Original article Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia * Thomas Roth a, * , David Seiden b , Stephen Sainati c , Sherry Wang-Weigand c , Jeffrey Zhang c , Phyllis Zee d a Sleep Disorders and Research Center, Henry Ford Hospital, 2799 West Grand Boulevard, CFP-3, Detroit, MI 48202, USA b Broward Research Group and Sleep Wake Disorders Center of South Florida, Pembroke Pines, FL, USA c Takeda Global Research and Development Center, Lincolnshire, IL, USA d Northwestern University, Chicago, IL, USA Received 7 October 2005; received in revised form 3 January 2006; accepted 4 January 2006 Abstract Background and purpose: To assess the efficacy and safety of ramelteon, a selective MT 1 /MT 2 receptor agonist, for chronic insomnia treatment. Patients and methods: Randomized, double-blind, placebo-controlled 35-night outpatient trial with weekly clinic visits at multiple centers. Patients include older adults (R65 years; NZ829) with chronic insomnia. Placebo, ramelteon 4 mg, or ramelteon 8 mg were taken nightly for five weeks, and patient-reported sleep data were collected using sleep diaries. Primary efficacy was sleep latency at week 1. Sustained efficacy was examined at weeks 3 and 5. Rebound insomnia and withdrawal effects were evaluated during a 7-day placebo run-out. Results: Both doses of ramelteon produced statistically significant reductions in sleep latency vs. placebo at week 1 (ramelteon 4 mg: 70.2 vs. 78.5 min, PZ.008; ramelteon 8 mg: 70.2 vs. 78.5 min, PZ.008). Patients continued to report reduced sleep latency at week 3 with ramelteon 8 mg (60.3 vs. 69.3 min, PZ.003), and at week 5 with ramelteon 4 mg (63.4 vs. 70.6 min, PZ.028) and ramelteon 8 mg (57.7 vs. 70.6 min; P!.001). Statistically significant increases in total sleep time were observed with ramelteon 4 mg at week 1 (324.6 vs. 313.9 min, PZ.004) and week 3 (336.0 vs. 324.3 min, PZ.007) compared with placebo. There was no evidence of significant rebound insomnia or withdrawal effects following treatment discontinuation. The incidence of adverse events was similar among all treatment groups; most were mild or moderate. Conclusions: In older adults with chronic insomnia, ramelteon significantly reduced patient reports of sleep latency over five weeks of treatment with no significant rebound insomnia or withdrawal effects. q 2006 Elsevier B.V. All rights reserved. Keywords: Chronic insomnia; Elderly; Ramelteon; Melatonin; Sleep latency; Psychiatric disorders 1. Introduction Insomnia is a common symptom, especially among older adults (R65 years of age), with major quality of life consequences [1–3]. Reports of difficulty falling asleep, increased nighttime wakefulness, or waking too early tend to increase with age [4]. Inability to have restful sleep results in poor daytime functioning, impaired memory, and decreased enjoyment of personal relationships [5,6]. Age- related changes in sleep architecture and variability in sleep stage patterns can contribute to the incidence of sleep disturbances in older adults [7]; also, insomnia often coexists with other medical and psychiatric disorders [8]. In addition to sleep hygiene education and cognitive behavioral therapy, which have been shown to have benefits in older adults with insomnia [9], pharmacologic agents are typically indicated [10]. Currently available hypnotics indicated for insomnia include traditional benzodiazepine receptor agonists (BzRAs) (e.g. temazepam, triazolam) and newer BzRAs (e.g. zolpidem, zaleplon, eszopiclone), which all act via gamma-aminobutyric acid (GABA)-A receptor Sleep Medicine 7 (2006) 312–318 www.elsevier.com/locate/sleep 1389-9457/$ - see front matter q 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2006.01.003 * This research was supported by a grant funded by Takeda Pharmaceuticals North America, Inc. * Corresponding author. Tel.: C1 313 916 5171; fax: C1 313 916 5167. E-mail address: troth1@hfhs.org (T. Roth).