2]. In multiple randomized trials, no single pharmacological agent has consistently prevented intensive care unit (ICU) delirium. Among potential candidates, melatonin, a pleiotropic neurohormone that regulates circadian rhythm, has received increasing attention for its putative role in delirium prevention in the ICU.

During critical illness, serum melatonin levels are lower in patients with delirium than in those without delirium [3]. Furthermore, melatonin exhibits anti-inflammatory and immunomodulatory properties, which can potentially protect the brain from injury [4–7]. Thus, numerous trials have sought to determine whether melatonin prevents delirium during critical illness.

The latest of these trials was published recently in *Intensive Care Medicine* [8]. Mekontso-Dessap and colleagues presented the results of the DEMEL trial, a multicenter, adaptive, phase 2b/3 randomized controlled trial designed to assess whether melatonin prevents delirium in mechanically ventilated ICU patients. More specifically, the trial was designed to first identify the most appropriate melatonin dose based on pharmacokinetic targets (activity phase) and then to evaluate the efficacy of the selected dose in reducing the incidence of delirium (efficacy phase) [8].

Though several previous trials of melatonin included mechanically ventilated patients, the DEMEL trial was the first large-scale, multicenter study specifically designed to evaluate melatonin in invasively ventilated ICU patients. It was also the first to include a pharmacokinetic pre-selection phase before evaluating clinical outcomes. In the activity phase, low-dose melatonin (0.3 mg) achieved more optimal pharmacokinetic profiles than the more commonly used 3 mg dose and was therefore selected for the efficacy phase. However, in the final analysis, low-dose melatonin did not reduce the incidence of delirium compared to placebo (54.4% vs. 55.2%). No significant differences were observed across 48 secondary outcomes, including sleep quality, sedative use, ventilator-free days, length of stay, or mortality.

These findings provide lessons but also raise questions. DEMEL found that high doses (3 mg) of melatonin can result in next-morning supraphysiologic concentrations, which may disrupt rather than restore circadian physiology. At the same time, the trial raises questions about the optimal dose of melatonin in this patient population. The investigators advanced the lower dose (0.3 mg) to the second phase because it more often led to what they defined as the optimal pharmacokinetic profile, but whether that profile is most effective during critical illness remains unclear. It is possible, therefore, that the higher dose of melatonin would have been more effective at reducing delirium despite the fact that the lower dose more often led to the “optimal” pharmacokinetic profile, as defined by DEMEL investigators. DEMEL ultimately found that the lower dose (0.3 mg) of melatonin failed to prevent delirium, but only 50% of patients in the 0.3 mg group achieved the predefined optimal pharmacokinetic target, raising additional questions about interindividual variability and the feasibility of achieving precise plasma melatonin levels in critically ill patients.
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Melatonin remains attractive in principle. It is inexpensive, safe, and its effect on sleep is mechanistically plausible. Several early trials and a recent meta-analysis, which was conducted to inform the 2025 focused update to the SCCM PADIS guidelines, suggested melatonin can improve sleep quality and prevent delirium in ICU patients [4]. However, the impact of melatonin as a delirium prevention strategy during mechanical ventilation is now seriously questioned. Three recent, high-quality randomized controlled trials—Pro-MEDIC [9], Burry [10] and DEMEL [8]—all failed to find that melatonin led to a significant reduction in delirium incidence during critical illness. These trials differed in populations, doses, and timing, yet converged in their conclusions as reported in a recent meta-analysis [11]. Several methodological differences explain why this analysis [11] leads to different estimates than the SCCM meta-analysis [4]. First, it included only randomized controlled trials comparing melatonin directly with placebo, whereas the SCCM meta-analysis combined placebo-controlled trials with studies comparing melatonin to multimodal interventions or bundles of care. Second, the SCCM analysis also included trials evaluating ramelteon, while this recent analysis focused exclusively on melatonin. Finally, the inclusion criteria in the recent analysis were more stringent with respect to risk of bias and outcome definitions, resulting in a smaller but more methodologically homogeneous evidence base. Thus, melatonin alone may be insufficient to prevent delirium in ICU patients. Additionally, targeting sleep without addressing other delirium risk factors is unlikely to modify the complex trajectory of delirium for many ICU patients. At the same time, the confidence intervals around estimates of melatonin's effect on delirium prevention (and mortality, in fact) in the ICU remain wide, indicating ongoing uncertainty.

Delirium in the ICU is a complex, multifactorial syndrome [12]. Disruption of sleep and circadian rhythms is only one of many contributing factors. It is unlikely that a single intervention targeting one pathway can consistently alter this trajectory for ICU patients on average, but the available evidence does not rule out the possibility that melatonin benefits certain ICU subgroups. Future studies should consider integrating melatonin into multimodal preventive strategies, ideally layered on established bundles such as ABCDEF [4].
Importantly, research should also assess long-term outcomes, including cognition, sleep disorders, and quality of life in ICU survivors.

The DEMEL trial was a rigorous and well-conducted study that advances our understanding of melatonin pharmacokinetics in critical illness. It also delivers a wise message: even a biologically promising and theoretically sound intervention may fail to deliver clinical benefit. For now, bundled approaches remain the cornerstone of delirium prevention in the ICU (Fig. 1).

**Funding**

None.

**Availability of data and materials**

Not applicable.

**Declarations**

**Conflicts of interest**

SJ received consultant fees from Mindray, Fisher-Paykel, Baxter, Fresenius, Medtronic and Drager. IL received fees from presentations from Viatris and AOP Health. TG receives research funding from the National Institutes of Health, US Department of Defense, and Ceribell and served previously on an advisory board for Lungpacer Medical Inc. No other potential conflict of interest relevant to this article was reported. SJ is the Editor in Chief of Intensive Care Medicine. He has not taken part in the review or selection process of this article.

**Consent for publication**

Not applicable.

**Ethics approval and consent to participate**

Not applicable.

**Conflict of interest statement**

Declarations. Conflicts of interest: SJ received consultant fees from Mindray, Fisher-Paykel, Baxter, Fresenius, Medtronic and Drager. IL received fees from presentations from Viatris and AOP Health. TG receives research funding from the National Institutes of Health, US Department of Defense, and Ceribell and served previously on an advisory board for Lungpacer Medical Inc. No other potential conflict of interest relevant to this article was reported. SJ is the Editor in Chief of Intensive Care Medicine. He has not taken part in the
review or selection process of this article. Consent for publication: Not applicable. Ethics approval and consent to participate: Not applicable.

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