Committed to Breaking New Ground in the Understanding and Care of Psychiatric Conditions

In the early 1990s, John Krystal, MD, and his colleagues were studying ketamine and its influence on the neurotransmitter glutamate in symptoms of schizophrenia when Dr. Krystal began to contemplate glutamate’s role in major depression as well. This was a new line of inquiry because previous research had focused almost exclusively on the neurotransmitter serotonin (and later, norepinephrine).

In a seminal study, Dr. Krystal, now the chair of psychiatry at Yale School of Medicine, and his collaborators discovered that ketamine produces antidepressant effects by working on an entirely different brain system than current antidepressants do. Traditional antidepressants target serotonin, norepinephrine, and dopamine systems in the brain. Ketamine works by altering the glutamate system. Subsequently, Dr. Ronald Duman, also in psychiatry, showed that ketamine produced its antidepressant effects by triggering the release of glutamate, which then stimulates growth of new synapses between brain cells. As a result, ketamine is effective in patients with major depressive disorder who are resistant to common antidepressants. It takes effect in a matter of hours, rather than weeks.

Dr. Krystal’s findings were published in a now widely cited paper and his work brought about a revolution in the understanding of depression — which afflicts tens of millions of people worldwide. In 2019, citing its major benefits for those with treatment-resistant depression, the Food and Drug Administration (FDA) expedited approval of esketamine, derived from ketamine, and administered as a nasal spray. In one clinical trial, 70 percent of patients who did not respond to other treatments improved on esketamine. It is the first fundamentally new treatment for depression approved by the FDA in over 50 years. This is revolutionary, because esketamine triggers long-term positive changes in the brain that last beyond the duration of the drug in the system. This accounts for why patients may maintain the benefits of ketamine treatment with one dose every two weeks or even once a month.

Often, one groundbreaking discovery leads to others. Without the clinical trial volunteers, whose willingness to participate in clinical research benefited themselves and future patients, this groundbreaking treatment would never have been available to those who need it.