Friday, February 3, 2006
Session 5: Psychopharmacology and Psychiatric Disorders in Children
Biederman, M.D., Professor of Psychiatry, Harvard Medical
School, and Chief, Pediatric Psychopharmacology, Massachusetts
General Hospital, Boston, Massachusetts
CHAIRMAN PELLEGRINO: I think in deference to
our speaker to allow him sufficient time for presentation and
you sufficient time for interrogation in the best sense of that
word — this is not a hearing. I needed to modify that — this
morning we switch our attention to the field of
psychopharmacology in children, part of our overall attempt
to look at some of the important ethical issues in childhood.
Dr. Biederman is the Professor of Psychiatry at Harvard Medical
School and Chief of Pediatric Psychopharmacology at Massachusetts
General Hospital. There are no extended introductions, and he
understands that and knows that you're familiar with his curricula
Professor Biederman, I turn it over to you.
DR. BIEDERMAN: Well, first of all, the interrogation
part is a very serious matter, and I was sure torture would not
DR. BIEDERMAN: So it is a great pleasure to
be with you. This subject that I'm going to cover is an area
of enormous interest, enormous amount of media attention, and
I'm glad that you are taking this on.
I am a practicing clinician and a scientist. So all of the issues
that have interested me have been driven by clinical concerns.
In any event, I would like to share with you some general issues.
Let me see. Where is my presentation?
First of all, as you know, the scope of mental disorders affecting
children is extraordinarily large. It is maybe between 12 and
22 percent of children in this country and perhaps all over the
world have major mental illnesses. This translates into seven
and a half to 40 million children affected. About ten percent
of those children are thought to have severe functional impairment.
Those are children that are institutionalized in foster placement,
require massive amounts of psychosocial and psychoeducational
However, less than 20 percent of these children receive any mental
health services, and they never see a child or adolescent psychiatrist.
Many of these children, of course, would benefit from a treatment
that may enhance their ability to be in a less restrictive environment,
and so if you have a major psychiatric illness and the only intervention
is institutionalization, it may not be the best service that the
child can receive.
There is a serious problem in our field regarding manpower.
There are less than 6,300 trained child and adolescent psychiatrists
currently practicing in this country, and we estimate that probably
by the amount of children that are affected with mental illness
is that we may need at least 30,000 to meet current demand.
So I would like to say to you that of those 6,300 not all practice
child psychology. Many just do psychotherapeutic interventions
and do not take on the medical aspects of the profession. This
need is projected to greatly increase over the years. So we probably
will need something like 50,000. We probably are never going
to get there.
So the next hope or the next best choice is to count on informed
primary care physicians that will take on some of these responsibilities
and help manage the many children in many parts of the country
where there is not a single child psychologist to be found.
I would like to editorialize a little bit that the problem of
manpower is extraordinarily severe. Remember that affects not
only the number of child psychologists that we have, but the quality
of our ability to train the next generation of child psychiatrists.
So if we don't have a critical mass of high level child psychiatrists,
we are not going to educate at the level that the new generation
may need to be aware of the problems and the issues in front of
I suggested when I was invited to focus on one neurobiological
problem like ADHD as the model of the problem of linking behaviors
with the brain. In pediatric psychiatry we have very little approved
medications beyond the treatment of ADHD. This has changed somewhat
in the last few years, but not dramatically. In the last few
years not only that we don't have approval for many drugs,
but we have black boxes for all of them that create issues that
I would like to make you aware of — what is the impact in
our society and in the minds of the clinicians practicing out
So there is a vicious circle that immediately has created concerns
about children, creates a bad climate to do research on children
that is considered perhaps not ethical. So if we don't have
evidence, what is more ethical, not to treat? We still have to
treat. To treat in the absence of evidence or to do the studies
that would allow us to have the evidence to treat ethically?
So that's the dilemma.
There is also an enormous amount of prejudices and misconceptions
in our society about psychopathology in children. There is some
kind of naive belief that all children are angelical, and there
is something wrong to the child. Somebody is doing something
bad to the child. So there is no recognition of the fact that
children, like adults, have bona fide psychopathology disorders
that translate in aberrant behaviors, and the assumptions that
it's just all psychosocial and if every child were to have
loving parents and loving teachers, no child would be affected
is really extraordinarily naive.
There is very poor public acceptance of the use of medications
in children. There is an enormous amount of bad faith. I don't
know. Probably you know more than me, but every week there is
some kind of poisoning of the children, over-medicating, and so
on and so forth. And periodically we are dealing with this alarming
statistics about bad things, and some of these alarming statistics
led to, I believe, all psychotropics having black boxes.
I would like to address two of those alarming statistics: This
issue about suicidality and suicidal behaviors with the use of
serotonergic antidepressants — as a context I would like
to say that the serotonergic antidepressants provided the field
of psychiatry in general and child psychiatry with very safe medicines,
medically speaking. Before that we had tricyclic antidepressants
and drugs like imipramine or amitriptyline or desipramine drugs
that had very narrow margin of safety. Overdoses could be lethal.
They require a high level of monitoring. These drugs could be
arrhythmogenic. So the advent of the serotonergic drugs from
the strictly speaking medical context provided a very safe environment.
As you know, these drugs over time became useful to treat an
enormous chunk of psychopathology, not only the patient, but anxiety,
obsessive-compulsive disease, social anxiety, post-traumatic stress
disorders, eating disorders. So it provided a very safe environment
to treat children.
So this data that started with paroxetine, then extended to venlafaxine,
included all under the present, particularly as its rise led the
British regulatory agency to proscribe altogether the use of
SSRIs in the end.
The FDA took a less drastic position that has changed now over
time and has been softened in light of evidence that has emerged.
Part of the problem is that in clinical trials, two problems may
have driven these statistics.
I would like to say this about the three percent versus about
one and a half percent of placebo that we're talking about
here: Part of the problem is that in the clinical trials with
depression and all over the world there is a very high placebo
response, and there is a little bit of a disconnect. I wish I
had a placebo response when I have three depressed youngsters.
I would like to make sure that you are aware that for reasons
that have to do with the selection of subjects that participate
in clinical trials, a child that may be in a deprived environment
when participating in a clinical trial has an enormous amount
of attention. People are taking care of the child and the family.
The child is immediately a very important person, and so on and
so forth, and that has very impactful effects, even though it's
not the treatment, on allowing people to feel better. So the
placebo effect that has been so high did not permit the separation
of the active ingredient from the placebo. It's not that
the drug did not work, but it did not separate from placebo.
The magnitude, the absolute magnitude of effect, was as high as
in adult depression, but the placebo was higher.
So what I would speculate is many of the children that were
entered in this clinical trial may have had some psychosocial
type of adjustment difficulties with depressed features instead
the melancholic problems that we face.
The concern that I would like to tell you is that in clinical
practice treating depressed youngsters is a nightmare. I wish,
again, I had the 60 percent of placebo that we have in clinical
trials. That is not true to life in what I have to take care
to do when I deal with depression in the young in my clinic.
So I would like to tell you the numbers, that out of 4,400 cases
that participated in controlled clinical trials, largely adolescents,
there were 78 that had some kind of [suicidal ideation]. Nobody
died. I believe that nobody was even hospitalized. It was defined
as ideation that the youngster reported to the treating clinician
or the family reported. And that was larger than 3.8 versus 2.1
if you take all of these 4,400 kids.
What I would like to share with you is these numbers here, that
if you take what is the rate of suicidality, including very serious,
injurious suicide attempt in high school children in this country,
look at these numbers. In the population, we're dealing with
20 or 30 percent, not three percent. So depression, as you know,
increases this risk, does not decrease this risk.
So what we see in clinical trials is a small blip to the problem.
These are not depressed. These are population rates. These are
the Center for Disease Control statistics.
So suicidal ideations are extraordinarily common in our society.
The data that we have regarding the life saving components of
the antidepressants is in the opposite direction. In statistics
available, and this is a paper published in a very reputable psychiatric
journal, the Archive of General Psychology, your increased
use of antidepressants in the '90s, largely SSRIs, led to
a decrease in the rate of suicide, not an increase.
And there is a paper that I enclosed in the outline, this paper
by Dr. Greg Simon that took a very large database to examine this
issue that I just briefly would like to mention, and if you take
the young children and adolescents, the risk for suicidality is
much higher before you start medication than after you start medication.
These are months. If you look at weeks, so this is before and
this is after. So in a large population, this is more true to
life. We don't have any evidence that that's the case.
However, a black box, the public and the treating community may
not distinguish the potential remote risk from the tangible and
present risk, and the results are that families may be handed
by the pharmacy a handout that would say that this will make your
child commit suicide. The primary care physicians that otherwise
would have been able to prescribe these medications for the depressed
youngster or somebody with severe anxiety or OCD will not do that
anymore and will refer to psychiatrists.
As I said to you before, they are nowhere to be found. Okay?
So the result is the children will not be treated with the drugs
that can be lifesaving.
The other thing that I would like briefly to mention is the paper
that was published in JAMA re Dr. Zito. Let me just go back.
In this paper, she looked at the trends in the last decade in
prescribing medications to preschoolers, and what she was reporting
in the paper is that less than two percent of preschoolers were
receiving psychotropics. The way that the data were presented
in that paper, instead of percentages were presented as per thousand.
So for the uninformed reader, as you know, as you present data
when you change your vertical and horizontal axis, anything can
be one from 1.2, if you present it in particularly alarming ways,
can be quite alarming.
I would say 90 percent of the conditions that emerge in childhood
emerge in the preschool years. So I said to you before that about
at a minimum ten percent of children have serious mental illnesses.
Most of these mental illnesses will emerge in the preschool years,
and if we treat 1.5 percent of those, and most of these treatments
have to do with enursis, doing imipramine for enursis, not that
they were taking something more than that.
So I would make the argument that we are not doing a good job
in treating proximally to the onset of the disease the conditions
that we ought to treat.
As you know, when the paper was published, Ms. Clinton asked
the field — we had many committees that participated, also myself
— about treating preschoolers. I would like to tell you that
in my clinic everybody has a structured interview, and we do not
select patients by race, social class, and we do not ask them
to declare a diagnosis. We consider the diagnostic responsibilities
are clinical issues upon us.
So we have a sizable number of preschoolers representing about
ten percent of our referral pool. These preschools have an enormous
amount of psychopathology. There is an average age, a defined
preschoolers, children six or younger. Okay? Average age, about
These children not only have single diagnosis, but frequently
have multiple diagnoses, including serious mood disorders, serious
anxieties or a combination of behavior disorders, ADHD, et cetera,
et cetera. So, for example, a small percentage of them have four
diagnoses. Think about an adult patient with metabolic syndrome,
diabetes, hypertension, and a wide range of difficulties. So
this is a very compromised child. Okay?
So they are coming to a clinic. We did not get them. They are
coming to us, asking us for help with very serious psychopathological
What I wanted to point out here even though these children have
an average age of 5.2, okay, the onset of the symptoms were at
least a year and a half to two years before they reached our shores.
So even in the preschool setting, we have a big gap from the time
of the symptoms onset to the time that somebody is referred.
That gap, of course, is much larger. The average duration, the
distance from onset of symptoms for ADHD to onset of treatment
is somewhere in the order of magnitude of seven to nine years.
If you think about if that distance where to apply to the treatment
of a cavity, for example, what that will do to the affected person
in the sense of chronicity, the impact of a repeat of seven years,
you have many opportunities to ruin your life.
Okay. Children have long memories. A child that is a pain in
kindergarten, even if the child improves, will never be forgotten
by his peers for many years to come.
So we have the larger issue that because as prejudice is concerned,
the difficulties in conducting studies in children and so on and
so forth, that very few drugs do not have FDA approval, and as
a consequence we are in kind of a Never-Never Land regarding risk.
We have to make sure that you are aware that we still have to
prescribe with or without FDA approval. Okay?
The recent past legislation has mandated pharmaceutical companies
to conduct research in children and adolescents. The recent experience
with SSRIs certainly had produced a very chilling event in the
minds of pharmaceutical manufacturers. So the state of affairs
of not having approval creates the uncertainties that lead to
not knowing how to use, what to use, what is safe, what is not
safe, et cetera, et cetera. So it has greatly limited the possibilities
of using psychotropics safely and effectively in the management
of children with serious psychopathology.
So I would like to switch to ADHD as a prototype. It is one
of the most common disorders that we have in child psychiatry.
It's one of the most common problems that pediatricians that
deal with; [it generates] emotional issues faced all over the
world; it is a highly heterogeneous illness, like all medical
and psychiatric conditions. We know that genes have a lot to
do with this, and I will tell you a little bit in my talk. We
know quite a bit about anatomy and neurochemistry.
So here we are, with a condition that is one of the most beleaguered
conditions that we have in psychiatry. It's among the most
well established neurobiologically speaking, and I hope I will
be able to make that point as a product of this discussion.
We know that environmental factors are a contributor to the disease.
I would like to mention that what I call environmental factors
are in themselves like family conflict, poverty, maternal and
paternal psychopathology. Those are not sociological factors
of bad mothers and bad schools and bad teachers. Those are conditions
that themselves are given by genes.
So a child that is living with a parent that has a serious mental
illness has two problems: she has the genes that the parent transmits,
plus the bad environment that the parent transmits. If CNS incidents,
of course, closed head injuries, accidents of other types damage
the same regions of the brain that genes damage, [they] will produce
a syndrome that is known as ADHD.
So think about ADHD as a final common pathway of multiple interlocking
process that could come from different origins. The most common
one is this one. It's one of the most genetic conditions
in psychology and in medicine as I'm going to tell you in
You probably heard many times that the children are over-diagnosed,
over-medicated. This is an American disease. Data coming from
all over the world — we actually published a paper in the World
Psychiatry Journal — document [worldwide prevalence]. This
is just an example of what I'm showing.
But no matter what definition you use, five to ten percent of
children all over the world, (including Asia and China a few months
ago, the five to ten percent numbers are there, too). Very, very
As you know, this is a chronic illness, and the children of today
are going to be the adults of tomorrow, and the adults of today
have been children yesterday. So we're talking about a condition
that is only temporary in pediatrics, but will be a condition
in adults as the child matures.
How do we know that? There have been several follow-up studies.
My follow-up studies into adulthood, my study of boys with ADHD
was just published in a very prestigious journal that is called
Psychological Medicine This Month. What I wanted to show
you is that there are many studies, very few into adulthood though,
using different definitions.
DSM-2 emphasize hyperactivity. This is my study, the previous
published study. By age of 15, we had 85 percent of persistence.
So if you average this, it is about 50 percent of the minimum.
In my recent analysis of how persistent it is, we calculated
that 80 percent of our original sample that was ascertained in
childhood, by the age of 30 continued to have some form or another
of ADHD into adulthood, 80 percent.
So we always imputed that, estimated that adult ADHD based on
these follow-up studies of persistence may be common. Okay?
So we now know from this paper that we published recently, and
there is another one by Dr. Kessler that has done the national
co-morbidity survey that is responsible to provide us with the
statistics for all mental illnesses in our society.
The data emerging today are about five percent, between three
and five percent of adults in our society have this condition.
Okay. Remember that we have many more adults than children and
people spent longer time being adults. Not only there is five
percent, but I would like to share with you some statistics on
how morbid it is. This is an adult.
I also wanted to mention to you this is strictly defined. People
that have lifelong problems, the average age of the sample is
about 40. The vast majority of those people have never been diagnosed
in childhood. The vast majority of these people, despite diagnosis,
have never been treated. Okay? So we have here a very peculiar
situation that these people received the diagnosis perhaps in
their communities, but they're not treated. It's estimated
that 20 percent of adults are actually treated.
But what I wanted also to mention to you is that variations of
these syndromes are extraordinarily common. In our study people
that have less than required symptoms, a few less or they had
a different age of onset and it ended up being up to 16 percent
in Dr. Kessler's study. He had another five percent of adults
that had a lot of symptoms in adulthood, not so many symptoms
in childhood, kind of the reverse of what we see in the traditional
definition of ADHD, a disorder that starts in grade school and
This is not a disorder, by the way, [such] that people have attacks.
So you have it chronically all the time. The frustrating component
of this condition is that it's a behavioral syndrome, and
the symptoms, like in depression actually — it's not very
different — overlap with symptoms that all of us have. All of
us may be distracted, inattentive, impulsive, but not to the degree
that produces the symptoms all the time, and not to the degree
that produces morbidity, dysfunction, disability, suffering.
So the distinctive point is the number of symptoms. You have
to have a lot. Okay? And you have to have symptoms that produce
dysfunction. And "dysfunction" is a relative term.
Okay? It's not absolute dysfunction that you cannot do any
school work. The child with ADHD may not be able to use his or
her intellectual ability to the fullest.
Just before I came yesterday we were calculating if you look
at my follow-up, if you look at the ADHD children that completed
college compared with those that don't have ADHD, the ADHD
group had to have 30 points higher of IQ compared with the average
IQ of the control that completed college was 110. The average
IQ of the ADHDs that completed college was 130.
Well, that means that the intellectual abilities of the person,
his or her endowment that would allow the person to succeed, are
substantially diminished by the conditions. So you are functioning
effectively at the lower level.
Remember there is a connection between what you accomplish in
school and where you end up in life. So these are not minor issues.
We also know that the ADHD individuals — that the level of education
is not predictive of level of functioning of occupations. So
they have under occupation relative to their education. So they
get two hits. One is that they have under education because they
cannot get as high as their intellectual abilities will allow
them, and those that get it, they have under occupational consequences.
So the gap from where you could have been, from where you are
in society is very large. Okay? And we recently estimated that
the cost of under employment of ADHD may be in the order of magnitude
of $70 to $100 billion a year just from under employment.
So the frustrating situation in the clinic with ADHD is that
the symptoms are not in front of us. So the patient is not dysmorphic.
The patient doesn't have any different colors. They're
not blue, yellow... The patient is not in acute pain. So it's
a very different environment in capturing this syndrome. The
patient may look like you and me. Okay? And the clinician then
has to elicit the symptoms outside the office. The symptoms occur,
are situation sensitive. They occur in situations that you are
not interested in.
So, for example, a child can play Nintendo for many hours or
watch Saturday morning cartoons for many hours, but may not be
able to do homework for two minutes. That always has been interpreted
If you look at the history, the first description medically speaking
of ADHD was done by Professor George Steele in 1905 in London,
in the Royal Academy of Sciences, I believe, and he described
the symptoms very well, and the conclusion is that it's a
moral disease. Why is it a moral disease? Because of the situation
that the child can do; it's not an absolute failure of attention,
but it's fluctuating and context sensitive.
That, by the way, is not different than other psychiatric illnesses
or medical conditions. The patient with chest pain does not have
it all the time. The patient with seizures does not seize in
front of the doctor to document that they have a seizure.
So the symptoms occur in situations that they're uninterested.
So a child will have symptoms in school in some classes, not
in all, depending on interest or capabilities or how fascinating
the teacher is in teaching. The adult may have difficulties
in paper work. Physicians, for example, with these conditions
do well when they are in one-to-one with their patients. They
tend to have a lot of difficulties when they are called to administer
clinics or to organize something, and then they have no idea what
they are doing.
The symptoms of impassivity and hyperactivity are very age sensitive.
They tend to decline early on in life, and that has been the reason
that this condition has been assumed to be a childhood adolescent
diagnosis. Not to worry; things will disappear.
We know very well that things do not disappear. The most covert
symptoms, those of inattention, those that we don't see, are
The other problem that we have is that the symptoms are very
variable. They vary in the frequency in which they occur, and
they vary in the degree that they impair the individual, and that
also creates a lot of confusion. There is an expectation that
I don't think applies to any other medical condition, that
you have to be near death to qualify for a psychiatric diagnosis.
We don't have that standard for hypertension or for strep
throat, by the way. So here the idea is if you have — as I said
to you before, a child who is very bright will not fail school,
will do okay in school. The distance of doing okay in school
for a bright student is the same distance as somebody that is
not so bright that fails. It is exactly the same distance.
So there is no expectation that we need to demand that a child
be failing school or the adult being incarcerated to consider
a diagnosis. So the issue of impairment is a matter of judgment
and is relative, not absolute.
As I said before, I treat a lot of adults, and many of them are
in the high professions. So you can say, well, if you made it
to medical school, law school, architectural school, how can you
Well, many of these people are really brilliant and they're
able to pass their exams, but they're not able to practice.
They have a lot of problems in life. They have difficulties in
their marriages. They have difficulties with their children.
There are difficulties in managing their household chores, and
so on and so forth. So life is not a picnic for many of these
As I said before, the symptoms of hyperactivity tend to decline
around the age of 12, those of impulsivity. It's not that
they disappear. They go below radar. They are less prominent.
So you no longer see a child in my waiting room at the age of
15 that is running on my furniture.
That does not mean that the child is out of the woods. What
they will tell me is that they have this horrendous inner sense
of restlessness. Many of these adults are always doing something.
There's a different flavor than being hyperactive. They cannot
sit still. Many of these adults, for example, do not know how
to relax. So these are the Blackberry people, people that are
at the beach, have five computers and a telephone. So they are
Many people go to the office because they do not know what to
do with unstructured time. This is not a condition that is adult-
or marriage-friendly. It is not a condition in pediatrics that
is family-friendly. It is highly impactful.
I would like to go a little bit to the brain because contrary
to accusations by the Church of Scientology that this is all kind
of an invented disease, as you know, the Church of Scientology
has several class action suits against American Psychiatric Association,
the American Academy of Child Psychiatry, claiming that they
are in cahoots with pharmaceutical companies to invest the disease
to sell medications.
The literature from MRIs in pediatrics [is based on] small studies...
To my knowledge, we have now more than 30 studies. To my knowledge,
there is not a single MRI study that has been negative in ADHD.
The findings are different, but in areas of the brain that are
clearly associated with the disease, [one finds] asymmetry of
the caudate nucleus; differences in size and shape of the corpus
callosum; smaller right frontal area, and the frontal lobe is
a key region for cognition, as you know; smaller right basal ganglia;
and the cerebellum is increasing recognized as particularly vermis
— the cerebellum is important in cognition, attention and ADHD.
These studies were criticized because many of the children had
been medicated. So you can then argue that what you see in the
MRIs are the consequences of the treatment, not the consequences
of the disease.
This study that was published in JAMA in 2002 by our colleagues
at the National Institute of Mental Health, (Dr. Castellanos was
the lead author). It's a very large study. The previous
study had ten, 12 subjects, maybe 20. This has 152 children and
adolescents, boys and girls, and a sizable number of controls.
The study's objectives were to assess volumetric changes
over time and to address directly the issue of medication, and
therefore, they have medicated and unmedicated youngsters.
What this study found is that the cerebral and cerebella volumes
were significantly reduced in the order of magnitude of three
percent in children with ADHD. This volumetric abnormality, with
the exception of the called weight, persisted with age. This
was not a neurodegenerative condition that things went progressively
worse over time. There were no degenerative instances, and there
was some evidence that these volumetric changes were correlated
with the severity of ADHD.
So the visual of this is this. So in girls we have data up to
15 and boys up to 20. This is brain volume. This is age. So
these are the males, and these are the females. You see that
in both genders you have the same magnitude of smaller cerebral
The conclusion of this paper is that either genetic or early
environmental influences in brain development in ADHD are fixed,
nonprogressive and unrelated to stimulant treatment. It's
a very important finding for the field in reassuring that what
we see is not just the toxic effects of medication.
So if you look at some of the key regions of the brain in all
of us, not in people with ADHD, there are regions that we know
are involved in key cognitive processes. The anterior cingulate,
the dorsal anterior cingulate, and the cognitive division are
associated with executive control — the ability to inhibit thought
and behavior, the ability to direct attention to things that were
not interested. The dorsal (unintelligible) prefrontal cortex,
right frontal lobe, and these are, of course, highly interconnected
areas of the brain.
We can use imaging. So what I'm going to show you is imaging
of this region. Okay? This is really very exciting data. We
just completed this study. So this is not yet published. I promise
you that it will be published, but I would like to share it with
you nonetheless. So this is the anterior cingulate gyrus here
which I am depicting. Okay?
You can measure with MRI volume, of course, but you can also
use the latest technology to measure cortical thickness. How
thick or thin is the cortex?
So in this paper that we were able to document, I believe, for
the first time, that in an adult with ADHD unmedicated, what I'm
showing here is the statistical comparison of the average brains
of adults with ADHD compared with adults without ADHD looking
specifically at cortical thickness.
So you see here this is the dorsal anterior cingulate, the same
area of the brain that I showed you before that we know is involved
in cognition. It's not a diffuse, encephalopathic process,
and we also have thinness here. This is significantly thinner
in the dorsal and the frontal cortex, also a key area of the brain
involved in the processes that can lead to the symptoms that we
know as ADHD.
These findings are remarkably congruent with what neuropsychologists
conceptualize as ADHD from a neuropsychological perspective.
In a very interesting and special issue in Biological Psychiatry
on ADHD, on the neuroscience of ADHD, there is a group of extraordinary
review articles on the genetics neuroimaging. Dr. Sonuga-Barke
did the review in the neuropsychology of ADHD, and he argues that
the process of ADH and the circuits of attention was called directed
attention, essentially paying attention to things that we're
So the person with ADHD cannot put his or her brain in four wheel
drive when confronted with the task that the person is not interested
in, and equally important is their disturbances in the reward
circuit. The person with ADHD will not be able to not do something
that may be pleasurable.
And as you know, if you go for things that are rewarding and
pleasurable without some kind of scrutiny, you are going to engage
in a wide range of difficulties in our society. The issue of
difficulties with delay aversion, so many people with ADHD will
very rapidly approach something, drugs, alcohol, sex, in a manner
that may lead them to a wide range of difficulties.
Going back a little bit to the dorsal-anterior cingulate, the
cingulate gyrus, this area here in red, is tightly organized into
a cognitive and an emotional division. This is the general here.
The blue is the emotional division. Well, what is remarkable
is these are different studies that can activate this area of
the anterior cingulate using functional MRI and a very simple
You can consistently activate this area of the brain using imaging
techniques, particularly functional MRI.
In a study that we did, Dr.Bush, this is a neuroscientist in
in our group, who is called George Bush. Now, what a name, no?
But it's not the one in the White House.
This is a coronal view of the brain, and in normal controls if
the person is asked to do a simple cognitive task, you will activate
the anterior cingulate. If you put adults with ADHD in the scanner,
the same region is blank, does not activate. Instead they activate
the insula. So the adult with ADHD can do this task, but it's
recruiting areas of the brain that are not particularly designed
to do the task. Therefore, they are going to do the task more
slowly and less efficiently.
We have emerging data that you can correct that with treatment.
So when you prescribe treatments like stimulants, methylphenidate,
that normalizes. Distal imaging data that I just showed you has
to be seen as interesting, linking the disease or the condition,
the syndrome, with the brain, but not useful for diagnostic purposes
because we are not yet like we are in chest X-rays, that it's
always the same. These are group data. There's very large
Another very important component of ADHD is that ADHD is a genetic
illness. How do we know it's a genetic illness? The first
signal comes from family studies. Familiality, of course, is
not evidence for genetics, but if there is no familiality, there
is very little impetus to pursue a genetic hypothesis.
Twin studies are very important in pursuing a genetic hypothesis
because twins come in two varieties, monozygotic and dizygotic,
and in genetic illnesses we expect that the concordance will be
higher in dizygotic twins.
Also, twin studies are important because they allow us to compute
coefficients of variability that tells us how much of the variance
of the disease can be accounted for by genes.
Adoption studies, if you find a genetic illness, you expect biological
relatives to be more affected than adopting relative.
And finally, you look for genes. So as a final product, this
is a polygenic disease. So looking for genes is not a minor undertaking,
as you know.
This condition has been documented for three decades to be highly
familiar. There is a five to seven-fold increased risk in relatives
of children with ADHD, irrespective of what criteria we use.
This is my study. I did probably the most on documenting familiality.
This is DSM-III. We documented with DSM-IIIR. We documented
with DSM-IV. That is very familiar. We documented in Caucasian
samples, in African American samples, in boys and in girls. Clearly,
But even in the '70s, before my time, Dr. Kant with Morrison
and Stewart documented the same. So if you started with the child,
it is much more prevalent in relatives, first degree relatives
of children with ADHD than in relatives of controls.
Coefficients of variability, briefly, they are based on twin
studies. There's first a lot of twin studies. These twin
studies are remarkably heterogeneous. They use questionnaires,
teacher report, parent report. It does not matter. I'll
show you the results in a second.
The coefficients of variability range from zero percent of the
volumes accounted for by genes to one, 100 percent of the variance
accounted for by genes. So look how consistent these studies
are. The average coefficient of variability of ADHD is close
to 80 percent. Comparison of high to highly inheritable trait,
about 90 percent. Schizophrenia, bipolar illness, about 80 percent.
In the genome issue of Science, in the part that was
written on psychiatry, they had three conditions likely to be
genetic: schizophrenia, bipolar, and of course, ADHD was the
Panic disorder and major depression are genetic illness, but
not as genetic as bipolar and schizophrenia; about 50 percent
genetics. Breast cancer is about 30 percent or so.
So this is a very genetic condition, 80 percent chances to be
And the first genes that we have looked at in ADHD were candidate
genes that had to do with polymorphism on the dopaminergic system,
a polymorphism on the dopamine transporter gene, and a polymorphism
in the dopamine receptor default genes.
The reason that we focused first on dopamine genes is because
the drugs that are effective in ADHD are highly dopaminergic like
So ADHD is conceptualized as a hypodopaminergic disease. So
you can get to be hypodopaminergic by not having an adequate production.
This is presynaptic/post synaptic. You can have hypodopaminergic
situation if the presynoptic vesicles do not release dopamine.
You can have a hypodopaminergic state if the transporters take
too much dopamine back to the dopamine presynaptic neuron or if
you have receptors that couple with dopamine, but do not transmit
So what I'm going to show you in a second are the data. Consistent
data are emerging, and perhaps as consistent or more consistent
as other major psychiatric illnesses linking polymorphism in the
dopamine transporter gene. The polymorphism that has been identified
in ADHD over expresses dopamine transporter in animal studies.
So if you have too many dopamine transporters, there's a lot
of dopamine going back to the presynaptic neuron.
The genes that have been associated with ADHD are some receptor
genes, dopamine receptor IV and V that are localized in the prefrontal
cortex and are this polymorphism produced, some kind of a defective
I would like to remind you that the stimulus in general, and
methylphenidate, in particular, block the dopamine transporter.
So if you block the dopamine transporter, you can compensate for
deficiencies over expressed transporter or defective genes.
So the odds ratios on several genes, I don't want to bother
you, but this includes the dopamine transporter gene. There is
a gene that is called SNAP25 that is involved in the encapsulation
of dopamine. So if this gene produces a difficulty in releasing
dopamine, you will have a hypodopaminergic ZDBH. This is the
.1 or .10 polymorphism in dopamine transporter gene. There are
receptor genes D4 and D5. One particular one, these are the alterations
today at close to two with this gene. This polymorphism here
is called a seven repeat allele, and has been identified in the
personality trait that is called sensation seeker.
So these are vulnerability genes, not disease genes. Having
those genes increases the odds of having the disease. So if you're
going back to the DRD4, again, localized dopamine receptor genes,
heavily localized in the prefrontal cortex, anterior cingulate,
if these genes produce faulty receptors, you may have inadequate
risk of dopamine, inadequate transporter, but signal is not, the
transmitter is not propagated.
If the transporter is overactive, as I said, too much dopamine
goes out. Not enough dopamine remains at the synaptic cleft to
activate the receptors, and if you prescribe treatment for that,
Briefly, another known risk factor that we have identified that
has been confirmed by many other groups is maternal smoking during
pregnancy. This is a significant risk factor for ADHD even after
controlling for genetics, social class and IQ in both parents.
We still have a significant independent effect of maternal smoking
in contrast to genes. Maternal smoking is a preventable problem.
ADHD is heavily co-morbid with a wide range of other psychiatric
disorders. That's the reason that I selected this one from
ADHD. You see a wide range of problems, oppositional defiance
disorder, enuresis. Measure a patient's anxiety disorders,
conduct disorders, and mood disorders, bipolar disorders. Okay.
It's a very serious, morbid illness that can profoundly impact
the life of the children.
One of the co-morbidities that emerges in adolescents and adult
years is addiction, and it's a major concern. It was the
most feared complications of ADHD. In the untreated state, we
estimate that about half of the people with ADHD will have significant
problems with alcohol abuse or dependence or drug abuse or dependence,
twice as much as the population.
Another issue that has been controversial in the treatment of
ADHD is that there is a similarity of mechanism of action between
cocaine and methylphenidate. Both block the dopamine transporter
and improve the signal. Okay? They both act here in a transporter.
The work done by Dr. Nora Volkow, now the director of NIDA, attempted
to clarify that the mechanism of action is not the entire story.
If you inject IV, this is work done with SPECT. If you inject
IV cocaine, you have a very rapid uptake into the brain and a
very rapid decoupling. It is this very rapid ascension to the
brain that you can attain with IV cocaine, similarly with IV methylphenidate.
This is what produces the high. Okay?
Remember that we administer medications orally. If you give
oral methylphenidate, there is a slow uptake into the brain and
no euphorism effects. So that's the reason that many of the
children or individuals that use inappropriately our medicines,
insufflate them, snort them, because that's the way that you
get the high. The addict is not looking for oral administration.
The new generation of slow acting compounds, are in some ways
protective because you cannot extract easily the methylphenidate.
You can crush the pill and snort it, but you cannot take the methylphenidate
out... and you cannot snort the pebbles of those that have microbead
We published perhaps the first evidence against the argument
that treating children with drugs like stimulants will enhance
the risk for drug abuse. In the paper that we published, we first
presented it in the NIH consensus conference and then in Pediatrics
in 1999, we were able to show that children who were medicated
in childhood and when we looked at substance abuse, abuse or dependence
on alcohol or drugs in adolescents, had an indistinguishable risk,
whereas those that were unmedicated had a threefold increased
Since then, a colleague of mine, Dr. Williams, published a meta-analysis
that incorporated four other studies showing the same, that the
treatment of a child with ADHD protects the child against emergence
of abuse or dependency in those areas.
ADHD is associated with car accidents and car accidents are a
leading cause of mortality in the young. So this is not only
a problem of school. People with ADHD frequently are unemployed
or under employed when there are 15 hour statistics in the community
and a thousand subjects, 500 with ADHD, 500 without. Fifty percent
were unemployed. Okay? Adults with ADHD frequently have multiple
jobs and about 50 percent had to leave a job directly as a consequence
And as I said before, the estimated cost to society of all of
these job related problems is about 70 to $100 billion.
ADHD is a highly impairing condition in terms of parental stress,
family conflict, accidents and injuries, substance abuse, legal
difficulties, problems with relationships, marital difficulties,
school failure and heavy dose of psychiatric co-morbidity, including
So if you look at the treatments that we have, I would like to
briefly say to you that medications are considered as the fundamental
part of the treatment. This study that was funded by the National
Institute of Mental Health and the Department of Education is
the largest effort to show that behavioral treatment is more effective
or equally effective as medication.
This study randomized about 600 children in five sites in the
country to medication, stimulants in good doses across the day.
A behavioral treatment, very comprehensive, very expensive, both
of them, medication and behavior management and treatment as usual.
What this study found is that medication was as effective as
medication plus a very sophisticated treatment, and I would like
to point out that this is considered the ideal treatment, the
massive behavioral treatment and very aggressive medication, up
to 60 percent, not more, not 100 percent. So herein we have a
very common illness leaving 40 percent of our subjects not responding
to our best treatments.
Behavioral treatment was less effective, was less effective as
management in the community most with medication. Most of the
data on treatment that we have are on children six to 12 years
old, but data from preschoolers, adolescents and adults document
that the treatments work across the life cycle.
And from the treatments that we have..., stimulants in particular,
treat these, the core symptoms, but there was a variety of other
situations like oppositionalism, like aggressivity, social interactions,
academic deficiency, and academic accuracy, areas that if not
attended to can produce serious morbidity in the child.
And the medicines that we have have what's called moderate
to large effect sizes. So they're not little treatments.
So we know, for example, that approved medications like the stimulants,
long acting and short acting, have very large effect sizes, close
to one. Although the non-stimulants have moderate effect sizes,
they're potent treatments to treat people with ADHD.
So we are dealing with a very serious neurobehavioral disorder
largely beleaguered... in our society, [with a] complex etiology,
neurobiological basis, strong genetic components, affects millions
of people all over the world, boys and girls, men and women, highly
persistent, at least 50 percent, and has a very large impact in
multiple areas of function.
Thank you very much.
CHAIRMAN PELLEGRINO: Thank you very much, Dr.
Biederman, for a very, very clear and orderly and stimulating
We'll turn now to questions from the Council. I'd like
to just put forward a question I do not wish you'll answer
right now because you may want to think about it more. But what
are some of the ethical issues that derive from these data which
you present to us and what recommendations could a body like this
make to deal with some of those issues?
But I would hold those for the time being and turn to the members
of the Council. I saw Dr. Dresser's hand first, and Dan.
DR. DRESSER: Thank you.
That was a really good overview, and we've heard a lot about
issues with overtreatment with drugs in this population, and I
think you've emphasized the problems with under treatment.
Do you see any problems with overtreatment yourself?
And second, given limited resources, what approach do you think
would be best to minimize overtreatment and minimize under treatment?
DR. BIEDERMAN: I don't think that there
is evidence for overtreatment. It's only in the hands and
minds and eyes and ears of the people that want to see that.
The evidence is in the opposite direction.
The majority of children with ADHD are not treated. Okay? So
the statistics that are frequently used is if you see an increase
in treatment, you can conclude there is overtreatment. But the
rate of treatment does not catch up with the rate of the disease.
So I would say that's under treatment.
Most parents are on the fence, but most of my struggles every
day when I go to the office is to encourage the families to tolerate
adverse effects. No, I don't have anybody that is looking
forward for the next prescription.
The data that we have parenthetically on continuation of treatment
is very dismal. It's worse than any other therapeutic entity.
Over a bit of a year 80 percent of patients prescribed medicine
no longer will take it. People with ADHD do not follow through.
So they initiate treatment. Maybe every often the child has a
mother or father with ADHD who will initiate treatment and will
get tired. It's too inconvenient, et cetera, et cetera.
So the issue of therapeutics, the burden is in the other direction,
that we are not treating a condition that is treatable. So the
tragedy here is that this is a very morbid condition that will
produce a wide range of impairments, functional life as we know
from the adult data. What you see in the adults, this is the
I do not have time to tell you that the rate, everything is disturbed,
the rate of divorce and separation, the number of automobile accidents,
the use of tobacco, alcohol, drugs, bad health habits. There's
not a single area from loving to friendship to working to studying
that they're not worse. Okay? Economically worse off.
So this gives you a flavor of what the children of today will
reach tomorrow and the cost to society. So I would argue that
we have a very difficult task ahead of us with who is going to
prescribe. There is under treatment, under monitoring, under
prescribing, and I see that as an ethical problem in my mind where
I sit, okay, because I know from our follow-up studies what awaits
my patients tomorrow, and it's not going to be a kind, soft
landing at the end of the road.
DR. DRESSER: I was just wondering. Do you
have any recommendations for addressing the situation? I mean
DR. BIEDERMAN: Yeah.
DR. DRESSER: — it's problematic if people
are refusing to continue treatment. How do you feel about that?
DR. BIEDERMAN: I don't. Unfortunately,
you have a difficult task. The problem is extraordinarily complicated.
The bad media lets parents be on the offense for years. So parents
are heavily tortured when they come to the doctor's after
hearing the same music year after year from the teachers. The
child is clearly at risk. He's beginning to do serious academic
work and obviously has massive holes in his or her knowledge,
and at that point, seven, eight years later when the child has
been compromised, self-esteem is in the basement, the child is
not doing well, the parents come to the doctor's office, and
at that point we start the process of treatment that may not be
necessarily simple. The child may not respond to Drug A. It
may take months or at that point remember we have a child in school.
This is a year that's in progress, whatever we do. So the
child may miss another year of education after we find our way
around it. The media approach to this problem is consistently
So I do not know what to do. There is a lot of charlatanism
in this profession. In a free society, anybody, everybody is
entitled to say whatever they want, but there is no way to distinguish
opinions, prejudices from facts. So I try to present at least
what we know, and I tortured you with the charts for a reason
because if I were just to extemporaneously tell you all of these
things, it's not an opinion. I mean, it's as good as
somebody that just had that thought yesterday and will tell you
that this is what they believe, and if there is enough pathos
in the voice, you will believe it.
There is another complication that what I do is very boring in
the sense of there's not a track to capture the attention
of the talk shows and things like that. When people write anything
in a book that could be totally unsubstantiated, the likelihood
of being an Oprah on a "Today Show" is very high, and
this is what the public will listen. They will not know that
the brain is affected. My genetic word is a little too technical.
What does it really mean, et cetera, et cetera?
So those prejudices are the ones that are largely propagated.
So I do not know how to combat them. I wish I had the solution,
how to combat prejudices, misinformation, dissemination of the
wrong information. I have no idea.
The Web offers incredible possibilities only if you know where
to look. So you can be bombarded with nonsense and how will you
know what is nonsense from facts?
In the NIH conference, I don't remember the name of the person
that sat at the conference. He said to all of us, "Remember
that anecdotes are not the plural of datum." Okay?
CHAIRMAN PELLEGRINO: Dr. Carson.
DR. CARSON: Yes, I have a number
of questions about your presentation.
In the situations where you say the brain volumes were decreased
in children who were affected with this disease, were those studies
controlled for body weight and body size?
DR. BIEDERMAN: Yes.
DR. CARSON: Is it possible
that early environmental factors can affect the development of
the brain? In other words, is there something else going on that
may cause certain areas of the brain to be smaller rather than
that being the primary problem?
And in children of parents with ADHD, you indicated that they
have a significant, fivefold increase incidence of developing
the problem themselves. Has anyone looked at a situation in which
those children were raised in an environment that was "normal"?
Did they still have that high incidence?
And — well, I'll let you answer those ones first.
DR. BIEDERMAN: So you're counting on my
The data on the brain study controlled for social class. So,
yes, I think that you need to make the argument. You need to
take a sample of children that came from very unprivileged environment
and look at their brains. Usually not the cognitive area are
selectively affected. Many of the children, they work the closest,
and they can tell you in extreme cases where people that were
traumatized different areas of the brain light up in those children.
Usually they had composed, say, with high levels of cortisone.
What I just showed you, in our work these were adults that were
not traumatized. These are adults that had high IQ, very well
matched with controls. All of these studies are well controlled.
Our adults in the selective findings on the cortex of attention,
these adults did not have any particular history of having been
traumatized from coming from unprivileged backgrounds, and so
on and so forth.
Your second question has to do with — what was the second part?
DR. CARSON: In children who
grow up in normal environments who have had children who are parents.
DR. BIEDERMAN: Yes. I think that the rate
of ADHD is not due to social class. We included in our studies
and other class status. Well, all social class set, and I'm
not sure what you call normal because —
DR. CARSON: That's why
I said, "Quote, normal."
DR. BIEDERMAN: Yes. We corrected by social
class using Holligshead-
Redlich social class (SES) stratification. The rate of ADHD was
high in all
social class strata. It was not driven by socioeconomic differences
DR. CARSON: Okay, and then lastly,
is the incidence of ADHD increasing or was it simply that two
or three decades ago people didn't recognize it?
DR. BIEDERMAN: Correct. I think that this
is one of the most commonly asked questions. The answer in my
mind is no. This is a similar issue. You may face or not with
the autism-PDD dilemma. I think that the main reason that children
were not diagnosed is because if the diagnosis leads to a particular
treatment that you do not want to deploy, the best way to avoid
the treatment is to avoid the diagnosis. So you don't have
anything. Boys are boys. This is what has happened a lot in
Today with the availability of non-stimulant treatments and so
on and so forth, people are more willing to make the diagnosis.
Also, diagnosis is sensitive to how you define it. So if you
use a broad umbrella, you have more people. If you demand very
strict criteria, you have small numbers.
Let me give you an example. If you define alcoholism only by
those people that need to go to a detox center, you have very
different numbers than if you define it just by misusing or having
total dependence on alcohol. So our definition leads to the prevalence
of the condition, but there is no epidemic of ADHD. We're
just more clinicians willing to make the diagnosis, more awareness
that this is a brain disorder, not just bad manners, more aware
that the treatments that we have despite controversy are safe
CHAIRMAN PELLEGRINO: Dr. Meilaender.
PROF. MEILAENDER: Yes, I feel as if I ought
to apologize at the start because I think I'm about to ask
the kind of question that drives you crazy. So —
DR. BIEDERMAN: As long as torture is not involved,
PROF. MEILAENDER: No, no, no. Well, there
may be some mental torture, but —
PROF. MEILAENDER: Somebody has to speak on
behalf of all those people who were never interested in school,
and I certainly wasn't. I don't know how to frame the
question exactly, but I mean, I don't doubt that there are
some people who are genuinely ill. Okay? But what I'm struck
by is the fact that, on the one hand, the narrowing imaging techniques
are not useful for diagnosis, you said, at least not now and,
therefore, other methods sort of in the clinical interaction you
have to make judgments about diagnosis, and then you say in describing
those interactions that, you know, you have to sort of elicit
the symptoms. Symptoms occur in circumstances where they're
not interested, and it turns out that some of these studies depend
on teachers' reports and things like that.
And you know, there may be a lot of misinformation and charlatans
out there, and I may be one of them. I don't know, but there's
an awful lot that goes on in school that you shouldn't be
interested in. You know, I'd tell my children they had to
more or less behave, but I wouldn't for a moment pretend they
should be interested in it. It's not interesting.
And I'd worry if, even thinking back to my own teachers,
if I were to be judged primarily on their reports. So you know,
I think I understand your appeal to expertise, and I understand
your worry about misinformation and so forth, and I'm not
trying to exacerbate those problems for you, but it seems to me
that has to be addressed somehow.
If this is the way diagnosis takes place and inattentiveness
when confronted with things that are inherently boring is part
of the diagnosis, I mean, then we do have to worry a little bit.
Somehow you have to address that, it seems to me.
Now, I may just be off base, and that's a simple minded question,
but could you speak to it?
DR. BIEDERMAN: Yes, sure. I certainly can.
I think that you're right that you are kind of representing
the kind of misconceptions and prejudices of our —
DR. BIEDERMAN: I will give you that. I think
that you need to distinguish. I have no doubts that there are
boring things in school. I have no doubts that there are boring
schools in our everyday lives also.
So if you are a physician and when you practice you cannot attend
to the latest regulations of Medicaid Part D or you cannot go
to the very interesting meeting about how HIPAA should be discussed
with your patients and you sleep and daydream and you have no
idea what are you doing, you can be a very gifted physician when
you examine your patient and have made a diagnosis, but you have
a lot of troubles in real life deployment.
So what I'm talking about is not the teachers expecting the
children to be lobotomized and quiet in the classroom. Remember
one more time that there is a seven-year gap that occurs and the
demands for diagnosis are not just a little bit of not liking
the math teachers well. Those are children that have a part of
the symptoms. The symptoms are very well operationalized, and
I will not banalize.
You have to have a lot of symptoms. That distinguishes you or
the affected person from the nonaffected person. The symptoms
have to be associated with impairment. They have to be associated
with disability. So it's not just the presence of the symptoms
that define the diagnosis, but the associated impairment. The
child is not able to make academic progress.
And I would like to remind you one more time that academic progress
is a fundamental passport for a good life. Okay? Under any circumstance.
So the data that the child that has the ability to complete school
and go to college, the child with ADHD may not be able to do
just that. They will get four scores on their standardized test.
They may have four scores in their grades. The doors rapidly
close on you, okay, and that's it.
So I think that the idea that this is just a little problem that
you don't like a particular class and not everything is interesting
at school, I'm not talking about that.
CHAIRMAN PELLEGRINO: Dr. Foster.
DR. FOSTER: I just want to make a comment.
In non-psychiatric medicine, we have many powerful drugs, and
what's striking about the data that you showed is the great
percentage changes between treatment and nontreatment, whereas
in these very powerful drugs that we use, the conclusions if you
look at hundreds of thousands of patients, for example, we have
a very good study that says that estrogen protects against heart
disease and then another that says, well, it doesn't, or we
look at cancer or chemotherapy drugs and so forth. We're
talking about usually a few percentage of differences. You know,
you'll live two months longer if you use this new, powerful
So what I'm having a little bit of trouble with — I very
much appreciate your showing the data, much of which I did not
know — was the very giant changes in drugs that nonpsychiatric
medicine would not necessarily consider to be in the same order
of power as the drugs that you're going to use to treat hypertension
with, and yet with terrific drugs in terms of hypertension, the
differences — we still get people to take them and so forth —
are small, and so it's one of the most — I read a lot, a
lot in Science and so forth and have edited journals —
but I think the thing that was most astonishing, that there was
not a single negative view about, you know, the treatment and
these things were so large, and that seems to me to be very unusual
for just science itself, and scientific medicine, and I just wondered.
I don't doubt the data. I don't mean that what you are
saying is not true, but one has to have sort of a — I have a
little bit of suspicion when everything that I deal with is so
small changes that these are universal and nobody except the press,
you know, seems to have a negative view about it.
That's the only comment I want to make. I don't know
that you can answer that, and I don't know of any —
DR. BIEDERMAN: Well, I think that the meta-analytic
data of enormous amount of studies that have been done and double
blind conditions are extraordinary... just as you said, that this
is a condition that responds very well to treatment. Those are
The effect size is... what is analyzed there. The critical mind
just hit another one. Again, the issue is how much stimulant
and non-stimulant is produced. But even the non-stimulants that
have an effect size of close to .7, those are very good effect
sizes for general medical standard. Those are based on double
blind randomized studies. Some are very large. So we have probably
now somewhere in the order of magnitude of 15,000 people if you
put the meta analytic efforts all together.
So it's very robust evidence supporting the effectiveness
of these treatments. I'm not saying that these are ideal
treatments. They have side effects and so on and so forth, but
so do any other medical interventions that I know of.
And so the expectation that taking children with psychotropics
should be safer than crossing the street may be high order expectation.
CHAIRMAN PELLEGRINO: Dr. Hurlbut.
PROF. HURLBUT: Yesterday one of our speakers
talked about the fast pace of input that children experience,
telephone, rapid sequence events, and video games. This isn't
my real question, but do you think that has any impact on this
DR. BIEDERMAN: No. No, I don't.
PROF. HURLBUT: Okay. What I really want to
ask you is about the placebo effect. Is that what you said at
the beginning of your talk? I think it was related to —
DR. BIEDERMAN: In depression. ADHD has low
placebo effect. The depression studies did not separate from
placebo because it was a gigantic placebo effect.
PROF. HURLBUT: Yeah, but not in ADHD.
DR. BIEDERMAN: Not in ADHD effects. The placebo
effects are in the order of magnitude of 30 percent. In the depression
study they were more than 60 percent.
PROF. HURLBUT: Okay. Since the placebo effect
is real in any case, I just wanted to know have there been any
studies on the genetics of the placebo effect itself.
DR. BIEDERMAN: No, but we are actually — most
of the neuroimaging, fascinating neuroimaging studies on Parkinson's
disease and in pain with the placebo, it's really telling
that it's a real effect, that the same changes in the Science
paper and Parkinson's disease, the same changes were documented
on people that improved on placebo as they improved on the dopaminergic,
We collect DNA in all our studies. So we are poised. The effort,
of course, is to identify genes that moderate efficacy, but we
can equally examine genes that enhance the likelihood of response
PROF. HURLBUT: But it isn't been done?
DR. BIEDERMAN: It has not been done.
PROF. HURLBUT: Is it enduring as an effect?
DR. BIEDERMAN: The placebo? No.
PROF. HURLBUT: No. It's fast.
DR. BIEDERMAN: Yeah. Remember the studies
that we conduct, we can now conduct studies for five years.
PROF. HURLBUT: Yeah.
DR. BIEDERMAN: So the studies are usually a
few weeks long. For example, in the study that we did that carried
the treatment for six months blindly, there was a very precipitous
decline in the placebo patients that were months ensuing the acute
PROF. HURLBUT: Finally I wanted to ask you.
You said school is the passport for a good life, and my immediate
response was as successful life within a social context.
DR. BIEDERMAN: Yes.
PROF. HURLBUT: But not necessarily a good life.
DR. BIEDERMAN: Pardon my use of an incorrect
or confusing word. I'm not making a moral judgment. I'm
not in any capacity trying to define what good life is.
PROF. HURLBUT: Right.
DR. BIEDERMAN: Okay? I only meant that it
is a direct relationship between the job that you can get and
your education. This is all what I meant, not that if you are
making millions that you're happier than if you are not making
millions. That's not what I'm talking about.
PROF. HURLBUT: Well, I didn't mean to put
you under any criticism on that. I just wanted to play on that
to ask you. It seems to me that in some context we're not
emphasizing the right core values in our civilization. We had
speakers yesterday that said this essentially, that we're
putting children under a lot of pressure. Performance is so much
talk in our society about the economic value of various things,
and I think, I mean, I don't know. You hear different people
say different things about this, but it does seem true to me that
there is a decreased emphasis on what people used to call character
qualities or spiritual qualities or fundamental values in children.
And when you look at what children want by self-report, it isn't
necessarily noble or virtuous. It usually has to do with social
standing, and I wonder what effect you think that might be having.
I mean, after all, finally what the brain relates to the mind
and the mind relates to images and values and goals in life, ideals,
aspirations, can you say a little something about that?
DR. BIEDERMAN: Yes, absolutely. I never intended
to say that. I was not talking about economical impact of what
will be your paycheck at the end of the day. Let me give you
Let's say that somebody has a true passion to take care of
animals, to be a veterinarian. Okay? Veterinarians are not making
— I'm just using this as an example — so that's what
you would like to pursue. You'd like to become a nurse or
a teacher. Okay? That also are not millionaires at the end of
In order for you to become a teacher, you have to pursue a path
of some academic competence. If you cannot graduate from high
school, you're never going to pursue a teaching career, a
nursing career, a veterinarian career. I'm not talking about
being a master of the universe in the Bonfire of the Vanities
lingo. I'm actually very saddened when I routinely ask children
that come to care, "So what would you like to do or what
would you like to be?"
So the model answer is to be a millionaire. So I say, "If
being a millionaire if a profession, like in a bagel store, you
take a number. In college you take Millionaire 101 and Millionaire
DR. BIEDERMAN: So it's really amazing,
but I agree with you that I'm a physician and not a moralist,
and I don't pretend to have solutions for society's ills.
So the kind of desires, the examples of millionaires in our sports
arena and now with the Super Bowl this weekend, that somebody
that knows how to throw a ball is discussing 50 or $100 million.
That's not available to most human beings, but besides that,
I think what I alluded to is when you have a dream that you'd
like to pursue, okay, there are very little things in our society
that you could do from being a social activist to being a religious
leader that does not require some academic foundation.
If you have the vocation to be a religious leader and you cannot
learn anything in school or you are thrown out of school or you
became a drug addict, at some point in your life those dreams
are shattered. Okay?
So I'm not talking about or I'm not measuring success
by the amount of money that you bring at the end of the day; that
if you don't make seven figure salaries, then you're a
But none of your dreams, even if you have other vocations, may
be accomplishable if you in your past, you have serious complications
as the one that these conditions can bring in the untreated state.
PROF. HURLBUT: You know, this is a two-way
arrow though. That's my point.
DR. BIEDERMAN: A two-way?
PROF. HURLBUT: I mean, you know, you see children,
and it's like with Parkinson's disease and attention tremor.
The closer you get to the goal, the more your hand shakes, you
When a child is put under pressure, if their whole construction
of what makes a meaningful life relates to doing well on a test,
that test is going to put them under anxiety in a way it wouldn't
if it was just a stepping stone to, you know, one of many things
My point is: is the reality of ADHD or other psychiatric disorders
in childhood exasperated by the value system that children are
growing up in?
DR. BIEDERMAN: I really don't think so.
I'd like to distinguish what you do. The test is a final
product of your knowledge. So if you're not doing well in
the test, it does not matter. Of course, if you have a test you're
going to be anxious, you should be anxious.
The tests measure what you know. Okay? So incremental learning
in mathematics, if you did not learn Chapter 3, you will not be
able to understand Chapter 4 or 7 or 8 or whatever comes after.
So I think that the issue that you need to distinguish and what
I'm trying to say is that a people that struggle, it's
not that they're anxious about the next test. It's that
they're not acquiring knowledge. They have holes in their
information systems that you can drive a truck through. So they
really are ignorant.
They grab it from high school. They may not have the information
that they need to do anything. So I think that they are not talking
about somebody who is aspiring to get A's in every class. Okay?
But you still need to be competent in whatever your education
is to be able to move to the next step and have some basic knowledge
to be able to confront the multiple demands if you're illiterate
or you have no ability to do the most basic calculations. You
cannot work as a cashier in a local supermarket here.
And so those are things that could be profoundly interfered,
not just core values. I'm not talking about those issues,
and I am fully supportive of the fact that we need to do a much
better job in promulgating dose than just the media will magnify
the amount of income that an actor or singer makes and this is
glorified to a sports figure. Those are the role models of our
young, not somebody that is helping the world in Africa and dealing
with poverty to the right and to the left.
DR. SCHAUB: Could I have just a very quick
follow-up to Bill's question?
CHAIRMAN PELLEGRINO: Okay.
DR. SCHAUB: Just one sentence.
CHAIRMAN PELLEGRINO: All right.
DR. SCHAUB: Would ADHD have had an effect on
life performance two centuries ago?
DR. BIEDERMAN: Yeah, absolutely. Some people
talk about the hunters-gatherers, the idea that the hunters-gatherers'
inattention and distractibility would be good for them. I think
it's a true mistake to think that in the primitive society
of hunters-gatherers, the person with ADHD would be carried by
the group, but would not be an asset to the group. Okay?
This is not a condition that is associated with decreased fertility.
So the genes for this disease are more extensively promulgated,
if you want, because people with ADHD tend to be more disinhibited
in that way than schizophrenics, for example, that will have fertility
issues and will not date, but the people with ADHD have no problems
dating and impregnating or being impregnated.
So I don't think that it has ever been adaptive. Why some
conditions that are not adaptive are maintained in the genetic
pool, we have a steady rate of schizophrenia from Biblical times.
It's not an adaptive trait, or autism and so on, or mental
retardation, et cetera, et cetera.
So I don't think that at any point in evolution even before
the Nintendo and before our high tech society, being inattentive
is a disability. I always try to use as an example when I was
a few years ago in a photograph safari in Africa. I had an opportunity
to follow a cheetah hunting. The cheetah is looking at the pray
moving an inch an hour. The inattentive cheetah does not eat.
DR. BIEDERMAN: I will tell you that.
CHAIRMAN PELLEGRINO: I have requests from three
speakers, and a response. I'd like to ask
Dr. Biederman if you'd be good enough to hold off your response
to the three and summarize it and caution you that there is less
than ten minutes left, and I would like to stay to the time requirement
if at all possible.
Our first request is from Dr. McHugh.
DR. MCHUGH: Dr. Biederman, this was an impressive
presentation, and I'm sure there's gold in here.
Let me though begin by saying that the suspicions that you're
receiving from this group by other groups come not in relationship
simply to your data, but through the history of Americans'
relationships to psychiatry over the last 50 or so years when
the characteristic of psychiatry has been to pathologize people
and to increase the numbers out of proportion to the number of
ill people that there are out there.
It began with the Manhattan study, and I have to go over these
things with you, but the Manhattan study and several others right
up till now so that these numbers begin to make anyone who has
any skepticism begin to wonder about what is being described.
The phenotype that you're describing here and persuading
us to use this powerful general stimulant that affects everybody
if they take it is as you say, something that you'd call a
final common pathway from a number of different things.
There's another way of describing a final common pathway
of this sort, and that's called a waste basket, and yesterday
we heard from the Eides that the patients that are sent to them
from all over the country for assessment with diagnoses like ADHD
or artistic spectrum disorder, that with those diagnoses they
don't know what they're going to see, and they see all
kinds of different children with very different disorders more
specifically related to aspects of their social situation, aspects
of their neuropsychological dysfunctions of particular sorts,
each one of which can be differentiated from one another, all
of which though are affected by the stimulants.
And when you show us the brain material that you have, it also
is very general. It is not at all — you can tie it together,
but it's scattered and not diagnostic.
So I think you're in a tough spot really more than anything
else, that I think this term ADHD, along with several other terms
that have become current in psychiatry, in particular in child
psychiatry, are just that. They need to be broken down much more
specifically and have to be differentiated in relationship to
more specific treatments depending upon the specific pathology
What would you say to that? That really we are still groping.
What I believe — I spoke about it yesterday — is a very large
amount of science in psychiatry is being done in relationship
to checklist assessments; that they do not rest like medical diagnoses
and developments do on full psychiatric assessments, external
informants, developmental histories, psychological testings, all
combined together to determine what the case really is both before
So with a generic diagnosis and a generic treatment, a treatment
that you admit has problems of side effects to it, we're still
skeptical. That's all. We certainly want to do the best
we can by children, but at the same time, we don't want to
presume that everybody who is skeptical about it has some kind
of other ax to grind other than the experience with psychiatry
over the last 50 years.
CHAIRMAN PELLEGRINO: Dr. Rowley.
DR. ROWLEY: Well, my question is a follow-on
to reports and work of the Council last year and the year before
on Beyond Therapy, and there was a whole segment in that
admitting that for properly diagnosed patients with ADHD, that
various stimulants seem to be effective.
But that the same stimulants, ritalin, for example, is being
used and the council's concern was misused in situations where
children don't have that particular diagnosis or disorder,
but often by parents who would like to have the child be particularly
up for exams or other sorts of things.
So I guess my question is really: in your experience or as you
view the scene, how much of these stimulants are being misused,
if you will, for things other than what in your view would be
their proper use?
CHAIRMAN PELLEGRINO: And the last question
from Dr. Carson.
DR. CARSON: You indicated that children with
ADHD can have selective manifestations, that is, you know, there
are some times when they appear to be affected and other times
when they are not. I'm very intimately familiar with a young
man who gets into a lot of trouble in school, doesn't seem
to pay much attention, but is a whiz at anything he's interested
in, games and things of that nature.
Is that person likely to be suffering from the disease or is
he just bored at school?
CHAIRMAN PELLEGRINO: Dr. Biederman.
DR. BIEDERMAN: Let me see. Just for working
memory issues, I will start with your question and then we'll
All of these things are empirical questions. We did an analysis
in our sample in children that had IQs about 120 with and without
ADHD to address the boredom hypothesis. Okay? Unfortunately
they had the same level of familiality, the same level of co-morbidity,
the same level of neuropsychological deficits that are the fingerprints
of ADHD compared with children with the same IQ that did not have
As I said to you before, you have to have many more IQ points
to do the same if you have ADHD. Remember that life, as I said
before, has a wide range of non-exciting things in front of us
every day. So if you can only attend to the things that you like,
you will be seriously handicapped in your job. It is no different
for a child. For child, school is their job.
So the fact that you can build engines very well because that's
your hobby and you cannot do anything else and you're a wizard
with your engines does not mean that you can forego all the other
things that you may be required to know to be an informed citizen
of our society, and a very complicated society that you're
going to navigate.
DR. CARSON: Just to follow
up, that child was me.
DR. BIEDERMAN: But remember that you should
be very careful. There are people that are survivors, people
that go through greata trials and come out reasonably well. Okay?
I certainly had my own history of misfortunes, but you cannot
use that to generalize.
When I look at these things, I look from the broader panorama,
not the few that will be able to navigate the waters very well
and come out, but the majority may not be as successful as you
But in any event, the other question about misuse, as I said
before, under medication and misusage, there is very little evidence
that that is true. Okay? In medicine if a pediatrician prescribes
an antibiotic to a child that has a viral infection because of
parental pressure or something like that, well, that's not
a good, necessarily medical disposition, but we should be very
careful in my opinion not to throw the baby with the bath water.
And bad medicine in psychiatry or in outside psychiatry is bad
medicine. So somebody that does not have a fever will not benefit
from an antipyretic.
Dr. McHugh was saying about nonspecific treatments. Well, steroids
are very nonspecific. They still help a wide range of medical
conditions, and without steroid treatments, people will die.
So we have to be careful in equating absence of specificity with
the fact that this is a waste basket kind of condition. You know,
many of the treatments that we do in medicines are not curative.
If we give antihypertensive to people that have hypertension secondary
to a wide range of medical problems, they are not ecological treatments,
but can save lives, can allow people to make the progress that
they need to have to maintain a decent existence.
So I would like to caution you that this is not just a waste
basket. The fact that this is heterogeneous, again, you can conclude
that it's a waste basket. All medical conditions are heterogeneous.
There are syndromes, genetic syndromes, that are produced by different
genes that produce a very similar phenotype.
So it does not mean that it's a waste basket. If you get
the flu, you cannot look at a patient and way that you know which
pathogen, which type of virus hits you because they all look physically
So the fact that it's a conglomerate of diseases with similar
phenotype should not necessarily lead to banalization. The patients
that we assess over the last 20 years, and we are now doing our
15 years follow-up, were very comprehensively assessed. These
children had not only questionnaires. They have questionnaires
with the parents. Each questionnaire, each structured interview
takes two or three hours to administer.
We have similar information from the parents. We have neuropsychological
testing. We have blood for genes. So there is a convergence
here from neuroimaging, two cores, neurological testing, serious
co-morbid psychiatric conditions that these people have.
So I think it's not just that you did a questionnaire and
they had something that we call disease.
I would also like to stress that no clinician treats people.
I don't recruit patients in the streets. "Come and see
me because I have this wonderful stimulants to give you."
People wait a year to see me, and as I told you before, I never
close my clinic. I always see patients, but you have to wait.
The idea is that the treatment that you can — people are tortured
with the notion that they will have — the childhood medications.
They're not looking forward to what was described, that parents
want to advance the children's interest. It's not necessarily
something that I contend. Most of the families that I deal with
are tortured. They waited seven, eight years, and only if the
child is unbelievably unfair, is not able to make the progress
that the child could be expected to make, is failing school, is
having difficulty socially, is having difficulty with his family,
has no self-esteem.
At that point, the child can benefit from treatment. So it's
not cosmetic... pharmacology.
CHAIRMAN PELLEGRINO: Thank you very much, Dr.
We will have a very short break. Be back at 10:15 so we can
stay on schedule.
Thank you very much.
(Whereupon, the foregoing matter went off
the record at 10:07 a.m. and went back on the record at 10:16