Depression is one of the most common and most debilitating mental health disorders, affecting some 17 million adults in the US. It also continues to be a misunderstood, often hard-to-treat illness. Researchers have worked for decades to better understand the neurobiology underpinning depression. For patients with severe, treatment-resistant depression, spending months or even years searching for good treatments can be totally disabling. The prevailing hypothesis for years was that depression was regulated by the neurotransmitter’s serotonin and norepinephrine. Eventually, data began to suggest that maybe something much larger and more global was involved in the brain to account for depression, which led researchers to begin working with glutamate and GABA, the most abundant neurotransmitters in the brain. These chemicals are involved in neuroplasticity – the brain’s ability to adapt to change and protect itself against stressful events. Neuroplasticity is a physical thing, too: it manifests itself “in terms of synapses, how these neurons are actually touching each other and communicating with each other,” explains Gerard Sanacora, PhD, MD, Director of the Yale Depression Research Program. “And we know that in depression, the number and strength of these interconnections decreases,” says Rachel Katz, MD, a professor of Clinical Psychiatry at Yale. Ketamine – originally developed and still used as an anesthetic – works on those two neurotransmitters and was discovered to have rapid antidepressant effects. Some experience an improvement in symptoms in 24 hours or less. “We think that one of the things that Ketamine does, that helps to explain its antidepressant effects, is help the brain to regrow the synapses, the connections between nerve cells,” says John Krystal, MD, Chair of the Department of Psychiatry at Yale. Because Ketamine seems to work on a totally different system in the brain than typical antidepressants, “that may be why Ketamine works so well, even for patients who have not had success with a number of standard antidepressants,” says Dr. Katz. Ketamine as a treatment for depression gained FDA approval last year with the release of Spravato (esketamine), and for now, it remains a treatment reserved for patients who haven’t found success with at least two other antidepressant treatments. Dr. Sanacora explains that other treatments, including cognitive behavioral therapy, are important to use in conjunction with ketamine, “to develop new ways of adapting and having new cognitive strategies of dealing with future stressors to prevent relapse.” New therapies like ketamine are changing how depression is understood, and may pave the way for future research that helps us understand the brain in all of its complexity.