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.