Matinum

Taking Charge of Your Health


>>From the Library of
Congress in Washington, DC.>>Robert L. Gallucci: Ladies and
gentlemen, welcome to the Library of Congress to the Kluge Center and to our meeting today
Exploring Important Questions around Depression and
its Treatments. I’m Bob Gallucci. I am the director of Kluge Center. I’d ask you at this time
to do what I’m going to do which to put your cellphones
on stun or silence or whatever works well for you. Also a word of announcement/warning,
today’s program is being filmed for the Library of Congress and
the Kluge Center websites as well as well for Kluge Center
YouTube and iTunes’ U Channels. The Kluge Center where you now
are was created 15 years ago through a generous gift from
philanthropist John W. Kluge. It brings together scholars and
researchers to distill wisdom from the library’s rich
resources and to interact with policy-makers and the public. The center also awards the Kluge
Prize which recognizes achievement and the study of humanity. It was awarded to philosophers
Jürgen Habermas and Charles Taylor last year, 2015. The scholars’ council is here today. The panel we are hosting is led by Scholars Council member
Philip W. Gold as a part of the annual Scholars Council
meeting at the Library of Congress. Scholars Council is a body of
distinguished scholars convened by the Library of Congress to advise
on matters related to scholarships at the library with
special attention to the Kluge Center
and the Kluge Prize. Information since 2001, the council
comprises 14 leading thinkers and includes winners of the
Pulitzer Prize, the Holberg Prize, Balzan Prize, Guggenheim-Fulbright
Fellowships, and those listed among Time
Magazine’s Most Influential People. Dr. Philip Gold has been a member
of the Scholars Council since 2004. He received his undergraduate
medical degrees at Duke University and his post-graduate
medical training at the Harvard Medical School. He has been at the NIH Clinical
Center since 1974 where he served as chief neuroendocrine research in the NIMH intramural
research program. Dr. Gold and his colleagues
had pioneered the elucidation of fundamental mechanisms of
the neurobiological– biology– excuse me– of the stress response and its dysregulation
in major depression. He is an author of more than 500
publications including a series of 9 full-length articles in the
New England Journal of Medicine. The Kluge Center is all about
bringing scholars together from different disciplines
and encouraging conversations and reflection that might
not otherwise happen. Our panel today does exactly this. Dr. Phil Gold has been
thinking about these topics for decades from a scientific angle. In addition, as a medical
doctor, he brings a deep concern for the human condition and a drive
to improve the lives of patients. As he wrote for a recent
interview for the Kluge Center blog and I now quote Dr. Gold, depression
is an insidious illness infiltrating core attributes that
define our humanity. For this reason I have an abiding and profound antipathy
for its treachery. Depression humbles us by making
us seem far less than who we are. In so doing it robs of the
major epics of our lives, past, present, and future. I’m glad he and his distinguished
colleagues are with us today and will be reflecting on
these important topics. Dr. Gold. [ Applause ]>>Dr. Philip W. Gold: Thank you
very much for those kind words. It’s a pleasure to be here and back
at the Scholars Council meeting. This will be my last. And it’s been a magical experience. We have three speakers today. I will start and speak on general
aspects of major depression and how we’ve come to understand it as a neurodegenerative
systemic disorder. And then Dr. Ray DePaulo who
is chairman of the department of psychiatry at Johns
Hopkins University and head of their depression
research program and one of the world’s outstanding
geneticist and psychiatry will be speaking on
genetics of psychiatric disorders and especially depression
and bipolar disorder. And Dr. Carlos Zarate
who is a laboratory chief at the NIH has made, I think, one
of the most important discoveries in the last 25 years in
psychiatry by finding that the drug ketamine is able to
produce rapid and full remission in treatment-resistant patients
in as little as an hour. And just yesterday I saw a
preprint of his paper which appeared in the journal of nature where
they have worked out the mechanisms of action of ketamine and
discovered other compounds that have similar effects
with fewer side effects. We’ll each speak for about 40
minutes and take 10 or 15 minutes of questions after our talks and
that will still about 15 minutes at the end of the session
for questions. Let me just type in my information
here so I can get online. Pardon me just a moment. Oh no. All right. This is bound to happen. I’ll try it again. Forgotten my initials here. I don’t believe it
as I have assigned. Now I don’t even have a hint here. I’ve been using this
password for years. All right. Ready to go. Thank you. OK. Not seeing my [inaudible]. Oops! I’m at the back here. I’m so sorry. This is going so slowly. I do research in stress and
now I know what it’s like. Let’s see. OK. Here we go. What I’m talking about
depression is a dysregulation of the stress response and
we’ll be describing some of the newer findings that have
emerged which established depression as a full-blown disease, a
systemic full body disorder which neurodegenerative aspects
and is a progressive disease, much more serious, I think, than
we had previously appreciated. The slide there is a
schematic of something that Hippocrates said 2000
years ago that we’re all beset by disturbing forces that
maintain, balance, equilibrium, and fortunately they’re
counteracting, reestablishing forces that reestablish the
balance, equilibrium. And today we call the disturbing
factors, stressors, the balance or the equilibrium homeostasis
and the counteracting, reestablishing forces as adaptive
responses and two adaptive responses so the stress system
and the immune system. Galen referred to these
counteracting, reestablishing forces as these [inaudible] the
healing forces of nature. And as I mentioned, we know that
depression is a dysregulation of the stress response and
I’ll talk with you a bit about what the stress
response is all about. We first presented this
in a two-part series in the New England Journal of
Medicine entitled “Clinical and biochemical manifestations
of depression, Relation to the neurobiology
of stress.” And what is the stress response? Say you’re being chased by a
bear and you fear for your life. The first of fear-related
behaviors and anxiety and these are essential
for survival. Without them, there is
not sufficient motivation to escape the threatening stimulus. There is a very extensive
central nervous system apparatus for generating anxiety deep in
the brain and it sends many, many fibers to the cortex to announce the conscious
experience of fear. But the cortex sends relatively few
wires down to the anxiety center and for that reason, we can’t really
persuade ourselves not to be afraid or not to be anxious and that’s the
price we pay, I think, for survival. But I think it’s one of the
tragedies of human evolution. There is a decreased capacity for
pleasure and the reason for that or one of the reasons for that is
to prevent distraction along the way since the attention must be focused
only on the threatening stimulus. Similarly, there’s an
inflexible mood and cognition. The mood should not
be bouncing around and cognitive style is really
very fundamental either programs that had been generated during
past stressful experiences or somewhat instinctive responses. Stress hormone production
is always an invariable part and I’ll be talking a bit about
some of these stress hormones, cortisol and norepinephrine. There is redirection of fuel to
the bloodstream and the brain and this increases plasma
glucose which the brain– the stressed brain needs in order to
mount an effective stress response. It occurs through insulin
resistance. And I can talk a little
bit about that later on. I’m going to show you some data. There is premonitory inflammation. And so when we are stressed,
whether it’s psychological stress or whether it’s a physical stress,
there is a premonitory activation in the inflammatory response. And presumably, that occurs perhaps
to prime the system to respond to a possible injury
that is inflicted by the stressful situation. And there’s also similarly an
activation of coagulation as a stay against plasma hemorrhage
so that the body is ready for this before it happens. Inhibition of neurovegetative
program for one of these– again, these occur in order to
prevent distraction or the wasting of calories on programs
that are not essential. So that if you’re being
chased by a bear or if you’re very stressed,
you won’t stop and eat. You won’t stop and look
at a beautiful scene. You won’t stop to rest. You won’t stop to sleep. You won’t stop to participate
in sexual activity. All of these are suspended
during the acute stress response. And there is something called– increased neuroplasticity
and neurogenesis. We just learned that not long ago. And I’ll mention a little bit
about that in the next few slides. But these are intercellular changes that occur invariably during a
stress response that is controllable and of which the individual
fields they can master. And as to the effective termination
of the response, it has to stop when it’s no longer needed
rather than to linger for long periods of time. Now, what do I mean by
neuroplasticity in b there and c? You see these are projections
from neurons. They’re like trees, dendritic trees. And normally, they’re quite robust with very severe stress
down at the bottom. They are diminished significantly. And with stress that is
manageable, mild manageable stress, actually this neuroplasticity
increases. On the right you see two slides. The bottom one shows neurogenesis. We now know the brain
makes new neurons. They’re born and they make
connections with other neurons and they’re essential for
an adaptive response stress. The bottom micrograph shows
what that is like at baseline. And on top, that is the staining of these new cells during
controllable stress response. This shows again on the left the
control, normal dendritic tree and below, how it’s paired off in the prefrontal cortex
and hippocampus. On the right, what happens actually
is that this tree actually burgeons in the amygdala, the amygdala
fear center which is essential for the conscious experience of fear and which plays a very
important role in the experience of depression. Now, there are several
forms of depression. I’ll talk about two principles. The first is melancholic depression
and it affects about 35% of patients who develop major depressions. And this term– this form of depression belies the term
depression in that in a state of hyperarousal, its cardinal
manifestation is anxiety, directed at the self, and
experienced as a sense of worthlessness and
meaninglessness. And so it’s an existential state. Inhibition of the capacity to
anticipate or experience pleasure. Inhibition of sleep,
appetite, and interest in sex. There is– Inflammation is activated
during depression really rather considerably and there’s
some data to suggests that not only it may be premonitory
but that it may even occur and predate the onset
of the depression. Insulin resistance, so blood sugar
rises to help the stressed brain. Increased blood clotting. And these events occur even
during psychological stressors, just as powerfully as if when
we’re chased by a dangerous animal. Inhibition of the growth hormone
and reproductive endocrine systems to save energy for
the stress response. And there’s a marked decreased
in depression of neuroplasticity and neurogenesis which
are not very much involved in a depressive pathophysiology. So, melancholic depression,
this really is a rendition of virtually exactly to
what I had earlier showed as what transpires
during a stress response. Fear-related behaviors, the
inflexible mood and cognition, stress hormone production,
redirection of fuel to the bloodstream and brain,
inflammation and coagulation, inhibition of neurovegetative
functions, here, decreased neurogenesis
and neuroplasticity, and there is insufficient
termination of the stress response. It gets stuck as it
were in the on position. Here is a schematic of the brain. If you look at the green area,
sort of in the center to the left, that’s called the subgenual
prefrontal cortex which Wayne Drevets discovered
was significantly reduced in size and its activity is
abnormal in patients with familial major depression. These are people who are depressed and who have first degree
relatives who are depressed. And this plays a very important
role in the depressive syndrome and during the stress response. It regulates and restrains
the amygdala fear system and hopes to– and
is working properly. It prevents being maladaptive
levels of high anxiety. It plays a large role
in self-assessment on how we feel about ourselves. It estimates the likelihood
of punishment or reward. It modulates the pleaser
and the reward centers. It restrains cortisol secretion
and norepinephrine secretion. And in patients with
familial depression, it’s reduced by as much as 40%. And here you see the healthy
volunteers and the bipolar, unipolar depressed patients
showing how a significant decreases in the volume of the prefrontal–
of the subgenual prefrontal cortex. And so what you get is a syndrome
where there’s excessive anxiety; self-assessment is feeling of
worthlessness that goes along with anxiety about the
self; increased the estimate of the likelihood of
punishment, down regulation of the reward center;
release of increased cortisol and norepinephrine secretion;
and this neuropathic change which is one of many in depression. This is not the only one. But there are many that
occur in various centers that control cognition, bodily
functions, sleep and so on. Down at the bottom you see
amygdala and there is– the arrow goes to the–
that yellow structure. And the amygdala fear
system is essential for the conscious experience
to fear. It restrains that subgenual
prefrontal cortex. It makes it more abnormal. And it really puts a break on
the pleasure and reward center. It’s very hard to anticipate
your experience pleasure when you’re very anxious. Severe anxiety is virtually the
absence of any good feeling. It stores negatively
charge emotional memories. It activates cortisol and norepinephrine secretion
stress hormone secretion. It’s increased in size and
there is more neuroplasticity during depression. So the amygdala is really
firing at full force in the midst of a depression. And its neuroplasticity is actually
increased during depression, which is what we wouldn’t
like to see. And there’s an area
called ventral striatum, which you see there’s an arrow there
to the red structure which is just to the right of the
subgenual prefrontal cortex. The ventral striatum plays the most
significant role in the anticipation and experience of pleasure
and it’s involved in reinforcement and
in drug addiction. It sets the tone of
motivational salients. In response to pleasurable
stimuli patients who are depressed have a subnormal
activation of the ventral striatum, do not respond to pleasurable
stimuli. And its size is significantly
diminished in depression which is lost during
the act of depression. And so this is responsible for
one component of the depression which we termed anhedonia or the
inability to experience pleasure. And one last structure I’m
talking about is the hippocampus. And it’s a horseshoe-like
shape structure. This is a different cut
of [inaudible] brain. The hippocampus served
multiple memory functions, regulate special relations. It modulates the subgenual
prefrontal cortex as an area in the front of the hippocampus
called the anterior hippocampus which sends a single wire
without prior connections to the subgenual prefrontal
cortex and is thought to modulate it significantly. It sustains cortisol and
norepinephrine secretion. It’s the principle site where
neurogenesis takes place in the brain where it increased
during normal stress response and decreased during severe
stress with depression. And its size and we’ve known this from quite awhile is
significantly reduced in patients with depressive illness. So there’s loss of tissue. There’s more loss of
tissue in depression than there is in Parkinson’s
disease. And depression is all
more problematic. Parkinson’s disease
is a terrible disease but it’s generally a
disorder of older individuals. Depression has its own, so
not infrequently in children and adolescents and young adulthood
and it’s a lifetime disorder. And there’s an area called the
hypothalamus which you see there at the base of the brain and
it connects to the pituitary and it produces a hormone
called CRH, which our lab has worked
considerably. CRH is released from the brain, stimulates the anterior pituitary
just outside of the brain, and that stimulates the
secretion of cortisol. But it’s the brain that
drives cortisol secretion and its secretion is highly
elevated with depression. We’ve now finally nailed down that
depression is really a full-blown systemic neurodegenerative
disease rather than a simple chemical imbalance. This concept comes a lot
in research that shows which I just shown you
will also gain tissue in several highly specific
sites in brain. And these pathologic
changes in brain progress if the depression is
not effectively treated. The damage to the areas
perform functions relevant to the core biological and psychological dimensions
of depression. And I’ll just repeat these again. But you’ll see these are the
major components of depression. Anxiety, how we perceive ourselves,
the likelihood of punishment and reward, the capacity to
anticipate or experience pleasure. We now know precisely
where these tissues are, what the tissues look like, which
cells are destroyed and what’s going on in remaining dysfunctional cells. One new thing that we’ve
learned about antidepressants is that almost all antidepressants
significantly improve neuroplasticity and neurogenesis. This makes some remarkable compounds
that few others if any compounds which actually increase neurogenesis and people are experimenting
using antidepressants to try to treat disease of the
retina, for instance, to get neurogenesis active there
and other sites of the body. So neurogen and if you
give an antidepressant which increases neurogenesis
and neuroplasticity, if you block the neurogenesis you
don’t get the antidepressant effect so that for reasons that we don’t yet understand neurogenesis
is essential for antidepressant efficacy. And so this leads us to a
search for other compounds that promote neuroplasticity and
neurogenesis for the treatment of depression and in
tissue engineering. One other thing that we know which
is disturbing about depression is that there are systemic or
total body manifestations. The pathological losses or gains
in tissue in specific sites set into motion pathologic
changes outside of the brain. They’re responsible
for the premature onset of coronary artery disease,
stroke, diabetes, and osteoporosis. So depression is really
the tip of the iceberg of the syndrome is a serious
and systemically widespread. Patients with depressive illness
lose approximately seven years of life, much is untreated
hypertension predictably shortens a life. Now I’m going to talk
a little bit about CRH which is the main driver
of cortisol. It actually does many things
in addition to driving cortisol and I don’t think it’s core
abnormality in depression but it confers many of
its observable features. And if you give it centrally to experimental animals it induces
fear-related behaviors, anxiety, and increased vigilance,
inflexible mood and cognition, the hypercortisolism and
increased norepinephrine secretion. It produces the enzyme resistance,
the proinflammatory state, and increased coagulation. And it inhibits food intake,
sleep, sexual activity and the endocrine program
[inaudible] growth and reproduction. Now here’s a study that we
did sort of an ambitious study to really get a good picture with
this where we put lumbar drains in where you would do a
spinal tap and left in there for 30 consecutive hours. The neurosurgeons would do this after all much all
neurosurgical procedures, the incidence of infection
is virtual nil and there are virtually
no side effects. And what we saw is cortisol
was elevated around the clock in the upper left even while
people slept so that this anxiety and hyperarousal does not
require consciousness. And in the lower right, you see [inaudible] reverse the
CRH is significantly elevated around the clock in patients with major depression
including when they are asleep. Now, I’ve mentioned, Norepinephrine
before, norepinephrine has many of the same effects
as CRH and it’s– induces fear-related behavioral,
inflexible mood and so on, activation of the amygdala,
increased blood pressure and pulse rate, the
insulin resistance and proinflammatory state,
increased coagulation and it inhibits the
neurovegetative programs. And in that study,
when we execute CSF for 30 hours, this is what we found. First thing that we
found, this is a picture of showing the 24 hour
levels of norepinephrine and the cerebral spinal fluid and
it’s elevated around the clock. And the slide below shows the
restoration of normal secretion after electroconvulsive treatment. And electroconvulsive treatment
seems to be very draconian and we try to avoid using it. But actually, if we had
say an 80-year-old person who become very depressed and
stop eating and was wasting away and we wanted to get a rapid
antidepressant response before Dr. Zarate came along, we will
use ECT and it would work in over 90% of the cases. This is the curve in red of the
24 hour norepinephrine secretion in plasma and it is
restored to normal after ECT. And here is the 24 hour
pattern of cortisol and its level comes
down after ECT as well. The top three showing you curves
that are virtually superimposable, these are all cardiotoxic compounds. And when they peak early
in the morning, near end– at the very end of the slide,
what– that is the time that occurs, that is the maximum
time of susceptibility to heart attacks and
to sudden deaths. And here’s epinephrine or adrenaline
which is elevated around the clock and only is partially
restored after the ECT. This is a study we did in another
group of depressed patients who are not as severely depressed
and we put a cannula in an artery and infused radioactive
norepinephrine so that we could get calculation
of its disappearance rate and this gives us the
spill of rate and you see in melancholic depressed
patients the baseline is elevated. They get an increased
response during a video game which is a mild stressor and rather
substantial rise after [inaudible] which is a drug that increases
norepinephrine secretion. So, both CRH and Norepinephrine
are excavated and they synergize with one another, they
stimulate each other’s response and each other’s activities. Now, I mentioned earlier,
the systemic manifestations of the depression and the pathophysiology is
essentially what I’ve shown you before, the inflammation
is part of depression. It’s a very much a part
of this pathophysiology. Coronary artery disease is
principally an inflammatory disease and the major marker for
coronary artery disease, CRP which you get drawn in your
doctor’s office is an index of the cardiovascular risk
and if it levels over two, you’re at somewhat high risk
[inaudible] at greater risk and CRP is an inflammatory marker because the atherosclerosis is
largely due to an inflammation of the veins– of the arteries. Increased cortisol secretion
has multiplicity of effects. Every cell in the body
has a cortisol receptor. Sympathetic nervous
system activation, the insulin resistance causes
much physiologic morbidity and the increased clothing. Let me show you some data that we’ve
done looking at insulin resistance. I’ll describe insulin
resistance a little bit. I hope this seems clear. Insulin is a hormone that secreted– that causes glucose to exit
the bloodstream into the cell and if you lack insulin
you have diabetes. And so, blood does not get into
the cells and instead it builds up and you have very high blood sugars. During stress and in depression,
we get slightly insulin resistance, so what happens is that the
insulin doesn’t really promote as much glucose transported
into the cell. It builds up in the blood supply and
high glucose levels go to the brain which doesn’t need insulin to
transport glucose across the neuron. And for that reason insulin
resistance is a clever way to increase plasma glucose acutely and to promote optimal brain
function during distress. And we see that in our depressed
patients who are remitted, they’re not suppressed any longer, they have increased
plasma insulin levels. The insulin is going
up and up trying to get the glucose into the cell. It does mange to do it completely and the plasma glucose
levels are elevated in patients with depression. They’re not abnormally elevated. The insulin levels don’t
get abnormal, 100, 110. So, here, it’s really 90s or a low
90s but it’s significantly higher than we see in healthy
controls who are matched for BMI, age, and gender. Then we see elevated fasting
triglycerides and total cholesterol in remitted patients
with major depression. They have high triglycerides. They’re not outside the normal
range which is about over 160, they have high cholesterol
not outside the normal range but it’s 185 compared
to the total cholesterol in very closely matched controls. And next is a compound
call adiponectin which is very essential
for insulin sensitivity. I won’t go into this in detail. But adiponectin promotes
insulin sensitivity and its levels are reduced
completely in patient with major depression around
the clock at every time point. One of the things that
happens during depression because of high cortisol levels
and at the top of that sphere, high insulin level, high IL-6
which promotes inflammation. And that increases the secretion of
adipose tissue but a special form of adipose tissue which intraabdominal,
we call it visceral fat. And visceral fat is a very
active biochemical machine. And on there right there,
you see it makes a variety of proinflammatory compounds
that cause inflammation. IL-6 for the side with receptor,
you don’t need to know these, TNF-alpha resistant and so forth. And actually, the levels of the circulating proinflammatory
compounds correlate with BMI. So, if you have child who’s
moderately overweight, they’re in a proinflammatory state. And anyone who’s overweight or
obese is in a proinflammatory state and that confers along the mobility. It goes all along with obesity. The insulin has a variety of–
it’s elevated in depression, a variety of negative effects. It promotes inflammation and it stimulates the
sympathetic nervous system, it produces bad liquids
and increases clotting. Now, this is some studies we’ve
done, there are many others done by others that show inflammation
in patients with major depression. And there– the inflammation story in depression is very
exciting, really. It’s present in a very large
percentage of depressed patients. It’s present in the bloodstream,
it increase stimuli compounds that stimulate inflammation, and there is increased
inflammation in the brain. And this seems to precede
the major depression. So some people feel that inflammation may be a
primary trigger to depression and some have used antiinflammatory
compounds and with mix results, but there have been
several which show that they have antidepressive
effects. This is an around the clock
study we did with plasma IL-6 which is a proinflammatory compound. It’s elevated around the
clock in our patient. These are in patients who are
no longer depressed and not on medication and they
have high levels as you see on the right there, CRP, this compound that predicts
coronary artery disease and they have high levels of something called serum amyloid
A. There is a peripheral CRH that we’ve shown and it comes out
of sympathetic nerve terminals. And it is proinflammatory. It stimulates white cells and it stimulates a cell called
the mast cell which contains– it’s a bag of proinflammatory
compounds that can do great harm
if uncontrolled. And IL-6, one of the proinflammatory
compounds has a whole variety of other effects. These things all influence
one another. They are synergistic
in their actions, the positive feed back loops. Nature has really designed
this system so that you can really
get the stresses ramped up in dire emergency. But I think that provides
the context for being so much depressive illness because
depression apparently affects 16% of the American population at
one time during their lives. Now, why my patients with
major depression be inflamed, this is speculative on my part. But there is a new
form of inflammation which has been described
called parainflammation. And it occurs in the
context of stimuli to which we’re not exposed
in our early evolution. And so, it become inflamed in
this context during at old age, which was not present long, long
ago during overfeeding or obesity and underactivity with disruption
of the ordinary light-dark cycle with artificial lighting with synthetic chemicals
and drugs and so forth. And I suggest again speculatively that major depression may be
apparent inflammatory disease. Because early in our evolutionary
history, we may not have experience, the everyday multiple small
stressors that are incurred in our everyday social interactions
or living in chronic conditions. There are several markers for
parainflammation that we’re looking for to see if we can verify
that this process is transpiring in patients with major depression. And in coagulation,
we see the patients with the major depression have
increased plasma fibrinogen which is a clotting factor. And the next slide, I
won’t dwell on these. But just to show you again that
both in the morning and the evening, patients with depression have
increased clotting factors. One is called PAI-1 and the
other is called factor-VIII. We reported in the New
England Journal of Medicine that even premenopausal women with
major depression have osteoporosis. And here is the schematic
slide of the hip. And if you look at that normogram, you’ll see that the darkened
area is the normal range and this patient is way down
in the osteoporotic range. This is 35-year-old woman
with major depression. Now, they don’t get fractures
because of their youth, the protein [inaudible] ammonia
is very strong and intact. But as they age, they become
progressively more susceptible to osteoporosis or its
precursor of osteopenia. These are the bone mineral
density markers at various sites. They’re all reduced in a depressed
patient in multiple sites in the hip and multiple sites in the spine. This next slide are–
the first is ostocalcium. It’s a compound that
promotes bone growth and it’s reduced in
depressed patients. And it’s– On the right side there’s
something called deoxypyridinium links, cross links which go up
when there is bone reduction and they are reduced in
patients with depression. Here’s a biopsy that we did from one of our most severely
osteoporotic premenopausal women. On the left is normal
architecture of the bone. They are what we called
trabeculae or canals. Oh yeah. They are trabeculae
or canals that are made of tough material that suspend the
bone and give them a strong matrix. And in the osteoporosis, the
patients with major depression, that structure is markedly
disrupted. And I just mentioned something
about atypical depression. I don’t have enough time to show
you the data that we have in it. But atypical depression
is another form of depression affects
another 30 to 40% of patients with depressive illness. And in contrast to
melancholia which is a state of pathological hypoarousal,
atypical depression is characterized by profound lethargy and fatigue. The patients feel much less alive
than usual rather than anxious. They also have decreased
capacity to experience pleasure. Instead of losing their appetite,
they have increased appetite and weight gain, increased sleep. Whereas in melancholia, the
depression is worse in the morning and gets a little better
in the evening. In atypical depression, the
severity is less in the morning and more severe in the evening. And the patients feel ward off
from themselves and others and say that they feel painful loneliness
which is hard to escape even when they’re around other people. And we’ve shown that these patients
have those stress hormone levels, have increased indices
of inflammation, have decreased activity of the
growth hormone or reproductive axes, and they have increased
heart disease. I’m going to close
this with a concept that people becoming
more interested in and I think will have
more biological markers for in the next few years, but
it’s the concept of resilience. The American Phycological
Association defines resilience as the process of adapting well
in the face of adversity, tragedy, trauma, threats, and even
significant sources of threat. Then what confirms resiliences? There are genetic factors. If one identical– in identical
twins, if one has PTSD, the other twin has a
40% chance of having it. So even though they share
100% of their genes, there’s not a 100% of concordance. So 60% of it is environmental. Repeated childhood trauma
to uncontrollable stressors. And people that study children
who were housed in institutions and those who were adopted
later, they study them, they were more anxious, and
they did bring scans on them, and they had amygdala– amygdalae that were increased
in size and activity. On the other hand, mild to
moderate controllable stress early in life can have an
inoculating effect. Such experience leads to increased
neuroplasticity and neurogenesis, and increases the size of the
subgenual prefrontal cortex. An enriched, nurturing environment
and early life with exposure to manageable novelty increases
resilience later in life. Positive emotion, optimism,
loving caretakers, flexibility, the capacity to reframe adversity, and strong social support
also increase resiliency. And finally altruism,
commitment to a valid cause, a capacity to extract meaning from
adverse situations, and a tolerance for emotional pain and sadness
promote resiliency as well. And people are developing a panel
of biomarkers for resiliency that hopefully can– will be
validated in the years to come. So I’ll stop at this
point and take questions. OK. [ Applause ]>>I’m not sure, I actually
understood some of the chart and things that when you’re
talking about a depressed person and then a nondepressed
person and compare things, did you have a depressed person and then a depressed person
who– after treatment?>>Dr. Philip W. Gold: Most of the depressed people
we’ve studied we hope to study while they’re
not on treatment so that the studies are not
confused by the impacts of the drug. So all the patients that
I showed you were people who were depressed
but medication free.>>All right. Thanks.>>Well, in response to the last
question, I’m a little bit puzzled by the definition of depression. Is there a neurobiological correlate
that enables you to identify it or do you just go by
patient’s report? Is it just that the patient
is seeking treatment? I mean, I look for lessons in
your account and it seems to me, one of the lesion is we all ought
to be taking antidepressants because it’s going to
improve our brains. I’m sure that’s not
what you intended?>>Dr. Philip W. Gold: Yeah.>>But it would be nice to know
what exactly is the working medical definition of depression
and then a correlate that is is there a precise
neurobiological correlate in a sense that with runner’s high we know
it’s in Keflins and endorphins. What is it for depression?>>Dr. Philip W. Gold:
Well, runner’s high– it’s the same problem
with runner’s high. There is overlap in
these abnormalities between depressed patients
and controls. They’re not completely separated. So we don’t have what is a
definitive biomarker and that is, I think, one of the
most active areas of research, in depression research. They have many abnormalities that
is levels of things that are higher or lower, systems that seemed
to be going array together and complications which make sense
in terms of those abnormalities, but not a definitive
biological marker, which I think would
be the holy grail. And I think it’ll probably
be a genetic marker.>>OK. So why shouldn’t we take
antidepressants for neurogenesis?>>Dr. Philip W. Gold: I don’t know.>>Well, I got a lesson
from you then.>>Thank you for that. In addition to genetics
and childhood trauma, I’m wondering to what extent
environmental factors like air, food, et cetera play in the
development of depression?>>Dr. Philip W. Gold: I don’t
know if there are any data about environmental
factors like air. There are scattered reports for
that being one predisposing factor to depression with a number
of other factors involved. But they’re not real
systematic studies of these kinds of environmental factors. There are more studies that have
to do with adverse psychological and physical environments for
children and so forth and adults. Yes?>>Thank you Phil. That was a really interesting talk. You seem to– well, more
than suggest, but you– we are stacking an evolutionary
loop in the sense that we are living with a system that is
wired for a primitive time.>>Dr. Philip W. Gold: Yes.>>And, you know, there are course
in the evolutionary trajectory. We have lost hair, we have
increased our head size, we’ve done enormous advances to
adjust to our modern lifestyle, how– what do you– how can you
speak to the fact that this is one of place where the human
body has not evolved?>>Dr. Philip W. Gold:
It’s a very good question. I don’t know. Because the anxiety is so necessary
for survival and we’re so surrounded by stressors and especially early
in our environment but even now, that I’m not sure there
have been mutations that weaken stress response
that increase survival better. I don’t have a really good
answer for that, but it’s true. We’ve evolved in some ways,
apparently not in this way. Yes.>>You pointed out that depressed
people have increased insulin resistance and other markers that
normally would lead to obesity in depressed peo– yet, so– but the medications also get
blamed for causing weight gain.>>Dr. Philip W. Gold: Right.>>So, if you don’t treat the
patient then they’re going to gain weight, so what– which
is really the better way to go?>>Dr. Philip W. Gold: Right. The insulin resistance usually
occurs in the melancholic patients who are also lose their appetite. So they don’t become
obese in that regard. And there are some
antidepressants do cause weight gain but newer antidepressants
are coming along that don’t have that side effect. But there are serious side
effects of some antidepressant.>>Phil. This goes back
to the first question. And I’m not sure I fully
understood the answer so I’m going to press you a little on this. If I understood correctly, you
have characterized depression as a progressive disease and
not a simple biochemical issue. You have described different
kinds or variations on the theme of depression that different
kinds of depressed people. The phenomenon I’m mostly interested
in is that the confidence– scientific confidence that can
be expressed to capture this in that way that when I’m
getting to hear is the indicators and the extent to which they are
definitive markers for depression and what’s behind the
question is in the experience, and I suspect they’re not the only
one who has had– has people– have people with depression in their
family, but there’s a large part of the family that rejects
depression as a disease or a physical illness and instead
looks for a character weakness. And if there were definitive
scientific marker that would I think help
in terms of reactions.>>Dr. Philip W. Gold: Well, I think that there have longitudinal
studies, neuroimaging studies that show that the loss of volume of that subgenual prefrontal
cortex is progressive over time. And that the changes in the amygdala
are also progressive over time. There are also some
data, this doesn’t apply to every depressed
patient by any means, but there’s an epidemiological
sense especially with recurrent depressions that this
is already gets worse over time. The episodes are more severe
and they come closer together. And rather than requiring an
environmental precipitant, they occur autonomously. But I think those are
the data that we have. But I think that given
all the imaging data, the physiological data, the responses to pharmacological
treatments and so forth, the fact that it’s a– and the
systemic disease that patients with depression get, that it’s
fundamentally incontrovertible, that really is a systemic disease. The World Health Organization
recently had an international conference where they decried
the propensity for people to see depression as a
personal failure in view of the incontrovertible data
about its biological roots and urged more money for research and treatment facilities
to treat it. Sixty percent of depressed patients
in the United States are untreated. Yes.>>Thank you for bringing
this and talk. You mentioned at one point
that in terms of a certain type of depression, anxiety is
the cardinal manifestation. So I’m wondering what
is the difference between an anxiety disorder and
depression which has anxiety as its cardinal manifestation?>>Dr. Philip W. Gold: You
know, I think, you know, they both respond to
similar medications. They have some genetic
roots in common. I think there’s an overlap. One of the things that is absent in
anxiety disorder is the upsetness with itself, a feeling
of worthlessness. People with that kind of
anxiety disorder are more worried about accidents, things happening
that could harm them and so forth or coming down with certain disease
that can shorten their lives, but not this anguish
over the state itself that is the cardinal manifestation
of melancholic depression. Anxiety disorders generally are
not associated with alterations in appetite or sleep and some
of the neurovegetative findings. They don’t necessarily
have increases in secretion of cortisol and norepinephrine. They’re generally normal
in patients with anxieties or where there is genetic
and clinical overlap. That’s a good question.>>[Inaudible] depression that
hopefully will go away in its own. But is there a current
research that we can learn from like how long is too long
to have situational depression and if it might turn into major
depression and should we run for treatment after
a certain timeframe?>>Dr. Philip W. Gold: Right. Well, you know, the diagnostic
criteria, say, only after two weeks of major depressive symptoms. But ones that are really
severe, early morning awakening, loss of weight, loss of appetite,
terrible upsetness with self, relative incapacity and so forth. So they say that really
after two weeks, but I would watch longer than that. But I think if something
going on for a month or so, I would begin to feel
concerned about it. That one issue is there
used to be the idea that if there were a situation that cause a depression,
it was not biological. I don’t think that’s the case. I think stress often
precipitates depression, a loss in the personal
realm or of a loved one. And people can become depressed and remained depressed
after those losses. And they should– it should not be
considered that they are impervious to depression, but are merely sad, if they really show
all the manifestations of depressive disorder. It is the phenomenology rather than the precipitant
I think that matters. Yes.>>Thank you. Just as we have public awareness
on drugs, STDs from your lecture, I’m beginning to think that
we may now be at this stage in which we have to mount
the public awareness on this?>>Dr. Philip W. Gold:
I think that’s right. The NIMH is mounting that but
it has a limited resources. But I think that over time and as
the new findings are coming out, more neuroimaging findings, the
kind of findings that Dr. Zarate has with immediate responses
to new drugs and genetics, I think we’ll capture the
imagination of the public and make it clear that it’s a
serious disorder that’s progressive and it needs to be treated.>>Hi there. I’m a psychotherapist working
in East Tennessee with children, adolescents and adults, and
I was particularly interested in your brief tour
resilience in children. And when you’re working
with children who have not necessarily
have that resilience, perhaps have reactive
attachment disorder, is there research being going on,
are you doing some things about how to help a child get resilience
if they don’t already have it?>>Dr. Philip W. Gold: You
know, I’m not an expert and I’ve read some papers
and there are strategies to develop resilience, you
know, promoting challenges that are manageable with the support
of assistance of an adult and or ward and progressively
increasing the challenge and systematically
going ahead like that.>>It’s over time.>>Dr. Philip W. Gold: Yeah. OK. One more question I think. Yes.>>Sir, perhaps this is
appropriate for the last question. What is the state of the art in repairing the brain
from this disease? What can we do, what do you
expect we’ll be able to do to repair the neurology
that’s the genesis of this?>>Dr. Philip W. Gold:
There’s been– They’re into efforts to do pcych–
so-called psychosurgery, you– implanting electrodes in treatment-resistant depressed
patients who had terrible and completely treatment-resistant
depressed patients. The insertion of an electrode and stimulating the subgenual
prefrontal cortex produces immediate and sometimes lasting response. And also there have been
electrodes that have been placed into the reward center and stimulating the
reward center also seems to produce an antidepressant
response. I think people are working on all
kinds of ways trying to influence, you know, the brain activity
without being invasive. There are now magnetic resonance
treatments for depressions. Some people even say that
MRIs are helpful for treatment with depression and
other noninvasive ways of affecting many areas. As we learn more about the areas
that are affected and find others that may be larger and more
amenable to external manipulation. That may be new strategies for
treating depression that way.>>Do you believe it will actually
prepare ourselves eventually?>>Dr. Philip W. Gold:
It’s a good question. I think that we will know
enough about cellular repair in neurogenesis and other factors
that repair would be possible. Also, psychotherapy is very
important in treating depression. And the best treatment for
depression is a combination of psychotherapy and medication. That is by far more effective. And there have been data
that show that people who have successfully responded to
psychotherapy have positive changes in the subgenual prefrontal
cortex and the amygdala and in the ventral striatum. So experience can also
modify the brain. Thank you. [ Applause ] [ Inaudible Discussion ] Our next speaker is
Dr. Carlos Zarate, who runs a very large
laboratory and research program at the NIH Clinical
Center, looking for new and rapid antidepressant treatments. He’s made, where I considered
many do conceal the most important discovery perhaps in the last
25 years in studying depression and that is the capacity of
economy to induce a remission in treatment-resistant patients with
depression in as a little as a half in hour and sometime
lasting for days. And I know he’s just
published the paper that is actually has
discovered other compounds that can do this even better that
they’re attempting to develop and synthesize to treat depression. And anytime you get an effective
treatment with depression, you also have a tremendously
important tool for figuring out the mechanism of
the depressive syndrome. If you know what’s the drug is
and it’s make people better, then you learn something
about the underlying disease. So I’d like to call on Dr. Zarate. He will reveal his experience
with this very promising field. [ Applause ]>>Sure.>>Dr. Carlos Zarate
Jr: Good afternoon. Thank you so much Dr.
Gold and others for inviting me her
to speak of our work. And I’ve a series of cartoons
and animation, hopefully, will summarize our work
and make it understandable. And at the end, I’ll be
glad to take questions. So the title of today’s talk is
Relief from Severe Depression and Suicidal Thoughts from– within hours and our work going
from synapses to symptoms, and most recently two
candidate drugs that can actually accomplish
this rapid response. This is my disclosure. I’m a full time employer
in the federal government with the National Institute
of Mental Health. So, briefly summarizing, mood disorders is common
chronic and recurrent. We have major depressive
disorder and bipolar disorder. Our next speaker will go more
in detail into bipolar disorder. But it’s not only– presents itself
as manifestations of problems of mood, but there’s problems of
behavior, now circadian rhythms and activity level is crucial. We’ll see problems with excess
activity levels or mania and decreased activity
levels during depression. And why is that? Well, if you ask our patients or
their family members, it’s very hard to recall in the past
states of elevated energy and mood based on subjective report. What is very easy or
easier to recognize is when they have increased activity
levels that they can go on and on our patients for
hours without sleeping. And now it’s not viewed
as Dr. Gold mentioned, simply as neurochemical
disturbances, but the mood and the behaviors are
the– in circadian rhythm, disturbances are the
results of disturbances as synapses and circuits. But these synapses and
circuits, of course, are– have influences from genetics
and environment as well. Now, we have a general negative in
mood-behavior has been reported. Most of our patients
have both depression and anxiety at the same time. There is irritability. Many of our patients are
very angry and hostile and that’s unfortunately a concept
that has been lost over the years in terms of what you see
with your patients is really that there’s hostility and
risk of violence and suicide. There is also the opposite extreme which is the manic
mood and behavior. We have excess energy
levels, activity levels and increased risk-taking behavior. We’re not going to get more into
that because our next speaker will. But towards the right,
you see an image of the same person during their
state of depression, sitting still, looking in a distance, probably
have a poverty of thoughts, thinking probably of death,
not eating and not sleeping. And that’s actually what
you see in the same woman at the opposite extreme, where
you could see probably dressed with many layers of clothes, given
belongings away, so on and so forth. Our patients can have also psychotic
symptoms or cognitive symptoms. The psychotic symptoms are impaired
reality test and psychotic symptom– and cognitive symptom
is destructibility and impaired cognition. And what’s very interesting in
our patients with both depression and with bipolar disorder, you
could have a mixture of any of these symptoms over
the course of your life. And one episode is not necessarily
the same as another episode. You may have had 30 years
which makes it very difficult to diagnose our patient’s
accurately. Now, we talk about
symptoms and categories, but this is a real
patient, one of our patients on the research unit
here in Bethesda. This is Bob, a 53-year-old
married male with a 35 year history of severe, refractory major
depression, co-morbid anxiety, phobia, PTSD, and alcohol
dependence. Has had 10 major depressive
episodes. Mother had anxiety disorder,
brother had a history of depression and alcohol abuse. He, very smart, went to school,
the best schools, got a BS, was– running big prominent organizations,
had a suicide attempt with overdose of nortriptyline, that’s one
of our treatments or Pamelor for depression, and nearly died. Was admitted to our hospital
with thoughts of stabbing himself with a knife or driving
off a cliff with a car. I’ll come back to Bob later on. Now, as been mentioned before,
these are very commonly associated with manic conditions,
other psychiatric disorders, if you have depression, but
the very impair and in terms of the amount of disability. This is a rank order list of
the conditions or disorders that are associated from
number one to number seven of those causing major disability. And you can see what is at the top. Neuropsychiatric disorders. We have mental-behavioral
disorders much more than neurological disorders. But this group of categories
are much more disabling than cardiovascular disease,
musculoskeletal disease, diabetes and so on and so forth. And remember, these are chronic
disabling disorders of the young as already mentioned before. Cardiovascular disease
starts later in life. But you have deprived and robbed our
young ones with having this illness. They have not been able
to date, finish school, be able to buy their house,
get a job and so forth, and they start with
disabling symptoms. So we have to do better. These are the– and not
only it is associated with significant morbidity
but significant mortality. These are lethal illnesses. If you look towards the left,
this is the peak, 1965 to 1995, peak percent of the illness. And what’s happened with our– with
the treatments over those decades and how it’s– it affected
the prevalence or the rates of these illnesses over time. And you can see in general,
leukemia, ALL leukemia has come down with new information
in terms of pathophysiology, new treatments, so on and so forth. We’re doing a good job there. And also in heart disease, you can now decrease one million
deaths per year with exercise, diet, better medications and treatment. We’ve also made progress in AIDS. As you know, people can now
live into very late age– years of their life with treatments. And also stroke, we can now, if
you show up to an emergency room within two hours, one-third of there
can really have a good outcome. So very important, if you
have symptoms of stroke, go to emergency room right away. However, look what
happens with suicide. Despite 50 years, 30 to 40
different antidepressants, the rates of depression
have not decreased and– for suicide has not
decreased over the years. In fact, if you think of a measure
of success is decreased in the rates of serious mental illness. Despite all our treatments, we’ve
not made a significant then. In fact, the suicide is wrong. In fact, there has been an increase. Recent report show actually there’s
been a 24% increase in suicide. That’s a major issue and I’ll
talk about a little bit later. Not only do you die
from– because of suicide, but the excess deaths
are due to other factors. Many of what Dr. Gold
has mentioned, problems– proinflammatory conditions,
coagulation, homeostatic conditions, so on and so forth, there’s
an excess risk of death from cardiovascular disease,
from suicide and from accidents. So our patients with mood disorders, particularly bipolar
disorders die at younger age. It’s not unusual to
live 10 to 20 years less if you have a major mood disorder. And I’ll already mentioned,
you start already with significant disability
from young age. Now, this summarizes a little
bit what Dr. Gold was talking. This is the course of illness. You have in the upper left corner
a diagram showing in the blue, major depressive episodes,
yellow are the well-being, the euthymic intervals and then in green are the hypomanic
or manic episodes. And generally, for significant
number of our patients, as time goes by, your
depressions last longer. You can see in the figure,
they’re more severe. And the good times are
the well being is shorter and shorter, the yellow,
you can see. Each of those episodes
have a significant impact. We’re already told about
significant impact on bone, on brain and heart and so on and so forth. You can see the personal disruption
to one’s life, personal family, occupational disruption
significantly affected with each of those episodes, as well as economic well-being,
society is affected. And then there’s a risk
of suicidal behavior. Towards the bottom, you can see
how problematic our disorders are. But it’s even made worse that most of the time you do not find
bipolar disorder alone. Ninety percent of the time, you
find some other comorbid psychiatric syndrome or disorder. Seventy percent of the time you have
three or more psychiatric disorders, each sometimes requiring
different types of treatment. Towards the upper right, you see
a figure looking at the time of– this study was about 120
patients with bipolar disorder that were followed for 13 years. And you can see in the bars is
the percent of time in weeks that they have been affected. Half of the time of that 13
years, 6.5 years they spent in– having symptoms of the
illness, half of the time. One-third of the time
was in depression. The killer and the big
problem of our patient with bipolar disorder
is the depression. In about 5%, they had rapid for– rapid cycling or mixed forms
of the illness having both high and low at the same time. Now, each episode causes that significant social
individual disruption but it has the toll on the brain. And we talked about, has
already been mentioned, towards the bottom
right are neurons, the dendrites and the branches. There’s atrophy and
shrinkage of the spine, those places where
you have connection from one circuit to another. In this diagram, you can see here
that there’s a, in the bottom right, a little circuit, and that if it’s intact might explain why are
patients have different symptoms. Dr. Gold and I made both– made criteria for major
depressive episode, but we overlapped on
only one symptom. That’s very common
and very possible. So depression, and people
are asking the definition is, hundreds of disease. Hundreds, each with its
separate etiologies. So, you can see how the clinical
presentation might vary from him to me and so on and so forth, depending on the circuits
that are affected. We see that, for example here, the
circuit is missing or it’s affected and you have anhedonia,
lack of drive and pleasure, very common problem in our patients. And another circuit
might be affected and you have suicidal thoughts
or in fact suicidal behavior. So, towards the upper
left, we see the spines and the circuits are very intact. That looks like a tree in spring. We have branches and leaves that
can absorb the moisture and the rain and propagate the neurochemical
signal. Unfortunately, because of the
cortisol as mentioned by Dr. Gold, the gluco– excess glucose and
glutamate, I’ll talk about, it looks like a tree on
winter, deprived of the branches and the leaves that can absorb
the chemicals, the moisture or the neurochemicals and
propagated downstream. Towards the right, we see that
there are many possible explanations for the shrinkage or
atrophy of those branches, so it looks like a tree in winter. We have towards the
bottom right, we have BDNF, brain-derived neurotrophic factor. Those are the Miracle-Gro factors
which have you have in your garden and make things branch out. There are also these natural
endogenous brain chemicals that maintain the neurons
and the branches healthy. And you have the cortisol and
stress and so on and so forth. So there’s a different mechanisms. The one I will talk
is in the right– on right side of the
figure called glutamate. Glutamate is an excitatory amino
acid and its regulation seems to be important to depression. So, we talked about– we have and
people have talked about criteria. We have what we called DSM,
Diagnostic Statistical Manual, and that has been one way of how
we communicate with each other with families, our
patients and with clinicians on our patient who’s in front of us. So it is a common language for
describing psychopathology. In general, we do a fairly good
job describing and agreeing that this person has a
major depressive episode. There, unfortunately,
is a significant overlap in symptoms and syndromes. I already mentioned
how there’s 40 to 50% of our patients have many
comorbid psychiatric disorders and the symptoms unfortunately
do not map onto the brain. And so that has been one of the
reasons why we have not been able to find more effective treatments. And so, what had– has been
proposed at the National Institute of Mental Health, NIMH, is to break
it down into the more simpler– to more simple elements, anhedonia,
motor activity or drive, suicide. In those trends, you can then
understand it in a better way. Going into units of analysis
all the way, for example, in anhedonia from the behavior lack
of driving pleasure, staying in bed and not enjoying things all the way
to genetics, going through circuits and cells and that will give
us a better understanding of these illnesses. And RDoC does focus on understanding
the more simple elements that cross– go across
many of these disorders. You can have anhedonia and panic
and obsessive-compulsive disorder and depression or schizophrenia
for that matter. Now, what do we know–
need new treatments? Well, OK, there’s you know, 30,
40 different antidepressants, and this is the time course
of discovery from the 1950’s. And we’ve started– the first
antidepressant was discovered by serendipity, and that’s
unfortunately what happens in psychiatry. Clinical observation which is a
good thing, and I think will lead to continued discoveries is
really the only way we’ve come up with better treatments, just by
observing our patients being exposed to different medicines out there. The first was a drug, an
antibiotic given for tuberculosis. It was given at high doses and they
noticed the patients were dancing in their units and
enjoying themselves and talking a mile a
minute and not sleeping. And so, then people thought,
Oh, this, you know, you’re high, that means it’s probably good for
your depression and started coming up with different forms of it,
known as the MAO inhibitors, monoamine oxidase inhibitors. And then the next 50 years,
it was trying to go, well, the first few drugs were
nonselective affecting serotonin, norepinephrine, dopamine,
choline, cholinergic systems. And people said, the industry said,
“Oh, they’re not well tolerated and they’re very lethal
in overdose”, like tric– like nortriptyline, like
Bob was taking, Pamelor. So let’s go to more
simpler antidepressant that affect predominantly serotonin,
you know that as the SSRIs, Prozac, Zoloft, Paxil, so on and so forth. And then some of the clinicians
out there and patients said, “Well, probably they’re not as
effective as the older one.” OK, let’s go back to two,
dual reuptake inhibitors, two neurotransmitter, SNRIs. And then now there’s– going back
to triple reuptake inhibitors. So most of drug discovery
has been about me, two drugs. They’re pretty much the same,
serotonin-norepinephrine. Most of the patients probably do not
benefit much more than what we have from existing treatments. So they are suboptimal. Clinicians, patients
and family said, “Well, probably our medications
are not effective. And so not effective or effective
for some, let’s figure it out.” So NIMH did do this very
large study called STAR D. That was a systemic way
of giving levels of care. Everybody at level I started
with the first antidepressant, citalopram, for 10 to 14 weeks. If you didn’t respond, you
went to the next for 10 to 14 weeks, so on and so forth. OK. What we’ve– What we
see in the first bar is that about 33%, 36%
achieve remission. Remission means doing very well. But it took 10 to 14 weeks. Moving to the second bar, 50%
achieved remission, but that takes about 6 months to antidepressant
transfer half of our people to achieve remission. That’s way too slow in my opinion. And then after four treatments
including psychotherapies, I didn’t mentioned here,
one year later, only– one-third are still not
achieving remission, one-third. And not only that, of those
who responded, begin 40 to 60% in those first two
bars are relapsing. So what we see is low remission
rates, a significant lag of onset, personal-social problems and
the risk of killing yourself if the medication is not
working or the therapy. OK. This is drug discovery for those who are interested in
the economics of it. This is how we develop drugs. OK. We come up with– we have
preclinical and clinical phases. This takes about 15 years and 4 to $11 billion studying 10,000
compounds to get one possibly that might make it to the market. OK. And these are the success rates. Infectious disease, the highest. Why? Because we know
what the targets are. OK. The lowest are, what, brain
disorders because they’re complex and we really don’t know
what the exact targets are. The success rates for
CNS is about 8% after spilling all–
spending all that money. And you can see why industry has
been leaving psychiatry altogether. Now, this is a summary of why
we need improved therapeutics and what happens. In this cartoon, you see in
blue the depressive episode. We started antidepressant. OK. Any of them currently
on a market, it takes about 10 to 14 weeks. They affect monoamine systems which
is serotonin and norepinephrine. That’s what I mean. Our goal is to shift this
curve towards the left so that the next generation
treatment, we will have treatments that work in a few hours that
way [inaudible] depression use [phonetic] suicidal thoughts. And if you remember, that
time I showed the figure over your lifespan, how much
time you spend in depression. Imagine for each of those episodes
which range from 4 to 9, average, number of episodes for each patient, or half of the time you
spent ill in your life. Within one to three days, if
you have symptoms of depression and you treat that, it goes away, and the next one it
comes it goes away, you can imagine the
cumulative number of episodes, accumulative depression of your
lifetime will be very short, thus your health, physical, as
Dr. Gold said will be better and your brain will be better. So that is the goal of our program
is to develop rapid-acting agents. We come up with targets,
in this case, glutamate. Our studies are what was
mentioned, drug-free, double blind, placebo control on our inpatient
unit here, a few miles from here. And we study multiple biomarkers,
both peripheral blood measures and brain measures at the same time
to better understand our patient. So our patients are great
and they really spend– altruism was mentioned. They’re really altruistic and really
want to understand these diseases and help others to come
up with better treatments. So towards the upper right, you see
that we are looking at interventions that cause rapid antidepressants
effects such as ketamine, an anesthetic, I’ll take about scopolamine,
that’s for sea sickness. We’re also looking now
at neuro devices, TMS, electroconvulsive therapy. So our studies are double
blind, placebo controlled, and what we do is at the beginning, we obtain multiple biological
measures and what we try to do is link these with our
traditional rating scales of depression which are not good,
but it’s all we have at this time. And we obtain responders
or nonresponders. The goal of this is to link
the biological measure, whatever that might be,
with our depression scores to see who’s the respondent and
nonrespondent so that we can come up with more biologically-enriched
subgroup. I already talked about
depression is hundreds of diseases. This strategy will lead to more
enriched group to really tease out what is the etiology
of these illnesses. And not only that, we obtain
these biological measures before, during the study, and
after the study. And I’ll give very brief
examples about that. That rather than focusing on
what is the cause of depression, because we talked it’s hard,
hundreds of depressions. We’re going to figure
out what is the mechanism of the response process. Who response and not response? And why is that important? Well, response is probably going to
be more similar across individuals in depression and at
least that’s the belief. So, one area let’s look at
is the glutamate system. OK. And I’ll talk a
little bit what this does, evidence in postmortem studies, looking at people who’ve had
depression or who have suicided. There is evidence that some of the
glutamate receptors are affected in the brain and there’s
also evidence through– we use assays or what we called
animal models of depression, animals that are stressed. And for example, forced swim test,
you have animals in the cylinders, Plexiglas that are
struggle, struggle. That’s viewed as a good sign,
but when they stop struggling, that’s viewed as helpless
as they’ve given up. And that’s supposed
to mimic depression. And I said, well, you know,
you do that in a few minutes, but our patients have been
depressed for 30 years, is that a really good model? Probably not. But it’s what we had been
relying on for 50 years or so. But there was early evidence that
the– or antidepressant affected a– or glutamate receptor called NMDA, and that’s going be very
important as I talk about. And that if you give drugs
that block that receptor, those animals that were made to be
stressed and depressed got better. And so in early study done in the
year 2000, trying to study cognition because that’s really affected in
our patient with schizophrenia, psychosis and depression, notice that the depressed
patients got better. Seven or 8 patients got better within a few hours
and that was ketamine. And so we have done for the work on
that and I’ll talk about that now. OK. This is a very simple
diagram explaining the glutamate. OK. Glutamate are those
little white balls there. We have three, the top is
the presynaptic neuron, the bottom is the postsynaptic
neuron and towards the right,
we have the glia. This is the tripartite system,
important for regulating glutamate. Glutamate is an excitatory
amino acid. It’s very important for learning, memory and the plasticity
Dr. Gold mentioned. OK. So it synthesized and store in these little presynaptic
vesicles and it’s released. And it’s very tightly regulated. And it’s believed that if
the levels are excessive, that leads to neurodegenerative
disease such as Alzheimer’s, Parkinson’s and in
this case, depression. Depression might be
more the regulation or the cycling of the system. There’re mechanisms to
control the amount of glutamate within that space,
extracellular space. One is the EAAT, excitatory
amino acid transporter, that grabs the glutamate
and puts inside the glia. That’s the cell in the right. And there is this metabotropic,
mGlu. That’s the thermostat that goes up
and down based on the temperature of the room, goes up and down
based on the amount of glutamate. And then there’s the postsynaptic
receptors, NMDA and the AMPA. All these, the Miracle-Gro,
brain-derived neurotrophic factor that leads to the spines,
very healthy trees in connections is what the glutamate
is important for, plasticity. And what happens in depression? The nondepressed looks like this,
very health, we talked about, and in our depressed patients. OK. So it’s not s much about
regulating glutamate but even if you regulate dopamine, serotonin,
glutamate, what is important to have that tree healthy. And so our treatments have
to be plasticity enhancers, make that tree going from
winter to spring and be healthy. OK. Now, as you can see
it is a complex system. I tried to summarize it here but there are multiple
targets that one can pursue. We and others had been
looking at that over the years. And this is just a
summary of the studies. About 8 to 10 years ago, most
of the companies had dropped out of psychiatry developing drugs and we’re just using
off-label drugs, I mean, drugs that their patent had expired. Now since the ketamine
started 2006 or so, many of these companies have jumped in to pursue drugs that
regulate glutamate. Predominantly, if you look at
the bottom, NMDA, that target is where everybody has been going
on, NMDA receptor antagonist through our studies and other
studies, and I’ll talk an example. The prototype drug is ketamine. OK. Ketamine is an anesthetic agent
that’s been out for several decades. It’s one of the most
safest anesthetics. In fact, it’s used in many
countries around the world without a physician, nurses
in really remote areas because it doesn’t affect– it
doesn’t cause CNS depression, problems with breathing and
other complications that might– you might need a significantly
trained anesthesiologist to manage. There are many drugs. I’m not going to go into detail,
but if we understand ketamine, we can get a sense of where we
were heading in our research. OK. Now, that receptor I
mentioned is blown up here. You can see. This is a channel,
inotropic channel. This is one receptor where you
have the sodium and calcium into the channel and point for
learning, memory and plasticity. OK. Now, in the channel,
you can see PCP. That is the drug called PCP. Ketamine is a derivative
of that drug of abuse, PCP, but it’s 10 times to
40 times less potent. It happens to bind
to the same receptor. When it does bind to that
receptor, the channel closes. And so while you receive ketamine
or infusion, what is affected? Your learning, memory,
and plasticity, right? Because we say that’s important
to the function of the channel. And you might say, why are we
exposing our patients to these drugs that affect learning, memory and
cause symptoms of dissociation? Well, the important thing is,
I’ll mention that in a minute, is our patients are
very severely ill. Now, when you block that
channel with ketamine, you have psychological
symptoms, decreased awareness, you might be disconnected,
distractible, have trouble communicating
while during infusion. You stopped the infusion and
that reverts very rapidly within 30 to 40 minutes. You might have symptoms of
out-of-body experiences, thrills of like muffled sounds, and your blood pressure
and pulse might go up. Now, when our patients came, because
we were interested in the question, if you block the NMDA
receptor, will that bring about rapid antidepressant effects because this is the most
available direct blocker of NMDA. And for that reason,
we studied patients, because of the side
effects, were severely ill. And this is in our research
unit a few miles up the road. Our patients had been ill for
24 years, most were disabled, 90% were not able to work. They had failed seven
antidepressants, 60% have failed ECT, one of
the most effective treatments, 50% of our patients had
suicide attempts, some multiple. And so we really made sure
they had failed everything. OK. And you’d expect very little
chance of respondent, wouldn’t you. OK. And this is what happened
in our study exactly almost to the date 10 years ago. And you see towards the left,
these little lines on the y-axis, you see the Hamilton depression, higher number greater
severity depression. Towards the x-axis, you see
the time in minutes and days. One infusion of ketamine,
that’s one infusion of ketamine for 40 minutes led to rapid
antidepressant effects within two hours, lasting about one
week, with just in one infusion. You can see in red
the control condition. Towards the right are response rate. It means you are 50% better
than when you start it. To the extreme right,
you see in light blue, monoaminergic antidepressants
already mentioned. You get about 60 to
65% response rate. But at eight weeks, taking
the pill everyday in people who are not treatment-resistant
depression and if you look in green, it’s ketamine response rate. You got comparable response rates
within a few hours that is the same as taking a pill everyday for
weeks, but in people who failed, on average, six antidepressants. Same thing here. Well, what about Bob? Bob participate in a study, you know
about him, 53 year old, depression, 10 episodes, suicide attempt. This is what happens within
a few hours, his depression and suicidal thinking was gone
and it lasted 20 days, OK, with one infusion,
drug-free, no other treatment. Now, I’m not saying
everybody responds, but about 50 to 60%
will have a response. So then the trick is, how do you
go from something that you know that does work much
more effectively? Get rid of the side effects, get
rid of the risk of addiction, because there’s a risk of addiction
and continue maintaining response. We made some progress there. Now, in the psychological sciences,
one of the biggest problem also in other areas of medicine
is replication. Other labs cannot find it. OK. If you look at the figures here, these are two other
studies than by our lab. Depression scores MADRS
goes down within one hour, lasting a good part of the week. Another replication study
showing exactly the same. What is very eerie, strikingly eerie
here is the curves almost overlap which is unheard of in
psychiatry especially with antidepressant treatment speaks to a true biological
phenomena that’s going on and really a mechanism. People have moved onto, then after
five of our controlled study, and NIMH decided to a
larger two sites study and you can see here
exactly the same. Within one day, no earlier
time points were obtained. Rapid antidepressant effects with ketamine lasting a
good part of the week. More recently, Johnson & Johnson,
and this study was led by Jas Singh, who actually was my fellow in the
first study but went to industry, decided to pursue this with
Dr. Manji and they looked at giving ketamine two times a
week versus three times a week. If you look in the green dots,
down means greater improvement and then time over
the next two weeks. So we’d repeat those is two
times or three times a week, you bring down depression
scores and they still will– stay well for at least two weeks. Now, the question is how do you
go about making safer ketamine without the side effects
that I mentioned that it won’t affect the
brain, cause problems and the risk of addiction? OK. Now, Johnson &
Johnson has gotten the way of developing Esketamine, one
of the isomers of ketamine in the hopes it’s going
to lead to and improve. And so if you see towards
the top right, Esketamine by Johnson & Johnson has
received breakthrough designation. They are doing phase three studies
and are planned to be on a market for 2018 based in the
work we’ve been doing. So we’re excited about that. People have jumped
in back into industry but specific glutamate drugs
and not drugs for all psychiatry at some point to keep in mind. There are multiple grants being
funded by NIH on this line of work with preclinical and clinical. The second area is can we develop
more ketamine-friendly drugs, meaning ketamine, if you look
at is like this building. OK. In this room is the efficacy and
some other room it’s the side effect so that’s what we called
units or subunits. So how do you figure to get the
drug in this unit and stay in room and stay away from the other rooms
or units and that’s the trick. Well, you can come with
more subunit selected drugs. And there have been
some studies doing that and I’ll talk about
that in a minute. So, we have done a number of studies with these other more
subunit selected drugs and this is the summary
of all those studies. Ketamine has rapid onset, robust
effect and sustained action. No doubt about that, but
it has its side effects. OK. Dr. Insel, who’s no longer
a director in the NIMH moved on, but summarized this, after
all our studies and others, and says that other medications that block these receptors
are not antidepressants. OK. I would say that’s not the case. I would say, they are but
probably not as robust and sustained as ketamine. I do think they have
antidepressant properties. But they still have that
side effect liability. OK. In fact, this is a summary. We’ve done all these studies
except for the one of them. But we have– you could
see memantine is for Alzheimer’s disease, blocks that
NMDA receptor and there’s others, MK, a drug by Merck, now Cerecor. Then there’s a Pfizer
drug and AstraZeneca. These are the companies
that went back in. And you could see some
minuses, maybe a plus and minus. So bottom line, these
drugs are not as robust and as effective acutely
as ketamine is. And so that’s another
we have to go into. So I think the other area we’ve
gotten into is mechanism of action. So– And what we called
this is reverse engineering. OK. So we talked about how
ketamine is very unique and different than other treatments. So, you know, why not science
the heck out of this drug. OK. As– I’m borrowing
a quote from a movie. And we could take advantage
of our facilities at the intramural program. OK. We have polysomnography,
sleep studies, the ability to do neurochemical
studies, look at glucose or glutamate in the brain. We could do magnetic
encephalography. That is a machine that measures how
one neuron talks to another neuron. We can do functional studies,
structure imaging studies, so on and so forth, to understand,
if you look at the bottom, every thing that goes from
genes, cells, circuits, all the way through symptoms
to the RDoC criteria. If you can understand and
fill in the gaps of knowledge, you might be able to understand
how this rapid antidepressant works and develop other treatments
and we have done those studies. First of all, towards the top
right, this represents rats that had measurements in, while they
were moving around glutamate levels. And you can see here when you give
an injection of ketamine, at 20, 40, 60, 80 and 100 minutes, keep in mind
those minutes, That’s very similar to the response rates,
the time of response to ketamine, but this is in rodents. You see very quick increases in
glutamate extracellular levels. So we did a study in the forced
swim test in 2008, Dr. Manji. And this is the forced swim test. It’s that’s rodent that’s
struggling and you can see in green, ketamine decreased the mobility. That means it has
antidepressant-like properties. Towards the right, you
see an AMPA blocker, remember next to the
NMDA receptor was that other glutamate
receptacle, AMPA. And so here, the study
was looking if we pretreat with an AMPA blocker would that
abolish the antidepressant effects of ketamine, OK, because
NMDA is blocked by ketamine. And the answer is yes. You can see towards this– the
right and ketamine plus AMPA, the antidepressant effects
of ketamine go away in mice. So it seems that these AMPA
receptors are important. And I’ll come back in a minute. Going back to that– those
apartments or the rooms, subunits selective drugs
and are to be antagonist, we see that it does
decrease the mobility. It means it has antidepressant-like
properties. But also if you pretreat
with AMPA blocker, the antidepressant effects go away, suggesting AMPA receptors
are important for the antidepressant effects
of this compound as well. Now, here’s a cartoon that
puts everything together what I’ve mentioned. OK. You have the presynaptic
neuron, the postsynaptic neuron. OK. So you have ketamine binds to
the NMDA receptors as we mentioned on this GABA interneurons,
another part of the brain. So the scopolamine, it’s
a sea sickness patch, but here we give it
intravenously, binds to its receptor on the same GABA interneuron. What both appear to have in common
is this glutamate surge burst, I already talked about
that increase in glutamate, that preferentially targets,
in yellow, this AMPA receptors and causes this intracellular
signaling cascade, similar to what Dr. Gold was talking
about, and causes this increase in BDNF, brain-derived
neurotrophic factor. Those are the growth factors that maintain the neurons
and dendrites healthy. And so in this cartoon, you
increase the number of spines, you restore the synaptic connections
that were affected that I talked– that I began talking about. And you restore that homeostatic
balance that was affected because of stress,
glutamate, and cortisol. And that’s at least
the prevailing theory. Now this study is quite complex
but we haven’t just finished where we obtained all these measures
in our patients who are depressed to better understand the
biology of the response process. In here, they’re listed. But the goal to understand
the neurobiology of the response and relapse process. And just to show, very similar. The study I just finished
is identical the curve to all the previous studies. Very rapid onset, people stay
better for one week or more. OK. And this is the example, some
of the tasks we used that taps into these regions or circuits
that Dr. Gold was talking about. One is you exposed on
anybody healthy, control or depressed patients’ faces. And the faces will
light up certain parts of the brain, the visual cortex. Of course, the back of the head
occipital is one of the regions. And you will pay attention to the
gender or the valance, meaning happy or sad in the face and you have to
react very quickly when it’s shown. And it’s shown in milliseconds
and so it’s supposed to be subconscious when you do this. And you can look to the left is
the accuracy rate of being exposed to these faces when it’s
positive and before ketamine and after ketamine
in depressed patients and you can see the negative
valance, the bias towards going to a person that trigger the
button so the negative goes down. OK. And towards the right, these are
what we called evoked potentials. It’s a electrophysiological
measure of the visual cortex taken into account the gender
or the valance that is happy or sad or angry face. And you can see here with
ketamine, it increases the positive. So you start biasing your
responses to more happy things and the bias towards the negative
angry, sad face start going down precisely what you
want in depressed patients. And so, this is an example
of a noninvasive biomarker that could predict ahead
of time who might respond or not to a certain drug. Now, to get into a little bit
more complex but I’m trying to make it simpler
is Dr. Gold talked about subgenual anterior
cingulate cortex ventral striatum. OK. And if you look into the
figure towards the right, you see all those little regions
lined up one after another. And this is what we refer to
as a matrix of correlations, how one region correlates
to another. It’s now viewed as a bit simplistic
to study one region in isolation. Now what we try to do is to study
one region related to another. The brain talks– oops, sorry. The brain– sorry. So, one area of the brain
is talking to another. So if you have a computer in your
office, OK, and there’s a problem with the computer, many times it’s
not the problem over the computer, that’s one region, but it’s the
problem with all the network. OK. You have networks of
computer and you have a server and that server is the
hub of the networks. And so that’s what we try to
understand is not one computer at time but every computer
at the same time, how one computer talks to another. And not only that, you can go
from your building to the building across the street into
the whole community. That’s how we’re studying
now our mental illnesses and this is referred to as
functional connectivity, how one region talks to another. And these matrices you
can see in the warm or red colors are positive
correlations. They work in sync. And the lighter, cooler colors are
how they work against each other. And you could measure this
through functional imaging. This is to show– towards the
top is 101 represents one subject to receive five scans during
the study, five function scans. And if you look to the
bottom is at baseline, two days after ketamine,
why at two days? Well, we already said the
peak of response is there. So you can understand
the biology response. And then 10 days later,
why 10 days later? Because I said the ketamine
effects last about seven days. So you’re looking at the relapse. So here, we’re looking
at biology, the response, nonresponse process and the relapse. So that’s very important because
you might be able to predict who will respond and who will
relapse, OK, as an example. OK. I should move on. Getting into some examples of
anhedonia or lack of pleasure. I talked about we pull out the
strings to better understand it. One example is we looked at
lack of drive or anhedonia and this is measured by the SHAPS. Ketamine produces a rapid decrease,
stays down and for about two weeks, people’s lack of drive
and anhedonia stay well. And this is measured FDG,
fluorodeoxyglucose scan. That’s a surrogate of
glutamate function. And we can show here towards
the left is the relationship or correlation between
ventral striatum, that’s the reward circuit
in glutamate levels, OK. So the greater the bold
signal, the better the response. And in this area happens to
be dorsal cingulate cortex. And finally, I’m going to get into last three slides I
hope I have is the paper that came out yesterday. OK. So this was– it was a– this
is a collaboration by Maryland and Chapel Hill and I
mentioned several institutes. And in terms of trying to
understand the mechanism of ketamine, the better ketamine. OK. And this started
when I was bothered, remember in green are
the response rates. OK. The side effects
go away in 40 minutes. The half-life of the
drug is about one hour. So why does it last in seven,
you know, days or longer? And so, what we said is let’s
look at the metabolites. In older papers, it said
it’s inactive some of them. Well, inactive for
anesthesia but they didn’t know about depression back then. So we looked at all of
them, a bunch of them. And I have come up
with a can of drug. So this is a cartoon, hopefully,
that explains the study now in here. OK. RS are the two
isomers of ketamine. OK. That’s the chemical structure. Here, we give ketamine
intravenously. OK. It goes through the
liver and within 10 minutes, you have towards the right,
hard to see, but what was that, all those metabolites
within 10 minutes in the– in periphery and the brain. OK. And towards the extreme
right you see are the measures of those metabolites. And we found that metabolites will
last in three days and seven days. That’s interesting. If the half life of
ketamine is gone in an hour and the response last seven
day, maybe it’s one of these. We know that ketamine is associated
with side effects, risk of addiction and rapid antidepressant effects. So, through the collaboration,
NCATS, National Center for Advance Translational Research, the principal investigator
is Todd Gould from University of Maryland and our collaboration. What was done is one creates a
deuterium form, a dideuterium form of ketamine, means what you do
is you attach something to one of its molecules or add carbons and what you do is you
prevent its metabolism. And when you do that,
this is what happens. OK. You don’t have the rapid
antidepressant effects anymore, or very little, but you
still have the side effects and the risk of addiction. Interesting. OK. So then you go to one of
those metabolites who are hanging around HNK, hydroxynorketamine. In animals, in mice we found it
had rapid antidepressant effects but without the side
effects of ketamine. OK. So, that’s about it. I’m going to stop there and
thank you for your attention. [ Applause ]>>Philip W. Gold: Our
last speaker today, I’m pleased to introduce Dr.
Raymond DePaulo who is the chairman of the Department of Psychiatry and
Behavioral Medicine at Johns Hopkins and is the psychiatrist and
chief there and has been one of the world’s experts on psychiatric genetics
especially in bipolar disorder. And he’s going to share some of– what has really become an
extraordinarily exciting area of medicine. And as I mentioned
earlier, I think the one that will yield us the
biomarker that we lack. Yeah.>>Raymond DePaulo: OK. OK. How it worked?>>Philip W. Gold:
I didn’t use that.>>Raymond DePaulo: Oh,
you didn’t use that one? OK. Well, we’ll figure it out.>>Philip W. Gold: OK.>>Raymond DePaulo: All right. Well, thanks very much everybody. It’s nice to be here. You know, I haven’t regularly
come to the Library of Congress since I was– since
1966 when I was– spent my summer in DC on
Capitol Hill, and I loved it because it was the most
peaceful place around. And you didn’t have to do
anything particularly special like you do these days. Didn’t have to go through
any– didn’t have to take– I didn’t have an iPhone but you
wouldn’t have had take it off them. OK. Well, listen, I’m a clinician
first, OK, teacher second and then I’m researcher third. OK. I’ve had a lot of
fun doing research. And I have a lot of opinions. OK. And I’ve loved the first two
talks but even more than the talks, I’ve really liked the questions, OK, because that’s really what
our field is about, OK, is getting the right questions. OK. So let me see if I can
start this little talk. And by giving me the issue of the
genetics of depression, you know, I thought that sort of ruled out
proclaiming victory on the genetics of bipolar disorder, OK, which is
not exactly victory but it’s a– it’s certainly a heck of a
bunch bigger start than we have on so-called the unipolar
depression, that is people that have depressions
but not bipolar disorder. So I’m going to talk and I’m going
to show you some genetics studies but I’m going to show you the
genetics studies really of kind of in stairstep fashion
of schizophrenia just to show the rapid progress that’s
been made there for whatever it is. OK. Then a little bit on bipolar
disorder and then, oh my God, depression, why haven’t
we done more there. OK. And then I’m going
to talk about what– why is that and also
where is the problem. And I think, let’s say the genetic
understanding of depression, there are two operative words
there, genetics and depression. OK. So, what is the right genetic
question and what is depression, which you all have already asked. OK. So, let’s go at it. OK. So, I do have no
financial conflicts with this although whenever
my faculty get up and do this, they always say I’m
employed by Johns Hopkins, they make me do all kinds of things. And I’m saying that you
will understand what we know about the genetics
of major depression, that is the big challenges. And that you will see how the
genetics of depression may be harder than for bipolar and schizophrenia. And that you will understand
the need for large stable collaborations, more careers studying
serious mental disorders like depression, and better ideas. The technology is getting
better every day. OK. And I’ve been blessed to be able
to work with the people starting since 1985 with the people who made
the first map of genome and I got to work with them starting about
two years before they made it. And by the way, the progress
has just catapulted since then. And so I made– Eric Lander
who was 29 at the time and didn’t really have
an appointment. He was an unofficial fellow
at Whitehead Institute. He now runs the Broad Institute, OK, which is a very large
genetic operation. I was just there about
two weeks ago. And it’s progressed just like
the field has progressed. What do you expect? It’s really cool. All right. So, one of the reasons I
like to do science is I get to meet really smart
people and listen to the talks and Carlos’ work. You know, today he showed me
some things I haven’t seen before which is really great. That is the active– the parent
compound may not be the ticket. Well, that’s important news. Now, let’s see here. Ah, I can see it right here if I– now, I just put on my
glasses and I can read it. Well, this is disease
burden by illness. I’m not going to spend
much time here. Carlos and Phil and I have all
referred to this the global burden of disease studies, OK, in one
way or another to make the point that depression is big, OK. And so you can see that that’s the
number one on this particular thing. That was 2004. I noticed Carlos had it
a little differently. He was looking in 2010. The main thing is– by the way, this
was the biggest surprise in the– in these global burden
of disease studies. They were actually
had to be persuaded to include psychiatric conditions. OK. And actually the person that
persuaded them was the brother of one of my faculty members,
Kay Jamison’s brother Dean, a health economist persuaded
them, they needed to do it. And now they say, “Oh my God,
why didn’t we do it before? OK. These are big.” OK. And– OK. So, what is major depression? OK. And so let me go right at that. And then the second question
really is that is, is it– is that’s what is it,
what DSM-5 says? OK. Is that really it, a
checklist of nine things? And by the way, I was on DSM-5. Carlos was a consultant. You are on it. You are member, too. You and I both members, right? And we both have gotten, you
know, witness protection. So don’t try anything funny. But it is great that we’ve had
the challenge to this approach. OK. And it’s not that
these things are wrong. If you were going to
come up with a checklist, way back when these things
started, George Winokur from Iowa, now the late George Winokur, and I
said I didn’t really like this way of doing it in DSM-3
and it’s very similar. And he said, OK, just come
up with something better. Just come up with a
better checklist. I want a checklist. So just give me a better one. And I tried 4 and 5
and I said, OK, George, one works about as
well as the other. But these things came–
oops, I’m sorry. These things came from some bright
people at Wash U in St. Louis and where they came from
was the walls inside where the clinical
research groups were. OK. And so what the
young fellow named Finer in the FINER criteria became to
DSM criteria, sort of, you know, by little switches and committees
that morphed [inaudible] other. He went around to the anxiety
group and the depression group and said how do you–
who gets into your study? OK. Here son, go mimeograph this. OK. That’s how they get in. That’s our checklist. OK. And that’s what this is. And he– When he initially published
it, it was for research, OK. And I think that’s what they
serve and not in the sense of guiding the research at all. Just in saying we got to have
some minimal qualification. OK. So, OK. So anyway, so this will
do pretty well, OK, especially when it’s recurrent,
especially when it’s early onset. You’ve heard about that. And then especially if it
has the other manifestations that Carlos talked about,
psychotic symptoms, suicidal– severe suicidal symptoms, et cetera. But– So but anyway, as this
is going on, the controversy about this approach of diagnosis
which has been very much deserved. OK. Some have said we even invented
it and I just want to make one slide to say we didn’t invent it. OK. This is Burton’s “The
Anatomy of Melancholy”, 1621. But you’ve already heard
about Hippocrates and Galen. They knew about this too, OK. So, that question is answered. OK. By the way, I do want
to come up with an answer about why we haven’t evolved out
of it and I’ll tell you that later. OK. OK. So, melancholia, OK,
and as you know this comes from the ancient disease model which
had to do with the four humors. OK. And in this room,
people know what that is. When I go to medical students
and I ask who knows, you know, the derivation of the
word melancholia and essentially it’s zero to two
people in a room of 50 will know. OK. So, too much black bile
was thought to be the source. But Kraepelin really
didn’t buy that. And Kraepelin was an early applier of the modern disease
model to psychiatry. OK. And he was a pretty
fair pathologist. He had a better one as one of his
students, Alois Alzheimer, OK. And the guy who started our
department, Adolf Meyer, was a very good pathologist and he
didn’t like Kraepelin doing this because for what he
call dementia praecox and manic-depressive insanity. He says because you don’t
have a pathology yet and that’s the centerpiece
of the modern disease model. And he said, if you do that,
if you allow these things to be called diseases without
a pathology, there is no limit to the number of things you
might call diseases, right? And Dr. McKee [assumed
spelling] used to hold up DSM-4 in its thick form and say this book
should be called Meyer’s Revenge. OK. Anyway, but here’s
a patient and– but, you know, I can’t
get away from. This is also from Kraepelin’s text
and he showed the woman who had, in two pictures, I’m showing
the man who had two pictures. It took a little work. You had to go through it a couple
of times because these pictures were about 50 pages apart and
they didn’t tell you, “Hey, this is the same person
who’s on page 20.” OK. So– But here’s the
fellow in melancholia. He have been said to be
like this, wide-eyed stare, having maybe persuaded to pull
the covers down a little bit so they could take
a photograph of him. OK. He had no interest in anything. And you can see he’s unshaved
and he looks a lot better than he probably felt
at this moment. OK. And so that’s melancholia
and that’s the picture of melancholia, all right? Now here’s another patient that has
melancholia and I’m going to talk to you a little bit
about these two patients. I’m not going to talk about Bob. I’m going to talk about
these two people. So, here is a woman and by
the way, without a checklist, what would we say are the
central features of the syndrome of depression, if you will? And we would say it’s a
change in mood or affect, change in self attitude
and a change in vitality. OK. And they express
themselves slightly differently. Actually, only about 50% of
people that I would diagnose with depression would say that that’s a good description
of what they’re feeling. They also often say they’re not
so much sad as they are anxious, apathetic, don’t care, or even numb. And people have told
me I can’t even cry. I didn’t– I couldn’t cry
at my father’s funeral. OK. There’s something wrong with me. I can’t feel anything. OK. The change in self attitude
which is so characteristic of what we call melancholia, OK,
is really– it comes in degrees. You can have just decreased
self-confidence. You know, I don’t trust any of my
decisions now, tells the businessman to me even though he’s
still going to work. But in the worse case, a lady like this often feels
hopeless and worthless. OK. And then vitality– some
people use the word vital since but I like just the word vitality
and that is lacking normal, physical and mental energy. OK. And the issue we talk
about poor concentration. But that really is
that it takes energy. That’s one of the reasons
many people don’t want to see other people. I got to get up. I got to look half decent, you know. And actually, I’ve gotten a number
of patients to appear on various– be filmed in one thing or another. And, you know, when the people
come and say, hey, look, we want to film a patient
before and after and I say, well, OK, good luck. Most patients tell me when
I go in and they’re feeling like this lady is feeling, you
know, Dr. DePaulo, you know, I’m not sure I really want my family to see me making a debut
while I’m feeling like this. Could we go a few more days till
I’m feeling a little bit better? OK. And because this is the
time in which you don’t feel like doing much of anything. And in fact, here’s
what she’s saying. “I’m falling down in my head.” She– This is in Paris,
so it’s a translation. “I’m falling down in my head,
I no longer wish to live, to see anything, hear
anything, feel anything. I’m fed up with life. I’ve had enough. I don’t want to live any more.” I mean, now, therein
the better description of depression that we’ve got. But of course, it’s a
cross-sectional thing and so let me talk to you about her. This lady had Parkinson’s disease. She’d never had depression before. OK. And when they put in
the electrodes and let that surgery heal, they were
going to try to help her tremor in Parkinson’s disease with this
deep brain stimulation electrode. OK. And the first time
that they had her on, because this is an early case, they videotaped her
when they turned it on. They were, hey, this is
going to be good, right? And the– it didn’t come up
the way they anticipated. OK. And so you could see here in A, and I don’t think I have
a pointer here, do I? Do I really? No, I just screwed
that up, didn’t I? OK. And in section A there,
there she is as she came in to get ready for the thing. And then in B is after 17 seconds
after they turned on the stimulator. Four minutes and 16 seconds
is when she’s telling us that this life is worthless, OK,
that there’s no point in going on. And then of course being very
smart and one of the great things about surgeons and
people that use treatments like this is somebody said turn that
blasted thing off, you know, bang, hit the thing and very
quickly she recovered. OK. And said something like did
somebody get the license plate, you know, on that truck
that just ran over me? And in fact, as she recovered, she
actually had a little over-recovery and started playing
with her surgeon’s tie. OK. But that– and that went
away very fast, just momentary. So, this is one of the reasons why
we think the modern disease paradigm is appropriate for this. But this paradigms,
these models, you know, you got to remember what the
great statistician Box said– George E. P. Box said
to his students, all models are wrong
but some are useful. OK. So, it’s a contract. That’s all it is. OK. Only the patients are
real, I tell my students. All right. So, now that’s one patient. Now here’s the other
patient from his depression to show him now in an altered state. You know, a year or so or several
months later and you may not be able to make it out but he’s– you
can see the cigar he is smoking. And if you’re good, you can
kind of see the pipe in his– and on his lap, that’s
actually another pipe. OK. So this guy is really indulging
at least one particular appetite. OK. And it seems– and he– and by the way, he’s also wearing
a boot [inaudible], take notice. And he no longer has that big beard but he does have a nice
handlebar mustache. OK. So– And this, you know, Kraepelin said I don’t have
any particular treatments for this disorder. These were people who
were living there and they were just
mostly observing them. OK. So– And just to make the
point, the central features of mania are similar,
almost a mirror image of depression, not completely. And so the mood is mostly elated but not just elated,
irritable, expansive. Self attitude is up, grandiose,
overconfident and imperious often. And vitality is increased,
energy, and the decrease– a perception of a decreased need for
sleep and in fact patients can go, as you know three or
four days without sleep. And then increased speed of
thinking and speech usually. And again, with both of them, there
tends to be an episodic course and in fact, in Kraepelin’s
day, he grouped people together who had only depressions and
manias and depressions together because he thought, look, that’s
the best predictor I have. And so, that’s actually one of the
ways we had to divide depressions. OK. Those that have mania
and those that don’t. OK. And it’s still salient. OK. Well, here’s the modern
disease model, if you will. I don’t– this is not a
definition of the word because you can’t get anybody to
agree on the definition of the word. But this is the structural model. We doctors like simple things
that you can operationalize. OK. And so here’s the model. You have a clinical syndrome. You validate that as a modern
disease with a pathology and abnormal body part,
OK, in some patient. And then you– then that leads
you to search if you do things in that order, in the
right order in a sense for an original cause or etiology. OK. Now, the problem for us is that
none of these areas are simple. In cancer, etiology is very
complex and we learn a lot from them in studying etiology because
they know the methods, they know how to go at that. OK. It’s really good. But once you get a
cancer, by the way, the pathology is not complicated, it’s just stuff growing
where it shouldn’t be. OK. It doesn’t look very good, kind of ugly stuff growing
where it shouldn’t be. OK. And the syndromes
were also not complex. They usually block something
or it causes pain, right, or it causes a protrusion. OK. So– And the reason I’m
mentioning this is I was invited to speak at the Salk
Institute annual symposium on biological complexity. And I saw that much of their earlier
ones were on cancer and I said, well, Jiminy Christmas, if you’re
going to make me talk, I got to say, you know, my talk was
entitled complexity squared. I should have said cubed, OK, because each of these
is a complex state, OK, and it is not in all
likelihood going to be explainable solely
by its parts. OK. And that’s really a key thing. Now that’s what makes it
so wonderful and amazing to study the patients
and to work with them. But, this is complicated,
folks, and therefore, we’re working on systems
within systems. OK. So, now, I said the
course was episodic. This is an early slide,
one of the slides that where they used
lithium in patients. By the way, unipolar
and bipolar in here. The black bars are the depressions, the hatched bars are
mostly the manias. And the– and you can
see the lithium is where that little pencil
underlinings are. OK. And each line is a patient,
OK, from 1960 to 1968, OK. And it looks pretty
good, doesn’t it? That looks terrific. You’re going, man, you
should keep yourself with that pencil line
going underneath you. And it didn’t turn out to be that
good but it did turn out to be good. OK. So– And this was 1969 and the– and my teacher from the Maudsley
Hospital Institute of Psychiatry in London though didn’t
like this study. And so, he wrote a paper with his
fellow called “Prophylactic Lithium: Another Therapeutic Myth”. OK. That generated both
heat and eventually light because they got some
really good studies. But everybody was really
mad for awhile and so forth. Now, why did I end up going there? OK. I’m not sure. I’m going to come back
to this a minute. OK. Right. OK. So, here we’re
going to talk about– I’ll come back just a minute. That in general, genetics of
psychiatric disorders that is at least the ones schizophrenia,
bipolar, and depression have been
difficult and I started in the area got our grant
in 1988 and, you know, through about 2005 it was–
what we got was experience and of course experience is the name
you give to your mistakes, right? And I did discover, had
three great discovers and those are three young people
that were much smarter than me and they are now actually running
great programs around the country. But eventually when we
started coalescing samples into very large samples and
had access to every, you know, sequence variant in the genome and easily could do a
million variants at one time. And now it can actually sequence
the whole genome as well. We– Things started coming out. OK. And this is just to show you. This is the 12 or so
for bipolar disorder. Although you’ll notice
down at the bottom that it says BD plus schizophrenia. OK. So that there are both
overlapping ones with schizophrenia and ones that don’t
appear to be overlapping. Down at the very bottom, you
see bipolar disorder and RUD. That is recurrent unipolar
depression. OK. And so, you know, that’s– it’s very interesting but
the one that’s been toughest to do is depression
in any of its forms. Bipolar depression better than
non-bipolar depression, but why? It’s so much more common? It’s about eight times more
common than bipolar disorder. And we’ve– and I’ll show
you some of the samples that have been ascertained. But I’m going to probably– I’m thinking if the
slides are in the order. I’m hoping they’re in. Yes. I’ll be telling you a little
bit about how the progress has gone when you have funding– sufficient
funding and sufficient samples. OK. And basically, the sampling
methods when Dr. Insel stop wanting to pay for phenotypes, the
investigators are resourceful people and they went and purchased
everybody in Sweden, right. All their DNA is from Sweden or
from Denmark and that’s really good. Those people have health systems,
that absolutely was the right thing to do and they had a reasonably
robust way of making diagnoses. And so, by 2011, once they
started doing that, they did– they could do a million markers. OK. Each one against– and this is–
you can see here it’s chromosome 1 on the left if you can see
it, and the chromosomes are 1 through 22 living out
the X and Y chromosome. And so, these are– if
you can think of them, is tipped over on their side. And then up at the top, going
up above this line where you see between 7 and 8 is the point at which things become
statistically significant. But this requires like
10,000 samples to do it. And that’s not easy to come by. OK. And so, the group,
particularly, at the Broad Institute and with collaboration from the
clinicians and toilers in the field who actually see the patients
came up with this in 2011 and then they just got
a few more samples. Double the sample size,
triple the sample size. And by 2013, they actually
ended the red line, it’s at the same place
by the way folks. It’s just the scale
here has changed. The top of the other scale was
12, the top of the scale is 30 and that’s the exponent
of the P value. OK. For those of you
who live in that world. But the point is they now have
here 108 loci, presumably, for the most part, genes. OK. Sometimes, they
can’t tell if a loci is of this particular gene
or that one or both. But– And you can see by the way
the tallest one, there is that– in schizophrenia forever has
been on chromosome 6 right in the major histocompatibility
region which has been in one sense, the Bermuda Triangle for
geneticist trying to dissect it because it’s so complicated. OK. But that has now been dissected
quite well in schizophrenia and we now have a component
of the compliment system, C4, that appears to be quite
abnormal in schizophrenia. OK. Not necessarily
in all schizophrenics, but with the sample size like
this they could dissect it down. And so, it looks like it’s
going to be an important clue. And by the way, did I ever expect that we would fine the
cause of all forms of these? No, I didn’t. Keep in mind, these are syndromes,
you know, going back to that model. And whether it’s congestive heart
failure, if we did a genetic study of congestive heart failure, you
know, that would be too complicated. Well, these are syndromes and we
don’t know really if there’s a level of congestive heart failure, for us
which might be simple versus dropsy. OK. So that– we don’t know where
we are because haven’t yet created– we don’t have a pathology. OK. Really the simplest
way looking at it. Now, these studies have been
very important and I’m going to go backwards here to pick up
this slide and that people notice that so many of the genes that
were being identified had multiple diseases they were associated with. OK. And so this early on
led some people to say well, Kraepelin was wrong, it isn’t manic,
depress, insanity, schizophrenia, it’s all really one thing. OK. They are now, I think,
not saying that anymore. And you do want to wait and
see how things turn out. And– But there’s no doubt
about it that there are a lot of shared genes in this thing. OK. And I’m going to get to
the question a little bit about why have we not
evolved out of depression. OK. And so that what you can see
is ADHD, BPD or bipolar disorder, schizophrenia, major depression
and autism spectrum disorder, and that’s just the
heritability for each. OK. And then what they’ve done then
is looked at the co-heritabilities between disorders and you
can kind of to see that. And what you can see is that bipolar
disorder and MDD are related, it seems, but no more
so than schizophrenia and unipolar disorder are. OK. And schizophrenia and
bipolar disorder do seem related at least in some significant way. OK. So that’s– shouldn’t
be too surprising, I mean, the genetic overlap between asthma
and Crone’s disease is substantial. But they are importantly
different diseases. Not– But they also are
importantly the same in some ways, some molecular level. OK. So I’ve done that. So look that’s the
kind of, if you will, the sort of the story of genetics. Now the real issue is you got to– what we want though is if we
can’t find everybody’s model of their disease, what we’d
like to do is at least find one. OK. And say, can I figure out how Mother Nature made
one case of bipolar disorder? In fact that was my goal
when I started these things. Just need to find one because that
will at least gives us something to look for other things to come. And just like the– in
Alzheimer’s disease, the APP mutation amyloid
precursor protein was tremendous in that way even though it counts
for less than 1% of the disease. But it gave him a model. And the model by the way, now, has
put the amyloid hypothesis on the– little bit on the back burner–
whoa, I did something bad. What do I do? Hit, hit, right, oh, good, thanks. Thank you. I feel much better. My stress level just went
down, oh, everything. But I stop degenerating
there for a minute. OK. The– sorry, where
the heck was I? At any rate, I want to find out how
Mother Nature made one case, OK, and then [inaudible] other diseases. OK. Now, OK, this is
the one [inaudible]. This is the study I
was going to show– last study on this to show you when
they put five disorders together, OK, and pretended that
they all had the same, the five that you’ve already seen, they could still find things
that were significant. I think this is– to be honest
with you, kind of child’s play. OK. I don’t think it’s
terribly helpful because we know ADHD is different
than bipolar disorder and the fact that they have some
overlap, terrific, good, that should tell us
something important. But that– this is not
to me too surprising or too informative,
but it is what it is. So, now, here is– look, the point
is that people have now gotten on to major depression and
they’ve collected large samples. And the thing is we don’t have much
to show for it and we should by now. In fact, with these disorders that
are so heterogeneous and complex, you can actually calculate
and since, we assumed they are
basically polygenic because we haven’t done
any autosomal dominant or autosomal negative or x link
forms of it that are simple. OK. You would think by the
number of people we’ve collected with major depression
now, we should have 20 or 30 loci link to
it, OK, and we don’t. And so, well, you could say that’s
terrible, you can feel discouraged. But you can also say, all
right, time for an idea, right, time for somebody to look
at this in a different way. OK. And we’ll just talk about that because there’s some
simple ways to do it. But I’m– But there is some
interesting ways as well. They might be a new treatment that gives you insight
or lot of other things. OK. So, they– if the group– the major depression
disorder working group, again, a large collaboration had 18,759
independent, unrelated subject of Europe ancestry, 9000 and
some were had major depression and 9500 were controls. And then, they had a replication
phase because in these days, with this big machinery
you don’t want to publish a finding unless
you can also replicate it. They had second sample waiting where they have 6700
cases and 50,000 controls. OK. And no gene or a locus
achieved genome wide significance. OK. Now, again, that doesn’t
mean there aren’t any. It just means that with
all these multiple testing, testing a million markers
at one time is going to cost statistical issues for you
because you can– you don’t have– if you lower your threshold
you’ll have more false positives than true passers. No, we don’t want that, obviously. Now– And so, it’ interesting. The– And then, actually,
even in their secondary looks at major depression, they took
ones were males and females because there’s a big
difference there, recurrent versus nonrecurrent,
recurrent and early onset, and just age of onset by itself. And none of them came up either. Now, each of those by the way
would shrink the example size. OK. But that’s where we are. And in the MDD-bipolar
cross-disorder analysis which is the thing– one the things
that we think is going to important. There were 15 SNPs that did– but they’re all at one
place on chromosome 3. OK. That did exceed the
genome-wide significance. But in bipolar disorders, I was
saying, we now have about 12, some people would say may be it’s
going to be up 30 in a few months. But the issue for schizophrenia
and for us is for the most part, we still can’t turn those genes
into a story, into a model. OK. And that’s the– And
that’s why we need insights, non-genetic insight, as well
as digging away at the genes and looking at what
they actually do. OK. And the technology even for
doing that is amazing these days. And like the CRISPR
technology actually allows you to keep modifying a variant
and seeing what it does in cell cultures, you know,
about how it acts differently. And so that’s really cool. It blows my mind. OK. So, now, here’s a
point I want to mention. OK. And actually on the
one hand of replication, its true Carlos is
hard in psychiatric. But there are a thousand slides that
look like this, OK, as you know. And this is some antidepressant
and placebo. This one is actually lucky. They were very lucky. And I have– they got [inaudible]
in 28 days, as Carlos says, it usually takes longer than that. But basically, what this is showing
is two things to keep in mind, that do make this not so easy. One is, the first week placebo is
working darn well, wouldn’t it? OK. That’s number one. And the restoration of hope, you
know, I know what’s wrong with you. I’m going to treat you. You’re going to get better. But as I tell my young psychiatrist after a week you better
have something in the pill. OK. And then after the one week
is over, they separate but it’s– this doesn’t really
show you the scatter. OK. And what you’ll see
with the tricyclics is that some people get
just flat out well. OK. And some people might go back,
go– get even worse than this. OK. Having said that, but there’s–
as you saw from the STAR D study that about 30%, only about 30% of
patients will go into remission in some reasonable time period. OK. And the others will get, you
know, at least 50% improvement. By the way, 50% improvement if you
have a bad depression, you know, do not brag about that one. OK. Because people still, you know,
don’t want to get up the next day on 50% improvement with these
kind of patients who, by the way, these people are starting
with the Hamilton score of 30. That’s big. That’s a patient that
[inaudible] patient unit. OK. Now, everybody says, but
wait a second, we’re treating so many people with
antidepressants now. OK. And we got them. You know, why aren’t we reducing
suicide rates and why aren’t we, you know, reducing the prevalence, at least the point
prevalence f depression? And here’s part of the answer and
this comes from a young man who’s– he did this work when
he was at Colombia, Ramin Mojtabai, whose
a joint recruit. He’s in the Department of Primaries
and Department of Mental Health, Hopkins has the only Department
of Mental Health in any school of public health in the world
as far as we could tell. If somebody knows differently
I’ll be happy to hear it. But I think that’s tremendous. And they have a group of people. They are kindred spirits
and our secret weapon. OK. So, Ramin went out and looked at
this and what he saw was that most of the increase, OK, in the use
of antidepressants is in patient where the doctor isn’t even giving a
psychiatric diagnosis in the chart. Now, many of those people
probably have anxiety disorders. These things– The SSRIs
work quite well for anxiety. OK. Some of them– who knows
what they’re getting for. OK. So– And the interesting thing
is you can study severe forms of major depression. There’s not an appreciable
in the percentage of them being treated
actively with the treatment that would be a sugar pill. OK. So, the antidepressants
are multiplying. Their use is multiplying, 80% of course are prescribed
by non-psychiatrist. But the psychiatrist aren’t perfect. I don’t want to put us up is
the– as the goal standard. But we– But it is true that in
the primary care clinic, thank God, they’re now talking about
putting us with them in the primary care clinics
and trying to help them because they know this
is a problem for them. OK. So, now, how else
might get there? Carlos showed you one way. If we can track back through the MDA
receptor and he showed us both the– that receptor and the AMPA receptor, each of those look
like great targets. OK. That’s can’t– we’re going
to– well, that’ll be useful. Here’s one that we heard the other
day in bipolar disorder from one of the members– by the way the–
I’m going to stop being chairman of the department at
Hopkins in June after 7– after 14 years, seems like
17, but it’s only been 14. But I am already the
chairman of the board of the National Network
of Depression Centers. I do want to mention
that because we’re going to need that, OK, I think. OK. I think– and so– But
here if you can see it, if you can make it out, the red and
the purple and then the light green and the darker green are cell
lines, OK, that are occurring. These are deprogrammed cells that are then programmed
to be like neurons. OK. And what you can see in the top
bar, the red and the light green, these are in their native state without lithium onboard
in the cell culture. OK. And they are firing
in a hyperactive way. Actually, I don’t’ know
that you can tell that. But this is hyperactive firing. OK. But these people that
we’re sell lines were made from were already treated for number
years for their bipolar disorder. And some of them were selected to
be excellent lithium responders. They’re kind of people that
just seem to get well on it. OK. And others were not so
good lithium responders. OK. And in the ones that
were lithium responders, that’s LR up here. OK. OK. And in LR,
look what happened in the purple compared to the red. OK. So– And only in them though. You go down below light
green to dark green, really not much happen at all. OK. So, it does seem that there may
be something about this, you know. And if it were hyperexcitable
neurons, that would be great because then we think about mania
and have a visual image of it. But, you know, at any
rate it is useful. And this was done out at UC
San Diego with John Kelsoe as the lead psychiatrist
and Fred Gage as the stem cell guy, if you will. OK. So, by the way, at the end of the day they’re comparing very
small number of people cell here. OK. So, we need to replicate this. And if confirmed, we need way to
test it in larger populations to see if we can turn it into
something that’s robust, just like we’re trying to do
with the ketamine response. We know there are people
that respond to it. How can we turn it into
something as robust? OK. So, at any rate, look, on the
one hand we still want the genes. Why? Because even thought
we have a lot of stories that make partial sense
of these conditions, we still need to have a parts list. And that’s the– Eric
Lander would use that term. I want the parts list. And then, let’s see how we– it’ll
still take awhile to construct them. Put them back. Put them together in some
forms that look rational. And to do that, we’re going
to need 30,000 cases or more. OK. And looking at particular
treatment as Carlos is doing and they’re molecular targets
and associate them with generic and other molecule variations,
certainly a good idea. And– But if the genetics and the neuroscience doesn’t tell
us what depression is, OK, we– ours is a working hypothesis. OK. If they don’t tell us,
then we’re going to have to try and redefine it ourselves to see
if then they could do it, right? OK. So, that is really the
question, what is depression as much as how do you do the
genetics of this thing. So, Phil mentioned
prominently, melancholia, and I think that is an
important point because many of the older professors like Phil
who are very smart have said, wait a second, with that checklist
you’re including way too many people in this thing. OK. And is that the problem? OK. Now, one problem with
undoing that and is that we know from past studies that
people that didn’t– wouldn’t qualify for
melancholia, they didn’t look like they had melancholia. They look like had
pretty garden variety mild or moderate depressions. Some of them respond quite
well to antidepressant, too. And I don’t want deprive
them of treatment. The problem is they look identical
to their brethren and out there and that part of the Venn diagram. OK. And some of them are
responders, some of them are not. And so probably what we
got is [inaudible] mixture of some sort out there. OK. So, that’s– So where
do you draw the circle? Now, by the way, the
folk who don’t go back and read the old literature
they say, but Ray, if you do that yours going to
take you another 20 years just to get sample because
you’re going to lose power if you don’t have a big sample size. Well, OK, next question. OK, right? So, well, how else
might we divide it? So, melancholia versus the major
depression that’s not melancholy would be one sensible way if
we could get enough samples. Major depression associated
with stroke. There’s a very regular
relationship on depression that follows stroke
and brain lesions. But there’s probably a genetics just like there’s a genetics least
resistance to HIV infection, right? Major depression associated with bipolar disorder,
we’ve already mentioned. But also major depression
associated with Parkinson’s. Lady had the brain stimulation. Fifty percent of patients with
Parkinson’s get depression. And they get it early before
their motor symptoms are dramatic. And by the way, seminally,
Huntington’s disease patients do and some of them get
bipolar disorder. And it usually comes
early in their illness. By the way, that part of the brain
is now a very hot topic for us as well, has been for
about 30 years. But 40 years ago, we
certainly didn’t. In 1966, no one was thinking
that the vasoganglia were going to give anything to
psychiatry, but they’re key. So– And then, again, said my favorite category is major
depressive disorder associated with who knows what. OK. Right. So, now look, that–
but I was told by Phil that this thing was called
depression cannot be cured. It says right here
on the top of page. And [inaudible] that really
is vexed question, Phil. And, look, on the one hand, we
need better treatment for sure. There’s just no doubt about that. OK. So that– go ahead,
keep seeking that. But my oncology friend, they rarely
used the word “cure” anymore. They say actually some of the more– [inaudible] ones tell me that a
cure is when die of something else, you know, when you’re not depressed. OK. And so in that by that
account I’ve cured a couple people. OK. So whether the cure
longstanding remission, I’ll take longstanding
remission, too, although by the way, you can cure. Why wouldn’t we? But it may be legit. You know, we’ll have to see. This– And it may be that that’s
not a realistic way to look at this disease if Phil was right. Because if it is– why is– why
have we not evolve out of it? Well, it’s got to impair your
reproduction, number one. OK. And two, it cannot
involve things that are vital for your– for the body to work. OK. So– And with a hundred genes
likely, maybe a thousand genes and it’s part of this,
hey, guess what? These things are probably
important as Phil said. So, sorry, we didn’t turn
out perfect, you know. But– And this may be, as
he says, the price we pay. Having said that, if we can get
good at knowing it when we see it, we can do what he’s suggesting. And that is working with the
patient, OK, in all manner of ways. OK. To help them manage this. OK. And that’s what I
do and I love doing it. And they used to talk about it. One of the things I didn’t like
when many of our colleagues were out there doing drug
studies and saying, treat to remission,
treat to remission. I say, great just tell me how, I’ll
do it you know, I do it sometimes, but it doesn’t happen
all that often. And when I– I like better
the recovery concept, because that means
recover your life. OK. So if I can get the person
functioning again, I say, be careful, you know,
everything I do is empirical. So the next thing we do,
let’s take a little time, you’re actually functioning
a little bit now, let’s use that for a little bit
and then let’s come back and think about treatment again later. So I do think that this
may be the nature– part of the nature of our
machine and our mechanism. It may not be curable
on the one hand. On the other hand, this
work as you can see I think and with these two people in front
of you is for the committed but also for the well-supported and not
just financially but that, too, OK. And it’s not a quick way to fame
and fortune as they can attest. Answers may come in small
steps though also like cancer. So before– now I’m going to switch to that other talk just
to show a couple things. OK. And we’ll– yes. OK, thanks. And this is my National Network of
Depression talk and I’m just going to say, look, we do need these
large multicenter networks that are stable, that aren’t
changing every five years as funding changes. OK. I believe. But now it’s going to take awhile. Because we need very large samples
with the power to find genetic and brain imaging changes that
will illuminate causal pathways. We need to go beyond
expert opinions in setting up our so-called guidelines. Evidence-based medicine is really
expert-based medicine in our field. And we need to have a way of– we– our plans is to have
about 20,000 people under care using the
same essential record or instruments and
to share the data. So that– although that’s
observational and therefore, hypothesis generating, it can be
a little bit hypothesis testing in the practical world to say, hey, you think it’s that
way, let’s go look. Let’s take a quick look and
see how the people look. So there’s lot of reasons
why we need this. And so we do have a network of– National Network of
Depression Centers and there is an forming I
think a network of networks. So there’s a Canadian group of
six centers and there’s a group in Germany that looks like
they will come in as well. And we have 25 centers under working
to collect patients in this manner. And I just thought I’d mentioned
that because that’s going to keep me busy for awhile. So why don’ I stop there
and answer questions. Thanks very much. [ Applause ] And I’m told we have
really short time and the other two guys should come
up here and join in the questions. Other questions? Yes sir?>>Well that’s a terrific talk. I have a lot of questions. First of all, is there– are there
cultural variations in depression? The reason I asked that is
I’m a visiting professor all over the world and in my
own scientific observation, there are huge cultural variations. The Norwegians are the most damned
depressed people in the world. And the Italians– I’ve been a
visiting professor all over Italy, the Southern Italians
are the least depressed. And I wonder if this–>>Dr. Raymond DePaulo:
I wish that were true. My name is DePaulo. I wish that were true.>>Yeah, OK. Is there any scientific
basis for cultural variation?>>Dr. Raymond DePaulo:
A little bit. There is a milder form of
depression or even what used to be called bipolar II where there
is a distinct seasonal variation and which you will see maybe
different some seasonal variation. OK. But by in large, these things– even Kraepelin way back in the 1890s
took a trip to Java at one point. So he could find out how it
looked in Java and he say, hey, it’s basically the same. So the rates and the rates vary
but it maybe that translating that checklist into 12
languages doesn’t get you there. So we don’t have– the evidence
is not robust [inaudible]. OK.>>OK. Can I ask another one?>>Dr. Raymond DePaulo: Yeah, sure.>>That checklist I
think is very suspicious. The checklist is doubtful
because some– that was a good checklist
for old age. You have less energy, do you
think more about death, you know– I mean, what that proves
is you’re old.>>Dr. Raymond DePaulo:
Tell me about it. That’s right. That’s right>>I’d like to know more about that.>>Dr. Raymond DePaulo: Yeah.>>OK. But I don’t know how
many questions I’m get to ask, but I’d like to ask one
thing about the medicines. The second speaker told us that ketamine were just
great only they’re addictive.>>Dr. Raymond DePaulo: Yeah.>>Well, thanks a lot. I mean, I can assure a lot
of symptoms with cocaine but you got a side effect
that’s very unfortunate.>>Dr. Raymond DePaulo: Yeah. Well, look, I mean, that’s right.>>The other part of that question
is what ever happened to lithium? When I was a kid, an undergraduate,
everybody had depression and they all got cured by lithium. Whatever happened to that?>>Dr. Raymond DePaulo: Well,
actually, it’s interesting because though it– as an
acute treatment for depression, it doesn’t seem to be as
good as we thought back then. OK. But it does seem to be have
prophylactic value in unipolar, severe unipolar patients and in
bipolar patients, but not for all, as we could show even in
our some of our studies where we’re looking at mechanism. So, it’s dag un-good. And when– And now
that we’ve learned to use it better we have fewer
renal side effects in the long haul. It’s a drug that’s
underutilized in this country. But it’s still treatment of choice
in Europe for bipolar disorder. Yeah, go ahead.>>Dr. Carlos Zarate: I could address the
second part about ketamine.>>Dr. Raymond DePaulo: Yeah.>>Dr. Carlos Zarate: So, you
know, again, I think I conveyed that we studied people
who are very ill.>>Dr. Raymond DePaulo:
Yeah, absolutely.>>Dr. Carlos Zarate: And in fact
they have failed all the treatments for bipolar disorder for
depression and ECT and, you know, most were having suicide attempts.>>Dr. Raymond DePaulo:
Yeah, you’d take anything if you were in that side.>>Dr. Carlos Zarate: I
think the bright side– But you do bring up a point. And so, it’s an issue, a progress. We thought back then it was ethical to study a decade ago
and it does work. And so as researchers,
we don’t give up. We just try to find
something better. And I think the recent studies
suggest we can find something better that’s not addictive
hopefully more studies–>>Dr. Raymond DePaulo: But this
is– It is a great heuristic value. It’s got us looking at a
different part of the mechanism.>>Dr. Carlos Zarate: The
issue would be, for example, the Wright brothers, you know,
who would have gotten up in plane. Nobody today would
probably go in that. But yet, we travel all the time because of progress
that has been made.>>Dr. Raymond DePaulo: So
that’s true in RRB [phonetic].>>Dr. Carlos Zarate:
They had to put in RRB.>>Dr. Raymond DePaulo: Yes ma’am? And we go with her. Go ahead. Yeah.>>Thank you. I have a question for both of
you particularly for Dr. Zarate about how open this data are. I mean, given the amount of
investments over long periods of time, this is very
obvious case for open data. So can you tell us a bit more
about where this get deposited, how standard the protocols are,
how readily reusable they are, and how much reuse
they’ve actually gotten?>>Dr. Raymond DePaulo: Well look,
this is an idea that goes way back and it’s a very good idea. OK. And when I again work with
David Bobstein [assumed spelling], he said that’s what he wanted. He wanted our data to
be out there on the web. Actually, the woman Mary-Claire
King who deserves so much credit for the breast cancer genes,
that’s exactly what she did and that’s why she
didn’t clone the gene because she had a company working
alongside her, looking at her data on a daily basis every 24
hours and they clone the genes and then misuse the patent
which was later revoke. But that’s what we should be doing. OK. In this era of quote
unquote team science, it’s not just team science,
it’s a crowd science. OK. We got to quit. We got to– we help
people make progress. OK. And so I think there is
still some protectiveness. And– But the other– But
there’s another point. Not all data sets are
equally readable. OK. And there’s a lot of– unless
you really are good at setting up your data set, your
database, you can get it back and it doesn’t look like much. Now, so talk to me
about what you have–>>Dr. Carlos Zarate: Oh,
there at NIH and I mean, there are consorted
efforts that, you know, you won’t get funded unless you put
your data in a public repository. And there’s some rules
about one year or two years protection
for the main thing. But that being said, the IT and the infrastructure is
one database doesn’t talk to the other database, the
quality of data obtained at many sites is probably
not as best as we would like. But there are those efforts. Then it’s not only that, it’s the
computing power once you have these humongous sites, how
do you analyze it? And so computation is really–>>Dr. Raymond DePaulo:
It should be done and now they’re requiring
people to do it. But that doesn’t mean
it’s being done in a way that’s terribly
illuminating. OK. I always think back
to Art Buchwald from– the late Art Buchwald
from Washington. And he– whenever talking about
how to do the MX missiles for those of you old enough to remember that. He favored the idea that we would
put them on rails and round them around the country and he
said we should give the– we should a Russian a schedule. They’ll never figure it out. OK. That’s the way you feel when
you look at some of these databases. OK. I want you to say that when I
did start this research in 1988, I started in ’86, but we
didn’t get funded till ’88. What I said is what
can we guarantee? We can only guarantee that we do
really high quality assessments in patients, that we create an
excellent clinical database, and then we make good DNA. OK. I want you to know,
we did all three. And what I say is what I
discovered were three young people that were really terrific. OK. Yes ma’am? Right behind you. There’s lady right behind
you that her hand up, right.>>Have there been studies
that people look who are– have severe depression, they use
a treatment, they get much better, does anybody– has anybody
followed some of these people to see like if it stopped their
medication, did they continue better or did they get worse and then have to have another treatment,
the same treatment.>>Dr. Raymond DePaulo:
Good questions. Carlos you can start there. I mean– well, I mean
the answer is yes and basically what we can
tell you is for the most part that what get you well
will keep you well. And if you go off of it, you’re likely are nothing
for the most part. And recurrent depression that’s
the thing they mostly found. Having said that–>>They’re not really cured–>>Dr. Raymond DePaulo:
No, absolutely right. They’re not cured. I agree with you. That’s remission at best. No, I completely agree with you. OK.>>Dr. Carlos Zarate: And we
now prescribe medications. Think about, you know, usually
you’re given antidepressant and that’s the acute phase
which could be 6 to 12 weeks. And then, if you’re responding,
there’s a continuation phase that goes six months
or a little bit longer. And then there’s a
maintenance phase. And for the first episode of
depression, some have argued, you could do psychotherapy first,
CBT, or you could do antidepressant. But I after, you know, 9 months or
12 months, maybe a little bit long if you have one episode
and you have family history that don’t have significant
family history, you may be able to
consider coming off. But the problem with that is if
you have stronger family history, and the more episodes of
depression you have if you had one, there’s a 25 % chance
of a second and second. If you have two, there’s
a– you know, it goes to 50. And for each subsequent, it goes
up to, you know, 75 even higher. And so if you had somebody
who’s already had several bouts of depression plus family history, that the likelihood they will
need treatment for a long time.>>Dr. Raymond DePaulo: By the way. Let me add other thing
there and that is the– I thought you’re going to
ask me a tougher question. That one was kind of a softball. And that is, the one that really
is frustrating is the patient that gets very well on a drug and continues the drug
and relapses, terrible. And that was at one point
called the Prozac poop out. It’s not about Prozac. It didn’t change. Huh? It does, especially in
certain kinds of patients. I think we’d– probably
in the patients that have these chronic depressions
where they have a little bit– at least a little bit of
depression almost all the time. Those patients and
have that [inaudible]. Other questions? We got a couple here.>>I don’t have a scientific– I do
not have a scientific background, so let me see if I can phrase
this question properly. If you have– supposed you showed in
your genome that you express enough of the genes that showed you
how the genetic predisposition for depression, but you
might not get depressed.>>Dr. Raymond DePaulo: Yeah. Absolutely.>>But suppose, have you done
studies on children specifically and I don’t know how you would
do that when you’re studying, you know, your focuses on genes. I come from a background where I believe I know I developed
depression because of situations that affected me when I was a child.>>Dr. Raymond DePaulo: Sure.>>And I also think that there’s
a predisposition to depression in my family and I have
a brother and sister who have not been as
affected as badly. And I’m the oldest
child in the family. But I think that there is
a tragic lack of attention to children especially who
are symptomatic and possibly in a variety of ways and if anybody
was paying any attention to them?>>Dr. Raymond DePaulo:
Yeah, well, we have a great–>>– would notice– and they–>>Dr. Raymond DePaulo: —
and we do pay attention. We do pay attention. But I do want to tell you that in
terms of the genetic part of it, those studies are not
yet really being done. I mean, because there– right now
we don’t have a sufficient set of genetic markers that we can
say this person has a 50-50 chance of getting depression. OK. We don’t– We’re
not that powerful yet. OK. Having said that, people have
taken any particular gene that seems to be related and they studied in
children who do not have depression. And it’s very interesting
what they find because they often find some
change like in their cognition, their concentration
and things like that. But those studies are things
we absolutely want to do. OK. And– But it– you
know, we first got to come up with parts list I think.>>Dr. Carlos Zarate: Well,
I mean, you kind of respond but there is a more,
more– because of– as you can see in a polar depression
and bipolar, the findings are not as robust as we would like if
you’re going to put on a very little that now studies– genetic studies,
you know, are moving that you need to consider the environment and
the family and all that as well. If you’re not considering
those two thing– I mean, maybe it’s more information that hopefully will
give us more insights. And so most of the studies that
I’m hearing at least, you know, the collaborators I work with
are really going that way. How do you do that
and it’s very hard.>>Dr. Philip W. Gold: If you
take the two identical twins who share 100% of their
genes and one of the identical twins
developed depression, only 50% or so of the other identical
twins will develop depression.>>Dr. Raymond DePaulo: Yeah. So– And why is that? Good question. Don’t know, don’t know. OK.>>Well, I want to follow
up on the cultural question that he posts earlier on
in a different direction. I’m posting question from my own
background in which Pentecostalism, the bible, is taking as an answer
and Pentecostalism is on the rise. Part of this belief system,
it has no scientific– [inaudible] time we had to
talk about this science. Part of what is able to capture
is a capability to treat many of what you have discussed. And they do make that claim, very
powerfully that they able to do so–>>Dr. Raymond DePaulo: Yeah. Some–>>I don’t have any
way validating it.>>Dr. Raymond DePaulo: Yeah.>>But it gives rise to a question. Is there a way in which alternative
non-medical suggestion can be formulated because I also come from
the culture where there’s a lot of belief on witchcraft
and sorceries and they approach them
via meteorologist that are different from us. And we’re beginning to say
let’s start questioning them, let’s now begin to understand them. And, you know, there is this famous
Nigerian, Lambo, who became the head of [inaudible] organization. He’s dead now.>>Dr. Raymond DePaulo: OK. Listen you’ve got a
very good question. (Inaudible) Phil take a shot at it. So how about religious
cures if you will. How would you look at them for the
people lets’ say, gee, in our church or in our way of believing
we can take care of this. What do you think?>>Dr. Philip W. Gold: Well, one
of the most important aspects of the psychotherapy
is the development of a therapeutic alliance. There is something that is
helpful and that can be useful when one person meets with
another they develop a meaningful relationship and they
begin to trust one another. Their placebo effects also. But I think that, you know,
there are many different forms of psychotherapy that work and I think the common element
generally is that alliance between the two– the trust
between the two and the commitment to try and to understand.>>Dr. Raymond DePaulo:
If I could off that. I mean, I mean see an
awful– [inaudible] families, and I would see lots of
families who are not identified as having depression but who
did and who got well as soon as their sibling or their
parent or their child got well. OK. So– And by the way. That’s the thing now that we’re
doing is brain imaging studies. We see that physiological
things just as well as pharmacological things. Change the brain. OK. So, that we– you know, this
issue of psychology or even belief. And I think the psychiatry
was inappropriately unfriendly to religion on the one hand. On the other hand, I think
eventually I’m going to want to see some data to tell me that this is a good
thing to do for people.>>Dr. Carlos Zarate: Yeah. And so– And even Dr. Gold presented
slides where you had, for example, altruism, there could be issues of
social good faith-based treatments or at least the aspects,
self-rewarding, being part of a group, a
network of family that does go and that is actually affected
with depression and those things as altogether might help depression. So, we don’t think it’s a
magic drug, a magic therapy but it’s really the totality
of the individual in the family and the community that’s
going to be important in heal.>>Dr. Raymond DePaulo:
This is strange disease. We’re using the model, but it’s
a strange one because it comes and goes even without us going
anything on the one hand. So– And– But the thing I would
tell you is when people– you can– we can tell whether somebody didn’t
want it, just didn’t go on away. And on the one hand, the
kind of things you’re talking about in some ways are– I’d
like to say are even better than simply be treated
for your symptoms, right. It’s about, you know, really
purpose and that sort of thing, an altruism and that sort of thing. So– But it’s very hard to access
that if you’re terribly depressed. So I just don’t want to
deprive somebody of something that I can demonstrate
that it works. [ Inaudible Remark ] That’s right. That’s right. That’s very interesting. That’s right.>>Dr. Carlos Zarate: So I
could know what is your language so I could know the example?>>Dr. Raymond DePaulo:
And your language. What’s–>>Dr. Carlos Zarate:
What’s your language? [ Inaudible Remark ]>>Dr. Raymond DePaulo: Actually it
was interesting because that was– there was an interesting study done
from the Department of Mental Health at Hopkins on psychotherapy
and interpersonal psychotherapy in Uganda, in women
with milder depressions. OK. And Myrna Weissman, they
called Myrna who’s at Columbia, wonderful woman, who developed
this interpersonal therapy and she is very rigorous. They asked her if she want to
be involved and she said, yeah, that sounds really interesting
but we’ve got to show that our nine basic contracts of interpersonal therapy
translate into that culture. And eight of them translated fine. The one that didn’t
translate at all, loneliness, because they’re never alone. Right. Exactly. So it’s very interesting. Those things are all relevant. Yes sir? Yes ma’am?>>Hi. I just wanted to thank
you for putting so much of this into layman’s language that’s
understandable to generalists. I was interested when
someone mentioned that neuroplasticity increases
at the point of depression.>>Dr. Philip W. Gold:
Now there’s a– Neuroplasticity increases in the
amygdala in depressed patients. That is the component
that is responsible for the conscious experience
of fear and anxiety. That actually develops
neuroplasticity increases in size and has proportionally
greater effect on person’s behavior and thinking.>>Dr. Raymond DePaulo: I think
you’re also saying is hippocampus that actually goes
down, isn’t that right? And the hippocampus which that’s
where more action [inaudible] that seems to go down in depression.>>Dr. Philip W. Gold:
And the prefrontal cortex. That’s down too.>>I’d like to ask the last
question and then I’m going to invite everybody to
metaphorically attack our speakers at the reception back there. So, the last question which is
an up to being a last question, it was interesting to me that
in response to the question about witchcraft, you
went to psychotherapy which is exactly what
I was wondering about and that is the comfort you have
that psychotherapy can be part of the treatment but the
metaphor of this being a disease and the way people commonly
understand disease or accident, a broken leg or something which is
heavily biological one would not think that let’s get a
psychotherapist in here to help them maybe deal with
the symptoms but not as part of the cure or the remission. And I’m still struggling
to understand something and that is the extent to which
this depression of various kinds that you all have described
can be considered or ought to be considered psychical if you
still want to include psychotherapy in not the cure but the remission.>>Dr. Raymond DePaulo: Excellent.>>Dr. Philip W. Gold: Yeah. If the– I think we don’t know
really what systems entirely transduce the depressive syndrome. But if the stress system
is importantly involved, then psychological stress and
experience play a great role in how the brain is going
to be wired and the extent to which the depression can develop. And so I think it’s understandable
that a biological disorder that is responsive to
stress is responsive both to medication and the psychotherapy.>>Dr. Raymond DePaulo:
Let me add in. Phil started off this way in
his talk about psychotherapy and I appreciate his– reminding
me of my teacher Jerome Frank. When he studies psychotherapy, he was the fist great
researcher of psychotherapy. He studied the things that were
different between psychotherapies or the things that were common
between different psychotherapies and the alliance with
the patient seemed to be the most important thing. Now today, the trend is to
teach what you do in the room. Is this method IPT better
than CBT better than BBT. And I think those things do matter. You can show they do
have some difference. But I think the alliance
probably still carries a lot more, number one. And I only say that, you know, first off that the
psychotherapies for the person. It’s not– if you could show me that psychotherapy never cured
anyone would I stop doing it? Not me. If I don’t address
the suffering of my patient, I have no right to be their doctor. OK. So, how do you do
it and– is one thing. But if we don’t listen and
then– and talk to our patients, get to know them, let them
get to know us enough. I don’t think we’re doing our
job and that’s one of my problems with taking the disease models
as if and redefining it. OK. All models are wrong. OK. Yeah. Thank you.>>Ladies and gentlemen
please [inaudible]. [ Applause ]>>This has been a presentation
of the Library of Congress. Visit as at loc.gov.

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