The Disordered Mind

by Eric R. Kandel

  One fascinating aspect of lithium treatment for mania is that it does not take effect for several days, and its effects do not disappear immediately after treatment is discontinued.

  Today, bipolar disorder is treated with a combination of mood-stabilizing drugs and psychotherapy. Psychotherapy helps people with bipolar disorder recognize the particular emotional and physical situations that trigger depressive or manic episodes and emphasizes the importance of managing and reducing stress. Depressive episodes of bipolar disorder that are not contained by mood stabilizers such as lithium, atypical antipsychotics, or antiepileptic drugs are treated with antidepressants. While lithium reduces the severity and frequency of manic episodes in many patients, not everyone with bipolar disorder responds to it. Moreover, lithium has unpleasant side effects. We therefore need to find even better treatments.

  MOOD DISORDERS AND CREATIVITY

  The association between mood disorders and creativity, particularly the relationship between creativity and bipolar disorder, has been noted throughout history, from ancient Greece to the modern era. Vincent van Gogh, for example, suffered from depression during much of his adult life and committed suicide at the age of thirty-seven. Yet despite suffering from severe episodes of psychotic depression and mania during the last two years of his life, he produced three hundred of his most important works during that time. These works have proven to be important in the history of modern art because van Gogh used color not to convey the reality of nature but arbitrarily, to convey mood.

  Empirical studies of contemporary artists and writers have found high rates of bipolar disorder among these groups. We will further consider the relationship between creativity and mood disorders in chapter 6.

  THE GENETICS OF MOOD DISORDERS

  For the most part, our genes determine whether we are likely to develop a mood disorder. As we saw in chapter 1, studies of identical twins who are reared apart—the best way to separate nature from nurture—indicate that if one twin has bipolar disorder, the other twin has a 70 percent chance of developing it. For major depression, the likelihood is 50 percent.

  Scientists have recently discovered that complex brain disorders such as depression, bipolar disorder, schizophrenia, and autism share some genetic variants that increase the risk of developing one of these disorders. Thus, bipolar disorder emerges from an interaction of genetic and developmental factors with environmental factors. Scientists have also found two genes that may create a risk for both schizophrenia and mood disorders. Thus, it is clear that no single gene significantly affects the development of either bipolar disorder or schizophrenia. Many different genes are involved, and they work together with environmental factors in a complicated way. We discuss these and other findings of genetic research in more detail in chapter 4.

  Recently, an international team analyzed genetic information from 2,266 people with bipolar disorder and 5,028 comparable individuals without the disorder. They merged their information with information on thousands of other individuals from previous studies. Altogether, the database included genetic material from 9,747 people with bipolar disorder and 14,278 people without the disorder.

  The researchers analyzed about 2.3 million different regions of DNA. Their search led them to five regions that appeared to be connected to bipolar disorder.17 Two of the regions contain new candidate genes that are likely to predispose a person to bipolar disorder, one on chromosome 5 and one on chromosome 6; the remaining three regions, previously suspected of a connection, were confirmed to be linked to the disorder. One of the newly discovered genes, ADCY2, was of particular interest. This gene oversees the production of an enzyme that facilitates neural signaling, a finding that fits very well with the observation that information transfer in certain regions of the brain is impaired in people with bipolar disorder.

  Identifying the genes that make us susceptible to bipolar disorder, as this team did, is an important step in understanding how mood disorders develop. Once we understand their biological foundations, we can begin work on more effective and accurately targeted treatments. We can also recognize individuals at risk, leading to earlier intervention and an understanding of the environmental factors that interact with genes to create mood disorders. Finally, by understanding the biology of mood disorders we also begin to understand the biological underpinnings of the normal mood states that underlie our everyday emotional well-being.

  LOOKING AHEAD

  Our understanding of the genetics of depression and bipolar disorder is still in the early stages. These are, after all, very complex diseases. They disrupt the connections between the brain structures responsible for emotion, thought, and memory—connections that are crucial to our sense of self. This is why people with mood disorders experience such an array of psychological and physical symptoms. Only recently have neuroscientists been able to see, in real time, what goes on in the brains of people with these disorders, thus offering the possibility of correlating genetics, brain physiology, and behavior.

  Nevertheless, tremendous advances have been made in other areas of research, particularly research on depression—finding the neural circuit for depression, using deep-brain stimulation to change the firing of neurons in that circuit, viewing the disconnect between the brain structures responsible for emotion and for thought, and understanding the biological nature of psychotherapy. These and other advances have led to improved treatments for people with mood disorders.

  Today, with constant vigilance, proper treatment, and expert, compassionate assistance from informed clinicians, most people with mood disorders can regain and maintain emotional equilibrium and hold their lives together. With understanding on the part of family members and friends—understanding of both the patient’s experience and the science of the illness—damage to relationships can be avoided or repaired. As a result of our gaining a biological understanding of the self, mood disorders have become treatable illnesses.

  4

  THE ABILITY TO THINK AND TO MAKE AND CARRY OUT DECISIONS: SCHIZOPHRENIA

  Schizophrenia probably begins before birth, but it usually doesn’t become apparent until late adolescence or early adulthood. When it does appear, schizophrenia often has devastating effects on thinking, volition, behavior, memory, and social interaction—the underpinnings of our sense of self—just at the time in their lives when young people are becoming independent. Like depression and bipolar disorder, schizophrenia is a complex psychiatric disorder affecting numerous regions of the brain and ultimately undermining the integrity of the self.

  The biology of schizophrenia is particularly difficult to sort out because of the disorder’s wide-ranging effects on the brain and behavior. This chapter presents what brain scientists have been able to discover about schizophrenia thus far: what circuits it disrupts in the brain, what treatments are available to patients, and what genetic and developmental components underlie the disorder. The emerging view of schizophrenia as a neurodevelopmental disorder that, unlike autism, manifests itself later in life has arisen from the considerable genetic research done on the disease.

  Recent technical advances in genetics and brain imaging have given scientists new insights into the biology of schizophrenia. Based on those advances, we are now beginning to understand how schizophrenia affects the brain and to develop animal models that allow us to test specific hypotheses and to explore how the disease begins. These recent advances may provide a path to early intervention and treatment.

  THE CORE SYMPTOMS OF SCHIZOPHRENIA

  Schizophrenia produces three types of symptoms, each resulting from disturbances in a different region of the brain. This makes schizophrenia a particularly difficult disorder to understand and to treat.

  The positive symptoms of schizophrenia—called “positive” not because they are good but because they represent new types of behavior for the person who has them—are the symptoms most frequently associated with the disease and the ones patients often recognize first. Positive symptoms reflect disordered
volition and thinking. Disordered thought detaches a person from reality, leading to altered perceptions and behavior, such as hallucinations and delusions. These psychotic symptoms can be terrifying, not just for people who experience them but also for people who witness them. They are also a major cause of the stigma attached to people with schizophrenia.

  The English artist Louis Wain conveyed his experience of the positive symptoms of schizophrenia (notably, altered perception) in his drawings of cats (fig. 4.1). As Kraepelin appreciated, and as we shall see in chapter 6, remarkable artistic capabilities sometimes manifest themselves for the first time in people who have developed schizophrenia. Thus, artists who become schizophrenic may continue to paint, and some people with schizophrenia who never painted before may take up painting as a means of giving voice to their feelings.

  Hallucinations, the most common positive symptom, can be visual or auditory. Auditory hallucinations are very troubling: patients hear voices saying harshly critical, sometimes abusive things to them. The voices may cause them to harm themselves or others. Delusions, or false beliefs with no basis in fact, are also common. Of the several categories of delusions, the most common type is paranoid delusions. Patients often feel as though other people are out to get them, or following them, or trying to harm them. It is not uncommon for patients to believe that someone is trying to poison them, particularly with their medications.

  Another very common type of delusion involves reference, or control. Patients feel that they’re receiving special messages, just for them, from the television or the radio; they often feel that other people can control their minds. Finally, patients may have delusions of grandeur, the feeling of having special powers.

  Figure 4.1. Drawings of cats by the artist Louis Wain (1860–1939), who had schizophrenia

  The negative symptoms of schizophrenia—social withdrawal and lack of motivation—are typically present before the positive symptoms, but they are generally overlooked until a person experiences a psychotic episode. Social withdrawal may not entail actually avoiding people but rather being walled off and wrapped up in a separate world. Lack of motivation is evident in listlessness and apathy.

  The cognitive symptoms of schizophrenia reflect problems with volition, with the executive functions involved in organizing one’s life, and with working memory (a form of short-term memory), as well as early features of dementia. Patients are sometimes unable to gather their thoughts or to follow a train of thought. In addition, they may be unable to do the everyday things needed to be successful at work or to sustain relationships with others. As a result, they have great difficulty holding a job or marrying and raising children.

  Brain scans of untreated people with schizophrenia reveal, over time, a subtle, but perceptible, loss of gray matter, which contains the cell body and dendrites of neurons in the cerebral cortex. This loss of gray matter, which contributes to the cognitive symptoms of schizophrenia, is thought to result from excessive pruning of dendrites during development, which leads to loss of synaptic connections among neurons, as we shall see later in this chapter.

  To get a sense of how completely these symptoms of schizophrenia can loosen our hold on reality and sabotage our independence and sense of self, let us turn to someone who has the disorder: Elyn Saks (fig. 4.2), a professor of law at the University of Southern California and founder of the Saks Institute for Mental Health Law, Policy, and Ethics. In 2007 Saks published a book titled The Center Cannot Hold, in which she presents a frank and moving portrait of her experience of schizophrenia as well as a plea that we not impose limitations on people with schizophrenia but rather allow them to find their own limits. In September 2015 she was awarded a MacArthur Foundation “genius” grant. She described her terrifying initial psychotic experience:

  Figure 4.2. Elyn Saks

  It’s ten o’clock on a Friday night. I am sitting with my two classmates in the Yale Law School Library. They aren’t too happy about being here; it’s the weekend, after all—there are plenty of other fun things they could be doing. But I am determined that we hold our small-group meeting. We have a memo assignment; we have to do it, have to finish it, have to produce it, have to … Wait a minute. No, wait. “Memos are visitations,” I announce. “They make certain points. The point is on your head. Have you ever killed anyone?”

  My study partners look at me as if they—or I—have been splashed with ice water. “This is a joke, right?” asks one. “What are you talking about, Elyn?” asks the other.

  “Oh, the usual. Heaven, and hell. Who’s what, what’s who. Hey!” I say, leaping out of my chair. “Let’s go out on the roof!”

  I practically sprint to the nearest large window, climb through it, and step out onto the roof, followed a few moments later by my reluctant partners in crime. “This is the real me!” I announce, my arms waving above my head. “Come to the Florida lemon tree! Come to the Florida sunshine bush! Where they make lemons. Where there are demons. Hey, what’s the matter with you guys?”

  “You’re frightening me,” one blurts out. A few uncertain moments later, “I’m going back inside,” says the other. They look scared. Have they seen a ghost or something? And hey, wait a minute—they’re scrambling back through the window.

  “Why are you going back in?” I ask. But they’re already inside, and I’m alone. A few minutes later, somewhat reluctantly, I climb back through the window, too.

  Once we’re all seated around the table again, I carefully stack my textbooks into a small tower, then rearrange my note pages. Then I rearrange them again. I can see the problem, but I can’t see its solution. This is very worrisome. “I don’t know if you’re having the same experience of words jumping around the pages as I am,” I say. “I think someone’s infiltrated my copies of the cases. We’ve got to case the joint. I don’t believe in joints. But they do hold your body together.” I glance up from my papers to see my two colleagues staring at me. “I … I have to go,” says one. “Me, too,” says the other. They seem nervous as they hurriedly pack up their stuff and leave, with a vague promise about catching up with me later and working on the memo then.

  I hide in the stacks until well after midnight, sitting on the floor muttering to myself. It grows quiet. The lights are being turned off. Frightened of being locked in, I finally scurry out, ducking through the shadowy library so as not to be seen by any security people. It’s dark outside. I don’t like the way it feels to walk back to my dorm. And once there, I can’t sleep anyway. My head is too full of noise. Too full of lemons, and law memos, and mass murders that I will be responsible for. I have to work. I cannot work. I cannot think.1

  HISTORY OF SCHIZOPHRENIA

  As we learned in chapter 3, Emil Kraepelin, the founder of modern scientific psychiatry, divided the major psychiatric illnesses into disorders of mood and disorders of thought. He was able to make this distinction because he brought to his studies of mental illness not only very astute clinical observations but also his training in the laboratory of Wilhelm Wundt, the pioneer of experimental psychology. Throughout his career Kraepelin strove to base the concepts of psychiatry on sound psychological research.

  Kraepelin called the primary disorder of thought dementia praecox, the dementia of young people, because it starts earlier in life than Alzheimer’s dementia. Almost immediately, the Swiss psychiatrist Eugen Bleuler took issue with the term. Bleuler thought dementia was only one component of the disease. Moreover, some of his patients had developed the disease later in life. Others functioned well after many years with the disease: they were able to work and have a family life. For these reasons, Bleuler called the disease the schizophrenias. He saw schizophrenia as a splitting of the mind—a disorientation of feelings from cognition and motivation—and he used the plural noun to recognize the several disorders embedded in this category. Bleuler’s ideas are fundamental to our understanding of the disease, and his definition still holds.

  TREATING PEOPLE WITH SCHIZOPHRENIA

  Schizophrenia i
s not a rare disorder. It affects about 1 percent of people worldwide and roughly 3 million people in the United States. It strikes without regard to class, race, gender, or culture, and it varies greatly in severity. Many people with severe schizophrenia have difficulty forming or sustaining personal relationships, working, or even living independently. On the other hand, some people with milder forms of the disorder, such as the writer Jack Kerouac, the Nobel Prize winner in Economics John Nash, and the musician Brian Wilson, have had notable careers. Their symptoms are mostly kept in check by treatment with drugs and psychotherapy.

  The drugs developed to treat people with schizophrenia initially focused on alleviating the positive symptoms of the disorder—that is, the psychotic symptoms: hallucinations and delusions. Antipsychotic drugs have been quite effective; in fact, most of the drugs we have today will alleviate positive symptoms to some extent for up to 80 percent of people with schizophrenia. However, antipsychotics are not very effective against the negative and cognitive symptoms of the disorder—and those symptoms can be the most pernicious and debilitating for patients.

  Psychotherapy is also an essential treatment for people with schizophrenia. Interestingly, psychotherapy is now being used preemptively as well, for both the cognitive and the negative symptoms, to try to prevent the onset of psychotic symptoms in adolescents and young adults identified as being at risk. One of the many things that psychotherapy can accomplish is to help patients realize that they have a disorder, a disease: they are not a bad person but a good person suffering from delusions or hallucinations.

  BIOLOGICAL TREATMENTS

  Scientists got an initial glimpse into the biology of schizophrenia in the same way they got their initial look at the biology of depression—when the first effective drug appeared. In each case, that first drug emerged by chance, from drugs designed to work on another problem.