MARCH 8, 1999
By Joannie M. Schrof; Stacey Schultz
Mention Prozac to Christine Margaret and she replies with a sardonic laugh. Been there. Zoloft? Tried that. And Paxil. And Elavil and Welbutrin. And a dozen other medications that have failed to alleviate the depression that denies the former actress her sleep, that landed her in the hospital, that left her weighing as little as 80 pounds, and that keeps her from holding a job. "Nobody comprehends what a beast this is," she says. "It has stolen my life." For more than a decade, Margaret has been suffering privately amid a loud public debate over the merits of the phenomenally famous Prozac and other antidepressants. As 35 million people flocked to Prozac alone, many began to ask: Are too many people taking the drugs, and for the wrong reasons? Do they fundamentally alter personality? Do we as a society expect too much, to be "better than well"?
All but lost in the clamor are some dispiriting facts: Prozac has not turned out to be a magic bullet against depression, and the problem is now worse than ever. In fact, many who study depression say that we are entering an "Age of Melancholy," where people are getting depressed at younger and younger ages, with episodes that are severe and frequent. By some measures, depression has already doubled since World War II, an increase not simply due to greater awareness, says Columbia University epidemiologist Myrna Weissman, but due also to factors such as more stress, fewer family and community ties, even nutritional deficiencies. Depression is on pace to be the world's second-most-disabling disease (after heart disease) by the year 2020; already, the World Health Organization ranks it first among women and fourth overall. In the United States, depression afflicts 18 million people at any given time, 1 in 5 over the course of a lifetime, and costs over $40 billion a year in lost work and health care.
Pills and pitfalls. To be sure, antidepressant medications and the psychotherapies that often accompany them have been absolute lifesavers for many of the tens of millions of people who have sought help. But 3 out of 10 depression sufferers don't respond at all to a given antidepressant, and the 7 out of 10 who respond do so only partially or find that the benefits wear out. Others cannot tolerate side effects such as gastrointestinal problems, sexual dysfunction, and grogginess. "Given how common depression is, it is a major public health threat that 20 percent of people don't get more than a modest benefit from any of our therapies," says National Institute of Mental Health Director Steven Hyman. This summer, the NIMH will launch an ambitious study to address the problem, which has come to be known as "treatment-resistant depression."
Such studies are desperately needed. Researchers claim that progress has been slowed because many people--including many physicians--still mistake chemical imbalances for weakness of character and don't take the disease seriously. Even though depression takes a greater cumulative toll on society than, say, heart disease, it receives less than one tenth the federal funding. The very name depression, some contend, is responsible for much of the problem, because the word is misleading. "People confuse it with the everyday sensation of feeling despondent and dismiss it," says NIMH neuroscientist Philip Gold. "In fact, it takes an incredibly strong person to bear the burden of the disease, which ought to be given a more appropriate name." He suggests "hypothalamo-pituitary-adrenal axis dysfunction"--an appropriately jargony medical description that is accurate but would never make it into the headlines. At least 12 million people are now suffering from the disease without any treatment at all, some with the mistaken belief that one can will oneself to be well. For those who do seek help, it's not unusual to consult with as many as three doctors over 10 years just to get the right diagnosis--let alone an effective remedy.
Progress in treating depression has been halting since the disorder was listed in psychiatry's first diagnostic manual in 1952. Early on, it was often treated (like most psychiatric disabilities) with Freudian psychoanalysis, but many experts now consider those techniques counterproductive, largely because exploring the past and focusing on problems exacerbates the tendency to remain "stuck" in negative ruminations. Electroconvulsive therapy--popularly known as electroshock--was and still is one of the most effective treatments against depression, but it requires anesthesia and carries a lingering stigma from a time when ill-trained practitioners caused unnecessary trauma. In the 1970s, researchers turned to two types of medication--so-called tricyclics and monoamine oxidase (MAO) inhibitors--to lessen a great many sufferers' symptoms, but both had serious side effects, and an overdose could cause death.
Mixed results. It's no wonder then that when Prozac came along in 1988, it was welcomed as a godsend. Even though it is slightly less effective than the earlier antidepressants, its side effects are not as severe. A large number of those who have taken Prozac say they owe their lives to it. But there are problems even for those who do respond. Many who try Prozac and its cousin Zoloft complain of sexual dysfunction or are struck by another bout of depression while still on medication, a problem known as "Prozac poop-out."
That's not to say that current treatments should be abandoned. In fact, some experts are convinced that treatment resistance is as much a failure of the health care system as it is of pharmacology. "I'm convinced that given enough care and expertise, a great many of the people we call treatment resistant could be helped with treatments that are currently available," says Gold. But that is easier said than done at a time when insurers frown on lengthy, time-consuming treatment, he notes.
It takes an enormous amount of trial and error to find the right medications and dosages for any given person, and people in the throes of depression are often ill-equipped to persist in the face of treatment failure. Side effects tend to come first, while benefits may not surface for up to six weeks--a period that can seem like an eternity. "Every minute seems like a week when I'm waiting to see if something will work," says Margaret. "My doctor has already tried every medication on the market and thrown up his hands in despair." Yet Bob Olson of Worcester, Mass., is glad he didn't accept the "treatment resistant" label. After 15 medications and 21 ECT sessions, Olson is finally finding relief with Tegretol (a drug that hadn't worked at first) and has been depression free for five years.
These mixed results don't really surprise the experts, given the fact that no one yet knows exactly what depression is. The disorder is so complicated, and manifests itself in so many ways, that most researchers now think of it not as one disease, but many. "I refer to them as the 'depressions,' " says Mark George, a neurologist at the Medical University of South Carolina who uses brain imaging to study depressed patients. "It's obvious from symptoms and from what we see happening in the brain that the people we group together as depressed are suffering from different problems."
For some time, specialists have divided depression into two categories. The first, called "melancholic depression," is marked by hyperarousal in the brain, a sort of chronic stress response that can't turn off and that makes it difficult to sleep or eat. The second, "atypical depression," involves an increase in sleeping and eating, a sort of numb hibernation. Other types, each with different symptoms, continue to emerge, such as seasonal affective disorder, or wintertime depression; dysthymia, a milder but longer-lasting form of depression; cyclothymia, repeating bouts of highs and lows; and the more severe manic depression (or bipolar disorder), which sends sufferers to dangerous, sometimes delusional highs and suicidal lows. "I wouldn't be surprised if, in 10 years, there were 10 known types of depression, each with its own biological abnormalities and each calling for a separate treatment," says George.
As if this weren't complicated enough, it turns out that depression is often entangled with other health problems, making it difficult to tease out one or another problem for treatment. For example, alcoholism often accompanies depression, but antidepressants are not as effective if alcohol (a depressant) is consumed as well. Illnesses as simple as the flu or as serious as heart disease almost always worsen depression, and in turn depression is known to cause a great many physical problems, ranging from bone-density loss to a greater risk of cardiovascular disease and even cancer. In fact, when all other elements are factored out, studies find depressed people at least twice as likely to die during any given period. And that's not counting suicide, an act that a depressed person is 35 times more likely than others to commit.
Spurred by these dire reports, researchers are painstakingly re-examining depressive disorders and developing a far more nuanced understanding of the illnesses. More sophisticated knowledge may not only yield better treatments but also help to erase much of the stigma surrounding depression. Already, the research results are overturning some long-entrenched notions. For instance: Not just sadness. UCLA neuropsychiatrist Peter Whybrow suggests that people who want to know what severe depression feels like can get a glimpse of it by combining the anguish of profound grief with the bodily sensations of severe jet lag. Boston native and longtime depression sufferer Evie Barkin describes it this way: "It's like the worst migraine of your life, and it seems like it will never go away." Even though depression is called a "mood" disorder, mood is only one of more than a dozen bodily functions interrupted by a depressed, misfiring brain.
The brain, says Whybrow, has been designed by eons of evolution to strive for harmony with the environment. Depression disrupts that process, so that the brain's basic housekeeping rhythms are thrown off. Sleeping and eating become disordered (along with libido), and energy levels dissipate, so that the simplest chore or social interaction can seem impossible. Further, the depressed brain fires off counterproductive distress signals of doom, gloom, fear, anxiety, panic, and self-destruction. Cognitive abilities like concentration and memory are sabotaged. In fact, the symptoms are so varied that it can be hard to recognize that a person has depression. One person may eat constantly and be unable to sit still, while the next may seem like a zombie. Another may suffer severe headaches, muscle pain, and upset stomach.
The myth of misfortune. Depression is not caused by bad circumstances or cured by good ones, even though it often seems that way to a sufferer. It's a cruel trick of the brain that when everything feels wrong, it's almost impossible for a victim to recognize brain malfunction as the source of the problem. As a result, the depressed person looks for an explanation in the events of the world. Certainly, stressful events--the death of a loved one, for example--can trigger depression, but only in someone whose brain is vulnerable to the disease, which Whybrow labels a "neuro-biological Achilles heel." That's why the disease runs in families, and also why, although most people experience grief when a loved one dies, only 5 percent develop clinical depression.
Paradoxically, the real-world triggers for depression and the illness itself frequently decouple once the disorder is set in motion. When a severe brain disorder takes over, it causes suffering that is "only distantly related" to sad life events, according to Whybrow, and that does not ease when circumstances improve. The upside to this is that even those people who would seem to have every reason to stay depressed can often be helped. For example, University of Iowa neuropsychiatrist Robert Robinson finds that most stroke victims who become depressed quickly respond to treatment. "Even though they are unable to talk, walk, or feed themselves," says Robinson, "they are mentally well and ready to make the most of what they are left with."
While good or bad circumstances cannot dictate the course of depression, the way people think about them can exert either a damaging or a palliative effect. Typically, the depressed brain's misguided stress signals foster rumination and worry, which in turn fuel further detrimental physiological reactions and worsen the disease. It is possible to learn to avoid thoughts that exacerbate the brain's already-out-of-whack stress response, but such mind control is difficult enough for a healthy individual, let alone one whose brain is caught in red-alert mode.
That's why psychotherapy can be so critical in treating the illness. Most psychiatrists now believe that in severe depression, medication is needed to restore enough bodily and cognitive functioning for a sufferer to then attack the unhealthy thinking that has grown out of the illness. Most of the more than 20 types of psychotherapy show some success with depression, but those with the best track record are designed to be fairly short, lasting less than a year, and focus on correcting distorted thought patterns. For example, a typical way of thinking that exacerbates depression is known as the "romantic worldview," in which a person crumbles whenever circumstances don't turn out as planned. Working with a therapist, depression sufferers learn to adopt more of a "tragic" worldview (the philosophical belief that for every loss something is gained, and vice versa), which tends to reduce stress-inducing thoughts.
The most therapeutic thing about counseling may ultimately be the genuine concern a therapist shows for a patient. "Depression turns people on themselves, and they enter therapy expecting a therapist to see them as negatively as they see themselves," says NIMH's Gold. "When that doesn't happen, a trust develops that allows a patient to re-examine faulty assumptions."
Not a happy pill. Many people shy away from medication, and others are suspicious of those who take it, because of a misguided notion that antidepressants alter the personality, providing a fast, false high. "People always tell me they don't want to alter themselves," says Gold. "But I tell them they already are altered, and the medication will restore them to their normal state." Antidepressants work slowly, as the brain responds to the medication by restructuring its faulty messaging machinery. In normal brains, the antidepressants do not elevate mood.
A lifelong disorder. It can be especially devastating when, after a year of medication and therapy--just about when life seems to be getting back to normal--a person is clobbered by another depression for no apparent reason. Until recently, recurrences of depression were thought to be a rare exception to the rule, but now scientists know otherwise. The majority of sufferers first experience depression by adolescence, and it tends to surface in regular cycles, lasting an average of nine to 16 months and then remitting for a similar period. Given this cycling, says Richard Glass, deputy editor of the Journal of the American Medical Association, it is best to manage it like any other chronic illness, such as diabetes or high blood pressure. While many people now take antidepressants until they feel better, Glass and others recommend that they continue for at least 18 months after the depression lifts. Still other clinicians feel that, given the enormous consequences of relapse, it is not unwise to keep severe depression sufferers on medication for life.
The serotonin craze. Prozac acts on the brain chemical serotonin, and in part because of the drug's initial hype, that one neurotransmitter has been singled out as the prime culprit behind depression. But depression cannot be explained by a shortage of any single brain substance. "Nothing disturbs me more than when someone tries to describe something as complicated as a mental state with something as simplistic as serotonin levels," says Hyman. "It's as if the brain were nothing but a water bottle full of chemicals." Although often branded the brain's "feel good" chemical, serotonin is just one of several substances the brain uses to regulate its sense of well-being. Dopamine, for example, is a chemical that seems to drive the brain's reward systems, and some of the older antidepressants act upon it. It is also the chemical implicated in addictions and could explain why depression and substance abuse go hand in hand.
Similarly, the neurotransmitter norepinephrine appears to act as the brain's watchdog, firing when there is cause for worry or fear. Norepinephrine is probably a key player in the neurological underpinnings of depression's anxious features. Melatonin, a chemical that governs sleep cycles, seems to be off kilter in winter depression.
Hormones that bathe the brain also play a role in depression. Much of the worst long-term damage from depression can be linked to cortisol, a stress hormone. It is harmless in small doses but ravages the body when pumped continuously into the system by depression or anxiety. The sex hormones also seem to be involved in depression and may explain why the disorder is so common in adolescence--and also why women (who have more variable levels of sex hormones) appear more vulnerable to depression than do men.
In addition to biochemical changes, brain structures themselves appear to behave differently in depression. In imaging studies, the left prefrontal cortex seems to be especially sluggish. And studies of depression sufferers who have improved, both after medication and after therapy, show an increase in that region's activity. One study even shows that the left prefrontal cortex is more active following exercise, offering a physiological explanation for why workouts elevate mood. In addition to the prefrontal cortex, connected centers deep in the primitive, emotional brain are also implicated in depression. In one study of people hit with depression for the first time after age 65, brain scans showed that 85 percent of them had actually suffered a "silent" or unknown stroke in one of these regions. Silent strokes in other areas of the brain do not cause depression.
New treatments. Armed with a better understanding of depression, researchers are developing new ways to conquer it. At least 18 new antidepressants are in the pharmaceutical pipeline, and most of them attempt to attack depression through just one or two of the chemical pathways. (Unfortunately, each time a brain chemical is tinkered with, a host of side effects appears, making it infeasible to design a medication that would alter several chemicals at once.) Pharmacia & Upjohn, for example, is working on an antidepressant that targets norepinephrine. Other companies are looking at drugs to inhibit a chemical known as corticotropin-releasing factor, the substance that tells the pituitary and adrenal glands to flood the body with cortisol. And some are studying a chemical known as Substance P. Still others are developing new drug-delivery systems, such as skin patches, which may alleviate many side effects by releasing the medication very slowly.
Jump-start. Scientists have long searched
for a depression treatment that works faster, and now they think they've
found it. Using a promising experimental procedure known as "rapid transcranial
magnetic stimulation," scientists say they are getting results after six
days. A new twist on an old idea, RTMS uses a powerful magnet to deliver
an electric jolt to the brain, in the same fashion as electroconvulsive
therapy but without electric stimulation to unnecessary parts of the brain.
The idea is something like a defibrillator for the heart: The electric
voltage that passes through the brain causes many neurons to fire at once,
and something about this action seems to reset the rate at which the brain
releases the various chemicals implicated in depression.
No one yet knows whether the beneficial effects of RTMS last for longer than six months, but that is likely to be determined by the time RTMS is approved for general use in another two to three years. "It could be a great thing to use in conjunction with medication," says George of the Medical University of South Carolina. "RTMS could step in first to offer fast relief, then medication could kick in later to maintain well-being over the long haul."
The science of depression has advanced to the point where even the most cautious researchers speak of finding a true cure in their lifetime. "I'm very optimistic about our ability to lick this disease medically," says former NIMH director Frederick Goodwin. But he is more pessimistic about social elements--stresses that fuel depression and misguided notions that keep it shrouded in shame. "I still have people tell me that I should cheer up because I have nothing to be depressed about," Chistine Margaret says. "As if I had a choice in the matter."
CHRISTINE MARGARET: She is one of the many walking wounded. None of psychiatry's tools has managed to lift her debilitating depression.
SAM GILMAN: Sam Gilman says he was a "closet depressive" for half a century, but unlike many depressed people he was plagued mostly during his leisure time. He endured the constant lack of energy and ambition he felt by throwing himself into his law practice and community work. But weekends and holidays were tough: "I was unhappy and these were times when I'd go a little to seed."
Three years ago, when Gilman was in his mid-70's, his depression worsened, and he sought treatment for the first time. But by then his illness was well entrenched, and it has been nearly impossible to treat. A rarely used drug called Dexedrine has brought him "partial response," but he still struggles with lethargy and joylessness. His doctor believes that if he had sought help earlier, the depression might have been easier to contain. "There is a sense of shame that goes with depression," says Gilman. " I guess that's why I waited so long."
SHANNON PARRIS: Three years ago, Shannon Parris went to her doctor complaining of a persistent sore throat, trouble getting out of bed, and flu-like aches. When asked if she had ever been treated for depression, she responded with both mortification and relief. "How dare you say that about me," she recalls thinking. "At the same time I thought, 'Thank God somebody has figured this out.' "
But that was not the end of the struggle for the former schoolteacher and mother of twins. Over more than two years, Parris has tried five different antidepressants, which she says made her either the "woman from hell" or a slugabed. So last December, she opted for an experimental two-week treatment that uses a powerful magnet to alter the brain's electrical activity. After seven days her energy was back and life looked good again. Two months later Parris still feels great, but she is on guard against the possibility of relapse. "So many people have worked hard to make me well, so I'm trying my damnedest to cope with this."
GREGORY WRIGHT: Gregory Wright says he would not be here today if not for the professional help he received during the darkest days of his depression after a devastating divorce in 1987. A psychologist helped him avoid "blowing my brains out" for four years before deciding that he needed medication. In 1990, a psychiatrist told him that his depression was related to a condition called obsessive-compulsive disorder, which was flooding his mind with a relentless stream of repetitive fears. Wright was prescribed Prozac, but after six months it didn't seem to be working, so his medication was switched to a combination of Anafranil and Paxil, two antidepressants thought to be especially suited to OCD. Wright has since remarried. He says that his wife is "a rock," and his boss and colleagues are supportive. This summer, he and his wife will take their 5-year-old daughter on her first trip to Disney World: "I'm so glad I didn't let go of the rope, or I would have missed all this."
DENNIS HAGLER: In 1970, while working as a young Peace Corps volunteer in Malaysia, Dennis Hagler had a religious experience. "I felt I was becoming one with the universe. It was quite beautiful," he remembers. "But it didn't go away and it grew more frightening." Hagler was diagnosed as manic depressive, and the standard treatment of lithium failed to stabilize his moods. For the next 15 years, he would struggle against suicidal lows and maniacal highs.
As he struggled, he began treating himself with alcohol. When he went to an Alcoholics anonymous meeting for help with his addition, he was told that his antidepressants were a big part of the problem. So he stopped taking them, because he says, "I wanted to believe more than anything that I didn't have a mental illness. Abut then the disease really took over."
Two drugs became available in 1989 that helped Hagler return to normal. But his healing was also helped by the support group he joined in 1990. "I was alone in the world with my illness," he says. "Then, for the first time, I was home."
BYLINDA BROWN: Fifteen years ago, Bylinda Brown bought a gun for protection, but she soon found herself sitting with the loaded weapon for hours at a time, contemplating suicide. "I felt like I had already died inside," she recalls. When she asked her doctor for help, he told her that she was going through menopause. "I was 36 years old then," she says. "Today I'm 46, and I still have not hit menopause." For seven years, Brown would often wake before dawn, convinced she was having a heart attack. She became so disoriented that she lost her business. Then, three years ago, she received Prozac as part of a study, and she gradually began to feel like herself again. When the study ended, the uninsured Brown had to choose between paying the rent or $400 a month for Prozac. She chose Prozac and took work caring for an elderly woman in exchange for room and board. "I'm still trying to crawl my way back. But it's like going uphill through cold molasses."
Article: 'Meloncholy Nation' by Joannie M. Schrof; Stacey Schultz
Reprinted from: U.S. News and World Report March 8, 1999, Newsbank Archives