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Hydroxynorketamine

From Wikipedia, the free encyclopedia

Hydroxynorketamine
(2R,6R)-Hydroxynorketamine
(2S,6S)-Hydroxynorketamine
The four possible stereoisomers of Hydroxynorketamine
(2R,6S)-Hydroxynorketamine
(2S,6R)-Hydroxynorketamine
Clinical data
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
Formula C12H14ClNO2
Molar mass 239.70 g/mol
3D model (JSmol)

Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a minor metabolite of the anesthetic, dissociative, and antidepressant drug ketamine.[1] It is formed by hydroxylation of the intermediate norketamine, another metabolite of ketamine.[1]

The major metabolite of ketamine is norketamine (80%).[2] Norketamine is secondarily converted into 4-, 5-, and 6-hydroxynorketamines (15%), mainly HNK (6-hydroxynorketamine).[2] Ketamine is also transformed into hydroxyketamine (5%).[2] As such, bioactivated HNK comprises less than 15% of a dose of ketamine.[2]

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  • Can Depression Be Cured? New Research on Depression and its Treatments

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>> 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.

Pharmacology

In contrast to ketamine and norketamine, HNK is inactive as an anesthetic and psychostimulant.[3][4] In accordance, it has only very weak affinity for the NMDA receptor (Ki = 21.19 µM and > 100 μM for (2S,6S)-HNK and (2R,6R)-HNK, respectively).[5] However, HNK does still show biological activity, having been found to act as a potent and selective negative allosteric modulator of the α7-nicotinic acetylcholine receptor (IC50 < 1 µM).[5] Moreover, (2S,6S)-HNK was tested and was found to increase the function of the mammalian target of rapamycin (mTOR), a marker of the antidepressant activity of ketamine, far more potently than ketamine itself (0.05 nM for (2S,6S)-HNK, 10 nM for (S)-norketamine, and 1,000 nM for (S)-ketamine (esketamine), respectively), an action that was observed to correlate closely with their ability to inhibit the α7-nicotinic acetylcholine receptor.[6][7][8] This finding has led to a call of reassessment of the understanding of the rapid antidepressant effects of ketamine and their mechanisms.[9] However, subsequent research has found that dehydronorketamine, which is a potent and selective antagonist of the α7-nicotinic acetylcholine receptor similarly to HNK, is inactive in the forced swim test at doses up to 50 mg/kg in mice, and this is in contrast to ketamine and norketamine, which are effective at doses of 10 mg/kg and 50 mg/kg, respectively.[10]

In May 2016, a study published in the journal Nature determined that HNK, specifically (2S,6S;2R,6R)-HNK, is responsible for the antidepressant-like effects of ketamine in mice; administration of (2R,6R)-HNK demonstrated ketamine-type antidepressant-like effects, and preventing the metabolic conversion of ketamine into HNK blocked the antidepressant-like effects of the parent compound.[11][12] As (2R,6R)-HNK, unlike ketamine, is not an NMDA receptor antagonist, and produces no dissociative or euphoric effects, it has consequently been concluded that the antidepressant effects of ketamine may in fact not be mediated via the NMDA receptor.[11][12] This is tentative, as confirmation that the findings translate to humans is still needed,[13] but it is notable that published human data show a positive association between the antidepressant responses of ketamine and plasma (2S,6S;2R,6R)-HNK levels.[11][12] In accordance with the notion that the NMDA receptor is not responsible for the antidepressant effects of ketamine, dizocilpine (MK-801), which binds to and blocks the same site on the NMDA receptor that ketamine does, lacks antidepressant-like effects.[11] Moreover, the findings would explain why other NMDA receptor antagonists such as memantine, lanicemine, and traxoprodil have thus far failed to demonstrate ketamine-like antidepressant effects in human clinical trials.[11] Instead of acting via blockade of the NMDA receptor, (2R,6R)-HNK increases activation of the AMPA receptor via a currently unknown/uncertain mechanism.[9][11] The compound is now under active investigation by researchers at NIMH for potential clinical use, and it is hoped that use of HNK instead will mitigate the various concerns (such as abuse and dissociation) of using ketamine itself in the treatment of depression.[11][12]

However, a June 2017 study found that (2R,6R)-HNK does in fact block the NMDA receptor, similarly to ketamine.[15][16] These findings suggest that the antidepressant-like effects of (2R,6R)-HNK may not actually be NMDA receptor-independent and that it may act in a similar manner to ketamine.[15][16]

Ketamine, (2R,6R)-HNK, and (2S,6S)-HNK have been found to be possible ligands of the estrogen receptor ERα (IC50 = 2.31, 3.40, and 3.53 µM, respectively).[17]

See also

References

  1. ^ a b Ronald D. Miller; Lars I. Eriksson; Lee A Fleisher; Jeanine P. Wiener-Kronish; William L. Young (24 June 2009). Anesthesia. Elsevier Health Sciences. pp. 743–. ISBN 1-4377-2061-7.
  2. ^ a b c d Mion, Georges; Villevieille, Thierry (2013). "Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings)". CNS Neuroscience & Therapeutics. 19 (6): 370–380. doi:10.1111/cns.12099. ISSN 1755-5930.
  3. ^ Leung, Louis Y.; Baillie, Thomas A. (1986). "Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine". Journal of Medicinal Chemistry. 29 (11): 2396–2399. doi:10.1021/jm00161a043. ISSN 0022-2623.
  4. ^ Wainer, Irving W. (2014). "Are basal D-serine plasma levels a predictive biomarker for the rapid antidepressant effects of ketamineand ketamine metabolites?". Psychopharmacology. 231 (20): 4083–4084. doi:10.1007/s00213-014-3736-6. ISSN 0033-3158. PMID 25209678.
  5. ^ a b Moaddel, Ruin; Abdrakhmanova, Galia; Kozak, Joanna; Jozwiak, Krzysztof; Toll, Lawrence; Jimenez, Lucita; Rosenberg, Avraham; Tran, Thao; Xiao, Yingxian; Zarate, Carlos A.; Wainer, Irving W. (2013). "Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors". European Journal of Pharmacology. 698 (1–3): 228–234. doi:10.1016/j.ejphar.2012.11.023. ISSN 0014-2999. PMC 3534778.
  6. ^ Paul, Rajib K.; Singh, Nagendra S.; Khadeer, Mohammed; Moaddel, Ruin; Sanghvi, Mitesh; Green, Carol E.; O’Loughlin, Kathleen; Torjman, Marc C.; Bernier, Michel; Wainer, Irving W. (2014). "(R,S)-Ketamine Metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine Increase the Mammalian Target of Rapamycin Function". Anesthesiology. 121 (1): 149–159. doi:10.1097/ALN.0000000000000285. ISSN 0003-3022. PMC 4061505. PMID 24936922.
  7. ^ van Velzen, Monique; Dahan, Albert (2014). "Ketamine Metabolomics in the Treatment of Major Depression". Anesthesiology. 121 (1): 4–5. doi:10.1097/ALN.0000000000000286. ISSN 0003-3022.
  8. ^ Hymie Anisman (6 May 2015). Stress and Your Health: From Vulnerability to Resilience. John Wiley & Sons. pp. 256–. ISBN 978-1-118-85028-2.
  9. ^ a b Singh, Nagendra S; Zarate, Carlos A; Moaddel, Ruin; Bernier, Michel; Wainer, Irving W (2014). "What is hydroxynorketamine and what can it bring to neurotherapeutics?". Expert Review of Neurotherapeutics. 14 (11): 1239–1242. doi:10.1586/14737175.2014.971760. ISSN 1473-7175. PMID 25331415.
  10. ^ Sałat K, Siwek A, Starowicz G, Librowski T, Nowak G, Drabik U, et al. (2015). "Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: Role of activity at NMDA receptor". Neuropharmacology. 99: 301–7. doi:10.1016/j.neuropharm.2015.07.037. PMID 26240948.
  11. ^ a b c d e f g Zanos, Panos; Moaddel, Ruin; Morris, Patrick J.; Georgiou, Polymnia; Fischell, Jonathan; Elmer, Greg I.; Alkondon, Manickavasagom; Yuan, Peixiong; Pribut, Heather J.; Singh, Nagendra S.; Dossou, Katina S. S.; Fang, Yuhong; Huang, Xi-Ping; Mayo, Cheryl L.; Wainer, Irving W.; Albuquerque, Edson X.; Thompson, Scott M.; Thomas, Craig J.; Zarate Jr, Carlos A.; Gould, Todd D. (2016). "NMDAR inhibition-independent antidepressant actions of ketamine metabolites". Nature. 533: 481–486. doi:10.1038/nature17998. ISSN 0028-0836. PMC 4922311. PMID 27144355.
  12. ^ a b c d NIH/National Institute of Mental Health. (2016, May 4). Ketamine lifts depression via a byproduct of its metabolism: Team finds rapid-acting, non-addicting agent in mouse study. ScienceDaily. Retrieved May 7, 2016
  13. ^ Collins, Francis (2016-05-10). "Fighting Depression: Ketamine Metabolite May Offer Benefits Without the Risks". Director's Blog. National Institutes of Health. Retrieved 2016-05-14.
  14. ^ Morris PJ, Moaddel R, Zanos P, Moore CE, Gould T, Zarate CA, Thomas CJ (2017). "Synthesis and N-Methyl-d-aspartate (NMDA) Receptor Activity of Ketamine Metabolites". Org. Lett. 19: 4572–4575. doi:10.1021/acs.orglett.7b02177. PMC 5641405. PMID 28829612.
  15. ^ a b Suzuki K, Nosyreva E, Hunt KW, Kavalali ET, Monteggia LM (2017). "Effects of a ketamine metabolite on synaptic NMDAR function". Nature. 546 (7659): E1–E3. doi:10.1038/nature22084. PMID 28640258.
  16. ^ a b Kavalali ET, Monteggia LM (2018). "The Ketamine Metabolite 2R,6R-Hydroxynorketamine Blocks NMDA Receptors and Impacts Downstream Signaling Linked to Antidepressant Effects". Neuropsychopharmacology. 43 (1): 221–222. doi:10.1038/npp.2017.210. PMC 5719113. PMID 29192654.
  17. ^ Ho MF, Correia C, Ingle JN, Kaddurah-Daouk R, Wang L, Kaufmann SH, Weinshilboum RM (June 2018). "Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression". Biochem. Pharmacol. 152: 279–292. doi:10.1016/j.bcp.2018.03.032. PMID 29621538.


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