Glucagon-like Peptide-1 receptor agonists as emerging therapeutics in bipolar disorder: a narrative review of preclinical and clinical evidence

Abstract

Bipolar disorder (BD) is a chronic and disabling psychiatric illness characterized by complex pathophysiological mechanisms. Traditional treatments often fail to address these multidimensional processes, highlighting the need for novel therapeutic strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for metabolic disorders, have emerged as promising candidates for a range of neuropsychiatric conditions due to their broad neurobiological effects. This narrative review synthesizes preclinical, clinical, and real-world evidence evaluating the therapeutic potential of GLP-1RAs in BD. These agents modulate neurotransmission, reduce neuroinflammation and oxidative stress, enhance mitochondrial and neurotrophic function, and improve insulin sensitivity and hypothalamic-pituitary-adrenal (HPA) axis regulation. These mechanisms are implicated in the neurobiology of BD, and preliminary findings suggest benefits across core psychopathological domains and common comorbidities, including depression, anxiety, mania, cognitive dysfunction, weight gain, and substance use disorders. While human data—particularly in BD populations—remain limited, evidence points to potential adjunctive benefits, especially in individuals with metabolic or cognitive vulnerabilities. Given their pleiotropic actions and established safety profile, GLP-1RAs represent compelling candidates for drug repurposing in BD. Well-powered, controlled trials are needed to confirm efficacy and safety, identify optimal subgroups, and evaluate long-term outcomes.