Melatonin and agomelatine for preventing seasonal affective disorder
Abstract
Background
Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly occurs during autumn or winter and remits in spring. The prevalence of SAD in the United States ranges from 1.5% to 9%, depending on latitude. The predictable seasonal aspect of SAD provides a promising opportunity for prevention. 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.
Objectives
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 patient‐centred outcomes among adults with a history of SAD.
Search methods
We conducted a search of the Specialised Register of the Cochrane Depression, Anxiety and Neurosis Review Group (CCDANCTR) to 11 August 2015. The CCDANCTR contains reports of relevant randomised controlled trials from EMBASE (1974 to date), MEDLINE (1950 to date), PsycINFO (1967 to date) and the Cochrane Central Register of Controlled Trials (CENTRAL). Furthermore, we searched the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Knowledge, The Cochrane Library and the Allied and Complementary Medicine Database (AMED) (to 26 May 2014). We conducted a grey literature search (e.g. in clinical trial registries) and handsearched the reference lists of all included studies and pertinent review articles.
Selection criteria
To examine efficacy, we planned to include randomised controlled trials (RCTs) on adults with a history of winter‐type SAD who were free of symptoms at the beginning of the study. To examine adverse events, we intended 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 (SGA), light therapy, psychological therapies or lifestyle changes. We also intended to compare melatonin or agomelatine in combination with any of the comparator interventions listed above versus the same comparator intervention as monotherapy.
Data collection and analysis
Two review authors screened abstracts and full‐text publications against the inclusion criteria. Two review authors planned to independently extract data and assess risk of bias of included studies. We planned to pool data for meta‐analysis when participant groups were similar and when studies assessed the same treatments by using the same comparator and presented similar definitions of outcome measures over a similar duration of treatment; however, we identified no studies for inclusion.
Main results
We identified 2986 citations through electronic searches and reviews of reference lists after de‐duplication of search results. We excluded 2895 records during title and abstract review and assessed 91 articles at full‐text level for eligibility. We identified no controlled studies on use of melatonin and agomelatine to prevent SAD and to improve patient‐centred outcomes among adults with a history of SAD.
Authors' conclusions
No available methodologically sound evidence indicates that melatonin or agomelatine is or is not an effective intervention for prevention of SAD and improvement of patient‐centred outcomes among adults with a history of SAD. Lack of evidence clearly shows the need for well‐conducted, controlled studies on this topic. A well‐conducted RCT of melatonin or agomelatine for prevention of SAD would assess the comparative benefits and risks of these interventions against others currently used to treat the disorder.
PICOs
Plain language summary
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 a depression that seriously affects their daily lives. Up to two‐thirds experience depressive symptoms every winter.
Who will be interested in this review?
• Anyone who has experienced winter depression.
• Relatives and friends of people who have experienced winter depression.
• General practitioners, psychiatrists and pharmacists.
• Professionals working in adult mental health services.
What questions does this review aim to answer?
Because of the seasonal pattern and high recurrence of SAD, melatonin/agomelatine could be used during fall and winter months to prevent the onset of depressed mood. The goal of this report is to examine whether benefits outweigh harms of melatonin/agomelatine when used in healthy people to prevent onset of SAD for those 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 and is of importance for those who have suffered winter depression. 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 August 2015 for studies on melatonin/agomelatine for prevention of winter depression. Among 2986 records, we found no randomised controlled studies.
What does evidence from the review reveal?
Our literature search yielded no studies that addressed the efficacy of melatonin or agomelatine in preventing SAD, and we can make no recommendations in support of, or against, its use to treat individuals with SAD.
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 versus other effective treatments such as light therapy, antidepressants and lifestyle or psychological therapies to determine the best treatment option for prevention of SAD.
Authors' conclusions
Background
Description of the condition
Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly occurs during autumn or winter and remits in spring or summer (Rosenthal 1984). In addition to the predictable seasonal pattern of depression, persons suffering from SAD commonly experience atypical symptoms such as hypersomnia, carbohydrate craving with increased appetite and weight gain and extreme fatigue (Sohn 2005). Prevalence in the United States ranges from 1.5% in southern Florida to 9% in northern regions (Rosen 1990). In northern latitudes, the prevalence of SAD is estimated to be around 10% (Byrne 2008). SAD is a multi‐factorial condition in which chronobiological mechanisms related to circadian rhythms, melatonin, serotonin turnover and photoperiodism (length of dark hours relative to light hours over a 24‐hour period) are thought to play a role (Ciarleglio 2011; Levitan 2007). A quintessential and especially impairing quality of this illness is its high risks of recurrence and persistence. Approximately two‐thirds of those diagnosed with SAD will face recurrence of these distressing symptoms the following winter (Rodin 1997). In the five to 11 years following initial diagnosis, 22% to 42% of patients still suffer from SAD, and 33% to 44% develop a non‐seasonal pattern in subsequent episodes; the disorder resolves completely in only 14% to 18% of patients (Magnusson 2005; Schwartz 1996). Indeed, many patients who suffer from SAD experience this type of depression every year, which makes it particularly amenable to preventive treatment (Westrin 2007).
Description of the intervention
Research into the origin of SAD has focused on the role of circadian rhythms and melatonin (Lam 2006). Lewy et al suggested that relative phase shifting of circadian rhythms in relation to the timing of sleep‐wake rhythm is responsible for the genesis of SAD (Lewy 1988). As a rhythm‐regulating factor, and as a hormone involved in the regulation of sleep, melatonin is essential for control of mood and behaviour (Srinivasan 2012). Appropriately timed administration of melatonin has chronobiotic properties and can assist with phase shifting of the circadian system (alone or, more typically, in combination with light exposure) (Hickie 2011). The relatively novel antidepressant agomelatine, which is a metabolic stable analogon of melatonin, is a melatonergic (MT1 and MT2) receptor agonist and a serotonin‐2c receptor antagonist. Previous studies have shown that agomelatine can restore disrupted circadian rhythms, which are implicated in the pathophysiology of SAD (Kasper 2010; Pjrek 2007). It was approved by the European Medicines Agency (EMEA) in 2009 for the treatment of major depressive disorders (Srinivasan 2012). Other established treatments used in the prevention of SAD include light therapy, second‐generation antidepressants (SGAs) and psychological therapies. Light therapy has been shown to be an effective non‐pharmacological treatment for SAD and is often used as first‐line therapy for this disorder (Terman 2005a). Decreased seasonal exposure to light is thought to be a reason for the development of SAD, which occurs through phase shifts in circadian rhythms, resulting in alterations of serotonin metabolism. As a consequence, light therapy has been studied intensively as treatment for SAD (Partonen 1998). One SGA (drugs typically used to treat major depressive disorder) ‐ bupropion XL extended‐release ‐ is currently licenced for use in preventing SAD (Modell 2005). At the neurochemical level, changes in both serotonergic and catecholaminergic transmitter systems seem to play a key role in SAD (Neumeister 2001). Targeting these systems with serotonin or noradrenaline reuptake inhibition, or both, provides biological plausibility for the mechanism of action of SGAs. The rationale for using SGAs for prevention of SAD is based on the efficacy of SGAs in the treatment of SAD (Thaler 2010). Finally, several psychological interventions have been evaluated for their effectiveness in treating SAD. Among these are behavioural therapy/behaviour modification, cognitive‐behavioural therapy (CBT), third‐wave CBT and psychodynamic psychotherapy. Psychological therapy, regardless of the specific modality, may prevent SAD by helping individuals intentionally engage in cognitive or behavioural activities (or both) that directly counter those cognitive patterns or behavioural responses that might be inherent sequelae of the worsening mood symptoms commonly associated with SAD.
How the intervention might work
Given that nearly all successful treatments for mood disorders affect circadian rhythms, drugs that cause shifts, resetting and stabilisation of rhythms are considered effective for treatment of mood disorders (Srinivasan 2012). On the neurochemical level, melatonergic systems seem to play a substantial role in SAD. Targeting these systems with melatonin or agomelatine provides biological plausibility for their mechanism of action. Melatonin has a sleep‐enhancing and antidepressant effect above its agonistic behaviour at melatonergic (MT1 and MT2) binding sites. Even at low physiological doses, it can cause advances (shifts to an earlier time) or delays (shifts to a later time), depending on when on its phase‐response curve it is administered (Lewy 2006). Although melatonin might improve sleep‐wake timing and might increase sleep duration in patients with major depressive disorder, more specific antidepressant effects are few (Hickie 2011). Agomelatine represents the only available MT1/MT2 melatonergic receptor agonist and 5‐HT2c antagonist that has been shown to induce resynchronisation of circadian rhythms and antidepressant actions in humans. By avoiding 5‐HT2a stimulation, agomelatine shows a more favourable side effect profile than selective serotonin reuptake inhibitors (SSRIs) in terms of sexual functioning and gastrointestinal disturbances. However, use of agomelatine has been discontinued in the United States because cases of hepatotoxicity have been reported (Srinivasan 2012).
Why it is important to do this review
The predictable seasonal aspect of SAD provides a specific and promising opportunity for prevention. However, both patients and clinicians face much uncertainty in their collaborative decisions about the choice of a preventive intervention (Westrin 2007). Although a recent Cochrane review assessed the efficacy and risk of harms of SGAs for short‐term treatment of SAD (Thaler 2010), to date no review has determined the efficacy, effectiveness and risk of harms of melatonin and agomelatine for preventing recurrent SAD.
Our findings were intended to provide insights into (1) available evidence on the benefits and harms of competing interventions for prevention of SAD with respect to patient‐centred outcomes, and (2) gaps in the evidence base that will inform future research needs.
This is one of four reviews of interventions to prevent SAD. The others focus on light therapy (Nussbaumer 2014), SGAs (Gartlehner 2014) and psychological therapies (Forneris 2014) as preventive interventions.
The methods followed in this review were set out in the published protocol (Kaminski‐Hartenthaler 2014).
Objectives
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 patient‐centred outcomes among adults with a history of SAD.
Methods
Criteria for considering studies for this review
Types of studies
Efficacy (beneficial effects)
We planned to include randomised controlled trials (RCTs) (including cross‐over studies and cluster‐randomised trials) of melatonin and agomelatine for prevention of SAD.
Adverse effects
We planned to include:
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RCTs (including cross‐over studies and cluster‐randomised trials) of melatonin and agomelatine for SAD; and
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controlled non‐randomised studies of melatonin and agomelatine for SAD.
Types of participants
Participant characteristics
Male and female adults (≥ 18 years of age) of all races, ethnicities and cultural groups with a history of SAD who do not fulfil the criteria for a current major depressive episode.
Diagnosis
We defined SAD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) (APA 2013) as a seasonal pattern of recurrent major depressive episodes. However, we restricted the definition to winter‐type SAD (i.e. major depression in autumn/winter with full remission in spring/summer), and we did not include patients with bipolar disorder and a seasonal pattern. We intended to include studies that had used definitions from prior versions of the DSM (APA 1980; APA 1987; APA 2000).
Co‐morbidities
We planned to exclude studies that enrolled participants with depressive disorder due to another medical condition. We intended to include populations at risk of SAD with common co‐morbidities (e.g. diabetes, cardiovascular disease) that were not the cause of the depressive episode.
Setting
We planned to include studies in all settings.
Subset data
We planned to include studies that provided data on subsets of participants of interest, as long as the subset met our eligibility criteria. We planned to not include studies with 'mixed' populations if researchers did not adequately stratify data with respect to our population of interest.
Types of interventions
Experimental interventions
We planned to include melatonin and agomelatine and combination therapies of melatonin/agomelatine with any of the comparator interventions listed below.
Comparator interventions
We planned to compare melatonin/agomelatine with:
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melatonin/agomelatine;
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placebo;
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second‐generation antidepressants;
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light therapy;
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psychological therapy; and
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lifestyle interventions (e.g. exercising, making the environment sunnier (open blinds), spending regular time outside, adapting nutrition (low‐fat diet, reduction in refined sugars)).
We also planned to compare melatonin/agomelatine in combination with any one of the comparator interventions listed above versus the same comparator intervention as monotherapy (see Data extraction and management).
Types of outcome measures
We planned to include studies that met the above inclusion criteria regardless of whether investigators reported on the following outcomes. In consultation with clinical experts, we selected the following outcomes a priori.
Primary outcomes
1. The primary outcome for benefit was the incidence of SAD, measured as the proportion of participants with a SIGH‐SAD (Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders (Williams 2002)) score of 20 or higher.
2. The primary outcome for harm was the overall rate of adverse events related to preventive interventions.
Secondary outcomes
3. Severity of the SAD episode or SAD‐related symptoms, as measured by a validated tool (e.g. Hamilton Depression Rating Scale (Hamilton 1960)).
4. Quality of life, as measured by a validated quality of life tool (e.g. Short Form (SF)‐36 (Ware 1992)).
5. Quality of interpersonal and social functioning, as measured by a validated tool (e.g. the Range of Impaired Functioning Tool (LIFE–RIFT) (Leon 1999)).
6. Proportion of participants with serious adverse events.
7. Rates of discontinuation of preventive intervention due to adverse events.
8. Overall rate of discontinuation.
Timing of outcome assessment
Depending on available data, we planned to synthesise outcomes at different time points (e.g. short‐term, medium‐term and long‐term) throughout an entire six‐month period of risk during an autumn‐winter season.
Hierarchy of outcome measures
Our main focus was on patient‐centred outcomes, that is, outcomes that patients notice and care about. If several measures could be used to assess the same outcome, we consulted with clinical experts regarding the validity and reliability of individual outcome measures and prioritised accordingly.
Search methods for identification of studies
The Cochrane Depression, Anxiety and Neurosis Group (CCDAN) maintains two clinical trials registers at its editorial base in Bristol, UK: a references‐based register and a studies‐based register. The CCDANCTR‐References Register contains more than 39,000 reports of RCTs on depression, anxiety and neurosis. Approximately 60% of these references have been tagged to individual coded trials. The coded trials are held in the CCDANCTR‐Studies Register, and records are linked between the two registers through the use of unique study ID tags. Coding of trials is based on the EU‐Psi coding manual and uses a controlled vocabulary; the CCDAN Trials Search Co‐ordinator can provide further details. Reports of trials for inclusion in the Group registers are collated from routine (weekly) generic searches of MEDLINE (1950‐), EMBASE (1974‐) and PsycINFO (1967‐); quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL); and review‐specific searches of additional databases. Reports of trials were also sourced from international trials registers c/o the World Health Organization trials portal (the International Clinical Trials Registry Platform (ICTRP)), pharmaceutical companies and handsearching of key journals, conference proceedings and other (non‐Cochrane) systematic reviews and meta‐analyses.
Details of CCDAN's generic search strategies (used to identify RCTs) can be found on the Group's website.
Electronic searches
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The CCDAN Trials Search Co‐ordinator (TSC) ran an initial search of its Specialised Register (CCDANCTR‐Studies and CCDANCTR‐References Registers) (all years to 12 April 2013) using terms for condition only.
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("seasonal affective disorder*" or "seasonal depression" or "seasonal mood disorder*" or "winter depression" or SIGH‐SAD*).
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Updated searches were performed to 11 August 2015.
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On both occasions, we screened the search results for records of trials involving melatonin and agomelatine.
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In addition, we searched the following electronic databases (to 26 May 2014) to ensure that no studies had been missed from the CCDANCTR (Appendix 1).
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International Pharmaceutical Abstracts.
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Cumulative Index to Nursing and Allied Health Literature (CINAHL).
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Web of Knowledge (includes Web of Science, Current Contents Connect, Conference Proceedings Citation Index, BIOSIS, Derwent Innovations Index, Data Citation Index, SciELO Citation Index).
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The Cochrane Library.
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Allied and Complementary Medicine Database (AMED).
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We searched international trials registries via the World Health Organization trials portal (ICTRP) and ClinicalTrials.gov to identify unpublished and ongoing studies. The CCDAN TSC searched these registries again (to 11 August 2015).
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We applied no restrictions on date, language and publication status.
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Searching other resources
Grey literature
To detect ongoing or unpublished studies, we checked the following sources.
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International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) Clinical Trials Portal.
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OpenGrey.
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GreyMatters.
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National Institute of Health RePORTER.
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Health Services Research Projects in Progress (HSRPROJ).
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Hayes Inc. Health Technology Assessment.
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The New York Academy of Medicine's Grey Literature Index.
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Conference Papers Index.
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National Registry of Evidence‐Based Programs and Practices (NREPP).
Reference lists
We intended to handsearch the references of all included studies and pertinent review articles.
Correspondence
We contacted trialists and subject experts for information on unpublished and ongoing studies, or to request additional trial data.
Data collection and analysis
Selection of studies
Two review authors independently screened the titles and abstracts of all studies identified by the searches. We retrieved full‐text copies of all studies that potentially met the inclusion criteria based on this initial assessment, and two review authors screened them independently to determine their eligibility.
If the two review authors did not reach consensus, they discussed disagreements with a third party, who resolved them. We contacted trial authors if relevant information was missing. We tracked all results in an EndNote X5 database.
We recorded the selection process in sufficient detail to complete a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) flow diagram and the Characteristics of excluded studies table.
Data extraction and management
We intended to use a data collection form, which was piloted on at least two studies in the review, to extract study characteristics and outcome data. Two review authors (AK, BN) planned to independently extract study characteristics and outcome data from included studies. We planned to resolve discrepancies by reaching consensus or by involving a third review author. We planned to report whether studies were detected by searches of databases of published studies, by handsearches or by grey literature searches.
We planned to extract the following study characteristics.
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Methods: study design, duration of study, details of any 'run‐in' period, duration of treatment period, number of study centres and locations, study setting, withdrawals and dates of study.
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Participants: number of participants, mean age, age range, proportion of women, number of prior depressive episodes, diagnostic criteria, inclusion criteria and exclusion criteria.
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Interventions: intervention, comparison, concomitant interventions and excluded interventions.
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Outcomes: primary and secondary outcomes specified and collected and time points reported.
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Notes: funding for studies and notable conflicts of interest of study authors.
We planned to note in the Characteristics of included studies table if outcome data were not reported in a useable way. We planned to resolve disagreements by reaching consensus or by involving a third person (BG). It was planned that one review author (AK) would transfer data into the Review Manager file (RevMan 2012). We intended to double‐check that data were entered correctly by comparing data presented in the systematic review versus data provided in the study reports. We planned that a second review author (BN) would spot‐check study characteristics for accuracy against the trial report.
Main planned comparisons
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Melatonin versus placebo.
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Agomelatine versus placebo.
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Melatonin versus agomelatine.
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Melatonin versus second‐generation antidepressants.
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Agomelatine versus second‐generation antidepressants.
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Melatonin versus light therapy.
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Agomelatine versus light therapy.
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Melatonin versus psychological therapy.
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Agomelatine versus psychological therapy.
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Melatonin versus lifestyle intervention.
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Agomelatine versus lifestyle intervention.
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Agomelatine/melatonin + comparator intervention (as listed in Types of interventions) versus placebo.
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Agomelatine/melatonin + comparator intervention (as listed in Types of interventions) versus the same comparator intervention as monotherapy (e.g. agomelatine + light therapy versus light therapy alone).
Assessment of risk of bias in included studies
We planned that two review authors (AK, BN) would independently assess the risk of bias of included randomised trials using the Cochrane 'Risk of bias' tool, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This tool allows assessment of random sequence generation; allocation concealment; blinding of participants, personnel and outcome assessors; incomplete outcome data; selective reporting; and other potential threats to validity. Specifically, we planned to assess attrition in these trials and reasons for attrition, particularly when attrition rates between two groups in a trial differ substantially. In addition, we planned to assess whether all relevant outcomes for the trial were reported in the published articles. We intended to assess each domain as having high risk of bias, low risk of bias or unclear risk of bias.
For non‐randomised studies, we planned to use the Newcastle‐Ottawa Scale, which involves selection of cases or cohorts and controls, adjustment for confounders, methods of outcomes assessment, length of follow‐up and statistical analysis (Wells 2009).
Measures of treatment effect
We planned to use data extracted from the original studies to construct 2 × 2 tables for dichotomous outcomes. When multiple studies allowed for quantitative analysis, we planned to calculate the risk ratio with 95% confidence intervals for each outcome. We chose risk ratio as an effect measure because for decision makers, risk ratios are easier to interpret than odds ratios, particularly when event rates are high.
We planned to pool continuous data using the mean difference (MD) when an outcome was measured on the same scale, or the standardised mean difference (SMD) when an outcome was measured on different scales. When available, we planned to use final measurements rather than changes from baseline to estimate differences between treatments. When it was considered necessary to use both change and post‐intervention scores in a comparison, we planned to present these by subgroup using the MD rather than the SMD.
When time‐to‐event data were available, we intended to calculate a pooled hazard ratio, or to dichotomise data at multiple time points into response/no response (e.g. at one week, two weeks, four weeks, etc.).
The same time points as specified under 'Timing of outcomes assessment' were intended to form the basis for dichotomisation into response/no response.
For non‐randomised studies, we planned to use adjusted treatment effects when available.
Unit of analysis issues
Cluster‐randomised trials
To incorporate cluster‐randomised trials, we planned to reduce the size of each trial to its 'effective sample size'. If intracluster correlation co‐efficients were not reported, we intended to try to find external estimates from similar studies. We planned to undertake sensitivity analyses to assess the impact of including such trials.
Cross‐over trials
To avoid carry‐over effects, we planned to include data only from the first period of cross‐over studies.
Studies with multiple treatment groups
For included trials that had multiple treatment groups (e.g. differing doses of one drug vs placebo), we planned to include data for the treatment arms and to halve data from the placebo arm, or to collapse data for different doses into one group when this was clinically appropriate (Hansen 2009).
Dealing with missing data
We intended to use intention‐to‐treat analysis when data were missing for participants who dropped out of trials before completion. When data regarding an outcome of interest were not reported, we planned to contact the authors of publications to obtain missing results. We planned to document all correspondence with trialists and to report responses in the full review.
Assessment of heterogeneity
We planned to use the Cochran Chi2 test (Q‐test) to assess heterogeneity. A P value less than 0.10 is considered statistically significant. We planned to use the I2 statistic to estimate the degree of heterogeneity. This measure describes the percentage of total variation across studies that results from heterogeneity rather than from chance. We planned to interpret the importance of heterogeneity in terms of its magnitude and the direction of effects. We planned to not consider thresholds; instead, we planned to adopt the overlapping bands, as suggested in the Cochrane Handbook for Systematic Reviews of Interventions. For example, we consider an I2 value between 0% and 40% as probably not important, between 30% and 60% as representing moderate heterogeneity, between 50% and 90% as representing substantial heterogeneity and between 75% and 100% as representing considerable heterogeneity (Higgins 2011).
Assessment of reporting biases
If we found more than 10 studies, we planned to perform a funnel plot analysis. A funnel plot is a graph used to detect publication bias. We planned to look at whether the largest studies were near the average and small studies spread on both sides of the average. Variations from this assumption can indicate the existence of publication bias, but asymmetry may not necessarily be caused by publication bias. In addition, we planned to use Kendell's tau (Begg 1994), Egger's regression intercept (Egger 1997) and Fail‐Safe N (Rosenthal 1979) to assess reporting biases.
Data synthesis
We planned to analyse data using Review Manager software (RevMan 2012). We planned to pool data for meta‐analysis when participant groups were similar; when studies assessed the same treatments versus the same comparator; and when investigators used similar definitions of outcome measures over a similar duration of treatment. In general, we intended to use random‐effects models to combine results because we did not expect the true effect to be the same for all included studies. We planned to employ fixed‐effect models to determine differences in treatment effects between random‐effects and fixed‐effect results. We intended to weigh studies using the Mantel‐Haenszel method and to rate the strength of evidence using the system developed by the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) Working Group. We planned to perform qualitative analyses of data on adverse effects by comparing crude rates, and to conduct quantitative analyses of the rate of adverse effects only if we located a sufficient number of prospective observational studies or randomised trials that provide data on adverse effects that are suitable for pooling.
Subgroup analysis and investigation of heterogeneity
Sex, age, history of non‐seasonal major depressive episodes and psychiatric co‐morbidities are potential effect measure modifiers for prevention of SAD. When data were sufficient, we planned to conduct subgroup analyses for primary outcome measures. Subgroup analyses should be performed and interpreted with caution because multiple analyses could lead to false‐positive conclusions. We intended to conduct subgroup analyses based on:
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men versus women;
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history of non‐seasonal major depressive episodes versus no history of non‐seasonal major depressive episodes;
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age younger than 65 years versus 65 years and older; and
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Axis I, Axis II co‐morbidities versus no Axis I, Axis II co‐morbidities.
Sensitivity analysis
The purpose of sensitivity analyses is to test the robustness of decisions made during the review process.
We planned to conduct sensitivity analyses:
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excluding small studies (i.e. studies with fewer than 30 participants);
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excluding studies with high risk of bias (i.e. studies that have been rated as having high risk of bias in one or more domains);
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excluding studies published only in abstract form;
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with adjusted versus unadjusted results; and
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excluding cluster‐randomised trials.
'Summary of findings' tables
We planned to assess the quality of evidence by using the GRADE approach and to present the results for our main comparisons and outcomes in 'Summary of findings' tables (as listed in Types of outcome measures). We did not expect to be able to stratify populations into low‐, medium‐ and high‐risk groups. For 'assumed risk', we planned to use prevalence studies from countries in northern latitudes (e.g. Scandinavia, Canada, northern United States) in which SAD leads to substantial burden of disease.
We planned to use GRADEpro to rate the quality of evidence and to prepare the 'Summary of findings' tables (GRADEpro 2008).
Results
Description of studies
We identified 2986 citations through electronic searches and reviews of reference lists after de‐duplication of search results. We excluded 2895 records during title and abstract review, and we included 91 articles for full‐text review and assessment for eligibility. We included zero studies in this review. The PRISMA flow chart (Figure 1) documents the disposition of the literature in this review.
Study flow diagram.
Results of the search
We found no completed studies that met our eligibility criteria. We also found no ongoing studies and no studies awaiting classification. This clearly indicates that more research is needed on melatonin and agomelatine as preventive measures against seasonal affective disorder.
Included studies
We found no controlled studies assessing the effectiveness of melatonin or agomelatine in preventing SAD.
Excluded studies
Overall, we assessed 91 references as full‐text articles and excluded all of them. The Characteristics of excluded studies section shows all records that narrowly missed the inclusion criteria for this systematic review. We excluded studies because included participants did not suffer from SAD (but rather from major depressive disorder or subsyndromal SAD), or because they already had depressive symptoms when the study started. We mentioned studies that were included in the review on light therapy (Nussbaumer 2014) and SGA (Gartlehner 2014) under Characteristics of excluded studies, and we explained why they are not included in this review.
Risk of bias in included studies
We included no studies.
Allocation
We included no studies.
Blinding
We included no studies.
Incomplete outcome data
We included no studies.
Selective reporting
We included no studies.
Other potential sources of bias
We included no studies.
Effects of interventions
We included no studies.
Discussion
Summary of main results
Overall, we identified no controlled studies that provided evidence for or against the effectiveness of melatonin or agomelatine in preventing SAD.
Overall completeness and applicability of evidence
Despite extensive searches of the grey literature, we found no eligible studies.
We contacted the pharmaceutical company Les Laboratoires Servier to include unpublished data on the efficacy and safety of agomelatine but received no information on unpublished trials.
Quality of the evidence
We included no studies.
Potential biases in the review process
Publication bias is a threat for any systematic review. Although we conducted extensive searches of grey literature, we cannot be sure that we have detected each study conducted in this field.
Agreements and disagreements with other studies or reviews
We found no other studies that addressed the research question.
