TALKING WITH TITANS OF PSYCHOPHARMACOLOGY
On the 2025 American Psychiatric Affiliation (APA) Annual Assembly, Psychiatric Occasions‘ Editor in Chief, John J. Miller, MD, sat down with leaders in psychopharmacology to debate the subjects they discover most essential.
John H. Krystal, MD, is greatest identified for main the invention of ketamine’s speedy antidepressant results.1,2 He shared his newest insights on NMDA glutamate receptors and ketamine with Miller.
“If we had been having this dialogue within the Nineteen Nineties, we most likely solely would have spoken about norepinephrine and serotonin,” stated Krystal. “One of many issues that the work with ketamine has achieved is to broaden our concepts concerning the biology of despair, and embrace in our pondering the biology of the cerebral cortex and the limbic system. When you do this, you understand that the primary excitatory transmitter within the cerebral cortex—the knowledge freeway of the upper facilities of our mind—is glutamate.”
In his analysis, Krystal has discovered 3 totally different sorts of glutamate synaptic abnormalities: (1) lack of glutamate synapses, (2) diminished effectiveness of glutamate synapses, and (3) and abnormalities in glutamate homeostasis. All 3 have one thing to say about why ketamine is a quickly appearing antidepressant.
“Once you give a dose of ketamine, you make synapses more practical by taking internalized glutamate receptors, known as AMPA glutamate receptors, and ship them to the floor the place they’re delicate to glutamate that’s being realized. You’ll be able to restore synaptic functioning, synaptic quantity, and synaptic stability,” stated Krystal.
Ketamine appears to be the simplest remedy for treatment-resistant signs in despair, noninferior to ECT, and has about double the efficacy of adjunctive antipsychotic remedy. Moreover, it’s about twice as efficient in stopping relapse to despair as soon as response is achieved in comparison with antidepressant remedy alone, shared Krystal.
Importantly, esketamine reveals main reductions in suicide makes an attempt long-term, demise by suicide, and all-cause mortality, in comparison with different antidepressant remedies.
“Ketamine, by advantage of being a more practical antidepressant, can also be defending individuals from whole-body results of despair,” shared Krystal. “To me, that is actually extraordinary.”
Dr Krystal is Robert L. McNeil, Jr. Professor of Translational Analysis and Professor of Psychiatry, of Neuroscience, and of Psychology at Yale College. Krystal can also be codirector of the Yale Middle for Medical Investigation; chair of Psychiatry; physician-in-chief of Psychiatry at Yale New Haven Hospital; director of the Nationwide Institute on Alcohol Abuse and Alcoholism Middle for the Translational Neuroscience of Alcoholism; and director of the Medical Neuroscience Division on the VA Nationwide Middle for PTSD.
Dr Miller is Medical Director, Mind Well being, Exeter, New Hampshire; Editor in Chief, Psychiatric Occasions; Voluntary Consulting Psychiatrist at Seacoast Psychological Well being Middle, Exeter/Portsmouth, NH; Consulting Psychiatrist, Perception Meditation Society, Barre, Massachusetts.
References
1. Krystal JH, Abdallah CG, Sanacora G, et al. Ketamine: a paradigm shift for despair analysis and remedy. Neuron. 2019;101(5):774-778.
2. Duerr HA. Krystal JH. John Krystal, MD: exploring the way forward for ketamine and psychedelic remedy. Psychiatric Occasions. September 20, 2024. https://www.psychiatrictimes.com/view/john-krystal-md-exploring-the-future-of-ketamine-and-psychedelic-treatment
