Department of Affiliated Mental Health Center & Hangzhou Seventh People's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine , Hangzhou 310058, People's Republic of China.
2 papers in the library · 202 citations · publishing 2023-2024
Ketamine's antidepressant effects last much longer than its short half-life because the drug becomes trapped in NMDA receptors in the lateral habenula, and its release depends on neural activity. In mice, a single injection suppressed burst firing and blocked NMDA receptors in the lateral habenula for up to 24 hours. This sustained action results from use-dependent trapping, not endocytosis. By activating the lateral habenula and opening local NMDA receptors at different plasma ketamine concentrations, the duration of antidepressant effects could be shortened or prolonged. These findings explain the mechanism behind ketamine's sustained effects and suggest ways to modulate its therapeutic duration.
Ketamine, an NMDAR antagonist, has superior antidepressant efficacy compared to traditional monoamine-targeting drugs, acting faster and more potently. While substantial evidence supports an NMDAR-antagonism-based hypothesis for its mechanisms, controversial results from other NMDAR inhibitors have led to alternative arguments. This article reviews the historical development of the NMDAR-centered hypothesis, classifies NMDAR inhibitors by their mechanisms, and evaluates preclinical and clinical evidence of their antidepressant effects. It critically analyzes debates over ketamine's NMDAR-dependent and independent actions, aiming to clarify molecular targets to guide future depression treatments.