Incretin receptor agonists (IRAs), including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual/triple receptor co-agonists, have transformed the treatment of obesity, type 2 diabetes mellitus, and cardiovascular disease. Given the extraordinary burden of cardiometabolic comorbidity and excess premature mortality in persons living with psychiatric disorders, IRAs represent a highly relevant and potentially transformative pharmacologic class for this population. Beyond their established metabolic indications, a triangulation of preclinical, neuroimaging, observational, and emerging controlled trial evidence suggests that IRAs may exert direct central nervous system effects-augmenting neurogenesis, neuroplasticity, and functional brain connectivity-that underpin putative psychiatric benefits. Replicated evidence supports effects on alcohol and substance use disorders, and preliminary data indicate benefits in mood and neurocognitive disorders. However, controlled trial evidence remains limited and mixed, and several clinical considerations specific to psychiatric populations-including suicidality surveillance, sarcopenia, constipation risk, drug-drug interactions, and aspiration risk with ketamine-require careful attention. Whether IRAs ultimately meet the evidentiary threshold to be classified as psychiatric drugs remains to be determined by ongoing phase III trials. In the interim, their use for cardiometabolic indications in psychiatric populations is well-justified and may confer meaningful mortality reduction.
