Treatment of severely symptomatic patients with generalized anxiety disorder (GAD) raises particular concerns for clinicians. This 12-week double-blind study evaluated the efficacy of agomelatine (25-50 mg/day) in the treatment of patients with severe GAD, using escitalopram (10-20 mg) as active comparator. The primary outcome measure was the change from baseline of the total score on the Hamilton Anxiety scale (HAM-A) at week 12. Secondary outcome measures included rate of response to treatment (at least 50% score reduction from baseline) in the HAM-A psychic and somatic anxiety sub-scores, Clinical Global Impression severity and change scores, the Toronto Hospital Alertness Test, the Snaith-Hamilton Pleasure Scale, and the Leeds Sleep Evaluation Questionnaire Scores. Sixty one clinical centers (Australia, Canada, Czech Republic, Finland, Germany, Hungary, Poland, Russia, Slovakia) participated from April 2013 to February 2015. Patient characteristics and demographic data were comparable between treatment groups. Both treatments were associated with a clinically significant decrease in HAM-A total score at week 12; the non-inferiority of agomelatine versus escitalopram was not demonstrated (E(SE) = -0.91(0.69), 95%CI = [-2.26, 0.44], p = 0.195). At week 12, the response rate was 60.9% in the agomelatine group, and 64.8% in the escitalopram group. In both treatment arms, HAM-A psychic and somatic anxiety scores decreased, alertness and sleep parameters improved, and ability to experience pleasure increased. In these secondary outcome measures, there were no significant differences between the treatment groups. Agomelatine was well-tolerated, with a lower incidence of adverse events than escitalopram. Agomelatine and escitalopram are efficacious in treating GAD patients with severe symptoms.

Department for Therapy of Mental Disorders Moscow Research Institute of Psychiatry 3 Poteshnaya street 107076 Moscow Russia

Department of Psychiatry and Behavioural Neurosciences McMaster University 1057 Main St West Suite L02 Hamilton Ontario L8S 1B7 Canada

Department of Psychiatry and Psychotherapy Semmelweis University Balassa u 6 H 1083 Budapest Hungary

Department of Psychiatry and Psychotherapy University Hospital Carl Gustav Carus Fetscherstr 74 01307 Dresden Germany

Institut de Recherches Internationales Servier 50 rue Carnot 92284 Suresnes Cedex France

Institute of Psychiatry and Neurology 3rd Department of Psychiatry Sobieskiego 9 02 0957 Warszawa Poland

Mehilainen Clinic Runeberginkatu 47 A 00260 Helsinki Finland

National Institute of Mental Health Topolová 748 250 67 Klecany Czechia

Private Psychiatric Practice Vavrušová Consulting s r o Záporožská 12 851 01 Bratislava Slovakia

Toowong Specialist Clinic Level 2 54 Jephson Street Toowong QLD 4066 Australia

University of Cape Town Department of Psychiatry and MRC Unit on Risk and Resilience in Mental Disorders Groote Schuur Hospital Anzio Road Cape Town 7925 South Africa

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