The Pill of Pills

“This man was addicted to moanin’,
Confusion, edema and groanin‘,
Intestinal rushes,
Great tricolored blushes,
And died from too much serotonin.”

As a third-year medical student forty years ago, I gratefully used this limerick to help me remember the signs and symptoms exhibited by patients harboring an unusual chemical-secreting tumor called carcinoid. The lines had been composed by the most nimble-witted of the great professors of medicine of that time, William Bean of the University of Iowa.

Dr. Bean was a physician renowned not only for a series of uniquely conceived contributions to medical knowledge but also for his enviable gifts for language and whimsy. Among the most celebrated manifestations of his literary talent was a seemingly instinctive ability to produce instantaneous and faultless rhymes to suit any and every clinical situation in which he found himself. When attending large meetings, Bean would customarily take a seat near the rear of the auditorium, so that he might best absorb a panoramic sense of the atmosphere. Called upon to comment (and he was always called upon to comment), he would slowly make his way to the lectern while silently composing an appropriate fragment of doggerel, which, when he began his remarks by reciting it, invariably sent his colleagues into transports of howling delight. In biblical and classical times, poetry was used to facilitate remembering, and so it has been for the cleverly couched cadenced wisdom of William Bean, still cherished by the generation of American physicians privileged to be exposed to it.

Were Bean alive today, he would read Listening to Prozac with an amused skepticism, and wonder what Peter Kramer was trying to do, beyond writing a best-selling book. The author’s uncertain gropings for proof of a fanciful theory of the self would doubtless inspire couplets, quatrains, and not a few limericks, the Iowa sage’s puckish way of dismissing an author who has played fast and loose with the most basic principles by which physicians evaluate clinical experience and propose new ways of explaining or treating illness.

Those principles require (1) meticulous and personally made observations of an illness or maladaptive state; (2) even-handed review of all pertinent publications that bear on the problem; (3) scrupulous attention to every fragment of clinical evidence, whether or not it supports the observer’s evolving hypothesis; and (4) a commitment not to speculate beyond what is justified by the accumulated data and its supportable implications. These are the criteria by which the work of any physician should be judged, whether he or she is making a diagnosis, recommending therapy, or introducing a new theory.

Nowadays, the human mind is no longer so unchartable a territory that its investigators should not be held to the same standard. Admittedly, this has not always been the case, especially during the period of pioneering psychological investigations when so little was known of the physiology of the nervous system. But even Sigmund Freud said he yearned for the day when his doctrines might be subject to the testing and kinds of proof that are attainable only in laboratories.

In view of the scrupulous standards of modern laboratory and clinical investigation, non-specialist readers have a right to expect that theories placed before them have measured up to the straightforward expectations of any careful physician. Unfamiliar with arcane professional literature and unable to judge personal experience to which they have not been witness, readers are too often, in this age of instant celebrity, subjected to the arguments of seemingly authoritative physicians and scientists who propose views that don’t stand up to the scrutiny of trained professional eyes. Especially when the authors have excellent credentials, write readable prose, and are obviously sincere in their beliefs and genuine desire to do good—especially then—do facile arguments become dangerously attractive.

Though I sense in his work a genuine concern for patients and readers, and a genuine belief in the promise of his speculations, I am equally convinced that Peter Kramer, a Harvard-schooled, Yale-trained, Providence-based psychiatrist, has allowed his objectivity as a clinical physician to be suffocated by his desire to help humanity. Shortly before Prozac was introduced in 1988, a psychologist asked Dr. Kramer for help in the treatment of a depressed woman in her early thirties, whom he then “worked with only around issues of medication.” Because psychotherapy was not being effective, Dr. Kramer was asked to recommend a psychotropic drug and manage its administration. He chose Tofranil, and saw the patient “for fifteen minutes every month or two.” She recovered from her illness, but not as fully as he or the young woman wished; a “soft sign or two” of depression remained unyielding to the treatment.

Just at the point when increasing the dose of Tofranil was found to be without effect, Prozac was approved by the Food and Drug Administration, and Dr. Kramer decided to try it. Within weeks, he observed a remarkable phenomenon. The woman’s entire life’s history (even before her depression became clinically evident) had been characterized by social failure, masochism, low self-esteem, depleted energy, and strong feelings of hopelessness. Now she apparently became “transformed.” Not only had her depression lifted completely, but her entire personality was altered by what Dr. Kramer calls “the bounties of science.” Those bounties extended even to the little things that tell a person she has the enviable qualities that make for a vivacious life, the qualities that magnetically attract others to us: “People on the sidewalk ask me for directions!” the woman said, and she had as many as “three dates a weekend.” It was, she said, as if “I had been in a drugged state all those years and now I am clearheaded.” For the first time in her life, she had been given “the courage to do what needs to be done.”

Dr. Kramer witnessed a similar result with the second patient treated with Prozac. His two experiences had a deep effect on the thirty-nine-year-old psychiatrist’s concept of the possibilities of treatment with drugs. He hadn’t ever seen “a drug’s effect to be so global—to extend social popularity, business acumen, self-image, energy, flexibility, sexual appeal,” and at the same time to be so free of unwelcome side-effects. This was not mere healing—this was transformation.

Not surprisingly, the experience of seeing such an astonishing metamorphosis set Dr. Kramer to pondering the biological and emotional structure of the self. He became increasingly doubtful about the validity of such long-held certainties as the continuity in a person’s psychological makeup. Can one’s personality be all at once so radically redefined, reshaped, reconstituted? Can a new self, in fact, emerge? If a drug can bring about this kind of transformation, described by his patient, does that not prove that the influence of biology on personality is much more all-encompassing than psychiatric theory and our culture have heretofore been willing to admit?

Such ruminations are not unfamiliar in the history of science, philosophy, and theology. The magical prospect of being reborn with one’s defects of perspective purified is not a novel one in human experience, as can be seen by its recurrence in folklore, fantasy, and in the beliefs of those who seek it through religious faith. And here, in the form of a safe pill that can be taken once a day, Peter Kramer began to believe he had found it.

Dr. Kramer searched the professional literature for evidence to suit his emerging hypothesis, and found it, he thought, in monographs and articles published over a period of years by eminent researchers. He took what he needed, interpreted it through the filtered light of his own convinced Weltanschauung of freshly formulated psychiatric theory, and sought further support for his beliefs in the responses of a few of the patients he subsequently treated with Prozac.

Without providing systematic evidence or argument for his conclusion, he took the view that emotional responses and behavior are the result of “inborn, biologic temperament” rather than of “slowly acquired, history-laden character.” From this assumption, he went on to posit that a chemical might redesign that temperament and do so as though the old had been erased and the new had taken its place. He saw all of this as proof not only that biology is destiny, but that destiny itself can be changed by swallowing the right stuff.

In describing Dr. Kramer’s thesis, I’ve used more than the usual number of direct quotes from his book, in order to convey some of the evangelical fervor of its message. By the end of Listening to Prozac he has made himself into something like a messiah. His epistle to the reader holds out the prospect that Prozac is a drug that can remove those aspects of our personality that we find objectionable.

Prozac is a very effective agent against the major pathology of clinical depression. But Dr. Kramer refers here not to treating severe symptoms of clinical depression such as suicidal tendencies but to getting rid of the burdensome personality traits and moods that are the daily experience of most if not all of us: the ordinary anxieties and angers and sadnesses that merge into feelings of being “down in the dumps.” With Prozac, those who are dissatisfied with their own temperament and the feelings that go with it can be remade into something quite new and wonderful, so that “a substantial minority” are “transformed.” These claims have far less substance than Dr. Kramer would have us believe.

Dr. Kramer’s misbegotten message is based on the story of serotonin, brought up to date. That story begins long before Bean composed his limerick and even long before the chemical itself had been discovered. The “miracle” of Prozac finds its beginnings in the work of two friends, one an Englishman and the other an Austrian Jew, who together won the Nobel Prize in 1936. Before the researches of Sir Henry Dale and Otto Loewi, it had always been assumed that the transmission of an impulse from nerve to muscle or across the tiny gap (called the synapse) between the branches of successive nerve cells was caused by directly propagated continuity of the electrical wave that accompanies the impulse. In a series of elegant experiments done quite independently of one another in the early 1920s, Loewi and then Dale demonstrated that the impulse is actually-passed through the gap between cells not via an electrical wave but rather by means of chemical substances liberated at the nerve terminals, which then transmit the stimulus across the synapse and onward toward its destination. Following Loewi’s proof of the principle of chemical transmission, Dale identified acetylcholine to be the substance that functions at the junction between a nerve ending and the muscle it activates. Additional chemical agents were discovered in succeeding decades, each carrying its own kind of message across the synapses of various parts of the complex wiring of the nervous system. These were given the general designation of “neurotransmitters.” Thus, a neurotransmitter is a chemical substance that is secreted at the terminal of a nerve cell and that carries information across the synapse to a target on the other side.

In 1948, researchers at the Cleveland Clinic identified the chemical nature of a substance long known to exist in blood serum, and to have the property of being able to constrict small vessels. Since it was discovered in serum, and since its function was to increase the ability of a vessel to tighten (scientists refer to this quality as “tone”), the substance was given the name of serotonin, and so it has been called ever since. Further research revealed that serotonin, whose chemical designation is 5-hydroxytryptamine, is to be found in many different tissues of the body. It was shown to be capable of a variety of actions, including inducing a contraction of the involuntary muscle found in the walls of tubular organs such as the intestines and lungs.

Because of this characteristic, an excess of serotonin can lead to such distressing symptoms as overstimulation of intestinal peristalsis and tightening of the small bronchioles in the lungs. Carcinoid tumors were later found to secrete serotonin as well as smaller amounts of other highly active substances, all combining to produce the diarrhea, wheezing, flushing, and mental confusion of Bill Bean’s limerick.

By this time, the early 1950s, serotonin had been found in the brain, and it was not long before researchers began evaluating its possible role in mental illness. Their interest may have been encouraged by the fact that elements in its chemical structure are similar to LSD and several other so-called psychedelic or hallucinogenic drugs. These compounds when ingested have the effect of increasing people’s sensory awareness and apparent clarity of perception, while at the same time lessening their conscious control over their behavior.

Gradually it came to be recognized that serotonin functions as a neuro-transmitter in the brain. This finding was a major factor in the outburst of research that resulted in the emergence of the field of psychopharmacology during the 1960s and 1970s. From observations of new antidepressant medications, it began to appear that depression might, at least in theory, be related to a decreased concentration at the synapse of certain neurotransmitters, among them serotonin. The decreased concentration was thought to occur because the neurotransmitter is “taken back” into the transmitting nerve cell, where it is rendered inactive by certain enzymes. The action of the commonly used antidepressants such as Tofranil, Elavil, and others was believed to lie in their ability to slow down the process by which one or another transmitter is taken back into the cell—“re-uptake” is the term used—or in preventing its destruction by enzymes.

The introduction of Prozac by the Eli Lilly Company in 1987 was the result of a strenuous effort to synthesize a compound that would selectively inhibit the re-uptake of serotonin, and only serotonin, without affecting the other neurotransmitters. It was the first antidepressant in the class now called selective serotonin re-uptake inhibitors, or SSRI’s.

Unfortunately for what would at first glance appear to be a tidy theory, it remains anything but certain that clinical depression is, in fact, caused by a decrease in serotonin or its fellows at the synapse. The truth is that the basic causes of the disease called depression are still unknown. The precise role in brain function of chemicals or other organic factors is hypothetical and not yet proven by the rigorous standards of science. The only thing that can be said for certain is that a number of drugs known to increase the concentration of neurotransmitters do indeed have a high frequency of success in the actual treatment of patients for depressive symptoms. Success is measured by the degree the patient’s personality returns to what it was before the onset of the morbid state we call clinical depression.

The first antidepressant drugs were introduced as early as 1958. Among those currently being used, Prozac is remarkable for its having relatively few adverse effects—not only psychiatric effects such as increased anxiety, but physical side effects such as dry mouth, urinary retention, dizziness, and palpitations—and for the relative ease with which dosage can be regulated and maintained. For most patients, Prozac has no higher a rate of success in lifting depression than do the standard agents used before it was introduced, such as Tofranil, Elavil, and Pamelor, which are effective in 65 to 70 percent of cases. Other than its relative safety and ease of administration, the only matter in which Prozac seems to exceed its pharmacologic fraternity brothers is in the extensive advertising blitz that introduced it, and in the vast commercial success that has continued to increase with each passing year. According to a recent article in the Wall Street Journal, the drug had sales of $1.3 billion in 1993, up 30 percent from the previous year. It is one of the ten best-selling drugs in the world and its sales have far outstripped those of any other antidepressant. Much of this is being attributed to the messianic heraldry of Listening to Prozac.

It is true that thousands upon thousands of “Prozac pens” flooded medical offices in 1987 as an advertising gimmick and that perhaps millions of hours of promotional pep-talks have been given to America’s physicians by well-prepared Eli Lilly hucksters. All this notwithstanding, there does exist a very effective antidepressant that goes by the name of Prozac. Its usefulness in fulfilling the only function for which the FDA has approved it—treatment of major depression and of obsessive-compulsive disorder—is not in question. But is it, as claimed by Peter Kramer, a psychiatric wonder drug that will not only transform patients, but also transform our culture’s entire view of the basic factors that determine human personality? Will Prozac and newer drugs based on pharmacological principles similar to those of SSRI’s have the effect on ordinary anxiety and other uncomfortable feelings that the antibiotics, for example, have until very recently had on infectious disease? At the moment, the question may be unanswerable, but Dr. Kramer’s book, for all its enthusiastic advocacy of such a probability, provides no evidence whatever to support it.

The first of Dr. Kramer’s problems is inherent in the title he has chosen for his book. As he defines it, “listening to” a drug is a way of using its effect to “tell us something about how human beings are constituted.” He goes on to say, “For the last half-century, scientists have relied on medication response to infer the cause of disease.” This is not a new idea. The great Otto Loewi himself reported that as early as 1897 he “looked at pharmacology as the science whose main goal is revealing physiological functions by the reactions of living matter to chemical agents.” Although such reasoning has been useful in elucidating some other functions of cells and organs, it has not been notably successful in helping researchers to understand mental illness.

Dr. Kramer knows this but he does not clearly inform the reader about it. Twice he points out that the great result of “listening to drugs” for our theoretical understanding of mental functioning has been the the theory that depression results from the action of biogenic amines, of which serotonin is one. He himself acknowledges that this theory has been shown to be “demonstrably false or incomplete,” an admission supported by a statement in the 1992 edition of the classic medical text The Pharmacological Basis of Therapeutics, commonly known by the name of its founding authors as simply “Goodman and Gilman.” In describing what they call “the neurotransmitter hypothesis of mood disorder” (note that they don’t dignify the idea by using the word “theory”), the authors point out that “the data are inconclusive and have not been consistently useful either diagnostically or therapeutically.”

Dr. Kramer, having seen a few patients “transformed” by Prozac into being “better than well,” decides to ignore the absence of definitive justification for his hypothesis about the causes of depression in order to develop his fantasized concept of the biologic determinacy of human behavior. Periodically, he admits, for example, that, “my speculations…are far ahead of the evidence,” but such apparent scruples are trampled beneath the sheer weight of his claims to have “evidence,” a word he uses without discriminating for the reader between valid scientific conclusions and the results of studies that are merely somewhat suggestive and open to widely differing interpretation.

Dr. Kramer has cobbled together bits and pieces of other people’s research in order to create the appearance of some authoritative, but still not adequately acknowledged, support for his thesis. It appears that, having made up his mind about what he wants his conclusions to be, he thereafter views all possible evidence in such a way as to lead ineluctably to these conclusions. As one reads about study after study that seems to aim in Dr. Kramer’s chosen direction, it is tempting to wonder just what these researchers must think about their work being used in this way. Only a reader familiar with the specialized literature can appreciate just how much squeezing of data Dr. Kramer has done in order to fit the findings of others into the structure of his own all-inclusive theory of behavior. Not being a researcher himself, the problem may simply be that he has no appreciation of how badly he is serving his sources, or, for that matter, his audience. This is hardly Dr. Bean’s criterion of what I have called “even-handed review of all pertinent publications that bear on the problem.”

Nor does Dr. Kramer provide “scrupulous inclusion of every fragment of clinical evidence, whether or not it supports the observer’s evolving hypothesis.” A reader of Listening to Prozac comes away with the impression that the “transformative powers of Prozac” are so commonly experienced by users that the very existence of the drug poses heretofore unthinkable ethical problems for our society. Is it right to use “cosmetic psychopharmacology” (a term coined by the author) to give each of us a buoyantly confident personality we never had before? What should the medical profession do to protect against possible misuse of this awe-in-spiring pharmacologic power? Are anxiety and depression necessary factors in human understanding and fulfillment, or are we better off using universal Prozac to free ourselves of such distractions that prevent a state of pleasurable optimism?

The author addresses such questions in the same way he uses his melange of citations—he wants us to treat his theory as though it is, if not actually proven, so well validated that its consequences must now be explored with due regard for their philosophical implications. We may not notice that by giving serious consideration to the possible consequences of this unsubstantiated theory, we are in effect agreeing that it carries weight. We may also incautiously accept Dr. Kramer’s preposterous claim that “the capacity of modern medication to allow a person to experience, on a stable basis, the feelings of someone with a different temperament and history is among the most extraordinary accomplishments of modern science.”

Of course, Prozac is capable of transformations such as the one claimed by the woman I earlier mentioned, but how often do they actually take place? The highest estimate I have been able to find is 10 percent, and most of my sources say that this is far too generous a figure.

Professor Robert Byck, a psychopharmacologist and a consulting psychiatrist who teaches at Yale, where Peter Kramer was trained, says that the transforming effect, “though impressive when it occurs, is very rare.” “Very rare” is exactly the term used by other experienced psychiatrists to whom I have spoken. Perhaps it’s not the most perfect of analogies, but an obvious question presents itself: Would a plastic surgeon recommend a cosmetic procedure whose effectiveness is “very rare” when he has no way of even knowing which patients will clearly benefit from it? The unabashed self-congratulation with which Dr. Kramer introduces the phrase “cosmetic psychopharmacology” justifies such a question—he should be made to stand by his own innovative use of language.

Yet another claim might lead to a dismissive limerick or two by Bill Bean. Any clinical physician knows that it is neither valid nor possible to draw conclusions about a patient’s behavior unless that behavior has been the subject of the investigator’s personal observation. Second-hand information, especially when it is gathered by less highly trained associates, is suspect. Too many of the wonder-patients described in this book were referred to Dr. Kramer not for evaluation and treatment but for what he calls “medication backup.” They were referred to him by “a handful of psychologists and social workers in my community.” We don’t find this out unless we read the footnotes in the back of the book. An alert reader will be troubled by the author’s willingness to draw sweeping conclusions from the therapeutic outcomes of patients he knows less well than the text would make it appear.

Prozac is an excellent drug for treating depression, but probably no more effective for that purpose than several others that have been available for decades. Because it is relatively safe (at least so far as we know during the still brief period during which it has been available) and easy to administer, it is widely and justifiably used by many of the millions of people suffering from depression or obsessive-compulsive disorder. For a very small group of people, some of whom are only minimally depressed, it has also achieved the remarkable benefit of seeming to create what Peter Kramer has called, “The New You,” and for this reason it has become the subject of much interest and considerable publicity. While it may occasionally transform one person or another, Prozac will not transform either our society or our culture’s understanding of the workings of the human mind.

Much has been made of the claim that Prozac is relatively free from side effects, compared to the antide-pressants that preceded it. Although that claim is entirely valid, it should not be interpreted to mean that those who take the drug are guaranteed a comfortable or even a safe ride. For example, even Dr. Kramer admits (albeit only in the notes following the appendix at the back of his book) that “Prozac can cause difficulty in achieving orgasm, more noticeably in men but in women as well…Clinicians see it fairly often.” Moreover, there is a standard caveat to be remembered when evaluating any drug during the first years following its introduction, namely that it is still too early to arrive at a reliable estimate of possible dangers that may appear in the long term. It is worth noting that, according to the Physicians’ Desk Reference,

15 percent of approximately 4,000 patients who received Prozac in US premarketing clinical trials discontinued treatment due to an adverse event. The more common events causing discontinuation included: psychiatric (5.3 percent), primarily nervousness, anxiety, and insomnia; digestive (3.0 percent), primarily nausea; nervous system (1.6 percent), primarily dizziness; body as a whole (1.5 percent), primarily asthenia and headache; and skin (1.4 percent), primarily rash and pruritus.^*

Listening to Prozac is filled with the kind of free-form thinking one might expect from an enthusiastic psychiatrist who is innocent of the ways of serious research and all too willing to release himself from the constraints that govern the objective evaluation of evidence and the logical construction of a serious thesis. The result is a psychopharmacological fantasy that, in the name of science, offers readers an exciting prospect: simple, painless self-transformation if you take the right pill. Perhaps it is not surprising that the widespread American religious experience of being “born again” should now have a secular, chemical counterpart, along with an attractive young medical evangelist to promote it.