A Shift in the Way We Think About the Biology of Depression: A Conversation With John H. Krystal, MD

TALKING WITH TITANS OF PSYCHOPHARMACOLOGY

At the 2025 American Psychiatric Association (APA) Annual Meeting, Psychiatric Times' Editor in Chief, John J. Miller, MD, sat down with leaders in psychopharmacology to discuss the topics they find most important.

John H. Krystal, MD, is best known for leading the discovery of ketamine's rapid antidepressant effects.^1,2 He shared his latest insights on NMDA glutamate receptors and ketamine with Miller.

"If we were having this discussion in the 1990s, we probably only would have spoken about norepinephrine and serotonin," said Krystal. "One of the things that the work with ketamine has done is to broaden our ideas about the biology of depression, and include in our thinking the biology of the cerebral cortex and the limbic system. Once you do that, you realize that the main excitatory transmitter in the cerebral cortex—the information highway of the higher centers of our brain—is glutamate."

In his research, Krystal has found 3 different kinds of glutamate synaptic abnormalities: (1) loss of glutamate synapses, (2) reduced effectiveness of glutamate synapses, and (3) and abnormalities in glutamate homeostasis. All 3 have something to say about why ketamine is a rapidly acting antidepressant.

"When you give a dose of ketamine, you make synapses more effective by taking internalized glutamate receptors, called AMPA glutamate receptors, and send them to the surface where they are sensitive to glutamate that is being realized. You can restore synaptic functioning, synaptic number, and synaptic balance," said Krystal.

Ketamine seems to be the most effective medication for treatment-resistant symptoms in depression, noninferior to ECT, and has about double the efficacy of adjunctive antipsychotic medication. Additionally, it is about twice as effective in preventing relapse to depression once response is achieved when compared with antidepressant treatment alone, shared Krystal.

Importantly, esketamine shows major reductions in suicide attempts long-term, death by suicide, and all-cause mortality, when compared with other antidepressant treatments.

"Ketamine, by virtue of being a more effective antidepressant, is also protecting people from whole-body effects of depression," shared Krystal. "To me, that's really extraordinary."

Dr Krystal is Robert L. McNeil, Jr. Professor of Translational Research and Professor of Psychiatry, of Neuroscience, and of Psychology at Yale University. Krystal is also codirector of the Yale Center for Clinical Investigation; chair of Psychiatry; physician-in-chief of Psychiatry at Yale New Haven Hospital; director of the National Institute on Alcohol Abuse and Alcoholism Center for the Translational Neuroscience of Alcoholism; and director of the Clinical Neuroscience Division at the VA National Center for PTSD.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Voluntary Consulting Psychiatrist at Seacoast Mental Health Center, Exeter/Portsmouth, NH; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

References

1. Krystal JH, Abdallah CG, Sanacora G, et al. Ketamine: a paradigm shift for depression research and treatment. Neuron. 2019;101(5):774-778.

2. Duerr HA. Krystal JH. John Krystal, MD: exploring the future of ketamine and psychedelic treatment. Psychiatric Times. September 20, 2024. https://www.psychiatrictimes.com/view/john-krystal-md-exploring-the-future-of-ketamine-and-psychedelic-treatment