Prucalopride repurposing: 5-HT₄ receptor agonists in anxiety and depression

Major depressive disorder remains a leading cause of disability worldwide, and current antidepressant treatments are limited by a delayed onset of action, modest remission rates, and residual symptoms. Emerging evidence suggests that selective targeting of specific serotonergic receptors may offer faster and more precise therapeutic strategies. Among these targets, the serotonin type 4 (5-HT₄) receptor has gained increasing attention due to its involvement in corticolimbic circuits regulating mood, cognition, and stress responses. Preclinical studies demonstrate that 5-HT₄ receptor agonists produce rapid antidepressant- and anxiolytic-like effects, accompanied by early neuroplastic adaptations. Prucalopride, a highly selective 5-HT₄ receptor agonist approved for chronic idiopathic constipation, has recently emerged as a promising candidate for drug repurposing in psychiatry. Converging evidence from animal models, experimental human studies, and epidemiological analyses suggest that prucalopride may modulate mood-related neural circuits and cognitive processes. This perspective discusses the translational potential of 5-HT₄ receptor agonism as a novel therapeutic avenue for mood disorders.