Stories Behind the Science: Dennis S. Charney, MD, and Psychiatry
Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai, created a legacy by serving as Dean for 18 years—one of the longest tenures of any medical school dean in the United States. His research career has been just as illustrious over the decades.
Rooted in psychiatry, pharmacology, and neurobiology, Dr. Charney’s research has resulted in treatment breakthroughs for depression, enhanced medical and scientific understanding, and led to two U.S. Food and Drug Administration (FDA)-approved therapies. He has published more than 800 articles, which have been cited more than 198,000 times, according to Google Scholar, and was elected to the prestigious National Academy of Medicine in 2000.
One of his biggest research milestones was discovering that ketamine can be used as a fast-acting antidepressant, offering a useful alternative for patients who do not respond well to conventional therapies. However, pursuing that discovery was not easy amid societal stigma at the time.
“We were looked at like we were pursuing a PCP study or something,” said Dr. Charney, referring to the recreational street drug. “But we knew we had something big on our hands. We were on the verge of discovering something that could change the lives of patients, and we were very motivated. We weren’t scared, and we went about doing it the right way.”
In addition to discovering the antidepressive effects of ketamine, Dr. Charney is known for his work on the science of resilience, and for his role in the first FDA-approved digital therapeutic for depression.
Read more below about the decades of Dr. Charney’s research efforts, and what it was like being at the frontier.
The Beginnings:
A Focus on Bringing
Bench to Bedside
A young Dr. Charney (right) with mentor and collaborator George Heninger, MD (left), photo taken in 1996.
In the early 1980s, working at the Yale School of Medicine in conjunction with the Connecticut Mental Health Center, Dr. Charney was focused on understanding the pathophysiology of serious forms of depression, along with panic and anxiety disorders and obsessive-compulsive disorder.
“We wanted to develop better treatments for these conditions,” said Dr. Charney.
At the time, the neurotransmitters serotonin and norepinephrine were known to be involved in some psychiatric conditions, and Dr. Charney and his team members were developing methods of examining those relationships closely.
“It’s fair to say we developed, at that time, more sophisticated ways of studying those neurotransmitters,” he said, adding, “although they’re probably not considered sophisticated today.”
Those efforts led to the study of yohimbine, an alkaloid of the bark of the yohimbe tree, which revealed that excessive norepinephrine function was involved in panic disorder and PTSD (Arch Gen Psychiatry, 1984, now JAMA Psychiatry).
“That study was a great example of a combination of going from the lab to studying patients,” he said.
While a number of serotonin and norepinephrine reuptake inhibitors were emerging at the time, Dr. Charney’s findings were showing that targeting these neurotransmitters alone were insufficient to move the needle on treating depression.
“However, I felt that just looking at serotonin and norepinephrine couldn’t tell us the whole story about depression,” said Dr. Charney.
Finding Alternatives: Ketamine and the Glutamate System
Starting in the late 1980s, the treatment of major depression moved toward using selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). However, there was still a notable proportion of patients for whom these drugs were not effective enough.
“In patients who were not doing better, we tried to augment the serotonin system,” said Dr. Charney. “It didn’t work.”
“With all the studies we’ve been doing in depression, we thought monoamines told only part of the story in depression,” he noted, referring to the class of neurotransmitters that includes dopamine, serotonin, and norepinephrine. “So we thought maybe there is another system that was, in part, regulated by the monoamines, but would be more fundamentally involved in depression.”
In the early 1990s, Dr. Charney and his collaborator at Yale, John H. Krystal, MD, began looking for a pathway affected by monoamine neurotransmitters, and through a logical progression of studies, focused on the glutamate system and, soon, on ketamine—an anesthetic with known effects on the glutamate system. This work yielded some of Dr. Charney’s top-cited papers (Arch Gen Psych, 1994).
In the mid-1990s, Drs. Charney and Krystal did a series of studies on ketamine, first on healthy volunteers and then a small trial on seven patients with major depressive disorder (MDD). The results were shocking.
“The patients got better in a few hours,” recalled Dr. Charney. “I was like, ‘Are you kidding me?’ As an investigator watching it, it was like a miracle.”
Dennis S. Charney, MD (right) with John H. Krystal, MD (left), being awarded the Colvin Prize at the Brain and Behavior Research Foundation Gala, November 2019.
Drs. Charney and Krystal published their findings (Biological Psychiatry, 2000), but faced skepticism from both the scientific and general communities. The study was dismissed as not being replicable, and additionally for the fact that the researchers were working with a compound that was stigmatized for its recreational use.
When Dr. Charney went to the National Institute of Mental Health (NIMH) in 2000, he sought to repeat history. “Nobody believed it, nobody was trying to replicate it, so we’re going to have to do it ourselves at NIMH,” he said. “In the second study, we replicated it dead on.”
At the end of his stint at NIMH in 2004, Dr. Charney brought his findings with him to the Mount Sinai School of Medicine (now the Icahn School of Medicine), where he began his career as Dean of Research.
Dr. Charney is a named co-inventor on patents filed by Mount Sinai relating to the use of ketamine for the treatment of treatment-resistant depression and suicidal ideation. Mount Sinai licensed those patents to Janssen Pharmaceuticals, Inc. for the development of SPRAVATO (esketamine) by Janssen, which received FDA approval in 2019. Its approval makes it the first antidepressant of its kind to target N-methyl-D-aspartate (NMDA) receptors—introducing the first new class of antidepressant drugs since the 1950s.
A Prescription for Resilience
In the 1990s, Dr. Charney turned his focus to studying trauma and PTSD, in collaboration with Steven M. Southwick, MD. That journey led to some of Dr. Charney’s most impactful work on understanding resilience.
“My buddy, Steve Southwick, was really involved in that work,” said Dr. Charney of his colleague, who passed away in 2022. “He’s on a lot of my papers, and he became my closest friend.” The ties between the two researchers dated back to before the 1980s.
Drs. Charney and Southwick tackled understanding PTSD from all angles—psychological, biological, social, pharmacological. Then, they had an idea to take their findings a step further to help patients.
“Back then, we thought, ‘If we studied people who were resilient—people who had been traumatized but didn’t develop PTSD—perhaps we could learn something from it, and apply those lessons to help patients with PTSD,” said Dr. Charney. “That’s how I ended up studying resilience for over 30 years.”
Dr. Charney’s paper on resilience (Am. J. Psychiatry, 2004) became one of his most cited works after his publications on ketamine in depression. He and Dr. Southwick then published a book called “Resilience: The Science of Mastering Life’s Greatest Challenges” (Cambridge University Press, 2012).
The book, now in its third edition, is rooted in the hundreds of interviews Drs. Charney and Southwick did with people who faced challenges in their lives—including prisoners of war and survivors of sexual and physical abuse. It includes a “prescription” for being resilient—10 steps that people can take to overcome life challenges.
From left to right, Dennis S. Charney, MD; Steven M. Southwick, MD; and John H. Krystal, MD.
“Not just for others—our research on resilience was also a personal journey,” said Dr. Charney. In 2016, Dr. Charney survived being shot, and he credits the lessons on resilience for overcoming that ordeal.
Those resilient factors also helped Dr. Charney navigate the stresses of the COVID-19 pandemic, and he established the Center for Stress, Resilience and Personal Growth in 2020 to extend that support to Mount Sinai staff.
Through Boldness,
a New Therapy Emerges
In 2024, the FDA approved a new class of treatments: digital therapeutics. In that class was REJOYN, a prescription smartphone app by Click Therapeutics and Otsuka Precision Health for major depressive disorder. That novel treatment had its beginnings through Dr. Charney’s research.
“This goes back to when we were interviewing prisoners of war who were subject to solitary confinement in Vietnam,” said Dr. Charney. “Some of them said that when they were in solitary, all they could do was think.”
A Life Magazine cover from 1967, featuring a prisoner of war from the Vietnam War, whom Drs. Charney and Southwick had interviewed as part of their research on resilience. That body of work eventually led to the development of Rejoyn, a digital app for treating depression.
Over time, some of those individuals reported developing cognitive capacities they never had before, such as being able to do complex multiplication with just their mind. “To me, that suggested evidence of neuroplasticity, where you can change the chemistry and circuits in your brain through repeated tasks,” said Dr. Charney.
With that inspiration, Dr. Charney pondered whether neuroplasticity could be tapped to “correct” the brain circuitry of patients with depression and improve their symptoms.
“We knew something about the circuits of depression that involved the prefrontal cortex and subcortical regions, like the amygdala. What if we developed a task that involved both of those regions?” he said.
Brian Iacoviello, PhD, Assistant Professor of Psychiatry at the Icahn School of Medicine, and Dr. Charney developed the Emotional Faces Memory Task and ran two randomized controlled studies. The findings (npj Digital Medicine, 2018) showed that patients who did the task repeatedly had improvements in their depression symptoms.
Drs. Charney and Iacoviello are co-inventors of patents filed by Mount Sinai for the Emotional Faces Memory Task intervention for the treatment of depression and related psychiatric disorders. Mount Sinai licensed the patents to Click Therapeutics, Inc. and Otsuka Precision Health for the development of REJOYN, a digital treatment for depression. REJOYN received FDA clearance in 2024, as the first prescription adjunctive treatment for adults with MDD.
“Like with ketamine for depression, I see going for a digital approach for depression as a story about being bold,” said Dr. Charney. “Each time, it was a realization that our current understanding isn’t enough, and it’s worth it to take a different approach.”
With more than 50 patents, and a slew of scientific achievements, what’s next for Dr. Charney? “Resilience will continue to inspire me after I step down as Dean,” he said.
Dr. Charney steps down as Dean from the Icahn School of Medicine on Monday, June 30, and Eric J. Nestler, MD, PhD, has been appointed Interim Dean.
“I’m going to need to figure out how to be inspired next. I’m going to continue my research in depression and resilience,” said Dr. Charney. One option that’s underway is working on the fourth edition of his book on resilience. But there might be other bold options out there too.
“I have two therapies on the market,” said Dr. Charney. “My goal is to discover a third. I’m not sure if anyone in psychiatry has ever done that.”