The Disordered Mind

by Eric R. Kandel

  Second, children suppress and render unconscious the conflicts between early needs and prohibitions, as well as early traumas. These repressed feelings may result in symptoms of mental illness in adulthood. In the course of free association during psychoanalysis, the patient liberates his or her repressed conflicts. The therapist’s interpretations of those revelations can help resolve the conflicts, thereby relieving the patient’s mental symptoms.

  Third, the patient’s relationship with the therapist reenacts the patient’s early relationships. This reenactment is called transference. Transference and the interpretation of the transference by the therapist play a central role in the therapeutic process.

  Psychoanalysis heralded a new method of psychological investigation, a method based on free association and interpretation. Freud taught analysts to listen carefully to patients in ways that no one had before. He also outlined a provisional way of making sense out of patients’ seemingly unrelated and incoherent associations.

  While psychoanalysis has historically been scientific in its aims, it has rarely been scientific in its methods (see chapter 11). Indeed, Freud and the original founders of psychoanalysis made few serious attempts to establish proof of the efficacy of psychotherapy. That way of thinking changed in the 1970s, when Aaron Beck, a psychoanalyst at the University of Pennsylvania, set out to test Freud’s ideas about depression.

  Freud held that depressed people feel hostile toward someone they love, yet they have difficulty harboring negative feelings about a person who is important to them. They therefore repress the negative feelings and unconsciously direct them inward. This anger ultimately leads to feelings of worthlessness and low self-esteem, which are characteristic of depression.

  Yet Beck found that his depressed patients actually exhibited less hostility than his other patients. Instead, the depressed patients consistently saw themselves as losers, had unrealistically high expectations of themselves, and handled even the simplest disappointment badly. This pattern of thinking reflects a disorder of cognitive style, of how we perceive ourselves in the world.

  Beck wondered if identifying those negative beliefs and thought processes and then helping the patient replace them with more positive thoughts might relieve depression without having to deal with specific unconscious conflicts. He tested his idea by presenting patients with evidence of their accomplishments, achievements, and successes, thus challenging their negative views of themselves. His patients often improved with remarkable speed, feeling and functioning better after just a few sessions.

  This positive result encouraged Beck to develop a short, systematic psychological treatment for depression based on a patient’s cognitive style and distorted way of thinking. He called the treatment cognitive behavioral therapy. Once he was certain that it worked repeatedly, he wrote a manual on it so that other people could carry out the same treatment.10 Finally, he conducted outcome studies.

  The outcome studies showed that for mild and moderate depression, cognitive behavioral therapy was better than a placebo and as good as, if not better than, antidepressant drugs. For severe depression, the therapy was not as good as an antidepressant; however, therapy and the antidepressant were synergistic—that is, the two treatments together benefited the patient more than either treatment by itself.11

  Cognitive behavioral therapy has had a mighty impact on psychiatry and on psychoanalytical thought. It showed that a complex process like psychotherapy can be studied and that its outcomes can be evaluated. As a result, psychotherapy is now being tested empirically.

  Psychiatrists used to think that psychotherapy and drugs work in different ways, that psychotherapy acts on our mind and drugs act on our brain. Now they know better. The interaction between therapist and patient can actually change the biology of the brain. This finding should not be surprising. My own work has shown that learning leads to anatomical changes in the connections between neurons. This anatomical change underlies memory—and psychotherapy, after all, is a learning process.

  Thus, insofar as psychotherapy produces persistent changes in behavior, it is also producing changes in the brain. In fact, studies are now giving us a better idea about what kinds of psychotherapy work best and for what kinds of patients.

  COMBINING DRUGS WITH PSYCHOTHERAPY

  All pharmacological treatments come with undesired side effects, ranging from annoying to life-threatening, and as a result patients often discontinue use of these drugs. Psychotherapy, which is known to be effective, does not have such side effects. Thus, for many people with depression, the best treatment is a combination of drugs and psychotherapy.

  In the 1990s clinical investigators such as Beck figured out how to use drugs and psychotherapy synergistically. While medication helps to restore the balance of chemicals in the brain, psychotherapy provides a consistent, supportive, and healthy relationship with a therapist. These are the key ingredients to turning mental illness around and enabling people to live a fulfilling, productive life.

  Kay Redfield Jamison, who is co-director of the Mood Disorders Center at The Johns Hopkins School of Medicine and who herself has bipolar disorder, strongly agrees with this point. In her book An Unquiet Mind, she writes that psychotherapy “makes some sense of the confusion, reins in the terrifying thoughts and feelings, returns some control and hope and possibility of learning from it all. Pills cannot, do not, ease one back into reality.”12

  Andrew Solomon concurs:

  Once I had begun to return to some reasonable facsimile of myself … I had to figure out what triggered my episodes and how to control them. This I did with the analytically trained therapist with whom I had begun working.… Once you have been depressed, and particularly once you have allowed medication to reshape your mental states, you need to understand who you are at the most fundamental level.…

  I now have a psychopharmacologist and a psychoanalyst, and I would not be who I am today without their work and without the work I have done with them both. The fashion for biological explanations of depression seems to miss the fact that chemistry has a different vocabulary for a set of phenomena that can also be described psychodynamically. Neither our pharmacology nor our analytic insight is advanced enough to do all the work; to approach the problem of depression from both angles is to figure out not only how to recover, but also how to live the life that must follow on recovery.13

  In a recent study of people with depression, Mayberg provided each person with either cognitive behavioral therapy or an antidepressant medication. She found that people who started with below-average baseline activity in the right anterior insula responded well to cognitive behavioral therapy but not to the antidepressant. People with above-average activity responded to the antidepressant, but not to cognitive behavioral therapy. Thus, Mayberg found that she could predict a depressed person’s response to specific treatments from the baseline activity in the right anterior insula.14

  These results show us four very important things about the biology of brain disorders. First, the neural circuits disturbed by psychiatric disorders are complex. Second, we can identify specific, measurable markers of a brain disorder, and those biomarkers can predict the outcome of two different treatments: psychotherapy and medication. Third, psychotherapy is a biological treatment; it produces detectable, lasting physical changes in our brain. And fourth, the effects of psychotherapy can be studied empirically.

  Many psychotherapists have been slow to investigate the empirical basis of their treatment, in part because a number of them believe that human behavior is too difficult to study in scientific terms. The finding by Mayberg that cognitive behavioral therapy is a biological treatment now provides an opportunity for evaluating the outcome of psychotherapy in a rigorously objective manner.

  BRAIN STIMULATION THERAPIES

  Some people with depression do not respond to drugs or psychotherapy. For many of these people, therapies such as electroconvulsive therapy and deep-brain stimulation have proved beneficial.

 
Electroconvulsive (shock) therapy gained a bad reputation during the 1940s and ’50s because patients were given high doses of electricity without any anesthesia, resulting in pain, fractured bones, and other serious side effects. Today, electroconvulsive therapy is painless. It is administered after the patient has been given general anesthesia and a muscle relaxant, it uses small electric currents to induce a brief seizure, and it is often very effective. Many patients have six to twelve sessions over a period of several weeks. Scientists are still not clear about how it works, but it is thought to relieve depression by producing changes in the chemistry of the brain. Unfortunately, the effects of electroconvulsive therapy usually do not last very long.

  In the 1990s deep-brain stimulation was refined to treat people with Parkinson’s disease by Mahlon DeLong at Emory University and Alim-Louis Benabid at the Joseph Fourier University in Grenoble, France. In this treatment, surgeons place an electrode in the dysfunctional region of a neural circuit and implant a device elsewhere in the patient’s body that sends high-frequency electrical impulses into the region—much as a pacemaker regulates the heartbeat. The impulses block the firing of neurons whose abnormal signals cause the symptoms of Parkinson’s disease.

  Mayberg was familiar with these advances and thought that slowing the firing rate of neurons in area 25 might relieve the symptoms of depression. She used deep-brain stimulation in the anterior insula region to treat twenty-five people whose depression was resistant to treatment. She collaborated with a team of neurosurgeons, first at the University of Toronto and then at Emory, who implanted the electrodes. When she turned on the electricity in the operating room, she saw almost immediate changes in the patients’ mood. The patients no longer felt the unending psychic pain characteristic of depression. Moreover, the other symptoms of depression gradually lifted as well. People recovered and were stabilized for the long term.15

  BIPOLAR DISORDER

  Bipolar disorder is characterized by extreme changes in mood, thought, energy, and behavior that generally alternate between depression and mania. These alternating moods distinguish bipolar disorder from major depression.

  Manic episodes are characterized by an elevated, expansive, or irritable mood, together with several other symptoms, including heightened activity, racing thoughts, impulsiveness, and decreased need for sleep. These episodes are often associated with high-risk behaviors such as substance abuse, sexual promiscuity, excessive spending, or even violence. During a manic episode, people may say and do things that strain their relationships with others. They may get into trouble with the law or at work. Manic episodes can be frightening, both for people with bipolar disorder and for the people close to them.

  About 25 percent of people with major depression go on to experience a manic episode. The initial manic episode is usually triggered by a personal situation, an environmental circumstance, or both. Common triggers include stressful life events, whether positive or negative; conflict or stressful relations with other people; disrupted routine or patterns of sleep; overstimulation; and medical illness. The manic episode is then followed by a depressive episode. While bouts of depression typically recur in any form of depression, they recur twice as often in bipolar disorder. And since bipolar disorder consists of alternating periods of mania and depression, this means the manic episodes recur equally often.

  Once the first manic episode is initiated—usually at the age of seventeen or eighteen—the brain is changed in ways we do not yet understand, such that even minor events can trigger a later manic episode. After the third or fourth manic episode, a trigger may not be required. As a person with bipolar disorder grows older, the disease advances and the intervals between episodes may become shorter, particularly if he or she discontinues treatment.

  Bipolar disorder affects about 1 percent of Americans, or more than 3 million people. While depression affects more women than men, bipolar disorder affects men and women equally. The disorder takes several forms, but the most common forms are known as bipolar I and bipolar II. People with bipolar I disorder have manic episodes, and sometimes cross over into psychosis with symptoms such as delusions and hallucinations, whereas people with bipolar II disorder have less severe, hypomanic episodes. Some people experience symptoms of both mania and depression at the same time, a condition known as a mixed state.

  We do not know exactly what causes bipolar disorder, but we do know that its origins are complex and involve genetic, biochemical, and environmental factors. We are all subject to fluctuating moods: an exciting event may cause us to feel euphoric, while an unpleasant one may make us feel cast down. Most of us return to the normal state in a short time. Yet the same event may cause a person with bipolar disorder to plunge into extreme depression or mania for a long time. Two risk factors are particularly important in bipolar disorder: first, a genetic predisposition, as indicated by a sibling or a parent with the disorder; and second, periods of great stress.

  The depressive episodes in bipolar disorder are similar to those in major depression. Thus the research carried out on the biology of major depression—the critical role of stress, the neural circuit of depression, the disconnect between thought and emotion, the action of antidepressants, and the importance of psychotherapy—applies to the depressive phase of bipolar disorder as well. Unfortunately, our understanding of the molecular underpinnings of mania is not as advanced as our understanding of the underpinnings of depression.

  TREATING PEOPLE WITH BIPOLAR DISORDER

  People with bipolar disorder may not see the need for continued treatment, particularly during a manic phase. It’s very difficult, for example, to convince an eighteen-year-old who’s staying up all night—full of energy, full of seemingly great ideas, thinking fast and furiously—that he or she is sick. But as the mania progresses, the person can become disorganized, psychotic, and self-destructive.

  Kay Jamison (fig. 3.2), whom we met earlier, first realized that she was ill when she was about seventeen years old and a senior in high school. She has described her bipolar illness and the interaction of medication and psychotherapy in treating it:

  Figure 3.2. Kay Redfield Jamison

  There is a particular kind of pain, elation, loneliness, and terror involved in this kind of madness. When you’re high it’s tremendous. The ideas and feelings are fast and frequent like shooting stars, and you follow them until you find better and brighter ones. Shyness goes, the right words and gestures are suddenly there, the power to captivate others a felt certainty. There are interests found in uninteresting people. Sensuality is pervasive and the desire to seduce and be seduced irresistible. Feelings of ease, intensity, power, well-being, financial omnipotence, and euphoria pervade one’s marrow. But, somewhere, this changes. The fast ideas are far too fast, and there are far too many; overwhelming confusion replaces clarity. Memory goes. Humor and absorption on friends’ faces are replaced by fear and concern. Everything previously moving with the grain is now against—you are irritable, angry, frightened, uncontrollable, and enmeshed totally in the blackest caves of the mind. You never knew those caves were there. It will never end, for madness carves its own reality.16

  Imaging studies of brain function have shown widespread differences between healthy brains and the brains of people with bipolar disorder. That’s no surprise. But if manic episodes are what distinguishes bipolar disorder from depression, then we should see additional or different changes in the brains of people with bipolar disorder, changes that cause the symptoms of mania and the cycling from one state to the other. In fact, however, convincing differences have been difficult to document. The best insights have come from attempts to understand how lithium, the most successful treatment for manic illness, affects the brain.

  In the second century B.C. the Greek physician Soranus treated his manic patients with alkaline waters now known to be high in lithium. The benefit of lithium was rediscovered in 1948 by the Australian psychiatrist John Cade, who noticed that the substance made guinea pigs temporarily let
hargic. Cade formally introduced lithium into the modern treatment of bipolar disorder in 1949, and it has been used ever since.

  Unlike other medications used to treat psychiatric illnesses, lithium is a salt; consequently, it does not bind to a receptor on the surface of a neuron. Rather, it is actively transported into the neuron through sodium ion channels in the cell membrane that open in response to an external stimulus (see chapter 1). When a sodium ion channel opens, both sodium and lithium move into the cell. The sodium is subsequently pumped out, but the lithium remains inside. There, lithium may stabilize mood swings by affecting the action of neurotransmitters, either directly or through interaction with a second messenger system.

  As we have seen, neurotransmitters bind to receptors on the cell membrane. This activates second messenger systems, which transmit signals from the receptors to molecules inside the neuron. Lithium may blunt the activation of second messenger systems, thus reducing signal transmission. Lithium may also damp down a neuron’s responsiveness to neurotransmitters inside the cell. This could explain why lithium works so effectively in bipolar disorder: it may decrease a neuron’s sensitivity to both external and internal stimuli. In addition, lithium affects the modulatory neurotransmitters serotonin and dopamine as well as the mediating neurotransmitter GABA. Thus, its efficacy may be attributable to its wide-ranging neurobiological effects rather than to a single mechanism.

  Another possible way that lithium exerts its beneficial effects is by resetting ionic homeostasis in overly active neurons. The idea here is that lithium returns neurons to their resting state by increasing or decreasing their sensitivity to stimuli. Again, lithium may act directly on the surface receptors of neurons or through its interaction with intracellular second messenger systems.