Friday, August 28, 2009

Incidental Enhancement

[Text of lecture presented in somewhat shorter form and with a longer title (“Incidental Enhancement: Cosmetic Psychopharmacology Two Decades Out,") at the conference Human Nature and Self Design hosted by the Interdepartmental Centre of Ethics in the Sciences and Humanities, Eberhard Karls Universität Tübingen, Tübingen, Germany, August 1, 2009]

Allow me to open with an apology that might come from the field of psychiatry as well. You have invited me to update you on the prospects of cosmetic psychopharmacology twenty years after the introduction of Prozac in the United States. There is, sadly, little to say, because there has been scant progress in the development of psychotherapeutic drugs. While substances with diverse modes of action have shown success in the laboratory, in the clinic, with few exceptions we have had to make do with chemicals that affect monoamine transmission and other familiar therapeutic targets, such as receptors for gamma-aminobutyric acid. As a result, the discussion of cosmetic psychopharmacology has also been static.

So: little movement to report in either drug development or medical ethics. On that second front, I do hope by the end of the talk to share with you one idea that I believe to be novel and grounded in recent science. But let me begin by reviewing the historical context.
To the best of my knowledge, the phrase “cosmetic psychopharmacology” first appeared in March of 1990 in a column I wrote for a trade paper, The Psychiatric Times. For years, I hesitated to claim priority for this for this coinage, but almost two decades have passed without the discovery of a prior usage, and colleagues have made the assertion for me. I will quote from that essay at length (but with some omissions as well in the interests of time) both to define our topic and to convince you that the philosophical ground has changed little.

In 1990, I described a series of depressed patients then in treatment. On the new antidepressant, they showed no signs of hypomania. Nonetheless, the patients appeared “livelier, more optimistic, less vulnerable, more decisive even than they were in their ‘premorbid state . . .’” In the essay, I then harked back to a patient I had written about in May of the prior year — an architect who on Prozac had recovered from an episode of paranoia and found himself “better than well,” less obsessive and better able to remember and concentrate:

. . . I do not know whether fluoxetine improves memory and concentration . . . New drugs are sometimes accompanied by patient reports of extraordinary changes. Perhaps Prozac will seem more ordinary with time, perhaps there will be late bad reports. But before we know more, I would like to propose some thought experiments that go beyond Prozac to the brave new world of more specific and more powerful drugs.

. . .[W] hat ought I to do if the architect were to approach me and say, "I have an important project at hand; I am not depressed, but I would like to go on Prozac for a time, to get the work under way?"

. . . To inch another step along the way: what if it is demonstrated that a psychotherapeutic medication has salubrious effects on normals, that . . . [it] improves memory, work performance, pattern recognition, social skills? None of which strikes me as implausible in the near future. How should such a medication be used? Will "normals" — people who have never been depressed — be candidates for it?

This question must have answers at three levels: personal, cultural, and professional. Jean-Paul Sartre said he wrote his last book while on amphetamines, fully believing he was hastening his death but preferring his version of Achilles' choice: the short, productive life. In America, we would withhold this option, because, since amphetamines are habituating and cause paranoia, we have reached a professional and legal consensus that they should be used only to treat certain specific syndromes. A doctor might face Sartre and say, the choice is not yours: The book goes, you stay; we are caretakers for a whole society, not potentiators of your work.

I hope the example of Sartre makes clear the arbitrary or contingent nature of our boundary-setting. Surely the boundaries might change if the facts were to change. What if chemists find amphetamine-like drugs which have few side effects? Can we imagine cosmetic psychopharmacotherapy?

Rogaine, the topical version of minoxidil, is socially and governmentally accepted as a treatment for "vertex androgenetic alopecia," or balding. In dermatology, the line between medical and cosmetic pharmacology is a thin one — and cosmetic pharmacology is not shameful.

If we discover a cure for them, mild social phobias and cognitive limitations may develop equally treatable names; or perhaps we will consider medicating for them even if they are not fully medical disorders.

For years, psychotherapists have been under suspicion of treating the "worried well," or merely "enhancing human potential" or encouraging "self-actualization." . . [W]e all understand the analogy, which is to plastic surgery: the same treatment can be medical or cosmetic depending on the use to which it is put.

. . . I can imagine some strains of the American consensus preferring pharmacologic to psychologic self-actualization. Steroids for mental gymnastics, medicinal attacks on the humors, Anti-Wallflower Compound — these will be hard to resist. Since you live only once, why not do it as a blond? Why not as a peppy blond? . . . whatever the consensus, it is psychiatrists. . . who will be considered best qualified to modify cognition and personality in useful, attractive ways. Cosmetic psychopharmacotherapy: there is a specialty that will bring us respect.

Later in the essay, I turned to the question of unknown side effects, saying that the late news about medications is rarely favorable:

Some day we will know whether Prozac has long-term effects. In the interim we will have more drugs, and it seems to me likely that among them will be ones that can change people in ways they want to be changed — not just away from illness but toward some desirable psychological state. . . The idea of cosmetic psychopharmacology may make us uneasy; but . . . its allure may be hard to resist.

These thoughts were the ones I developed in Listening to Prozac. I asked what our objections might be to a substance that took a person from a normal but socially disadvantaged state to another normal state that was considered more desirable. In particular, I looked at the distinction between competitive and non-competitive situations, ones that resembled the use of steroids in sports (where those who do not want to take medicine may implicitly be coerced to do so) and ones that did not — again using the example of the late work of Sartre.

I hope that this liberty I have taken, quoting my own writing, has helped to define our topic and also to convince those of you who have followed more recent debates that there is little new under the sun. For five years, scholars have discussed “cosmetic neurology.” That literature is disturbingly ahistorical — it echoes yet never references my discussion of cosmetic psychopharmacology. We can think of other interventions — brain surgery, genetic engineering, electric and magnetic stimulation; but in the cosmetic neurology monographs, the imagined enhancement is achieved through medication, indeed, often through the antidepressants, stimulants, and beta-blockers discussed in Listening to Prozac. The relevant ethical concerns center on the issues of competition and implicit coercion raised in my writing. Even the metaphors — the comparisons with plastic surgery and with sports — are similar. “Cosmetic neurology” is “cosmetic psychopharmacology” writ small. The unacknowledged paralleling, in these papers, of cosmetic psychopharmacology, suggests that scientific developments of the past two decades have been less dramatic in their philosophical implications than I had anticipated.

I do not want to give the impression that pharmacology, broadly taken, has made no progress whatsoever. In part because of interest in such conditions as dementia and daytime somnolence, we have seen new medications that heighten or preserve attention and memory. A recent article by Hans Förstl in Nervenarzt provides an extensive list of candidate drugs for cognitive enhancement— again, out of concern over “soft coercion.” But the list of innovative drugs in the area of central concern to me, mood and personality, would be short.

This stasis influenced the choice of subjects in my writing. My interest in cosmetic psychopharmacology concerned the distinction between treatment and enhancement. My impression was that we would move into an era where the use of medication for undiagnosed clients would become more common. I wanted an open discussion of that doctorly function, rather than one obscured by what I called “diagnostic bracket creep.”

But as time passed, I judged that the most extensive changes worthy of a ethicist’s attention were in our understanding of the mood disorders. Major depression was looking more ominous. Neuroscientists were able to associate it with differences in the brain anatomy, particularly in the hippocampus and prefrontal cortex. Those alterations did not look like normal variants but like frank pathology. Elderly patients with small strokes in the same regions suffered depression. Meanwhile, the association of depression with pathology in the heart and blood vessels, blood elements, endocrine glands, and bones, was ever better established; the risk extended down to minor levels of mood disruption. So did the risk of premature death overall. Depression had established itself as an ordinary, if especially debilitating multisystem disease, with consequences over a broad spectrum of severity.

This new perspective on depression moved the boundary of frank disorder, not on the basis of diagnostic bracket creep but via legitimate health concerns. The theoretical considerations remain unchanged, but some of what might once have been judged cosmetic had become mainstream treatment.

Instead of writing a second Listening to Prozac, I wrote about this changed geography of mood disorder, in a book titled Against Depression. I asked how we might embrace the notion of depression-as-disease. Is eradication our goal? Would we want to conquer mood disorder so that no human being need ever suffer depression again? In constructing a thought experiment, I tried to imagine something like the polar opposite of cosmetic psychopharmacology, a preventative for depression that would have the most minimal effect on confidence, optimism, and the like.

To illustrate the concept, I introduced readers to a paradigm of depression that guides much contemporary research, one in which depression arises from stress-induced harm to neurons in relevant parts of the brain. I referenced rodent-model research by the neuroscientist Robert Sapolsky that entails using stress-responsive viruses to alter nerve cell genes so that, when the brain registers indicators of adversity, the neurons manufacture neuroprotectants that prevent cell death. My intention was to evoke an image of “clean” interventions, ones that might eliminate depression without otherwise altering personality.

The beauty of the Sapolsky model lies in the inertness of the intervention. For the most part, the embedded virus does nothing; even when it springs into action, it only affects the final cell in the cascade of neurons that represent mood in the brain; and the benefit that the virus confers is merely that the cell remains unharmed. In Against Depression, I wrote:

In this model, you are who you are most of the time — glum or perky, empathetic or clueless. You may experience unease, anxiety, alienation, and despair. But even after a humiliating loss, your stress switch will not stay stuck in the “on” position. In due course — and before they shrink your hippocampus or disrupt your prefrontal cortex — your stress hormones will abate. They will not take you farther down the road to chronic depression.

This thought experiment allows us to consider protection from depression as distinct from the diminution of ordinary melancholy or neurosis. If we use the model as the basis for discussion, we can create clear distinctions between a campaign to conquer depression through medical means and the effort to sculpt personality via cosmetic pharmacology.

But what if neuroprotection were not so clean? What I would like to do for the rest of our time together is to think about a murkier model of progress. The Sapolsky experiment involves opening the rodent brain and injecting viruses into relevant areas. What if we restrict our interest to pathways to resilience that are practical clinically?

Models of depression often address disruptions to chemical factors that protect neurons, allow for the growth of new neurons, and encourage the establishment of new connections between neurons. Chief among these substances in terms of research interest is brain-derived neurotrophic factor, or BDNF.

To simplify a complex argument: depression seems to be a state in which nerve cell growth and connectivity in the brain are diminished. Standard treatments like antidepressants, lithium, and electroconvulsive therapy help restore these capacities. (Speculatively, psychotherapy may as well.) In animal experiments where the chemical interventions are tried but new cell growth is blocked, medications lose their effects. BDNF appears to be one of the critical factors in these processes. Where BDNF is plentiful, stress is less harmful, and recovery is more robust. Problems with BDNF production or utilization have been associated with a host of diseases from depression to schizophrenia, obsessive-compulsive disorder, eating disorders, and dementias

Here I want to step back and say that I am not concerned with BDNF as it is in the world, which is to say in our brains. Although I will continue to refer to actual findings regarding this neuroprotectant, I want to use BDNF here as I used Prozac in my book when discussing cosmetic psychopharmacology. I said there that “even if Prozac were shown to cause one or another serious physical illness, that reality would have little to say about this other question: How is it that taking a capsule for depression can so alter a person's sense of self?” Similarly, I do not finally want to become stuck on the particulars of any specific neurotrophic factor. BDNF may turn out to be of less importance and manipulating it of less benefit than we imagine, and still a quasi-imaginary BDNF may be a useful way in to a discussion of the theoretical consequences of resilience as an ideal.

Let me begin with a curious correlation. Lithium salts, which are used to treat mood disorders, also occur naturally in ground water. Over twenty years ago, studies in Texas found that communities with high levels of lithium in the tap water had low levels of suicide and violent crime. A recent study explored a similar finding in the Oita prefecture in Japan. Looking at 18 municipalities, communities with more lithium in the drinking water had lower levels of suicide. The maximum lithium levels in the water in the Japanese study were less than half the maximum levels in the Texas study. This result is sufficiently promising that an editorialist in the British Journal of Psychiatry suggested cautious movement toward evaluating the utility of adding lithium to drinking water, as a public health measure.

Given therapeutically in the treatment of bipolar disorder, lithium helps prevent suicides. But the levels of lithium in the bloodstream of patients treated for mood disorder are fifty or a hundred times greater than the levels of lithium in the tap water of the regions studied in Texas and Oita; a reasonable guess is that a resident of a high-lithium town would be ingesting one thousandth of a therapeutic dose of lithium daily. The mechanism of action of minute doses of lithium is unknown, but on his list of possibilities the BJP commentator included effects on neurotrophic factors.

For our thought experiment, let us adopt this hypothesis. Assume that low levels of lithium in the water supply, such as occasionally occur in nature, augment the activity of neurotrophic factors and further assume that this augmentation improves resilience in the brain. The public health benefits I have in mind include a decrease in the expression of psychiatric and neurological disease and also a slowing of the normal dementia of old age. Real BDNF may be associated with an increase in scratching in childhood eczema and an increase in seizures in temporal lobe epilepsy, so that researchers I have proposed searching for treatments that “interfere with the actions of BDNF.” (Epil. Curr) But for the purposes of our thought experiment, it may be well to imagine that the negative medical effects of BDNF augmentation are so minor as to constitute no impediment to any pro-resilience project we might consider. The question then becomes, ought we to add lithium to the water supply, as communities in the United States (but not Germany) now add fluoride to prevent tooth decay — or rather, what ought we to consider as we make our decision?

To enrich our picture, let us add details from various studies, some controversial, few validated through replication, concerning BDNF. Animal research shows that aberrantly low levels of BDNF lead to problems in serotonergic transmission, defects that can be alleviated either through the administration of antidepressants or through the infusion of BDNF into a relevant part of the brain. That is to say, we can think of BDNF as something like an endogenous Prozac.

Apropos, in 2003, a group including the evolutionary psychiatrist Randolph Nesse, looked at the relationship between personality traits and alleles of genes that influence BDNF usage in the brain. One allele, call it the favored variant, was predicted to produce “higher activity or more efficient processing of BDNF.” The researchers found that the favored allele was associated with lower — and a disfavored allele with higher — neuroticism. Neuroticism is a measure of negative emotionality that we might link loosely to melancholy or neurosis. The particular aspects of neuroticism that showed through in the study were depression, self-consciousness, anxiety, vulnerability, and openness. This cluster is close to the one I worry over in Listening to Prozac — the disfavored traits that a societal adoption of mood brighteners might push aside.

There are probably many ways to elevate BDNF production. A recent animal study involved vaccination with a central nervous system-related peptide. Normal rats were injected with the peptide. In rats not exposed to stress, the immunization had no effect. But in the face of stress, the immunization conferred both behavioral and neurologic protection. Starting one week after the immunization with the protein or a placebo, groups of rats were subjected to a month of chronic mild stress consisting of such challenges as cage-tilting, water deprivation, and intrusive lights and sounds. The placebo-injected rats developed a depressive-like syndrome — seeking food less avidly and giving up more quickly on a swim test. The rats vaccinated with the peptide looked like the unstressed rats. The vaccinated rats also had higher brain levels of BDNF and more new cell formation in the hippocampus.

Here, then, is the conceptual problem, the thought experiment I have been constructing: let us imagine that we can induce resilience, preventing a host of diseases and perhaps also inducing cognitive robustness: better learning capacities, better memory, and the like. The price, or let us say, the secondary effect, is a change in the array of temperaments within the population. Is the bargain one we will accept?

On the individual level, I posed a similar question in Listening to Prozac. Discussing a patient who in treatment recovered from compulsive hair-pulling and also found herself less self-destructive socially, I wrote that in certain circumstances mood-brightening might resemble a side effect, “one about which an ethically punctilious clinician might warn: We can diminish your hair pulling, but I must warn you, you may feel more contented.” What is at issue, I suggested, is transformation of the person.

On the societal level, this possibility, transformation as side effect, is eerier. And yet in the consideration of neuroresilience, were that health benefit possible, these personality issues would be incidental to the discussion. In effect, if we could provide or obtain it, likely we might favor neuroprotection — say, via widespread vaccination or the addition of simple salts to the water supply at a level that occurs in nature — and then, in judging whether to enact this public health measure, we would ask about side effects.

For a moment, let us imagine that we discover, to our surprise, that our resilience inducer acts in the opposite direction from the one attributed to lithium, so that the incidental effect is to make water drinkers irritable, impulsive, and violent. Well, then the decision would be simple. We would hold off and undertake further research in hopes of getting the benefit without the cost. At least, that is my guess.

But what about a loss of neuroticism? That bargain is one we might well take. Indeed, the mere association of vulnerability and neuroticism, of mental decline and negative emotionality, would make the personality trait seem like pathology. To be resilient, in one use of the term, is to be free of melancholy, neurosis, and the rest, along with the tendency toward mood disorder.

That is to say, we can imagine a tropism toward a constrained and conventional, mainstream and boring view of mental wellness. Preventive and health-giving measures with no side effects would be instituted, but so would ones linked to the reinforcement of valued or tolerated personality states. I am thinking of a Darwinian selection that, as between effective forms of prophylaxis, favors those interventions that induce socially valued temperaments over any that induce less conventionally undesirable traits. This line of reasoning contains a host of assumptions, among them that medications that protect the brain might also nudge personality in one or another direction. But that belief conforms to evidence in the model we have been examining, BDNF as an exemplary neuroprotectant.

This case seems to mark a new point on our spectrum of ethical dilemmas. At one extreme we have cosmetic psychopharmacology, the use of medicine to tweak personality, in the absence of mental illness; here, the intent is movement in direction of traits that are culturally favored or rewarded. At the other, we have straightforward treatment of disease, governed by standard criteria of risk and benefit. Treatment may not be entirely free of a favoritism, tolerating some side effects more than others. But then treatment is directed toward people in grave need, including those whose personalities have, in a sense, failed them. And treatment does allow for a variety of outcomes. We can imagine administering a medication or psychotherapy leaves a patient more irritable, when the alterative (depression or delusions, say) is worse.

In the middle we have the resilience example. Its goal is medical, the prevention of disease and deterioration. Any comparison with cosmetic surgery would be inapt; the intent is not to reshape personality. Still, the push is likely to be all in one direction. Perhaps a proper term for this result is [inadvertent, incremental, or] “incidental enhancement.” The sort of result I have in mind, in what is admittedly a science fiction scenario, is a subtle shift in the spectrum of temperament-related traits, but for a broad population. And although the personality shaping is more or less unintended, it of the sort we worry over, toward conformity and uniformity.
Does this prospect resemble the one that the philospher-novelist Walker Percy warned against in The Thanatos Syndrome? Percy imagined the introduction of a substance he called Heavy Sodium into the water, causing housebound Emily Dickinsons to become bold and unselfconscious. A principal difference is that Percy’s fantasy concerns social engineering. In our thought experiment, personality change is a more or less unexamined consequence of a societal investment in health in its ordinary sense — so that a straitening of the temperaments is merely a price we pay for such legitimate goals as the prevention of mental illness, memory loss, and other forms of neurological and psychiatric deterioration.

That’s where my thinking stands twenty years after the introduction of Prozac. We have, I fear, few novel medications. But we have new science. Its findings point in two directions. One is toward a legitimate expansion in the domain of disease. The other is toward legitimate concern about unintended forms of social control — impingements on diversity that I want to set beside cosmetic psychopharmacology. Of course, “incidental enhancement” is most truly incidental when it is unexamined. Sometimes, to name a category is to destroy it, through the creation of awareness.

But is awareness sufficient protection in the face of the American, and even the Western, mania for health? When the resilience of brain cells is at issue, other considerations may fade. Given the chance to protect mind and brain, and understanding “incidental enhancement” as insidious, we may instead permit a disturbing form of diagnostic bracket creep in which traits such as neuroticism are understood as markers of vulnerability and thus labeled as defect.


Thursday, March 6, 2008

Unreliable Narrative: The Aesthetics of Depression

[This presentation was delivered at the Center for Cultural Analysis of Rutgers University, March 5, 2008, as an introduction to a dialogue with Dr. Jerome C. Wakefield]

With sincere humility—and not only in the spirit of the political season—I want to say what an honor it is to be on the platform with Dr. Jerome Wakefield before this audience. Dr. Wakefield is an original thinker and a distinguished scholar. He has advanced a complex theoretical position regarding diagnosis, one I reference respectfully in my work. I want to remind you that, in contrast, I am what we at Brown call a clinical, by which we mean an ersatz, professor of psychiatry. I am not a researcher. What theoretical contributions I make are, more often than not, presented in popular writing for general audiences.

Still, I gather that we are to have a debate.

I am to take the position at the core of my book, Against Depression, that depression is a disease. I am to say that the seriousness of depression is often underestimated and that depression can be falsely romanticized.

Dr. Wakefield is to take a contrasting view, that depression is over-diagnosed and that the signal cultural threat comes from subsuming adaptively useful sadness into the category of disorder.

I want to begin by saying that from my own perspective, I have already conducted this debate.

In Listening to Prozac, which I wrote in the early 1990s, I expressed concern over the potential for what I called “cosmetic psychopharmacology,” the use of medications to take a person from a normal but socially disfavored state to an equally normal state that is better valued or rewarded. I worried that cosmesis might take place covertly, through what I called “diagnostic bracket creep,” the expansion of categories of illness to embrace available treatments. In particular, I feared that as a culture we would lose our taste for melancholy.

Against Depression
, from 2005, can be seen as my attempt to delimit that concern—to outline the domain of non-cosmetic, legitimately medical psychotherapy and psychopharmacology. In that book, I spend time exposing shortcomings of our current diagnostic system. I find it flawed. Still, with demurrers, I locate the boundary around depression more or less where my profession, psychiatry does.

To the extent that there is matter for debate, then, Dr. Wakefield will be arguing that psychiatry has drawn that line incorrectly.

So Dr. Wakefield and I share an interest in this matter of domains. We both recognize an entity, depression; we both value the preservation of the ordinary as ordinary and take distinctions between health and illness to be culturally important. In fact—based on my reading of Dr. Wakefield’s book, The Loss of Sadness, along with the monograph that seems to form the statistical justification for the book, his reanalysis of data from the National Cormorbidty Survey or NCS—I have the impression that Dr. Wakefield and I agree on a number of points.
Let me list some points of agreement, in the manner of legal stipulations that need not later be at issue.

We agree that depression is a disorder, and a grievous one.

We agree that this disorder is imperfectly captured by current diagnostic systems. There are problems of validity although, to be fair, we don’t know as much as we might about the underlying entity, the platonic ideal of depression.

We agree that the Diagnostic and Statistical Manual, or DSM, can be misleading in the individual case, especially when symptoms are of short duration or mild severity.

We agree that most sadness is not depression, though here I would add a point that Dr. Wakefield downplays, that you can have substantial depression without sadness.

Like Dr. Wakefield, I am open to the possibility that certain epidemiologic studies may overstate the prevalence of depression.

Certainly we agree that medications used to treat depression have a wide range of indications and that they may also mitigate symptoms in people who have no specified disorder; Dr. Wakefield quotes me to this effect.

We agree that pathologizing normality has a price. We also agree that there are cases where a doctor might reasonably prescribe and a patient take medication, or recommend and participate in psychotherapy, in the absence of a diagnosis, and that even in these cases, clarity about categories is a matter of good faith.

We mistrust Big Pharma; I write about that mistrust frequently, though that part of my work tends to be overlooked.

I apologize for taking to much time on this matter of agreement. Again, there may be something in the air. But I hope that this introduction will minimize later occurrences of the straw man problem, which I encounter now and then. I want to sharpen the subsequent discussion about points of disagreement.

Because we are to debate, I will need to set aside most of what I write about in Against Depression. I hope you will read that book. In it, I say that I had hoped, after a decent interval, to return to the question of psychotherapeutic medications and the ethical dilemmas they generate. But twelve years after the publication of Listening to Prozac, what had changed was not the pharmacopoeia but doctors’ knowledge about mood disorders. Depression’s standing as a disease had been solidified. I wanted to trace the consequences of that new understanding—to see how the culture had been affected by our past inability to treat depression and to imagine how a society might be changed by a decision not to romanticize depression but to accept it simply as a disease, and an ordinary one, like diabetes or cancer. I write about Van Gogh and Picasso and Bonnard—trying to trace the origins and consequences of depression as a marker of creativity and emotional refinement.

As I say, I will set that line of thought aside, as it overlaps so little with Dr. Wakefield’s concerns. In order to engage him, I will need to discuss his ideas more than my own. To begin the debate:

I assume that you know what depression is. It is a common affliction characterized by extended hopelessness, mental paralysis, emotional pain, low self-regard, and a loss of interest in the future, along with the features the standard diagnostic manual recognizes, problems with memory and cognition, disruption of sleep and appetite, loss of energy, excessive guilt, and suicidality. If you have suffered this disorder, or if someone you care for has, you will know how painful, how overwhelming, how debilitating it can be.

In one guise or another, depression has been understood as a disease for as long as there has been writing about disease; alternative viewpoints have an equally distinguished lineage.

DSM says that if you have five signal symptoms, including low mood or anhedonia, for two weeks and if they are of sufficient severity, then you are depressed. Here is how the manual defines the necessary level of impact: “The symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.”

As I point out in Against Depression, this mechanical diagnosis is more prognostic than descriptive. I write: “In twenty years of practice, I have never seen a new patient who complains of just two weeks of moderate depressive symptoms. If such a patient were to consult me, I might tread water—extend the period of evaluation. If the despair lifted, my thought might be that the episode was self-limiting. More likely, I would tell myself,
He was never really depressed.” But the diagnosis has predictive validity. If you have two weeks of the syndrome, you will likely go on to many months and then the career of recurrent depression.

This flawed working definition has been revolutionary for research.

It has defined a sufficiently homogeneous group to allow scientists to identify marked differences associated with or inherent to depression: differences in the brain (most recently the focus has been on the hippocampus and prefrontal cortex), and in the hormonal, circulatory, and skeletal systems, and elsewhere.

The definition has allowed for public health research that finds excess death across the life cycle, much of it from cardiac disease.

The definition has allowed for social scientific inquiries showing associations between depression and under-education, underemployment, and poor social supports.

And it has led to thought-provoking findings in genetics, including some we may discuss here, regarding the so-called “Woody Allen gene.” Early in life, this gene, for a serotonin transporter, seems to modulate the effect of stress on mood disorder. Young people with the protective version of the gene, even if they are otherwise prone to depression, will remain very largely immune to adversity; they may get “uncaused” but not “caused” depression.

Dr. Wakefield disputes whether this scientific progress is as substantial as I suppose or as probative regarding diagnosis. He challenges the method of diagnosis as containing a category error. He thinks that when the relevant syndrome is not severe and when it arises from a clear cause, it should be deemed mere sadness. Here, he points to the example of bereavement.

I have so far given an incomplete account of the
DSM algorithm. You are not diagnosed depressed if your cluster of symptoms arises from your response to the death of a loved one . . . unless your condition includes suicidality, morbid preoccupations with worthlessness, marked functional impairment, frank psychosis, or a type of general mind-and-body slowing called psychomotor retardation—or unless the standard syndrome lingers for two months.

The exception is narrow: between two and eight weeks, if you are bereaved, symptoms causing clinically significant impairment but not marked impairment do not qualify for a diagnosis.

Dr. Wakefield asks, why only the loss of a loved one? Why not the loss of a job or a marriage? Unless the syndrome is severe, aren’t we better off also calling those “caused” brief depressions ordinary sadness? Aren’t we robbing the culture of sadness when, regarding a person who has reason to be distressed, we call a month of anhedonia and loss of mental acuity and the rest depression?

I am sympathetic with this concern. But we should begin by saying that in operational terms it is limited. How often do doctors treat caused, moderate depressions? Rarely, I should think. We will need to know whether the new sort of definition improves on the sort that has proved useful over decades. And we will want to ask how this change looks in historical context.

Let's begin at the height of Freudianism, at mid-century. Freud's followers believed that virtually all psychological symptoms were caused.

Freud wrote about melancholia, which corresponds to the serious end of the depressive spectrum. He discerned psychological causation, related to loss of an “ambivalently held object”—a loved one (and secretly a hated one) who aroused strong mixed feelings. Meanwhile, neurotic depression was a bread-and-butter target of analysis. Personally, Freud was sophisticated about biological underpinnings for a variety of conditions. But it would overstate the case only slightly to say that fifty or sixty years back, in American psychiatry, which was dominated by psychoanalysis, there were no uncaused depressions, only insufficiently curious patients and doctors.

Of course, in analytic theory, which held sway for most of the twentieth century, the cause of a depression might extend back past the current adversity; that stressor might stand in for a prior loss which itself echoes inner conflict over unacceptable impulses from infancy. But for psychoanalysis, spontaneous mental affliction was something like an oxymoron, suggesting an error in epistemology. So it is not at all clear that it is culturally intuitive for depression to be uncaused.

In contrast, today's highly biological psychiatry is fond of multiplying etiologies , or categories of causes, for depression. Small, otherwise inapparent strokes, medications like interferon, hormonal shifts or deficits, and a variety of psychic stressors, not all related to loss, can trigger mood disorders. The most common variety, what I would call wear-and-tear depression, seems related to genetic liability, early life trauma, and then later adversity. Behavioral genetics, and here I am thinking particularly of the work of my friend Ken Kendler, has traced the course of this chronic, recurring and relapsing condition. Generally, early episodes of depression have identifiable social or psychological triggers. As the disease progresses, later episodes are likelier to be spontaneous. Otherwise, in a life history of depression, caused and uncaused episodes generally proceed or alternate without evident pattern. A mixture of major and minor episodes is common.

The data are not perfect, but depressions, whether from stroke or interferon or wear and tear, look similar. The same parts of the brain are implicated. The same social supports afford protection. The same treatments avail. The notion that uncaused episodes are pathognomonic, or characteristic, runs counter to the model.

The opposition of caused and uncaused is closest to the theories that arose in an intermediate period, as psychoanalysis was losing ground to medical models. Researchers—Dr. Wakefield says as much in his book—repeatedly but unsuccessfully tried to define and sustain a distinction between caused and uncaused depressions. Initially, they hoped that caused or neurotic depressions would prove to be psychological and best treated with psychotherapy while the uncaused or genetic episodes would respond to drugs. No such distinction held up. Ten years ago, the great mind in this field, George Winokur, wrote a valedictory paper titled, “All Roads Lead to Depression: Clinically Homogeneous, Etiologically Heterogeneous.” Winokur did not quite throw in the towel, but he had come to believe that the commonalities among depressions, once under way, were more important than the differences.

Repeatedly, depression has revealed itself as depression, with (almost) the only differentiator being severity of symptoms.

The symptom-based unitary diagnosis is in part a response to the failure of attempts to subdivide the depressions. I should add that biological psychiatrists, like psychoanalysts, understand that stressors are not uniform, that the death of an older relative after a debilitating illness might—or might not—differ from the unexpected death of a vital, young family member. Given the poor relationship between category and meaning it is remarkable that surveys, which form the basis for diagnostics and genetics, do as well as they do in advancing our understanding of disease.

All researchers recognize that the current criteria are flawed. They represent a compromise of convenience, not a means of carving nature at the joints. But the direction of the error remains unclear. Patients with only four symptoms (or only 10 days of symptoms, or symptoms of mild severity) may suffer substantially, function poorly, and go on to quite bad outcomes. Meanwhile, groups of depressed patients who say they have suicidal thoughts have only slightly worse outcomes than those without. Research that attempts to bound depression sharply generally ends in finding it seamless.

So: Our diagnostic system is inexact. It is not clear whether it is over- or under-inclusive. Cause has been an inherent element in mood disorder for decades. All the same, past research failures and current theories suggest that setting aside caused depressions will not create a cleaner version of the disorder.

Nor, I think, would Dr. Wakefield’s reformulation impact clinical practice. I have referred to my acknowledgment in Against Depression that I don't rush to treat brief, moderate depression. My colleagues, including general practicioners, have the same leanings. Evidence comes from Dr. Wakefield’s own work, his reanalysis of the NCS data.

There, Dr. Wakefield took the bereavement exclusion and extended it to other losses, removing from the category of depression episodes that were set off by, say, a divorce, and were not characterized by markers of severity like morbid preoccupations. Here, I am turning to the principal piece of evidence that Dr. Wakefield brings to bear in his critique of the current method for defining depression. Since his analysis of the data is so important, I want to spend a few minutes with it. I hope you will excuse me if what follows sounds technical; I think it gets to the crux of the problem before us.

What happens to the patients, with early, milder, caused syndromes, the ones that Dr. Wakefield says are misdiagnosed if we call them depressed? In the NCS, fewer than five per cent of people with uncomplicated triggered depressions had
ever in their lifetime taken a medication to treat depression. These patients were about thirty-four years old and had gone through an average of about three of these episodes. So: sixteen years of adulthood, recurrent symptoms in response to stress, and almost no prescriptions.

A reasonable estimate—I can say later how I arrived at it—is that five per cent of American adults took an antidepressant in 1992. So the
one-year rate for Americans in 1992 may well have been the same as the sixteen-year rate for the interviewees Dr. Wakefield picked out. And it is not all clear that the syndromes he identified were uncomplicated, according the bereavement criterion; Dr. Wakefield’s analysis shows that these “uncaused,” uncomplicated depressions lasted not two but five months on average.

Annual probabilities compound. Think about it: if the independent probability of getting an antidepressant in a given year were only one per cent, the odds of receiving one ever in sixteen years is almost fifteen per cent. Dr. Wakefield seems to have identified a group of Americans almost uniquely shielded from exposure to antidepressants. Doctors just do not prescribe for people who respond to adversity with mild depressive symptoms.

There may be another reason that doctors did not prescribe for certain patients labeled depressed in the NCS: the patients were
not depressed, not even under the DSM system. You will recall that symptoms are not enough to qualify a person for a diagnosis; those symptoms must cause moderate impairment. For reasons we can discuss later, the original NCS analysis did not include the severity criterion. That’s right—a good percentage of the people counted as depressed in the NCS did not qualify for the ordinary diagnosis of depression. And the problem was a failure to ask about the factor that comes closest to Dr. Wakefield’s own criterion for disorder: harmful dysfunction.

How many subjects were mistakenly counted as depressed? Darrel Regier reran the data using proxies for the severity criterion and found an over-diagnosis of 20 per cent, roughly the same percentage Dr. Wakefield reports. (Dr. Wakefield's monograph brackets the over-diagnosis between fifteen and 25 per cent.) The groups newly excluded in the two reanalyses may contain the very same people. In Dr. Wakefield’s version , only twelve per cent of subjects in the “uncomplicated loss-triggered” category said that their episodes interfered with life a lot. So Dr. Regier, using the
DSM, and Dr. Wakefield, using the loss exclusion, make the same cuts, for different reasons. Again: of the subjects Dr. Wakefield focuses on, the ones he calls merely sad, 88 per cent would have been diagnosed by DSM, properly applied, as not depressed. It’s not clear that Dr. Wakefield has found any over-diagnosis, relative to the current diagnostic algorithm. Nothing in the NCS data, nothing in Dr. Wakefield’s application to that data of his narrower definition of depression, suggests that we are losing sadness.

One further point about the NCS data. Almost all the subjects interviewed mentioned some cause in association with their syndrome. If you look at those who were diagnosed depressed, fewer than ten per cent either named no cause or failed to answer the survey question. Depression most often is associated with some change in a person’s life. (Parenthetically, we don’t know that people are always right about the direction of causation; in another of my books, Should You Leave?, I suggest that depression causes divorce as often as the reverse—though people tend to recall events as causing mood change.) Casting suspicion on caused depressions risks removing from the disease category the vast majority of those patients who go on to heart and blood vessel disease, recurrent mood disorder, and the other serious consequences. Dr. Wakefield’s proposal may look incremental, but it is radical. For the most part, causation—certainly, the immediate trigger—is characteristic of depression and always has been.

So much for practice. Let’s spend a minute on
theory by looking further at the bereavement exception. It has two justifications and an explanation.

The explanation is political. It’s simply hard to tell the public why grief should sometimes be considered depression. But many serious researchers make that grouping. In behavioral genetics, where it is critical to distinguish subtle signals from loud noise, researchers tend not to exclude bereavement. If stress triggers depression, the result is counted as depression. The character of the stress is irrelevant. There is some external justification for this choice. Grossly, bereavement looks like depression in some of its consequences. A recent overview in the
Lancet found that loss of a loved one causes startling increases cardiac death and suicide. Like the symptoms of depression, those of bereavement respond to psychotherapy and antidepressants. Some bereavement is depression.

The opposing case, that bereavement is exceptional, is twofold. The death of a spouse or child is a stronger, more disruptive stressor than others we recognize. And grief differs from depression: grief is at once more various and more particular. Bereavement can look like an anxiety disorder (or even psychosis) rather than depression, or the syndromes can be mixed. And the depressive symptoms of bereavement have their own cast. The grieving tend not to have psychomotor retardation—that’s why that consideration enters into the standard manual. They tend to ruminate over sins of omission, not commission. They cry more than the depressed. As I have said, depression is not really like sadness. It’s more an oppressive flattening of feeling.

But when bereavement looks just like depression, it contains much of the risk of depression.

The choice might be impractical clinically, in terms of the distinctions that would need to be specified, but in scientific terms, it might make more sense to lift the bereavement exclusion than to extend it to other stressors. Parenthetically, in Dr. Wakefield’s data, when you compare uncomplicated depression to uncomplicated bereavement, many more bereaved people receive medication. Partly, that’s because bereaved people can be depressed; partly, it’s because medication use is a poor marker for depression.

I hope I have been responsive to the notion of debate by turning immediately to these issues of interest to Dr. Wakefield. They are less important to me. If we all agreed that depression is a grievous disease, but that if relatively mild it should not be diagnosed until day 56, so long as we did that well—so long as we followed the early, milder cases attentively, monitoring the patients for any deterioration—that change might not disturb me. More to the point, it might strike a prudent public health policy maker as a reasonable alternative to applying a more expansive standard haphazardly. But here we are discussing pragmatism, not science or theory. There is no scientific or theoretical reason for demanding a more stringent set of criteria for caused than for uncaused depressive episodes.

I want to end by expressing concern over less technical issues—Dr. Wakefield’s repeated use in his book of the terms loss and sadness. For instance, he begins by saying, “By depressive disorders, we mean sadness that is caused by a harmful dysfunction of loss response mechanisms.”

Bereavement entails loss. But loss is a narrow word for stress or adversity. Depression has any number of social and psychological triggers—consider spousal abuse. In what is probably the most respected research in the behavioral genetics of depression, the following stressors were found to be influential: being robbed or assaulted, facing housing or financial problems, losing a job or encountering serious work problems, encountering major marital problems or undergoing divorce or separation, losing a close confidant, and encountering illness or death or a grave crisis in the life of a child, parent, or sibling, or entering into substantial interpersonal conflict with one of those relatives. Some of these misfortunes are losses, some are not. The following sequence is common in depression: pressures at the workplace trigger depression, which leads to job loss. Isn’t stress the operative factor here?

Caused depressions need not resemble grief. Dr. Wakefield uses a bereavement metaphor to gain sympathy for his view that caused episodes are not depression, but that metaphor ignores the best-developed model of the disease. Depression looks much more like a global decompensation of mind and brain in the face of recurrent adversity, whether or not the adversity resembles loss.

And depression and sadness are only vaguely linked. Consider the form of depression called pseudodementia, where patients appear to have the cognitive impairment of late-stage Parkinsonism but respond to antidepressants; these patients turn out to have personal and family histories of depression. Depression is not about sadness, it is about a disruption of a number of functions of brain and mind, resulting in apathy, hopelessness, and mental anguish.

Dr. Wakefield makes this distinction in his monograph (“We use the term ‘sadness’ as a generic label for normal and abnormal depressive responses to various losses”), but it does not inform the line of thought in his book. Caused depressions need not arise from loss; and sadness need not be the signal feature of depression. Why frame a discussion about depression in terms of loss and sadness? Dr. Wakefield is making a cultural point at the expense of medical accuracy; surely we would worry less about
The Loss of Apathy.

Here is where I will explain my talk’s title.

It seems to me that one of our cultural tropes, a way of expressing humanism and sophistication, is to say that we Americans scant or squelch true emotion, we look for the quick fix, we have, as a hypercapitalist culture, a systematic investment in inauthentic happiness.

I don’t entirely disagree with this position. My favorite among my own books is my novel, Spectacular Happiness. It takes its title from The Society of the Spectacle, a radical critique that applies Marxist and anarchist theory to cultures in which celebrity has supplemented wealth as a social good.

But I take exception to critiques that embody this tendency—blind meliorism—in our treatment of depression. The target is too easy, the metaphors are too automatic. And too often the evidence is lacking.

In the many books that make the same point—that our culture fears pain and overvalues happiness —the authors demand a much higher level of certainty for medical than for social scientific truth. They seem simply to
know that doctors prescribe thoughtlessly and promiscuously. They seem simply to know that Americans are heedlessly self-indulgent and that antidepressant use is a cause and effect of that defect. The position of these critics of medical psychiatry—and here I am pointing not at Dr. Wakefield but at many others—is frankly smug and superior. Patients' lives are at stake. There is room for both perspectives: If the culture is sometimes superficial, still, one of its strengths is the increasing attention to and destigmatization of depression as an ordinary disease.

Yes, we should be more contemplative. Yes, our fate is characterized by absurdity. Yes, the melancholic perspective has its appeal. But we need to separate that series of contentions from this other debate over the proper diagnosis and treatment of medical conditions. In that domain, we might acknowledge that we are making reasonable, though always frustratingly slow, progress against the particular disease depression, not least through our willingness to see depression even in cases where the provocation for particular episodes is apparent.

[A note on the text: When discussing my own writing, generally I speak ex tempore or from brief notes. Because at this meeting I was critiquing a colleague’s work, and because I wanted to cover a broad territory compactly, I wrote out the whole of my remarks. When delivering them, I revised on the fly, suppressing certain sentences and adding others. From memory, I have inserted some of the ad libbed thoughts here. During the question period, it became clear that a couple of points remained unclear to the audience. I have taken phrases from one or two of my answers and stitched them in as well. But for the most part, the talk as represented here can be thought of as the “advance text” of a delivered speech.]