How does ketamine elicit a rapid antidepressant response?

• Ketamine triggers a rapid antidepressant response in patients with major depression.
• Ketamine elicits rapid translation of brain-derived neurotrophic factor (BDNF).
• Rapid BDNF translation requires deactivation of eukaryotic elongation factor2 kinase.
• Ketamine, but not memantine, blocks resting NMDAR-mediated neurotransmission in Mg2+.
• Block of resting NMDAR-mediated synaptic responses is essential for ketamine action.

A single sub-psychotomimetic dose of ketamine, an ionotropic glutamatergic n-methyl-d-aspartate (NMDA) receptor antagonist, produces a fast-acting antidepressant response in patients suffering from major depressive disorder. Depressed patients report alleviation of core symptoms within 2 h of a single low-dose intravenous infusion of ketamine with effects lasting up to 2 weeks. The rapidity of ketamine action implies that major symptoms of depression can be alleviated without substantial structural plasticity or circuit rewiring. Therefore, the ability of ketamine to exert a rapid effect provides a unique opportunity to elucidate the types of acute synaptic plasticity changes that can be recruited to counter depression symptoms.