I got sicker and sicker until finally one day I woke up and actually thought that perhaps I’d had a stroke. I remember lying in bed and thinking that I’d never felt so bad in my life and that I should call someone. From my bed I looked at the telephone on my nightstand, but I could not reach out and dial a number. I lay there for four or five hours, just staring at the telephone. And finally it rang. I managed to answer it. I said, “I’m in terrible trouble.” And that was when I finally sought antidepressants and began the serious treatment of my illness.…2
Depression and stress appear to set off the same biochemical changes in the body: they activate the neuroendocrine system’s hypothalamic-pituitary-adrenal axis, prompting the adrenal gland to release cortisol, the body’s primary stress hormone. While the release of cortisol for a short period is beneficial—it heightens our vigilance in response to a perceived threat—the long-term release of cortisol in major depression and chronic stress is harmful. It causes the changes in appetite, sleep, and energy that depressed and highly stressed people experience.
Excessive concentrations of cortisol destroy synaptic connections between neurons in the hippocampus, the region of the brain that is important in memory storage, and neurons in the prefrontal cortex, which regulates a person’s will to live and influences a person’s decision making and memory storage. The breakdown of synaptic connections in these regions leads to the flattening of emotion and to the impaired memory and concentration that accompany major depression and chronic stress. Many brain-imaging studies of people with depression have shown a decrease in the overall size and number of synapses between neurons in the prefrontal cortex and hippocampus; similar changes have been found in postmortem studies. Moreover, studies in mice and rats reveal that, when under stress, these animals also lose synaptic connections in the hippocampus and prefrontal cortex.
Animal models have given us valuable insights into the neural circuit of fear that underlies stress. Studies reveal that both instinctive fear and learned fear recruit the amygdala and the hypothalamus. The amygdala, as we know, determines what emotion is recruited at any given time, and the hypothalamus carries it out. When the amygdala calls for a fear response, the hypothalamus activates the sympathetic nervous system, which elevates heart rate, blood pressure, and secretion of stress hormones and regulates erotic, aggressive, defensive, and escape behavior.
These findings are all consistent with the idea that prolonged stress—which prompts the long-term release of cortisol and the consequent loss of synaptic connections—is an important component of depressive disorders, including the depressive phase of bipolar disorder.
THE NEURAL CIRCUIT OF DEPRESSION
Until quite recently psychiatric disorders were notoriously difficult to trace to particular regions in the brain. But today’s brain-imaging technologies, specifically PET and functional MRI, have enabled scientists to identify at least some components of the neural circuit responsible for depression. By examining this circuit systematically in patients who have volunteered for studies, scientists have come to understand which patterns of neural activity are altered and can examine the effects of antidepressant drugs and psychotherapy on those abnormal patterns of activity. Moreover, recent brain-imaging technology has allowed scientists to identify biological markers in the brain that indicate which patients need just psychotherapy and which need both drug treatment and psychotherapy.
Helen Mayberg, a neurologist now at Emory University, found that the neural circuit of depression has several nodes, two of which are particularly critical: cortical area 25 (the subcallosal cingulate cortex), and the right anterior insula.3 Area 25 is a region where thought, motor control, and drive come together. It is also rich in neurons that produce serotonin transporters—proteins that remove serotonin from the synapse. This is important because serotonin is a modulatory neurotransmitter released by a class of nerve cells to help regulate mood. Modulatory transmitters don’t simply transmit an impulse from one cell to the next, but “tune” whole circuits or regions. Serotonin transporters are particularly active in depressed people and are partially responsible for lowering the concentration of serotonin in area 25. The second critical node, the right anterior insula, is a region where self-awareness and social experience come together. The anterior insula connects to the hypothalamus, which helps regulate sleep, appetite, and libido, and to the amygdala, the hippocampus, and the prefrontal cortex. The right anterior insula receives information from our senses about the physiological state of our body and, in response, generates emotions that inform our actions and decisions.
Another brain structure that is consistently implicated in both major depressive and bipolar disorders is the gyrus, or raised fold, of the anterior cingulate cortex. This structure runs parallel to the corpus callosum, the band of nerve fibers that connects the left and right hemispheres of the brain. The anterior cingulate gyrus is divided functionally into two regions. One region (the rostral and ventral subdivision) is thought to be involved in emotional processes and autonomic functions; it has extensive connections to the hippocampus, amygdala, orbital prefrontal cortex, anterior insula, and the nucleus accumbens, an important part of the brain’s dopamine reward and pleasure circuit, as we will see in chapter 9. The other region (the caudal subdivision) is thought to be involved in cognitive processes and in the control of behavior; it connects with the dorsal areas of the prefrontal cortex, secondary motor cortex, and posterior cingulate cortex.
Both regions function abnormally in people with mood disorders, which accounts for their varied emotional, cognitive, and behavioral symptoms. The region concerned with emotion is consistently overactive during major depressive episodes and the depressive phase of bipolar disorder. Indeed, as we shall see, successful treatment with antidepressant drugs is correlated with decreased activity in a particular part of this region, the subgenual area of the anterior cingulate gyrus.
THE DISCONNECT BETWEEN THOUGHT AND EMOTION
At the same time that she found hyperactivity in area 25, Mayberg found underactivity in other parts of the prefrontal cortex of people with depression.4 The prefrontal cortex, as we know, is responsible for concentration, decision making, judgment, and planning for the future. It connects directly to the amygdala, hypothalamus, hippocampus, and insular cortex, and each of these regions, in turn, connects directly to area 25. Conversations among these areas of our brain make use of emotion and thinking to help us plan our day and respond to the world around us in a healthy way.
Brain imaging has revealed several changes in the structure of the brain that may account for some of the symptoms that people with mood disorders experience. For example, imaging has shown that people with depression have an enlarged amygdala, and that people with depression, bipolar disorder, and anxiety disorders have increased activity in the amygdala. Scientists have suggested that increased activity of the amygdala may account for the hopelessness, sadness, and mental anguish that people with depression feel. Imaging has also found that, like many other disorders, depression may result in fewer and smaller synapses in the hippocampus. In fact, longer depressive episodes are correlated with reductions in the volume of the hippocampus. This correlation would account for the problems with memory that people with depression experience. Defective functioning of the hypothalamus, as revealed in imaging, may account in part for the loss of drive in people with depression, whether the drive for sex or the appetite for food. Finally, defective functioning of the insular cortex, a structure involved with bodily sensations, may account for why people with depression are without vitality, why they often feel dead inside.
Studies of depression suggest that whenever area 25 becomes hyperactive, the components of the neural circuit concerned with emotion are literally disconnected from the thinking brain, leading to a loss of personal identity. Mayberg’s brain-imaging studies of depression reveal where these breaks in the circuit occur and help explain why depression can cause bodily sensations that patients can’t place or cons
ciously do anything about.5
TREATING PEOPLE WITH DEPRESSION
The most important reason to develop effective treatments for depression is to prevent suicide. Depression accounts for more than half of the forty-three thousand suicides that occur in the United States each year. Moreover, nearly 15 percent of people with depression commit suicide. That rate is much higher than the suicide rate among people with terminal illnesses, it equals the rate of homicide in the general U.S. population, and it has overtaken the rate of traffic fatalities in the United States. Although twice as many women suffer from depression as men, and women attempt suicide three times more often than men, men are three or four times as likely to actually kill themselves. The reason is that men tend to choose more aggressive methods—guns, jumping off bridges, throwing themselves under a subway train—and such methods are more likely to be fatal.
DRUG TREATMENTS
The first drugs used to treat people with depression were discovered by sheer accident. That accident not only proved providential for patients, it also provided the first insight into aspects of the biochemical disturbance underpinning depression.
In 1928 Mary Bernheim, a graduate student in the Department of Biochemistry at the University of Cambridge in England, discovered monoamine oxidase (MAO), an enzyme that breaks down a class of neurotransmitters known as monoamines.6 (Neurotransmitters, as we have seen, are chemical messengers that neurons release into the synapses to communicate with other neurons.) Her discovery led to the introduction of a drug called iproniazid, which was used to treat people with tuberculosis. In 1951 doctors and nurses working on the tuberculosis ward of Sea View Hospital on Staten Island, New York, noticed that their patients taking iproniazid seemed less lethargic and much happier than those who were not taking the drug. Subsequent clinical trials revealed that iproniazid had antidepressant properties. Shortly thereafter, imipramine, a drug developed initially to treat people with schizophrenia, was also found to relieve symptoms of depression, by blocking the reuptake of monoamines into nerve terminals. Reuptake is a process that recycles the neurotransmitters and stops the signaling.
The antidepressant effects of iproniazid and imipramine suggested that monoamines were somehow involved in depression. But how?
Researchers discovered that monoamine oxidase breaks down and removes from the synapses two neurotransmitters: noradrenaline and serotonin. Without enough of these neurotransmitters, people experience symptoms of depression. The scientists reasoned that inhibiting the action of the enzyme that removes the monoaminergic transmitter from the synapse leaves more noradrenaline and serotonin in the synapses, thereby relieving the symptoms of depression. Thus, the idea of monoamine oxidase inhibitors as a treatment for depression was born. Later, researchers found that iproniazid and imipramine also lead to an increase in the size and number of synapses in the hippocampus and the prefrontal cortex, the brain regions in which synaptic connections are damaged by stress and depression.
Understanding how these two antidepressants work led to the development of the monoamine hypothesis, which holds that depression results from partial depletion of noradrenaline or serotonin, or both. This hypothesis also cleared up a mystery surrounding the drug reserpine, which had been used in the 1950s to treat high blood pressure and which induced depression in 15 percent of the people who took it. Reserpine, it turns out, also depletes noradrenaline and serotonin in the brain.
The monoamine hypothesis of depression was modified in the 1980s with the introduction of drugs such as fluoxetine (Prozac), which are known as selective serotonin reuptake inhibitors (SSRIs). These drugs increase concentrations of serotonin in the synapse by blocking the reuptake of serotonin; they do not act on noradrenaline. This finding led researchers to conclude that depression is related specifically to depletion of serotonin and not the depletion of noradrenaline.
In time, however, scientists realized that treating depression is more than a simple matter of flooding the synapses with serotonin. To begin with, boosting serotonin didn’t help all patients get better. Conversely, reducing serotonin didn’t consistently worsen symptoms in depressed people, nor did it produce depression in all healthy people. Moreover, antidepressant drugs such as Prozac increase serotonin very rapidly in depressed people, yet people don’t show improvement in their mood or synaptic connections for weeks. While the monoamine hypothesis ultimately fell short of fully explaining the biology of depression, it spurred many good studies of the brain and helped clarify the important role that serotonin plays in the regulation of mood. In doing so, the hypothesis improved the lives of many people with depression.
Since selective serotonin reuptake inhibitors take about two weeks to take effect—a delay that can open the door to suicide attempts—and since a significant number of people do not respond at all to these reuptake inhibitors, new drugs were clearly needed. But despite intensive efforts, twenty years elapsed before a fast-acting drug emerged to treat people with depressive disorders.
That drug was ketamine, a veterinary anesthetic. Ketamine, whose mechanism of action was discovered by Ronald Duman and George Aghajanian at Yale,7 acts within hours in people with treatment-resistant depression. What’s more, the effect of that single dose can last for several days. Ketamine also appears to reduce suicidal thoughts and is now being explored as a possible short-term treatment for depressive episodes in people with bipolar disorder.
Ketamine works differently from traditional antidepressants. To begin with, it targets glutamate, not serotonin. To understand why this is important, we must first know that neurotransmitters fall into two categories: mediating and modulatory. Mediating neurotransmitters are released by a neuron at the synapse and act directly on the target cell, either exciting the target cell or inhibiting it. Glutamate is the most common excitatory transmitter, and GABA (gamma aminobutyric acid) is the most common inhibitory transmitter. Modulatory neurotransmitters, on the other hand, fine-tune the action of excitatory and inhibitory neurotransmitters. Dopamine and serotonin are modulatory neurotransmitters.
Because ketamine acts on the excitatory neurotransmitter glutamate, which directly affects the target cell, the drug reduces depression more quickly than drugs that act on the modulatory transmitter serotonin. In addition, ketamine prevents the transmission of glutamate from one neuron to the next by blocking a particular glutamate receptor on the target cell. Since a receptor blocked by ketamine can’t bind glutamate, the neurotransmitter can’t affect the target cell. The demonstration of the antidepressant effect of ketamine profoundly changed the way we think about depression.
Ketamine’s beneficial effects reveal yet another mechanism contributing to depression. As we have seen, depression is caused not simply by insufficient serotonin and adrenaline but also by stress, which results in the release of excessive cortisol, damaging neurons in the hippocampus and the prefrontal cortex. As it happens, high concentrations of cortisol also cause an increase in glutamate, and large doses of glutamate damage neurons in exactly the same areas of the brain.
Almost all antidepressants, including ketamine, promote the growth of synapses in the hippocampus and prefrontal cortex, thus countering the damage caused by cortisol and glutamate and providing an additional explanation for why these drugs are so effective. Moreover, in rodents ketamine acts quickly to induce the growth of synapses and to reverse the atrophy caused by chronic stress. As a result, the discovery of ketamine has been hailed as the most important advance in depression research in the last half century. However, because it produces side effects such as nausea, vomiting, and disorientation, ketamine cannot be taken over the long term and therefore cannot replace the selective serotonin reuptake inhibitors. Instead, because of its rapid action, ketamine is used to lessen the risk of suicide during the approximately two weeks required for the serotonin-enhancing drugs to take effect.
PSYCHOTHERAPY: THE TALKING CURE
Psychotherapy is an integral part of treatment for most people with psychiatric illness
es. Put simply, it is a verbal exchange between a patient and a therapist within a supportive relationship. While various forms of psychotherapy may have somewhat different theoretical bases, they all share this essential element. Psychotherapy has been used to treat patients for over a century, but scientists are only now beginning to understand how it works on the brain.
The first form of psychotherapy was psychoanalysis, which originated with Josef Breuer, a senior colleague of Freud’s at the Vienna School of Medicine. In 1895 Freud joined Breuer in publishing a paper about a patient, Anna O., who was suffering from paralysis on the left side of her body—a paralysis that had no neurological basis.8 Breuer encouraged Anna O. to talk at random about her memories, fantasies, and dreams. In the course of this free association, as he later called it, she remembered traumatic events. The recovery of those memories led to relief from her paralysis.
Freud was much impressed with this case. He picked up Breuer’s technique and used it to obtain insights into his own patients. From their fantasies and memories Freud inferred that the origins of mental illness lie in infancy and early childhood. Three modern scholars of psychoanalysis, Steven Roose of Columbia University College of Physicians and Surgeons, Arnold Cooper of Weill Cornell Medical Center, and Peter Fonagy of University College London, point to three key observations of Freud’s that are central to psychoanalysis.9
First, children have sexual and aggressive behavioral instincts. The social prohibitions that hold these instinctual needs in check begin early in life and carry onward into adulthood. In other words, sexuality and aggression do not arise in adulthood; they are present in infancy.
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