Depression - Symptoms, Causes and Treatment

Depression (Psychology)

Brain Activity in Bipolar Disorder

These positron emission tomography scans of the brain of a person with bipolar disorder show the individual shifting from depression, top row, to mania, middle row, and back to depression, bottom row, over the course of 10 days. Blue and green indicate low levels of brain activity, while red, orange, and yellow indicate high levels of brain activity.

Dr. Michael Phelps/Lewis Baxton/UCLA School of Medicine

Depression (psychology), mental illness in which a person experiences deep, unshakable sadness and diminished interest in nearly all activities. People also use the term depression to describe the temporary sadness, loneliness, or blues that everyone feels from time to time. In contrast to normal sadness, severe depression, also called major depression, can dramatically impair a person’s ability to function in social situations and at work. People with major depression often have feelings of despair, hopelessness, and worthlessness, as well as thoughts of committing suicide.

THAT FINE MADNESS

Fifty-five years ago, on a brisk March morning, the novelist Virginia Woolf walked from her country house at Rodmell, in Sussex, England, to the banks of the nearby River Ouse. There she lay down her walking stick and picked up a large stone, forcing it into the pocket of her coat. Then she walked on. The stone did the trick; it was three weeks before her body surfaced on the far shore.

To Leonard, her husband, she had left a note propped on the mantelpiece. 'Dearest,' it read, 'I feel certain I am going mad again … and I shan't recover this time. I begin to hear voices, and I can't concentrate.… I don't think two people could have been happier till this terrible disease came.… V.'

The diary Woolf kept from 1915 until four days before her suicide suggests that her 'terrible disease' may have been manic depression, now also known as bipolar illness. This condition, classed by psychiatrists as a mood disorder, involves a series of emotional peaks and valleys that over time often become higher, lower, and closer together. Some sufferers experience deep depressions and moderate manic episodes; others have moderate, short-lived depressions but become so manic they begin to hallucinate.

Woolf's depressive episodes were cyclic—sometimes seasonal, sometimes connected with finishing a book. Yet in between her depressions and episodes of outright mania, she managed to be highly productive and was often lively and charming. 'I always felt on leaving her that I had drunk two glasses of excellent champagne,' her friend Nigel Nicolson has recalled. 'She was a life enhancer.'

If accurate, the diagnosis of bipolar disease puts Woolf in impressive company. It's not just that she is thereby entitled to join the ranks of 'mad' artists who have always figured in the popular image of creativity. Bipolar illness elevates her to a more elite group. Over the past two decades a swelling chorus of psychologists, psychiatrists, and even a few neuroscientists have begun to suggest that bipolar illness somehow enhances the ability to make art. This mysterious and still hypothetical link, they say, may account for the persistence of the more generalized hoary stereotype.

Even the most ardent advocates of the connection concede that most creativity has nothing to do with mental illness and that most of the mentally ill, bipolar or otherwise, are no more creative than the rest of us. Yet it must be more than coincidence, they say, that the life and work histories of so many giants of Western culture show patterns reminiscent of bipolar illness.

Johns Hopkins University psychologist Kay Redfield Jamison, whose many books and articles on the subject have made her the de facto point person for the art-and-madness link, has compiled a roll call of the artists in this unhappy club that reads like the A-list for the cocktail party of the millennium. Among them are poets William Blake, John Keats, Percy Bysshe Shelley, Edgar Allan Poe, Emily Dickinson, and Anne Sexton; novelists Emile Zola, Mary Shelley, Leo Tolstoy, Maxim Gorky, and Robert Louis Stevenson; playwright Eugene O'Neill; visual artists Michelangelo, Théodore Géricault, Edvard Munch, Paul Gaugin, Vincent van Gogh, Mark Rothko, and Georgia O'Keeffe; and musicians from Handel to Charlie Parker. She includes, in fact, practically every famously tormented artist in the canon.

The very inclusiveness of this list, however, has raised a few eyebrows. Skeptics charge that giving dead artists retroactive psychiatric diagnoses, then treating those diagnoses as evidence, is a parlor game, not science. 'There's a long tradition regarding inspiration as divine,' says psychiatrist Frank Johnson of the University of California at San Francisco, who until his retirement two years ago participated in a program treating artists for their psychological and physical problems. 'The more modern, technological version of this in the medical literature makes madness the condition for writing poetry or doing philosophy.'

Furthermore, as critics like Johnson point out, bipolar illness is only the latest in a list of organic conditions correlated with creativity. In the 1960s, for example, alcoholism was the literary disease of choice; earlier in the century epilepsy and syphilitic paresis were linked to genius. Is it possible, as Susan Sontag observed in Illness as Metaphor, that insanity is merely 'the current vehicle of our secular myth of self-transcendence'?

Critics of the self-transcendence myth point out that the gifts of many of the same artists who are now postmortem draftees to the bipolar ranks—Keats, Shelley, Poe, Gorky, Stevenson, and O'Neill, among others—were once routinely attributed not to mental illness but to the mysterious and often fatal physical illness tuberculosis. Like manic depression, TB involved alternating periods of hyperactivity and lassitude; it, too, was thought to create a mental exaltation that predisposed its victims to extraordinary insights. So widespread was the belief in this association that one turn-of-the-century critic attributed the perceived decline in quality of literature and the arts to the gradual disappearance of consumption.

There is another objection—less subtle but perhaps more heartfelt than any of the academic cavils—raised by people who have experienced bipolar illness firsthand. They point out that between 10 and 15 percent of people with severe forms of the illness eventually take their own life. Even if there is a link between art and madness in some small and unquantifiable subset of creative people, so what? The push to emphasize this link, they feel, glamorizes a killer, sugarcoats its destructiveness, and makes life even harder for ordinary people trying desperately to stay on an even keel. 'It's bad enough to be sick,' says Laura M., who has had bipolar disease for 15 years, attempted suicide twice, and is currently running several bipolar support groups. 'Why should we have to deal with people expecting us to be creative?” Adds Katherine T., a fellow sufferer and group member who, through medication, manages to function successfully as a potter and painter, 'I hate for people to admire the creativity and support an illness that ends in something so criminal to the self as suicide.'

The notion of a link between creative genius and madness has had a long, if checkered, history in Western thought. Plato believed that poetry 'untouched by the madness of the Muses' was always 'eclipsed by the performances of the inspired madman.” And Aristotle wondered, “Why is it that all men who are outstanding in philosophy, poetry, or the arts are melancholic?'

Ancient Greek opinion shaped popular Western attitudes until the eighteenth century, when tranquillity briefly superseded angst as the supposed wellspring of inspiration. 'A painter ought to have a Sweet, and Happy Turn of Mind,' wrote essayist Jonathan Richardson in 1715, 'that Great and Lovely Ideas may have a Reception there.' 'It is impossible to imagine a mad Shakespeare,' commented Charles Lamb 111 years later, in an apostrophe to the necessary partnership of genius and sanity. (Like many people interested in the subject, Lamb wrote from personal experience: his sister and literary collaborator, Mary, stabbed their mother to death during a manic episode, and Charles himself spent time in a madhouse.) But Lamb was out of step with his time. With nineteenth-century poets Byron, Shelley, and Coleridge—Lamb’s contemporaries—Western culture was gripped anew by the image of the wild-eyed, suffering artist who was channeling some power greater than himself.

More recently, works such as R. D. Laing's 1960s campus classic The Politics of Experience suggested that schizophrenics create some of the truest art because the mad are more closely in touch with their inner selves than are the sane. In retrospect, this conclusion seems like the triumph of politics over rationality; contemporary schizophrenia researchers are more impressed by the destructiveness of the disease than its creative fecundity.

Why should the idea of a link between art and madness have such a hold on the popular imagination? Some clinicians attribute it to a rather unpleasant human trait: extraordinary accomplishments, they say, make the rest of us nervous. 'We have only two ways to react to creative people in this culture,' says Harvard psychiatrist Albert Rothenberg. We either worship them or we're jealous.'

'We do this with athletes' as well as artists, adds Johnson. 'We call their skills 'uncanny,' which is a backhanded pathologizing of achievement, instead of crediting perseverance.'

According to Johnson's view, an observation like Baudelaire's lofty 'I have felt the wind of the wing of madness' is comforting; it provides us a little frisson, then allows us to settle back and fish between the sofa cushions for the remote. No need to make the effort to create a poem or anything else; art is the province of the mad.

But there may be a simpler reason that the question seems to intrigue each generation anew: the data that might resolve it are so hard to obtain. If researchers look to the great artists of the past for answers, a standoff is inevitable. Both sides have their lists. Does a cheerful Jane Austen trump a melancholy Virginia Woolf? Does the businesslike, bourgeois Anthony Trollope outrank the hard-drinking, depressive Ernest Hemingway? Was Mark Rothko, who cut open the arteries of his arms, somehow a more real artist than Pierre-Auguste Renoir, who died peacefully in bed?

And studying living artists isn't any easier. Some researchers have elected to approach people who have been socially defined as creative—recipients of prizes, for instance—and tried to assess their mental health. But these artists may not be representative of the art world as a whole: many avant-garde writers and painters never make it into the canon. And this strategy may not achieve an accurate sample of even these mainstream geniuses. Subjects may refuse to participate because of the stigma of mental illness. 'Depression is sort of respectable,' says Kay Jamison, acknowledging the problem, 'but mania isn't. If you’re manic, you're really crazy.'

Nevertheless, the two studies that effectively launched the revival of interest in the question opted for this approach. In 1974, while doing a residency in psychiatry at the University of Iowa, Nancy Andreasen began looking to test the then current idea of a link between schizophrenia and creativity. Andreasen, a Ph.D. in English literature, initiated interviews with 30 faculty members at the prestigious University of Iowa Writers’ Workshop and matched the faculty members with control subjects in nonartistic professions. She found that 80 percent of the participating writers revealed they had suffered either depression or manic depression, compared with 30 percent of the control subjects. (Two of the writers eventually took their own lives.) 'The bipolar connection,' she recalls, 'just leaped out at me.'

But when the results of her work were published in 1987, the connection didn't leap out at everyone. Rothenberg objects to her control group, which he says was not really comparable with the group of creative people, and points out that Andreasen herself did the interviews and made the diagnoses, with none of the customary cross-checking to ensure objectivity. Rothenberg himself has spent 30 years interviewing eminent creative people—Nobel and Pulitzer Prize winners among them—and is convinced that creativity is facilitated by mental health, not illness. Andreasen, however, is as firm in her beliefs as Rothenberg is in his. 'The link between bipolar illness and creativity is genuine and extremely robust,' she maintains.

Kay Redfield Jamison's first work on the subject, a 1989 study of mood disorders among creative people, gained even more public attention than Andreasen's. While on a sabbatical at Oxford, Jamison had approached a large group of eminent Britons and asked them to complete exhaustive questionnaires about mood swings and creativity. Her eventual sample included only the heaviest of cultural heavy hitters: members of the Royal Academy, Booker Prize winners, contributors to The Oxford Book of Twentieth-Century English Verse.

What she found was psychic distress in spades. In the general population, rates of bipolar illness hover at about 1 percent, and major depression affects between 5 and 15 percent of the population. In Jamison's sample, however, 38 percent of the artists had been treated for affective illness (including simple depression as well as bipolar illness), and for three-quarters of that group the treatment had gone beyond talk therapy to lithium, antidepressants, electroshock, or all three. Clearly, intense emotional pain went hand in hand with creativity for even the most successful of these artists.

Jamison admits that the number of artists in each category was small—eight novelists, for instance, and eight playwrights—but still thinks the results are telling. 'Of course our studies have methodological problems,' she says. 'But they all point to the same association. So you have to ask yourself: Is there a trend? Is the trend in the same direction? And if the answer is yes, then you at least have to entertain the possibility that the studies are right.'

The largest study done to date does seem to confirm the association found by Andreasen and Jamison. The subtitle of Arnold Ludwig's book The Price of Greatness says it all: Resolving the Creativity and Madness Controversy. For a decade Ludwig and his research associates have been sifting through upwards of 2,200 biographies of 1,004 eminent men and women in an effort to learn what factors combine to produce the kind of high-order creativity that makes historians sit up and take notice.

By using secondary sources, Ludwig avoids some of the sampling problems for which Jamison and Andreasen were criticized. And he has an answer to the objection that biographies have biases of their own. 'On the whole, I think biographers—who spend years getting to know their subjects—will have a better perspective than a clinician asking standardized questions or administering a questionnaire, which has built-in theoretical or diagnostic assumptions,' he says. 'After all, what you get in a clinical interview is autobiography, and that's the most inaccurate record of all.'

Ludwig found that, as a group, creative artists displayed much higher levels of mental illness than did their creative counterparts in more structured occupations. As adolescents, between 29 and 34 percent of eminent-artists-to-be exhibited psychiatric symptoms—ranging from hypochondria and 'moody and introspective fits' all the way to psychotic hallucinations and suicide attempts—compared with 3 to 9 percent of future achievers in the sciences, sports, and business. (The precise percentage depends on the strictness of diagnostic criteria.) The differences among adults are equally striking, with rates of between 70 and 77 percent for poets, musical performers, and fiction writers; 59 to 77 percent for painters, composers, and nonfiction writers; and only 18 to 29 percent for eminent natural scientists, politicians, architects, and business people.

Ludwig differs from Jamison and Andreasen in the significance he attaches to that finding. Andreasen and Jamison argue that bipolar illness enhances artistic vision, while Ludwig's explanation is more prosaic. Creative people who are mentally ill find themselves, almost by default, he thinks, in the arts rather than in business or the sciences.

As Ludwig sees it, the reasons are self-evident. “In the scientific world, advantageous traits include rationality, persistence, and levelheadedness,' he says. 'You need to write grant proposals, do experiments, get along with people, show up for work.' The alternating episodes of wild enthusiasm and paralyzing depression that can characterize bipolar illness would be fatal to scientific achievement, he says, but an artist might draw on them as a source of inspiration.

And for cultural reasons, an aspiring poet has little impetus to curb flamboyant behavior; in fact, a certain amount of drama is de rigueur. 'If a politician drinks or is depressed,' says Ludwig, 'he or she will try to hide it. Look at what happened to Thomas Eagleton, for instance, when people found out he'd been hospitalized for depression.' (Eagleton spent two weeks as the running mate of presidential candidate George McGovern in 1972, before being dropped from the ballot.) 'But when you hear that a poet drinks or has been mentally ill, you think, `So, what else is new?''

However, Ludwig doesn't buy into the stereotype of the inspired artist, creating only when the mood is right. Anybody who achieves creative greatness is dedicated,' he says. 'These people persevere; they're almost monomanical. Think of Picasso, or Cézanne.' In his view this dedication leads to the real price of greatness, which isn't madness but the seemingly inevitable trail of domestic destruction. 'Work is paramount to great artists, and there's a lot of family fallout,' he says. 'You can't fly that close to the sun without getting singed.'

The real sticking point for any theory about a synergy between art and mental illness is explaining how the mechanism works. Some clinicians have concluded that all sorts of mental and physical problems—from depression to severe childhood illness—confer outsider status, and that feeling outside the mainstream can help motivate people to become artists. 'It doesn't necessarily have to be madness,' says psychiatrist Bob Klitzman of Columbia University. 'You can feel like an outsider because you're gay, or a woman, or a Southerner, or black. Anything that gives you the sense that the world you see isn't the world that others see can motivate you to want to tell your own story.'

Other explanations, while often appealing and intuitive, can be maddeningly vague. Even Ludwig’s straightforward, sociological explanation turns softer when he tries to pin down the intersection of creativity and madness. He invokes the idea of psychological unease, which he calls 'a kind of restlessness, discomfort, need to express oneself.' Emotionally healthy creative people have it, and they attach it to a problem, he thinks; when the problem is solved, it motivates them to seek out a new problem to work on. The mentally ill have it, too, he says, but their unease is more pervasive and free-floating. They have, in his words, 'more trouble putting their psychological lids back on.'

But the most visionary explanations are reserved for the creative processes of bipolar artists. 'I think bipolars are open to contradiction, they take risks, they defy order,' says Andreasen. 'These are traits that make them both more vulnerable and more original than the rest of us.'

And when Kay Jamison talks about the effects of bipolar disease, she sounds downright mystical. Jamison, who in 1995 revealed in her memoir An Unquiet Mind that she has been manic depressive since adolescence, describes a preternatural awareness of surroundings, a sensitivity to the environment that is more animal-like than human. Bipolar illness confers 'a great range and intensity' to moods, she says, which can then be translated into art. 'You can't predict what you'll be like tomorrow. I think the moods of bipolarity mirror the natural world, which is so seasonal and fluid. It’s a dangerous, amphibious sort of existence.'

Short of putting a poet in a brain scanner and instructing her to write a sonnet, it is difficult to imagine how creativity could be assessed in a culturally neutral way. Through functional neuroimaging techniques, researchers are in fact slowly beginning to understand what goes on in the brains of mood-disordered patients, but most of what they've learned has concerned the depressive end of the spectrum, for a purely practical reason: mania involves physical as well as mental restlessness. Someone in the middle of a manic episode is incapable of staying still long enough for a brain scan. Yet neuroscientists studying language in the brain have noticed a pattern that may help explain at least one element of bipolar creativity: verbal fluency.

Emil Kraepelin, the German psychiatrist who first described bipolar illness, remarked that his patients delighted in rhymes and puns, an observation that has been confirmed by other therapists and researchers. One of the official diagnostic criteria for mild mania, in fact, is rapidity of speech that may include 'jokes, puns, plays on words, and irrelevancies.'

Cognitive neuroscientist Michael Posner and co-workers at the University of Oregon recently attached a large number of electrodes to volunteers’ scalps and measured the electrical activity in their brains as they performed two sets of word-association tasks. For the first test the subjects were asked merely to read a list of nouns, such as 'hammer' and 'broom,' and to come up with a prosaic use for each noun: something like 'pound' for hammer and 'sweep' for broom.

The straightforward word-generation tasks produced activation in the front and side of the left hemisphere. This isn't news; neuroscientists have long understood those regions to be involved in language. But when subjects were asked to come up with a less usual association for each noun—'witch' with 'broom,' and 'throw' with 'hammer'—things changed. The electrical activity was coming from an area in the right parietal hemisphere—the mirror image of the one on the side of the left hemisphere.

Hints that some language skills lay in the right hemisphere had already emerged: right-hemisphere strokes can blunt sensitivity to words, making such stroke patients very literal, incapable of understanding metaphors or puns. While early hypotheses that mania is a right-hemisphere phenomenon and depression a left-hemisphere one have been discarded as too simplistic, clearly the right hemisphere is implicated in some kinds of mania. Certain epileptic seizures in the right hemisphere, for example, induce manic-like symptoms.

So is it at least possible that someone in a manic phase, by virtue of some disruption in right-hemisphere functioning, might have readier access to an area in the brain associated with wordplay? 'This might be a bit of a leap,' says Posner. And it doesn't explain how mania could affect activities, such as music, thought to involve the left hemisphere.

Such speculations leave defenders of creativity as a product of mental health unconvinced. Rothenberg continues to maintain that the essence of the creative process is the ability to hold several antithetical ideas in the mind at once, a task that demands robust mental health. The idea of a thin line between art and madness may make a good sound bite, he says, but the psychological processes are worlds apart.

Rothenberg's ultimate objection is a philosophical one. To attribute creativity to mental illness is the worst sort of aesthetic reductionism, he thinks. 'The tragic worldview is just that,' he says, 'It’s a way of seeing the world. To call it a symptom of depression is to trivialize it, to say, `I don't have to take this seriously.’' He also suspects that linking art and madness is destructive to the mentally ill. 'If people think mental illness is somehow making them creative,” he says, “it gives them a reason not to try to get better.'

Yet listening to the anguish of people struggling with bipolar illness, this last possibility seems remote. 'Sometimes I think God gave me the gift of creativity as a consolation prize,' says support-group member Katherine T. in her small, drug-thickened voice, “but I'm still suffering. I don't know where this disease came from, but I sure wish it would go away.'

Depression can take several other forms. In bipolar disorder, sometimes called manic-depressive illness, a person’s mood swings back and forth between depression and mania. People with seasonal affective disorder typically suffer from depression only during autumn and winter, when there are fewer hours of daylight. In dysthymia (pronounced dis-THI-mee-uh), people feel depressed, have low self-esteem, and concentrate poorly most of the time—often for a period of years—but their symptoms are milder than in major depression. Some people with dysthymia experience occasional episodes of major depression. Mental health professionals use the term clinical depression to refer to any of the above forms of depression.

Surveys indicate that people commonly view depression as a sign of personal weakness, but psychiatrists and psychologists view it as a real illness. In the United States, the National Institute of Mental Health has estimated that depression costs society many billions of dollars each year, mostly in lost work time.

Abraham Lincoln

Abraham Lincoln, 16th president of the United States, suffered from episodes of severe depression throughout his life. In 1841 he wrote: “I am now the most miserable man living. If what I feel were equally distributed to the whole human family, there would not be one cheerful face on the earth. Whether I shall ever be better, I cannot tell.”

Hulton Deutsch

Depression is one of the most common mental illnesses. At least 8 percent of adults in the United States experience serious depression at some point during their lives, and estimates range as high as 17 percent. The illness affects all people, regardless of sex, race, ethnicity, or socioeconomic standing. However, women are two to three times more likely than men to suffer from depression. Experts disagree on the reason for this difference. Some cite differences in hormones, and others point to the stress caused by society’s expectations of women.

Depression occurs in all parts of the world, although the pattern of symptoms can vary. The prevalence of depression in other countries varies widely, from 1.5 percent of people in Taiwan to 19 percent of people in Lebanon. Some researchers believe methods of gathering data on depression account for different rates.

A number of large-scale studies indicate that depression rates have increased worldwide over the past several decades. Furthermore, younger generations are experiencing depression at an earlier age than did previous generations. Social scientists have proposed many explanations, including changes in family structure, urbanization, and reduced cultural and religious influences.

Why Are So Many Women Depressed?

Women may be more sensitive—physiologically, at least—to certain changes in the environment. And this responsiveness might help explain the high rates of depression in their ranks

The symptoms of depression range from uncomfortable to debilitating: sleep disturbances, hopelessness, feelings of worthlessness, difficulty concentrating, fatigue and sometimes even delusions. Most of us have watched a relative or friend struggle with depression—and many of us have experienced it ourselves. Even so, few people realize just how common depression is, how severe it can be or that it is most prevalent among women. In 1990 the World Health Organization found depression to be the leading cause of 'disease burden' (a composite measure including both illness and death) among women, noting that it affects almost 20 percent of the female population in the developed world. Epidemiological studies indicate that 12 percent of U.S. women—compared with only 6 percent of U.S. men—have suffered from clinically significant depression at some time in their lives.

The big question, of course, is why such a gender gap exists. Over the years various explanations have surfaced to account for the fact that, from one study to the next, depression is between two and three times more common among women than it is among men. Some mental health workers have pointed to psychology, arguing that women are better trained to recognize their feelings and seek help, so they come to the attention of health professionals more often than men. Others have suggested that oppression—in the form of physical or sexual abuse, harassment or discrimination—is to blame. Others still have attributed the increased rates of depression among women to the female reproductive system and the menstrual cycle.

But it isn't that simple. Data from a variety of studies show that depression clearly has psychological, environmental and biological roots. Modern neuroscience is beginning to teach us how these roots can become intertwined and reinforce one another. In other words, an increased risk for depression in women might stem from genetics, the effects of stressful events or social pressures, or some combination of all three. Neuroimaging of the brain's circuitry by PET and MRI scans reveals that psychological phenomena such as anger and sadness have biological underpinnings; we can now see circuits of brain cells becoming activated when these emotions arise.

Similarly, neuroimages demonstrate that environmental and psychological experiences can alter our brain chemistry. For example, Lewis R. Baxter and his colleagues at the University of California at Los Angeles found similar changes on the PET scans of patients with obsessive-compulsive disorder who responded to treatment, regardless of whether the patients were treated with medication or with behavioral therapy.

To figure out why depression is more common among women, scientists have to study how genetics and environment divide the sexes—and how the two conspire to produce the symptoms we describe as depression. It is difficult work, and progress is necessarily slow. But what is coming into focus is that certain environmental factors—including stress, seasonal changes and social rank—may produce different physiological responses in females than they do in males. These findings, which I will outline, are small pieces in what is proving to be an incredibly complex puzzle. Laying them out at this stage does not begin to explain depression's double standard. 

Nevertheless, it could help scientists develop more effective treatments for depressed individuals—both women and men—in the meantime.

Stress and Cortisol

Many scientists have wondered whether there is some quirk in the way depression is inherited, such that a depressed parent or grandparent is more likely to pass on a predisposition for the disorder to female than to male descendants. Based on studies that trace family histories of depression, the answer to that question appears to be no. Women and men with similar heritage seem equally likely to develop the disorder. Simply tracing family histories, though, without also considering environmental influences, might not offer a complete picture of how depression is inherited.

Indeed, Kenneth S. Kendler and his colleagues at the Medical College of Virginia found in a study of 2,060 female twins that genetics might contribute to how women respond to environmental pressures. The researchers examined twins with and without a family history of depression; some twins in both groups had recently undergone a trauma, such as the death of a loved one or a divorce. The investigators found that among the women who did not have a family history of depression, stressful events raised their risk for depression by only 6 percent. But the same risk rose almost 14 percent among the women who did have a family history of depression. In other words, these women had seemingly inherited the propensity to become depressed in the wake of crises.

A similar study has not been done in men, leaving open the question of whether environmental stress and genetic risk for depression interact similarly in both sexes. But research is being done to determine whether men and women generally experience similar amounts and types of stress. Studies of key hormones hint that they do not. Hormones are not new to depression researchers. Many have wondered whether the gonadal steroids estrogen and progesterone—whose cyclic fluctuations in women regulate menstruation—might put women at a greater risk for depression. There are at least two ways in which they might do so.

First, because of differences between the X and Y chromosomes, male and female brains are exposed to different hormonal milieus in utero. These hormonal differences may affect brain development so that men and women have different vulnerabilities—and different physiological reactions to environmental stressors—later in life. Indeed, animal experiments show that early hormonal influences have marked behavioral consequences later on, although the phenomenon is of course difficult to study in humans.

Second, the fact that postpubertal men and women have different levels of circulating gonadal steroids might somehow put women at higher risk for depression. Research shows girls become more susceptible to depression than boys only after puberty, when they begin menstruating and experience hormonal fluxes. Even so, scientists have never been able to establish a direct relation between emotional states and levels of estrogen and progesterone in the blood of women. For example, Peter J. Schmidt and David R. Rubinow of the National Institute of Mental Health recently reported that manipulations of estrogen and progesterone did not affect mood, except in women who suffer from severe premenstrual mood changes.

It now appears, however, that estrogen might set the stage for depression indirectly by priming the body's stress response. During stressful times, the adrenal glands—which sit on top of the kidneys and are controlled by the pituitary gland in the brain—secrete higher levels of a hormone called cortisol, which increases the activity of the body's metabolic and immune systems, among others. In the normal course of events, stress increases cortisol secretion, but these elevated levels have a negative feedback effect on the pituitary, so that cortisol levels gradually return to normal.

Evidence is emerging that estrogen might not only increase cortisol secretion but also decrease cortisol's ability to shut down its own secretion. The result might be a stress response that is not only more pronounced but also longer-lasting in women than in men.

For example, Nicholas C. Vamvakopoulos, George P. Chrousos and their colleagues at the National Institute of Child Health and Human Development recently found that increased levels of estrogen heighten the activity of the gene for human corticotropin-releasing hormone (CRH). This gene controls the secretion of CRH by a region of the brain called the hypothalamus. CRH makes the pituitary gland release adrenocorticotropic hormone (ACTH), which circulates in the blood and eventually reaches the adrenal glands, where it prompts the secretion of cortisol. Thus, estrogen can, by increasing CRH secretion, ultimately boost cortisol secretion. And Elizabeth A. Young of the University of Michigan and others have shown that female rats are more 'resistant' to cortisol's negative feedback effects than are either male rats or spayed female rats. She has also shown that women have longer-lasting cortisol responses during the phase of the menstrual cycle when estrogen and progesterone levels are high.

It is unclear whether depression is a cause or a consequence of elevated cortisol levels, but the two are undoubtedly related. Over the past few decades, a number of studies have shown that cortisol levels are elevated in about half of all severely depressed people, both men and women. So the idea is this: if estrogen raises cortisol levels after stress or decreases cortisol's ability to shut down its own secretion, then estrogen might render women more prone to depression—particularly after a stressful event.

Light and Melatonin

Despite their importance, estrogen and cortisol are not the only hormones involved in female depression, and stress is not the only environmental influence that might hold more sway over women than men. Recent findings by Thomas A. Wehr, Norman E. Rosenthal and their colleagues at the National Institute of Mental Health indicate that women might be more responsive physiologically than men to changes in exposure to light and dark. These investigators have had a long-standing interest in seasonal affective disorder (SAD), or so-called winter depression (although it can occur in the summer as well), and the role that the hormone melatonin might play in the illness. Similar to the gender ratio in other forms of depression, SAD is three times more common in women than in men.

Melatonin has been a prime suspect in SAD because organisms (including humans) secrete it only when they are in the dark and only when the body's internal clock (located in the hypothalamus) believes it is nighttime. The pineal gland, a small structure that resides deep in the mammalian brain, begins to secrete melatonin in the evening, as daylight wanes. Melatonin levels drop in the morning, when light hits the retinas of the eyes. Because nights are longer in winter than in summer, animals living in the wild secrete melatonin for longer periods each day during winter. 

Among animals that breed in summer, the onset of this extended daily melatonin secretion signals the presence of winter and shuts down the secretion of gonadal steroids that facilitate reproduction.

SAD researchers have long wondered whether a wintertime increase in the duration of melatonin secretion might also trigger depressive symptoms in susceptible individuals. In a series of ongoing studies designed to address this question, Wehr and his colleagues first asked whether humans, like animals, undergo seasonal changes in melatonin secretion. It is an important question, given that artificial light provides humans with an 'endless summer' of sorts compared with animals in the wild. To find out, Wehr measured melatonin secretion in 15 humans when they were exposed to 14 hours of darkness and later to only eight hours of darkness each night. The results of this experiment, conducted mostly among men, were positive: people experiencing longer periods of darkness secreted melatonin for longer periods during the night, as wild animals do.

Next, the researchers asked whether this natural sensitivity to the seasonal day-length change persisted when people were allowed to follow their usual schedules, turning on artificial lights at night as they normally would. Here the researchers were surprised to find a gender difference. Under normal living conditions, women were more likely than men to retain a sensitivity to seasonal changes in day length. In other words, for women the duration of nocturnal melatonin secretion was longer in winter than summer; in men, however, there was no seasonal difference.

These results suggest that women are more sensitive to natural light than men—and that in a society where artificial light is everywhere, women somehow still detect seasonal changes in natural day length. Whether this gender difference puts women at increased risk for SAD is unclear; paradoxically, there is evidence that women with SAD symptoms may be less likely than unaffected women to have an increased duration of melatonin secretion in winter.

To complicate the story further, the relation between these findings and those regarding cortisol and estrogen are also unclear, because we don't know whether the duration of melatonin secretion affects reproductive function in women, as it surely does in animals. Researchers are now working to unravel the complicated relations between these hormonal systems and to determine whether, and how, they may influence individuals' risk for depression.

Social Rank and Serotonin

If women's bodies are in fact particularly sensitive to environmental changes, the explanation may lie within the system that controls serotonin, one of many so-called neurotransmitters that nerve cells use to communicate with one another. Serotonin modulates both cortisol and melatonin secretion. (The similarity in names between serotonin and melatonin is no accident: the latter is synthesized directly from the former, and the two have very similar chemical structures.) And a great deal of evidence indicates that dysfunction in the serotonergic, or serotonin-secreting, system contributes to depression and anxiety disorders, which are also more common in women than men. Recently research in animals and humans has provided preliminary, but key, insights into this system.

First, it appears that the serotonergic system serves as a link between an animal's nervous system and its physical and social environment. That is, not only do stress and daylight act via the serotonergic system but an animal's social rank also appears to affect its serotonin level. A number of studies show that blood and brain serotonin levels change as an animal moves up or down dominance hierarchies. For instance, dominant male monkeys often have higher blood serotonin levels than subordinate ones do. In addition, a recent study by Shih-Rung Yeh and his colleagues at Georgia State University shows that the sensitivity of an animal's neurons to serotonin varies according to that animal's status. Specifically, Yeh found that neurons taken from crayfish that had recently won a fight responded to serotonergic stimulation more strongly than neurons taken from losing crayfish.

There also appear to be significant gender differences in the serotonergic systems of both animals and humans. Mirko Diksic, Sadahiko Nishizawa and their colleagues at McGill University recently provided the most dramatic example: to measure serotonin synthesis in the human brain, they devised a new technique using PET neuroimaging and found that the average synthesis rate was 52 percent higher in men than in women. The investigators note that with the exception of estrogen binding sites, this gender difference in the brain is one of the largest ever reported. The lower rate of serotonin synthesis in women might increase their overall risk for depression—especially if serotonin stores are depleted during stress or winter darkness.

A Gender Difference

Meir Steiner and his co-workers at McMaster University suggest that if serotonin mediates between an organism and its environment and if the neurotransmitter is regulated differently in men and women, it might explain gender patterns not only in depression but also in a range of psychiatric illnesses. Specifically, whereas depression and anxiety are more common among women, alcoholism and severe aggression are more common among men. And just as low serotonin levels have been implicated in depression and anxiety disorders in women, they have also been found in the brains of men with severe forms of alcoholism and aggression.

Such gender differences in the serotonergic system might ensure that females respond to stress with psychiatric disturbances that involve behavioral inhibition, whereas men respond to stress with a loss of behavioral control. Steiner suggests that such gender differences in the serotonergic system evolved because child rearing is more successful (in the narrow sense of more children surviving to adulthood) in species in which aggressive impulses are curtailed in females.

A researcher espousing either the sociological or psychological explanation of depression's gender bias might counter Steiner's theory by arguing that men are socialized to respond to stress with 'acting out' behaviors, such as alcoholism or aggression. In contrast, society teaches women to respond to stress with 'acting in' behaviors, such as depression. To support this idea, they might point to epidemiological studies done in Amish and Jewish populations. In these communities, alcoholism is less common than in the population at large, and, interestingly, the rates of depression are as high in men as in women.

These contradictory data leave no doubt that the explanations behind depression and other psychiatric diseases are not straightforward. Biological and social influences not only coexist but also probably reinforce one another. After all, we would expect gender socialization patterns to evolve so that they complement biological differences between the sexes. In other words, we would expect 'nurture' to reinforce rather than oppose 'nature.' And because nurture involves learning—and learning occurs when certain neural connections in the brain are strengthened—it is clear that both nurture and nature involve biological processes.

Scientists have made tremendous strides in treating depression. With the advent of such antidepressants as Prozac (which acts on the serotonergic system), more than 80 percent of depressed patients now respond to medication or psychotherapy, or a combination of the two. But much more work remains to be done. Because depression is so common, its cost to society is high. The National Institute of Mental Health estimates that depression claims $30.4 billion in treatment and in lost productivity from the U.S. economy every year.

And these costs are on the rise: depression is becoming more common in successive generations (the so-called cohort effect). No one knows what is causing the cohort effect—but it is moving much too quickly to have a genetic basis. Theories about what is causing the cohort effect range from increased drug abuse and familial disarray to the suggestion that perhaps older people are simply more likely to forget past depressive episodes when asked. The cohort effect and depression in general remain very much a mystery. And for the men and women who suffer from it, it is a mystery that cannot be solved soon enough.

SYMPTOMS

Although it may appear anytime from childhood to old age, depression usually begins during a person’s 20s or 30s. The illness may come on slowly, then deepen gradually over months or years.

 On the other hand, it may erupt suddenly in a few weeks or days. A person who develops severe depression may appear so confused, frightened, and unbalanced that observers speak of a “nervous breakdown.” However it begins, depression causes serious changes in a person’s feelings and outlook. A person with major depression feels sad nearly every day and may cry often. People, work, and activities that used to bring them pleasure no longer do.

Symptoms of depression can vary by age. In younger children, depression may include physical complaints, such as stomachaches and headaches, as well as irritability, “moping around,” social withdrawal, and changes in eating habits. They may feel unenthusiastic about school and other activities. In adolescents, common symptoms include sad mood, sleep disturbances, and lack of energy. Elderly people with depression usually complain of physical rather than emotional problems, which sometimes leads doctors to misdiagnose the illness.

Symptoms of depression can also vary by culture. In some cultures, depressed people may not experience sadness or guilt but may complain of physical problems. In Mediterranean cultures, for example, depressed people may complain of headaches or nerves. In Asian cultures they may complain of weakness, fatigue, or imbalance.

If left untreated, an episode of major depression typically lasts eight or nine months. About 85 percent of people who experience one bout of depression will experience future episodes.

A.

Appetite and Sleep Changes

Depression usually alters a person’s appetite, sometimes increasing it, but usually reducing it. Sleep habits often change as well. People with depression may oversleep or, more commonly, sleep for fewer hours. A depressed person might go to sleep at midnight, sleep restlessly, then wake up at 5 am feeling tired and blue. For many depressed people, early morning is the saddest time of the day.

B.

Changes in Energy Level

Depression also changes one’s energy level. Some depressed people may be restless and agitated, engaging in fidgety movements and pacing. Others may feel sluggish and inactive, experiencing great fatigue, lack of energy, and a feeling of being worn out or carrying a heavy burden. Depressed people may also have difficulty thinking, poor concentration, and problems with memory.

C.

Poor Self-Esteem

People with depression often experience feelings of worthlessness, helplessness, guilt, and self-blame. They may interpret a minor failing on their part as a sign of incompetence or interpret minor criticism as condemnation. Some depressed people complain of being spiritually or morally dead. The mirror seems to reflect someone ugly and repulsive. Even a competent and decent person may feel deficient, cruel, stupid, phony, or guilty of having deceived others. People with major depression may experience such extreme emotional pain that they consider or attempt suicide. At least 15 percent of seriously depressed people commit suicide, and many more attempt it.

D.

Psychotic Symptoms

In some cases, people with depression may experience psychotic symptoms, such as delusions (false beliefs) and hallucinations (false sensory perceptions). Psychotic symptoms indicate an especially severe illness. Compared to other depressed people, those with psychotic symptoms have longer hospital stays, and after leaving, they are more likely to be moody and unhappy. They are also more likely to commit suicide. See Psychosis.

CAUSES

Some depressions seem to come out of the blue, even when things are going well. Others seem to have an obvious cause: a marital conflict, financial difficulty, or some personal failure. Yet many people with these problems do not become deeply depressed. Most psychologists believe depression results from an interaction between stressful life events and a person’s biological and psychological vulnerabilities.

The Neurobiology of Depression

In his 1990 memoir Darkness Visible, the American novelist William Styron—author of The Confessions of Nat Turner and Sophie's Choice—chillingly describes his state of mind during a period of depression:

“He [a psychiatrist] asked me if I was suicidal, and I reluctantly told him yes. I did not particularize—since there seemed no need to—did not tell him that in truth many of the artifacts of my house had become potential devices for my own destruction: the attic rafters (and an outside maple or two) a means to hang myself, the garage a place to inhale carbon monoxide, the bathtub a vessel to receive the flow from my opened arteries. The kitchen knives in their drawers had but one purpose for me. Death by heart attack seemed particularly inviting, absolving me as it would of active responsibility, and I had toyed with the idea of self-induced pneumonia—a long frigid, shirt-sleeved hike through the rainy woods. Nor had I overlooked an ostensible accident, á la Randall Jarrell, by walking in front of a truck on the highway nearby.… Such hideous fantasies, which cause well people to shudder, are to the deeply depressed mind what lascivious daydreams are to persons of robust sexuality.”

As this passage demonstrates, clinical depression is quite different from the blues everyone feels at one time or another and even from the grief of bereavement. It is more debilitating and dangerous, and the overwhelming sadness combines with a number of other symptoms. In addition to becoming preoccupied with suicide, many people are plagued by guilt and a sense of worthlessness. They often have difficulty thinking clearly, remembering, or taking pleasure in anything. They may feel anxious and sapped of energy and have trouble eating and sleeping or may, instead, want to eat and sleep excessively.

Psychologists and neurobiologists sometimes debate whether ego-damaging experiences and self-deprecating thoughts or biological processes cause depression. The mind, however, does not exist without the brain. Considerable evidence indicates that regardless of the initial triggers, the final common pathways to depression involve biochemical changes in the brain. It is these changes that ultimately give rise to deep sadness and the other salient characteristics of depression. The full extent of those alterations is still being explored, but in the past few decades—and especially in the past several years—efforts to identify them have progressed rapidly.

At the moment, those of us teasing out the neurobiology of depression somewhat resemble blind searchers feeling different parts of a large, mysterious creature and trying to figure out how their deductions fit together. In fact, it may turn out that not all of our findings will intersect: biochemical abnormalities that are prominent in some depressives may differ from those predominant in others. Still, the extraordinary accumulation of discoveries is fueling optimism that the major biological determinants of depression can be understood in detail and that those insights will open the way to improved methods of diagnosing, treating and preventing the condition.

Pressing Goals

One subgoal is to distinguish features that vary among depressed individuals. For instance, perhaps decreased activity of a specific neurotransmitter (a molecule that carries a signal between nerve cells) is central in some people, but in others, overactivity of a hormonal system is more influential (hormones circulate in the blood and can act far from the site of their secretion). A related goal is to identify simple biological markers able to indicate which profile fits a given patient; those markers could consist of, say, elevated or reduced levels of selected molecules in the blood or changes in some easily visualizable areas of the brain.

After testing a depressed patient for these markers, a psychiatrist could, in theory, prescribe a medication tailored to that individual's specific biological anomaly, much as a general practitioner can run a quick strep test for a patient complaining of a sore throat and then prescribe an appropriate antibiotic if the test is positive. Today psychiatrists have to choose antidepressant medications by intuition and trial and error, a situation that can put suicidal patients in jeopardy for weeks or months until the right compound is selected. (Often psychotherapy is needed as well, but it usually is not sufficient by itself, especially if the depression is fairly severe.)

Improving treatment is critically important. Although today's antidepressants have fewer side effects than those of old and can be extremely helpful in many cases, depression continues to exact a huge toll in suffering, lost lives and reduced productivity.

The prevalence is surprisingly great. It is estimated, for example, that 5 to 12 percent of men and 10 to 20 percent of women in the U.S. will suffer from a major depressive episode at some time in their life. Roughly half of these individuals will become depressed more than once, and up to 10 percent (about 1.0 to 1.5 percent of Americans) will experience manic phases in addition to depressive ones, a condition known as manic-depressive illness or bipolar disorder. Mania is marked by a decreased need for sleep, rapid speech, delusions of grandeur, hyperactivity and a propensity to engage in such potentially self-destructive activities as promiscuous sex, spending sprees or reckless driving.

Beyond the pain and disability depression brings, it is a potential killer. As many as 15 percent of those who suffer from depression or bipolar disorder commit suicide each year. In 1996 the Centers for Disease Control and Prevention listed suicide as the ninth leading cause of death in the U.S. (slightly behind infection with the AIDS virus), taking the lives of 30,862 people. Most investigators, however, believe this number is a gross underestimate. Many people who kill themselves do so in a way that allows another diagnosis to be listed on the death certificate, so that families can receive insurance benefits or avoid embarrassment. Further, some fraction of automobile accidents unquestionably are concealed suicides.

The financial drain is enormous as well. In 1992 the estimated costs of depression totaled $43 billion, mostly from reduced or lost worker productivity.

Accumulating findings indicate that severe depression also heightens the risk of dying after a heart attack or stroke. And it often reduces the quality of life for cancer patients and might reduce survival time.

Genetic Findings

Geneticists have provided some of the oldest proof of a biological component to depression in many people. Depression and manic-depression frequently run in families. Thus, close blood relatives (children, siblings and parents) of patients with severe depressive or bipolar disorder are much more likely to suffer from those or related conditions than are members of the general population. Studies of identical twins (who are genetically indistinguishable) and fraternal twins (whose genes generally are no more alike than those of other pairs of siblings) also support an inherited component. The finding of illness in both members of a pair is much higher for manic-depression in identical twins than in fraternal ones and is somewhat elevated for depression alone.

In the past 20 years, genetic researchers have expended great effort trying to identify the genes at fault. So far, though, those genes have evaded discovery, perhaps because a predisposition to depression involves several genes, each of which makes only a small, hard-to-detect contribution.

Preliminary reports from a study of an Amish population with an extensive history of manic-depression once raised the possibility that chromosome 11 held one or more genes producing vulnerability to bipolar disorder, but the finding did not hold up. A gene somewhere on the X chromosome could play a role in some cases of that condition, but the connection is not evident in most people who have been studied. Most recently, various regions of chromosome 18 and a site on chromosome 21 have been suggested to participate in vulnerability to bipolar illness, but these findings await replication.

As geneticists continue their searches, other investigators are concentrating on neurochemical aspects. Much of that work focuses on neurotransmitters. In particular, many cases of depression apparently stem at least in part from disturbances in brain circuits that convey signals through certain neurotransmitters of the monoamine class. These biochemicals, all derivatives of amino acids, include serotonin, norepinephrine and dopamine; of these, only evidence relating to norepinephrine and serotonin is abundant.

Monoamines first drew the attention of depression researchers in the 1950s. Early in that decade, physicians discovered that severe depression arose in about 15 percent of patients who were treated for hypertension with the drug reserpine. This agent turned out to deplete monoamines. At about the same time doctors found that an agent prescribed against tuberculosis elevated mood in some users who were depressed. Follow-up investigations revealed that the drug inhibited the neuronal breakdown of monoamines by an enzyme (monoamine oxidase); presumably the agent eased depression by allowing monoamines to avoid degradation and to remain active in brain circuits. Together these findings implied that abnormally low levels of monoamines in the brain could cause depression. This insight led to the development of monoamine oxidase inhibitors as the first class of antidepressants.

The Norepinephrine Link

But which monoamines were most important in depression? In the 1960s Joseph J. Schildkraut of Harvard University cast his vote with norepinephrine in the now classic 'catecholamine' hypothesis of mood disorders. He proposed that depression stems from a deficiency of norepinephrine (which is also classified as a catecholamine) in certain brain circuits and that mania arises from an overabundance of the substance. The theory has since been refined, acknowledging, for instance, that decreases or elevations in norepinephrine do not alter moods in everyone. Nevertheless, the proposed link between norepinephrine depletion and depression has gained much experimental support. These circuits originate in the brain stem, primarily in the pigmented locus coeruleus, and project to many areas of the brain, including to the limbic system—a group of cortical and subcortical areas that play a significant part in regulating emotions.

To understand the recent evidence relating to norepinephrine and other monoamines, it helps to know how those neurotransmitters work. The points of contact between two neurons, or nerve cells, are termed synapses. Monoamines, like all neurotransmitters, travel from one neuron (the presynaptic cell) across a small gap (the synaptic cleft) and attach to receptor molecules on the surface of the second neuron (the postsynaptic cell). Such binding elicits intracellular changes that stimulate or inhibit firing of the postsynaptic cell. The effect of the neurotransmitter depends greatly on the nature and concentration of its receptors on the postsynaptic cells. Serotonin receptors, for instance, come in 13 or more subtypes that can vary in their sensitivity to serotonin and in the effects they produce.

The strength of signaling can also be influenced by the amount of neurotransmitter released and by how long it remains in the synaptic cleft—properties influenced by at least two kinds of molecules on the surface of the releasing cell: autoreceptors and transporters. When an autoreceptor becomes bound by neurotransmitter molecules in the synapse, the receptors signal the cell to reduce its firing rate and thus its release of the transmitter. The transporters physically pump neurotransmitter molecules from the synaptic cleft back into presynaptic cells, a process termed reuptake. Monoamine oxidase inside cells can affect synaptic neurotransmitter levels as well, by degrading monoamines and so reducing the amounts of those molecules available for release.

Among the findings linking impoverished synaptic norepinephrine levels to depression is the discovery in many studies that indirect markers of norepinephrine levels in the brain—levels of its metabolites, or by-products, in more accessible material (urine and cerebrospinal fluid)—are often low in depressed individuals. In addition, postmortem studies have revealed increased densities of certain norepinephrine receptors in the cortex of depressed suicide victims.

Observers unfamiliar with receptor display might assume that elevated numbers of receptors were a sign of more contact between norepinephrine and its receptors and more signal transmission. But this pattern of receptor 'up-regulation' is actually one that scientists would expect if norepinephrine concentrations in synapses were abnormally low. When transmitter molecules become unusually scarce in synapses, postsynaptic cells often expand receptor numbers in a compensatory attempt to pick up whatever signals are available.

A recent discovery supporting the norepinephrine hypothesis is that new drugs selectively able to block norepinephrine reuptake, and so increase norepinephrine in synapses, are effective antidepressants in many people. One compound, reboxetine, is available as an antidepressant outside the U.S. and is awaiting approval here.

Serotonin Connections

The data connecting norepinephrine to depression are solid and still growing. Yet research into serotonin has taken center stage in the 1990s, thanks to the therapeutic success of Prozac and related antidepressants that manipulate serotonin levels. Serious investigations into serotonin's role in mood disorders, however, have been going on for almost 30 years, ever since Arthur J. Prange, Jr., of the University of North Carolina at Chapel Hill, Alec Coppen of the Medical Research Council in England and their co-workers put forward the so-called permissive hypothesis. This view held that synaptic depletion of serotonin was another cause of depression, one that worked by promoting, or 'permitting,' a fall in norepinephrine levels.

Defects in serotonin-using circuits could certainly dampen norepinephrine signaling. Serotonin-producing neurons project from the raphe nuclei in the brain stem to neurons in diverse regions of the central nervous system, including those that secrete or control the release of norepinephrine. Serotonin depletion might contribute to depression by affecting other kinds of neurons as well; serotonin-producing cells extend into many brain regions thought to participate in depressive symptoms—including the amygdala (an area involved in emotions), the hypothalamus (involved in appetite, libido and sleep) and cortical areas that participate in cognition and other higher processes.

Among the findings supporting a link between low synaptic serotonin levels and depression is that cerebrospinal fluid in depressed, and especially in suicidal, patients contains reduced amounts of a major serotonin by-product (signifying reduced levels of serotonin in the brain itself). In addition, levels of a surface molecule unique to serotonin-releasing cells in the brain are lower in depressed patients than in healthy subjects, implying that the numbers of serotonergic cells are reduced.

Moreover, the density of at least one form of serotonin receptor—type 2—is greater in postmortem brain tissue of depressed patients; as was true in studies of norepinephrine receptors, this up-regulation is suggestive of a compensatory response to too little serotonin in the synaptic cleft.

Further evidence comes from the remarkable therapeutic effectiveness of drugs that block presynaptic reuptake transporters from drawing serotonin out of the synaptic cleft. Tricyclic antidepressants (so-named because they contain three rings of chemical groups) joined monoamine oxidase inhibitors on pharmacy shelves in the late 1950s, although their mechanism of action was not known at the time. Eventually, though, they were found to produce many effects in the brain, including a decrease in serotonin reuptake and a consequent rise in serotonin levels in synapses.

Investigators suspected that this last effect accounted for their antidepressant action, but confirmation awaited the introduction in the late 1980s of Prozac and then other drugs (Paxil, Zoloft and Luvox) able to block serotonin reuptake transporters without affecting other brain monoamines. These selective serotonin reuptake inhibitors (SSRIs) have now revolutionized the treatment of depression, because they are highly effective and produce much milder side effects than older drugs do. Today even newer antidepressants, such as Effexor, block reuptake of both serotonin and norepinephrine.

Studies of serotonin have also offered new clues to why depressed individuals are more susceptible to heart attack and stroke. Activation and clumping of blood platelets (cell-like structures in blood) contribute to the formation of thrombi that can clog blood vessels and shut off blood flow to the heart and brain, thus damaging those organs. Work in my laboratory and elsewhere has shown that platelets of depressed people are particularly sensitive to activation signals, including, it seems, to those issued by serotonin, which amplifies platelet reactivity to other, stronger chemical stimuli. Further, the platelets of depressed patients bear reduced numbers of serotonin reuptake transporters. In other words, compared with the platelets of healthy people, those in depressed individuals probably are less able to soak up serotonin from their environment and thus to reduce their exposure to platelet-activation signals.

Disturbed functioning of serotonin or norepinephrine circuits, or both, contributes to depression in many people, but compelling work can equally claim that depression often involves dysregulation of brain circuits that control the activities of certain hormones. Indeed, hormonal alterations in depressed patients have long been evident.

Hormonal Abnormalities

The hypothalamus of the brain lies at the top of the hierarchy regulating hormone secretion. It manufactures and releases peptides (small chains of amino acids) that act on the pituitary, at the base of the brain, stimulating or inhibiting the pituitary's release of various hormones into the blood. These hormones—among them growth hormone, thyroid-stimulating hormone and adrenocorticotropic hormone (ACTH)—control the release of other hormones from target glands. In addition to functioning outside the nervous system, the hormones released in response to pituitary hormones feed back to the pituitary and hypothalamus. There they deliver inhibitory signals that keep hormone manufacture from becoming excessive.

Depressed patients have repeatedly been demonstrated to show a blunted response to a number of substances that normally stimulate the release of growth hormone. They also display aberrant responses to the hypothalamic substance that normally induces secretion of thyroid-stimulating hormone from the pituitary. In addition, a common cause of nonresponse to antidepressants is the presence of previously undiagnosed thyroid insufficiency.

All these findings are intriguing, but so far the strongest case has been made for dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis—the system that manages the body's response to stress. When a threat to physical or psychological well-being is detected, the hypothalamus amplifies production of corticotropin-releasing factor (CRF), which induces the pituitary to secrete ACTH. ACTH then instructs the adrenal gland atop each kidney to release cortisol. Together all the changes prepare the body to fight or flee and cause it to shut down activities that would distract from self-protection. For instance, cortisol enhances the delivery of fuel to muscles. At the same time, CRF depresses the appetite for food and sex and heightens alertness. Chronic activation of the HPA axis, however, may lay the ground for illness and, it appears, for depression.

As long ago as the late 1960s and early 1970s, several research groups reported increased activity in the HPA axis in unmedicated depressed patients, as evinced by raised levels of cortisol in urine, blood and cerebrospinal fluid, as well as by other measures. Hundreds, perhaps even thousands, of subsequent studies have confirmed that substantial numbers of depressed patients—particularly those most severely affected—display HPA-axis hyperactivity. Indeed, the finding is surely the most replicated one in all of biological psychiatry.

Deeper investigation of the phenomenon has now revealed alterations at each level of the HPA axis in depressed patients. For instance, both the adrenal gland and the pituitary are enlarged, and the adrenal gland hypersecretes cortisol. But many researchers, including my colleagues and me at Emory University, have become persuaded that aberrations in CRF-producing neurons of the hypothalamus and elsewhere bear most of the responsibility for HPA-axis hyperactivity and the emergence of depressive symptoms.

Notably, study after study has shown CRF concentrations in cerebrospinal fluid to be elevated in depressed patients, compared with control subjects or individuals with other psychiatric disorders. This magnification of CRF levels is reduced by treatment with antidepressants and by effective electroconvulsive therapy. Further, postmortem brain tissue studies have revealed a marked exaggeration both in the number of CRF-producing neurons in the hypothalamus and in the expression of the CRF gene (resulting in elevated CRF synthesis) in depressed patients as compared with controls. Moreover, delivery of CRF to the brains of laboratory animals produces behavioral effects that are cardinal features of depression in humans, namely, insomnia, decreased appetite, decreased libido and anxiety.

Neurobiologists do not yet know exactly how the genetic, monoamine and hormonal findings piece together, if indeed they always do. The discoveries nonetheless suggest a partial scenario for how people who endure traumatic childhoods become depressed later in life. I call this hypothesis the stress-diathesis model of mood disorders, in recognition of the interaction between experience (stress) and inborn predisposition (diathesis).

The observation that depression runs in families means that certain genetic traits in the affected families somehow lower the threshold for depression. Conceivably, the genetic features directly or indirectly diminish monoamine levels in synapses or increase reactivity of the HPA axis to stress. The genetically determined threshold is not necessarily low enough to induce depression in the absence of serious stress but may then be pushed still lower by early, adverse life experiences.

My colleagues and I propose that early abuse or neglect not only activates the stress response but induces persistently increased activity in CRF-containing neurons, which are known to be stress responsive and to be overactive in depressed people. If the hyperactivity in the neurons of children persisted through adulthood, these supersensitive cells would react vigorously even to mild stressors. This effect in people already innately predisposed to depression could then produce both the neuroendocrine and behavioral responses characteristic of the disorder.

Support for a Model

To test the stress-diathesis hypothesis, we have conducted a series of experiments in which neonatal rats were neglected. We removed them from their mothers for brief periods on about 10 of their first 21 days of life, before allowing them to grow up (after weaning) in a standard rat colony. As adults, these maternally deprived rats showed clear signs of changes in CRF-containing neurons, all in the direction observed in depressed patients—such as rises in stress-induced ACTH secretion and elevations of CRF concentrations in several areas of the brain. Levels of corticosterone (the rat's cortisol) also rose. These findings suggested that a permanent increase in CRF gene expression and thus in CRF production occurred in the maternally deprived rats, an effect now confirmed by Paul M. Plotsky, one of my co-workers at Emory.

We have also found an increase in CRF-receptor density in certain brain regions of maternally deprived rats. Receptor amplification commonly reflects an attempt to compensate for a decrease in the substance that acts on the receptor. In this case, though, the rise in receptor density evidently occurs not as a balance to decreased CRF but in spite of an increase—the worst of all possibilities. Permanently elevated receptor concentrations would tend to magnify the action of CRF, thereby forever enhancing the depression-inducing effects of CRF and stress.

In an exciting preliminary finding, Plotsky has observed that treatment with one of the selective serotonin reuptake inhibitors (Paxil) returns CRF levels to normal, compensates for any gain in receptor sensitivity or number (as indicated by normal corticosterone production lower down in the axis) and normalizes behavior (for instance, the rats become less fearful).

We do not know exactly how inhibition of serotonin reuptake would lead to normalization of the HPA axis. Even so, the finding implies that serotonin reuptake inhibitors might be particularly helpful in depressed patients with a history of childhood trauma. Plotsky further reports that all the HPA-axis and CRF abnormalities returned when treatment stopped, a hint that pharmaceutical therapy in analogous human patients might have to be continued indefinitely to block recurrences of depression.

Studies of Bonnet macaque monkeys, which as primates more closely resemble humans, yielded similar results. Newborns and their mothers encountered three foraging conditions for three months after the babies' birth: a plentiful, a scarce and a variable food supply. The variable situation (in which food was available unpredictably) evoked considerable anxiety in monkey mothers, who became so anxious and preoccupied that they basically ignored their offspring. As our model predicts, the neonates in the variable-foraging condition were less active, withdrew from interactions with other monkeys and froze in novel situations. In adulthood, they also exhibited marked elevations in CRF concentrations in spinal fluid.

The rat and monkey data raise profound clinical and public health questions. In the U.S. alone in 1995, more than three million children were reportedly abused or neglected, and at least a million of those reports were verified. If the effects in human beings resemble those of the animals, the findings imply that abuse or neglect may produce permanent changes in the developing brain—changes that chronically boost the output of, and responsiveness to, CRF, and therefore increase the victims' lifelong vulnerability to depression.

If that conclusion is correct, investigators will be eager to determine whether noninvasive techniques able to assess the activity of CRF-producing neurons or the number of CRF receptors could identify abused individuals at risk for later depression. In addition, they will want to evaluate whether antidepressants or other interventions, such as psychotherapy, could help prevent depression in children who are shown to be especially susceptible. Researchers will also need to find out whether depressed adults with a history of abuse need to take antidepressants in perpetuity and whether existing drugs or psychotherapy can restore normal activity in CRF-producing neurons in humans.

The stress-diathesis model does not account for all cases of depression; not everyone who is depressed has been neglected or abused in childhood. But individuals who have both a family history of the condition and a traumatic childhood seem to be unusually prone to the condition. People who have no genetic predisposition to depression (as indicated by no family history of the disorder) could conceivably be relatively protected from serious depression even if they have a bad childhood or severe trauma later in life. Conversely, some people who have a strong inherited vulnerability will find themselves battling depression even when their childhoods and later life are free of trauma.

More work on the neurobiology of depression is clearly indicated, but the advances achieved so far are already being translated into ideas for new medications. Several pharmaceutical houses are developing blockers of CRF receptors to test the antidepressant value of such agents. Another promising class of drugs activates specific serotonin receptors; such agents can potentially exert powerful antidepressive effects without stimulating serotonin receptors on neurons that play no part in depression.

More therapies based on new understandings of the biology of mood disorders are sure to follow as well. As research into the neurobiological underpinnings progresses, treatment should become ever more effective and less likely to produce unwanted side effects.

A.

Biological Factors

Depression runs in families. By studying twins, researchers have found evidence of a strong genetic influence in depression. Genetically identical twins raised in the same environment are three times more likely to have depression in common than fraternal twins, who have only about half of their genes in common. In addition, identical twins are five times more likely to have bipolar disorder in common. These findings suggest that vulnerability to depression and bipolar disorder can be inherited. Adoption studies have provided more evidence of a genetic role in depression. These studies show that children of depressed people are vulnerable to depression even when raised by adoptive parents.

Genes may influence depression by causing abnormal activity in the brain. Studies have shown that certain brain chemicals called neurotransmitters play an important role in regulating moods and emotions. Neurotransmitters involved in depression include norepinephrine, dopamine, and serotonin. Research in the 1960s suggested that depression results from lower than normal levels of these neurotransmitters in parts of the brain. Support for this theory came from the effects of antidepressant drugs, which work by increasing the levels of neurotransmitters involved in depression. However, later studies have discredited this simple explanation and have suggested a more complex relationship between neurotransmitter levels and depression.

An imbalance of hormones may also play a role in depression. Many depressed people have higher than normal levels of hydrocortisone (cortisol), a hormone secreted by the adrenal gland in response to stress. In addition, an underactive or overactive thyroid gland can lead to depression.

A variety of medical conditions can cause depression. These include dietary deficiences in vitamin B₆, vitamin B₁₂, and folic acid (see Vitamin); degenerative neurological disorders, such as Alzheimer’s disease and Huntington’s disease (see Chorea); strokes in the frontal part of the brain; and certain viral infections, such as hepatitis and mononucleosis. Certain medications, such as steroids, may also cause depression.

B.

Psychological Factors

Psychological theories of depression focus on the way people think and behave. In a 1917 essay, Austrian psychoanalyst Sigmund Freud explained melancholia, or major depression, as a response to loss—either real loss, such as the death of a spouse, or symbolic loss, such as the failure to achieve an important goal. Freud believed that a person’s unconscious anger over loss weakens the ego, resulting in self-hate and self-destructive behavior.

Cognitive theories of depression emphasize the role of irrational thought processes. American psychiatrist Aaron Beck proposed that depressed people tend to view themselves, their environment, and the future in a negative light because of errors in thinking. These errors include focusing on the negative aspects of any situation, misinterpreting facts in negative ways, and blaming themselves for any misfortune. In Beck’s view, people learn these self-defeating ways of looking at the world during early childhood. This negative thinking makes situations seem much worse than they really are and increases the risk of depression, especially in stressful situations.

In support of this cognitive view, people with “depressive” personality traits appear to be more vulnerable than others to actual depression. Examples of depressive personality traits include gloominess, pessimism, introversion, self-criticism, excessive skepticism and criticism of others, deep feelings of inadequacy, and excessive brooding and worrying. In addition, people who regularly behave in dependent, hostile, and impulsive ways appear at greater risk for depression.

American psychologist Martin Seligman proposed that depression stems from “learned helplessness,” an acquired belief that one cannot control the outcome of events. In this view, prolonged exposure to uncontrollable and inescapable events leads to apathy, pessimism, and loss of motivation. An adaptation of this theory by American psychologist Lynn Abramson and her colleagues argues that depression results not only from helplessness, but also from hopelessness. 

The hopelessness theory attributes depression to a pattern of negative thinking in which people blame themselves for negative life events, view the causes of those events as permanent, and overgeneralize specific weaknesses as applying to many areas of their life.

C.

Stressful Events

Psychologists agree that stressful experiences can trigger depression in people who are predisposed to the illness. For example, the death of a loved one may trigger depression. Psychologists usually distinguish true depression from grief, a normal process of mourning a loved one who has died. Other stressful experiences may include divorce, pregnancy, the loss of a job, and even childbirth. About 20 percent of women experience an episode of depression, known as postpartum depression, after having a baby. In addition, people with serious physical illnesses or disabilities often develop depression.

People who experience child abuse appear more vulnerable to depression than others. So, too, do people living under chronically stressful conditions, such as single mothers with many children and little or no support from friends or relatives.

TREATMENT

Depression typically cannot be shaken or willed away. An episode must therefore run its course until it weakens either on its own or with treatment. Depression can be treated effectively with antidepressant drugs, psychotherapy, or a combination of both.

Despite the availability of effective treatment, most depressive disorders go untreated and undiagnosed. Studies indicate that general physicians fail to recognize depression in their patients at least half of the time. In addition, many doctors and patients view depression in elderly people as a normal part of aging, even though treatment for depression in older people is usually very effective.

A.

Antidepressant Drugs

Up to 70 percent of people with depression respond to antidepressant drugs. These medications appear to work by altering the levels of serotonin, norepinephrine, and other neurotransmitters in the brain. They generally take at least two to three weeks to become effective. Doctors cannot predict which type of antidepressant drug will work best for any particular person, so depressed people may need to try several types. Antidepressant drugs are not addictive, but they may produce unwanted side effects. To avoid relapse, people usually must continue taking the medication for several months after their symptoms improve.

Commonly used antidepressant drugs fall into three major classes: tricyclics, monoamine oxidase inhibitors (MAO inhibitors), and selective serotonin reuptake inhibitors (SSRIs). Tricyclics, named for their three-ring chemical structure, include amitriptyline (Elavil), imipramine (Tofanil), desipramine (Norpramin), doxepin (Sinequan), and nortriptyline (Pamelor). Side effects of tricyclics may include drowsiness, dizziness upon standing, blurred vision, nausea, insomnia, constipation, and dry mouth.

MAO inhibitors include isocarboxazid (Marplan), phenelzine (Nardil), and tranylcypromine (Parnate). People who take MAO inhibitors must follow a diet that excludes tyramine—a substance found in wine, beer, some cheeses, and many fermented foods—to avoid a dangerous rise in blood pressure. In addition, MAO inhibitors have many of the same side effects as tricyclics.

Selective serotonin reuptake inhibitors include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). These drugs generally produce fewer and milder side effects than do other types of antidepressants, although SSRIs may cause anxiety, insomnia, drowsiness, headaches, and sexual dysfunction. Some patients have alleged that Prozac causes violent or suicidal behavior in a small number of cases, but the U.S. Food and Drug Administration has failed to substantiate this claim.

Prozac became the most widely used antidepressant in the world soon after its introduction in the late 1980s by drug manufacturer Eli Lilly and Company. Many people find Prozac extremely effective in lifting depression. In addition, some people have reported that Prozac actually tranforms their personality by increasing their self-confidence, optimism, and energy level. However, mental health professionals have expressed serious ethical concerns over Prozac’s use as a “personality enhancer,” especially among people without clinical depression.

Doctors often prescribe lithium carbonate, a natural mineral salt, to treat people with bipolar disorder (see Lithium). People often take lithium during periods of relatively normal mood to delay or even prevent subsequent mood swings. Side effects of lithium include nausea, stomach upset, vertigo, and frequent urination.

B.

Psychotherapy

Psychotherapy Session

A psychologist listens to her client during a psychotherapy session. Psychotherapy can be an effective treatment for many mental disorders. Some forms of psychotherapy try to help people resolve their internal, unconscious conflicts, and other forms teach people skills to correct their abnormal behavior.

Tom Stewart/Corbis

Studies have shown that short-term psychotherapy can relieve mild to moderate depression as effectively as antidepressant drugs. Unlike medication, psychotherapy produces no physiological side effects. In addition, depressed people treated with psychotherapy appear less likely to experience a relapse than those treated only with antidepressant medication. However, psychotherapy usually takes longer to produce benefits.

There are many kinds of psychotherapy. Cognitive-behavioral therapy assumes that depression stems from negative, often irrational thinking about oneself and one’s future. In this type of therapy, a person learns to understand and eventually eliminate those habits of negative thinking. 

In interpersonal therapy, the therapist helps a person resolve problems in relationships with others that may have caused the depression. The subsequent improvement in social relationships and support helps alleviate the depression. Psychodynamic therapy views depression as the result of internal, unconscious conflicts. Psychodynamic therapists focus on a person’s past experiences and the resolution of childhood conflicts. Psychoanalysis is an example of this type of therapy. Critics of long-term psychodynamic therapy argue that its effectiveness is scientifically unproven.

C.

Other Treatments

Light Therapy

A woman sits in front of a high-intensity light box as part of treatment for seasonal affective disorder. People with this disorder experience episodes of depression that usually begin during the winter months. Daily exposure to bright light helps prevent or lift depression for many people with the disorder.

Dan McCoy/Rainbow

Electroconvulsive therapy (ECT) can often relieve severe depression in people who fail to respond to antidepressant medication and psychotherapy. In this type of therapy, a low-voltage electric current is passed through the brain for one to two seconds to produce a controlled seizure. Patients usually receive six to ten ECT treatments over several weeks. ECT remains controversial because it can cause disorientation and memory loss. Nevertheless, research has found it highly effective in alleviating severe depression.

For milder cases of depression, regular aerobic exercise may improve mood as effectively as psychotherapy or medication. In addition, some research indicates that dietary modifications can influence one’s mood by changing the level of serotonin in the brain.

Contributed By:
Isay Mahams