Celso Arango, Jan K Buitelaar, Jörg M Fegert, Valérie Olivier, Pierre-François Pénélaud, Ute Marx, Damien Chimits, Bruno Falissard, Julia Barylnik, Laura Birdeanu, Gert P Bosch, Julia Boychevskaya, Igor Boyev, Enikõ Bugán, Olga Bukhanovskaya, Oleg Chaban, Iuliana Dobrescu, Gábor Feller, Halina Flisiak-Antonijczuk, Magdolna Gácser, Elena Grigorieva, Timo Holttinen, Svetlana Ivanovic-Kovacevic, Krisztina Kapornai, Lala Kasimova, Evgeniy Koren, Igor Martsenkovsky, Nataliya O Maruta, Mirela Matican, Tetiana Matkovska, Ellina Melnyk, Milica Pejovic Milovancevic, Olha Mostova, Peter Nagy, Laura Nussbaum, Petar Petrov, Bozena Pietraszczyk-Kedziora, Nadia Polnareva, Elena Predescu, Vladislava Razsolkova, Filip Rybakowski, Sofiia Rymsha, Juan P Schrönen, Dmitrii Shigashov, Andrii Skrypnikov, Miodrag Stankovic, Dejan Stevanovic, Markku Timonen, Juha-Matti Väänänen, Jannie van der Westhuizen, Gert van Niekerk, Olena Venger, Anatolii Voloshchuk, and Tomasz Wolañczyk
Major depressive disorder is a severe illness that frequently manifests before the age of 18 years, often recurring later in life. Paediatric medical treatment options are scarce. The melatonin receptor agonist and 5-hydroxytryptamineWe performed a 12 week, randomised, double-blind, parallel-group, multicentre, phase 3 trial in 46 specialist psychiatric units or centres in Bulgaria, Finland, Hungary, Poland, Romania, Russia, Serbia, South Africa, and Ukraine. Participants (aged 7-17 years) were eligible if they were unresponsive to psychosocial therapy during the 3-week run-in period (Children's Depression Rating Scale-revised [CDRS-R] score of ≥45). Ethnicity was not recorded. We investigated short-term antidepressant efficacy of agomelatine (10 mg or 25 mg per day) versus placebo with an active control (fluoxetine 10-20 mg depending on symptom severity) after 12 weeks of treatment in children (aged 7-11 years) and adolescents (12-17 years) with major depressive disorder. Patients were randomly assigned (1:1:1:1) to agomelatine 10 mg, agomelatine 25 mg, placebo, or fluoxetine via an interactive response system with permuted-block randomisation. Standardised manualised psychosocial counselling, developed for this trial, was initiated from selection and continued throughout the study, including the open-label extension. All people involved in the conduct of the clinical trial and patients were masked to treatment allocation. Study outcomes were measured using standardised interviews at each study visit. The primary endpoint was change in CDRS-R raw score from baseline to week 12. This study is registered with EudraCT, 2015-002181-23.Between Feb 23, 2016, and Jan 14, 2020, 466 individuals were assessed for eligibility and of 400 included patients, 396 (247 [62%] girls, 149 [38%] boys; mean age 13·7 years [SD 2·7]) were analysed (full analysis set). The primary objective was met; 25 mg/day agomelatine (n=94, with n=102 receiving 10 mg/day) resulted in an improvement versus placebo (n=101) in CDRS-R raw score of 4·22 (95% CI 0·63-7·82; p=0·040) at 12 weeks, with a similar effect for fluoxetine (n=99), establishing assay sensitivity. The overall effect was confirmed in adolescents (n=317), but not in children (n=79). No unexpected safety signals were observed with agomelatine, with no significant weight gain or effect on suicidal behaviours.This first study in a paediatric population supports the efficacy of 25 mg/day agomelatine, in addition to psychosocial counselling, in treating adolescent patients with major depressive disorder, with no unexpected safety signals. This medication could provide another option in the limited psychopharmaceutical repertoire for management of major depressive disorder.Servier. VIDEO ABSTRACT.