| Sumario: | Background: Disturbances in sleep–wake homeostasis (Process S) and circadian rhythm (Process C) are common precipitants of delirium, especially among older hospitalized adults. We conducted a systematic review and meta‐analysis to test whether four sleep‐modulation agents—melatonin, ramelteon, suvorexant, and lemborexant—lower delirium incidence or shorten its duration in hospitalized patients, with stratified analyses by drug class, age, and surgical status. Methods: We systematically searched PubMed, Embase, and CENTRAL through March 2025. We included randomized controlled trials (RCTs) and observational studies assessing delirium prevention with melatonin, ramelteon, suvorexant, and lemborexant in hospitalized adults (≥ 18 years), compared to placebo or standard care. Data synthesis was performed separately for RCTs and observational studies using random‐effects models. Meta‐regression was used to explore effect modifiers. Risk of bias was assessed using RoB2/ROBINS‐I tools. Certainty of evidence was graded using the GRADE assessment. Results: Thirty‐seven studies (27 RCTs, 10 observational) comprising 7845 patients were included. Among RCTs, melatonin (RR 0.94; 95% CI 0.72–1.22) and ramelteon (RR 0.63; 95% CI 0.39–1.03) showed no significant effect on delirium incidence, whereas orexin receptor antagonists were associated with a lower risk (RR 0.55; 95% CI 0.35–0.87). Evidence for a class difference was inconsistent across analytic approaches: a subgroup heterogeneity test suggested differential effects (interaction‐p = 0.09), but the meta‐regression found no between‐class difference (p = 0.14). No other specific test for subgroup differences was statistically significant in RCTs. Meta‐regression confirmed patient setting as a significant modifier in observational studies, but not in RCTs. Conclusion: Sleep–wake pharmacotherapies may reduce incident delirium in hospitalized adults. In randomized trials, melatonin and ramelteon did not significantly reduce delirium incidence, whereas dual orexin receptor antagonists showed a possible benefit, but the meta‐regression did not demonstrate a reliable between‐class difference, and the evidence remains limited. Adequately powered randomized trials across inpatient settings are needed to clarify any true differences and define clinical relevance. Summary: Key points ○In randomized trials of hospitalized adults, melatonin and ramelteon did not show a clear reduction in new‐onset delirium, whereas dual orexin receptor antagonists (suvorexant/lemborexant) were associated with fewer delirium cases. However, in prespecified statistical comparisons across drug classes, we did not find convincing evidence that any class is definitively superior. Accordingly, the apparent benefit of orexin antagonists should be considered hypothesis‐generating, given the very low certainty of the evidence.○No age subgroup or inpatient setting consistently modified effects across randomized evidence; setting‐specific signals in observational studies were not corroborated by RCTs and should be considered hypothesis‐generating.○Across > 3400 exposed patients, adverse events were mild and infrequent, with no signal for oversedation, respiratory compromise, or QT prolongation.Why does this paper matter? ○By integrating randomized and observational evidence, this review offers a balanced appraisal of sleep–wake pharmacotherapies for delirium prevention in older inpatients, clarifying both potential benefits and key evidence gaps. We distinguish mechanistic classes (circadian alignment vs. attenuation of orexin‐mediated wake drive) and explicitly compare analytic approaches: while a subgroup test suggested a class signal favoring orexin receptor antagonists, our prespecified random‐effects meta‐regression did not confirm between‐class differences. We therefore prioritize the meta‐regression and treat any apparent class contrast as exploratory, very‐low‐certainty evidence. These insights refine expectations for current practice and define priorities for adequately powered, class‐specific RCTs with standardized dosing/timing and instrument‐specified delirium outcomes.
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