Kasper 2008.

Methods	Study design: Multicentre, blinded, randomised controlled trial Duration of study: September 2002 ‐ June 2005 "Run‐in" period: This study was preceeded by an open‐label study period (25 mg agomelatine) of at least 18 weeks. Duration of treatment period: 1 year treatment period beginning in May Number of study centres and locations: 25 centres located in 8 countries: Austria, Canada, Finland, Germany, the Netherlands, Norway, Russia, Sweden Study setting: Ambulatory or hospitalized Withdrawals: 48% (108 of 225)
Participants	Number of participants: 225 (agomelatine: 112, placebo: 113) adults with a history of SAD who participated in a preceding open‐label study where their acute depressive episode was treated with agomelatine (25 mg/day) for at least 18 weeks. Those with stable remission for at least two months were included to the prevention study. Mean age: agomelatine group: 41.1 years (SD ± 11.2), placebo group 40.4 years (SD ± 10.9) Proportion of women: 75% in the agomelatine group and 70% in the placebo group Diagnostic criteria: DSM‐IV‐TR criteria for Major Depressive Disorder of fall‐winter pattern recurrent, moderate or severe without psychotic features, with or without melancholic features, without catatonic features and without postpartum onset. Total 29‐item score of 22 or higher on the SIGH‐SAD. Global Seasonality Score 11 or higher on the Seasonal Pattern Assessment Questionnaire and a seasonal problem score of "moderate" or greater at question 18. Seasonality Score. Requiring anti‐depressant treatment. Inclusion criteria: Confirmation of recurrent Major Depressive Disorder of fall‐winter pattern. Total 29‐item score of 22 or higher on the SIGH‐SAD. Results of laboratory tests available. Exclusion criteria: ‐ Suicide risk or previous attempts ‐ All types of depression other than Major Depressive Disorder with seasonal pattern (e.g., bipolar disorder) ‐ Depression onset within 3 months after a stroke ‐ Resistant depression ‐ Current panic disorder or obsessive compulsive disorder ‐ Acute stress or post traumatic stress disorder, acute chronic schizophrenia ‐ Alcohol or drug abuse or dependence within the past 12 months ‐ Patients treated with electro convulsive therapy within last 3 month before study ‐ Formal psychotherapy started within last 3 month before study ‐ Light therapy within 4 weeks before study ‐ Sleep deprivation therapy within one week before study ‐ SAD due to seasonal psychosocial stressors ‐ Any clinical relevant abnormality detected by the laboratory tests that could interfere with the conduct of the study (e.g., laboratory parameters indicating hepatic or renal failure, positive pregnancy test).
Interventions	Active treatment: agomelatine tablet containing 25 mg agomelatine, oral intake daily in the evening Control: placebo tablet, oral intake daily in the evening (taste and appearance identical to active treatment) Concomitant treatment: No other psychotropic treatment other than the study treatment was allowed
Outcomes	Measured outcomes that were relevant for this Cochrane review: Development of depression (SIGH‐SAD ≥ 16) Number of participants experiencing adverse events Severity of depression (SIGH‐SAD score) Number of participants experiencing severe adverse events Discontinuation rate due to adverse events Overall discontinuation rate
Notes	The study was funded by the pharmaceutical industry and identified through searches of the European Medicines Agency (EMA) database ‐ not published in a scientific journal.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central randomisation list, permuted blocks of 4 sent to the centres
Allocation concealment (selection bias)	Low risk	Sealed envelopes including the treatment allocation were used in the clinics and only the sponsors had the list of the treatment allocation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants were not aware whether they received placebo or active treatment. Tablets were identical in taste and appearance and prepared centrally by the sponsor.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study personnel were not aware whether people were allocated to active or inactive treatment. The main outcome was verified by an expert panel.
Incomplete outcome data (attrition bias) All outcomes	High risk	The dropout rate was very high (45% in the agomelatine group and 52% in the placebo group). Although ITT was used to analyse safety outcomes, only a modified ITT was used to analyse efficacy endpoints.
Selective reporting (reporting bias)	Low risk	Detailed trial data received by European Medicines Agency (EMA)
Other bias	Unclear risk	All participants received agomelatine for at least 18 weeks open‐label before study entry. This might not represent a real‐world prevention scenario and it is unclear how this impacted the prevention study.

DSM‐IV‐TR: Diagnostic and Statistical Manual of Mental Disorders ‐ text revision at time of selection
 ITT: intention‐to‐treat
 mg: milligrams
 SAD: seasonal affective disorder
 SD: standard deviation
 SIGH: Structured Interview Guide for the Hamilton Depression Rating Scale