The NMDA receptor antagonist ketamine produces rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression, contrasting with the modest effects of classic monoaminergic antidepressants that take weeks. Open-label and case studies support these properties. Preclinical research has identified three targets—mTOR, eEF2, and GSK-3—as key to its mechanism. Current efforts focus on prolonging ketamine's effects, developing selective NMDA receptor antagonists without its adverse effects, and identifying biomarkers of its antidepressant action.
Depression has long been treated with drugs that target monoamine brain systems, but these take weeks to work. Low doses of ketamine can improve core depressive symptoms—including mood, anhedonia, and suicidal ideation—within hours after a single dose, with effects lasting up to a week. This discovery has shifted thinking about how depression might be treated more effectively. This review covers clinical data on ketamine and other rapid-acting antidepressants and what is known about their mechanisms. It also discusses brain circuits engaged by these drugs and future medication targets such as hydroxynorketamine, metabotropic glutamate receptor 2/3 antagonists, and modulators of NMDA, AMPA, and GABA receptors.