The Revolutionary Discovery of Ketamine as an Antidepressant

The groundbreaking discovery of ketamine in the treatment of depression revolutionized mental health care, leading to the development of a rapid-acting antidepressant. Dennis S. Charney, MD, dean of the Icahn School of Medicine at Mount Sinai, along with his long-time collaborator John H. Krystal, MD, played a pivotal role in identifying ketamine as a potential treatment for severe depression.

"The initial discovery was at Yale, you know, where I was a faculty member, and so was John. We worked very closely together," Charney recalls. For years, research focused on the role of monoamines—serotonin and norepinephrine—in depression and how traditional antidepressants worked. However, these treatments were often slow to take effect and yielded incomplete results. "Antidepressant drugs took a while to work—weeks and months—and also the response was too frequently incomplete," Charney explains. Seeking alternative approaches, the pair turned their attention to the glutamate system, hypothesizing that it could play a crucial role in depression.

Ketamine, an anesthetic with known effects on the glutamate system, became their focus. In their first study, Charney and Krystal tested ketamine on 7 patients with severe depression. To their surprise, the patients showed significant improvement within hours. "Those patients got better right away, like within a few hours. It was remarkable," Charney recalls. The findings were published in 2000, but at the time, the scientific community largely dismissed the results, and little effort was made to replicate the study. "Frankly, the field did not believe it," he notes.

Undeterred, Charney continued his research. In 2000, he transitioned to the National Institute of Mental Health (NIMH), where he collaborated with researchers Carlos Zarate, MD, and Husseini Manji, MD, FRCPC. "I said to the group there... we should try to replicate the finding that we first observed at Yale," Charney recounts. Together, they conducted a larger study on treatment-resistant depression, confirming the initial findings. This time, the field took notice, and research groups worldwide began replicating the results. "Once we published that paper, the field started to pay attention, and literally, you know, many, many groups, maybe hundreds of groups, started to replicate the findings."

The growing body of evidence eventually led pharmaceutical company Janssen to conduct large-scale clinical trials. Their efforts culminated in FDA approval of intranasal esketamine (Spravato), offering new hope to patients with severe depression, including those experiencing suicidal thoughts. "So now it is on the market as Spravato. It is intranasal now, and it is helping many, many patients with serious forms of depression, including patients that might even feel suicidal."

Charney considers the ketamine journey one of his most rewarding achievements. While he wishes the research had progressed more quickly, he is ultimately satisfied with its impact. "Maybe we, you know, we could have got to it sooner. I am pretty satisfied with that approach—not a lot of regrets there," he says. He also acknowledges ketamine’s role as a precursor to ongoing studies on psychedelic treatments like psilocybin and MDMA, which may further transform mental health care in the future. "Ketamine is different from the psychedelic drugs that are being studied now... but it is, in a way, a forerunner to those studies, and hopefully well-designed studies will ultimately show that those drugs would be beneficial in some way to patients with serious forms of depression and post-traumatic stress disorder."

This is part 4 of a multipart video series. You can watch part 1 here, part 2 here, and part 3 here.

Dr Charney is the dean of the Icahn School of Medicine at Mount Sinai. He is the author of Neurobiology of Mental Illness, The Physician’s Guide to Depression and Bipolar Disorders, and Molecular Biology for the Clinician. He is a professor of psychiatry, neuroscience, and pharmacology and systems therapeutics at Icahn School of Medicine at Mount Sinai.