CPCP: Ramelteon for Delirium Prevention Study by Dr. Shailen Mhapsekar

Dr. Shailen Mhapsekar MD
Dr. Shailen Mhapsekar MD

So the first year Family Medicine resident, Dr. Shailen Mhapsekar, MD,  gave a very interesting Clinical Problems in Consultation Psychiatry (CPCP) on the Ramelteon for delirium prevention study [1]. The importance of the study is the high morbidity and mortality associated with delirium in the general hospital, especially in the cognitively impaired elderly, the population at highest risk for the syndrome.

This was an interesting study, single-blinded rather than double-blinded to attract more study participants, according to the authors. There were 33 patients who got ramelteon (a selective melatonin agonist) the study drug and 34 who got placebo. Only the raters were blinded.

In the methods section, the authors decided against using trazodone, an older antidepressant commonly used as a hypnotic nowadays, because a case series published in 1999 showed that it might prevent delirium [2]. Interestingly, trazodone was co-administered with other sedating agents including benzodiazpines in just seven patients. Further, a case report published only a year after that seemed to show that trazodone induce delirium [3]. The authors elected not to use zolpidem or zopiclone because it’s been associated with delirium (an observation with which I agree) but said neither was listed in the 2012 Beers Criteria  of drugs to avoid in the elderly. Zopliclone is not but zolpidem is.

Moreover, they elected to use hydroxyzine pamoate as a hypnotic, indicating they thought it was not very anticholinergic although the Beer’s list warns against using it because of its strong anticholinergic activity. The authors’ explanation for using it is based on their finding literature indicating that “…the available data indicate that it has weak anticholinergic effects.” However, just before that sentence, they acknowledge that Pfizer of Japan told them that they had no human data on the muscarinic receptor affinity values (though it’s low in bovine cerebral cortex) “because it’s an old drug.”

Raters assessed delirium using the Japanese version of the Delirium Rating Scale-Revised-98 and evaluated patients twice a day. Results indicated that delirium occurred in 11 patients in the placebo group and 1 patient in the ramelteon group, showing that ramelteon was associated with a lower risk of delirium. It was well-tolerated by patients none of whom suffered adverse events from the drug.

Dr. William R. Yates
Dr. William R. Yates

I checked with a colleague about the statistics section and their use of the power analysis for calculating the number of patients needed per group was credible. However, even the authors conceded the number of patients was small. I tweeted another colleague, Dr. William R. Yates, MD, about this, who tweeted back, “Looks impressive but a small trial. Safe drug and I might use in targeted pts. Need second bigger trial before wider use.”

The authors listed no conflicts of interest relevant to the study which was supported by the Japan Society for the Promotion of Science.

We thought this was an important study which advanced our knowledge although there are practical limitations for generalizing the results. The obvious ones are the small number of subjects. Another is the cost of ramelteon, which can be up to about $300 for 30 tablets. Compare that to melatonin, which may cost between $5 to $15 for 60 or more tablets (variable dosing and formulations) and this becomes an important consideration.money

Non-pharmacologic methods of delirium prevention are very important to remember and this may prevent 30-40% of cases when well-developed protocols are used, like HELP.

Thanks to Shailen’s help, we know a little more than we did yesterday about delirium prevention.


1. Hatta, K., et al. (2014). “Preventive effects of ramelteon on delirium: A randomized placebo-controlled trial.” JAMA Psychiatry 71(4): 397-403.
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

2. Okamoto, Y., et al. (1999). “Trazodone in the treatment of delirium.” J Clin Psychopharmacol 19(3): 280-282.

3. Lennkh, C., et al. (1998). “Occurrence of trazodone-induced delirium.” Int Clin Psychopharmacol 13(5): 225-228.
Trazodone, a triazolepyridine derivate, is both chemically and pharmacologically distinct from other serotonin reuptake inhibitors and possesses antidepressant, anxiolytic and hypnotic activity. We observed trazodone-induced delirium in three depressed patients who also suffered from preexisting organic cerebral lesions (two cases) or thyroideal dysfunction (one case). The appearance of hallucinations, psychomotoric agitation, and cognitive changes after initiation of trazodone therapy and their prompt cessation after drug discontinuation led to the impression that these were drug-induced phenomena. One possible hypothesis for the observed deliria is an oversensitivity to the effect of meta-chlorphenylpiperazine, which is a metabolite of trazodone with specific 5-HT agonistic properties.