Lateral Habenular Burst Firing as a Target of the Rapid Antidepressant Effects of Ketamine

The revolutionary discovery of the rapid antidepressant ketamine has been a milestone in psychiatry field in the last half century. Unlike conventional antidepressants that often take weeks to months to show efficacy, ketamine causes rapid antidepressant effects, emerging as early as within 1 h after administration. However, how ketamine improves mood symptoms so quickly has remained elusive. Here, we first introduce the historical background of ketamine as a rapid antidepressant. We then discuss current hypotheses underlying ketamine's rapid antidepressant effects, with a focus on our latest discovery that ketamine silences NMDAR-dependent burst firing in the 'anti-reward center', the lateral habenula. While ketamine may act on many brain regions, we argue that its rapid antidepressant effects are critically dependent on ketamine's action in the lateral habenula, with this brain region acting as a primary site of action (or one among a few primary nodes). This molecular-, cellular-, and circuit-based mechanism advances our understanding of the etiology of depression and suggests a new conceptual framework for the rapid antidepressant effects of ketamine.