The night
was late and soggy: It was
New York in July.
I was in my room, hiding,
hating the need to swallow.
Later, I read in Leonard Woolf’s diary his description of Virginia’s depressions: “If left to herself, she would have eaten nothing at all and would have gradually starved to death. It was extraordinarily difficult ever to get her to eat enough to keep her strong and well. Pervading her insanity generally there was always a sense of some guilt, the origin and exact nature of which I could never discover; but it was attached in some peculiar way particularly to food and eating. In the early acute, suicidal stage of the depression, she would sit for hours overwhelmed with hopeless melancholia, silent, making no response to anything said to her. When the time for a meal came, she would pay no attention whatsoever to the plate of food put before her. I could usually induce her to eat a certain amount, but it was a terrible process. Every meal took an hour or two; I had to sit by her side, put a spoon or fork in her hand, and every now and again ask her very quietly to eat and at the same time touch her arm or hand. Every five minutes or so she might automatically eat a spoonful.”
You are constantly told in depression that your judgment is compromised, but part of depression is that it touches cognition. That you are having a breakdown does not mean that your life isn’t a mess. If there are issues you have successfully skirted or avoided for years, they come cropping back up and stare you full in the face, and one aspect of depression is a deep knowledge that the comforting doctors who assure you that your judgment is bad are wrong. You are in touch with the real terribleness of your life. You can accept rationally that later, after the medication sets in, you will be better able to deal with the terribleness, but you will not be free of it. When you are depressed, the past and future are absorbed entirely by the present moment, as in the world of a three-year-old. You cannot remember a time when you felt better, at least not clearly; and you certainly cannot imagine a future time when you will feel better. Being upset, even profoundly upset, is a temporal experience, while depression is atemporal. Breakdowns leave you with no point of view.
There’s a lot going on during a depressive episode. There are changes in neurotransmitter function; changes in synaptic function; increased or decreased excitability between neurons; alterations of gene expression; hypometabolism in the frontal cortex (usually) or hypermetabolism in the same area; raised levels of thyroid releasing hormone (TRH); disruption of function in the amygdala and possibly the hypothalamus (areas within the brain); altered levels of melatonin (a hormone that the pineal gland makes from serotonin); increased prolactin (increased lactate in anxiety-prone individuals will bring on panic attacks); flattening of twenty-four-hour body temperature; distortion of twenty-four-hour cortisol secretion; disruption of the circuit that links the thalamus, basal ganglia, and frontal lobes (again, centers in the brain); increased blood flow to the frontal lobe of the dominant hemisphere; decreased blood flow to the occipital lobe (which controls vision); lowering of gastric secretions. It is difficult to know what to make of all of these phenomena. Which are causes of depression; which are symptoms; which are merely coincidental? You might think that the raised levels of TRH mean that TRH causes bad feelings, but in fact administering high doses of TRH may be a temporarily useful treatment of depression. As it turns out, the body begins producing TRH during depression for its antidepressant capacities. And TRH, which is not generally an antidepressant, can be utilized as an antidepressant immediately after a major depressive episode because the brain, though it is having a lot of problems in a depression, also becomes supersensitive to the things that can help to solve those problems. Brain cells change their functions readily, and during an episode, the ratio between the pathological changes (which cause depression) and the adaptive ones (which fight it) determines whether you stay sick or get better. If you have medications that exploit or aid the adaptive factors enough to put down the pathological ones once and for all, then you break free of the cycle and your brain can get on with its usual routines.
The more episodes you have, the more likely you are to have more episodes, and in general the episodes, over a lifetime, get worse and closer together. This acceleration is a clue to how the disease works. The initial onset of depression is usually connected either to kindling events or to tragedy; people with a genetic predisposition to develop depression are, as Kay Jamison—a charismatic psychologist whose texts, academic and popular, have done a great deal to change thinking about mood disorders—has observed, “like dry and brittle pyres, unshielded against the inevitable sparks thrown off by living.” The recurrences at some point break free of circumstance. If you stimulate seizures in an animal every day, the seizures eventually become automatic; the animal will go on having them once a day even if you withdraw the stimulation. In much the same way, the brain that has gone into depression a few times will continue to return to depression over and over. This suggests that depression, even if it is occasioned by external tragedy, ultimately changes the structure, as well as the biochemistry, of the brain. “So it’s not as benign an illness as we used to suppose,” explains Robert Post, chief of the Biological Psychiatry Branch of the National Institute of Mental Health (NIMH). “It tends to be recurrent; it tends to run downhill; and so one should in the face of several episodes consider long-term preventative treatment to avoid all the horrible consequences.” Kay Jamison thumps the table when she gets going on this subject. “It’s not like depression’s an innocuous thing. You know, in addition to being a miserable, awful, nonconstructive state, for the most part, it also kills people. Not only through suicide, but also through higher heart disease, lowered immune response, and so on.” Frequently, patients who are medication-responsive cease to be responsive if they keep cycling on and off the medications; with each episode, there is an increased 10 percent risk that the depression will become chronic and inescapable. “It’s sort of like a primary cancer that’s very drug-responsive, but then once it metastasizes, it doesn’t respond at all,” Post explains. “If you have too many episodes, it changes your biochemistry for the bad, possibly permanently. At that point, many therapists are still looking in completely the wrong direction. If the episode now occurs on automatic, what good is it to worry about the stressor that kicked off the original process? It’s just too late for that.” That which is mended is but patched and can never be whole again.
Three separate events—decrease in serotonin receptors; rise in cortisol, a stress hormone; and depression—are coincident. Their sequence is unknown: it’s a sort of chicken and chick and egg mystery. If you lesion the serotonin system in an animal brain, the levels of cortisol go up. If you raise levels of cortisol, serotonin seems to go down. If you stress a person, corticotropin releasing factor (CRF) goes up and causes the level of cortisol to go up. If you depress a person, levels of serotonin go down. What does this mean? The substance of the decade has been serotonin, and the treatments most frequently used for depression in the United States are ones that raise the functional level of serotonin in the brain. Every time you affect serotonin, you also modify the stress systems and change the level of cortisol in the brain. “I wouldn’t say that cortisol causes depression,” says Elizabeth Young, who works on this field at the University of Michigan, “but it may well exacerbate a minor condition and create a real syndrome.” Cortisol, once it is produced, binds to glucocorticoid receptors in the brain. Antidepressants increase the number of these glucocorticoid receptors—which then absorb the excess cortisol that is floating around up there. This is extremely important for overall body regulation. The glucocorticoid receptors actually turn on and off some genes, and when you have relatively few receptors being swamped with a lot of cortisol, the system goes into overdrive. “It’s like having a heating system,” Young says. “If the temperature sensor for the thermostat is in a spot that’s become drafty, the heat will never turn off even though the room is scalding. If you add
a few more sensors located around the room, you can get the system back under control.”
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—o
r, 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.
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