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Hatta K, et al. "Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial". JAMA Psychiatry. 2014. 71(4):397-403.
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Clinical Question

In newly admitted elderly patients, does ramelteon reduce the risk of delirium compared to placebo?

Bottom Line

Ramelteon substantially reduced the risk of developing delirium in elderly inpatients (65-89) when given nightly for 7 days.

Major Points

A 2007 Cochrane review[1] concluded that sparse evidence existed supporting any intervention to prevent delirium, citing only early geriatric consultation as an evidence-based intervention in patients with hip fracture. Since then, early physiotherapy has also found some support in the literature among ICU patients. Antipsychotics and anticholinesterase inhibitors have had variable results in the prevention of post-operative delirium, with possible benefit for low-dose haloperidol.

For generalized inpatients, no large randomized trials demonstrated significant benefit of pharmacologic agents until melatonin was tested in 145 patients in 2010.[2] In 2014, this benefit was redemonstrated with higher efficacy with the melatonin agonist ramelteon (also compared against placebo) in this small randomized controlled trial. Given the low side effect profile in this trial and prior studies, this low-risk intervention may prevent delirium in acutely hospitalized elderly inpatients, however a larger trial is needed to reproduce these results.


As of July 2016, no guidelines have been published that reflect the results of this trial.


  • Multicenter, single-blind, randomized, controlled trial
  • N=67
    • Ramelteon (n=33)
    • Placebo (n=34)
  • Setting: 5 centers in Japan
  • Enrollment: 2011-2012
  • Mean follow-up: 7 days
  • Analysis: Exploratory
  • Primary outcome: Incidence of delirium (by DSM IV criteria)


Inclusion Criteria

  • Age 65-89
  • Newly admitted due to serious medical problems
  • Expected inpatient stay >48 hours
  • Expected life expectancy >48 hours

Exclusion Criteria

  • Delirium present on admission
  • Psychotic or mood disorder
  • Alcohol or drug withdrawal
  • Lewy body disease
  • Severe liver dysfunction

Baseline Characteristics

No statistically significant differences between groups identified.

  • Mean age: 78 years
  • 19% had dementia
  • 21% used habitual sleeping pills
  • Admission diagnoses in the ramelteon group: 36% stroke, 12% infection, 18% fracture, 9% HF/MI


    • Randomized to ramelteon 8g/night or placebo for 7 days
      • Psychiatrists were trained and assigned to specific sites, and would make rounds every afternoon for 7 days to assess each patient for the onset of delirium after reading nursing reports and talking with each nurse.
    • DRS-R98 (delirium screening), APACHE II, and ECOG status were also recorded daily


Comparisons are ramelteon vs. placebo

Primary Outcomes

Incidence of delirium
3% vs 32% (RR: 0.09; 95% CI 0.01-0.69; P=0.003)

Secondary Outcomes

No statistical differences in sleep parameters, worst APACHE II, worst ECOG scores, or use of hydroxyzine

Subgroup Analysis

Incidence of delirium in patients not using PRN hydroxyzine
4% vs 32% (P=0.007)

Adverse Events

No adverse events potentially attributed to ramelteon were observed


  • Small sample sizes and the risk of publication bias limit the reliability of this study, though its intervention appears to be low-risk
  • Though the trial was not double blind, it was rater-blind, with concealed allocation, and not unmasked until after trial analysis, thus the study outcome of delirium was unlikely to have been affected by this limitation.
  • Nurses were not blinded to treatment group, though this would be unlikely to make them provide better delirium preventive care in the melatonin group.
  • Though the placebo arm received more hydroxyzine, primary outcome remained significant in subgroup analysis with these patients excluded


Funded by a grant from Japan Society for the Promotion of Science

Further Reading

  1. Siddiqi N et al. Interventions for preventing delirium in hospitalised patients. Cochrane Database Syst Rev 2007. :CD005563.
  2. Al-Aama T et al. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry 2011. 26:687-94.