The Disordered Mind

by Eric R. Kandel

  Some of the worms are solitary, however. While feeding, they distribute themselves separately on a lawn of bacteria. The difference between the social and the solitary strains is due to a natural variant in a single gene, which is attributable to a change in a single nucleotide.20

  Sociability and solitariness can also be traced to a single gene in more-complex animals. While Thomas Insel was at Emory University, he and his colleagues explored the role of the hormone oxytocin in the prairie vole, a ratlike rodent.21 They found that the hormone stimulates milk production and regulates maternal-infant bonding, as well as other social behavior. To raise their young, male and female prairie voles form enduring pair bonds. These bonds are stimulated by the release of oxytocin in the female vole’s brain during mating and the release of a related hormone, vasopressin, in the male’s brain. Vasopressin also contributes to paternal behavior.

  While male prairie voles form secure pair bonds and help the females raise their offspring, males of a closely related species, the montane vole, breed widely and promiscuously and exhibit no paternal behavior. The difference between the two species is correlated with the number of vasopressin receptors—and hence the amount of vasopressin—in the male brain. Prairie voles have large concentrations of vasopressin in the brain region that deals with pair bonding, whereas montane voles do not. In the two species, variations in oxytocin concentrations in specific areas of the brain account for the differences in pair and parental bonding.22

  Increasing evidence points to an important role for oxytocin and vasopressin in human pair bonding and child rearing as well. Oxytocin is a peptide hormone that is produced in the hypothalamus and released into the bloodstream by the posterior pituitary gland. Oxytocin regulates milk production by mothers in response to their infants’ suckling. Moreover, this hormone enhances positive social interaction by increasing our feelings of relaxation, trust, empathy, and altruism. Sarina Rodrigues at Oregon State University has found that genetic variations in oxytocin production affect empathic behavior: people with less of the hormone in their brain have more difficulty reading faces and feeling distress at other people’s suffering.23

  Other research has suggested that oxytocin may affect our social cognition.24 When inhaled, the hormone seems to dampen our response to frightening stimuli. It is also thought to enhance positive communication. In some rare cases, nasal inhalation of oxytocin has even improved the social skills of people with autism. Oxytocin increases trust and the willingness to bear risks—essential features for friendship, love, and the organization of family.

  As these studies illustrate, some of the same hormones—and therefore the same genes—contribute to social behavior in people and in animals, suggesting that mutations in those genes may contribute to autism spectrum disorders. One can also explore aspects of the biological basis of autism by creating animal models of the disorder. David Sultzer at UCLA and his colleagues, for example, have found a drug that restores normal synaptic pruning in mouse models of autism, thus reducing the animals’ autistic-like behavior.25 Clearly, genetic studies in animals, as well as in people, can be tremendously valuable in understanding how a system as complex as our social brain can go awry.

  LOOKING AHEAD

  Scientists have gone from largely searching in the dark to having the tools at hand to make major strides in the genetics of autism. With the new technologies that have emerged in the last few years—being able to sequence entire genomes rapidly and rather cheaply, for one—scientists should be able to identify more of the critical autism genes in the future.

  Four points stand out in this search. First, hundreds of different genes are capable of contributing to autism spectrum disorders—not necessarily hundreds of genes within a single person, but hundreds of genes across the population. Second, while a mutation in a single gene is responsible for some disorders, such as Huntington’s disease, single mutations do not cause most other brain disorders, including autism, depression, bipolar disorder, and schizophrenia. Third, if we can find the genes that contribute to autism, we will be well on the road to understanding what is going wrong at the cellular and molecular levels. Some of the earliest genetic discoveries in autism have pointed to malfunctioning synapses.

  Finally, as we identify the genes that contribute to autism, we will gain a better understanding of the genes and the neural pathways that give rise to the social brain—the genes that make us the social beings we are. Moreover, we will learn how genetic predisposition interacts with environmental factors to give rise to specific disorders.

  3

  EMOTIONS AND THE INTEGRITY OF THE SELF: DEPRESSION AND BIPOLAR DISORDER

  We all experience emotional states. In fact, our language overflows with colorful descriptions of how we feel: I got up on the wrong side of the bed. He’s singing the blues. She’s over the moon about her new job. In these contexts, we are describing emotion as a temporary state of mind that comes and goes. Such shifts of emotion are entirely normal—and desirable. Emotional awareness is vital to staying alive and to negotiating the complexities of human social existence.

  A person’s emotional state is usually transient and occurs in response to a specific stimulus in the environment. When a particular emotional state becomes fixed and extended in time, we call it a mood. Think of emotion as the daily weather and mood as the prevailing climate. Just as climates range widely across the globe, so individuals vary in their predominant mood. Some enjoy a stable, sunny disposition, while others see the world through a darker lens. Such variation in the way we engage the world (psychiatrists call it temperament) is woven into the fabric of human behavior. Thus, we are talking here about the biology of the self in its deepest, most personal sense.

  Psychiatric disorders are characterized by exaggerations of normal behavior, so if we experience a persistent and unusual change in mood ourselves, or observe it in someone else, we have cause for concern. Disorders of mood are pervasive, long-lasting emotional states. They are extreme emotions that color a person’s outlook on life and affect behavior. For example, depression is an extreme form of melancholy or sadness accompanied by a lack of energy and a lack of emotion, while mania is an extreme form of elation and hyperactivity. In bipolar disorder, mood alternates between these two extremes.

  In this chapter, we consider the role that emotion plays in our everyday life, in our sense of self. We then examine the characteristics of depression and bipolar disorder and what they tell us about ourselves. We explore several remarkable advances in brain science that point to the causes of depression and bipolar disorder and that have led to promising new treatments for these disorders. We examine the importance of psychotherapy for people with mood disorders, both separate from and in combination with drugs. Finally, we look at the contribution of genes to disorders of mood. These revelations underscore the vital link between studies of brain disorders and our understanding of how the healthy emotional brain works.

  EMOTION, MOOD, AND THE SELF

  Our emotions are coordinated by the amygdala, a structure that lies deep within each of the temporal lobes of the brain. The amygdala connects to several other structures in the brain, among them the hypothalamus and the prefrontal cortex. The hypothalamus regulates heart rate, blood pressure, sleep cycles, and other bodily functions involved in our emotional reactions. As such, it is the executor of emotion, including happiness, sadness, aggression, eroticism, and mating. The prefrontal cortex, the seat of executive function and self-esteem, regulates emotion and its influence on thought and memory. As we shall see, the connections among these structures account for the varied psychological and physical manifestations of mood disorders.

  Emotion is part of the brain’s early warning system and is intimately linked to the body’s ancient survival mechanisms. As Charles Darwin first pointed out, emotions are part of a preverbal system of social communication that we share with other mammals. In fact, even with our extraordinary facility for language, we use emotion every day to communicate
our desires to one another and to monitor our social environment. When our emotions signal that events are dangerous or not unfolding favorably, we experience feelings of anxiety, irritability, and vigilance, often followed by sadness. At the opposite end of the spectrum, falling in love and other positive emotions give us a wonderful feeling of renewed energy and optimism.

  Our subjective emotional experience is constantly changing as our brain monitors the opportunities and stresses of a shifting social world and signals the appropriate coping response. Without these emotional assessments, we would experience the world as a series of random events with no point of reference—that is, with no sense of self.

  Mood disorders are brain diseases that afflict the integrity of the self—that collection of vital emotions, memories, beliefs, and behaviors that shapes each of us as a unique human being. It is precisely because of emotion’s central role in both our thinking and our feeling—and because we experience normal shifts in mood every day—that we have such difficulty identifying and accepting a mood disturbance as potentially abnormal. That same difficulty helps explain why people with mood disorders are frequently stigmatized. To put it simply, despite advances in science and medicine, many people are still inclined to view mood disorders as a personal weakness, as bad behavior, rather than as a set of illnesses.

  DISORDERS OF MOOD AND THE ORIGINS OF MODERN PSYCHIATRY

  Emil Kraepelin, whom we met in chapter 1, was a founder not only of modern scientific psychiatry, but also of psychopharmacology, the study of drugs’ effects on mood, thought, and behavior. In 1883 he published Compendium of Psychiatry, the first edition of what would grow into his great multivolume Textbook of Psychiatry. In 1891 he began to teach at the University of Heidelberg and later moved to the University of Munich. Kraepelin held that mental illnesses are strictly biological and that they have a heritable basis. What’s more, he insisted that psychiatric diagnoses be founded on the same criteria as diagnoses in other areas of medicine.

  Kraepelin had set himself a difficult task. In his day, it was impossible to confirm diagnoses of psychiatric diseases at autopsy because such diseases do not leave dramatic marks on the brain, and brain-imaging technology wouldn’t appear on the horizon until a century later. In the absence of biological markers and imaging, Kraepelin had to base his diagnoses on clinical observations of his patients.

  To guide his observations, Kraepelin relied on the same three criteria used in general medicine: What are the symptoms of the disease? What is the course of the disease? What is the final outcome?

  Applying those criteria to mental illnesses, Kraepelin distinguished two major groups of psychotic disorders: disorders of thought and disorders of mood. He called the disorders of thought dementia praecox—the dementia of young people—because they start earlier in life than other dementias, such as Alzheimer’s, and he called the disorders of mood manic-depressive illness because they manifest themselves as either depressed or elevated feeling states. We now refer to dementia praecox as schizophrenia, and we refer to manic-depressive illness as bipolar disorder. We refer to depressed states alone, with no manic component, as major depression, or unipolar depression. The majority of people with depressive disorders are unipolar.

  The distinctions that Kraepelin observed between the two major psychiatric disorders—schizophrenia and bipolar—have carried forward to this day. However, because recent genetic studies suggest that some genes may contribute to both types of disorders, we now realize that there may be overlap between them. There may also be overlap between these disorders and autism, which was recognized fully half a century after Kraepelin’s classic work.

  Disorders of thought and disorders of mood not only affect people differently, they run different courses and have different outcomes. Schizophrenia is characterized by cognitive decline that begins with the first episode of illness, usually in young adulthood, and continues throughout life, often with no remission. Mood disorders, in contrast, are most commonly episodic, with months to years elapsing between episodes. Major depression generally begins in the late teens and early twenties, whereas bipolar disorder usually begins in late adolescence. The average length of remission in major depression is about three months. This indicates that, at least initially, the changes in neural circuitry and brain function that lead to depression are reversible. As a person ages, the episodes of depression tend to last longer and the intervals of remission become shorter. People with a mood disorder can function very well during periods of remission, and the outcome of mood disorders is often more benign than that of schizophrenia.

  Because they affect neural circuits in many regions of the brain, mood disorders also cause changes in energy, patterns of sleep, and thinking. Many depressed people, for example, have trouble getting to sleep and staying asleep; others sleep all the time, especially if they are more withdrawn than anxious. Sleep deprivation, which causes increased activity in the amygdala, can trigger manic episodes in some people with bipolar disorder.

  Treatments for people with psychiatric disorders have improved by fits and starts since Philippe Pinel liberated the inmates of Salpêtrière hospital from their chains. A century elapsed before Pinel’s insistence that psychiatric disorders are medical in nature and that heredity plays a role in them was carried forward by Kraepelin. It took equally long for Pinel’s humane treatment of patients to reach fruition in psychotherapy. Since then, we have developed new forms of psychotherapy, new drug therapies, and a greater biological understanding of how these therapies act and interact. An essential component of treatment is understanding and accepting that psychiatric disorders are lifelong. As a result, people with mood disorders must be constantly aware of their feelings and their state of mind.

  In this chapter we will examine depression and bipolar disorder separately, to see what mood disorders reveal about normal mood states.

  DEPRESSION

  Depression was first recognized in the fifth century B.C. by the Greek physician Hippocrates, who was one of the most influential physicians in history and is generally considered the father of Western medicine. Physicians at the time of Hippocrates did not believe that diseases affect particular organs of the body. Rather, they subscribed to the theory that all diseases are caused by an imbalance of the four “humors,” or fluids, of the body: blood, phlegm, yellow bile, and black bile. Thus, Hippocrates thought that depression results from an excess of black bile in the body. In fact, the ancient Greek term for depression, melancholia, means “black bile.”

  The clinical features of depression were first, and perhaps best, summarized by William Shakespeare, that great observer of the human mind, whose Hamlet declares, “How weary, stale, flat, and unprofitable seem to me all the uses of this world.” The most common symptoms of depression are feelings of persistent sadness and intense mental anguish, accompanied by feelings of hopelessness, helplessness, and worthlessness. Often, these feelings lead to withdrawal from the company of others; sometimes they lead to thoughts of, or attempts at, suicide. At any given time about 5 percent of the world’s population suffers from major depression, including 20 million Americans. It is the primary cause of disability in people age fifteen through forty-five.

  People with depression often describe feeling intense psychic suffering and isolation. In Darkness Visible, a memoir about his experience with depression, the American novelist and essayist William Styron wrote, “The pain is unrelenting, and what makes the condition intolerable is the foreknowledge that no remedy will come—not in a day, an hour, a month, or a minute.”1

  Today, we know that depression results not from black bile but from changes in brain chemistry. Still, we do not fully understand the mechanisms in the brain responsible for those changes. Scientists have made great strides, as we shall see, but depression is a complex disorder. In fact, depression is probably not one but several different disorders, with different degrees of severity and different biological mechanisms.

  DEPRESSION AND STRESS


  Stressful life events—the death of a loved one, loss of a job, a major move, or rejection in a love relationship—can trigger depression. At the same time, depression can cause or exacerbate stress. Andrew Solomon (fig. 3.1), a professor of clinical psychology at Columbia University and a superb writer, describes the onset of depression following several stressful events in his life:

  I had always thought of myself as fairly tough, fairly strong, and fairly able to cope with anything. And then I had a series of personal losses. My mother died. A relationship that I was in came to an end, and a variety of other things went awry. I managed to get through those crises more or less intact. Then, a couple of years later, I suddenly found myself feeling bored a lot of the time.… I remember particularly that, coming home and listening to the messages on my answering machine, I would feel tired instead of being pleased to hear from my friends, and I’d think, That’s an awful lot of people to have to call back. I was publishing my first novel at the time, and it came out to rather nice reviews. I simply didn’t care. All my life I had dreamed of publishing a novel, and now here it was, but all I felt was nullity. That went on for quite a while.…

  Figure 3.1. Andrew Solomon

  Then … [e]verything began to seem like such an enormous, overwhelming effort. I would think to myself, Oh, I should have some lunch. And then I would think, But I have to get the food out. And put it on a plate. And cut it up. And chew it. And swallow it.… I knew that what I was experiencing was idiotic. It was nonetheless vivid and physical and acute, and I was helpless in its grip. As time went on, I found myself doing less, going outside less, interacting with other people less, thinking less, and feeling less.

  Then the anxiety set in.… The most acute hell of depression is the feeling that you will never emerge. If you can alleviate that feeling, the state, though miserable, is bearable. But, if someone were to say to me that I had to have acute anxiety for the next month, I would kill myself, because every second of it would be so intolerably awful. It is the constant feeling of being absolutely terrified and not knowing what it is that you’re afraid of. It resembles the sensation you have if you slip or trip, the feeling you get when the ground is rushing up at you before you land. That feeling lasts about a second-and-a-half. The anxiety phase of my first depression lasted six months. It was incredibly paralyzing.…