The New Normal: How the definition of disease impacts enhancement

We’ve all been there. It’s exam week of your junior year of college
with two papers due the day after a final. You’re a new faculty member with a
semester of lectures to prepare and a lab to get started. You’re a tax
accountant and it’s early April. There is simply too much to do and not enough
hours in the day to get it all done while sleeping enough to keep your brain
working like you need it to. In that situation, where do you stand on cognitive
enhancement drugs? Most of us wouldn’t hesitate to grab a cup of coffee but
what about a caffeine pill, or a friend’s Adderall? Many discussions about
cognitive enhancement eventually come down to this question: where do we draw
the line? Currently most of the cognitive enhancers that create unease for
ethicists and the general public alike are prescription drugs that were
originally meant to treat conditions recognized as out of the realm of “normal”
such as diseases or deficits. Therefore, a key step in deciding where we should
stand on the acceptability of cognitive enhancement is to determine what is
normal and what needs to be medically treated. I’ll argue that one reason there
is so much gray area in the enhancement debate is that delineating normal from
diseased – particularly in the brain – is hardly a black-and-white matter.



Why does the definition of disease matter?
Enhancement is typically defined relative to normal abilities. Anjan Chatterjee of the
University of Pennsylvania suggested that “Therapy is treating disease, whereas
enhancement is improving “normal” abilities. Most people would probably agree
that therapy is desirable. By contrast, enhancing normal abilities gives pause
to many.”¹ However, many neuroethicists have wrestled with clearly
defining enhancement^2,3. The director of Emory’s Center for Ethics, Paul Root Wolpe argued
(2002) that the enhancement debate centers on the ability of substances or
therapeutics to directly affect the
brain in ways that are not necessary to restore health and, certainly, to date
the cognitive enhancement debate has focused primarily on pharmaceuticals, many
of which are approved to treat disorders but can have effects on healthy
individuals as well. Perhaps the best examples of this are methylphenidate
(Ritalin) and modafinil
(Provigil) which are prescribed for attention deficit hyperactivity disorder
(ADHD) and narcolepsy respectively, but are increasingly being used by students
and professionals to boost cognitive performance at school and in the workplace^3-5.

From nytimes.com

Although drugs such as methylphenidate and
modafinil do not directly increase IQ, this measure of “intelligence”, albeit
somewhat controversial⁶, provides another useful
example of the distinction between treatment and enhancement. IQ is scored
relative to the median performance on a given test, set at 100. This means that
because IQ is normally distributed throughout the population, every 15 points
above or below that mark represents one standard deviation. Therefore 95% of
the population should fall within two standard deviations of the mean and score
between 70 and 130. Intellectual disability is defined by a score that is far
to the left on the bell-shaped distribution and, by these standards, it would
be impossible for a large fraction of the population to fall into this category
because the median would then shift[a]. Enhancement,
in terms of IQ, would be a potential improvement within the typical IQ range or
above it. As ethicist and philosopher Julian Savulescu points out, increasing an individual’s IQ from 60-70 would be
considered treatment for a disease but making the same jump from 70-80 is
enhancement since the initial score is already within the normal range².
This is not simply a matter of semantics because, while no currently available
drugs can boost IQ like this, they are frequently being used for other, perhaps
more tangible, cognitive effects. A poll in Nature
found that more than 1 in 5 respondents under the age of 35 have used drugs
explicitly for cognitive enhancement⁷ and
experts expect these numbers to continue to climb^4,8.




In a competitive
setting such as a large undergraduate class that is graded on a “curve”, a
student’s grade is dependent not just on her performance but on how it ranks
among her classmates. Therefore using a so-called study drug without a medical
need could be considered cheating and, if it is a prescription drug it would be
illegal. In fact, Duke University’s student ethics
guide explicitly labels “the unauthorized use of prescription medication
to enhance academic performance” as cheating. Therefore, in some cases patients
have an incentive to define themselves as diseased and a natural way to
circumvent issues of legality and social acceptability is to obtain a
prescription. While it is not known exactly how common this approach is, diagnosis
for ADHD has increased dramatically in recent years. One study found that
outpatient treatment for ADHD increased roughly four-fold in a large cohort
from 1987-1997 ⁹ and
another, more recent study from the CDC, found a nationwide 42% increase in
ADHD diagnosis from 2003 to 2011¹⁰. There
are many reasons for this increase, which likely include a better understanding of
the disorder but, as some have
point out, this increase coincides with policy changes that allow individuals
with intellectual disabilities to be tutored and granted extra time on exams.
These benefits, in addition to the increasingly common knowledge that ADHD
medications can improve concentration even in healthy users, may make it seem
like there is no downside to a diagnosis and might in turn incentivize parents
and students to seek out physicians willing to write prescriptions without
rigorous examinations. In addition, physicians have the ability to prescribe
drugs off-label (in ways not explicitly approved by regulatory agencies) and do
so commonly. A prime example of this practice is modafinil, a drug that is
approved in the US for sleep disorders such as narcolepsy but was found to be
prescribed for off-label indications nearly 90% of the time from 2002-2009⁵.




Disease may not just be defined by physicians,
or demand from patients, but also on the supply side by drug makers themselves
who readily take advantage of the opportunity for direct to consumer marketing in the
US (New Zealand is the only other developed country that allows this practice).
Indeed, a drug has little value to any company unless there is a market for it
and one approach is to convince the public that a common nuisance or
frustration (think shyness) is actually a disease (e.g. social phobia). Wolpe
(2002) noted that, “what medicine chooses to treat is defined as disease, while
altering what it does not treat is enhancement” however I think the inverse is
also true, that whatever positive effects medicines have in the absence of a known
deficit could also be considered enhancement. Pharmaceutical companies have
been branding
diseases (or some say disease
mongering) for decades with the hope that changing the definition of normal and
diseased can broaden the market for their stable of drugs under patent. A
recent overt example of this practice is the ubiquitous marketing of
testosterone supplements to remedy “low T” 
(hypogonadism), a disorder that was once thought be a rare condition but is now
suggested to afflict most middle-aged men (if the ads are to
be believed). Unfortunately, unnecessarily manipulating this hormone can have
serious life-long health consequences, some of which the FDA is now investigating

Wolinsky, 2005

By contrast, an area where the definition of
disease may be less important is in age-related cognitive decline. How much
mental ability needs to be lost in elderly individuals before the line is
crossed into cognitive impairment and who gets to make that decision? If drug safety
could reasonably be established then perhaps adults at that stage in life
should be able to choose to use cognitive enhancers whether or not their
deficits reach clinical thresholds. One could make the case that drugs could
actually help to preserve
authenticity, another controversial area and a major concern with their use in
children and young adults. To reiterate the difficulty in diagnosing disorders
of the brain, it is debatable whether even a profoundly debilitating disease
such as Alzheimer’s can be definitively diagnosed without
post-mortem tissue examination.




Diagnostic
practices are sure to change, though, and it is likely that in the near future
researchers will discover new biomarkers for neuropsychiatric disorders. However,
this will not necessarily make it any easier. It is doubtful that any biomarker
will give a clear yes-or-no, black and white indication. As to whether a biomarker
indicates something is “out of the range of normal” is also subject to the
moving target of what humans consider “normal”. Instead, a normal range will
need to be determined, but by whom? Given what is at stake it is hardly cynical
to suggest that drug makers will have a significant role and, in the end,
physicians will continue to be able to prescribe approved drugs for off-label
use⁵. In the
meantime, instead of immediately accepting that drugs with cognitive enhancement
potential are always permissible with a doctor’s diagnosis, there should be further
discussion between physicians, regulators, ethicists and disability
advocates about how that diagnosis is made. This determination will have
widespread implications for healthcare providers, insurance companies, drug
companies, and the general public and society who are struggling to determine
what constitutes “the good life” and ultimate human flourishing.






References

 


1) Chatterjee,
A. Cosmetic neurology: the controversy over enhancing movement, mentation, and
mood. Neurology 63, 968-974 (2004).




2) Savulescu, J. Justice, fairness, and
enhancement. Ann Ny Acad Sci 1093, 321-338, doi:DOI
10.1196/annals.1382.021 (2006).




2) Wolpe, P. R. Treatment, enhancement,
and the ethics of neurotherapeutics. Brain
Cogn 50, 387-395 (2002).




3) Cakic, V. Smart drugs for cognitive
enhancement: ethical and pragmatic considerations in the era of cosmetic
neurology. Journal of medical ethics 35, 611-615,
doi:10.1136/jme.2009.030882 (2009).




4) Greely, H. et al. Towards responsible use of cognitive-enhancing drugs by the
healthy. Nature 456, 702-705, doi:10.1038/456702a (2008).




5) Penaloza, R. A., Sarkar, U., Claman,
D. M. & Omachi, T. A. Trends in on-label and off-label modafinil use in a
nationally representative sample. JAMA
internal medicine 173, 704-706,
doi:10.1001/jamainternmed.2013.2807 (2013).




6) Weinberg, R. A. Intelligence and Iq -
Landmark Issues and Great Debates. Am
Psychol 44, 98-104 (1989).




7) Farah, M. J. et al. Neurocognitive enhancement: what can we do and what should
we do? Nature reviews. Neuroscience 5, 421-425, doi:10.1038/nrn1390 (2004).




8) Maher, B. Poll results: look who's
doping. Nature 452, 674-675, doi:10.1038/452674a (2008).




9) Olfson, M., Gameroff, M. J., Marcus,
S. C. & Jensen, P. S. National trends in the treatment of attention deficit
hyperactivity disorder. The American
journal of psychiatry 160,
1071-1077 (2003).




10) Visser, S. N. et al. Trends in the parent-report of health care
provider-diagnosed and medicated attention-deficit/hyperactivity disorder:
United States, 2003-2011. Journal of the
American Academy of Child and Adolescent Psychiatry 53, 34-46 e32, doi:10.1016/j.jaac.2013.09.001 (2014).






[a] Not to mention the “Flynn effect", which describes the phenomenon of increasing IQ worldwide over time.






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Purcell, R. (2014). The New Normal: how the definition of disease impacts enhancement.  The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2014/07/the-new-normal-how-definition-of.html

Refried serotonin lunch

That title sounds like the prequel to a William Burroughs novel. I wish I'd come up with it myself, but I'm actually plagiarizing almost word for word from Dr. Steven Hyman, Director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. Last week, Emory awarded Dr. Hyman this year's Neuroscience and Ethics Award. Dr. Hyman spoke on "Addiction as a Window on Volitional Control", which shouldn't be surprising, given his molecular and genetic studies of the dopaminergic system.



Earlier in the day, Dr. Hyman stopped by the Emory Center for Ethics to have lunch with faculty and students from several schools and programs. He held forth on the state of translational neuropsychiatric research for an hour and a half, while the rest of us prevented him from eating by constantly barraging him with questions. I have a feeling I'm not the only one who found what he had to say both thought-provoking and provocative. He liberally spiced up his comments with colorful phrases like the aforementioned "refried serotonin meal" (which I will put in context at the end of this post).

Before I talk about what Hyman talked about, though, I have to put the man himself in context. Here's an interview with him and a talk he gave at a benefit, if you want to check them out. And here's the Cliff's Notes version of his career: Hyman started college as a philosopher, and then realized that neuroscientists were the ones working on the questions he wanted to answer, and so he snuck into the field through the back door of med school. Eventually he established his own lab. He then went on to head the National Institutes of Mental Health (NIMH) for five years, and followed that with a stint as provost at Harvard before becoming director of the Stanley Center. Let's relate all that to what he had to say at lunch. I guess his background explains, in part, his ability to turn a phrase. And his C.V. explains why those phrases tend to cast psychiatry and big pharma in a pretty harsh light.

Hyman leapt right into why we've had such a hard time curing mental health disorders. According to him, there's two main reasons. One is that research, for a long time, focused on drugs--the "paradigm dominate[d] the field". He conceded that research on drugs initially made sense: the drugs helped people with mental health problems when nothing had before. As he pointed out, Thorazine was just one of many antihistamines, which had great sedative properties, until doctors noticed it ameliorated some psychotic symptoms. The other reason we’ve had such a hard time curing mental health disorders, according to Dr.Hyman, is that psychoanalytics still casts a long shadow over psychiatry. He pointed to the DSM-III, released in 1980 (if you don't know, that's Diagnostic and Statistical Manual of Mental Disorders), which he said was based on "1970s science". With the DSM-III, he said, you had a case of extremely "bright people becom[ing] guardians of the holy writ". Even now, as the American Psychological Association puts together the DSM-V, "people will kill each other over the placement of a semi-colon".

The end result of the DSM is that disorders are defined in terms of symptoms. The problem with this is that human beings, especially those struggling with mental disorders, are not likely to be easily divided into groups based on their symptoms. No one who is depressed thinks, "Oh, it's been two weeks and I've only had three episodes of suicidal thoughts--I'd better get some stinkin' thinkin' goin’ to meet my quota." Yet, this is exactly the way that scientific studies were being framed when Hyman became head of the NIMH, and, because of the DSM, they’re still being framed that way. Hyman tried to change that. “I felt I was responsible for two billion dollars of taxpayer money--and if we are [funding] biological characterization of something that is not a natural kind, the study [was] stillborn.” In other words, we’ll never come up with a therapy for a mental disorder that doesn’t really exist.



In contrast, Hyman feels that “the genetics of neuropsychiatric disease is going to work”. The cost of sequencing genomes has come down something like 10-million fold. “It makes Moore’s law look pretty lazy.” He pointed out that we know that mental health issues run in families, even if the symptoms don’t always look the same. There are shared genes that put people at risk for mental health disorders in general: bi-polar patients show up in families with high incidence of schizophrenia. By the same token, Hyman said, all this genetic data has shown that phenotyping—i.e., looking at symptoms—is “worthless”. For example, there’s no correlations between genes and symptoms of schizophrenia that show that we can divide the disease into sub-classes. And while we do see a clear correlation between certain genes and the presence or absence of mental health problems in general in families, we still have to deal with 100s or 1000s of genes of small effect. “The hard problem is the genes to biology problem” in Hyman’s view.

There were a lot of other topics Dr.Hyman covered during the hour and a half that he talked with us. A couple of people asked questions about epigenetics, and I thought his answers came off as a bit glib. In case you don’t already know, the field of epigenetics studies changes in gene expression that are inherited but don’t require changes in DNA sequence. For example, DNA methylation patterns can be transferred from one generation of cells to the next, and these patterns affect transcription of genes. Epigenetics provides a way for the environment to affect the genome. In other words, this field could explain why one man suffers from a mental disorder when his identical twin doesn’t. Shouldn’t we be studying that, and worrying a little less about those 1000s of “genes of small effects”?



I also was a little taken aback to hear someone in Hyman’s position say that big pharma had woken up from its “refried serotonin meal”. I mean, I thought SSRIs were not so efficacious when I was watching my depressed friends in high school crush them up and smoke them, but I wasn’t head of the NIMH at the time. (And I guess I won’t be after writing this paragraph.) With the benefit of age and wisdom and stuff, I realize that they represent about the best we can do right now. So I have to agree with Dr. Hyman when he says “no one’s improved on Lithium,” in terms of efficacy, “and that was 1949.” To improve our therapies, we’ll have to overcome a lot of the baggage left over from that time in psychology when Freud stopped studying crawfish and started prescribing cocaine. (That’s my cynicism you hear in that sentence, not his.) Hyman’s take-home message is that we have an opportunity right now to make big leaps forward in treating psychiatric disorders. I think we can all agree on that.



--David Nicholson Neuroscience Graduate Student, Sober Lab







Want to cite this post?


Nicholson, D. (2012). Refried serotonin lunch. The Neuroethics Blog. Retrieved on
, from
http://www.theneuroethicsblog.com/2012/04/refried-serotonin-lunch.html