A single low dose of ketamine produces rapid and lasting antidepressant effects by blocking NMDA receptors containing the GluN2B subunit on specific GABA-releasing interneurons in the medial prefrontal cortex. Removing GluN2B from somatostatin-expressing interneurons prevented or masked ketamine's antidepressant actions and revealed sex-specific differences in excitatory signals onto principal neurons. The findings indicate that GluN2B-NMDA receptors on GABA interneurons are the initial cellular trigger for ketamine's rapid antidepressant effects.
Ketamine represents a new type of antidepressant that works quickly, helps people whose depression has not responded to other treatments, and reduces the chance of relapse. Its development came from a new understanding of depression's biology, and studying how ketamine works has deepened knowledge of depression and related conditions. Twenty-five years after the first findings on ketamine for depression were presented, this review examines what has been learned and suggests future ways to improve rapid-acting antidepressant therapy.