Major depressive disorder (MDD) in young people is a common psychiatric disorder, but treatment options are limited. Agomelatine has demonstrated short-term efficacy and safety in pediatric patients. We report here the results of a 92-week open-label extension (OLE). The international, multicenter, double-blind, study randomized 400 patients (80 children, 320 adolescents) with moderate-to-severe MDD to one of four treatment groups: agomelatine 10mg (n = 102), agomelatine 25mg (n = 95), placebo (n = 103), and fluoxetine 10-20mg (n = 100). After 12weeks, patients who could benefit from treatment continuation were offered entry into an optional OLE during which they received agomelatine 10 or 25mg for a further 92weeks. A total of 339 patients (271 adolescents) entered the OLE. Treatment groups considered for the OLE analysis reflected those received in the double-blind and OLE periods: agomelatine (10 or 25mg) in both (ago/ago, n = 170); placebo then agomelatine 10-25mg (pcb/ago, n = 85); or fluoxetine then agomelatine 10-25mg (fluox/ago, n = 84). Mean age (± SD) at entry into the double-blind phase (Week 0) was 13.6 ± 2.7years and 61.9% were female. Mean changes in Children's Depression Rating Scale revised (CDRS-R) raw total score from Week 12 to last post-Week 12 value in the three groups were - 16.3 ± 12.2 (ago/ago), - 18.9 ± 16.1 (pcb/ago), and - 16.1 ± 15.5 (fluox/ago), reflecting the difference in efficacy between treatments during the double-blind period, and heterogeneity at W12 between the treatment groups. Adverse events considered related to treatment occurred in 14.5% of patients: 15.3% ago/ago, 16.5% pcb/ago, and 10.7% fluox/ago. Three patients (all adolescents) experienced treatment-related severe adverse events: two treated with ago/ago and one treated with pcb/ago. Among the adolescents, one treatment-related severe adverse event in a patient in the pcb/ago group led to study withdrawal. Agomelatine was associated with continuous improvement in depressive symptoms without unexpected safety signals. These findings support the safe use of agomelatine in a pediatric population with moderate-to-severe MDD for up to 104weeks.Trial registration No: EUDRACT No. 2015-002181-23.