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Hypnotic and Melatonin/Melatonin-Receptor Agonist Treatment in Bipolar Disorder: A Systematic Review and Meta-Analysis

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Abstract

Background

Bipolar disorder (BD) is a chronic relapsing-remitting psychiatric disorder. Sleep and circadian rhythm disturbances persist during acute mood episodes of the disorder and during euthymia. However, the treatment potential of hypnotic agents that might be used to manage sleep disturbance in BD is not well understood. Similarly, melatonin and medications with a melatonin-receptor agonist mechanism of action may have chronotherapeutic potential for treating people with the disorder, but the impact of these substances on sleep and circadian rhythms and core symptoms in BD is unclear.

Objective

Our aim was to conduct a systematic review and meta-analysis evaluating the current evidence for hypnotic and melatonin/melatonin-receptor agonist pharmacotherapy for symptoms of sleep disturbance, mania, and depression in patients with BD.

Methods

AMED, Embase, MEDLINE and PsychINFO databases were searched for studies published in English from the date of inception to 31 October 2021. Studies included in this review were randomised controlled trials (RCTs) and non-controlled/non-randomised studies for BD that examined hypnotic medications selected based on a common pattern of usage for treating insomnia (i.e. chloral, clomethiazole, diphenhydramine, doxepin, doxylamine, promethazine, suvorexant, zaleplon, zolpidem, zopiclone, and eszopiclone) and melatonin and the melatonin-receptor agonist drugs ramelteon and agomelatine. Risk of bias was assessed using the RoB2 and AXIS tools. Pooled effect sizes for RCT outcomes were estimated using random-effects models.

Results

A total of eleven studies (six RCTs and five experimental feasibility studies) involving 1279 participants were included. Each study examined melatonin or melatonin-receptor agonists. No studies of hypnotics were found that fulfilled the review inclusion criteria. Pilot feasibility studies suggested beneficial treatment effects for symptoms of sleep disturbance, depression, and mania. However, the pooled effect of the two available RCT studies assessing sleep quality via Pittsburgh Sleep Quality Index scores was not statistically significant (g = − 0.04 [95% CI − 0.81 to 0.73]) and neither was the pooled effect for depressive symptoms (four studies; g = − 0.10 [95% CI − 0.27 to 0.08]). Some RCT evidence suggests ramelteon might prevent relapse into depression in BD. The largest efficacy signal detected was for manic symptoms (four studies; g = − 0.44 [95% CI − 1.03 to 0.14]) but there was substantial heterogeneity between studies and patient characteristics. In the two RCTs assessing manic symptoms during acute mania, adjunctive melatonin demonstrated superior treatment effects versus placebo.

Conclusions

There is a paucity of studies examining pharmacological interventions for sleep and circadian rhythm disturbance in BD. Few studies assessed sleep-related symptoms, and none quantitatively examined endogenous melatonin patterns or other circadian rhythms. Melatonin may be a promising candidate for the adjunctive treatment of bipolar mania. However, dose-finding studies and studies with larger sample sizes are needed to confirm its efficacy. We recommend parallel monitoring of sleep and circadian rhythms in future trials. Chronobiology-informed trial designs are needed to improve the quality of future studies.

Protocol registration

PROSPERO (CRD42020167528).

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Acknowledgements

We thank Professor Edward Norris and Professor Lakshmi Yatham for facilitating our requests for access to unreported data from the published Norris et al. and Yatham et al. studies. SDK and KEAS are supported by the NIHR Oxford Health Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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  1. Niall M. McGowan

    Present address: Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

Authors and Affiliations

  1. Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK

    Niall M. McGowan, Lampros Bisdounis & Kate E. A. Saunders

  2. Medical Sciences Division, Clinical Medical School, The John Radcliffe Hospital, University of Oxford Academic Centre, Oxford, UK

    David S. Kim & Marta de Andres Crespo

  3. Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

    Lampros Bisdounis & Simon D. Kyle

  4. Warneford Hospital, Oxford Health NHS Foundation Trust, Oxford, UK

    Kate E. A. Saunders

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NMMcG, LB, and KEAS conceived the original idea for the review. NMMcG, DSK, LB, and KEAS designed the review protocol. NMMcG and DSK conducted the literature searches and together with MdAC performed the eligibility screen. Studies that met inclusion criteria were assessed for risk of bias by DSK and MdAC with assistance from NMMcG. Data extraction, quantitative analysis and interpretation was performed by NMMcG with the assistance of LB. NMMcG wrote the draft manuscript with the assistance of DSK. KEAS and SDK critically revised the manuscript and contributed substantially to the discussion of findings. All authors contributed to and approved the final manuscript and agree to be accountable for the work presented in the manuscript.

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NMMcG, DSK, MdAC, LB, SDK, and KEAS have no conflicts of interest to disclose.

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McGowan, N.M., Kim, D.S., de Andres Crespo, M. et al. Hypnotic and Melatonin/Melatonin-Receptor Agonist Treatment in Bipolar Disorder: A Systematic Review and Meta-Analysis. CNS Drugs 36, 345–363 (2022). https://doi.org/10.1007/s40263-022-00911-7

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