Sleep and Biological Rhythms

, Volume 16, Issue 1, pp 69–75 | Cite as

A retrospective study of the efficacy of ramelteon for insomnia: relevance of dose and timing of administration

  • Akiko Watanabe
  • Marina Hirose
  • Tsuyoshi Kitajima
  • Satoe Tomita
  • Yuichi Esaki
  • Nakao Iwata
Original Article


The objective of the study was to investigate the efficacy of ramelteon for insomnia, particularly with circadian disturbance, focusing on the relevance of dose and timing of administration. We reviewed the chart data of 145 continuous patients who received ramelteon for insomnia for the first time at the sleep clinic of the Department of Psychiatry, Fujita Health University Hospital (Aichi, Japan) between October 2010 and May 2014. Treatment efficacy was assessed using the Clinical Global Impression of Improvement (CGI-I) scale and this relationship with the dose and timing of administration was further analyzed. Symptoms in 56.6% of patients were improved (CGI-I ≦ 3). In a subgroup of 114 patients, especially aiming for phase advance, the ratio of improvement was 64.0%. The ratio of patients reporting symptom improvement tended to be great in the low-dose (1 or 2 mg) group and the low-dose + early administration (> 5 h before habitual bedtime) group, as compared with the remaining group; however, this difference was not statistically significant. Significantly fewer cases in the low-dose group reported carry-over effects. In our specialized sleep clinic, there were many refractory cases of insomnia; however, ramelteon was effective in about half of such patients. Particularly, ramelteon tended to be more effective for patients with insomnia and circadian disturbances, although differences among groups were not statistically significant. The effectiveness of the low-dose administration or the combination of low-dose and early-administration was equal or slightly better and acceptability tended to be better than other modes of administration.


Ramelteon Melatonin receptors agonist Insomnia Circadian disturbance Dose and timing of administration Retrospective study 


Compliance with ethical standards

Ethical approval

This study protocol was approved by the ethics committee of Fujita Health University (Permission Number: 13–219).

Informed consent

Because this was a retrospective study, formal consent was not required.

Conflict of interest

Dr. Watanabe, Dr. Hirose, Dr. Tomita, and Dr. Esaki declare that they have no conflict of interest. Dr. Kitajima has received research grants from Eizai, Takeda Pharmaceutical Company, MSD, and has received personal fees from Eizai, Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Takeda Pharmaceutical Company, Eli Lilly Japan K.K., MSD, Meiji Seika Pharma Co., Yoshitomiyakuhin Corporation, Dainippon Suimitomo Pharma, Fukuda Life Tech Chubu KK, Shionogi, and Novo Nordisk. Dr. Iwata has received research grants from Otsuka, GSK, Tanabe-Mitsubishi, Dainippon-Sumitomo, and has received personal fees from Eli Lilly, Janssen, Otsuka, Shionogi, GSK, Dainippon-Sumitomo, Astellas, Yoshitomi, Meiji, Novartis, and Pfizer.


This is not an industry-sponsored study.


  1. 1.
    Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, Kawamata Y, Hinuma S, Miyamoto M. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 2005;48:301–10.CrossRefPubMedGoogle Scholar
  2. 2.
    Mayer G, Wang-Weigand S, Roth-Schechter B, Lehmann R, Staner C, Partinen M. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep. 2009;32:351–60.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Uchiyama M, Hamamura M, Kuwano T, Nishiyama H, Nagata H, Uchimura N. Evaluation of subjective efficacy and safety of ramelteon in Japanese subjects with chronic insomnia. Sleep Med. 2011;12:119–26.CrossRefPubMedGoogle Scholar
  4. 4.
    Kuriyama A, Honda M, Hayashino Y. Ramelteon for the treatment of insomnia in adults: a systematic review and meta-analysis. Sleep Med. 2014;15:385–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Burgess HJ, Revell VL, Eastman CI. A three pulse phase response curve to three milligrams of melatonin in humans. J Physiol. 2008;586:639–47.CrossRefPubMedGoogle Scholar
  6. 6.
    van Geijlswijk IM, Korzilius HP, Smits MG. The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis. Sleep. 2010;33:1605–14.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Morgenthaler TI, Lee-Chiong T, Alessi C, Friedman L, Aurora N, Boehlecke B, Brown T, Chesson AL, Kapur V, Maganti R, Owens J. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007;30:1445–59.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    American Academy of Sleep Medicine. International classification of sleep disorders, 3rd ed. Darien: American Academy of Sleep Medicine;2014.Google Scholar
  9. 9.
    Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), and irregular sleep-wake rhythm disorder (ISWRD). An update for 2015: an American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2015;11:1199–236.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Richardson GS, Zee PC, Wang-Weigand S, Rodriguez L, Peng X. Circadian phase-shifting effects of repeated ramelteon administration in healthy adults. J Clin Sleep Med. 2008;4:456–61.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Zee PC, Wang-Weigand S, Wright KP, Peng X, Roth T. Effects of ramelteon on insomnia symptoms induced by rapid, eastward travel. Sleep Med. 2010;11:525–33.CrossRefPubMedGoogle Scholar
  12. 12.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 2000 (Revison Text)Google Scholar
  13. 13.
    American Academy of Sleep Medicine. International classification of sleep disorders. 2nd ed. Diagnostic and coding manual. Westchester: Illinois; 2005.Google Scholar
  14. 14.
    Ando K, Hayakawa T, Ohta T, Kayukawa Y, Ito A, Iwata T, Okada T. Long-term follow-up study of 10 adolescent patients with sleep-wake schedule disorders. Jpn J Psychiatry Neurol. 1994;48:37–41.PubMedGoogle Scholar
  15. 15.
    Ohta T. Long-term follow-up study on sleep-wake rhythm disorders: comprehensive survey of patients in adolescent and adult. Jpn JPsychiatry Neurol. 1994;48:455–7.Google Scholar

Copyright information

© Japanese Society of Sleep Research 2017

Authors and Affiliations

  1. 1.Department of PsychiatryFujita Health University School of MedicineToyoakeJapan
  2. 2.Health Support CenterNagoya Institute of TechnologyAichiJapan

Personalised recommendations