From The Quarterly, Winter 2011

“I think we have arrived at a tipping point in the maturation of psychiatry,” says John H. Krystal, M.D., NARSAD Scientific Council Member. “In terms of drug discovery, it is fair to say that we’ve moved from a pre-scientific mode to a scientific mode. Insights about how the brain works provided by basic and clinical science have already led to new and in some cases unexpected treatments for a number of psychiatric disorders, and more are on the way. That’s what makes this one of the most exciting eras in the history of the entire field.”

These are words to remember, for Dr. Krystal is one of the most accomplished and well-respected figures not only in psychiatry, but in the related areas of neurobiology and neuropsychopharmacology – the science that studies how drugs interact with the biology of the brain. Having earned his M.D. at the Yale School of Medicine in 1984, he is today the chair of Yale’s psychiatry department and is chief of psychiatry at Yale-New Haven Hospital.

But there is much more, and therein lies an important story about Dr. Krystal and about the value of basic research into the brain supported by NARSAD grants. In addition to his duties at Yale, Dr. Krystal is Director of the Center for Translational Neuroscience at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), one of the National Institutes of Health. He is also, remarkably, Director of the Clinical Neuroscience Division at the Veteran Administration’s (VA) National Center for Post-Traumatic Stress Disorder (PTSD); Director of the VA Alcohol Research Center; and Medical Director of the VA Schizophrenia Biological Research Center.

Dr. Krystal, therefore, does not merely treat patients and conduct research at Yale, but also directs the work of teams of scientists and physicians at major national institutes and centers dedicated to studying and treating illnesses running the full gamut: anxiety disorders such as PTSD and OCD (obsessive-compulsive disorder); substance abuse disorders such as alcoholism; and the devastating illnesses of schizophrenia and major depression. One naturally wants to know: what unites these wide-ranging activities? What is the scientific thread that connects them?

Discoveries enable broad psychiatric advances

There is indeed a thread between these varied brain and behavior disorders, and as Dr. Krystal relates, it can be traced back to a subject that captured his interest at the very beginning of his career: the neurobiology of the glutamate system in the brain.

Glutamate is a message-carrying molecule, the most important and prevalent of the class of excitatory neurotransmitters, which stimulate the brain. When glutamate that has been released by one nerve cell “docks” with a receptor on a neighboring nerve cell, it increases the chance that the receiving cell will fire an impulse to yet another near-by nerve cell. Beyond a certain threshold of excitation, a cell will indeed fire, and the process repeats. This is how messages, the building blocks of our thoughts and actions, are conveyed – over the span of milliseconds – across the vast tangle of neural circuits in the brain.

Dr. Krystal’s interest in the glutamate system came at a moment when surprising observations linking brain and behavior in the 1960s were be- ginning to make scientific sense. It had been noted that a drug called PCP (also known as “angel dust”) produced symptoms in people resembling those of schizophrenia. This was mysterious. By the 1980s, scientists knew PCP’s molecular target: the NMDA receptor, a type of “docking port” found on the surface of a subset of neurons in the brain. In the late ‘80s, Dr. Krystal and colleagues began to study a relative of PCP called ketamine, which also produced schizophrenia-like symptoms in people. This line of research has informed efforts to develop a new class of drugs to treat schizophrenia.

What makes these recent developments in treatment applications for schizophrenia possible is the basic science that Dr. Krystal and other pioneers have accomplished. This is part of a larger process in which, as he notes, neuropsychiatry has become progressively more scientific, and able to explain the mechanisms that underlie the clinical phenomena of illnesses like schizophrenia and anxiety. Dr. Krystal’s first NARSAD grant, a 1997 Independent Investigator award, used ketamine as a tool for studying aspects of psychosis in schizophrenia, specifically the impact of amphetamines on psychosis. In his second NARSAD award – a 2000 Distinguished Investigator grant – he focused on several aspects of how glutamate signals are sent and in some cases inhibited in the brain’s cortex. And in his most recent award, a 2006 Distinguished Investigator grant, Dr. Krystal’s basic research was among the studies that shed new light on how the NMDA glutamate receptors work in the cortex.

This story runs in parallel to one that explains how Dr. Krystal, during the same years, became involved in research that has since borne fruit in anxiety disorders. While still in medical school at Yale, he and Dr. Eugene Redmond were studying the effects of stress in monkeys. “We were studying a system in the brain called the noradrenergic system, which releases an adrenaline-like substance called norepinephrine,” he remembers. “When we activated this system, I noticed that some of the behaviors the monkeys exhibited resembled symptoms I was seeing in my clinical training involving soldiers who had come back from Vietnam.”

Just as PCP and ketamine provided a path for Dr. Krystal and other scientists to learn about the biology of schizophrenia, the noradrenaline system offered a path into PTSD. With distinguished collaborators including Drs. Dennis Charney and Stephen Southwick, Dr. Krystal performed studies on veterans at the VA National Center for PTSD, one of the centers Dr. Krystal now directs. “We found that if you activate the noradrenaline system, you can produce the arousal symptoms associated with PTSD.

“At the time, we didn’t really under- stand much at all of the neurobiology of PTSD symptoms. We’d have a veteran in a quiet room start saying, all of a sudden, ‘Look over there – the helicopter’s going down! I can hear people screaming!’ Very vivid, very intense memories of trauma.

We also had people describing feeling detached from what was going on around them, feeling like time had slowed down, feeling numb and other kinds of bodily distortions.”

In a telling glimpse of how the discovery process works in science, Dr. Krystal, when faced with the mystery of these symptoms’ biological origins, thought of work he was doing around the same time on ketamine. “In addition to producing some of the cognitive impairments associated with schizophrenia, ketamine also produced some symptoms of this kind that we were seeing in PTSD, which I would call ‘dissociative.’”

The upshot of this observation was Dr. Krystal’s hypothesis that some of the different sets of symptoms produced by ketamine contained clues about “disorders other than schizophrenia, in which the glutamate system might be involved.” Since 1980, when PTSD was acknowledged by psychiatry as a distinct illness – a landmark moment that reflected an increasingly scientific, as opposed to purely anecdotal understanding of it – there have been only two drugs approved to treat its symptoms. Both are antidepressants of the SSRI (selective serotonin reuptake inhibitor) class: paroxetine (Paxil) and sertraline (Zoloft). But Dr. Krystal, while frustrated to note that neither drug helps a majority of patients, was able to draw on his much earlier work on the noradrenaline system to come up with a new treatment idea.

He asked, “What about some of the older antidepressants?” He had in mind drugs that blocked the molecule that transports noradrenaline between nerve cells. Zoloft and Paxil block the transporter for serotonin, another neurotransmitter. But if nor- adrenaline was involved in PTSD, then perhaps the antidepressant desipramine (Norpramin) might help. With colleagues, Dr. Krystal performed a study involving 88 veterans with PTSD. The results were surprising, but productively so. While Norpramin worked no better than Paxil in reducing PTSD symptoms, it had the completely unexpected effect of helping the patients control co-morbid alcoholism.

“I love in research when something turns out to work in an unexpected or paradoxical way,” Dr. Krystal says.

The Norpramin surprise is by no means the only time Dr. Krystal experienced this phenomenon, which each time marks a moment when our understanding of how the brain works takes a leap forward. Perhaps the most outstanding example in Dr. Krystal’s work relates to the concept of neuroplasticity, which can be defined as the response of cells and circuits in the brain to a person’s experiences.

“This idea of neuroplasticity is extremely important,” Dr. Krystal says. “The natural progression within an organism when it is ill is to try to heal itself. Paradoxically, sometimes the healing process itself can get in the way of recovery. That’s why we take aspirin, for instance – to reduce the pain of inflammation that is caused by the body trying to heal itself.

“Where the brain is concerned, some-times in order to get better, it is necessary to restore the capacity of the neural circuit to remodel itself. Some-times it is the deficit in that capacity – neuroplasticity – that is part of what we think of as the illness. In the case of stress disorders, we’ve learned that traumatic stress can cause the retraction of knob-like input centers called dendritic spines, which are the places where signals come into nerve cells. This is particularly true in glutamate neurons in the brain.”

Dr. Krystal points out that there is evidence of spine retraction in symptoms seen in stress and anxiety disorders: impaired memory function, and, importantly, impaired capacity to learn to respond to stressors in new and therapeutic ways. “If your capacity for neuroplasticity is impaired, in other words, the capacity of these networks to learn and adapt is compromised.”

Pre-scientific to scientific mode in psychiatry

Indeed, Dr. Krystal says every change in brain function and in behavior – “as far as we know” – has an underpinning in brain function. “Sometimes the change could be new connections; sometimes it could be elimination of existing connections, and sometimes it might be the fine-tuning of connections, either strengthening or weakening them.”

In an elegant example of how science can radically change the way we look at something we thought we understood, Dr. Krystal and colleagues have recently reported their success in a preliminary test using neuroplasticity as the target for a new class of treatments for anxiety disorders, mood disorders and schizophrenia. Rather than design a new treatment to address one or more observed symptoms of, say, panic disorder, the idea would be to find a way to correct a neuroplasticity impairment – the reduced capacity of a neural circuit to modify itself in response to stress or trauma.

This was attempted in 2009 on a pilot basis in patients with panic disorder. Researchers used a well-known drug called D-cycloserine (DCS) in combination with a short course (only five sessions) of cognitive behavioral therapy, a form of so-called exposure therapy that aims at conditioning someone repeatedly experiencing extreme fear or panic to learn new responses to thoughts, sensations or feelings. The success observed in this trial, Dr. Krystal notes, is not due to the capacity of DCS to address symptoms of panic. Rather, he hypothesizes, DCS performs work within the neural circuitry that then enhances the ability of psychotherapy to produce functional changes in circuitry that amount to the patient’s therapeutic learning.

Importantly, this preliminary positive outcome is the product of several layers of solid biological knowledge about the brain and brain chemistry – knowledge obtained in the last decade or two, as psychiatry has moved into a genuinely scientific era. From much prior work, it was known that DCS enhances activity at NMDA glutamate receptors. And those receptors, it is now understood, thanks to basic research, are fundamental facilitators of neuroplasticity – the process central to adaptation and new learning, which in this instance includes unlearning maladaptive responses to traumatic or other stressful memories.

“The idea of targeting plasticity deficits by facilitating neuroplasticity or harnessing it in novel ways is a concept I think has quite broad implications,” Dr. Krystal says. “What we must do next is move from these exploratory types of studies in panic disorder, OCD and PTSD, to larger-scale, more definitive studies, which I think will happen.”

John H. Krystal, M.D.

NARSAD Scientific Council Member

Chair, Department of Psychiatry, Yale University

Chief of Psychiatry, Yale-New Haven Hospital

Director, NIAAA Center for the Translational Neuroscience of Alcoholism

Director, Clinical Neuroscience Division, VA National Center for PTSD

Director, VA Alcohol Research Center

Medical Director, VA Schizophrenia Biological Research Center