Extending ketamine’s antidepressant effects

Depression is a leading cause of disability worldwide, which underscores the urgent need for effective, accessible treatments. Over the past decade, ketamine—an anesthetic and recreational drug—has gained substantial attention for its rapid and sustained antidepressant effects in patients with severe depression. Its off-label use is especially common in the US (1). Despite a short half-life, a single subanesthetic dose of ketamine has antidepressant effects lasting 1 to 2 weeks. Clinically, repeated ketamine infusions are needed to maintain these antidepressant benefits, but this increases the risk of side effects, such as psychotomimetic and dissociative reactions, as well as its potential for abuse (2). On page 646 of this issue, Ma et al. (3) report a strategy that extends ketamine’s effects by enhancing a specific signaling pathway in hippocampal neurons of the mouse brain. This approach prolonged ketamine’s antidepressant-like effects for up to 2 months.