The optimal dose of Ramelteon for the better treatment adherence of delayed sleep-wake phase disorder: a dropout rate study

Shunsuke Takagi; Genichi Sugihara; Hidehiko Takahashi; Yuichi Inoue

doi:10.3389/fneur.2023.1280131

The optimal dose of Ramelteon for the better treatment adherence of delayed sleep-wake phase disorder: a dropout rate study

Front Neurol. 2023 Sep 28:14:1280131. doi: 10.3389/fneur.2023.1280131. eCollection 2023.

Authors

Shunsuke Takagi^{1

2

3

4}, Genichi Sugihara¹, Hidehiko Takahashi^{1

5}, Yuichi Inoue^{2

4}

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
² Yoyogi Sleep Disorder Center, Tokyo, Japan.
³ Sleep Research Institute, Waseda University, Tokyo, Japan.
⁴ Japan Somnology Center, Institute of Neuropsychiatry, Tokyo, Japan.
⁵ Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.

Abstract

Background: Evidence regarding the effectiveness of melatonin receptor agonists in treating delayed sleep-wake phase disorder (DSWPD) remains limited. This study aimed to determine the optimal dose of ramelteon, a melatonin receptor agonist, for the better treatment adherence of DSWPD.

Methods: The patients who were diagnosed definitely as having DSWPD by board-certified physicians specialized in sleep medicine and started to receive strategically timed ramelteon medications after the diagnosis were included. Data on the initial ramelteon dose and follow-up duration (up to 24 months) were collected retrospectively. Patients with treatment discontinuation, changes in ramelteon dose, or the addition of other sleep-related medications were considered dropouts. Kaplan-Meier estimates, log-rank tests, and Cox regression analyses were performed.

Results: Overall, 373 patients were analyzed. The findings revealed that the 2 mg dose of ramelteon was associated with a lower dropout rate compared to the other doses (8 mg, 4 mg, and 1 mg). The dropout rate for the 2 mg group was estimated to have a hazard ratio (HR) of 0.5762 when compared with the 8 mg dose group. Sex did not reveal a significant HR, whereas older age exhibited a small but significant HR (0.9858).

Conclusion: For achieving better adherence, a dosing regimen of strategically timed 2 mg ramelteon may be the best for the treatment of DSWPD. The therapeutic dose window for better adherence seems to center approximately 2 mg of ramelteon. Furthermore, caution should be exercised when treating younger patients to prevent dropouts.

Keywords: delayed sleep–wake phase disorder; dropout rate; long-term treatment; melatonin receptor agonist; optimal dose.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. ST is financially supported by JSPS KAKENHI (Grant number: 20K16643). GS and HT are not supported by any grant for this project. YI is financially supported by Takeda Pharmaceutical Company Limited and Aculys Pharma, Inc.