Current Understanding of the Pathogenesis and Treatment of Generalized Anxiety Disorder

Background. Given the high prevalence of generalised anxiety disorder (GAD), as well as the lack of efficacy and high incidence of adverse events with relatively low adherence to therapy with drugs recommended for the treatment of GAD and affecting serotoninergic and noradrenergic neurotransmission, it is reasonable to assume the involvement of other pathophysiological factors in the genesis of GAD, while their study remains insufficient. This article presents current data on the factors of GAD pathogenesis, that may explain the mechanism of action of agomelatine. Methods. Search and analysis of publications from PubMed and eLIBRARY databases for 2019-2025 years by keywords: generalized anxiety disorder, pathogenesis, pharmacogenetics, gene polymorphism, therapy, agomelatine. Results. In order to identify neurobiological risk markers for the development of GAD, as well as to predict the efficacy and safety of therapy for the application of preventive and individualized therapeutic approaches, genetic studies are investigating both patterns of genomic associations in GAD and individual genes responsible for the severity and duration of anxiety. The results of neuroimaging studies in GAD remain controversial. The data obtained may mean both the absence of significant morphological changes in the brain in patients with GAD and the insufficiency of methods that examine simple linear associations and the need for a more comprehensive analysis of the results. In immunological studies of GAD, it is hypothesized that pro-inflammatory cytokines can be used as biomarkers to both diagnose GAD and predict response to psychopharmacotherapy. The anxiolytic efficacy of agomelatine may be attributed to its anti-inflammatory, immunomodulatory and anti-cytokine properties. The results of randomized clinical trials and meta-analyses suggest that agomelatine effectively manages anxiety in GAD: it is superior to placebo in remission rate and comparable to placebo in tolerability. In addition, it has high remission rate and low rate of therapy discontinuation. Conclusion. Agomelatine can be considered as a first-line treatment for GAD. © 2025 Elsevier B.V., All rights reserved.