Melatonin receptor agonists—ramelteon and melatonin—for bipolar disorder: a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials

Abstract

Objective: This study was a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials, investigating the efficacy and tolerability/safety of melatonin receptor agonists, such as ramelteon and melatonin, for patients with bipolar disorder.

Methods: We carried out a literature search through PubMed and the Cochrane Library from the date of inception to January 6, 2019. The risk ratio (RR), number needed to treat (NNT), and standardized mean difference (SMD) ±95% CI were calculated. The primary outcome was all-cause discontinuation.

Results: We identified three ramelteon (n=746) and two melatonin (n=53) studies. One of these two melatonin studies reported only data on all-cause discontinuation, whereas the other study did not report data relevant for a meta-analysis. We found no significant differences between the treatment and placebo groups regarding all-cause discontinuation, neither individually (p: ramelteon=0.86, melatonin=1.00) nor pooled together (p=0.85). Although we found no significant differences between ramelteon and placebo regarding the relapse due to mania/hypomania or mixed episode; Pittsburgh Sleep Quality Index scores; depression scales scores; Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form scores; and the incidence of individual adverse events, such as headaches, insomnia, somnolence, anxiety, and dizziness, ramelteon was associated with a lower incidence of relapse due to depression than placebo (RR=0.67, 95% CI=0.48–0.94, p=0.02, NNT=14).

Conclusion: Ramelteon might prevent relapse due to depression in patients with bipolar disorder. However, because of the small number of studies included in the present systematic review and meta-analysis, further studies comparing ramelteon and placebo with larger samples of patients with bipolar disorder are warranted. We also did not evaluate the efficacy and safety of melatonin for patients with bipolar disorder in detail.

Keywords:

• ramelteon
• melatonin
• bipolar disorder
• relapse
• systematic review, meta-analysis

Acknowledgments

We thank Takeda Pharmaceutical Company Limited (1-1, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo, Japan 〒103-0027) for providing detailed information about sublingual ramelteon. We also thank Mr. Miyanohara for his technical support. The present study was supported by the Health and Labor Sciences Research Grants (H29-seishin-ippan-001).

Disclosure

Dr. Kishi has received speaker’s honoraria from Daiichi Sankyo, Dainippon Sumitomo, Eisai, Janssen, Otsuka, Meiji, MSD, Yoshitomi, and Tanabe-Mitsubishi and has received a Health Labour Sciences Research Grant and a Fujita Health University School of Medicine research grant. Dr. Sakuma has received speaker’s honoraria from Otsuka and Torii. Dr. Nomura has received speaker’s honoraria from Meiji, MSD, Torii, Janssen, and Otsuka. Dr. Kitajima has received speaker’s honoraria from Eisai, Tanabe-Mitsubishi, Otsuka, Takeda, Eli Lilly, MSD, Meiji, Yoshitomi, Dainippon-Suimitomo, Fukuda, Shionogi, and Novo Nordisk and has had research grants from Eisai, Takeda, MSD. Dr. Mishima has received research support from the Japanese Ministry of Health, Labour and Welfare, the Japanese Ministry of Education, Science, and Technology, and the National Center of Neurology and Psychiatry Intramural Research Grant for Neurological and Psychiatric Disorders. He has also received speaker’s honoraria from Eisai, MSD, Takeda, Astellas, and Janssen Pharmaceutical along with research grants from Eisai, Nobelpharma, and Takeda. Dr. Iwata has received speaker’s honoraria from Astellas, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Yoshitomi, Otsuka, Meiji, Shionogi, Novartis, and Pfizer and has had research grants from GlaxoSmithKline, Meiji, and Otsuka. Dr. Tsuyoshi Kitajima reports grants, personal fees from Eisai, Takeda, and MSD, He has also received personal fees from Tanabe-Mitsubishi, Otsuka, Eli Lilly, Meiji, Yoshitomiyakuhin, Dainippon-Suimitomo, Fukuda, Shionogi, and Novo Nordisk, during the conduct of the study; Professor Kazuo Mishima reports grants from the Japanese Ministry of Health, Labour and Welfare, the Japanese Ministry of Education, Science, and Technology, the National Center of Neurology and Psychiatry, Eisai Co., Ltd., Nobelpharma Co., Ltd., and Takeda Pharmaceutical Co., Ltd., he has also received personal fees from Eisai Co., Ltd., MSD Inc., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., and Janssen Pharmaceutical KK, during the conduct of the study. The authors report no other conflicts of interest in this work.