A Psychiatrist’s Search for Neurobiological Answers to the Questions Underlying PTSD

A Psychiatrist’s Search for Neurobiological Answers to the Questions Underlying PTSD

Dr. John Krystal

Dr. John H. Krystal

As someone who has spent decades studying the effects of stress on the brain, Dr. John H. Krystal recalled his own stressful moment when he was a first-year medical student at Yale University School of Medicine. He was working with monkeys in the laboratory of Professor D. Eugene Redmond, studying the biology of fear, stress, and opiate dependence. This work focused on the noradrenaline systems implicated in “fight or flight” responses. “It seemed to me that symptoms of PTSD resembled the consequences of the activation of brain noradrenaline systems,” noted Dr. Krystal.

His father, Dr. Henry Krystal, a prominent psychiatrist who worked with Holocaust survivors, was serving as the discussant for one of the first symposia on the biology of PTSD at the American Psychiatric Association. When his discussion shifted to a presentation on the role of noradrenaline in the treatment of PTSD—without advance warning—he called his son to the podium to discuss possible links between noradrenaline systems in the brain, fear, and PTSD. “My noradrenaline system was extremely active at that point,” Dr. Krystal noted. “This was my first scientific presentation and I was speaking off-the-cuff to a huge audience.” It must have gone reasonably well because he was invited to join the organizers of the session to write one of the first review papers on the biology of PTSD.

Thus was launched a groundbreaking career.

Dr. Krystal followed in his father’s footsteps and became a psychiatrist interested in the neurobiological underpinnings of mental disease. He graduated from the University of Chicago in 1980, received his MD from Yale in 1984, and completed psychiatry residency at Yale in 1988. Since then, Dr. Krystal, now the Robert L. McNeil, Jr. Professor of Translational Research, Chair of the Department of Psychiatry, and Professor of Neuroscience at Yale, has published extensively on the neurobiology and treatment of PTSD, depression, alcoholism, and schizophrenia.

He was a leader of the discovery of the rapid antidepressant effects of the NMDA receptor-blocking drug ketamine in humans—a breakthrough that has led to research into a new class of antidepressants.

Director of the Clinical Neuroscience Division of the VA National Center for PTSD and Executive Committee Member for the VA/DOD Consortium to Alleviate PTSD, Dr. Krystal spoke at the 2016 Cohen Veterans Care Summit in September about the pharmacotherapy gap in treatments for the disorder.

“I think there’s a national challenge or crisis related to the development of medications for PTSD,” he told the attendees of the Summit, which was organized by Cohen Veterans Bioscience and Cohen Veterans Network

Only two medications, the selective serotonin reuptake inhibitors Zoloft® (sertraline) and Paxil® (paroxetine), have been approved by the U.S. Food and Drug Administration for the treatment of PTSD. Neither is effective for many patients who suffer with symptoms of PTSD, according to Dr. Krystal.

“We’re in a real conundrum,” he said. “At the VA, we have over 600,000 veterans who need treatment for PTSD and all we have to treat them are these two medications. Historically, the pharmaceutical industry has not had programs focused on developing treatments for PTSD. We need more industry investment in drug development, but we also need investment in basic and translational research to help reduce the risks for pharmaceutical companies who are interested in PTSD drug development.

The limited scope of PTSD pharmacotherapy research has resulted in a serious threat to the optimal treatment of veterans with chronic PTSD. Many veterans are being treated with three-to-four drugs for which there is little research on their risks or benefits,” Dr. Krystal added. “We need to really understand what the medications that are currently prescribed are doing and make sure there are new medications being tested.”

He called for definitive clinical trials looking at commonly prescribed medications as well as for early phase clinical trials of novel treatments.

At the same time, Dr. Krystal described exciting research in animal and translational neuroscience studies that are helping to identify circuit or molecular mechanisms that could possibly be targets for behavioral therapies or medications.

He cited a study led by his Yale colleague, Professor Ronald Duman, that is the first study of post-mortem brain tissue from PTSD sufferers. Looking at tissue from a part of the brain implicated in mood disorders, called the subgenual prefrontal cortex, Dr. Krystal noted that they found a reduction in the levels of the mRNA coding for a neural signaling protein, SGK1.

“The first question you ask is: What does that mean?” Dr. Krystal said.

Further studies in animals found that when animals were stressed, their SGK1 levels also showed a reduction. And when animals were genetically altered not to express this signaling molecule, “lo and behold, these animals look like they have PTSD, even though they have never been exposed to stress,” he said.

“That raises the next question: What if you could raise the level of SGK1 by overexpressing it in animals?” Dr. Krystal said. “Again, lo and behold, if you over-express SGK1, the animals become more resilient to the effects of stress.”

He said tests are underway in animals to see what medications might raise SGK1 levels.

“This is the kind of opportunity we have as a field right now, to capture the explosion in basic and translational research,” he said.

Dr. Krystal was ultimately optimistic about the future of research.

“It is the worst of times and the best of times because we are still grappling to come up with a treatment breakthrough,” he said. “Our depth of understanding is growing, yet it is somewhat superficial. However, we now have a growing array of paradigms for PTSD research.”