Ketamine's

Clayton had tried psychotherapy and an arsenal of traditional oral antidepressants over the years, but her severe depressive symptoms and suicidal ideations ...

And yet, she says, “it was almost impossible for me to be able to access this treatment, and I almost died in the process.” Before making the switch to industry, Manji served as the director of the mood and anxiety disorders program at the National Institutes of Health, and was a co-author on the first study to replicate Krystal’s findings in 2006. As more of these clinics begin to treat depression, Clayton worries that patients could be put at risk if the presence of a trained psychiatrist is not required. Many questions still remain, though, such as which receptors ketamine binds to in the brain. And in 2019 the FDA approved a ketamine-based antidepressant (tradename Spravato) for the first and, so far, only time to treat treatment-resistant depression, and later approved it to treat suicidal ideation and behavior in adults with major depression. Researchers have a good sense of where ketamine first binds in the higher brain centers to affect cognitive and emotional functioning. The success of Spravato has spurred other pharmaceutical companies to return to antidepressant development and the neuroscience field more broadly after a decades-long hiatus, says Carlos Zarate Jr., chief of experimental therapeutics and pathophysiology at the National Institute of Mental Health and Manji’s former NIH colleague. In many cases, a drug that’s widely prescribed for an off-label indication may never be FDA approved for that same treatment, especially if—like racemic ketamine—the drug is generic. In 1970, the FDA approved ketamine as a general anesthetic, and today it resides on the World Health Organization’s Model List of Essential Medicines. But research on ketamine’s antidepressant effects has only taken off in the last couple decades. In 2000, a team at Yale School of Medicine published the first randomized controlled trial to demonstrate ketamine’s antidepressant effects. At the time, in 2016, Clayton was participating in a Phase II clinical trial to determine the most effective dose of intravenous ketamine for alleviating depression. Trials such as these help determine a drug’s efficacy and dosing, before researchers can move on to the final testing phase and prepare an application for FDA consideration.