The Noonday Demon (11 page)

Under ordinary circumstances, cortisol levels stick to fairly straight-
forward rules. Cortisol’s circadian pattern is to be up in the morning (it’s what gets you out of bed) and then to go down during the day. In depressed patients, cortisol tends to remain elevated throughout the day. Something’s wrong with the inhibitory circuits that should be turning off the production of cortisol as the day wears on, and this may be part of why the jolted feeling that is usual first thing in the morning continues so far into the day for depressed people. It may be possible to regulate depression by addressing the cortisol system directly, instead of working through the serotonin system. Building on basic research done at Michigan, investigators elsewhere have treated treatment-resistant depression patients with ketoconazole, a cortisol-reducing medication, and almost 70 percent of these patients showed marked improvement. At the moment, ketoconazole causes too many side effects to be attractive as an antidepressant, but several major pharmaceutical companies are investigating related medications that may not have these negative side effects. Such treatment must be carefully regulated, however, since cortisol is necessary for fight-or-flight responses; for that adrenal energy that helps one to struggle on in the face of difficulty; for anti-inflammatory action; for decision making and resolution; and most importantly, for knocking the immune system into action in the face of an infectious disease.

Cortisol patterning studies have recently been done on baboons and air traffic controllers. The baboons who had long-term high cortisol tended to be paranoid, unable to distinguish between a real threat and a mildly uncomfortable situation, likely to fight as desperately over a banana next to a tree heavy with ripe fruit as over their life. Among air traffic controllers, those who were psychologically healthy had an exact correlation between the extent to which they were overworked and their level of cortisol, while those who were in poor condition had their cortisol skyrocketing and peaking all over the place. Once the cortisol/stress correlation gets distorted, you can get hysterical about bananas; you will find that everything that happens to you is stressful. “And that is a form of depression, and then of course being depressed is itself stressful,” observes Young. “A downward spiral.”

Once you’ve had a stress sufficient to cause a protracted increase of your cortisol levels, your cortisol system is damaged, and in the future it will not readily turn off once it has been activated. Thereafter, the elevation of cortisol after a small trauma may not normalize as it would under ordinary circumstances. Like anything that has been broken once, the cortisol system is prone to break again and again, with less and less external pressure. People who have had myocardial infarction after great physical strain are subject to relapse even while sitting in an armchair—
the heart is now a bit worn-out, and sometimes it just gives up even without much strain. The same thing can happen to the mind.

The fact that something is medical doesn’t contravene its having psychosocial origins. “My wife is an endocrinologist,” says Juan López, who works with Young, “and she sees kids with diabetes. Well, diabetes is clearly a disease of the pancreas, but external factors influence it. Not only what you eat, but also how stressed you are—kids in really bad homes get frantic and their blood sugar goes haywire. The fact that this happens doesn’t make diabetes a psychological disease.” In the field of depression, psychological stress transduces to biological change, and vice versa. If a person subjects himself to extreme stress, CRF is released and often helps bring about the biological reality of depression. The psychological techniques for preventing yourself from getting too stressed can help to keep down your levels of CRF, and so of cortisol. “You’ve got your genes,” López says, “and there’s nothing you can do about them. But you can sometimes control how they express themselves.”

In his research work, López went back to the most straightforward animal models. “If you stress the hell out of a rat,” he says, “that rat will have high levels of stress hormones. If you look at his serotonin receptors, they’re clearly screwed up by stress. The brain of a highly stressed rat looks very much like the brain of a very depressed rat. If you give him serotonin-altering antidepressants, his cortisol eventually normalizes. It is likely that some depression is more seratonergic,” López says, “and some is more tightly linked to cortisol, and most mixes these two sensitivities in some way. The cross talk between these two systems is part of the same pathophysiology.” The rat experiments have been revealing, but the prefrontal cortex, that area of the brain that humans have and that makes us more developed than rats, also contains many cortisol receptors, and those are probably implicated in the complexities of human depression. The brains of human suicides show extremely high levels of CRF—“it’s hyper, like they’ve been pumping this stuff.” Their adrenal glands are larger than those of people who die from other causes because the high level of CRF has actually caused the expansion of the adrenal system. López’s most recent work indicates that suicide victims actually show significant decrease in cortisol receptors in the prefrontal cortex (which means that the cortisol in that area is not mopped up as quickly as it should be). The next step, López says, is to look at the brains of people who can be subjected to huge amounts of stress and who can keep going despite it. “What is the biochemistry of their coping mechanism?” López asks. “How do they sustain such resilience? What are the patterns of CRF release in their brains? What do their receptors look like?”

John Greden, department chair for López and Young, focuses on the long-term effects of sustained stress and sustained depressive episodes. If you have too much stress and too high a level of cortisol for too long, you start destroying the very neurons that should regulate the feedback loop and turn down the cortisol level after the stress is resolved. Ultimately, this results in lesions to the hippocampus and the amygdala, a loss of neuronal networking tissue. The longer you remain in a depressed state, the more likely you are to have significant lesioning, which can lead to peripheral neuropathy: your vision starts to fade and all kinds of other things can go wrong. “This reflects the obvious fact that we need not only to treat depression when it occurs,” says Greden, “but also to prevent it from recurring. Our public health approach at the moment is just wrong. People with recurrent depression must stay on medication permanently, not cycle on and off it, because beyond the unpleasantness of having to survive multiple painful depressive episodes, such people are actually ravaging their own neuronal tissue.” Greden looks to a future in which our understanding of the physical consequences of depression may lead us to strategies to reverse them. “Maybe we’ll be trying selective injection of neurotropic growth factors into certain regions of the brain to make some kind of tissue proliferate and grow. Maybe we’ll be able to use other kinds of stimulation, magnetic or electric, to encourage growth in certain areas.”

I hope so. Taking the pills is costly—not only financially but also psychically. It is humiliating to be reliant on them. It is inconvenient to have to keep track of them and to stock up on prescriptions. And it is toxic to know that without these perpetual interventions you are not yourself as you have understood yourself. I’m not sure why I feel this way—I wear contact lenses and without them am virtually blind, and I do not feel shamed by my lenses or by my need for them (though given my druthers, I’d choose perfect vision). The constant presence of the medications is for me a reminder of frailty and imperfection; and I am a perfectionist and would prefer to have things inviolate out of the hand of God.

Though the initial effects of antidepressants begin after about a week, it takes as much as six months to get the full benefits. Zoloft made me feel awful, and so my doctor switched me to Paxil after a few weeks. I was not wild about Paxil, but it did seem to work and it had fewer side effects for me. I did not learn until much later on that while more than 80 percent of depressed patients are responsive to medication, only 50 percent are responsive to their first medication—or, indeed, to any particular medication. In the meanwhile, there is a terrible cycle: the symptoms of
depression cause depression. Loneliness is depressing, but depression also causes loneliness. If you cannot function, your life becomes as much of a mess as you had supposed it was; if you cannot speak and have no sexual urges, your romantic and social life disappear, and that is authentically depressing. I was, most of the time, too upset by everything to be upset by anything in particular; that is the only way I could tolerate the losses of affect, pleasure, and dignity that the illness brought my way. I also, inconveniently, had a reading tour to do immediately after my birthday. I had to go to a variety of bookstores and other venues and stand up in front of groups of strangers and read aloud from the novel I had written. It was a recipe for disaster, but I was determined to get through it. Before the first of these readings, in New York, I spent four hours taking a bath, and then a close friend who has had his own struggles with depression helped me to take a cold shower. He not only turned on the water, but also helped me to cope with exhausting difficulties such as buttons and fastenings, and stood in the bathroom so he could help me back out again. Then I went and read. I felt as though I had baby powder in my mouth, and I couldn’t hear well, and I kept thinking I might faint, but I managed to do it. Then another friend helped to get me home, and I went back to bed for three days. I had stopped crying; and if I took enough Xanax, I could keep the tension under control. I still found mundane activities nearly impossible, and I woke up every day in a panic, early, and needed a few hours to conquer my fear well enough to get out of bed; but I could force myself out into public for an hour or two at a time.

Emergence is usually slow, and people stop at various stages of it. One mental health worker described her own constant struggle with depression: “It never really leaves me, but I battle with it every day. I’m on medication, and that helps, and I have just determined that I will not let myself give in to it. You see, I have a son who suffers from this disease, and I don’t want him to think that it’s a reason for not having a good life. I get up every single day, and I make breakfast for my kids. Some days I can keep going, and some days I have to go back to bed afterwards, but I get up every day. I come into this office at some point every day. Sometimes I miss a few hours, but I’ve never missed a whole day from depression.” She had tears rolling down her face as we spoke, but her jaw was set and she went right on speaking. “One day last week I woke up and it was really bad. I managed to get out of bed, to walk to the kitchen, counting every step, to open the refrigerator. And then all the breakfast things were near the back of the refrigerator, and I just couldn’t reach that far. When my kids came in, I was just standing there, staring into the refrigerator. I hate being like that, being like that in front of them.” We talked about the day-to-day battle: “Someone like Kay Jamison, or
someone like you, gets through this with so much support,” she said. “My parents are both dead, and I’m divorced, and I don’t find it easy to reach out.”

Life events are often the triggers for depression. “One is much less likely to experience depression in a stable situation than in an unstable one,” Melvin McInnis of Johns Hopkins says. George Brown, of the University of London, is the founder of the field of life-events research and says, “Our view is that most depression is antisocial in origin; there is a disease entity as well, but most people are able to produce major depression given a particular set of circumstances. Level of vulnerability varies, of course, but I think at least two-thirds of the population has a sufficient level of vulnerability.” According to the exhaustive research he has done over twenty-five years, severely threatening life events are responsible for triggering initial depression. These events typically involve loss—of a valued person, of a role, of an idea about yourself—and are at their worst when they involve humiliation or a sense of being trapped. Depression can also be caused by positive change. Having a baby, getting a promotion, or getting married are almost as likely to kindle depression as a death or loss.

Traditionally, a line has been drawn between the endogenous and reactive models of depression, the endogenous starting at random from within, while the reactive is an extreme response to a sad situation. The distinction has fallen apart in the last decade, as it has become clear that most depression mixes reactive and internal factors. Russell Goddard, of Yale University, told me the story of his battles with depression: “I took Asendin and it resulted in psychosis; my wife had to rush me to the hospital.” He had better results with Dexedrine. His depression often escalated around family events. “I knew that my son’s wedding would be emotional,” he told me, “and that anything emotional, good or bad, sets me off. I wanted to be prepared. I’d always hated the idea of electroshock therapy, but I went and had it anyway. But it didn’t do any good. By the time the wedding came, I couldn’t even get out of bed. It broke my heart, but there was no way I could get there.” This puts a terrible strain on family and on family relations. “My wife knew she couldn’t do anything,” Goddard explained. “She’s learned to leave me alone, thank God.” But family and friends are often unable to do that, and unable to understand. Some are almost too indulgent. If you treat someone as totally disabled, he will see himself as totally disabled, and that can cause him to be totally disabled, perhaps more totally disabled than he need be. The existence of medication has increased social intolerance. “You got a problem?” I once heard a woman say to her son in a hospital. “You get on that Prozac
and get over it and then you give me a call.” To set the correct level of tolerance is necessary not only for the patient but also for the family. “Families must guard themselves,” Kay Jamison once said to me, “against the contagion of hopelessness.”