In addition to his groundbreaking work on memory, Kandel also made an impressive series of discoveries that enhanced our understanding of anxiety disorders, schizophrenia, addiction, and aging. For example, Kandel’s lab isolated a gene called RbAp48 that produces a protein involved in memory formation in the hippocampus. Kandel discovered that this gene is expressed less and less as we age, suggesting that treatments that sustain or increase the gene’s activity could potentially reduce age-related memory loss. As our expected lifespan continues to increase, RbAp48 might just hold the key to preserving our memories in our ever-lengthening golden years.
Kandel’s greatest contribution to psychiatry, though, may not have been any single neurobiological discovery, but his cumulative influence over psychiatry’s direction. As a new generation of psychiatrists came of age in the 1970s and witnessed the therapeutic effects of psychopharmaceuticals and the new images of living brains, they began to believe there was more to mental illness than psychodynamics. The brain beckoned as an unopened treasure chest of insights and therapies—but how to unlock the mysteries of this mysterious organ? There was little psychiatric scholarship on the brain itself, and even less research on the cellular and molecular mechanisms of the brain. The few dedicated brain researchers tended to focus on relatively tractable functions like vision, sensation, and movement. Very few possessed the audacity (or foolishness) to tackle the higher mental functions underpinning human behavior… and Eric Kandel was the first of these few.
Before Kandel, very few psychiatric researchers used the research methodologies routinely used in other areas of biomedical research, and those who did had to seek training in the laboratories of scientists outside psychiatry, as did Kandel. Kandel showed how brain functions could be studied at the cellular and molecular levels in a way that could inform our understanding of the operation of the mind. By the late ’70s, Kandel had emerged as the iconic role model of the psychiatric neuroscientist, inspiring a new generation of young research psychiatrists to incorporate brain science into their own careers.
Psychiatrists Steven Hyman (former NIMH director and Harvard provost) and Eric Nestler (chair of neuroscience at Mt. Sinai School of Medicine) were both the intellectual progeny of Kandel. In 1993, they published a seminal volume entitled The Molecular Foundations of Psychiatry that transformed the way psychiatrists thought about their own field. Inspired by Kandel’s three decades of pioneering research, Hyman and Nestler’s book described how basic neuroscience methods could be applied to the study of mental illness.
Ken Davis (CEO and dean of Mt. Sinai Medical Center) was another early psychiatric neuroscientist influenced by Kandel. Davis developed treatments based on the cholinergic theory of Alzheimer’s disease, which directly led to the most popular Alzheimer’s medications, including Aricept and Reminyl. Tom Insel (current director of NIMH) decided to shift his research career in midstream from clinical psychiatry to basic neuroscience—a gutsy move at the time—because of Kandel’s visionary research.
The generation of psychiatric neuroscientists that followed forged further inroads into the mysterious workings of the brain. Karl Deisseroth, a Stanford psychiatrist trained in molecular biology and biophysics, devised disruptively innovative techniques (optogenetics and clarity) to elucidate brain structure and function, which have won him widespread acclaim. In every way he is heir to Kandel’s legacy—a clinically attuned psychiatrist who continues to see patients and a world-class neuroscientist—including the fact that he is the leading candidate to be the next psychiatrist to win the Nobel Prize.
Kandel’s long, solitary journey in search of memory ultimately led to widespread acclaim. In 1983, he received the Lasker Award for Basic Science. In 1988, he was awarded the National Medal of Science. And in 2000 he received the greatest accolade available to any researcher, the Nobel Prize in Physiology and Medicine. Today, young psychiatrists take brain research for granted. MD-PhDs—researchers trained as both physicians and scientists—are now as common in psychiatry as in any other medical discipline. And while Kandel was only the second psychiatrist to receive the Nobel (Julius Wagner-Juaregg received the first for his malaria cure, and Moniz was a neurologist), after his trailblazing career I don’t think we will be waiting long for a third.
Eric Kandel with grandchildren at the Nobel ceremony in Stockholm, Sweden, December 10, 2000. (Photograph by Tomas Hökfelt, from Eric Kandel’s personal collection)
Reforming Talk Therapy
As dramatic breakthroughs in psychopharmacology, neuroimaging, and neuroscience strengthened biological psychiatry and fomented a brain revolution, the science of psychodynamic psychiatry was advancing on a parallel track. The 1960s saw the first meaningful advances in what was still psychiatry’s principal mode of treatment: talk therapy.
Ever since Freud first established the ground rules for psychotherapy at the beginning of the twentieth century, psychoanalysis had been king of the consulting room. For generations, the public associated a visit to a shrink with reclining on a couch or comfortable chair and unloading all the neurotic minutiae of their lives in an hour-long session, a characterization frequently depicted in the early films of Woody Allen. The unquestioned Freudian rules of engagement required the doctor to remain remote and impersonal; expressions of emotion and empathy were forbidden. Psychiatrists as recently as the 1990s were still being trained to stay aloof, deflecting a patient’s questions with questions of their own. Family photographs, diplomas, and any other personal emblems were kept out of the shrink’s office to maintain the illusion of impenetrable anonymity.
When change finally came to this ossified mode of talk therapy, it was at the hands of a disillusioned psychoanalyst. Many of the most disruptive challenges to psychoanalysis were instigated by onetime Freudians: ex-psychoanalyst Robert Spitzer eliminated neurosis as a psychiatric diagnosis in the 1970s; ex-psychoanalyst Nathan Kline pioneered psychopharmacological treatments in the 1960s; and in a moment akin to Martin Luther nailing his ninety-five theses to the Wittenberg church door, psychoanalyst Tim Beck committed professional heresy when he declared there was another means by which to effect therapeutic change, through psychotherapy rather than psychoanalysis.
Aaron “Tim” Beck was born in Rhode Island in 1921, the son of Russian Jewish immigrants. After graduating from the Yale University School of Medicine, Beck became a psychiatrist and embraced the prevailing theory of the age. In 1958 he wrote to a colleague, “I have come to the conclusion that there is one conceptual system that is peculiarly suitable for the needs of the medical student and physician-to-be: Psychoanalysis.”
Beck was so completely convinced that psychoanalytic theory represented the correct way to think about mental illness that he wanted to prove to skeptics that scientific research could test psychoanalytic theory. In 1959, he decided to carry out an experiment designed to validate a psychoanalytic theory of depression known as “inverted hostility.” This theory held that a person suffering from depression was angry at someone else (frequently a parent) but was unconsciously redirecting this anger toward himself. As an example, imagine that your significant other leaves you for someone more attractive; inverted hostility suggested that rather than expressing anger toward your ex, you’d say he had done nothing wrong at all, but you’d feel angry at yourself for having driven him away, which would express itself as sadness and paralysis.
One of the predictions of inverted hostility theory was that depressed individuals would feel better about themselves after a failure, while they should feel worse about themselves after a success. This convoluted logic was predicated on the idea that since a depressed individual was angry at herself (the “inverted hostility”), she did not deserve success and would want to punish herself, and therefore would feel satisfaction when the object of her hostility (herself) failed at a task. Beck rigged a card-sorting test so that he could control whether his subjects succeeded or failed, and then measured their self-esteem afterward. To his astonishment, his results showed t
he exact opposite of what he had expected: When depressed individuals were allowed to attain success at sorting cards, they felt much better; but when they were forced to fail, they felt worse. “After that, I became suspicious that the entire theory was wrong,” Beck says.
With his Freudian blinders loosened, Beck began paying careful attention to the precise nature of his depressed patients’ cognition. “Psychoanalytic theory insisted that depressed people should have excessive hostility in their dreams because of their inverted hostility. But when you looked at the content of their dreams, they actually had less hostility in them than normal people did,” Beck explains. Instead, Beck noticed that his depressed patients experienced streams of distorted thoughts that seemed to spontaneously surge forth. These “automatic thoughts,” as Beck labeled them, had nothing to do with anger but instead reflected “illogical ideas about themselves and the world they lived in.” A middle-aged woman who was attractive and accomplished might relentlessly describe herself as incompetent. Beck believed that this negativism rendered her perpetually distracted and cheerless and eventually led to her being depressed. This was a radical revision of psychiatry’s conception of depression—instead of characterizing depression as an anger disorder, he characterized it as a cognitive disorder.
Redefining the nature of depression was already the kind of thing that would have got Beck excommunicated by Freud had he still been alive, but then he made another heretical discovery: When he stopped trying to get patients to understand their buried neurotic conflicts and instead used talk therapy to help his patients correct their illogical thoughts and change their self-defeating perceptions, they became happier and more productive. Even more astonishing, these psychic improvements took place at a much faster rate than under psychoanalysis—weeks, instead of months or years.
I asked Beck what it was like when he first saw the rapid effects of his new technique. “My patients would have ten or twelve sessions and then say, Terrific, you’ve helped me a lot, thanks, I’m ready to go handle this on my own, bye! My patient list shrunk down to zero because everybody was getting helped so fast. My department chair saw all my patients leaving and told me, ‘You’re not making it in private practice, why don’t you try something else.’ ”
Rather than taking his chair’s advice, Beck formalized his technique into an unprecedented method of psychotherapy that helped patients become aware of their distorted thoughts and taught them how to challenge these thoughts. Beck called this method cognitive-behavioral therapy, or CBT. Here’s an abbreviated transcript of a conversation (from the book Cognitive-Behavioral Therapy for Adult Attention Deficit Hyperactivity Disorder) between a contemporary CBT therapist (T) and a patient with ADHD (P) who is afraid to sign up for a professionally necessary class because of his fears of what his ADHD will make him do:
T: What are your thoughts about the CPR course?
P: I’ve done a CPR course in the past and by the end it was hard to pay attention. I’d be worried I might make some mistakes, especially when I’m working in a group with others.
T: Can you describe your apprehension in more detail, what specifically makes you feel that way?
P: These are the people who’d be coworkers, who I’d be working with and interacting with. I’d be worried about messing up in front of them.
T: And what would the consequence of that be?
P: We’d have to start over from the beginning and get retested because of me and I’d hold up the entire class.
T: Do you remember having had any experiences in your life in which the worries you’ve described—making mistakes in front of others or holding up a group—actually happened?
P: I don’t know. It hasn’t happened a lot. I’ve been able to avoid big embarrassments. In one CPR course I made a mistake during one of the team exercises. I was tired and I lost my focus.
T: When you realized you made a mistake, what thoughts did you have?
P: “What’s wrong with me? Why can’t I do this right?”
T: Okay. So there was a situation in your past that is similar to what you’re concerned might happen in a longer CPR course. Recognizing you made a mistake is not a distorted thought. In this case, it was accurate—you made an error. However, it sounds as though the conclusions you drew that something was wrong with you may have been distorted. What was the reaction of your teammates when you had to redo the CPR sequence?
P: Nobody laughed, but I could see it in their faces that they were upset and that they were annoyed at me.
T: What did you see in their faces that was evidence that they were annoyed?
P: One lady rolled her eyes.
T: How long after the course do you think the lady thought about your mistake? Do you think she went home and told her family, “You won’t believe what happened in CPR class today? This guy made a mistake during our final test?”
P: (Laughing) No. She probably didn’t give it much thought.
Notice how the therapist listens carefully to what the patient says, and immediately responds to each assertion. The therapist is talking even more than the patient—a cardinal sin in psychoanalysis. Freud taught psychiatrists to remain remote and aloof, but the therapist in this exchange is engaged and supportive, and even injects some humor into his interactions with his patient. But the differences between Beck’s CBT and traditional psychoanalysis ran even deeper.
Whereas psychoanalysis attempted to unearth impulses deeply buried in the unconscious, Beck was interested in the thoughts circling around and around in the waking consciousness. Whereas psychoanalysis attempted to uncover the historic motives behind troubling emotions, Beck scrutinized the immediate experience of a person’s emotions. Whereas psychoanalysis was ultimately pessimistic, seeing neurotic conflict as the price for existing in a social world, Beck remained upbeat, suggesting that if people were willing to work hard on their problems, they could eliminate their neurotic tendencies.
CBT had an energizing and liberating effect on the field. Unlike psychoanalysis, which placed restrictions on the therapist’s conduct and was undefined and open-ended, possibly lasting for years, CBT had a defined set of instructions for therapists, entailed a finite number of sessions, and established specific goals. CBT’s therapeutic effects were soon validated in controlled experiments that compared the effects of CBT with a placebo and with different forms of psychoanalysis when treating depression, making CBT the first “evidence-based psychotherapy”—a form of talk therapy proven to work through a blind experiment. Since then, numerous studies have validated CBT’s effectiveness as a treatment for many mental disorders, including anxiety disorders, obsessive-compulsive disorder, and ADHD.
The unexpected success of CBT opened the door to other kinds of evidence-based psychotherapy by showing that it was possible to treat patients more quickly and effectively than traditional psychoanalysis allowed. In the 1970s, two Yale faculty members created “interpersonal psychotherapy,” a form of talk therapy for depressed patients that encourages patients to regain control of their moods and their lives. In the late 1980s, dialectical behavioral therapy, a highly focused form of psychotherapy for patients with borderline personality disorder, was created by a psychologist who suffered from the disorder herself. In 1991, two psychologists introduced motivational interviewing, a psychotherapeutic technique for treating addiction that fosters motivation.
Tim Beck’s venture beyond the rigid precepts of psychoanalysis to explore the true nature of neurotic depression through experimentation enabled him to create a unique form of psychotherapy that improved the lives of millions of patients. By doing so, he demonstrated that rigorous science was not solely the purview of biological psychiatrists but could also be wielded to dramatic effect by psychodynamic psychiatrists.
Too Many Genes, Too Few Genes
By the mid-1980s, psychiatry was using more effective forms of psychotherapy, more effective psychopharmaceuticals, and more effective brain imaging. The field of neuroscience was rapidly gaining s
trength. There was growing acceptance among psychiatrists that people suffering from mental illness had something wrong in their brain—especially severe mental illnesses that previously required institutionalization, like schizophrenia, bipolar disorder, autism, and depression. But if something was wrong with your mentally ill brain, then where did this wrongness come from? Were you born to it? Or was it forged within you by your experiences in life? The answer turned out to be quite different than anyone expected.
The relationship between genes and mental illness did not interest the Freudians (who emphasized the role of childhood experiences) or the social psychiatrists (who emphasized the role of family and cultural environments). But in the early 1960s, a physician-scientist named Seymour Kety decided to investigate the genetic basis of mental illness, following up on the work of the German psychiatrist Franz Kallman. It had been known for centuries that mental illness ran in families—but families have many things in common that are not genetic, such as wealth, religion, and table manners, that come from a shared or common environment. The first question Kety attempted to answer seemed straightforward enough: Is schizophrenia primarily caused by genes or the environment?
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