Ketamine and esketamine are effective, safe, and acceptable treatments for depression. A meta-analysis of 36 randomized controlled trials (2,903 participants, 57% female, average age 45 years) found that treatment with either form of ketamine improved response (2.14 times more likely), remission (1.64 times more likely), and depression severity compared to placebo. There was no difference in treatment retention, dropouts due to adverse events, or overall number of adverse events between ketamine and placebo.
Ketamine, originally developed as a dissociative anesthetic and a tool for modeling psychosis, has been repositioned as a rapidly acting antidepressant for treatment-resistant depression. This narrative review traces its trajectory over six decades, drawing on historical sources, clinical trials, and regulatory documents. By the early 2000s, trials showed rapid and robust antidepressant effects, challenging older monoamine-based theories and spurring new models involving glutamate and neuroplasticity. Its dissociative effects, once seen as drawbacks, are now debated but evidence suggests they are not necessary for efficacy.