Pharmacologic Modulation of Circadian Rhythms for Delirium Prevention: An Age-Stratified Systematic Review and Meta-Analysis.

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.