A modest proposal: introduce bioethical review into the drug approval process

There has been raucous furor over the decision of Kathleen Sibelius, the Secretary of Health and Human Services in the Obama administration, to overrule the FDA’s approval of the drug known as Plan B One-Step as an over-the-counter drug. It has never previously transpired that the FDA has been overruled on a matter that falls under its jurisdiction such as this, and FDA Commissioner Margaret Hamburg issued a carefully worded response which, given that Sibelius is her boss, was remarkable for its forthrightness: Continue reading

The medicalization of boyhood

As part of their ‘Failing Boys’ series, the Globe and Mail recently ran an article which calls attention to an issue that bedevils parents, teachers, and the medical establishment: has the diagnosis of ADHD led to the medicalization of boyhood, or is there something organically wrong with the brains of boys these days?

The article has a few choice quotes which are worth highlighting.

“prescriptions for Ritalin and other amphetamine-like drugs for Attention Deficit Hyperactivity Disorder shot up to 2.9 million in 2009, a jump of more than 55 per cent in four years.”

“ADHD is one of the most commonly diagnosed disorders of childhood, with core features that include an inability to focus, and hyper and impulsive behaviour. Increasingly, it’s seen as a chronic condition that 60 per cent of kids never outgrow and one that experts estimate affects five per cent of children worldwide.”

“some see a system of harried parents, school officials and general practitioners too ready to label rambunctious young males. While boys might be three times more likely than girls to develop ADHD, research suggests they are nine times more likely to be sent for a clinical assessment and five times more likely to be medicated for it.”

“With no blood test or any other biological means to confirm an ADHD case, psychiatrists, psychologists or a general practitioner diagnose children after a clinical assessment or, often, with behavioural reports from parents and teachers.”

Painting the diagnosis of ADHD as part of the growing list of phenomena in which society has medicalized normalcy is nothing new.  As is generally the case when medicalization occurs, there is likely to be some degree of veracity to the diagnosis, but, as Peter Conrad has pointed out, once the trifecta of physician endorsement, pharmacological marketing, and consumer acceptance line up together, over-diagnosis is sure to follow, and ADHD seems to be following that trend.  That is not to say that there are not young boys (and girls) who have ADHD and need our help – those who are most seriously afflicted certainly do.  But the convenience of having a pharmacological ‘quick-fix’ contributes to over-diagnosis, and runs the risk of treating young people with chemicals that alter their brains with unknown long-term consequences.

What is particularly poignant about this discussion is that it arises only days after the death of actress Barbara Billingsley who famously played the role of June Cleaver, mother of Theodore Cleaver, better known as ‘the Beaver’ in the popular TV show Leave it to Beaver.   In part famous for its depiction of the now mythical 1950′s nuclear family, the show centred around the antics of young Theodore who was into pretty much everything.  It is hard to imagine that the Beaver would not be diagnosed as having ADHD today and medicated to smooth out his rough edges.

Link to article in the Globe and Mail article

Link to Peter Conrad’s book The Medicalization of Society

Estimating the Costs of Medicalization

Peter Conrad, a sociologist at Brandeis has been a thoughtful commentator on the phenomenon of medicalization for the past four decades.  His team has just published a new paper in which they estimate the costs of medicalization.  The abstract sums the matters up nicely.

“Medicalization is the process by which non-medical problems become defined and treated as medical problems, usually as illnesses or disorders. There has been growing concern with the possibility that medicalization is driving increased health care costs. In this paper we estimate the medical spending in the U.S. of identified medicalized conditions at approximately $77 billion in 2005, 3.9% of total domestic expenditures on health care. This estimate is based on the direct costs associated with twelve medicalized conditions. Although due to data limitations this estimate does not include all medicalized conditions, it can inform future debates about health care spending and medicalization.”

In the paper, they are careful not to overstate their case, and provide appropriate cautions as to the interpretation of the data, recognizing that classifying indications as medicalized is fraught with subjectivity.  Nonetheless, this is an important contribution to the ongoing debate over the issue, and provides for the first time economic data.  From there, others can dissect the relevancy of the conditions they have chosen as well as challenge and refine their economic analysis.  From our perspective, the paper is timely, especially as the debate over DSM-V and its proposed introduction of dimensional measures continues.

Link to Estimating the Costs of Medicalization by Conrad et al. 2010 (subscription may be required).

Links (here, here, here, here, and here) to previous posts on the DSM-V controversy and medicalization in psychiatry.

Image Credit: Free Press Release

Public expression and DSM-V

The bible of Psychiatry, The Diagnostic and Statistical Manual of Mental Disorders (DSM), is the standard reference text by which psychiatric disorders are classified.  Every now and then, the psychiatric community revises the manual; the current version, DSM-IV was published in 1994 and in 2000 revisions of the text were added (hence the clumsy term DSM-IV-TR) but the categories of psychiatric disease remained unchanged.  At the moment, a committee is hard at work developing a new version, DSM-V, and the issue has morphed from scientific enterprise to public melodrama.

Over at H-Madness, a blog devoted to the history of psychiatry, the historian Hannah Decker has a wonderful post detailing the trials and tribulations of the controversies currently embroiling the production of DSM-V.  Entitled A Moment of Crisis in the History of American Psychiatry, Decker’s post covers all of the usual territory, some of which we have discussed previously (here and here). It bears repeating that the biggest challenge to the endeavour is the lack of objective criteria for defining psychiatric diseases: until neuroscience provides this clinical specialty with concrete insights into the relevant changes in human neurobiology that accompany psychiatric disease, the field will continue to be on shaky ground, defining and redefining ‘syndromes’ composed of constellations of symptoms rather than clearly understood alterations which result in pathology. Continue reading

Major step forward in developing ‘real’ pharmacological cognitive enhancers


Co-crystal structure of a representative methoxyphenyl allosteric modulator (D159153) bound to PDE4D

The prospect that drugs might be able to enhance one or more modalities of cognition has garnered a great deal of attention in the past few years, nowhere more so than among neuroethicists.  Much of the discussion revolves around existing drugs such as methylphenidate, but the truth is that the effects they produce are measurable but modest, and in my view the current situation is not as dire as some might suggest. That might not be the case in the future, especially once ‘real’ pharmacological cognitive enhancers are developed.  To date, the results have been disappointing.  [Warning: the rest of this post is weighted more towards science than neuroethics.]

The development of ampakines by Cortex Pharmaceuticals looked promising at first, with preliminary results suggesting that these compounds might improve at least some aspects of memory in humans, but then the drugs failed to reach their end point in Phase II clinical trials.  A great deal of excitement emerged from the idea that one might be able to enhance the activity of the transcription factor CREB, primarily by inhibiting the enzyme phosphodiesterase-4 (PDE4) which is responsible for breakdown of cAMP.  If successful, the increase in CREB activity was hypothesized to enhance long-term memory.  The prominent players in PDE4 development for cognitive enhancement to date have been Memory Pharmaceuticals and Helicon Pharmaceuticals;  both companies developed drugs which advanced to Phase II testing for age-associated memory impairment, but neither drug met the requisite endpoint at moderate doses, and at higher doses ran into troublesome side effects such as nausea which have begun to be seen as a general problem with PDE4 inhibitors.

But a good idea does not lay fallow long, and a new report in Nature Biotechnology from Alex Burgin and colleagues at deCODE biostructures opens up a new era in the pursuit of PDE4 inhibitors for cognitive enhancement.  The paper is a tour de force of structural biology and medicinal chemistry.  Essentially, Burgin et al. noticed that all previous attempts to develop PDE4 inhibitors were based on developing competitive inhibitors.  Reasoning that these compounds may have been more hammer than scalpel, they used insights from their crystallography work to design allosteric modulators which might allow better titration of the cAMP signal and presumably allow fine tuning of CREB activity.  Using this strategy they ultimately came up with 140 compounds that satisfied their criteria; the most promising of these were then demonstrated to the desired effects upon long-term memory and have many of the characteristics one might wish for in a bona fide cognitive enhancer. Continue reading

News from the medicalization of normalcy front

Ah, the medicalization of normalcy.  It never seems to end.

In yesterday’s New York Times, Natasha Singer has an article called “Sure, It’s Treatable. But Is It a Disorder?“.  The piece focuses upon drugs to treat premature ejaculation (PE), but the larger message is that drugmakers are now unabashedly in the business of transforming seemingly normal physiological variation into bona fide disease.  Singer tells us that,

The template goes something like this: Start with a legitimate quality-of-life issue — like fitful sleep or shyness — that does not yet have its own prescription medication and is debilitating to a few people a lot of the time. Next, position the quality-of-life issue as a medical condition with symptoms so common it covers vast numbers of people who had previously not identified themselves as having a health problem, or who thought they were just experiencing an occasional and normal annoyance. Continue reading

What is normal, anyway?

Asperger-Vienna-clinic

Hans Asperger (1906–1980) at work in the University Pediatric Clinic, Vienna performing a psychological test of a child.

Over at the Guardian, there is a delightful piece about an adolescent boy with a form of autism spectrum disorder known as Asperger’s disease. The entire article is worth reading for its insight into the life of an individual with Asperger’s, but one of the most telling lines emerges when the author tells us,

I begin to see what his mother means when she says Asperger’s can be more complex than the stereotypes suggest. “If there was a cure for Asperger’s,” she says, “I wouldn’t want it. Al’s just himself.”

Alex echoes his mother’s comments.

“I don’t think I’ve got a disability. I like being me.”

When patients say that they prefer the situation that they find themselves in, it is worth stopping and asking if the medicalization machine is moving too far too fast.

Hans Asperger first described the phenomenon in 1944, but the diagnosis of Asperger’s did not become official until 1992 when it was included in the International Classification of Diseases (ICD-10); in 1994, it was included in the Diagnostic and Statistical Manual of Mental Disorders, DSM-IV.  It is worth quoting from the ICD-10.

A disorder of uncertain nosological validity, characterized by the same type of qualitative abnormalities of reciprocal social interaction that typify autism, together with a restricted, stereotyped, repetitive repertoire of interests and activities. It differs from autism primarily in the fact that there is no general delay or retardation in language or in cognitive development. This disorder is often associated with marked clumsiness. There is a strong tendency for the abnormalities to persist into adolescence and adult life. Psychotic episodes occasionally occur in early adult life.

As it turns out, it seems likely that despite the ICD’s disclaimer of uncertain nosological validity for the diagnosis, there are indeed individuals out there with Asperger’s, and it is important to recognize them.  The important question is whether it should be considered a disease or not.  This question is raging as the field gears up for the arrival of DSM-V (I previously wrote about this here). In a broadside at the process that is being used to develop the new version of DSM, Allen Frances, the individual who chaired the DSM-IV Task Force, argues that the approach being taken is way off track.  The earnest group engaged in the herculean task of revisiting DSM push back. So it goes in academic medicine. [For a definitive historical look at DSM, I highly recommend Christopher Lane’s book Shyness.]

What concerns us is not squabbling over process or priority, but rather the impact that all of this has on individuals and society at large.  Amid a number of concerns, Dr. Frances rightly reserves his strongest objection to the potential of DSM-V to further medicalize normalcy.

Undoubtedly, the most reckless suggestion for DSM-V is that it include many new categories to capture the subthreshhold (eg, minor depression, mild cognitive disorder) or premorbid (eg, prepsychotic) versions of the existing official disorders. The beneficial intended purpose is to improve early case finding and promote preventive treatments. Unfortunately, however, the DSM-V Task Force has failed to adequately consider the potentially disastrous unintended consequence that DSM-V may flood the world with tens of millions of newly labeled false-positive “patients.” The reported rates of DSM-V mental disorders would skyrocket, especially because there are many more people at the boundary than those who present with the more severe and clearly “clinical” disorders. The result would be a wholesale imperial medicalization of normality that will trivialize mental disorder and lead to a deluge of unneeded medication treatments—a bonanza for the pharmaceutical industry but at a huge cost to the new false-positive patients caught in the excessively wide DSM-V net. They will pay a high price in adverse effects, dollars, and stigma, not to mention the unpredictable impact on insurability, disability, and forensics.

Dr. Frances’ goes on to say,

The incredible recent advances in neuroscience, molecular biology, and brain imaging that have taught us so much about normal brain functioning are still not relevant to the clinical practicalities of everyday psychiatric diagnosis. The clearest evidence supporting this disappointing fact is that not even 1 biological test is ready for inclusion in the criteria sets for DSM-V.

So long as psychiatric diagnosis is stuck at its current descriptive level, there is little to be gained and much to be lost in frequently and arbitrarily changing the system. Descriptive diagnosis should remain fairly stable until, disorder by disorder, we gradually attain a more fundamental and explanatory understanding of causality.

Here we get to the heart of the dilemma.  The field of psychiatry struggles to help patients, but the truth is that the neurosciences have yet to reveal the causes of psychiatric disorders.  Without objective criteria to guide them, physicians fall back on descriptors which are imprecise and therapies which do not treat the underlying (and still unknown) pathology. Lacking the confidence to distinguish normal behavior from diseased, the field inadvertently medicalizes normalcy.

And Alex, the boy with Asperger’s, finds himself squarely in the crosshairs of this raging dispute.