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.
A four-week Qi-based mindfulness therapy (QMT) program significantly reduced symptoms of depression, anxiety, and insomnia in adults with mild-to-moderate depression. In a self-controlled trial with 18 participants aged 18–65, scores on the 17 Hamilton Depression Rating Scale, Hamilton Anxiety Scale, Zung Self-rating Depression Scale, Self-rating Anxiety Scale, and Insomnia Severity Index all decreased significantly after the intervention compared to before. The findings suggest QMT is an effective nonpharmacological treatment for these symptoms in this population.