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Depression: What It Is and How it Can Be Treated – A Conversation with Philip W. Gold

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Members of the Scholars Council are appointed by the Librarian of Congress to advise on matters related to scholarship at the Library, with special attention to the Kluge Center and the Kluge Prize. The Council includes distinguished scholars, writers, researchers, and scientists. “Insights” is featuring some of the work of this highly-accomplished group of thinkers; Dan Turello continues the series interviewing Philip W. Gold.

Phil Gold has been at the National Institutes of Health Clinical Center since 1974, where he served as Chief of Neuroendocrine Research in the National Institute of Mental Health Intramural Research Program. An M.D. with training from Duke and Harvard, Gold and his colleagues pioneered the study of the neurobiology of the stress response and its dysregulation in major depression. They also developed one of the first hypothesis-based treatments for depressive illness based on their work with corticotrophin-releasing hormone. On March 26 and 27, 2012, Gold, along with former Kluge Chair in Technology and Society George Chrousos, organized a Kluge Center conference on “The Profound Impact of Stress.” In the interview below, Gold talks about his work on depressive illness, which along with stress, is a significant challenge facing advanced industrial societies. The Library of Congress collections, including the records of the American Psychological Association, are a resource for scholars interested in the history of psychiatry.

Philip W. Gold
Philip W. Gold, psychiatrist and member of the Library of Congress Scholars Council.

How is depression recognized and what are its cardinal symptoms?

Depression is an insidious illness infiltrating core attributes that define our humanity. For this reason, I have an abiding and profound antipathy for its treachery. Depression humbles us by making us seem far less than who we are. In so doing, it robs us of the major epochs of our lives, past, present and future. A depressed patient rarely seems proud of past achievements or good deeds. Rather, he focuses on emotional memories of negative experiences, or he loses touch with himself and his past and feels empty. When depressed, he is unable to feel pride in the person he has become, or in the work he does. Depressed patients also lose the capacity to experience pleasure, and have systematic alterations in sleep, appetite, and cognition. Finally, for someone who feels wholly inadequate, the future seems bleak and dangerous. “How,” a depressed patient might ask himself, “can I possibly accomplish anything?” “Who could possibly admire or love me?” Few other illnesses so frontally attack our dignity, so undermine our concept of ourselves, or so distort our expectations of the world. Depression is rendered more catastrophic because it is a disease that first presents in late adolescence or early adulthood, and often recurs throughout life.

It seems nurture versus nature represents a long-standing debate, in both evolutionary biology and philosophy. What are the relative roles of biology and life experience on the propensity to develop depressive illness?

The question of the extent to which life experience, or underlying biology influences our view of ourselves and the world has always intrigued me. Prior to becoming a biological psychiatrist, I trained in psychoanalytic psychotherapy in Boston in the early 1970’s. I felt then that psychiatric practice would be like applied literature: what I learned about myself, others, and the world could be used in the service of relieving suffering. I still feel that this approach has aesthetic and, more importantly, clinical relevance, and can help many patients. Otherwise, what have we learned if we cannot help individuals who have lost the will to live to find a way back to a tolerable existence?

On a physiological level recent neuroimaging research has allowed us to examine discrete areas of the brain that estimate the likelihood of punishment or reward; the extent to which our actions are succeeding or failing; the value of who we are and what we want; our propensity for anxiety or serenity; and our bias towards pleasure or despair. Via these neuroimaging studies, we now know that depressed patients have loss of tissue and metabolic abnormalities in each of these brain sites. Depressed patients often expect punishment, see themselves as failures, and undervalue who they are and what they want. Hence, they feel anxious and succumb to despair in a world which seems to have little meaning. Because antidepressant medications can sometimes overcome these stigmata of depression without psychotherapy, some argue that alterations in the anatomy of the brain and the biochemistry of nerve impulses play the primary role in how we view ourselves and the world. They argue that the study of the underlying biology of depression gives us invaluable information about a neurobiology of meaning and self-acceptance.

Few other illnesses so frontally attack our dignity, so undermine our concept of ourselves, or so distort our expectations of the world. Depression is rendered more catastrophic because it is a disease that first presents in late adolescence or early adulthood,  and often recurs throughout life.

At the same time, we know that learning and experience influence each of these biological processes. Thus, despite the strong biological elements of depression, life experience plays an equally important role. Multiple studies of identical twins reared apart reveal that if one twin suffers from depression, the other twin will have a depression only 60% of the time. The residual 40% represents the influence of environmental factors. As with coronary artery disease, major depression is a complex disease in which vulnerability reflects a combination of genetic and environmental factors. For coronary artery disease, the predisposing environment consists of the combined effects of overeating, underactivity, smoking, and chronic stress. For depression, the predisposing environment consists of early loss, abandonment, trauma, or sustained, inescapable stressors throughout adult life.

Though I had not seen the utilization of medications to treat depressive illness before arriving at the NIH in the mid-1970’s, I have come to appreciate the highly significant role that biology plays in the healing process. We know that some depressions do not yield to psychotherapy. It is clear that science, like psychotherapy, has an aesthetic of its own that is revealed when we observe how antidepressant medications restore the exquisite equilibria of biological systems whose regulations have gone awry. We now know that a combination of psychotherapy and psychopharmacology is more effective at treating depression than either method alone. Depression clearly falls at the intersection of genetic vulnerability with stressful, disturbing life experiences encoded in emotional memory. This intersection helps us to understand how psychotherapy can influence a disorder with biological vulnerability that is also responsive to medication.

You have already mentioned the importance of environmental factors. What is the relationship between stress and depression?

We now know that the stress system and depression have overlapping behavioral, physiological, and cognitive manifestations. They share similar neurotransmitter profiles and altered functions in multiple brain sites. The stress response, like the immune response, is an adaptive response. The stress response emerges in the context of both behavioral and physiological stressors, while the immune response is set into motion in the context of immune challenges. Adaptive responses can become dysregulated. When the immune system is disturbed, autoimmune disease occurs. I postulate here that depression represents the dysregulation of the stress response.

How does depression affect the rest of our physical health?

Depression’s effects on mood and behavior represent the tip of the iceberg of a syndrome associated with a variety of biochemical changes leading to other serious medical consequences. Depressed patients often demonstrate the premature onset of atherosclerotic heart disease, type II diabetes, and of osteoporosis or its precursor, osteopenia. Most dramatically, individuals with long lasting depressions have a doubling in the mortality rate at any age, independent of hypertension, smoking, and suicide, amounting to an approximate loss of seven years of life. In many ways, depression seems like a process of premature aging associated with a shortened lifespan. Because of the psychological and physical dimensions of depression, and its early onset as a lifetime illness, the World Health Organization ranks depression as the 3rd greatest burden of disease worldwide, and predicts that it will be the 2nd by 2020.

It is clear that science, like psychotherapy, has an aesthetic of its own that is revealed when we observe how antidepressant medications restore the exquisite equilibria of biological systems whose regulations have gone awry.

Are there any recent advances in our understanding of depression that offer particular hope?

Preliminary trials have revealed that a compound called ketamine can induce an almost immediate resolution of symptoms within one hour in otherwise treatment-resistant patients who are severely depressed. Responses to a single infusion last a week or more. Current antidepressants all take 2-4 weeks to work. For acutely suicidal patients, this is unacceptable. In addition to its rapid onset of action, ketamine also promotes robust remissions rather than partial ones. Ketamine blocks an important component of the glutamate neurotransmitter system, making glutamate a prime target for multiple psychotropic agents that could revolutionize the treatment of depression. Other rapid acting agents are also in clinical trials.

In addition we have now identified two processes, called neuroplasticity and neurogenesis, that are key to a normal stress response, but are markedly reduced by chronic stress, resulting in a depression-like behavioral syndrome. Neuroplasticity represents the growth of new nerve fibers that convey added information to other cells. Neurogenesis represents the production of new neurons that promote successful adaptation to stress. Recently developed antidepressants can reverse the stress-induced decrease in neuroplasticity and neurogenesis and resolve the depression-like behavioral syndrome.

We can foresee other advances that will come as a result of genomic medicine. Depression is an illness associated with mutations of many genes. When gene therapy becomes available, depression could be prevented or treated by replacing or repairing mutant genes, or by administering agents that repair damaged genes. Current studies sequence the entire genome in depressed patients and healthy volunteers to uncover potential genes involved in the pathophysiology of depressive illness. Soon, medications will be developed that alter the expression or actions of these genes.

This sounds promising. Will this kind of genomic medicine result in more personalized antidepressant therapy?

Pharmacogenomics is the branch of genomic science dealing with the influence of genetic variation on drug response in patients. Specific DNA sequences are linked to positive responses to specific drugs. Thus, scientists identify a specific genetic fingerprint to isolate those patients who are highly likely to respond to a specific medication. Such approaches promise the advent of personalized medicine in which drugs are optimized for each individual’s unique genetic makeup.

Philip W. Gold is a member of the Library of Congress Scholars Council. Check back for future interviews with Scholars Council members.

Past interviews in this series:

Related links: 



  1. Dear friends, members of the Library of Congress Scholars Council, Kluge Center scholars, guests and my host, the program today, Can Depression be Cured? inferred the hope in practice that the answer is certainly, yes. May the questions brought and request by Dr DePaulo made, for major investigative centers, has been realized in the amazing and new contribution of the Sanford Burnham Prebys (SBP) Medical Discovery Institute (La Jolla, California). {} Further reaches of human nature in the name of care. Great. Thank you for the concern for public learning. Best wishes!

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