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Original Investigation |

Preventive Effects of Ramelteon on Delirium:  A Randomized Placebo-Controlled Trial

Kotaro Hatta, MD, PhD1; Yasuhiro Kishi, MD, PhD2; Ken Wada, MD, PhD3; Takashi Takeuchi, MD, PhD4; Toshinari Odawara, MD, PhD5; Chie Usui, MD, PhD1; Hiroyuki Nakamura, MD, PhD6 ; for the DELIRIA-J Group
[+] Author Affiliations
1Department of Psychiatry, Juntendo University Nerima Hospital, Tokyo, Japan
2Department of Psychiatry, Nippon Medical School Musashikosugi Hospital, Kawasaki, Japan
3Department of Psychiatry, Hiroshima City Hospital, Hiroshima, Japan
4Department of Psychiatry, Tokyo Medical and Dental University, Tokyo, Japan
5Psychiatric Center Yokohama City University Medical Center, Yokohama, Japan
6Department of Environmental and Preventive Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
JAMA Psychiatry. 2014;71(4):397-403. doi:10.1001/jamapsychiatry.2013.3320.
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Importance  No highly effective interventions to prevent delirium have been identified.

Objective  To examine whether ramelteon, a melatonin agonist, is effective for the prevention of delirium.

Design, Setting, and Participants  A multicenter, rater-blinded, randomized placebo-controlled trial was performed in intensive care units and regular acute wards of 4 university hospitals and 1 general hospital. Eligible patients were 65 to 89 years old, newly admitted due to serious medical problems, and able to take medicine orally. Patients were excluded from the study if they had an expected stay or life expectancy of less than 48 hours.

Interventions  Sixty-seven patients were randomly assigned using the sealed envelope method to receive ramelteon (8 mg/d; 33 patients) or placebo (34 patients) every night for 7 days.

Main Outcomes and Measures  Incidence of delirium, as defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).

Results  Ramelteon was associated with a lower risk of delirium (3% vs 32%; P = .003), with a relative risk of 0.09 (95% CI, 0.01-0.69). Even after risk factors were controlled for, ramelteon was still associated with a lower incidence of delirium (P = .01; odds ratio, 0.07 [95% CI, 0.008-0.54]). The Kaplan-Meier estimates of time to development of delirium were 6.94 (95% CI, 6.82-7.06) days for ramelteon and 5.74 (5.05-6.42) days for placebo. Comparison by log-rank test showed that the frequency of delirium was significantly lower in patients taking ramelteon than in those taking placebo (χ2 = 9.83; P = .002).

Conclusions and Relevance  Ramelteon administered nightly to elderly patients admitted for acute care may provide protection against delirium. This finding supports a possible pathogenic role of melatonin neurotransmission in delirium.

Trial Registration  University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000005591

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Figure 1.
Trial Profile

Of 67 patients who met inclusion criteria and agreed to participate in the study, 34 were randomized to receive placebo and 33 to receive ramelteon.

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Figure 2.
Scattergrams of Each Patient’s Highest Total Score on the Delirium Rating Scale–Revised-98 (DRS-R98)

Each patient was assessed until the development of delirium or up to 7 days. The cutoff score was 14.5. However, 2 patients with dementia in the placebo group had scores of 17 and 19 but did not have a delirium diagnosis according to criteria in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).1

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Figure 3.
Time to Development of Delirium

The Kaplan-Meier estimates of the interval to the development of delirium were 6.94 (95% CI, 6.82-7.06) days for patients receiving ramelteon and 5.74 (5.05-6.42) days for those receiving placebo. Comparison by log-rank test showed that delirium developed significantly less frequently in the ramelteon group (χ2 = 9.83; P = .002).

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Ramelteon’s Possible Mode of Action in Prevention of Delirium in Elderly
Posted on April 2, 2014
Gulistan Bahat, Asli Tufan, Mehmet Akif Karan
Istanbul University, Istanbul Medical School, Department of Internal Medicine, Division of Geriatrics, Capa, 34390, Istanbul, Turkey
Conflict of Interest: None Declared
Dear Editor, We have read the article “Preventive Effects of Ramelteon on Delirium” by Hatta et al.1 with great interest. They have conducted a randomized placebo-controlled trial among a total of 67 elderly patients newly admitted due to serious medical problems. Subjects were randomly assigned to receive ramelteon or placebo every night for 7 days. They reported a lower risk of delirium (3% vs 32%; P = .003) in the ramelteon group. Consequently, they concluded that ramelteon administered nightly to elderly patients admitted for acute care may provide protection against delirium and their finding supports a possible pathogenic role of melatonin neurotransmission in delirium. We do appreciate the painstaking nature of their study and their remarkable result on effectiveness of ramelteon in prevention of delirium. However, we suggest that there are some limitations of the study which should be considered while interpreting the study results.In results section, they reported that 3 patients (9%) in the placebo group and 6 patients (18%) in the ramelteon group received hydroxizine as needed, with no significant difference in the rate of use between groups. Delirium developed in only 1 of these 9 patients on hydroxizine therapy, resulting in a delirium incidence of 1/9 (11.1%). As the authors noted, the proportion of patients with delirium in the placebo group was similar to what would be expected in this patient population as 32%. The lower incidence of delirium in hydroxizine group compared to the –what would be expected- is also remarkable as 11.1% vs 32%. Such a difference in expected and observed delirium by addition of a study drug may be already significant as was in the melatonin trial by Al-Aama et al.2 This finding may suggest protective effect of hydroxizine treatment- another known drug with sleep improving efficacy- by itself in prevention of delirium. Sleep restoration by several means has already emerged as a factor in preventing development of delirium in a recent meta-analysis of randomized trials.3 Hatta et al.1 stated that study nurses provided all patients equally with non-pharmacological preventive care. 1 However, among all the prevention intervention protocols, sleep protocol is the one with least complete adherence rates while adherence demonstrates a consistently strong and significant protective effect against delirium4. Therefore it is unlikely to suppose that sleep characteristics have been effectively managed by non-pharmacological measures. They have given an active drug -the ramelteon- known to improve sleep in this population and approved for the treatment of insomnia. 5 Hatta et al. analyzed sleep-metrics subjectively based on patient reports, nursing observations and records, and rater observations.1 As the authors have already noted, although their findings did not suggest any benefit of ramelteon for sleep parameters, larger samples are needed to statistically differentiate drug from placebo in studies based on self-report6 and their study was limited by its relatively small sample size. Remarkably, although the difference was non-significant, “difficulty falling asleep” was less in the ramelteon group than the placebo (30% vs 41%) -that is the indication it is approved for . This finding suggest the sleep improving effect of the ramelteon also in the study participants which could not be proved statistically due to the small number of patients to analyze as in other measures already depicted in the manuscript. The many other agents having sleep improvement effect as trazadone, antipsychotics, melatonin, dexmedetomidine sedation, bright light therapy, diazepam, flunitrazepam and pethidine also demonstrated effect in preventing delirium 2,3,7-9. We conclude that, -based on the aforementioned arguments- the proposition that their finding supports a possible pathogenic role of melatonin neurotransmission in delirium, is difficult and would be an over-interpretation of the study results. Ramelteon’s delirium preventing effect most probably may be due to their effect on sleep which was a mechanism also suggested by Lewis and Barnett for melatonin’s preventing effect. 10 References1.Hatta K, Kishi Y, Wada K, et al. Preventive Effects of Ramelteon on Delirium: A Randomized Placebo-Controlled Trial. JAMA Psychiatry. 2014;71(4):397-403.2. Al-Aama T, Brymer C, Gutmanis I, et al. Melatonin decreases delirium in elderly patients: a randomized,placebo-controlled trial. Int J Geriatr Psychiatry. 2011;26(7):687-94.3. Hao Zhang, Yan Lu, Meng Liu, et al. Strategies for prevention of postoperative delirium: a systematic review and meta-analysis of randomized trials. Crit Care. 2013;17(2): R47.4. Inouye SK, Bogardus ST Jr, Williams CS, Leo-Summers L, Agostini JV. The role of adherence on the effectiveness of nonpharmacologic interventions: evidence from the delirium prevention trial. Arch Intern Med. 2003;163(8):958-64.5. Roth T, Seiden D,Wang-Weigand S, Zhang J. A 2-night, 3-period, crossover study of ramelteon’s efficacy and safety in older adults with chronic insomnia. Curr Med Res Opin. 2007;23(5):1005-1014.6. Belanger L, Vallieres A, Ivers H, et al. Meta-analysis of sleep changes in control groups of insomnia treatment trials. J Sleep Res. 2007;16(1):77-84.7. Okamoto Y, Matsuoka Y, Sasaki T, Jitsuiki H, Horiguchi J, Yamawaki S. Trazodone in the treatment of delirium. J Clin Psychopharmacol. 1999;19(3):280-282.8. Ono H, Taguchi T, Kido Y, Fujino Y, Doki Y. The usefulness of bright light therapy for patients after oesophagectomy. Intensive Crit Care Nurs. 2011;27(3):158-66.9. Aizawa K, Kanai T, Saikawa Y, et al. A novel approach to the prevention of postoperative delirium in the elderly after gastrointestinal surgery. Surg Today. 2002;32(4):310-4.10. Lewis MC, Barnett SR. Postoperative delirium: the tryptophan dyregulation model. Med Hypotheses. 2004;63(3):402-6.
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