In Search of Memory: The Emergence of a New Science of Mind (43 page)

The clinical features of depression are easily summarized. In Hamlet’s words, “How weary, stale, flat, and unprofitable seem to me all the uses of this world!” Untreated, an episode of depression typically lasts four months to a year. It is characterized by an unpleasant mood that is present day in and day out for a majority of the time, as well as intense mental anguish, inability to experience pleasure, and a generalized loss of interest in the world. Depression is often associated with a disturbance of sleep, diminished appetite, loss of weight, loss of energy, decreased sex drive, and slowing down of thoughts.

Depression affects about 5 percent of the world’s population at some time in their lives. In the United States, 8 million people are affected at any given time. Severe depression can be profoundly debilitating: in extreme cases, patients stop eating or maintaining basic personal hygeine. Although some people have only a single episode, the illness is usually recurrent. About 70 percent of people who have one major depressive episode will have at least one more. The average age of onset is about twenty-eight years, but the first episode can occur at almost any age. Indeed, depression can affect young children, although it often goes unrecognized in them. Depression also occurs in the elderly; often, older people who become depressed have not had an earlier episode, and their depression is more resistant to treatment. Women are affected two to three times as often as men.

SEVERAL EFFECTIVE DRUGS HAVE BEEN DEVELOPED TO COMBAT
depression. The first one—a monoamine oxidase inhibitor (MAOI)—was initially developed to fight a very different disorder, tuberculosis. MAOIs act by decreasing the breakdown of serotonin and norepinephrine, thereby making more of these neurotransmitters available for release at synapses. Physicians soon noticed that patients receiving these MAOIs were amazingly upbeat, considering the continued seriousness of their illness. Before long, physicians realized the MAOIs are more effective against depression than against tuberculosis. This insight led to the development of a group of drugs that are now effective in 70 percent of patients with major depression.

Following in the wake of the discovery of antipsychotic agents, the discovery of antidepressants moved psychiatry into a new era. Far from being a field without effective treatments for the seriously ill, psychiatry now had an effective therapeutic armamentarium comparable to that of other areas of medicine.

Drugs that are effective against depression act primarily on two modulatory transmitter systems in the brain, one of which is serotonin; the other is norepinephrine. The evidence is particularly clear regarding serotonin, which is strongly correlated with mood states in humans: high concentrations of serotonin are associated with feelings of well-being, whereas low concentrations are associated with symptoms of depression. Indeed, people who commit suicide have extremely low concentrations of serotonin.

The most effective antidepressant drugs are known as selective serotonin reuptake inhibitors. These drugs increase the concentration of serotonin in the brain by inhibiting the molecular transport system that removes serotonin from the synaptic cleft, where it is released by presynaptic neurons. Based on this finding, a hypothesis was developed which holds that depression represents decreased availability in the brain of serotonin, norepinephrine, or both.

Although this hypothesis explains some aspects of a patient’s response to antidepressant drugs, it fails to account for a number of important phenomena. In particular, it fails to explain why antidepressant medications take only hours to inhibit the reuptake of serotonin in neurons, yet take at least three weeks to alleviate the symptoms of depression in people. If antidepressant drugs actually produce all of their actions by inhibiting the uptake, and thereby promoting the accumulation, of serotonin at the synapses, what accounts for the delay in the response? Perhaps it takes at least three weeks for the increased serotonin to affect key neural circuits throughout the brain—for the brain to “learn” how to become happy again. In addition, we now know that antidepressants affect other processes besides the reuptake and accumulation of serotonin.

One important clue to depression has come from the work of Ronald Duman at Yale and Rene Hen at Columbia. They have found that antidepressant drugs also increase the ability of a small region of the hippocampus, the dentate gyrus, to generate new nerve cells. Although the vast majority of nerve cells do not divide, this small nest of stem cells does divide and gives rise to differentiated nerve cells. Over a period of two to three weeks, the time it takes antidepressant drugs to work, a few of the cells are incorporated into the neural networks of the dentate gyrus. The function of these stem cells is unclear. To explore it, Hen used radiation to destroy the dentate gyrus in a mouse model of depression caused by stress. He found that antidepressants could no longer reverse depressionlike behavior in mice lacking the stem cells.

These remarkable new findings raise the possibility that antidepressants exert their effects on behavior in part by stimulating the production of neurons in the hippocampus. This idea is consistent with the finding that depression often compromises memory severely. Perhaps the damage done to the brain by depression can be overcome by restoring the ability of the hippocampus to produce new nerve cells. A remarkable idea! And one that will be challenging the imagination and skill of a new generation of psychiatric researchers in the decades ahead.

CLEARLY, MOLECULAR BIOLOGY IS POISED TO ACCOMPLISH FOR
psychiatry what it has already begun to do for neurology. Genetic models of major mental illnesses in mice might therefore be useful in at least two ways. First, as studies of human patients lead to the discovery of variant genes that may predispose people to mental disease (such as the variant of the D2 receptor gene that is a risk factor for schizophrenia), these genes can be inserted into mice and used to test specific hypotheses about the origins and development of particular illnesses. Second, genetic studies in mice will enable us to explore the complex molecular pathways underlying disease at a level of detail and precision impossible in human patients. Such basic neurobiological studies will enhance our ability to diagnose and classify mental disorders and will provide a rational foundation for the development of new molecular therapies.

In a larger sense, we are moving from a decade concerned with probing the mysteries of brain function to a decade of exploring treatments for brain dysfunction. In the fifty years since I entered medicine, basic science and clinical science have ceased to be worlds apart. Some of the most interesting questions in neural science today are directly related to pressing issues in neurology and psychiatry. As a result, translational research is no longer a limited endeavor carried out by a few people in white coats. Rather, the potential for therapeutic use guides much of the research done in neuroscience.

During the 1990s, known as the Decade of the Brain, we all became translational researchers. In the first decade of the twenty-first century, our progress is being transformed into the Decade of Brain Therapeutics. As a consequence, the disciplines of psychiatry and neurology are being brought intellectually closer to each other. One can foresee the day in the not-too-distant future when resident physicians in both disciplines will share a common year of training, comparable to the year of residency training in internal medicine for physicians who go on to specialize in widely different areas, such as heart disease or gastrointestinal disorders.

W
hen psychoanalysis emerged from Vienna in the first decades of the twentieth century, it represented a revolutionary way of thinking about mind and its disorders. The excitement surrounding the theory of unconscious mental processes increased as the century reached its midpoint and psychoanalysis was brought to the United States by émigrés from Germany and Austria.

As an undergraduate at Harvard, I shared this enthusiasm, not only because psychoanalysis presented a view of mind that appeared to have great explanatory power, but also because it conjured up the intellectual environment of Vienna in the early twentieth century, an environment that I admired and had missed out on. Indeed, what I so enjoyed in the intellectual life that surrounded Anna Kris and her parents were the insights and perspectives it gave me on life in Vienna in the 1930s. There was talk about
Die Neue Frei Presse (The New Free Press),
Vienna’s most important newspaper, which, according to the Krises, was neither terribly new nor terribly free. The Krises also recalled the dramatic, even histrionic, lectures of Karl Kraus, the cultural critic and student of language whom I admired very much. Kraus lashed out against Viennese hypocrisy, and his great play
The Last Days of Mankind
predicted what was to come: World War II and the Holocaust.

But by 1960, when I began clinical training in psychiatry, my enthusiasm had stalled. My marriage to Denise, an empirical sociologist, and my research experiences—first in Harry Grundfest’s laboratory at Columbia and then in Wade Marshall’s laboratory at the National Institute of Mental Health—tempered my enthusiasm for psychoanalysis. While I still admired the rich, nuanced view of mind that psychoanalysis had introduced, I was disappointed during my clinical training to see how little progress psychoanalysis had made toward becoming empirical, toward testing its ideas. I also was disappointed in many of my teachers at Harvard, physicians who were motivated to enter psychoanalytic psychiatry out of humanistic concerns, as I was, but who had little interest in science. I sensed that psychoanalysis was moving backward into an unscientific phase and, in the process, was taking psychiatry with it.

UNDER THE INFLUENCE OF PSYCHOANALYSIS, PSYCHIATRY WAS
transformed in the decades following World War II from an experimental medical discipline closely related to neurology into a nonem-pirical specialty focused on the art of psychotherapy. In the 1950s academic psychiatry abandoned some of its roots in biology and experimental medicine and gradually became a therapeutic discipline based on psychoanalytic theories. As such, it was strangely unconcerned with empirical evidence or with the brain as the organ of mental activity. In contrast, medicine evolved during this period from a therapeutic art into a therapeutic science, based on a reductionist approach derived first from biochemistry and later from molecular biology. During medical school, I had witnessed and been influenced by this evolution. I therefore could not help but note the peculiar position of psychiatry within medicine.

Psychoanalysis had introduced a new method of examining the mental life of patients, a method based on free association and interpretation. Freud taught psychiatrists to listen carefully to patients and to do so in new ways. He emphasized a sensitivity to both the latent and the manifest meaning of the patient’s communications. He also created a provisional schema for interpreting what might otherwise appear as unrelated and incoherent reports.

So novel and powerful was this approach that for many years not only Freud but other intelligent and creative psychoanalysts as well could argue that psychotherapeutic encounters between patient and analyst provided the best context for scientific inquiry into mind, particularly into unconscious mental processes. Indeed, in the early years psychoanalysts made many useful and original observations that contributed to our understanding of mind simply by listening carefully to their patients and by testing the ideas that arose from psychoanalysis—such as childhood sexuality—in observational studies of normal child development. Other original contributions included the discovery of different types of unconscious and preconscious mental processes, the complexities of motivation, transference (the displacing of past relationships onto the patient’s current life), and resistance (the unconscious tendency to oppose a therapist’s efforts to effect change in the patient’s behavior).

Sixty years after its introduction, however, psychoanalysis had exhausted much of its novel investigative power. By 1960 it was clear, even to me, that little in the way of new knowledge or insights remained to be learned by observing individual patients and listening carefully to them. Although psychoanalysis had historically been scientific in its ambitions—it had always wanted to develop an empirical, testable science of mind—it was rarely scientific in its methods. It had failed over the years to submit its assumptions to replicable experimentation. Indeed, it was traditionally far better at generating ideas than at testing them. As a result, psychoanalysis had not made the same progress as some other areas of psychology and medicine. Indeed, it seemed to me that psychoanalysis was losing its way. Rather than focusing in on areas that could be tested empirically, psychoanalysis expanded its scope, taking on mental and physical disorders that it was not optimally suited to treat.

Initially, psychoanalysis was used to treat what were called neurotic illnesses: phobias, obsessional disorders, and hysterical and anxiety states. However, psychoanalytic therapy gradually extended its reach to almost all mental illnesses, including schizophrenia and depression. By the late 1940s, many psychiatrists, influenced in part by their successful treatment of soldiers who had developed psychiatric problems in battle, had come to believe that psychoanalytic insights might be useful in treating medical illnesses that did not respond readily to drugs. Diseases such as hypertension, asthma, gastric ulcers, and ulcerative colitis were thought to be psychosomatic—that is, induced by unconscious conflicts. Thus by 1960 psychoanalytical theory had become for many psychiatrists, particularly those on the East and West coasts of the United States, the prevailing model for understanding all mental and some physical illnesses.

This expanded therapeutic scope appeared on the surface to strengthen psychoanalysis’s explanatory power and clinical insight, but in reality it weakened psychiatry’s effectiveness and hindered its attempt to become an empirical discipline aligned with biology. When Freud first explored the role of unconscious mental processes in behavior in 1894, he was also engaged in an effort to develop an empirical psychology. He tried to work out a neural model of behavior, but because of the immaturity of brain science at the time, he abandoned the biological model for one based on verbal reports of subjective experiences. By the time I arrived at Harvard to train in psychiatry, biology had begun to make important inroads in understanding higher mental processes. Despite these advances, a number of psychoanalysts took a far more radical stance—biology, they argued, is irrelevant to psychoanalysis.

This indifference to, if not disdain for, biology was one of the two problems I encountered during my residency training. An even more serious problem was the lack of concern among psychoanalysts for conducting objective studies, or even for controlling investigator bias. Other branches of medicine controlled bias by means of blind experiments, in which the investigator does not know which patients are receiving the treatment being tested and which ones are not. However, the data gathered in psychoanalytic sessions are almost always private. The patient’s comments, associations, silences, postures, movements, and other behaviors are privileged. Of course, privacy is central to the trust that must be earned by the analyst—and therein lies the rub. In almost every case, the only record is the analyst’s subjective accounts of what he or she believes happened. As research psychoanalyst Hartvig Dahl has long argued, such interpretation is not accepted as evidence in most scientific contexts. Psychoanalysts, however, are rarely concerned about the fact that accounts of therapy sessions are necessarily subjective.

As I began my residency in psychiatry, I sensed that psychoanalysis could be immeasurably enriched by joining forces with biology. I also thought that if the biology of the twentieth century were to answer some of the enduring questions about the human mind, those answers would be richer and more meaningful if they were arrived at in collaboration with psychoanalysis. Such a collaboration would also provide a firmer scientific foundation for psychoanalysis. I believed then, and I believe more strongly now, that biology may be able to delineate the physical basis of several mental processes that lie at the heart of psychoanalysis—namely, unconscious mental processes, psychic determinism (the fact that no action or behavior, no slip of the tongue is entirely random or arbitrary), the role of the unconscious in psychopathology (that is, the linking of psychological events, even disparate ones, in the unconscious), and the therapeutic effect of psychoanalysis itself. What particularly fascinated me, because of my interest in the biology of memory, was the possibility that psychotherapy, which presumably works in part by creating an environment in which people learn to change, produces structural changes in the brain and that one might now be in a position to evaluate those changes directly.

FORTUNATELY, NOT EVERYONE IN THE PSYCHOANALYTIC
community thought that empirical research was irrelevant for the future of the discipline. Two trends have gained momentum in the forty years since I completed my clinical training, and they are beginning to exert a significant impact on psychoanalytic thought. One trend is the insistence on an evidence-based psychotherapy. The second, more difficult trend is the attempt to align psychoanalysis with the emerging biology of mind.

Perhaps the most important force driving the first trend has been Aaron Beck, a psychoanalyst at the University of Pennsylvania. Influenced by modern cognitive psychology, Beck found that a patient’s major cognitive style—that is, the person’s way of perceiving, representing, and thinking about the world—is a key element in a number of disorders, such as depression, anxiety disorders, and obsessive-compulsive states. By emphasizing cognitive style and ego functioning, Beck was continuing a line of thought initiated by Heinz Hartmann, Ernst Kris, and Rudolph Lowenstein.

Beck’s emphasis on the role of conscious thought processes in mental disorders was novel. Traditionally, psychoanalysis had taught that mental problems arise from unconscious conflicts. For example, in the late 1950s, when Beck began his investigations, depressive illness was commonly viewed as “introjected anger.” Freud had argued that depressed patients feel hostile and angry toward someone they love. Because patients cannot deal with negative feelings about someone who is important, needed, and valued, they handle those feelings by repressing them and unconsciously directing them against themselves. It is this self-directed anger and hatred that leads to low self-esteem and feelings of worthlessness.

Beck tested Freud’s idea by comparing the dreams of depressed patients with those of patients who were not depressed. He found that depressed patients exhibited not more, but less hostility than other patients. In the course of carrying out this study and listening carefully to his patients, Beck found that rather than expressing hostility, depressed people express a systematic negative bias in the way they think about life. They almost invariably have unrealistically high expectations of themselves, overreact dramatically to any disappointment, put themselves down whenever possible, and are pessimistic about their future. This distorted pattern of thinking, Beck realized, is not simply a symptom, a reflection of a conflict lying deep within the psyche, but a key agent in the actual development and continuation of the depressive disorder. Beck made the radical suggestion that by identifying and addressing the negative beliefs, thought processes, and behaviors, one might be able to help patients replace them with healthy, positive beliefs. Moreover, one could do so independent of personality factors and the unconscious conflicts that may underlie them.

To test this idea clinically, Beck presented patients with evidence from their own experiences, actions, and accomplishments that countered, challenged, and corrected their negative views. He found that they often improved with remarkable speed, feeling and functioning better after a very few sessions. This positive result led Beck to develop a systematic, short-term psychological treatment for depression that focuses not on a patient’s unconscious conflict, but on his or her conscious cognitive style and distorted way of thinking.

Beck and his associates initiated controlled clinical trials to evaluate the effectiveness of this mode of therapy, compared with placebo and with antidepressant medication. They found that cognitive behavioral therapy is usually as effective as antidepressant medication in treating people with mild and moderate depression; in some studies, it appeared superior at preventing relapses. In later controlled clinical trials, cognitive behavioral therapy was successfully extended to anxiety disorders, especially panic attacks, post-traumatic stress disorders, social phobias, eating disorders, and obsessive-compulsive disorders.

Beck went beyond introducing a novel form of psychotherapy and testing it empirically. He also developed scales and inventories for assessing the symptoms and extent of depression and other psychiatric disorders, measures that have introduced new scientific rigor into psychotherapy-based research. In addition, he and his colleagues wrote manuals on how the treatments were to be carried out. Beck has thus brought to the psychoanalytic therapy of mind a critical attitude, a quest for empirical data, and a desire to find out whether a given therapy works.

Influenced by Beck’s approach, Gerald Klerman and Myrna Weissman created a second scientifically valid form of short-term psychotherapy, known as interpersonal psychotherapy. This treatment focuses on correcting patients’ mistaken beliefs and on changing the nature of their communications in various interactions with others. Like cognitive behavioral therapy, it has proven efficacious in controlled trials for mild and moderate depression and has been codified in teaching manuals. Interpersonal therapy seems to be particularly effective in situational crises, such as the loss of a partner or a child, whereas cognitive therapy appears to be particularly effective in treating chronic disorders. Similarly, although not yet as extensively studied, Peter Sifneous and Habib Davanloo have formalized a third short-term treatment, brief dynamic therapy, which focuses on the patient’s defenses and resistance, and Otto Kernberg has introduced a psychotherapy focused on transference.