Kamis, 13 Juli 2017

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osteoporosis injection treatment side effects

>> from the library ofcongress in washington, dc. >> robert l. gallucci: ladies andgentlemen, welcome to the library of congress to the kluge center and to our meeting todayexploring important questions around depression andits treatments. i'm bob gallucci. i am the director of kluge center. i'd ask you at this timeto do what i'm going to do which to put your cellphoneson 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 andthe kluge center websites as well as well for kluge centeryoutube and itunes' u channels. the kluge center where you noware was created 15 years ago through a generous gift fromphilanthropist john w. kluge. it brings together scholars andresearchers to distill wisdom from the library's richresources and to interact with policy-makers and the public.

the center also awards the klugeprize which recognizes achievement and the study of humanity. it was awarded to philosophersj√£¼rgen habermas and charles taylor last year, 2015. the scholars' council is here today. the panel we are hosting is led by scholars council memberphilip w. gold as a part of the annual scholars councilmeeting at the library of congress. scholars council is a body ofdistinguished scholars convened

by the library of congress to adviseon matters related to scholarships at the library withspecial attention to the kluge centerand the kluge prize. information since 2001, the councilcomprises 14 leading thinkers and includes winners of thepulitzer prize, the holberg prize, balzan prize, guggenheim-fulbrightfellowships, and those listed among timemagazine's most influential people. dr. philip gold has been a memberof the scholars council since 2004. he received his undergraduatemedical degrees at duke university

and his post-graduatemedical training at the harvard medical school. he has been at the nih clinicalcenter since 1974 where he served as chief neuroendocrine research in the nimh intramuralresearch program. dr. gold and his colleagueshad pioneered the elucidation of fundamental mechanisms ofthe neurobiological-- biology-- excuse me-- of the stress response and its dysregulationin major depression.

he is an author of more than 500publications including a series of 9 full-length articles in thenew england journal of medicine. the kluge center is all aboutbringing scholars together from different disciplinesand encouraging conversations and reflection that mightnot otherwise happen. our panel today does exactly this. dr. phil gold has beenthinking about these topics for decades from a scientific angle. in addition, as a medicaldoctor, he brings a deep concern

for the human condition and a driveto improve the lives of patients. as he wrote for a recentinterview for the kluge center blog and i now quote dr. gold, depressionis an insidious illness infiltrating core attributes thatdefine our humanity. for this reason i have an abiding and profound antipathyfor its treachery. depression humbles us by makingus seem far less than who we are. in so doing it robs of themajor epics of our lives, past, present, and future.

i'm glad he and his distinguishedcolleagues are with us today and will be reflecting onthese important topics. dr. gold. [ applause ] >> dr. philip w. gold: thank youvery much for those kind words. it's a pleasure to be here and backat 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 generalaspects of major depression and how we've come to understand it as a neurodegenerativesystemic disorder. and then dr. ray depaulo whois chairman of the department of psychiatry at johnshopkins university and head of their depressionresearch program and one of the world's outstandinggeneticist and psychiatry will be speaking ongenetics of psychiatric disorders and especially depressionand bipolar disorder.

and dr. carlos zaratewho is a laboratory chief at the nih has made, i think, oneof the most important discoveries in the last 25 years inpsychiatry by finding that the drug ketamine is able toproduce rapid and full remission in treatment-resistant patientsin as little as an hour. and just yesterday i saw apreprint of his paper which appeared in the journal of nature wherethey have worked out the mechanisms of action of ketamine anddiscovered other compounds that have similar effectswith fewer side effects.

we'll each speak for about 40minutes and take 10 or 15 minutes of questions after our talks andthat will still about 15 minutes at the end of the sessionfor questions. let me just type in my informationhere 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 itas i have assigned. now i don't even have a hint here. i've been using thispassword 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 andnow i know what it's like. let's see. ok. here we go. what i'm talking aboutdepression is a dysregulation of the stress response andwe'll be describing some of the newer findings that haveemerged which established depression as a full-blown disease, asystemic full body disorder

which neurodegenerative aspectsand is a progressive disease, much more serious, i think, thanwe had previously appreciated. the slide there is aschematic of something that hippocrates said 2000years ago that we're all beset by disturbing forces thatmaintain, balance, equilibrium, and fortunately they'recounteracting, reestablishing forces that reestablish thebalance, equilibrium. and today we call the disturbingfactors, stressors, the balance or the equilibrium homeostasisand the counteracting,

reestablishing forces as adaptiveresponses and two adaptive responses so the stress systemand the immune system. galen referred to thesecounteracting, reestablishing forces as these [inaudible] thehealing forces of nature. and as i mentioned, we know thatdepression is a dysregulation of the stress response andi'll talk with you a bit about what the stressresponse is all about. we first presented thisin a two-part series in the new england journal ofmedicine entitled "clinical

and biochemical manifestationsof depression, relation to the neurobiologyof stress." and what is the stress response? say you're being chased by abear and you fear for your life. the first of fear-relatedbehaviors and anxiety and these are essentialfor survival. without them, there isnot sufficient motivation to escape the threatening stimulus. there is a very extensivecentral nervous system apparatus

for generating anxiety deep inthe brain and it sends many, many fibers to the cortex to announce the consciousexperience of fear. but the cortex sends relatively fewwires down to the anxiety center and for that reason, we can't reallypersuade ourselves not to be afraid or not to be anxious and that's theprice we pay, i think, for survival. but i think it's one of thetragedies of human evolution. there is a decreased capacity forpleasure and the reason for that or one of the reasons for that isto prevent distraction along the way

since the attention must be focusedonly on the threatening stimulus. similarly, there's aninflexible mood and cognition. the mood should notbe bouncing around and cognitive style is reallyvery fundamental either programs that had been generated duringpast stressful experiences or somewhat instinctive responses. stress hormone productionis always an invariable part and i'll be talking a bit aboutsome of these stress hormones, cortisol and norepinephrine.

there is redirection of fuel tothe bloodstream and the brain and this increases plasmaglucose which the brain-- the stressed brain needs in order tomount an effective stress response. it occurs through insulinresistance. and i can talk a littlebit 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 perhapsto prime the system to respond to a possible injurythat is inflicted by the stressful situation. and there's also similarly anactivation of coagulation as a stay against plasma hemorrhageso that the body is ready for this before it happens. inhibition of neurovegetativeprogram for one of these-- again, these occur in order toprevent distraction or the wasting

of calories on programsthat are not essential. so that if you're beingchased by a bear or if you're very stressed,you won't stop and eat. you won't stop and lookat a beautiful scene. you won't stop to rest. you won't stop to sleep. you won't stop to participatein sexual activity. all of these are suspendedduring the acute stress response. and there is something called--

increased neuroplasticityand neurogenesis. we just learned that not long ago. and i'll mention a little bitabout that in the next few slides. but these are intercellular changes that occur invariably during astress response that is controllable and of which the individualfields they can master. and as to the effective terminationof the response, it has to stop when it's no longer neededrather than to linger for long periods of time.

now, what do i mean byneuroplasticity in b there and c? you see these are projectionsfrom neurons. they're like trees, dendritic trees. and normally, they're quite robust with very severe stressdown at the bottom. they are diminished significantly. and with stress that ismanageable, mild manageable stress, actually this neuroplasticityincreases. on the right you see two slides.

the bottom one shows neurogenesis. we now know the brainmakes new neurons. they're born and they makeconnections with other neurons and they're essential foran adaptive response stress. the bottom micrograph showswhat that is like at baseline. and on top, that is the staining of these new cells duringcontrollable stress response. this shows again on the left thecontrol, normal dendritic tree and below, how it's paired off

in the prefrontal cortexand hippocampus. on the right, what happens actuallyis that this tree actually burgeons in the amygdala, the amygdalafear center which is essential for the conscious experience of fear and which plays a veryimportant role in the experience of depression. now, there are severalforms of depression. i'll talk about two principles. the first is melancholic depressionand it affects about 35% of patients

who develop major depressions. and this term-- this form of depression belies the termdepression in that in a state of hyperarousal, its cardinalmanifestation is anxiety, directed at the self, andexperienced as a sense of worthlessness andmeaninglessness. and so it's an existential state. inhibition of the capacity toanticipate or experience pleasure. inhibition of sleep,appetite, and interest in sex.

there is-- inflammation is activatedduring depression really rather considerably and there'ssome data to suggests that not only it may be premonitorybut that it may even occur and predate the onsetof the depression. insulin resistance, so blood sugarrises to help the stressed brain. increased blood clotting. and these events occur evenduring psychological stressors, just as powerfully as if whenwe're chased by a dangerous animal. inhibition of the growth hormoneand reproductive endocrine systems

to save energy forthe stress response. and there's a marked decreasedin depression of neuroplasticity and neurogenesis whichare not very much involved in a depressive pathophysiology. so, melancholic depression,this really is a rendition of virtually exactly towhat i had earlier showed as what transpiresduring a stress response. fear-related behaviors, theinflexible mood and cognition, stress hormone production,redirection of fuel

to the bloodstream and brain,inflammation and coagulation, inhibition of neurovegetativefunctions, here, decreased neurogenesisand neuroplasticity, and there is insufficienttermination of the stress response. it gets stuck as itwere 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 subgenualprefrontal cortex which wayne drevets discoveredwas significantly reduced in size

and its activity isabnormal in patients with familial major depression. these are people who are depressed and who have first degreerelatives who are depressed. and this plays a very importantrole in the depressive syndrome and during the stress response. it regulates and restrainsthe amygdala fear system and hopes to-- andis working properly. it prevents being maladaptivelevels of high anxiety.

it plays a large rolein self-assessment on how we feel about ourselves. it estimates the likelihoodof punishment or reward. it modulates the pleaserand the reward centers. it restrains cortisol secretionand norepinephrine secretion. and in patients withfamilial depression, it's reduced by as much as 40%. and here you see the healthyvolunteers and the bipolar, unipolar depressed patientsshowing how a significant decreases

in the volume of the prefrontal--of the subgenual prefrontal cortex. and so what you get is a syndromewhere there's excessive anxiety; self-assessment is feeling ofworthlessness that goes along with anxiety about theself; increased the estimate of the likelihood ofpunishment, 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 thatoccur in various centers that control cognition, bodilyfunctions, sleep and so on. down at the bottom you seeamygdala and there is-- the arrow goes to the--that yellow structure. and the amygdala fearsystem is essential for the conscious experienceto fear. it restrains that subgenualprefrontal cortex. it makes it more abnormal. and it really puts a break onthe pleasure and reward center.

it's very hard to anticipateyour experience pleasure when you're very anxious. severe anxiety is virtually theabsence of any good feeling. it stores negativelycharge emotional memories. it activates cortisol and norepinephrine secretionstress hormone secretion. it's increased in size andthere is more neuroplasticity during depression. so the amygdala is reallyfiring at full force

in the midst of a depression. and its neuroplasticity is actuallyincreased during depression, which is what we wouldn'tlike to see. and there's an areacalled ventral striatum, which you see there's an arrow thereto the red structure which is just to the right of thesubgenual prefrontal cortex. the ventral striatum plays the mostsignificant role in the anticipation and experience of pleasureand it's involved in reinforcement andin drug addiction.

it sets the tone ofmotivational salients. in response to pleasurablestimuli patients who are depressed have a subnormalactivation of the ventral striatum, do not respond to pleasurablestimuli. and its size is significantlydiminished in depression which is lost duringthe act of depression. and so this is responsible forone component of the depression which we termed anhedonia or theinability to experience pleasure. and one last structure i'mtalking about is the hippocampus.

and it's a horseshoe-likeshape structure. this is a different cutof [inaudible] brain. the hippocampus servedmultiple memory functions, regulate special relations. it modulates the subgenualprefrontal cortex as an area in the front of the hippocampuscalled the anterior hippocampus which sends a single wirewithout prior connections to the subgenual prefrontalcortex and is thought to modulate it significantly.

it sustains cortisol andnorepinephrine secretion. it's the principle site whereneurogenesis takes place in the brain where it increasedduring normal stress response and decreased during severestress with depression. and its size and we've known this from quite awhile issignificantly reduced in patients with depressive illness. so there's loss of tissue. there's more loss oftissue in depression

than there is in parkinson'sdisease. and depression is allmore problematic. parkinson's diseaseis a terrible disease but it's generally adisorder of older individuals. depression has its own, sonot infrequently in children and adolescents and young adulthoodand it's a lifetime disorder. and there's an area called thehypothalamus which you see there at the base of the brain andit connects to the pituitary and it produces a hormonecalled crh,

which our lab has workedconsiderably. crh is released from the brain, stimulates the anterior pituitaryjust outside of the brain, and that stimulates thesecretion of cortisol. but it's the brain thatdrives cortisol secretion and its secretion is highlyelevated with depression. we've now finally nailed down thatdepression is really a full-blown systemic neurodegenerativedisease rather than a simple chemical imbalance.

this concept comes a lotin research that shows which i just shown youwill also gain tissue in several highly specificsites in brain. and these pathologicchanges in brain progress if the depression isnot effectively treated. the damage to the areasperform functions relevant to the core biological and psychological dimensionsof depression. and i'll just repeat these again.

but you'll see these are themajor components of depression. anxiety, how we perceive ourselves,the likelihood of punishment and reward, the capacity toanticipate or experience pleasure. we now know preciselywhere these tissues are, what the tissues look like, whichcells are destroyed and what's going on in remaining dysfunctional cells. one new thing that we'velearned about antidepressants is that almost all antidepressantssignificantly improve neuroplasticity and neurogenesis.

this makes some remarkable compoundsthat few others if any compounds which actually increase neurogenesis and people are experimentingusing antidepressants to try to treat disease of theretina, for instance, to get neurogenesis active thereand other sites of the body. so neurogen and if yougive an antidepressant which increases neurogenesisand neuroplasticity, if you block the neurogenesis youdon't get the antidepressant effect so that for reasons that we don't

yet understand neurogenesisis essential for antidepressant efficacy. and so this leads us to asearch for other compounds that promote neuroplasticity andneurogenesis for the treatment of depression and intissue engineering. one other thing that we know whichis disturbing about depression is that there are systemic ortotal body manifestations. the pathological losses or gainsin tissue in specific sites set into motion pathologicchanges outside of the brain.

they're responsiblefor the premature onset of coronary artery disease,stroke, diabetes, and osteoporosis. so depression is reallythe tip of the iceberg of the syndrome is a seriousand systemically widespread. patients with depressive illnesslose approximately seven years of life, much is untreatedhypertension predictably shortens a life. now i'm going to talka little bit about crh which is the main driverof cortisol.

it actually does many thingsin addition to driving cortisol and i don't think it's coreabnormality in depression but it confers many ofits observable features. and if you give it centrally to experimental animals it inducesfear-related behaviors, anxiety, and increased vigilance,inflexible mood and cognition, the hypercortisolism andincreased 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 wedid sort of an ambitious study to really get a good picture withthis where we put lumbar drains in where you would do aspinal tap and left in there for 30 consecutive hours. the neurosurgeons would do this after all much allneurosurgical procedures, the incidence of infectionis virtual nil

and there are virtuallyno side effects. and what we saw is cortisolwas elevated around the clock in the upper left even whilepeople slept so that this anxiety and hyperarousal does notrequire consciousness. and in the lower right, you see [inaudible] reverse thecrh is significantly elevated around the clock in patients with major depressionincluding when they are asleep. now, i've mentioned, norepinephrinebefore, norepinephrine has many

of the same effectsas crh and it's-- induces fear-related behavioral,inflexible mood and so on, activation of the amygdala,increased blood pressure and pulse rate, theinsulin resistance and proinflammatory state,increased coagulation and it inhibits theneurovegetative programs. and in that study,when we execute csf for 30 hours, this is what we found. first thing that wefound, this is a picture

of showing the 24 hourlevels of norepinephrine and the cerebral spinal fluid andit's elevated around the clock. and the slide below shows therestoration of normal secretion after electroconvulsive treatment. and electroconvulsive treatmentseems to be very draconian and we try to avoid using it. but actually, if we hadsay an 80-year-old person who become very depressed andstop eating and was wasting away and we wanted to get a rapidantidepressant response before dr.

zarate came along, we willuse ect and it would work in over 90% of the cases. this is the curve in red of the24 hour norepinephrine secretion in plasma and it isrestored to normal after ect. and here is the 24 hourpattern of cortisol and its level comesdown after ect as well. the top three showing you curvesthat are virtually superimposable, these are all cardiotoxic compounds. and when they peak earlyin the morning, near end--

at the very end of the slide,what-- that is the time that occurs, that is the maximumtime of susceptibility to heart attacks andto sudden deaths. and here's epinephrine or adrenalinewhich is elevated around the clock and only is partiallyrestored after the ect. this is a study we did in anothergroup of depressed patients who are not as severely depressedand we put a cannula in an artery and infused radioactivenorepinephrine so that we could get calculationof its disappearance rate

and this gives us thespill of rate and you see in melancholic depressedpatients the baseline is elevated. they get an increasedresponse during a video game which is a mild stressor and rathersubstantial rise after [inaudible] which is a drug that increasesnorepinephrine secretion. so, both crh and norepinephrineare excavated and they synergize with one another, theystimulate each other's response and each other's activities. now, i mentioned earlier,the systemic manifestations

of the depression and the pathophysiology isessentially what i've shown you before, the inflammationis part of depression. it's a very much a partof this pathophysiology. coronary artery disease isprincipally an inflammatory disease and the major marker forcoronary artery disease, crp which you get drawn in yourdoctor's office is an index of the cardiovascular riskand if it levels over two, you're at somewhat high risk[inaudible] at greater risk

and crp is an inflammatory marker because the atherosclerosis islargely due to an inflammation of the veins-- of the arteries. increased cortisol secretionhas multiplicity of effects. every cell in the bodyhas a cortisol receptor. sympathetic nervoussystem activation, the insulin resistance causesmuch physiologic morbidity and the increased clothing. let me show you some data that we'vedone looking at insulin resistance.

i'll describe insulinresistance a little bit. i hope this seems clear. insulin is a hormone that secreted-- that causes glucose to exitthe bloodstream into the cell and if you lack insulinyou have diabetes. and so, blood does not get intothe 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 theinsulin doesn't really promote

as much glucose transportedinto the cell. it builds up in the blood supply andhigh glucose levels go to the brain which doesn't need insulin totransport glucose across the neuron. and for that reason insulinresistance is a clever way to increase plasma glucose acutely and to promote optimal brainfunction during distress. and we see that in our depressedpatients who are remitted, they're not suppressed any longer, they have increasedplasma insulin levels.

the insulin is goingup and up trying to get the glucose into the cell. it does mange to do it completely and the plasma glucoselevels are elevated in patients with depression. they're not abnormally elevated. the insulin levels don'tget abnormal, 100, 110. so, here, it's really 90s or a low90s but it's significantly higher than we see in healthycontrols who are matched

for bmi, age, and gender. then we see elevated fastingtriglycerides and total cholesterol in remitted patientswith major depression. they have high triglycerides. they're not outside the normalrange which is about over 160, they have high cholesterolnot outside the normal range but it's 185 comparedto the total cholesterol in very closely matched controls. and next is a compoundcall adiponectin

which is very essentialfor insulin sensitivity. i won't go into this in detail. but adiponectin promotesinsulin sensitivity and its levels are reducedcompletely in patient with major depression aroundthe clock at every time point. one of the things thathappens during depression because of high cortisol levelsand at the top of that sphere, high insulin level, high il-6which promotes inflammation. and that increases the secretion ofadipose tissue but a special form

of adipose tissue which intraabdominal,we call it visceral fat. and visceral fat is a veryactive biochemical machine. and on there right there,you see it makes a variety of proinflammatory compoundsthat 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 proinflammatorycompounds correlate with bmi.

so, if you have child who'smoderately overweight, they're in a proinflammatory state. and anyone who's overweight orobese 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 thesympathetic nervous system,

it produces bad liquidsand increases clotting. now, this is some studies we'vedone, there are many others done by others that show inflammationin patients with major depression. and there-- the inflammation story in depression is veryexciting, really. it's present in a very largepercentage of depressed patients. it's present in the bloodstream,it increase stimuli compounds that stimulate inflammation, and there is increasedinflammation in the brain.

and this seems to precedethe major depression. so some people feel that inflammation may be aprimary trigger to depression and some have used antiinflammatorycompounds and with mix results, but there have beenseveral which show that they have antidepressiveeffects. this is an around the clockstudy we did with plasma il-6 which is a proinflammatory compound. it's elevated around theclock in our patient.

these are in patients who areno longer depressed and not on medication and theyhave high levels as you see on the right there, crp, this compound that predictscoronary artery disease and they have high levels of something called serum amyloida. there is a peripheral crh that we've shown and it comes outof sympathetic nerve terminals. and it is proinflammatory. it stimulates white cells

and it stimulates a cell calledthe mast cell which contains-- it's a bag of proinflammatorycompounds that can do great harmif uncontrolled. and il-6, one of the proinflammatorycompounds has a whole variety of other effects. these things all influenceone another. they are synergisticin their actions, the positive feed back loops. nature has really designedthis system

so that you can reallyget the stresses ramped up in dire emergency. but i think that providesthe context for being so much depressive illness becausedepression apparently affects 16% of the american population atone time during their lives. now, why my patients withmajor depression be inflamed, this is speculative on my part. but there is a newform of inflammation which has been describedcalled parainflammation.

and it occurs in thecontext of stimuli to which we're not exposedin our early evolution. and so, it become inflamed inthis context during at old age, which was not present long, longago during overfeeding or obesity and underactivity with disruptionof the ordinary light-dark cycle with artificial lighting with synthetic chemicalsand drugs and so forth. and i suggest again speculatively that major depression may beapparent inflammatory disease.

because early in our evolutionaryhistory, we may not have experience, the everyday multiple smallstressors that are incurred in our everyday social interactionsor living in chronic conditions. there are several markers forparainflammation that we're looking for to see if we can verifythat this process is transpiring in patients with major depression. and in coagulation,we see the patients with the major depression haveincreased plasma fibrinogen which is a clotting factor.

and the next slide, iwon't dwell on these. but just to show you again thatboth in the morning and the evening, patients with depression haveincreased clotting factors. one is called pai-1 and theother is called factor-viii. we reported in the newengland journal of medicine that even premenopausal women withmajor depression have osteoporosis. and here is the schematicslide of the hip. and if you look at that normogram, you'll see that the darkenedarea is the normal range

and this patient is way downin the osteoporotic range. this is 35-year-old womanwith major depression. now, they don't get fracturesbecause of their youth, the protein [inaudible] ammoniais very strong and intact. but as they age, they becomeprogressively more susceptible to osteoporosis or itsprecursor of osteopenia. these are the bone mineraldensity markers at various sites. they're all reduced in a depressedpatient in multiple sites in the hip and multiple sites in the spine.

this next slide are--the first is ostocalcium. it's a compound thatpromotes bone growth and it's reduced indepressed patients. and it's-- on the right side there'ssomething called deoxypyridinium links, cross links which go upwhen there is bone reduction and they are reduced inpatients with depression. here's a biopsy that we did from one of our most severelyosteoporotic premenopausal women. on the left is normalarchitecture of the bone.

they are what we calledtrabeculae or canals. oh yeah. they are trabeculaeor canals that are made of tough material that suspend thebone and give them a strong matrix. and in the osteoporosis, thepatients with major depression, that structure is markedlydisrupted. and i just mentioned somethingabout atypical depression. i don't have enough time to showyou the data that we have in it. but atypical depressionis another form of depression affectsanother 30 to 40%

of patients with depressive illness. and in contrast tomelancholia which is a state of pathological hypoarousal,atypical depression is characterized by profound lethargy and fatigue. the patients feel much less alivethan usual rather than anxious. they also have decreasedcapacity to experience pleasure. instead of losing their appetite,they have increased appetite and weight gain, increased sleep. whereas in melancholia, thedepression is worse in the morning

and gets a little betterin the evening. in atypical depression, theseverity is less in the morning and more severe in the evening. and the patients feel ward offfrom themselves and others and say that they feel painful lonelinesswhich is hard to escape even when they're around other people. and we've shown that these patientshave those stress hormone levels, have increased indicesof inflammation, have decreased activity of thegrowth hormone or reproductive axes,

and they have increasedheart disease. i'm going to closethis with a concept that people becomingmore interested in and i think will havemore biological markers for in the next few years, butit's the concept of resilience. the american phycologicalassociation defines resilience as the process of adapting wellin the face of adversity, tragedy, trauma, threats, and evensignificant sources of threat. then what confirms resiliences?

there are genetic factors. if one identical-- in identicaltwins, if one has ptsd, the other twin has a40% chance of having it. so even though they share100% of their genes, there's not a 100% of concordance. so 60% of it is environmental. repeated childhood traumato uncontrollable stressors. and people that study childrenwho were housed in institutions and those who were adoptedlater, they study them,

they were more anxious, andthey did bring scans on them, and they had amygdala-- amygdalae that were increasedin size and activity. on the other hand, mild tomoderate controllable stress early in life can have aninoculating effect. such experience leads to increasedneuroplasticity and neurogenesis, and increases the size of thesubgenual prefrontal cortex. an enriched, nurturing environmentand early life with exposure to manageable novelty increasesresilience later in life.

positive emotion, optimism,loving caretakers, flexibility, the capacity to reframe adversity, and strong social supportalso increase resiliency. and finally altruism,commitment to a valid cause, a capacity to extract meaning fromadverse situations, and a tolerance for emotional pain and sadnesspromote resiliency as well. and people are developing a panelof biomarkers for resiliency that hopefully can-- will bevalidated in the years to come. so i'll stop at thispoint and take questions.

>> i'm not sure, i actuallyunderstood some of the chart and things that when you'retalking about a depressed person and then a nondepressedperson and compare things, did you have a depressed person and then a depressed personwho-- after treatment? >> dr. philip w. gold: most of the depressed peoplewe've studied we hope to study while they'renot on treatment so that the studies are notconfused by the impacts of the drug.

so all the patients thati showed you were people who were depressedbut medication free. >> all right. thanks. >> well, in response to the lastquestion, i'm a little bit puzzled by the definition of depression. is there a neurobiological correlatethat enables you to identify it or do you just go bypatient's report? is it just that the patientis seeking treatment?

i mean, i look for lessons inyour account and it seems to me, one of the lesion is we all oughtto be taking antidepressants because it's going toimprove our brains. i'm sure that's notwhat you intended? >> dr. philip w. gold: yeah. >> but it would be nice to knowwhat exactly is the working medical definition of depressionand then a correlate that is is there a preciseneurobiological correlate in a sense that with runner's high we knowit's in keflins and endorphins.

what is it for depression? >> dr. philip w. gold:well, runner's high-- it's the same problemwith runner's high. there is overlap inthese abnormalities between depressed patientsand controls. they're not completely separated. so we don't have what is adefinitive biomarker and that is, i think, one of themost active areas of research, in depression research.

they have many abnormalities thatis levels of things that are higher or lower, systems that seemedto be going array together and complications which make sensein terms of those abnormalities, but not a definitivebiological marker, which i think wouldbe the holy grail. and i think it'll probablybe a genetic marker. >> ok. so why shouldn't we takeantidepressants for neurogenesis? >> dr. philip w. gold: i don't know. >> well, i got a lessonfrom you then.

>> thank you for that. in addition to geneticsand childhood trauma, i'm wondering to what extentenvironmental factors like air, food, et cetera play in thedevelopment of depression? >> dr. philip w. gold: i don'tknow if there are any data about environmentalfactors like air. there are scattered reports forthat being one predisposing factor to depression with a numberof other factors involved. but they're not realsystematic studies of these kinds

of environmental factors. there are more studies that haveto do with adverse psychological and physical environments forchildren and so forth and adults. yes? >> thank you phil. that was a really interesting talk. you seem to-- well, morethan suggest, but you-- we are stacking an evolutionaryloop in the sense that we are living with a system that iswired for a primitive time.

>> dr. philip w. gold: yes. >> and, you know, there are coursein the evolutionary trajectory. we have lost hair, we haveincreased our head size, we've done enormous advances toadjust to our modern lifestyle, how-- what do you-- how can youspeak to the fact that this is one of place where the humanbody has not evolved? >> dr. philip w. gold:it's a very good question. i don't know. because the anxiety is so necessaryfor survival and we're so surrounded

by stressors and especially earlyin our environment but even now, that i'm not sure therehave been mutations that weaken stress responsethat increase survival better. i don't have a really goodanswer for that, but it's true. we've evolved in some ways,apparently not in this way. yes. >> you pointed out that depressedpeople have increased insulin resistance and other markers thatnormally would lead to obesity in depressed peo-- yet, so--

but the medications also getblamed for causing weight gain. >> dr. philip w. gold: right. >> so, if you don't treat thepatient then they're going to gain weight, so what-- whichis really the better way to go? the insulin resistance usuallyoccurs in the melancholic patients who are also lose their appetite. so they don't becomeobese in that regard. and there are someantidepressants do cause weight gain but newer antidepressantsare coming along

that don't have that side effect. but there are serious sideeffects of some antidepressant. >> phil. this goes backto the first question. and i'm not sure i fullyunderstood the answer so i'm going to press you a little on this. if i understood correctly, youhave characterized depression as a progressive disease andnot a simple biochemical issue. you have described differentkinds or variations on the theme of depression that differentkinds of depressed people.

the phenomenon i'm mostly interestedin is that the confidence-- scientific confidence that canbe expressed to capture this in that way that when i'mgetting to hear is the indicators and the extent to which they aredefinitive markers for depression and what's behind thequestion is in the experience, and i suspect they're not the onlyone who has had-- has people-- have people with depression in theirfamily, but there's a large part of the family that rejectsdepression as a disease or a physical illness and insteadlooks for a character weakness.

and if there were definitivescientific marker that would i think helpin terms of reactions. >> dr. philip w. gold: well, i think that there have longitudinalstudies, neuroimaging studies that show that the loss of volume of that subgenual prefrontalcortex is progressive over time. and that the changes in the amygdalaare also progressive over time. there are also somedata, this doesn't apply to every depressedpatient by any means,

but there's an epidemiologicalsense especially with recurrent depressions that thisis already gets worse over time. the episodes are more severeand they come closer together. and rather than requiring anenvironmental precipitant, they occur autonomously. but i think those arethe data that we have. but i think that givenall the imaging data, the physiological data, the responses to pharmacologicaltreatments and so forth,

the fact that it's a-- and thesystemic disease that patients with depression get, that it'sfundamentally incontrovertible, that really is a systemic disease. the world health organizationrecently had an international conference where they decriedthe propensity for people to see depression as apersonal failure in view of the incontrovertible dataabout its biological roots and urged more money for research and treatment facilitiesto treat it.

sixty percent of depressed patientsin the united states are untreated. >> thank you for bringingthis and talk. you mentioned at one pointthat in terms of a certain type of depression, anxiety isthe cardinal manifestation. so i'm wondering whatis the difference between an anxiety disorder anddepression which has anxiety as its cardinal manifestation? >> dr. philip w. gold: youknow, i think, you know, they both respond tosimilar medications.

they have some geneticroots in common. i think there's an overlap. one of the things that is absent inanxiety disorder is the upsetness with itself, a feelingof worthlessness. people with that kind ofanxiety disorder are more worried about accidents, things happeningthat could harm them and so forth or coming down with certain diseasethat can shorten their lives, but not this anguishover the state itself that is the cardinal manifestationof melancholic depression.

anxiety disorders generally arenot associated with alterations in appetite or sleep and someof the neurovegetative findings. they don't necessarilyhave increases in secretion of cortisol and norepinephrine. they're generally normalin patients with anxieties or where there is geneticand clinical overlap. that's a good question. >> [inaudible] depression thathopefully will go away in its own. but is there a currentresearch that we can learn

from like how long is too longto have situational depression and if it might turn into majordepression and should we run for treatment aftera certain timeframe? well, you know, the diagnosticcriteria, say, only after two weeks of major depressive symptoms. but ones that are reallysevere, early morning awakening, loss of weight, loss of appetite,terrible upsetness with self, relative incapacity and so forth. so they say that reallyafter two weeks,

but i would watch longer than that. but i think if somethinggoing on for a month or so, i would begin to feelconcerned about it. that one issue is thereused 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 oftenprecipitates depression, a loss in the personalrealm or of a loved one.

and people can become depressed and remained depressedafter those losses. and they should-- it should not beconsidered that they are impervious to depression, but are merely sad, if they really showall the manifestations of depressive disorder. it is the phenomenology rather than the precipitanti think that matters. >> thank you.

just as we have public awarenesson drugs, stds from your lecture, i'm beginning to think thatwe may now be at this stage in which we have to mountthe public awareness on this? >> dr. philip w. gold:i think that's right. the nimh is mounting that butit has a limited resources. but i think that over time and asthe new findings are coming out, more neuroimaging findings, thekind of findings that dr. zarate has with immediate responsesto new drugs and genetics, i think we'll capture theimagination of the public

and make it clear that it's aserious disorder that's progressive and it needs to be treated. >> hi there. i'm a psychotherapist workingin east tennessee with children, adolescents and adults, andi was particularly interested in your brief tourresilience in children. and when you're workingwith children who have not necessarilyhave that resilience, perhaps have reactiveattachment disorder,

is there research being going on,are you doing some things about how to help a child get resilienceif they don't already have it? >> dr. philip w. gold: youknow, i'm not an expert and i've read some papersand there are strategies to develop resilience, youknow, promoting challenges that are manageable with the supportof assistance of an adult and or ward and progressivelyincreasing the challenge and systematicallygoing ahead like that. >> it's over time.

ok. one more question i think. >> sir, perhaps this isappropriate for the last question. what is the state of the art in repairing the brainfrom this disease? what can we do, what do youexpect we'll be able to do to repair the neurologythat'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 depressedpatients who had terrible and completely treatment-resistantdepressed patients. the insertion of an electrode and stimulating the subgenualprefrontal cortex produces immediate and sometimes lasting response. and also there have beenelectrodes that have been placed into the reward center and stimulating thereward center also seems to produce an antidepressantresponse.

i think people are working on allkinds of ways trying to influence, you know, the brain activitywithout being invasive. there are now magnetic resonancetreatments for depressions. some people even say thatmris are helpful for treatment with depression andother noninvasive ways of affecting many areas. as we learn more about the areasthat are affected and find others that may be larger and moreamenable to external manipulation. that may be new strategies fortreating depression that way.

>> do you believe it will actuallyprepare ourselves eventually? >> dr. philip w. gold:it's a good question. i think that we will knowenough about cellular repair in neurogenesis and other factorsthat repair would be possible. also, psychotherapy is veryimportant in treating depression. and the best treatment fordepression is a combination of psychotherapy and medication. that is by far more effective. and there have been datathat show that people

who have successfully responded topsychotherapy have positive changes in the subgenual prefrontalcortex and the amygdala and in the ventral striatum. so experience can alsomodify the brain. [ inaudible discussion ] our next speaker isdr. carlos zarate, who runs a very largelaboratory and research program at the nih clinicalcenter, looking for new and rapid antidepressant treatments.

he's made, where i consideredmany do conceal the most important discovery perhaps in the last25 years in studying depression and that is the capacity ofeconomy to induce a remission in treatment-resistant patients withdepression in as a little as a half in hour and sometimelasting for days. and i know he's justpublished the paper that is actually hasdiscovered other compounds that can do this even better thatthey're attempting to develop and synthesize to treat depression.

and anytime you get an effectivetreatment with depression, you also have a tremendouslyimportant tool for figuring out the mechanism ofthe depressive syndrome. if you know what's the drug isand it's make people better, then you learn somethingabout the underlying disease. so i'd like to call on dr. zarate. he will reveal his experiencewith this very promising field. >> sure. >> dr. carlos zaratejr: good afternoon.

thank you so much dr.gold and others for inviting me herto speak of our work. and i've a series of cartoonsand animation, hopefully, will summarize our workand make it understandable. and at the end, i'll beglad to take questions. so the title of today's talk isrelief from severe depression and suicidal thoughts from-- within hours and our work goingfrom synapses to symptoms, and most recently twocandidate drugs

that can actually accomplishthis rapid response. this is my disclosure. i'm a full time employerin the federal government with the national instituteof mental health. so, briefly summarizing, mood disorders is commonchronic and recurrent. we have major depressivedisorder and bipolar disorder. our next speaker will go morein detail into bipolar disorder. but it's not only-- presents itselfas manifestations of problems

of mood, but there's problems ofbehavior, now circadian rhythms and activity level is crucial. we'll see problems with excessactivity levels or mania and decreased activitylevels during depression. and why is that? well, if you ask our patients ortheir family members, it's very hard to recall in the paststates of elevated energy and mood based on subjective report. what is very easy oreasier to recognize is

when they have increased activitylevels that they can go on and on our patients forhours without sleeping. and now it's not viewedas dr. gold mentioned, simply as neurochemicaldisturbances, but the mood and the behaviors arethe-- in circadian rhythm, disturbances are theresults of disturbances as synapses and circuits. but these synapses andcircuits, of course, are-- have influences from geneticsand environment as well.

now, we have a general negative inmood-behavior has been reported. most of our patientshave both depression and anxiety at the same time. there is irritability. many of our patients arevery angry and hostile and that's unfortunately a conceptthat has been lost over the years in terms of what you seewith your patients is really that there's hostility andrisk of violence and suicide. there is also the opposite extreme

which is the manicmood and behavior. we have excess energylevels, activity levels and increased risk-taking behavior. we're not going to get more intothat because our next speaker will. but towards the right,you see an image of the same person during theirstate of depression, sitting still, looking in a distance, probablyhave a poverty of thoughts, thinking probably of death,not eating and not sleeping. and that's actually whatyou see in the same woman

at the opposite extreme, whereyou could see probably dressed with many layers of clothes, givenbelongings away, so on and so forth. our patients can have also psychoticsymptoms or cognitive symptoms. the psychotic symptoms are impairedreality test and psychotic symptom-- and cognitive symptomis destructibility and impaired cognition. and what's very interesting inour patients with both depression and with bipolar disorder, youcould have a mixture of any of these symptoms overthe course of your life.

and one episode is not necessarilythe same as another episode. you may have had 30 yearswhich makes it very difficult to diagnose our patient'saccurately. now, we talk aboutsymptoms and categories, but this is a realpatient, one of our patients on the research unithere in bethesda. this is bob, a 53-year-oldmarried male with a 35 year history of severe, refractory majordepression, co-morbid anxiety, phobia, ptsd, and alcoholdependence.

has had 10 major depressiveepisodes. 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 oneof our treatments or pamelor for depression, and nearly died. was admitted to our hospitalwith thoughts of stabbing himself with a knife or drivingoff 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, butthe very impair and in terms of the amount of disability. this is a rank order list ofthe conditions or disorders that are associated fromnumber one to number seven of those causing major disability. and you can see what is at the top.

neuropsychiatric disorders. we have mental-behavioraldisorders much more than neurological disorders. but this group of categoriesare much more disabling than cardiovascular disease,musculoskeletal disease, diabetes and so on and so forth. and remember, these are chronicdisabling disorders of the young as already mentioned before. cardiovascular diseasestarts later in life.

but you have deprived and robbed ouryoung ones with having this illness. they have not been ableto date, finish school, be able to buy their house,get a job and so forth, and they start withdisabling symptoms. so we have to do better. these are the-- and notonly it is associated with significant morbiditybut 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-- withthe treatments over those decades and how it's-- it affectedthe prevalence or the rates of these illnesses over time. and you can see in general,leukemia, all leukemia has come down with new informationin 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 milliondeaths per year with exercise, diet, better medications and treatment. we've also made progress in aids. as you know, people can nowlive into very late age-- years of their life with treatments. and also stroke, we can now, ifyou show up to an emergency room within two hours, one-third of therecan really have a good outcome. so very important, if youhave symptoms of stroke, go to emergency room right away.

however, look whathappens with suicide. despite 50 years, 30 to 40different antidepressants, the rates of depressionhave not decreased and-- for suicide has notdecreased over the years. in fact, if you think of a measureof success is decreased in the rates of serious mental illness. despite all our treatments, we'venot made a significant then. in fact, the suicide is wrong. in fact, there has been an increase.

recent report show actually there'sbeen a 24% increase in suicide. that's a major issue and i'lltalk about a little bit later. not only do you diefrom-- because of suicide, but the excess deathsare due to other factors. many of what dr. goldhas mentioned, problems-- proinflammatory conditions,coagulation, homeostatic conditions, so on and so forth, there'san excess risk of death from cardiovascular disease,from suicide and from accidents. so our patients with mood disorders,

particularly bipolardisorders die at younger age. it's not unusual tolive 10 to 20 years less if you have a major mood disorder. and i'll already mentioned,you start already with significant disabilityfrom young age. now, this summarizes a littlebit what dr. gold was talking. this is the course of illness. you have in the upper left cornera diagram showing in the blue, major depressive episodes,yellow are the well-being,

the euthymic intervals and then in green are the hypomanicor manic episodes. and generally, for significantnumber of our patients, as time goes by, yourdepressions last longer. you can see in the figure,they're more severe. and the good times arethe well being is shorter and shorter, the yellow,you can see. each of those episodeshave a significant impact. we're already told aboutsignificant impact on bone, on brain

and heart and so on and so forth. you can see the personal disruptionto one's life, personal family, occupational disruptionsignificantly affected with each of those episodes, as well as economic well-being,society is affected. and then there's a riskof suicidal behavior. towards the bottom, you can seehow problematic our disorders are. but it's even made worse that most of the time you do not findbipolar disorder alone.

ninety percent of the time, youfind some other comorbid psychiatric syndrome or disorder. seventy percent of the time you havethree or more psychiatric disorders, each sometimes requiringdifferent types of treatment. towards the upper right, you seea figure looking at the time of-- this study was about 120patients with bipolar disorder that were followed for 13 years. and you can see in the bars isthe percent of time in weeks that they have been affected.

half of the time of that 13years, 6.5 years they spent in-- having symptoms of theillness, half of the time. one-third of the timewas in depression. the killer and the bigproblem of our patient with bipolar disorderis the depression. in about 5%, they had rapid for-- rapid cycling or mixed formsof the illness having both high and low at the same time. now, each episode causes

that significant socialindividual disruption but it has the toll on the brain. and we talked about, hasalready been mentioned, towards the bottomright are neurons, the dendrites and the branches. there's atrophy andshrinkage of the spine, those places whereyou have connection from one circuit to another. in this diagram, you can see herethat there's a, in the bottom right,

a little circuit, and that if it's intact might explain why arepatients have different symptoms. dr. gold and i made both-- made criteria for majordepressive episode, but we overlapped ononly one symptom. that's very commonand very possible. so depression, and peopleare asking the definition is, hundreds of disease. hundreds, each with itsseparate etiologies.

so, you can see how the clinicalpresentation might vary from him to me and so on and so forth, depending on the circuitsthat are affected. we see that, for example here, thecircuit is missing or it's affected and you have anhedonia,lack of drive and pleasure, very common problem in our patients. and another circuitmight be affected and you have suicidal thoughtsor in fact suicidal behavior. so, towards the upperleft, we see the spines

and the circuits are very intact. that looks like a tree in spring. we have branches and leaves thatcan absorb the moisture and the rain and propagate the neurochemicalsignal. unfortunately, because of thecortisol as mentioned by dr. gold, the gluco-- excess glucose andglutamate, i'll talk about, it looks like a tree onwinter, deprived of the branches and the leaves that can absorbthe chemicals, the moisture or the neurochemicals andpropagated downstream.

towards the right, we see thatthere are many possible explanations for the shrinkage oratrophy of those branches, so it looks like a tree in winter. we have towards thebottom right, we have bdnf, brain-derived neurotrophic factor. those are the miracle-gro factorswhich have you have in your garden and make things branch out. there are also these naturalendogenous brain chemicals that maintain the neuronsand the branches healthy.

and you have the cortisol andstress and so on and so forth. so there's a different mechanisms. the one i will talkis in the right-- on right side of thefigure called glutamate. glutamate is an excitatory aminoacid and its regulation seems to be important to depression. so, we talked about-- we have andpeople have talked about criteria. we have what we called dsm,diagnostic statistical manual, and that has been one way of howwe communicate with each other

with families, ourpatients and with clinicians on our patient who's in front of us. so it is a common language fordescribing psychopathology. in general, we do a fairly goodjob describing and agreeing that this person has amajor depressive episode. there, unfortunately,is a significant overlap in symptoms and syndromes. i already mentionedhow there's 40 to 50% of our patients have manycomorbid psychiatric disorders

and the symptoms unfortunatelydo not map onto the brain. and so that has been one of thereasons why we have not been able to find more effective treatments. and so, what had-- has beenproposed at the national institute of mental health, nimh, is to breakit down into the more simpler-- to more simple elements, anhedonia,motor activity or drive, suicide. in those trends, you can thenunderstand it in a better way. going into units of analysisall the way, for example, in anhedonia from the behavior lackof driving pleasure, staying in bed

and not enjoying things all the wayto genetics, going through circuits and cells and that will giveus a better understanding of these illnesses. and rdoc does focus on understandingthe more simple elements that cross-- go acrossmany of these disorders. you can have anhedonia and panicand obsessive-compulsive disorder and depression or schizophreniafor 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 courseof discovery from the 1950's. and we've started-- the firstantidepressant was discovered by serendipity, and that'sunfortunately what happens in psychiatry. clinical observation which is agood thing, and i think will lead to continued discoveries isreally the only way we've come up with better treatments, just byobserving our patients being exposed to different medicines out there. the first was a drug, anantibiotic given for tuberculosis.

it was given at high doses and theynoticed the patients were dancing in their units andenjoying themselves and talking a mile aminute and not sleeping. and so, then people thought,oh, this, you know, you're high, that means it's probably good foryour 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 werenonselective affecting serotonin,

norepinephrine, dopamine,choline, cholinergic systems. and people said, the industry said,"oh, they're not well tolerated and they're very lethalin overdose", like tric-- like nortriptyline, likebob was taking, pamelor. so let's go to moresimpler antidepressant that affect predominantly serotonin,you know that as the ssris, prozac, zoloft, paxil, so on and so forth. and then some of the cliniciansout there and patients said, "well, probably they're not aseffective as the older one."

ok, let's go back to two,dual reuptake inhibitors, two neurotransmitter, snris. and then now there's-- going backto triple reuptake inhibitors. so most of drug discoveryhas been about me, two drugs. they're pretty much the same,serotonin-norepinephrine. most of the patients probably do notbenefit much more than what we have from existing treatments. so they are suboptimal. clinicians, patientsand family said, "well,

probably our medicationsare not effective. and so not effective or effectivefor some, let's figure it out." so nimh did do this verylarge study called star d. that was a systemic wayof giving levels of care. everybody at level i startedwith the first antidepressant, citalopram, for 10 to 14 weeks. if you didn't respond, youwent to the next for 10 to 14 weeks, so on and so forth. ok. what we've-- what wesee 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 antidepressanttransfer half of our people to achieve remission. that's way too slow in my opinion. and then after four treatmentsincluding psychotherapies, i didn't mentioned here,one year later, only--

one-third are still notachieving remission, one-third. and not only that, of thosewho responded, begin 40 to 60% in those first twobars are relapsing. so what we see is low remissionrates, a significant lag of onset, personal-social problems andthe risk of killing yourself if the medication is notworking or the therapy. ok. this is drug discovery for those who are interested inthe economics of it. this is how we develop drugs.

ok. we come up with-- we havepreclinical and clinical phases. this takes about 15 years and 4 to $11 billion studying 10,000compounds 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 knowwhat the targets are. ok. the lowest are, what, braindisorders because they're complex and we really don't knowwhat the exact targets are.

the success rates forcns is about 8% after spilling all--spending all that money. and you can see why industry hasbeen leaving psychiatry altogether. now, this is a summary of whywe need improved therapeutics and what happens. in this cartoon, you see inblue the depressive episode. we started antidepressant. ok. any of them currentlyon a market, it takes about 10 to 14 weeks.

they affect monoamine systems whichis serotonin and norepinephrine. that's what i mean. our goal is to shift thiscurve towards the left so that the next generationtreatment, we will have treatments that work in a few hours thatway [inaudible] depression use [phonetic] suicidal thoughts. and if you remember, thattime i showed the figure over your lifespan, how muchtime you spend in depression. imagine for each of those episodeswhich range from 4 to 9, average,

number of episodes for each patient, or half of the time youspent ill in your life. within one to three days, ifyou have symptoms of depression and you treat that, it goes away, and the next one itcomes it goes away, you can imagine thecumulative number of episodes, accumulative depression of yourlifetime will be very short, thus your health, physical, asdr. gold said will be better and your brain will be better.

so that is the goal of our programis to develop rapid-acting agents. we come up with targets,in this case, glutamate. our studies are what wasmentioned, drug-free, double blind, placebo control on our inpatientunit here, a few miles from here. and we study multiple biomarkers,both peripheral blood measures and brain measures at the same timeto better understand our patient. so our patients are greatand they really spend-- altruism was mentioned. they're really altruistic and reallywant to understand these diseases

and help others to comeup with better treatments. so towards the upper right, you seethat we are looking at interventions that cause rapid antidepressantseffects such as ketamine, an anesthetic, i'll take about scopolamine,that's for sea sickness. we're also looking nowat neuro devices, tms, electroconvulsive therapy. so our studies are doubleblind, placebo controlled, and what we do is at the beginning,

we obtain multiple biologicalmeasures and what we try to do is link these with ourtraditional rating scales of depression which are not good,but it's all we have at this time. and we obtain respondersor nonresponders. the goal of this is to linkthe biological measure, whatever that might be,with our depression scores to see who's the respondent andnonrespondent so that we can come up with more biologically-enrichedsubgroup. i already talked aboutdepression is hundreds of diseases.

this strategy will lead to moreenriched group to really tease out what is the etiologyof these illnesses. and not only that, we obtainthese biological measures before, during the study, andafter the study. and i'll give very briefexamples about that. that rather than focusing onwhat is the cause of depression, because we talked it's hard,hundreds of depressions. we're going to figureout what is the mechanism of the response process.

who response and not response? and why is that important? well, response is probably going tobe more similar across individuals in depression and atleast that's the belief. so, one area let's look atis the glutamate system. ok. and i'll talk alittle bit what this does, evidence in postmortem studies, looking at people who've haddepression or who have suicided. there is evidence that some of theglutamate receptors are affected

in the brain and there'salso evidence through-- we use assays or what we calledanimal models of depression, animals that are stressed. and for example, forced swim test,you have animals in the cylinders, plexiglas that arestruggle, struggle. that's viewed as a good sign,but when they stop struggling, that's viewed as helplessas they've given up. and that's supposedto mimic depression. and i said, well, you know,you do that in a few minutes,

but our patients have beendepressed for 30 years, is that a really good model? probably not. but it's what we had beenrelying on for 50 years or so. but there was early evidence thatthe-- or antidepressant affected a-- or glutamate receptor called nmda, and that's going be veryimportant as i talk about. and that if you give drugsthat block that receptor, those animals that were made to bestressed and depressed got better.

and so in early study done in theyear 2000, trying to study cognition because that's really affected inour patient with schizophrenia, psychosis and depression, notice that the depressedpatients got better. seven or 8 patients got better within a few hoursand that was ketamine. and so we have done for the work onthat and i'll talk about that now. ok. this is a very simplediagram explaining the glutamate. ok. glutamate are thoselittle white balls there.

we have three, the top isthe presynaptic neuron, the bottom is the postsynapticneuron and towards the right,we have the glia. this is the tripartite system,important for regulating glutamate. glutamate is an excitatoryamino acid. it's very important for learning, memory and the plasticitydr. gold mentioned. ok. so it synthesized and store in these little presynapticvesicles and it's released.

and it's very tightly regulated. and it's believed that ifthe levels are excessive, that leads to neurodegenerativedisease such as alzheimer's, parkinson's and inthis case, depression. depression might bemore the regulation or the cycling of the system. there're mechanisms tocontrol the amount of glutamate within that space,extracellular space. one is the eaat, excitatoryamino acid transporter,

that grabs the glutamateand puts inside the glia. that's the cell in the right. and there is this metabotropic,mglu. that's the thermostat that goes upand down based on the temperature of the room, goes up and downbased on the amount of glutamate. and then there's the postsynapticreceptors, 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 glutamateis 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 aboutregulating glutamate but even if you regulate dopamine, serotonin,glutamate, what is important to have that tree healthy. and so our treatments haveto be plasticity enhancers, make that tree going fromwinter to spring and be healthy. ok. now, as you can seeit is a complex system.

i tried to summarize it here but there are multipletargets that one can pursue. we and others had beenlooking at that over the years. and this is just asummary of the studies. about 8 to 10 years ago, mostof the companies had dropped out of psychiatry developing drugs and we're just usingoff-label drugs, i mean, drugs that their patent had expired. now since the ketaminestarted 2006 or so,

many of these companies have jumped in to pursue drugs thatregulate glutamate. predominantly, if you look atthe bottom, nmda, that target is where everybody has been goingon, nmda receptor antagonist through our studies and otherstudies, and i'll talk an example. the prototype drug is ketamine. ok. ketamine is an anesthetic agentthat's been out for several decades. it's one of the mostsafest anesthetics. in fact, it's used in manycountries around the world

without a physician, nursesin really remote areas because it doesn't affect-- itdoesn't cause cns depression, problems with breathing andother complications that might-- you might need a significantlytrained 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 wewere heading in our research. ok. now, that receptor imentioned is blown up here. you can see.

this is a channel,inotropic channel. this is one receptor where youhave the sodium and calcium into the channel and point forlearning, memory and plasticity. ok. now, in the channel,you can see pcp. that is the drug called pcp. ketamine is a derivativeof that drug of abuse, pcp, but it's 10 times to40 times less potent. it happens to bindto the same receptor. when it does bind to thatreceptor, the channel closes.

and so while you receive ketamineor infusion, what is affected? your learning, memory,and plasticity, right? because we say that's importantto the function of the channel. and you might say, why are weexposing our patients to these drugs that affect learning, memory andcause symptoms of dissociation? well, the important thing is,i'll mention that in a minute, is our patients arevery severely ill. now, when you block thatchannel with ketamine, you have psychologicalsymptoms, decreased awareness,

you might be disconnected,distractible, have trouble communicatingwhile during infusion. you stopped the infusion andthat reverts very rapidly within 30 to 40 minutes. you might have symptoms ofout-of-body experiences, thrills of like muffled sounds, and your blood pressureand pulse might go up. now, when our patients came, becausewe were interested in the question, if you block the nmdareceptor, will that bring

about rapid antidepressant effects because this is the mostavailable direct blocker of nmda. and for that reason,we studied patients, because of the sideeffects, were severely ill. and this is in our researchunit a few miles up the road. our patients had been ill for24 years, most were disabled, 90% were not able to work. they had failed sevenantidepressants, 60% have failed ect, one ofthe most effective treatments,

50% of our patients hadsuicide attempts, some multiple. and so we really made surethey had failed everything. ok. and you'd expect very littlechance of respondent, wouldn't you. ok. and this is what happenedin 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 greaterseverity depression. towards the x-axis, you seethe time in minutes and days.

one infusion of ketamine,that's one infusion of ketamine for 40 minutes led to rapidantidepressant effects within two hours, lasting about oneweek, with just in one infusion. you can see in redthe control condition. towards the right are response rate. it means you are 50% betterthan when you start it. to the extreme right,you see in light blue, monoaminergic antidepressantsalready mentioned. you get about 60 to65% response rate.

but at eight weeks, takingthe pill everyday in people who are not treatment-resistantdepression and if you look in green, it's ketamine response rate. you got comparable response rateswithin a few hours that is the same as taking a pill everyday forweeks, but in people who failed, on average, six antidepressants. same thing here. well, what about bob? bob participate in a study, you knowabout him, 53 year old, depression,

10 episodes, suicide attempt. this is what happens withina few hours, his depression and suicidal thinking was goneand it lasted 20 days, ok, with one infusion,drug-free, no other treatment. now, i'm not sayingeverybody responds, but about 50 to 60%will have a response. so then the trick is, how do yougo from something that you know that does work muchmore effectively? get rid of the side effects, getrid of the risk of addiction,

because there's a risk of addictionand continue maintaining response. we made some progress there. now, in the psychological sciences,one of the biggest problem also in other areas of medicineis replication. other labs cannot find it. ok. if you look at the figures here, these are two otherstudies than by our lab. depression scores madrsgoes down within one hour, lasting a good part of the week.

another replication studyshowing exactly the same. what is very eerie, strikingly eeriehere is the curves almost overlap which is unheard of inpsychiatry especially with antidepressant treatment speaks to a true biologicalphenomena that's going on and really a mechanism. people have moved onto, then afterfive of our controlled study, and nimh decided to alarger two sites study and you can see hereexactly the same.

within one day, no earliertime points were obtained. rapid antidepressant effects with ketamine lasting agood part of the week. more recently, johnson & johnson,and this study was led by jas singh, who actually was my fellow in thefirst study but went to industry, decided to pursue this withdr. manji and they looked at giving ketamine two times aweek versus three times a week. if you look in the green dots,down means greater improvement and then time overthe next two weeks.

so we'd repeat those is twotimes or three times a week, you bring down depressionscores and they still will-- stay well for at least two weeks. now, the question is how do yougo about making safer ketamine without the side effectsthat i mentioned that it won't affect thebrain, cause problems and the risk of addiction? ok. now, johnson &johnson has gotten the way of developing esketamine, oneof the isomers of ketamine

in the hopes it's goingto lead to and improve. and so if you see towardsthe top right, esketamine by johnson & johnson hasreceived breakthrough designation. they are doing phase three studiesand are planned to be on a market for 2018 based in thework we've been doing. so we're excited about that. people have jumpedin back into industry but specific glutamate drugsand not drugs for all psychiatry at some point to keep in mind.

there are multiple grants beingfunded by nih on this line of work with preclinical and clinical. the second area is can we developmore ketamine-friendly drugs, meaning ketamine, if you lookat is like this building. ok. in this room is the efficacy andsome other room it's the side effect so that's what we calledunits or subunits. so how do you figure to get thedrug in this unit and stay in room and stay away from the other roomsor units and that's the trick. well, you can come withmore subunit selected drugs.

and there have beensome studies doing that and i'll talk aboutthat in a minute. so, we have done a number of studies with these other moresubunit selected drugs and this is the summaryof all those studies. ketamine has rapid onset, robusteffect and sustained action. no doubt about that, butit has its side effects. ok. dr. insel, who's no longera director in the nimh moved on, but summarized this, afterall our studies and others,

and says that other medications that block these receptorsare not antidepressants. ok. i would say that's not the case. i would say, they are butprobably not as robust and sustained as ketamine. i do think they haveantidepressant properties. but they still have thatside effect liability. ok. in fact, this is a summary. we've done all these studiesexcept for the one of them.

but we have-- you couldsee memantine is for alzheimer's disease, blocks thatnmda receptor and there's others, mk, a drug by merck, now cerecor. then there's a pfizerdrug and astrazeneca. these are the companiesthat went back in. and you could see someminuses, maybe a plus and minus. so bottom line, thesedrugs are not as robust and as effective acutelyas ketamine is. and so that's anotherwe have to go into.

so i think the other area we'vegotten into is mechanism of action. so-- and what we calledthis is reverse engineering. ok. so we talked about howketamine is very unique and different than other treatments. so, you know, why not sciencethe heck out of this drug. ok. as-- i'm borrowinga quote from a movie. and we could take advantageof our facilities at the intramural program. ok. we have polysomnography,sleep studies,

the ability to do neurochemicalstudies, look at glucose or glutamate in the brain. we could do magneticencephalography. that is a machine that measures howone 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 fromgenes, cells, circuits, all the way through symptomsto the rdoc criteria. if you can understand andfill in the gaps of knowledge,

you might be able to understandhow this rapid antidepressant works and develop other treatmentsand we have done those studies. first of all, towards the topright, this represents rats that had measurements in, while theywere moving around glutamate levels. and you can see here when you givean injection of ketamine, at 20, 40, 60, 80 and 100 minutes, keep in mindthose 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 inglutamate extracellular levels.

so we did a study in the forcedswim test in 2008, dr. manji. and this is the forced swim test. it's that's rodent that'sstruggling and you can see in green, ketamine decreased the mobility. that means it hasantidepressant-like properties. towards the right, yousee an ampa blocker, remember next to thenmda receptor was that other glutamatereceptacle, ampa. and so here, the studywas looking if we pretreat

with an ampa blocker would thatabolish the antidepressant effects of ketamine, ok, becausenmda is blocked by ketamine. and the answer is yes. you can see towards this-- theright and ketamine plus ampa, the antidepressant effectsof ketamine go away in mice. so it seems that these ampareceptors are important. and i'll come back in a minute. going back to that-- thoseapartments or the rooms, subunits selective drugsand are to be antagonist,

we see that it doesdecrease the mobility. it means it has antidepressant-likeproperties. but also if you pretreatwith ampa blocker, the antidepressant effects go away, suggesting ampa receptorsare important for the antidepressant effectsof this compound as well. now, here's a cartoon thatputs everything together what i've mentioned. ok. you have the presynapticneuron, the postsynaptic neuron.

ok. so you have ketamine binds tothe nmda receptors as we mentioned on this gaba interneurons,another part of the brain. so the scopolamine, it'sa sea sickness patch, but here we give itintravenously, binds to its receptor on the same gaba interneuron. what both appear to have in commonis this glutamate surge burst, i already talked aboutthat increase in glutamate, that preferentially targets,in yellow, this ampa receptors and causes this intracellularsignaling cascade,

similar to what dr. gold was talkingabout, and causes this increase in bdnf, brain-derivedneurotrophic factor. those are the growth factors that maintain the neuronsand dendrites healthy. and so in this cartoon, youincrease the number of spines, you restore the synaptic connectionsthat were affected that i talked-- that i began talking about. and you restore that homeostaticbalance that was affected because of stress,glutamate, and cortisol.

and that's at leastthe prevailing theory. now this study is quite complexbut we haven't just finished where we obtained all these measuresin our patients who are depressed to better understand thebiology of the response process. in here, they're listed. but the goal to understandthe neurobiology of the response and relapse process. and just to show, very similar. the study i just finishedis identical the curve

to all the previous studies. very rapid onset, people staybetter for one week or more. ok. and this is the example, someof the tasks we used that taps into these regions or circuitsthat dr. gold was talking about. one is you exposed onanybody healthy, control or depressed patients' faces. and the faces willlight up certain parts of the brain, the visual cortex. of course, the back of the headoccipital is one of the regions.

and you will pay attention to thegender or the valance, meaning happy or sad in the face and you have toreact very quickly when it's shown. and it's shown in millisecondsand so it's supposed to be subconscious when you do this. and you can look to the left isthe accuracy rate of being exposed to these faces when it'spositive and before ketamine and after ketaminein depressed patients and you can see the negativevalance, the bias towards going to a person that trigger thebutton so the negative goes down.

ok. and towards the right, these arewhat we called evoked potentials. it's a electrophysiologicalmeasure of the visual cortex taken into account the genderor the valance that is happy or sad or angry face. and you can see here withketamine, it increases the positive. so you start biasing yourresponses to more happy things and the bias towards the negativeangry, sad face start going down precisely what youwant in depressed patients. and so, this is an exampleof a noninvasive biomarker

that could predict aheadof time who might respond or not to a certain drug. now, to get into a little bitmore complex but i'm trying to make it simpleris dr. gold talked about subgenual anteriorcingulate cortex ventral striatum. ok. and if you look into thefigure towards the right, you see all those little regionslined up one after another. and this is what we refer toas a matrix of correlations, how one region correlatesto another.

it's now viewed as a bit simplisticto study one region in isolation. now what we try to do is to studyone region related to another. the brain talks-- oops, sorry. the brain-- sorry. so, one area of the brainis talking to another. so if you have a computer in youroffice, ok, and there's a problem with the computer, many times it'snot the problem over the computer, that's one region, but it's theproblem with all the network. ok. you have networks ofcomputer and you have a server

and that server is thehub of the networks. and so that's what we try tounderstand is not one computer at time but every computerat the same time, how one computer talks to another. and not only that, you can gofrom your building to the building across the street intothe whole community. that's how we're studyingnow our mental illnesses and this is referred to asfunctional connectivity, how one region talks to another.

and these matrices youcan see in the warm or red colors are positivecorrelations. they work in sync. and the lighter, cooler colors arehow they work against each other. and you could measure thisthrough functional imaging. this is to show-- towards thetop is 101 represents one subject to receive five scans duringthe study, five function scans. and if you look to thebottom is at baseline, two days after ketamine,why at two days?

well, we already said thepeak of response is there. so you can understandthe biology response. and then 10 days later,why 10 days later? because i said the ketamineeffects last about seven days. so you're looking at the relapse. so here, we're lookingat biology, the response, nonresponse process and the relapse. so that's very important becauseyou might be able to predict who will respond and who willrelapse, ok, as an example.

ok. i should move on. getting into some examples ofanhedonia or lack of pleasure. i talked about we pull out thestrings to better understand it. one example is we looked atlack 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 driveand anhedonia stay well. and this is measured fdg,fluorodeoxyglucose scan. that's a surrogate ofglutamate function.

and we can show here towardsthe left is the relationship or correlation betweenventral striatum, that's the reward circuitin glutamate levels, ok. so the greater the boldsignal, the better the response. and in this area happens tobe dorsal cingulate cortex. and finally, i'm going to get into last three slides ihope i have is the paper that came out yesterday. ok. so this was-- it was a-- thisis a collaboration by maryland

and chapel hill and imentioned several institutes. and in terms of trying tounderstand the mechanism of ketamine, the better ketamine. ok. and this startedwhen i was bothered, remember in green arethe response rates. ok. the side effectsgo away in 40 minutes. the half-life of thedrug is about one hour. so why does it last in seven,you know, days or longer? and so, what we said is let'slook at the metabolites.

in older papers, it saidit's inactive some of them. well, inactive foranesthesia but they didn't know about depression back then. so we looked at all ofthem, a bunch of them. and i have come upwith a can of drug. so this is a cartoon, hopefully,that explains the study now in here. ok. rs are the twoisomers of ketamine. ok. that's the chemical structure. here, we give ketamineintravenously.

ok. it goes through theliver and within 10 minutes, you have towards the right,hard to see, but what was that, all those metaboliteswithin 10 minutes in the-- in periphery and the brain. ok. and towards the extremeright you see are the measures of those metabolites. and we found that metabolites willlast in three days and seven days. that's interesting. if the half life ofketamine is gone in an hour

and the response last sevenday, maybe it's one of these. we know that ketamine is associatedwith side effects, risk of addiction and rapid antidepressant effects. so, through the collaboration,ncats, national center for advance translational research, the principal investigatoris todd gould from university of maryland and our collaboration. what was done is one creates adeuterium form, a dideuterium form of ketamine, means what you dois you attach something to one

of its molecules or add carbons and what you do is youprevent its metabolism. and when you do that,this is what happens. ok. you don't have the rapidantidepressant effects anymore, or very little, but youstill have the side effects and the risk of addiction. interesting. ok. so then you go to one ofthose metabolites who are hanging around hnk, hydroxynorketamine.

in animals, in mice we found ithad rapid antidepressant effects but without the sideeffects of ketamine. ok. so, that's about it. i'm going to stop there andthank you for your attention. >> philip w. gold: ourlast speaker today, i'm pleased to introduce dr.raymond depaulo who is the chairman of the department of psychiatry andbehavioral medicine at johns hopkins and is the psychiatrist andchief there and has been one of the world's experts

on psychiatric geneticsespecially in bipolar disorder. and he's going to share some of-- what has really become anextraordinarily exciting area of medicine. and as i mentionedearlier, i think the one that will yield us thebiomarker 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 regularlycome to the library of congress since i was-- since1966 when i was--

spent my summer in dc oncapitol hill, and i loved it because it was the mostpeaceful place around. and you didn't have to doanything particularly special like you do these days. didn't have to go throughany-- didn't have to take-- i didn't have an iphone but youwouldn't have had take it off them. ok. well, listen, i'm a clinicianfirst, ok, teacher second and then i'm researcher third. ok. i've had a lot offun doing research.

and i have a lot of opinions. ok. and i've loved the first twotalks but even more than the talks, i've really liked the questions, ok, because that's really whatour field is about, ok, is getting the right questions. ok. so let me see if i canstart this little talk. and by giving me the issue of thegenetics of depression, you know, i thought that sort of ruled outproclaiming victory on the genetics of bipolar disorder, ok, which isnot exactly victory but it's a--

it's certainly a heck of abunch bigger start than we have on so-called the unipolardepression, that is people that have depressionsbut not bipolar disorder. so i'm going to talk and i'm goingto show you some genetics studies but i'm going to show you thegenetics studies really of kind of in stairstep fashionof schizophrenia just to show the rapid progress that'sbeen made there for whatever it is. ok. then a little bit on bipolardisorder and then, oh my god, depression, why haven'twe done more there.

ok. and then i'm goingto talk about what-- why is that and alsowhere is the problem. and i think, let's say the geneticunderstanding of depression, there are two operative wordsthere, genetics and depression. ok. so, what is the right geneticquestion and what is depression, which you all have already asked. ok. so, let's go at it. ok. so, i do have nofinancial conflicts with this although whenevermy faculty get up and do this,

they always say i'memployed by johns hopkins, they make me do all kinds of things. and i'm saying that youwill understand what we know about the geneticsof major depression, that is the big challenges. and that you will see how thegenetics of depression may be harder than for bipolar and schizophrenia. and that you will understandthe need for large stable collaborations,

more careers studyingserious mental disorders like depression, and better ideas. the technology is gettingbetter every day. ok. and i've been blessed to be ableto work with the people starting since 1985 with the people who madethe first map of genome and i got to work with them starting abouttwo years before they made it. and by the way, the progresshas just catapulted since then. and so i made-- eric landerwho was 29 at the time and didn't really havean appointment.

he was an unofficial fellowat whitehead institute. he now runs the broad institute, ok, which is a very largegenetic operation. i was just there abouttwo weeks ago. and it's progressed just likethe field has progressed. what do you expect? it's really cool. so, one of the reasons ilike to do science is i get to meet really smartpeople and listen

to the talks and carlos' work. you know, today he showed mesome things i haven't seen before which is really great. that is the active-- the parentcompound 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 myglasses and i can read it. well, this is diseaseburden by illness.

i'm not going to spendmuch time here. carlos and phil and i have allreferred to this the global burden of disease studies, ok, in oneway or another to make the point that depression is big, ok. and so you can see that that's thenumber one on this particular thing. that was 2004. i noticed carlos had ita little differently. he was looking in 2010. the main thing is-- by the way, thiswas the biggest surprise in the--

in these global burdenof disease studies. they were actuallyhad to be persuaded to include psychiatric conditions. ok. and actually the person thatpersuaded them was the brother of one of my faculty members,kay jamison's brother dean, a health economist persuadedthem, 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 questionreally is that is, is it-- is that's what is it,what dsm-5 says? ok. is that really it, achecklist 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, youknow, witness protection. so don't try anything funny. but it is great that we've hadthe challenge to this approach. ok. and it's not thatthese things are wrong. if you were going tocome up with a checklist, way back when these thingsstarted, george winokur from iowa, now the late george winokur, and isaid i didn't really like this way of doing it in dsm-3and it's very similar.

and he said, ok, just comeup with something better. just come up with abetter checklist. i want a checklist. so just give me a better one. and i tried 4 and 5and i said, ok, george, one works about aswell as the other. but these things came--oops, i'm sorry. these things came from some brightpeople at wash u in st. louis and where they came fromwas the walls inside

where the clinicalresearch groups were. ok. and so what theyoung fellow named finer in the finer criteria became todsm criteria, sort of, you know, by little switches and committeesthat morphed [inaudible] other. he went around to the anxietygroup 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 publishedit, it was for research, ok. and i think that's what theyserve and not in the sense of guiding the research at all. just in saying we got to havesome minimal qualification. ok. so, ok. so anyway, so this willdo pretty well, ok, especially when it's recurrent,especially when it's early onset. you've heard about that.

and then especially if ithas the other manifestations that carlos talked about,psychotic symptoms, suicidal-- severe suicidal symptoms, et cetera. but-- so but anyway, as thisis going on, the controversy about this approach of diagnosiswhich has been very much deserved. ok. some have said we even inventedit and i just want to make one slide to say we didn't invent it. ok. this is burton's "theanatomy of melancholy", 1621. but you've already heardabout hippocrates and galen.

they knew about this too, ok. so, that question is answered. ok. by the way, i do wantto come up with an answer about why we haven't evolved outof it and i'll tell you that later. ok. ok. so, melancholia, ok,and as you know this comes from the ancient disease model whichhad to do with the four humors. ok. and in this room,people know what that is. when i go to medical studentsand i ask who knows, you know, the derivation of theword melancholia

and essentially it's zero to twopeople in a room of 50 will know. ok. so, too much black bilewas thought to be the source. but kraepelin reallydidn't buy that. and kraepelin was an early applier of the modern diseasemodel to psychiatry. ok. and he was a prettyfair pathologist. he had a better one as one of hisstudents, alois alzheimer, ok. and the guy who started ourdepartment, adolf meyer, was a very good pathologist and hedidn't like kraepelin doing this

because for what hecall dementia praecox and manic-depressive insanity. he says because you don'thave a pathology yet and that's the centerpieceof the modern disease model. and he said, if you do that,if you allow these things to be called diseases withouta pathology, there is no limit to the number of things youmight call diseases, right? and dr. mckee [assumedspelling] used to hold up dsm-4 in its thick form and say this bookshould be called meyer's revenge.

ok. anyway, but here'sa patient and-- but, you know, i can'tget away from. this is also from kraepelin's textand he showed the woman who had, in two pictures, i'm showingthe man who had two pictures. it took a little work. you had to go through it a coupleof times because these pictures were about 50 pages apart andthey didn't tell you, "hey, this is the same personwho's on page 20." ok. so-- but here's thefellow in melancholia.

he have been said to belike this, wide-eyed stare, having maybe persuaded to pullthe covers down a little bit so they could takea photograph of him. ok. he had no interest in anything. and you can see he's unshavedand he looks a lot better than he probably feltat this moment. ok. and so that's melancholiaand that's the picture of melancholia, all right? now here's another patient that hasmelancholia and i'm going to talk

to you a little bitabout these two patients. i'm not going to talk about bob. i'm going to talk aboutthese two people. so, here is a woman and bythe way, without a checklist, what would we say are thecentral features of the syndrome of depression, if you will? and we would say it's achange in mood or affect, change in self attitudeand a change in vitality. ok. and they expressthemselves slightly differently.

actually, only about 50% ofpeople that i would diagnose with depression would say that that's a good descriptionof what they're feeling. they also often say they're notso much sad as they are anxious, apathetic, don't care, or even numb. and people have toldme i can't even cry. i didn't-- i couldn't cryat my father's funeral. ok. there's something wrong with me. i can't feel anything.

ok. the change in self attitudewhich is so characteristic of what we call melancholia, ok,is really-- it comes in degrees. you can have just decreasedself-confidence. you know, i don't trust any of mydecisions now, tells the businessman to me even though he'sstill going to work. but in the worse case, a lady like this often feelshopeless and worthless. ok. and then vitality-- somepeople use the word vital since but i like just the word vitalityand that is lacking normal,

physical and mental energy. ok. and the issue we talkabout poor concentration. but that really isthat it takes energy. that's one of the reasonsmany 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 numberof patients to appear on various-- be filmed in one thing or another.

and, you know, when the peoplecome and say, hey, look, we want to film a patientbefore and after and i say, well, ok, good luck. most patients tell me wheni go in and they're feeling like this lady is feeling, youknow, dr. depaulo, you know, i'm not sure i really want my family to see me making a debutwhile i'm feeling like this. could we go a few more days tilli'm feeling a little bit better? ok. and because this is thetime in which you don't feel

like doing much of anything. and in fact, here'swhat 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, hearanything, feel anything. i'm fed up with life. i've had enough. i don't want to live any more."

i mean, now, thereinthe better description of depression that we've got. but of course, it's across-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 inthe electrodes and let that surgery heal, they weregoing to try to help her tremor in parkinson's disease with thisdeep brain stimulation electrode.

ok. and the first timethat they had her on, because this is an early case, they videotaped herwhen they turned it on. they were, hey, this isgoing to be good, right? and the-- it didn't come upthe way they anticipated. ok. and so you could see here in a, and i don't think i havea pointer here, do i? do i really? no, i just screwedthat 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 secondsafter they turned on the stimulator. four minutes and 16 secondsis when she's telling us that this life is worthless, ok,that there's no point in going on. and then of course being verysmart and one of the great things about surgeons andpeople that use treatments like this is somebody said turn thatblasted thing off, you know, bang, hit the thing and veryquickly she recovered.

ok. and said something like didsomebody get the license plate, you know, on that truckthat just ran over me? and in fact, as she recovered, sheactually had a little over-recovery and started playingwith her surgeon's tie. ok. but that-- and that wentaway very fast, just momentary. so, this is one of the reasons whywe think the modern disease paradigm is appropriate for this. but this paradigms,these models, you know, you got to remember what thegreat statistician box said--

george e. p. box saidto his students, all models are wrongbut some are useful. ok. so, it's a contract. that's all it is. ok. only the patients arereal, i tell my students. so, now that's one patient. now here's the otherpatient from his depression to show him now in an altered state. you know, a year or so or severalmonths later and you may not be able

to make it out but he's-- youcan see the cigar he is smoking. and if you're good, you cankind of see the pipe in his-- and on his lap, that'sactually another pipe. ok. so this guy is really indulgingat least one particular appetite. ok. and it seems-- and he-- and by the way, he's also wearinga boot [inaudible], take notice. and he no longer has that big beard but he does have a nicehandlebar mustache. ok. so-- and this, you know,

kraepelin said i don't haveany particular treatments for this disorder. these were people whowere living there and they were justmostly observing them. ok. so-- and just to make thepoint, 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 forsleep and in fact patients can go, as you know three orfour days without sleep. and then increased speed ofthinking and speech usually. and again, with both of them, theretends to be an episodic course and in fact, in kraepelin'sday, he grouped people together who had only depressions andmanias and depressions together because he thought, look, that'sthe best predictor i have.

and so, that's actually one of theways we had to divide depressions. ok. those that have maniaand those that don't. ok. and it's still salient. ok. well, here's the moderndisease model, if you will. i don't-- this is not adefinition of the word because you can't get anybody toagree on the definition of the word. but this is the structural model. we doctors like simple thingsthat you can operationalize. ok. and so here's the model.

you have a clinical syndrome. you validate that as a moderndisease with a pathology and abnormal body part,ok, in some patient. and then you-- then that leadsyou to search if you do things in that order, in theright order in a sense for an original cause or etiology. ok. now, the problem for us is thatnone of these areas are simple. in cancer, etiology is verycomplex and we learn a lot from them in studying etiology becausethey know the methods,

they know how to go at that. ok. it's really good. but once you get acancer, by the way, the pathology is not complicated, it's just stuff growingwhere it shouldn't be. ok. it doesn't look very good, kind of ugly stuff growingwhere it shouldn't be. ok. and the syndromeswere also not complex. they usually block somethingor it causes pain, right,

or it causes a protrusion. ok. so-- and the reason i'mmentioning this is i was invited to speak at the salkinstitute annual symposium on biological complexity. and i saw that much of their earlierones were on cancer and i said, well, jiminy christmas, if you'regoing to make me talk, i got to say, you know, my talk wasentitled complexity squared. i should have said cubed, ok, because each of theseis a complex state, ok,

and it is not in alllikelihood going to be explainable solelyby its parts. ok. and that's really a key thing. now that's what makes itso wonderful and amazing to study the patientsand to work with them. but, this is complicated,folks, and therefore, we're working on systemswithin systems. ok. so, now, i said thecourse was episodic. this is an early slide,one of the slides

that where they usedlithium in patients. by the way, unipolarand bipolar in here. the black bars are the depressions, the hatched bars aremostly the manias. and the-- and you cansee the lithium is where that little pencilunderlinings are. ok. and each line is a patient,ok, from 1960 to 1968, ok. and it looks prettygood, doesn't it? that looks terrific.

you're going, man, youshould keep yourself with that pencil linegoing underneath you. and it didn't turn out to be thatgood but it did turn out to be good. so-- and this was 1969 and the-- and my teacher from the maudsleyhospital institute of psychiatry in london though didn'tlike this study. and so, he wrote a paper with hisfellow called "prophylactic lithium: another therapeutic myth". ok. that generated bothheat and eventually light

because they got somereally good studies. but everybody was reallymad for awhile and so forth. now, why did i end up going there? ok. i'm not sure. i'm going to come backto this a minute. ok. right. ok. so, here we'regoing to talk about-- i'll come back just a minute. that in general, genetics ofpsychiatric disorders that is

at least the ones schizophrenia,bipolar, and depression have beendifficult and i started in the area got our grantin 1988 and, you know, through about 2005 it was--what we got was experience and of course experience is the nameyou give to your mistakes, right? and i did discover, hadthree great discovers and those are three young peoplethat were much smarter than me and they are now actually runninggreat programs around the country. but eventually when westarted coalescing samples

into very large samples andhad access to every, you know, sequence variant in the genome and easily could do amillion variants at one time. and now it can actually sequencethe whole genome as well. we-- things started coming out. ok. and this is just to show you. this is the 12 or sofor bipolar disorder. although you'll noticedown at the bottom that it says bd plus schizophrenia.

ok. so that there are bothoverlapping ones with schizophrenia and ones that don'tappear to be overlapping. down at the very bottom, yousee bipolar disorder and rud. that is recurrent unipolardepression. ok. and so, you know, that's-- it's very interesting butthe one that's been toughest to do is depressionin any of its forms. bipolar depression better thannon-bipolar depression, but why? it's so much more common?

it's about eight times morecommon than bipolar disorder. and we've-- and i'll showyou some of the samples that have been ascertained. but i'm going to probably-- i'm thinking if theslides are in the order. i'm hoping they're in. yes. i'll be telling you a littlebit about how the progress has gone when you have funding-- sufficientfunding and sufficient samples. ok. and basically, the samplingmethods when dr. insel stop wanting

to pay for phenotypes, theinvestigators are resourceful people and they went and purchasedeverybody in sweden, right. all their dna is from sweden orfrom denmark and that's really good. those people have health systems,that absolutely was the right thing to do and they had a reasonablyrobust way of making diagnoses. and so, by 2011, once theystarted 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 seeit, and the chromosomes are 1

through 22 living outthe x and y chromosome. and so, these are-- ifyou can think of them, is tipped over on their side. and then up at the top, goingup above this line where you see between 7 and 8 is the point at which things becomestatistically significant. but this requires like10,000 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 theclinicians and toilers in the field who actually see the patientscame up with this in 2011 and then they just gota few more samples. double the sample size,triple the sample size. and by 2013, they actuallyended the red line, it's at the same placeby the way folks. it's just the scalehere has changed. the top of the other scale was12, the top of the scale is 30 and that's the exponentof the p value.

ok. for those of youwho live in that world. but the point is they now havehere 108 loci, presumably, for the most part, genes. ok. sometimes, theycan't tell if a loci is of this particular geneor that one or both. but-- and you can see by the waythe tallest one, there is that-- in schizophrenia forever hasbeen on chromosome 6 right in the major histocompatibilityregion which has been in one sense, the bermuda triangle forgeneticist trying to dissect it

because it's so complicated. ok. but that has now been dissectedquite well in schizophrenia and we now have a componentof the compliment system, c4, that appears to be quiteabnormal in schizophrenia. ok. not necessarilyin all schizophrenics, but with the sample size likethis they could dissect it down. and so, it looks like it'sgoing to be an important clue. and by the way, did i ever expect that we would fine thecause 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 heartfailure, if we did a genetic study of congestive heart failure, youknow, that would be too complicated. well, these are syndromes and wedon't know really if there's a level of congestive heart failure, for uswhich might be simple versus dropsy. ok. so that-- we don't know wherewe are because haven't yet created-- we don't have a pathology. ok. really the simplestway looking at it.

now, these studies have beenvery important and i'm going to go backwards here to pick upthis slide and that people notice that so many of the genes thatwere being identified had multiple diseases they were associated with. ok. and so this early onled 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 andsee how things turn out.

and-- but there's no doubtabout it that there are a lot of shared genes in this thing. ok. and i'm going to get tothe question a little bit about why have we notevolved out of depression. ok. and so that what you can seeis adhd, bpd or bipolar disorder, schizophrenia, major depressionand autism spectrum disorder, and that's just theheritability for each. ok. and then what they've done thenis looked at the co-heritabilities between disorders and youcan kind of to see that.

and what you can see is that bipolardisorder and mdd are related, it seems, but no moreso than schizophrenia and unipolar disorder are. ok. and schizophrenia andbipolar disorder do seem related at least in some significant way. ok. so that's-- shouldn'tbe too surprising, i mean, the genetic overlap between asthmaand crone's disease is substantial. but they are importantlydifferent diseases. not-- but they also areimportantly the same

in some ways, some molecular level. ok. so i've done that. so look that's thekind 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 wecan't find everybody's model of their disease, what we'dlike to do is at least find one. ok. and say, can i figure out how mother nature madeone case of bipolar disorder?

in fact that was my goalwhen i started these things. just need to find one because thatwill at least gives us something to look for other things to come. and just like the-- inalzheimer's disease, the app mutation amyloidprecursor protein was tremendous in that way even though it countsfor less than 1% of the disease. but it gave him a model. and the model by the way, now, hasput 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. i feel much better. my stress level just wentdown, oh, everything. but i stop degeneratingthere for a minute. ok. the-- sorry, wherethe heck was i? at any rate, i want to find out howmother nature made one case, ok, and then [inaudible] other diseases. ok. now, ok, this isthe one [inaudible].

this is the study iwas going to show-- last study on this to show you whenthey put five disorders together, ok, and pretended thatthey all had the same, the five that you've already seen, they could still find thingsthat were significant. i think this is-- to be honestwith you, kind of child's play. ok. i don't think it'sterribly helpful because we know adhd is differentthan bipolar disorder and the fact that they have someoverlap, terrific, good,

that should tell ussomething important. but that-- this is notto me too surprising or too informative,but it is what it is. so, now, here is-- look, the pointis that people have now gotten on to major depression andthey've collected large samples. and the thing is we don't have muchto show for it and we should by now. in fact, with these disorders thatare so heterogeneous and complex, you can actually calculateand since, we assumed they arebasically polygenic

because we haven't doneany autosomal dominant or autosomal negative or x linkforms of it that are simple. ok. you would think by thenumber of people we've collected with major depressionnow, we should have 20 or 30 loci link toit, ok, and we don't. and so, well, you could say that'sterrible, you can feel discouraged. but you can also say, allright, time for an idea, right, time for somebody to lookat this in a different way. ok. and we'll just talk about that

because there's somesimple ways to do it. but i'm-- but there is someinteresting ways as well. they might be a new treatment that gives you insightor lot of other things. ok. so, they-- if the group-- the major depressiondisorder working group, again, a large collaboration had 18,759independent, unrelated subject of europe ancestry, 9000 andsome were had major depression and 9500 were controls.

and then, they had a replicationphase because in these days, with this big machineryyou don't want to publish a finding unlessyou can also replicate it. they had second sample waiting where they have 6700cases and 50,000 controls. ok. and no gene or a locusachieved genome wide significance. ok. now, again, that doesn'tmean there aren't any. it just means that withall these multiple testing, testing a million markersat one time is going

to cost statistical issues for youbecause you can-- you don't have-- if you lower your thresholdyou'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 tookones were males and females because there's a bigdifference 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 waywould shrink the example size. ok. but that's where we are. and in the mdd-bipolarcross-disorder analysis which is the thing-- one the thingsthat we think is going to important. there were 15 snps that did-- but they're all at oneplace on chromosome 3. ok. that did exceed thegenome-wide significance.

but in bipolar disorders, i wassaying, we now have about 12, some people would say may be it'sgoing to be up 30 in a few months. but the issue for schizophreniaand for us is for the most part, we still can't turn those genesinto a story, into a model. ok. and that's the-- andthat's why we need insights, non-genetic insight, as wellas digging away at the genes and looking at whatthey actually do. ok. and the technology even fordoing that is amazing these days. and like the crisprtechnology actually allows you

to keep modifying a variantand 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 apoint i want to mention. ok. and actually on theone hand of replication, its true carlos ishard in psychiatric. but there are a thousand slides thatlook like this, ok, as you know. and this is some antidepressantand 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 showingis two things to keep in mind, that do make this not so easy. one is, the first week placebo isworking darn well, wouldn't it? ok. that's number one. and the restoration of hope, youknow, 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 betterhave something in the pill. ok. and then after the one weekis over, they separate but it's-- this doesn't reallyshow you the scatter. ok. and what you'll seewith the tricyclics is that some people getjust 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% ofpatients will go into remission in some reasonable time period. ok. and the others will get, youknow, at least 50% improvement. by the way, 50% improvement if youhave 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 thesekind of patients who, by the way, these people are startingwith the hamilton score of 30.

that's big. that's a patient that[inaudible] patient unit. ok. now, everybody says, butwait a second, we're treating so many people withantidepressants now. ok. and we got them. you know, why aren't we reducingsuicide rates and why aren't we, you know, reducing the prevalence, at least the pointprevalence f depression? and here's part of the answer andthis comes from a young man who's--

he did this work whenhe was at colombia, ramin mojtabai, whosea joint recruit. he's in the department of primariesand department of mental health, hopkins has the only departmentof mental health in any school of public health in the worldas far as we could tell. if somebody knows differentlyi'll be happy to hear it. but i think that's tremendous. and they have a group of people. they are kindred spiritsand our secret weapon.

ok. so, ramin went out and looked atthis and what he saw was that most of the increase, ok, in the useof antidepressants is in patient where the doctor isn't even giving apsychiatric diagnosis in the chart. now, many of those peopleprobably have anxiety disorders. these things-- the ssriswork quite well for anxiety. ok. some of them-- who knowswhat they're getting for. ok. so-- and the interesting thingis you can study severe forms of major depression. there's not an appreciablein the percentage

of them being treatedactively with the treatment that would be a sugar pill. ok. so, the antidepressantsare multiplying. their use is multiplying, 80% of course are prescribedby non-psychiatrist. but the psychiatrist aren't perfect. i don't want to put us up isthe-- as the goal standard. but we-- but it is true that inthe primary care clinic, thank god, they're now talking aboutputting us with them

in the primary care clinicsand trying to help them because they know thisis a problem for them. ok. so, now, how elsemight get there? carlos showed you one way. if we can track back through the mdareceptor and he showed us both the-- that receptor and the ampa receptor, each of those looklike great targets. ok. that's can't-- we're goingto-- well, that'll be useful. here's one that we heard the otherday in bipolar disorder from one

of the members-- by the way the--i'm going to stop being chairman of the department athopkins in june after 7-- after 14 years, seems like17, but it's only been 14. but i am already thechairman of the board of the national networkof depression centers. i do want to mentionthat because we're going to need that, ok, i think. ok. i think-- and so-- buthere if you can see it, if you can make it out, the red andthe purple and then the light green

and the darker green are celllines, ok, that are occurring. these are deprogrammed cells that are then programmedto be like neurons. ok. and what you can see in the topbar, the red and the light green, these are in their native state without lithium onboardin the cell culture. ok. and they are firingin a hyperactive way. actually, i don't' knowthat you can tell that. but this is hyperactive firing.

ok. but these people thatwe're sell lines were made from were already treated for numberyears for their bipolar disorder. and some of them were selected tobe excellent lithium responders. they're kind of people thatjust seem to get well on it. ok. and others were not sogood lithium responders. ok. and in the ones thatwere 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 lightgreen to dark green, really not much happen at all. ok. so, it does seem that there maybe something about this, you know. and if it were hyperexcitableneurons, that would be great because then we think about maniaand have a visual image of it. but, you know, at anyrate it is useful. and this was done out at ucsan diego with john kelsoe as the lead psychiatristand fred gage

as the stem cell guy, if you will. ok. so, by the way, at the end of the day they're comparing verysmall number of people cell here. ok. so, we need to replicate this. and if confirmed, we need way totest it in larger populations to see if we can turn it intosomething that's robust, just like we're trying to dowith the ketamine response. we know there are peoplethat respond to it. how can we turn it intosomething as robust?

ok. so, at any rate, look, on theone hand we still want the genes. why? because even thoughtwe have a lot of stories that make partial senseof these conditions, we still need to have a parts list. and that's the-- ericlander would use that term. i want the parts list. and then, let's see how we-- it'llstill take awhile to construct them. put them back. put them together in someforms that look rational.

and to do that, we're goingto need 30,000 cases or more. ok. and looking at particulartreatment as carlos is doing and they're molecular targetsand associate them with generic and other molecule variations,certainly a good idea. and-- but if the genetics and the neuroscience doesn't tellus 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 seeif then they could do it, right?

ok. so, that is really thequestion, what is depression as much as how do you do thegenetics of this thing. so, phil mentionedprominently, melancholia, and i think that is animportant point because many of the older professors like philwho are very smart have said, wait a second, with that checklistyou're including way too many people in this thing. ok. and is that the problem? ok. now, one problem withundoing that and is that we know

from past studies thatpeople that didn't-- wouldn't qualify formelancholia, they didn't look like they had melancholia. they look like hadpretty garden variety mild or moderate depressions. some of them respond quitewell to antidepressant, too. and i don't want deprivethem of treatment. the problem is they look identicalto their brethren and out there and that part of the venn diagram.

ok. and some of them areresponders, some of them are not. and so probably what wegot is [inaudible] mixture of some sort out there. ok. so, that's-- so wheredo you draw the circle? now, by the way, thefolk who don't go back and read the old literaturethey say, but ray, if you do that yours going totake you another 20 years just to get sample becauseyou're going to lose power if you don't have a big sample size.

well, ok, next question. ok, right? so, well, how elsemight we divide it? so, melancholia versus the majordepression that's not melancholy would be one sensible way ifwe could get enough samples. major depression associatedwith stroke. there's a very regularrelationship on depression that follows strokeand brain lesions. but there's probably a genetics just

like there's a genetics leastresistance to hiv infection, right? major depression associated with bipolar disorder,we've already mentioned. but also major depressionassociated with parkinson's. lady had the brain stimulation. fifty percent of patients withparkinson's get depression. and they get it early beforetheir motor symptoms are dramatic. and by the way, seminally,huntington's disease patients do and some of them getbipolar disorder.

and it usually comesearly in their illness. by the way, that part of the brainis now a very hot topic for us as well, has been forabout 30 years. but 40 years ago, wecertainly didn't. in 1966, no one was thinkingthat the vasoganglia were going to give anything topsychiatry, but they're key. so-- and then, again, said my favorite category is majordepressive disorder associated with who knows what.

so, now look, that--but i was told by phil that this thing was calleddepression cannot be cured. it says right hereon the top of page. and [inaudible] that reallyis vexed question, phil. and, look, on the one hand, weneed better treatment for sure. there's just no doubt about that. ok. so that-- go ahead,keep seeking that. but my oncology friend, they rarelyused the word "cure" anymore. they say actually some of the more--

[inaudible] ones tell me that acure is when die of something else, you know, when you're not depressed. ok. and so in that by thataccount i've cured a couple people. ok. so whether the curelongstanding remission, i'll take longstandingremission, 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'snot a realistic way to look at this disease if phil was right. because if it is-- why is-- whyhave we not evolve out of it? well, it's got to impair yourreproduction, number one. ok. and two, it cannotinvolve things that are vital for your-- for the body to work. ok. so-- and with a hundred geneslikely, maybe a thousand genes and it's part of this,hey, guess what? these things are probablyimportant as phil said.

so, sorry, we didn't turnout perfect, you know. but-- and this may be, ashe says, the price we pay. having said that, if we can getgood at knowing it when we see it, we can do what he's suggesting. and that is working with thepatient, ok, in all manner of ways. ok. to help them manage this. ok. and that's what ido and i love doing it. and they used to talk about it. one of the things i didn't likewhen many of our colleagues were

out there doing drugstudies and saying, treat to remission,treat to remission. i say, great just tell me how, i'lldo it you know, i do it sometimes, but it doesn't happenall that often. and when i-- i like betterthe recovery concept, because that meansrecover your life. ok. so if i can get the personfunctioning 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 functioninga little bit now, let's use that for a little bitand then let's come back and think about treatment again later. so i do think that thismay be the nature-- part of the nature of ourmachine and our mechanism. it may not be curableon the one hand. on the other hand, thiswork as you can see i think and with these two people in frontof you is for the committed but also for the well-supported and notjust financially but that, too, ok.

and it's not a quick way to fameand fortune as they can attest. answers may come in smallsteps though also like cancer. so before-- now i'm going to switch to that other talk justto show a couple things. ok. and we'll-- yes. ok, thanks. and this is my national network ofdepression talk and i'm just going to say, look, we do need theselarge multicenter networks that are stable, that aren'tchanging every five years

as funding changes. ok. i believe. but now it's going to take awhile. because we need very large sampleswith the power to find genetic and brain imaging changes thatwill illuminate causal pathways. we need to go beyondexpert opinions in setting up our so-called guidelines. evidence-based medicine is reallyexpert-based medicine in our field. and we need to have a way of-- we--

our plans is to haveabout 20,000 people under care using thesame essential record or instruments andto share the data. so that-- although that'sobservational and therefore, hypothesis generating, it can bea little bit hypothesis testing in the practical world to say, hey, you think it's thatway, let's go look. let's take a quick look andsee how the people look. so there's lot of reasonswhy we need this.

and so we do have a network of-- national network ofdepression centers and there is an forming ithink a network of networks. so there's a canadian group ofsix centers and there's a group in germany that looks likethey will come in as well. and we have 25 centers under workingto collect patients in this manner. and i just thought i'd mentionedthat because that's going to keep me busy for awhile. so why don' i stop thereand answer questions.

thanks very much. and i'm told we havereally short time and the other two guys should comeup 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 therecultural variations in depression? the reason i asked that isi'm a visiting professor all

over the world and in myown scientific observation, there are huge cultural variations. the norwegians are the most damneddepressed people in the world. and the italians-- i've been avisiting professor all over italy, the southern italiansare 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 scientificbasis for cultural variation? >> dr. raymond depaulo:a little bit. there is a milder form ofdepression or even what used to be called bipolar ii where thereis a distinct seasonal variation and which you will see maybedifferent some seasonal variation. ok. but by in large, these things-- even kraepelin way back in the 1890stook a trip to java at one point. so he could find out how itlooked in java and he say,

hey, it's basically the same. so the rates and the rates varybut it maybe that translating that checklist into 12languages doesn't get you there. so we don't have-- the evidenceis not robust [inaudible]. >> ok. can i ask another one? >> dr. raymond depaulo: yeah, sure. >> that checklist ithink is very suspicious. the checklist is doubtfulbecause some-- that was a good checklistfor old age.

you have less energy, do youthink more about death, you know-- i mean, what that provesis 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 howmany questions i'm get to ask, but i'd like to ask onething about the medicines.

the second speaker told us that ketamine were justgreat only they're addictive. >> well, thanks a lot. i mean, i can assure a lotof symptoms with cocaine but you got a side effectthat's very unfortunate. well, look, i mean, that's right. >> the other part of that questionis 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 anacute treatment for depression, it doesn't seem to be asgood as we thought back then. ok. but it does seem to be haveprophylactic value in unipolar, severe unipolar patients and inbipolar patients, but not for all, as we could show even inour some of our studies where we're looking at mechanism. so, it's dag un-good.

and when-- and nowthat we've learned to use it better we have fewerrenal side effects in the long haul. it's a drug that'sunderutilized in this country. but it's still treatment of choicein europe for bipolar disorder. yeah, go ahead. >> dr. carlos zarate: i could address thesecond part about ketamine. >> dr. carlos zarate: so, youknow, again, i think i conveyed that we studied peoplewho are very ill.

>> dr. raymond depaulo:yeah, absolutely. >> dr. carlos zarate: and in factthey have failed all the treatments for bipolar disorder fordepression 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: ithink 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 agoand it does work. and so as researchers,we don't give up. we just try to findsomething better. and i think the recent studiessuggest we can find something better that's not addictivehopefully more studies-- >> dr. raymond depaulo: but thisis-- it is a great heuristic value. it's got us looking at adifferent part of the mechanism. >> dr. carlos zarate: theissue would be, for example,

the wright brothers, you know,who would have gotten up in plane. nobody today wouldprobably go in that. but yet, we travel all the time because of progressthat has been made. >> dr. raymond depaulo: sothat'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.

i have a question for both ofyou particularly for dr. zarate about how open this data are. i mean, given the amount ofinvestments over long periods of time, this is veryobvious case for open data. so can you tell us a bit moreabout where this get deposited, how standard the protocols are,how readily reusable they are, and how much reusethey'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 withdavid bobstein [assumed spelling], he said that's what he wanted. he wanted our data tobe out there on the web. actually, the woman mary-claireking who deserves so much credit for the breast cancer genes,that's exactly what she did and that's why shedidn't clone the gene because she had a company workingalongside her, looking at her data on a daily basis every 24hours and they clone the genes and then misuse the patentwhich was later revoke.

but that's what we should be doing. ok. in this era of quoteunquote team science, it's not just team science,it's a crowd science. ok. we got to quit. we got to-- we helppeople make progress. ok. and so i think there isstill some protectiveness. and-- but the other-- butthere's another point. not all data sets areequally readable. ok. and there's a lot of-- unlessyou really are good at setting

up your data set, yourdatabase, you can get it back and it doesn't look like much. now, so talk to meabout what you have-- >> dr. carlos zarate: oh,there at nih and i mean, there are consortedefforts that, you know, you won't get funded unless you putyour data in a public repository. and there's some rulesabout one year or two years protectionfor the main thing. but that being said, the it

and the infrastructure isone database doesn't talk to the other database, thequality of data obtained at many sites is probablynot as best as we would like. but there are those efforts. then it's not only that, it's thecomputing power once you have these humongous sites, howdo you analyze it? and so computation is really-- >> dr. raymond depaulo:it should be done and now they're requiringpeople to do it.

but that doesn't meanit's being done in a way that's terriblyilluminating. ok. i always think backto art buchwald from-- the late art buchwaldfrom washington. and he-- whenever talking abouthow to do the mx missiles for those of you old enough to remember that. he favored the idea that we wouldput them on rails and round them around the country and hesaid we should give the-- we should a russian a schedule.

they'll never figure it out. ok. that's the way you feel whenyou look at some of these databases. i want you to say that when idid start this research in 1988, i started in '86, but wedidn't get funded till '88. what i said is whatcan we guarantee? we can only guarantee that we doreally high quality assessments in patients, that we create anexcellent clinical database, and then we make good dna. ok. i want you to know,we did all three.

and what i say is what idiscovered were three young people that were really terrific. ok. yes ma'am? right behind you. there's lady right behindyou that her hand up, right. >> have there been studiesthat people look who are-- have severe depression, they usea treatment, they get much better, does anybody-- has anybodyfollowed some of these people to see like if it stopped theirmedication, 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 meanthe answer is yes and basically what we cantell you is for the most part that what get you wellwill keep you well. and if you go off of it, you're likely are nothingfor the most part.

and recurrent depression that'sthe 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. >> dr. carlos zarate: and wenow prescribe medications.

think about, you know, usuallyyou're given antidepressant and that's the acute phasewhich could be 6 to 12 weeks. and then, if you're responding,there's a continuation phase that goes six monthsor a little bit longer. and then there's amaintenance phase. and for the first episode ofdepression, some have argued, you could do psychotherapy first,cbt, or you could do antidepressant. but i after, you know, 9 months or12 months, maybe a little bit long if you have one episodeand you have family history

that don't have significantfamily history, you may be able toconsider coming off. but the problem with that is ifyou have stronger family history, and the more episodes ofdepression you have if you had one, there's a 25 % chanceof a second and second. if you have two, there'sa-- you know, it goes to 50. and for each subsequent, it goesup to, you know, 75 even higher. and so if you had somebodywho's already had several bouts of depression plus family history,

that the likelihood they willneed treatment for a long time. >> dr. raymond depaulo: by the way. let me add other thingthere and that is the-- i thought you're going toask me a tougher question. that one was kind of a softball. and that is, the one that reallyis frustrating is the patient that gets very well on a drug and continues the drugand relapses, terrible. and that was at one pointcalled the prozac poop out.

it's not about prozac. it didn't change. huh? it does, especially incertain kinds of patients. i think we'd-- probablyin the patients that have these chronic depressionswhere they have a little bit-- at least a little bit ofdepression almost all the time. those patients andhave that [inaudible]. we got a couple here. >> i don't have a scientific-- i donot have a scientific background,

so let me see if i can phrasethis question properly. if you have-- supposed you showed inyour genome that you express enough of the genes that showed youhow the genetic predisposition for depression, but youmight not get depressed. absolutely. >> but suppose, have you donestudies on children specifically and i don't know how you woulddo that when you're studying, you know, your focuses on genes. i come from a background

where i believe i know i developeddepression because of situations that affected me when i was a child. >> dr. raymond depaulo: sure. >> and i also think that there'sa predisposition to depression in my family and i havea brother and sister who have not been asaffected as badly. and i'm the oldestchild in the family. but i think that there isa tragic lack of attention to children especially whoare symptomatic and possibly

in a variety of ways and if anybodywas 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 interms of the genetic part of it, those studies are notyet really being done. i mean, because there-- right nowwe don't have a sufficient set of genetic markers that we cansay this person has a 50-50 chance

of getting depression. ok. we don't-- we'renot that powerful yet. ok. having said that, people havetaken any particular gene that seems to be related and they studied inchildren who do not have depression. and it's very interestingwhat they find because they often find somechange like in their cognition, their concentrationand things like that. but those studies are thingswe absolutely want to do. ok. and-- but it-- youknow, 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 depressionand bipolar, the findings are not as robust as we would like ifyou're going to put on a very little that now studies-- genetic studies,you know, are moving that you need to consider the environment andthe family and all that as well. if you're not consideringthose two thing-- i mean, maybe it's more information

that hopefully willgive us more insights. and so most of the studies thati'm hearing at least, you know, the collaborators i work withare really going that way. how do you do thatand it's very hard. >> dr. philip w. gold: if youtake the two identical twins who share 100% of theirgenes and one of the identical twinsdeveloped depression, only 50% or so of the other identicaltwins will develop depression. so-- and why is that?

good question. don't know, don't know. >> well, i want to followup on the cultural question that he posts earlier onin a different direction. i'm posting question from my ownbackground in which pentecostalism, the bible, is taking as an answerand pentecostalism is on the rise. part of this belief system,it has no scientific-- [inaudible] time we had totalk about this science. part of what is able to captureis a capability to treat many

of what you have discussed. and they do make that claim, verypowerfully that they able to do so-- some-- >> i don't have anyway validating it. >> but it gives rise to a question. is there a way in which alternativenon-medical suggestion can be formulated because i also come fromthe culture where there's a lot of belief on witchcraftand sorceries and they approach themvia meteorologist

that are different from us. and we're beginning to saylet's start questioning them, let's now begin to understand them. and, you know, there is this famousnigerian, lambo, who became the head of [inaudible] organization. he's dead now. >> dr. raymond depaulo: ok. listen you've got avery good question. (inaudible) phil take a shot at it.

so how about religiouscures if you will. how would you look at them for thepeople lets' say, gee, in our church or in our way of believingwe can take care of this. what do you think? >> dr. philip w. gold: well, oneof the most important aspects of the psychotherapyis the development of a therapeutic alliance. there is something that ishelpful and that can be useful when one person meets withanother they develop a meaningful

relationship and theybegin 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 elementgenerally is that alliance between the two-- the trustbetween the two and the commitment to try and to understand. >> dr. raymond depaulo:if i could off that. i mean, i mean see anawful-- [inaudible] families,

and i would see lots offamilies who are not identified as having depression but whodid and who got well as soon as their sibling or theirparent or their child got well. ok. so-- and by the way. that's the thing now that we'redoing is brain imaging studies. we see that physiologicalthings just as well as pharmacological things. change the brain. ok. so, that we-- you know, thisissue of psychology or even belief.

and i think the psychiatrywas inappropriately unfriendly to religion on the one hand. on the other hand, i thinkeventually i'm going to want to see some data to tell me that this is a goodthing to do for people. >> dr. carlos zarate: yeah. and so-- and even dr. gold presentedslides where you had, for example, altruism, there could be issues ofsocial good faith-based treatments or at least the aspects,self-rewarding,

being part of a group, anetwork of family that does go and that is actually affectedwith depression and those things as altogether might help depression. so, we don't think it's amagic drug, a magic therapy but it's really the totalityof the individual in the family and the community that'sgoing to be important in heal. >> dr. raymond depaulo:this is strange disease. we're using the model, but it'sa strange one because it comes and goes even without us goinganything on the one hand.

so-- and-- but the thing i wouldtell you is when people-- you can-- we can tell whether somebody didn'twant it, just didn't go on away. and on the one hand, thekind of things you're talking about in some ways are-- i'dlike to say are even better than simply be treatedfor your symptoms, right. it's about, you know, reallypurpose and that sort of thing, an altruism and that sort of thing. so-- but it's very hard to accessthat if you're terribly depressed. so i just don't want todeprive somebody of something

that i can demonstratethat it works. [ inaudible remark ] that's very interesting. >> dr. carlos zarate: so icould 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? >> dr. raymond depaulo: actually itwas interesting because that was--

there was an interesting study donefrom the department of mental health at hopkins on psychotherapyand interpersonal psychotherapy in uganda, in womenwith milder depressions. ok. and myrna weissman, theycalled myrna who's at columbia, wonderful woman, who developedthis interpersonal therapy and she is very rigorous. they asked her if she want tobe involved and she said, yeah, that sounds really interestingbut we've got to show that our nine basic contracts

of interpersonal therapytranslate into that culture. and eight of them translated fine. the one that didn'ttranslate 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 thankyou for putting so much of this

into layman's language that'sunderstandable to generalists. i was interested whensomeone mentioned that neuroplasticity increasesat the point of depression. >> dr. philip w. gold:now there's a-- neuroplasticity increases in theamygdala in depressed patients. that is the componentthat is responsible for the conscious experienceof fear and anxiety. that actually developsneuroplasticity increases in size and has proportionallygreater effect

on person's behavior and thinking. >> dr. raymond depaulo: i thinkyou're also saying is hippocampus that actually goesdown, isn't that right? and the hippocampus which that'swhere 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 lastquestion and then i'm going to invite everybody tometaphorically attack our speakers

at the reception back there. so, the last question which isan up to being a last question, it was interesting to me thatin response to the question about witchcraft, youwent to psychotherapy which is exactly whati was wondering about and that is the comfort you havethat psychotherapy can be part of the treatment but themetaphor of this being a disease and the way people commonlyunderstand disease or accident, a broken leg or something which isheavily biological one would not

think that let's get apsychotherapist in here to help them maybe deal withthe symptoms but not as part of the cure or the remission. and i'm still strugglingto understand something and that is the extent to whichthis depression of various kinds that you all have describedcan be considered or ought to be considered psychical if youstill want to include psychotherapy in not the cure but the remission. >> dr. raymond depaulo: excellent.

if the-- i think we don't knowreally what systems entirely transduce the depressive syndrome. but if the stress systemis importantly involved, then psychological stress andexperience play a great role in how the brain is goingto be wired and the extent to which the depression can develop. and so i think it's understandablethat a biological disorder that is responsive tostress is responsive both to medication and the psychotherapy.

>> dr. raymond depaulo:let me add in. phil started off this way inhis talk about psychotherapy and i appreciate his-- remindingme of my teacher jerome frank. when he studies psychotherapy, he was the fist greatresearcher of psychotherapy. he studied the things that weredifferent between psychotherapies or the things that were commonbetween different psychotherapies and the alliance withthe patient seemed to be the most important thing.

now today, the trend is toteach what you do in the room. is this method ipt betterthan cbt better than bbt. and i think those things do matter. you can show they dohave some difference. but i think the allianceprobably still carries a lot more, number one. and i only say that, you know, first off that thepsychotherapies for the person. it's not-- if you could show me

that psychotherapy never curedanyone would i stop doing it? not me. if i don't addressthe suffering of my patient, i have no right to be their doctor. ok. so, how do you doit and-- is one thing. but if we don't listen andthen-- and talk to our patients, get to know them, let themget to know us enough. i don't think we're doing ourjob and that's one of my problems with taking the disease modelsas if and redefining it. ok. all models are wrong.

ok. yeah. thank you. >> ladies and gentlemenplease [inaudible]. >> this has been a presentationof the library of congress. visit as at loc.gov.

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