Innovative Approaches to Depression Therapy: The Antidepressant Efficacy and Mechanisms of General Anesthetics.

Depression represents a critical global health burden, ranking as the second leading cause of disability worldwide. Although drug therapies remain an important cornerstone in treating depression, we must acknowledge their significant shortcomings: they often take too long to work, cause difficult side effects, and fail to prevent relapse. Critically, while current drugs target specific symptoms, the disorder itself stems from a far more complex interplay of genetic, environmental, and biological factors. Notably, emerging evidence indicates that several general anesthetics exhibit both rapid and sustained antidepressant effects. Ketamine, through blocking N-methyl-D-aspartate (NMDA) receptors, has established a new paradigm for rapid-acting antidepressant intervention. Building on this breakthrough, researchers are now finding that other agents, including propofol, isoflurane, and specific opioids, show promising results across preclinical and clinical settings. This expanding evidence base significantly advances the therapeutic scope of anesthesiology while addressing treatment-resistant depression (TRD) affecting approximately one-third of patients. This review examines intravenous/inhalational anesthetics and opioid analgesics for depression management, synthesizing contemporary preclinical and clinical evidence with particular focus on randomized controlled trials and mechanistic studies. Our review highlights the specific biological changes that drive these effects. Beyond monoamine regulation, key factors include modulation of glutamate and GABA signals, which contribute to the restoration of synaptic plasticity in damaged brain circuits. Through combining what is known with what remains unclear, specifically focusing on dosing and long-term outcomes. We argue that targeting these mechanisms is key to creating new rapid antidepressants for patients who do not respond to standard care. Yet, success depends on balancing benefits against risks and establishing consistent treatment rules.