Commentary Magazine

Sadness, Gladness--and Serotonin

These days, psychiatrists tend to treat mental illness as principally an affliction not of the mind but of the brain—a condition, that is, marked by a deficiency or excess of certain neurochemicals, which medication can restore to healthy levels. The pill has replaced the couch as the therapeutic instrument of first resort.

Ever since the usefulness of some of the most important psychoactive drugs was discovered by serendipity—doctors could see that the drugs worked without knowing why—clinical practice has remained several large steps ahead of neurobiological theory. But the theory is catching up, and its influence on the culture at large will surely be as momentous as Freudian theory was during the last century. Two recent books, by distinguished professors of psychiatry writing for a lay audience, introduce the reader to the latest developments in the field. They also provoke far-reaching questions about the new world into which the innovations are taking us.

In Against Depression,
1 Peter D. Kramer, a clinical professor at Brown University, has written a kind of sequel to his pathbreaking Listening to Prozac of twelve years ago. The new book is in essence an assault on the idea of mental illness as a form of “heroic melancholy.” That idea, Kramer writes, has deep roots in the Western tradition. From Aristotle through Shakespeare's Hamlet to the Romantic poets to Tolstoy's Anna Karenina and well into our own time, we have been fixated by an image of nobility and genius that is inextricable from agonizing “inner struggle.” According to that image,

[t]he rumination of the depressive, however solipsistic, is deemed admirable. And this value applies even in cases when the interior examination fails due to a lack of moral courage. No matter that the protagonist remains callow and self-deluding. Melancholic sensitivity is noble by definition.

Kramer concedes that what melancholic writers have had to say about politics or the human condition—that “life is absurd, chaotic, and brief,” that “bourgeois contentment can be superficial,” that “the moral quest ennobles us”—might very well be true. But depression, he insists, is something quite different from alienation, anomie, or spiritual despair, and to use it as an all-purpose metaphor does a disservice to the mentally ill.

As against the tradition of heroic melancholy, Kramer offers a counter-tradition, going back to Hippocrates, according to which depression is a medical illness, demanding medical treatment. Without denying the greatness of the melancholic writers and their battered heroes, he hopes that advances in psychiatry will bring about a cultural shift for the better, and even produce better writers. “If we could treat depression reliably,” he declares, “we would have different artists, different subjects, different stories, different needs, different tastes”—in short, a healthier world.


Considered medically, depression is a syndrome, or group of concurrent symptoms, that manifests itself in varying pathological forms. There are nine fundamental symptoms; different patients may have different permutations of them, and the same patient may show different symptoms at different times. In Kramer's summary, the nine are: “depressed mood, problems experiencing pleasure, low energy, disrupted sleep, diminished or increased appetite, mental or physical agitation or slowing, feelings of worthlessness or guilt, difficulty concentrating, and suicidality.”

For a diagnosis of major depression to be made, five of the nine symptoms must be present, including one of the first two over a span of at least two weeks, and they must be severe enough to cause distress or affect behavior. Certain conditions of intense suffering—normal bereavement, for instance—do not qualify as depression, even though the relevant symptoms may be present. Occasionally, a single, sufficiently awful symptom—especially suicidality—warrants immediate treatment as though the entire syndrome were present.

There are also conditions—manic-depressive illness and schizoaffective disorder—in which depression alternates with mania, sometimes in prolonged cycles, sometimes in brief or rapid ones. Manic symptoms are high energy, little need for sleep, vast confidence, racing thoughts, cosmic certainty, and, at its worst, florid psychosis. Manic depression is discussed at length in Exuberance, by Kay Redfield Jamison,

3 the second of the two books I mentioned above; I shall return to it later on, only noting here that if depressives commit suicide at twenty times the rate of the normal population, manic depressives follow close behind at fifteen times the normal rate.

Ever since the first antidepressants were developed in the 1950's—these were the monoamine-oxidase inhibitors, or MAOI's—it has been known that the neurotransmitter serotonin, like another neurotransmitter, norepinephrine, profoundly affects mood. (Neurotransmitters assist in the movement of impulses across the synapses between nerve endings.) Although the pertinent molecular transactions in mental illness are far more complex than any simple model would indicate, researchers know for a certainty that depression is associated with low serotonin levels, well-being with high levels.

In 1990, Kramer wrote a series of columns in a psychiatric trade journal describing the extraordinary success he and other doctors were having with a new generation of drugs called selective serotonin reuptake inhibitors, or SSRI's, of which Prozac was the flagship brand. The SSRI's refined and focused the basic action of the MAOI's, without causing the side-effects that made MAOI's dangerous. It also soon became apparent that the clinical applications of SSRI's extended well beyond the treatment of depression.

SSRI's work effectively against panic attacks, eating disorders, attention-deficit disorder, obsessive-compulsive disorder, and various other syndromes and individual symptoms. Indeed, in Listening to Prozac, Kramer suggested that SSRI's ought more accurately to be called thymoleptics, drugs that affect the emotions. Prozac itself, for example, is actually more effective against various psychological aches and pains, including shyness, social anxiety, and low self-esteem, than it is against the more virulent forms of major depression.


Thanks to their multiform usefulness and good press, SSRI's became some of the most frequently prescribed drugs in America, and Kramer, through his medical columns and Listening to Prozac, became their trademark proponent. Now, in Against Depression, he presses for a campaign to eradicate depression altogether, just as medicine once eradicated smallpox.

Depression, Kramer states categorically, is an illness rooted in the physiology of the brain. Admittedly, its origins in any one individual are complex, involving the interplay of genetic predisposition, inborn temperament, and character. Some people are more liable to depression than others because they are unable to rebound from life's ordinary failures and disappointments, or perhaps from its most terrible tragedies. Low self-esteem, pessimism, dependency on others, and feelings of helplessness all incline one toward depression; neuroticism, in the limited sense of moodiness, actually predicts it.

Nevertheless, some generalizations hold. According to Kramer, the contribution made to the disease by one's genes, as opposed to environmental factors, runs between 35 and 40 percent; among those with persistent or frequently recurrent depression, the genetic contribution is over 50 percent. Moreover, whatever the exact origin of an individual's depression, or the exact nature of the interaction between genes and the environment, once the disease begins it “leads to a brittle state in which minor adversity becomes catastrophic. That adversity includes episodes of the disease itself.” Finally, depression causes actual physical injury—demonstrable by computer-aided mapping of the brain—which then contributes to further depression. The longer the depression lasts, the worse the brain damage. This means that any delay in treatment only makes it worse. “Every day counts.”

Damage can occur not only at the individual level but in the form of a public-health crisis. “Depression is the most devastating disease known to humankind,” Kramer asserts, backing up this strong claim with statistics from the World Health Organization, the World Bank, and Harvard's School of Public Health. As of 1990, major depression outdid the usual suspects among medical enormities, laying low over 16 percent of Americans during the course of a lifetime and over 6 percent in a given year. In losses to productivity, it is more costly than heart disease or all cancers combined.


How then, could anyone resist Kramer's call to wipe depression off the map? And yet, he tells us, although no one misses the presence of smallpox in our lives, there are those who are unwilling to see an end to depression—their own or others'. Heroic melancholy dies hard.

There are some bad reasons for this, among which Kramer puts his finger on a kind of moral vanity; but there are some good reasons as well, which he does not search deeply enough. As we have seen, Kramer himself acknowledges the extent to which antidepressants are increasingly used as “mood-brighteners,” prescribed for persons not generally considered mentally ill but looking to improve their quality of life. This stirs a moral hornets' nest. In brief, the new psychopharmacology championed by Kramer raises a very large question: what is everlasting in the human condition, and what can and ought to be changed?

One who has written acutely about these matters is Leon Kass, the biochemist, physician, and philosopher who until recently headed the President's Council on Bioethics. Kass is all for the treatment of mental illness with psychotropic drugs. But he fears that individuals obsessed with their own well-being and unable to resist the allure of safe chemical pleasure will habitually use Prozac's revved-up pharmacological descendants the same way that Aldous Huxley's fictional denizens of the future in Brave New World use “soma”: to induce a permanent state of unearned contentment, even bliss.

For Aristotle as for other great moral philosophers, Kass reminds us, happiness and moral virtue are to be found in activity done well, and are the products of will, effort, and devotion. Kramer, for his part, tries to be simultaneously on Prozac's side and Aristotle's. In his clinical experience, he reports somewhat defensively, “the people whose level of distress did not rise to the level of illness . . . did not resemble the struggling, handicapped, often socially isolated patients I had seen respond to Prozac.” Besides, he writes, episodes of apparently sub-clinical pain can frequently mark depression and manic depression in their early stages; prudent intervention before severe mental illness sets in can prevent years of suffering and change the course of a life. As for the fear that antidepressant drugs substitute the simulacrum of happiness for the real thing, Kramer replies that SSRI's do not make people happy; they only make it possible for them more ardently to pursue those “ordinary and even noble human activities” in which true happiness resides.

Be all that as it may, the moral perplexities that psychoactive drugs even more effective than Prozac will pose for the future are inescapable, and the cultural sea-change that Kramer wants psychiatry to bring about would extend far beyond the writing of happier poems and novels. The widespread success of Prozac and its supercharged descendants, not only in eradicating major depression but also in ameliorating ordinary unhappiness, would transform the way most people think of their lives.


Both biblical religion and classical philosophy, despite the irreconcilable differences between them, share a certain sense that human life is shot through with unavoidable suffering, and that there are fixed limits to human happiness. Wisdom resides in understanding and accepting those limits. It is essential to try to improve oneself, by strenuous moral effort, as far as one's nature allows—indeed, this endless aspiration toward an unattainable ideal defines moral life and intellectual life at their highest. But it is foolish and dangerous to think that nature, or human nature, can be altogether overcome.

The modern challenge to this ancient understanding hardly began with Prozac. It began, rather, with Francis Bacon and René Descartes, twin originators of the modern scientific project to conquer nature “for the relief of man's estate.” As Bacon wrote in The New Organon (1620), his definitive reply to Aristotle and Christianity, “Only let the human race recover that right over nature which belongs to it by divine bequest, and let power be given it; the exercise thereof will be governed by sound reason and true religion.”

Prozac—and by that word I include the more refined drugs yet to be developed—is Bacon's brainchild. To render neurosis and anxiety, even shyness and poor self-esteem, obsolete by prescribing a pill fulfills the prophecies of modernity's founders. In those prophecies, the understanding of human nature as something circumscribed by God or natural law gives way to a vision of the human substance completely malleable by human beings themselves. Nature's niggardliness with its gifts will be corrected by man's generous solicitude toward man. The inequities of fortune will be smoothed out.

That this alteration in human circumstance will itself require a new religion was something foreseen by Bacon, who in the passage quoted above referred to it rather as the “true religion.” In this new dispensation, the ancient Jewish notion of a people chosen by God for extraordinary suffering as well as for spiritual privilege will appear merely quaint, and the ancient Christian notion of God Himself choosing to die an unspeakable death to redeem human sin will be downright laughable. For human beings of every stripe, painful spiritual struggle will yield to contentment and peace of mind.

In the light of this pedigree, how can one pretend that the ultimate triumph of Prozac will not produce, contrary to Kramer's sunny fantasy, a transvaluation of the very idea of what life is and ought to be? How many of us, by now long accustomed to taking the body more seriously than the soul, are not already disposed to embrace the idea that human nature is reducible to the pertinent neural and endocrine processes? Kramer claims that neurobiology's displacement of mind (not to mention soul) in favor of brain and body is an advance comparable to those of Copernicus, Darwin, and Freud; he does not think to say that it will eventually complete the picture that those earlier theorists began to draw: the picture of man as just another animal in a morally indifferent universe.


The interplay of inborn temperament, moral choice, and divine will—or, if one prefers, cosmic accident—is one of the supreme mysteries of our nature. Out of it there emerge the naively wondering questions we begin to ask in childhood and never quite answer as adults. Why am I who I am? Why do I find myself in this particular body? Why this soul (or character) and not another?

Ironically, confidence that our fate is now more in our control than ever before has not dispelled such questions, at least not yet. As “masters and possessors of nature,” in Descartes's phrase, we are able to refashion the parts of our psyches that don't suit us; at the same time, however, as captives of the double helix, we operate under the uneasy suspicion of genetic fatefulness, a condition that can lead us to despair of ever knowing true freedom.

As it happens, the model of mental illness that Kramer propounds can accommodate this human complexity, but the brand of psychiatry that more and more doctors practice these days ignores its implications. In the so-called risk/stress description (risk being genetic predisposition, stress the effects of environment and choice), a person of susceptible inborn temperament makes a choice that most people would know to avoid; the ensuing distress makes him more likely to make another poor choice the next time, and the time after that; and eventually the gathering force of sad experience working on unfortunate material may plunge him into illness, from which his moral constitution and its neurochemical imprint make it hard if not impossible to recover.

Morally complex as a Sophoclean tragedy, the risk/stress description recognizes the malign and unavoidable forces to which certain persons are subject, yet also allows for the possibility of overcoming them through the exercise of moral choice, however rare such a triumph may be for those whom nature has marked for a very hard time. The reductionist explanation by biology alone, which Kramer leans toward and which his profession is rushing to embrace, does not do justice to this portrait, or to the mystery that is at the heart of the relation of character and fate.

Nor is anyone likely to penetrate that mystery any time soon. How one comes to be mentally ill is becoming clearer; why this ruinous conjunction of genetic predisposition and bad choice should befall one person rather than another remains dark.


But that is where Kay Redfield Jamison's Exuberance: The Passion for Life, comes in. Jamison, a clinical psychologist and professor of psychiatry at Johns Hopkins, is co-author of the standard medical textbook on manic depression and sole author of books on suicide and on manic depression in artists. A joyous study of the burning wish to take on the world, Exuberance is rich in both science and mystery.

Jamison, who laments psychiatry's “benign neglect” of vitality, resilience, pluck, daring, and sparkle, does much to make good the deficit. Exuberance, she writes,

carries us places we would not otherwise go—across the savannah, to the moon, into the imagination—and if we ourselves are not so exuberant, we will, caught up in the contagious joy of those who are, be inclined collectively to go yonder. By its pleasures, exuberance lures us from our common places and quieter moods; and—after the victory, the harvest, the discovery of a new idea or an unfamiliar place—it gives ascendant reason to venture forth all over again.

In particular, Exuberance celebrates a gallery of riproaring statesmen, naturalists, biologists, physicists, writers, explorers, soldiers, and heroes of cartoon strips and children's books. For Theodore Roosevelt and John Muir, about both of whom Jamison writes at length, gratitude for nature's riches established the mysterious sanctity of life on earth. The greatest scientists, too, have always regarded their calling as an exuberant initiation into sacred mysteries. And exuberance is the natural state of the faithful: as Jamison writes, “The great joy-filled Christian hymns continue the songs of praise from the Old Testament.” (That the hymnal is also replete with cries of despair and anguish does not impair this quality of reverent exultation.)

But belief in the Creator is not a prerequisite for ecstasy at creation; even those for whom nature is an inexplicable accident can marvel at its variety and refinement. In fact, Jamison believes that exuberance is itself a force of nature: most of the scientists she interviewed for this book agree that if you're not born with it, nobody will give it to you later in life. And like neuroticism and depression as Kramer describes them, exuberance and robust delight feed on each other: their confluence is the privilege of the healthy animal, non-human as well as human.

Still, nature, even as it dispenses its most lavish gifts, is not always kind. Jamison reminds us that the sheerest membrane separates rare exaltation from rampaging disease, and that it is all too easy to pass from one to the other. Some of her most distinguished and high-stepping biologists—Nobel-Prize winners like James Watson and Carleton Gajdusek among them—speculate that certain transports of exuberance overlap with mild attacks of mania. When one gets too exalted for his own good, exaltation can devastate. The poet Robert Lowell called his shattering outbreaks of mania “pathological enthusiasm.”

Jamison respects and fears these tempests of elation. Her 1995 memoir, An Unquiet Mind, recounted her own struggle with manic depression, a condition that lifted her well beyond the reach of reason and flung her broken to the ground. So thrilling were the manias that she did not even think she was ill until a Pacific sunset turned into a hallucinatory bloodbath. A later depression moved her to try suicide, at which she almost succeeded. These are the kinds of horror from which recovery seems truly all but impossible. But with the aid of lithium, and of aggressive psychotherapy, she has enjoyed a life rich in love and successful in work.


In the epilogue to An Unquiet Mind, Jamison wrote that she often asked herself whether, given the choice, she would want to be manic-depressive. Depression itself is something she finds “awful beyond words or sounds or images,” and wishes no further part of. But mania and hypomania (the latter is not quite manic, and can be more than agreeable) are another matter:

Even when I have been most psychotic—delusional, hallucinating, frenzied—I have been aware of finding new corners in my mind and heart. Some of those corners were incredible and beautiful and took my breath away and made me feel as though I could die right then and the images would sustain me. Some of them were grotesque and ugly and I never wanted to know they were there or to see them again.

However terrible the sights were, though, she decided she would choose manic depression, provided she had lithium to keep her under control.

Here, then, is a kind of answer to Kramer from within psychiatry itself. In the days before lithium therapy, Jamison would likely have wound up dead or ravaged beyond recognition. The new psychopharmacology has been the purest blessing for her, as it has been for many others. It has given her the freedom to declare that she would live her life over again, fully accepting her crystalline fragility, the terrors with the joys.

Yet it is not the medical technology, wonderful though it is, that excites the greatest admiration. It is, rather, the patient, whose own courage and fortitude and exuberance enabled her to come to terms with an illness that, despite the benefits of lithium, remains harrowing and pernicious. Not only has Jamison made a happy life for herself, she has used her turbulent experience to further the medical and the popular understanding of mental illness, and to ease the pain of fellow sufferers. Even as psychiatry increasingly becomes what Peter Kramer desires it to be—a neurochemical affair—the highest end of the care of souls, psychiatric and otherwise, must remain the enabling of persons damaged by nature to aspire to the free moral life.



1 Viking, 353 pp., $25.95.

2 A less dramatic form of depression, known as dysthymia, is a condition of depressed mood for most of the day, on more days than not, over two years or more in succession, with concurrent disturbances of sleep, appetite, energy, or concentration.

3 Knopf, 405 pp., $24.95.


About the Author

Algis Valiunas writes on culture and politics for COMMENTARY and other magazines. His "Goethe’s Magnificent Self" appeared in January.

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