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

Taro Kishi, Ikuo Nomura, Kenji Sakuma, Tsuyoshi Kitajima, Kazuo Mishima, Nakao Iwata

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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.

Original languageEnglish
Pages (from-to)1479-1486
Number of pages8
JournalNeuropsychiatric Disease and Treatment
Volume15
DOIs
Publication statusPublished - 01-01-2019

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Melatonin Receptors
Bipolar Disorder
Meta-Analysis
Randomized Controlled Trials
Melatonin
Placebos
Numbers Needed To Treat
Depression
Recurrence
Odds Ratio
Incidence
Sleep Initiation and Maintenance Disorders
Dizziness
Patient Safety
ramelteon
PubMed
Libraries
Headache
Sleep
Anxiety

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

@article{dae65b7816fc48c9b248ce3f1c6eaab3,
title = "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.",
author = "Taro Kishi and Ikuo Nomura and Kenji Sakuma and Tsuyoshi Kitajima and Kazuo Mishima and Nakao Iwata",
year = "2019",
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doi = "10.2147/NDT.S198899",
language = "English",
volume = "15",
pages = "1479--1486",
journal = "Neuropsychiatric Disease and Treatment",
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T1 - Melatonin receptor agonists—ramelteon and melatonin—for bipolar disorder

T2 - A systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials

AU - Kishi, Taro

AU - Nomura, Ikuo

AU - Sakuma, Kenji

AU - Kitajima, Tsuyoshi

AU - Mishima, Kazuo

AU - Iwata, Nakao

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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