Melatonin and agomelatine for prevention of winter depression

Why is this review important?

Many people in northern latitudes suffer from seasonal affective disorder (SAD), which occurs as a reaction to reduced sunlight. Three-quarters of those affected are women. Lethargy, overeating, craving for carbohydrates and depressed mood are common symptoms. In some people, SAD becomes depression that seriously affects their daily lives. Up to two-thirds experience depressive symptoms every winter.

Who might be interested in this review?

General practitioners, psychiatrists, pharmacists, other health professionals working in adult mental health services, and researchers could be interested in the results of this review. Anyone who has experienced winter depression, or who has friends or relatives who have experienced winter depression might also be interested.

What questions does this review aim to answer?

Because of the seasonal pattern and high recurrence of SAD, melatonin or agomelatine could be used to prevent the onset of depressed mood. The goal of this report is to examine whether benefits outweigh harms of melatonin or agomelatine when used to prevent onset of a new depressive episode in people with a history of SAD who were free of symptoms when the preventive intervention started. To date, this question has not been examined in a systematic way. This is one of four reviews on the efficacy and potential harms of interventions to prevent SAD.

Which studies were included in the review?

We searched databases up to June 2018 for studies on melatonin or agomelatine for prevention of winter depression. Among 3745 records, we found one randomised controlled study comparing agomelatine with placebo for one year. All 225 participants had a history of winter depression but were not depressed when the prevention study started.

What does evidence from the review reveal?

The included study showed neither a clear effect in favour nor against agomelatine as a preventive treatment. In addition, the certainty of evidence for all outcomes was very low, making it impossible to draw any conclusions about the efficacy and safety of agomelatine for the prevention of winter depression. No evidence on melatonin for prevention of SAD was identified.

Doctors need to discuss with persons with a history of SAD that currently evidence on agomelatine or melatonin for preventive treatment options for SAD is inconclusive, therefore treatment selection should be strongly based on peoples' preferences and reflect on the evidence base of all available treatment options.

What should happen next?

Review authors recommend that future studies should evaluate the efficacy of agomelatine or melatonin in preventing SAD and should directly compare these interventions against other treatment options, such as light therapy, antidepressants, or psychological therapies to determine the best treatment option for prevention of SAD.

Authors' conclusions: 

Given the uncertain evidence on agomelatine and the absence of studies on melatonin, no conclusion about efficacy and safety of agomelatine and melatonin for prevention of SAD can currently be drawn. The decision for or against initiating preventive treatment of SAD and the treatment selected should consider patient preferences and reflect on the evidence base of all available treatment options.

Read the full abstract...

Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly starts in autumn or winter and remits in spring. The prevalence of SAD depends on latitude and ranges from 1.5% to 9%. The predictable seasonal aspect of SAD provides a promising opportunity for prevention in people who have a history of SAD. This is one of four reviews on the efficacy and safety of interventions to prevent SAD; we focus on agomelatine and melatonin as preventive interventions.


To assess the efficacy and safety of agomelatine and melatonin (in comparison with each other, placebo, second-generation antidepressants, light therapy, psychological therapy or lifestyle interventions) in preventing SAD and improving person-centred outcomes among adults with a history of SAD.

Search strategy: 

We searched Ovid MEDLINE (1950- ), Embase (1974- ), PsycINFO (1967- ) and the Cochrane Central Register of Controlled Trials (CENTRAL) to 19 June 2018. An earlier search of these databases was conducted via the Cochrane Common Mental Disorders Controlled Trial Register (CCMD-CTR) (all years to 11 August 2015). Furthermore, we searched the Cumulative Index to Nursing and Allied Health Literature, Web of Science, the Cochrane Library, the Allied and Complementary Medicine Database and international trial registers (to 19 June 2018). We also conducted a grey literature search and handsearched the reference lists of included studies and pertinent review articles.

Selection criteria: 

To examine efficacy, we included randomised controlled trials (RCTs) on adults with a history of winter-type SAD who were free of symptoms at the beginning of the study. For adverse events, we intended also to include non-randomised studies. We planned to include studies that compared agomelatine versus melatonin, or agomelatine or melatonin versus placebo, any second-generation antidepressant, light therapy, psychological therapies or lifestyle changes. We also intended to compare melatonin or agomelatine in combination with any of the comparator interventions mentioned above versus the same comparator intervention as monotherapy.

Data collection and analysis: 

Two review authors screened abstracts and full-text publications, abstracted data and assessed risk of bias of included studies independently. We intended to pool data in a meta-analysis using a random-effects model, but included only one study.

Main results: 

We identified 3745 citations through electronic searches and reviews of reference lists after deduplication of search results. We excluded 3619 records during title and abstract review and assessed 126 full-text papers for inclusion in the review. Only one study, providing data of 225 participants, met our eligibility criteria and compared agomelatine (25 mg/day) with placebo. We rated it as having high risk of attrition bias because nearly half of the participants left the study before completion. We rated the certainty of the evidence as very low for all outcomes, because of high risk of bias, indirectness, and imprecision.

The main analysis based on data of 199 participants rendered an indeterminate result with wide confidence intervals (CIs) that may encompass both a relevant reduction as well as a relevant increase of SAD incidence by agomelatine (risk ratio (RR) 0.83, 95% CI 0.51 to 1.34; 199 participants; very low-certainty evidence). Also the severity of SAD may be similar in both groups at the end of the study with a mean SIGH-SAD (Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders) score of 8.3 (standard deviation (SD) 9.4) in the agomelatine group and 10.1 (SD 10.6) in the placebo group (mean difference (MD) -1.80, 95% CI -4.58 to 0.98; 199 participants; very low-certainty evidence). The incidence of adverse events and serious adverse events may be similar in both groups. In the agomelatine group, 64 out of 112 participants experienced at least one adverse event, while 61 out of 113 did in the placebo group (RR 1.06, 95% CI 0.84 to 1.34; 225 participants; very low-certainty evidence). Three out of 112 patients experienced serious adverse events in the agomelatine group, compared to 4 out of 113 in the placebo group (RR 0.76, 95% CI 0.17 to 3.30; 225 participants; very low-certainty evidence).

No data on quality of life or interpersonal functioning were reported. We did not identify any studies on melatonin.