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The biochemical basis of human mood

John Krystal
Photo by Robert A. Lisak
John Krystal

During his first summer in college, John Krystal, MD ’84, HS ’88, chair of Yale’s psychiatry department, traveled from the University of Chicago to help patients at a methadone-dispensing addiction clinic in Boston. In a biochemistry class that autumn, he learned about the discovery that the body makes opioid-like molecules called endorphins that act via the same receptors in the brain as drugs like heroin and methadone. An idea clicked. “That suggested to me that the problem of addiction might have a scientific underpinning,” Krystal, the Robert L. McNeil Jr. Professor of Translational Research, professor of psychiatry, and of neuroscience, said, “and that the complexity and unpredictability of clinical psychiatry work could be grounded in discoverable, scientific principles about brain–behavior relationships.”

The direct link between biological processes in the brain and a person’s behavior is widely accepted today, but it seemed radical three decades ago. When Krystal was an undergraduate, the late Yale psychiatry professor Daniel X. Freedman, MD, directed him toward the lab of Richard J. Miller, PhD, a pioneer in opiate-receptor research. Since then, Krystal has built a career bridging basic science with clinical understandings of depression, alcoholism, posttraumatic stress disorder (PTSD), and schizophrenia.

In this Yale Medicine Magazine interview, Krystal discussed a deep and wide range of topics from across his roles, which also include chief of psychiatry at Yale New Haven Hospital, editor of the journal Biological Psychiatry, director of clinical neuroscience at the Department of Veterans Affairs National Center for PTSD, and numerous advisory responsibilities.

Statistics generally show an upward trend in rates of depression, anxiety, and addiction. Are we dealing with an actual increase or just talking about mental health more openly? There is a lot of activity in the sphere of public mental health. First, the numbers of people diagnosed with anxiety and depression are going up. Second, the rate of serious consequences of inadequately treated mental illness, like disability and suicide, are going up. Third, we have a very serious shortage of psychiatrists and psychologists. We’ve tolerated this shortage because society has traditionally viewed mental illness as something that can be treated if there are resources available, a sort of add-on to health care. Many people, including myself, believe that we need a new model whereby mental health is a core element of primary medical care. In our society, more than two-thirds of people are routinely screened for various forms of cancer—but more than two-thirds of people are not screened for mental illness or addiction. We need to change that statistic.

Neuroscience research is progressing rapidly. Why might the public still think of mental illness as shrouded in mystery? The symptoms of mental illness—including changes in mood, patterns of thought, or behavior—can be confusing or even frightening. Providing a scientific foundation for understanding these symptoms that guides the processes of diagnosis and treatment could have profound implications for how society thinks about these problems.

What changes do we need in how mental illness is treated? I think we need a new model. As a society and as a medical specialty, we need to take responsibility for the outcomes of mental-illness treatment. To do that, we have to measure the outcomes of treatment and use this information to inform clinical practice. The current model has some parallels to the way we treat infection, in that the most commonly used treatments are not always the most effective. We save the most effective treatments for “treatment-resistant” symptoms. But that is not what we do in cancer. There, we initiate definitive treatment as soon as the problem is diagnosed. We need to offer more care like that. If we diagnose depression, we need to make sure you get a comprehensive array of services. Also, when people fail to respond to established cancer treatments, a high percentage of patients will enroll in a research study to test new treatments. That is not the way we deal with mental illness or addiction, where only a small fraction of patients participate in research.

Which mental health trend disturbs you most today, and which trend gives you the most energy? The trends that disturb me most also energize me the most: the increase in opiate-related deaths and the increase in suicide. Psychiatry is unique in that mortality from psychiatric illness is increasing, whereas mortality from practically every other diagnosis is decreasing. Cancer mortality, diabetes mortality, and heart-disease mortality are going down. But suicide and addiction-related deaths are going up. We have to do things differently—and not just as a department or health care system but as a country.

What is a dream you have for the future of psychiatry? We are working toward an era of precision psychiatry. By that I mean having tests that diagnose risk or disease processes for individuals and that enable us to engage specific prevention and treatment interventions. We envy cardiology, where one can diagnose and treat hypertension and thereby prevent myocardial infarction. We may be able to use genetics to identify people at risk for problems, but then we also may need to deal with the societal issues that increase risk, such as childhood exposure to violence, abuse, neglect, and maternal depression and addiction. Future treatments may involve gene- or cell-based therapies or procedures only imaginable on shows like Star Trek, where a scan is performed that tells us how to stimulate the brain to alleviate symptoms. Who knows what will come? Cure is not a word that we use in psychiatry, but that too is simply a reflection of the limits of our knowledge in comparison to the enormity of the challenge of understanding the brain.