REVIEW
The therapeutic or prophylactic effect of exogenous melatonin against depression and depressive symptoms: A systematic review and meta-analysis

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Abstract

Circadian- and sleep disturbances may be central for understanding the pathophysiology and treatment of depression. The effect of melatonin on depression/depressive symptoms has been investigated previously. This systematic review assesses the current evidence of a therapeutic- and prophylactic effect of melatonin in adult patients against depression or depressive symptoms. A search was performed in The Cochrane Library, PubMed, EMBASE and PsycINFO for published trials on November 14th 2013. Inclusion criteria were English language, RCTs or crossover trials. Our outcome was measurement of depression/depressive symptoms with a validated clinician-administered or self-rating questionnaire. PRISMA recommendations were followed and the Cochrane risk-of-bias tool used. Ten studies in 486 patients were included in the final qualitative synthesis and four studies, 148 patients, were included in two meta-analyses. Melatonin doses varied from 0.5–6 mg daily and the length of follow-up varied from 2 weeks to 3.5 years. Three studies were done on patients without depression at inclusion, two studies in patients with depression and five studies included a mixture. Six studies showed an improvement in depression scores in both the melatonin and placebo groups but there was no significant difference. One study showed a significant prophylactic effect and another found a significant treatment effect on depression with melatonin compared to placebo. The two meta-analyses did not show any significant effect of melatonin. No serious adverse events were reported. Although some studies were positive, there was no clear evidence of a therapeutic- or prophylactic effect of melatonin against depression or depressive symptoms.

Introduction

Depression is a common mental disorder and WHO estimates that more than 350 million people of all ages suffer from depression worldwide (www.who.int - 2013). Depression is the leading cause of disability worldwide, and is a major contributor to the global burden of disease (www.who.int- 2013). The antidepressants most commonly used today are thought to exert their actions based upon the classical mono-amine deficiency hypothesis (Belmaker and Agam, 2008). New approaches are in focus because the clinical effects of antidepressants used today can take up to two or more weeks to emerge, early discontinuaton rates are high, full remission rates are low and side effects are common (Malhi et al., 2013, Papakostas, 2008, Papakostas, 2010).

Circadian rhythms have been shown to be fundamentally disturbed in patients with depression (Germain and Kupfer, 2008) and insomnia and early-morning awakening are prominent symptoms of clinical depression (Germain and Kupfer, 2008, Srinivasan et al., 2009), suggesting a close link between the melatonergic system and depressed mood (Malhi and Kuiper, 2013, Pandi-Perumal et al., 2009, Srinivasan et al., 2009). Addressing the chronobiology of mood disorders with novel melatonin-based therapies, such as agomelatine has shown significant antidepressant effects with a favorable adverse effect and safety profile (Hickie and Rogers, 2011, Koesters et al., 2013). However, it is not known whether the antidepressant action of agomelatine is a synergistic effect or independently linked to the MT1/MT2 receptor binding properties or to the affinity to the 5-HT2c serotonin receptor (de Bodinat et al., 2010).

Major depressive disorder (MDD) was proposed as the “low melatonin syndrome” in 1979 (Wetterberg, 1979); a concept that focuses on low melatonin secretion as a biological marker of depression. As a consequence of this theory many studies investigating the secretion of melatonin in depression have followed (Srinivasan et al., 2009), although the results are ambiguous with findings of decreased and increased secretion (Srinivasan et al., 2009). Melatonin itself is known to promote sleep, and synchronization and entrainment of the circadian clock; all effects that could contribute to the possible antidepressant effect (Boyce and Hopwood, 2013). In addition, exogenous melatonin has shown anti-depressant-like effects in animal models (Binfare et al., 2010, Detanico et al., 2009, Raghavendra et al., 2000). Since the first clinical study investigating the antidepressant effect of exogenous melatonin in humans in 1976 (Carman et al., 1976) showing negative effects, several other studies have been conducted with both positive and negative findings and therefore no clear evidence of the effect of melatonin on mood has been concluded (Bellipanni et al., 2001, Dalton et al., 2000, Danilenko and Putilov, 2005, Del et al., 2013, Fava et al., 2012, Jean-Louis et al., 1998, Lewy et al., 1998).

The aim of this systematic review and meta-analysis was to assess the current evidence of a therapeutic- and prophylactic effect of melatonin in adult patients against depression or depressive symptoms.

Section snippets

Experimental procedures

This systematic review was conducted following The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) (Liberati et al., 2009), except that no formal review protocol was published.

Results

The database searches identified 372 records. After removal of duplicates, 304 titles/abstracts were screened, and 60 full-text articles were subsequently assessed for eligibility. Of these full-text articles, 50 were excluded due to various reasons (Figure 1) and 10 studies (Chojnacki et al., 2011, Garzon et al., 2009, Hurtuk et al., 2011, Kripke et al., 2006, Rahman et al., 2010a, Riemersma-van der Lek et al., 2008, Serfaty et al., 2010, Song et al., 2005, Lu et al., 2005, Williams et al.,

Discussion

This present systematic review does not support routine administration of melatonin for treatment or prophylaxis of depression, although two small studies (one prophylactic and one treatment) did find an effect compared to placebo and no studies found the opposite. The ten included studies were rather small with regard to number of included patients and heterogeneous with regard to type of patients included, melatonin dose, timing and duration of intervention, outcome measurement instrument and

Role of funding source

This work was supported by Grants from the University of Copenhagen, The Dagmar Marshalls Foundation and The Foundation of Poul Martin Christiansen and Spouse. These abovementioned funders have had no influence on the design and conduct of the study; collection, management analysis, and interpretation of data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. All these activities are done by the authors.

Contributors

All authors had full access to all the data in the study and take responsibility for the integrity of the data, the accuracy of the data analysis and had final responsibility for the decision to submit for publication. All authors have agreed to be accountable for all aspects of the work and have all approved the final version of the manuscript to be published. Furthermore following contributions were made:

  • MVH: guarantor for the study, planned the study, designed the study, initiated the study,

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgments

None.

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