Propofol for depression: mechanisms and therapeutic potential

Propofol, one of the most widely used intravenous anesthetics, is undergoing a transformative identity shift from a purely surgical agent to a potential therapeutic tool for neuropsychiatric disorders. This review synthesizes current evidence on the emerging field of propofol therapeutics, with a focus on its rapid antidepressant, anti-anhedonia, and anxiolytic effects. We first examine preliminary clinical evidence from open-label studies suggesting that propofol may produce dose-dependent mood-elevating effects in treatment-resistant depression; however, this evidence remains limited by small sample sizes and lack of large controlled trials. Next, we explore putative mechanisms, including GABA_A receptor modulation, dopamine transporter inhibition, BDNF/TrkB signaling, and network-level reorganization of the default mode network and sleep architecture. We then compare propofol with other anesthetic agents possessing antidepressant properties, particularly ketamine, highlighting their distinct receptor targets, efficacy profiles, and safety considerations. Finally, we discuss major challenges including optimal dosing strategies, tolerance with repeated administration, long-term safety concerns, and implementation barriers. Despite these challenges, propofol represents a promising candidate for anesthetic repurposing in psychiatry, offering a mechanistically distinct alternative to ketamine that targets both GABAergic and dopaminergic systems with a well-established clinical safety profile for surgical anesthesia.