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, China.
3 papers in the library · 302 citations · publishing 2020-2024
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, a rapid antidepressant, works by blocking N-methyl-d-aspartate receptors (NMDARs) specifically in the lateral habenula (LHb) of the brain, not in the hippocampus. In depressive-like mice, this regional selectivity depends on local neural activity and the availability of extrasynaptic NMDARs. Activating the hippocampus or inactivating the LHb reversed this sensitivity. Removing NMDARs from the LHb prevented ketamine's antidepressant effects and blocked the drug-induced rise in serotonin and brain-derived neurotrophic factor in the hippocampus. Identifying this primary brain target should help design more precise antidepressant treatments.
Adding ketamine to propofol-electroconvulsive therapy (ECT) improves outcomes for patients with depression resistant to ECT alone. In 28 patients, six alternating sessions of ketamine and propofol-ECT over two weeks increased global functional connectivity density in the left temporal and subgenual anterior cingulate cortex and decreased functional connectivity strength within the default mode network. Although the functional brain changes lasted 10 days, the clinical benefit—measured by the Hamilton Depression Scale—lasted only 7 days, indicating a disconnect between brain alterations and symptom relief. The combination offers a short-term improvement, but its effect is limited to one week.