Manic Depressive Illnes controversies - Nassir Ghaemi

0:00 [Music] thank you very much Michael for inviting me for your uh introduction thank you all for coming here today uh it's a pleasure to be here my first time in Sweden in Stockholm and uh first time in 47 years so can you hear me or might not be on okay see it's no is it on there oh okay is that okay now better okay so uh it's a pleasure to be here and uh I don't know when I'll be back so I'll tell you everything I know in one

0:46 hour um as best as I can do that uh so we dis we we chose a broad topic controversies in manic depressive illness and I thought I would focus on two basic uh aspects in terms of diagnosis as Michael just alluded to um a non-dsm based approach to diagnosing mood illnesses and specifically I'll discuss mixed depression and mood temperaments and in terms of treatment a hipocratico which is perhaps different than what you expect from hypoc from the term Hippocratic and really comes down to questioning most of our current research in terms of its validity and um

1:32 emphasizing maybe that there is much more than we think there is to lithium's benefits so we'll start with the diagnosis and uh I too started exactly the same years that you did in our field and I also accepted dsm3 and 3r and four without much doubt most of my career it was really not until the last 5 years or so when the dsm5 process started going and I began to interact with some of the leaders and some of the participants in the dsm5 process and I also finally met and interact with some of the DSM 4 leaders who you may know some of them were criticizing the dsm5 process I got

2:17 to interact with them for instance there was a big conference in Copenhagen a couple years ago where a lot of those people were present and I was able to be there and spend a few days with them not just an hour but hours and evenings in a bar with beer talking about DSM 4 and 5 and I learned some things I never heard before never read about never realized and in fact I became very disillusioned about our profession more so than I already was and now the last two or three years I've been starting to talk about it and write about it uh although it's difficult to do um because some of these kinds of ideas aren't the typical kinds of things that you can publish in a scientific peer rreview Journal there

3:03 were historical really facts or interpretations and that's not what scientific journals are for so I write about them in non-scientific Journal settings like newspaper essays and and books but I've started to publish some in the journals uh if you are interested in sources for what I'm going to describe there are a few new books that have come out about historical scholarship on the making of dsm3 by historian Hannah Decker and another historian Edward shter uh both of them went into the American Psychiatric association archives and documented a lot of material from the 1970s and 80s that no one had known except the participants they wouldn't necessarily agree with the interpretations that I'm

3:49 making but at least the factual documentation is in their books I've also interpreted it in on on my own in my most recent book on depression and I I've said I've start started to publish this in the scientific literature so there's this new article in the Australian Journal that I published where I discuss some of this and for that and for any of the other articles of mine that I mentioned I try to have them all on our website so that you can download them freely tmo.com so if you want to note that for your own later reference now in the 1970s the impetus for dsm3 was legitimate in many ways because before that time there was the problem

4:35 of a chaos in psychiatric diagnosis a complete lack of any organization to it a complete Anarchy and to some extent no one cared for some decades because psycho Psychiatry is very psychoanalytic and from the psychoanalytic perspective you just had a spectrum from Neurosis to psychosis and it didn't matter really to delineate diagnoses much more definitively than that the treatment was always psychoanalysis anyway so it didn't really matter but as the drugs began to be developed in the 1960s and 70s and people had drugs for psychosis and drugs for depression and lithium there was a return of practical interest in saying who was really schizophrenic and who

5:21 wasn't and who was really depressed or Manic and who wasn't and uh some researchers who identified with crepin ideas in the United States LED this effort they were primarily located in St Louis at the Washington University of St Louis which as you know is in the middle of the United States it's not a major city or a major university the major cities like Boston and New York and Washington and Los Angeles were all controlled by the psychoanalysts it was in the countryside that the kinian uh researcher started sort of like ma tongue in China started in the countryside and eventually took over the cities so it was very political really um in the 1970s these groups started doing research using kpp's ideas to see if

6:08 they could validate some of kin's Concepts as opposed to fraan Concepts they had the problem that if you wanted to say that you diagnose a certain way you didn't have a pathological specimen in Psychiatry you couldn't go as in some branches of medicine to the tissue in the organ and the liver or wherever and say yes it's hepatitis because see you can confirm the clinical symptoms based on this pathology in the absence of a pathology the clinical epidemiological standard was to identify multiple independent sources of evidence that point in the same direction besides symptoms genetics course of illness and then biological markers which if you did not have them you could use treatment response in a way as a pharmacological probe for biology of course you had to

6:55 be careful about that because many treatments are non-specific some even work in everybody like amphetamines or benzoin or opiates so a treatment effect is not translated into a diagnostic um validation but it can under certain circumstances more importantly course was very important and that was emphasized the most as kin had always said the diagnosis is prognosis if you don't know what the diagnosis is follow the patient for a few decades and then you'll figure it out and that's what he did of course if you want to treat them in the beginning that's a practical problem but from a purely scientific perspective the prognosis the course will tell you the diagnosis the outcome the number of episodes is it episodic what age did it

7:40 start at now the genetics was always considered relevant for some conditions at least that were considered relatively genetic like schizophrenia maybe manic depression now all of these sources of evidence were used to validate symptoms so the dsm3 grew out of this kind of research some of it that validated defining schizophrenia a certain way versus other ways because of genetics course and outcome and even biological markers but the interesting thing is even though they use genetics course and biology and treatment to validate the dsm3 definitions they didn't put genetics course and biology in the dsm3 definitions they only put

8:26 the symptoms there's a couple exceptions there's a Criterion for schizophrenia but the vast majority of DSM 3 4 and 5 criteria are purely cross-sectional symptoms but they're not based on cross-sectional symptoms they're based on course genetics biology and treatment but people have forgotten that because the the textbook itself the DSM book itself the criteria themselves are just symptoms so people act as if the symptoms are all that matter my my typical question is suppose you have pneumonia with chest pain and you have pneumonia without chest pain are those two different illnesses the symptoms are different why don't we call one bipolar pneumonia and

9:12 the other one unipolar pneumonia symptoms are different you have to say that the symptoms are diagnostically important based on some other criteria besides the symptoms so how do we know that it matters if somebody is bipolar and has Manan depression versus somebody who's unipolar and doesn't have Manan just has depression how do we know that those are different illnesses it's not just because the symptoms are different the claim was that they differed in their genetics and their course and their biology and their treatment that's what the research from the 60s and 70s suggested now that was rational if the evidence supported that a lot of that research was done by juwel a and uh was published by him was one big study the Zora cohort which he's still doing and

9:57 the second major study was published by um Italian researcher Carlo Paris in the active psychiatric of scandinavica 1966 those two big studies influenced the transition to the bipolar unipolar concept which I'll get two more so there was some science to it and the science led to the research diagnostic criteria which were about 20 diagnoses but those 20 diagnoses in 1978 or 16 or so almost 20 became became 292 in 2 years when dsm3 came out now there's no way that we suddenly discovered 270 illnesses in two years based on scientific research the fact is it wasn't the science supported 16

10:44 diagnoses dsm3 gave us 270 more if you just divide those numbers out it tells you that DSM 3 was 91% unscientific by definition so people say is DSM scientific or not well it's not 9 1% unscientific it's 9% scientific sort of it's not all or nothing and then in 14 years we added another 70 or 80 and then 20 years later since we're really afraid to change we've only added a couple dozen more so we're at about 400 but if you ask the question go to the scientific literature for these 400 diagnoses how much evidence do you have on symptoms course genetics biology and treatment effects that these are

11:30 different from each other and validly different the answer will be that you don't have that kind of evidence for more than 10 maybe 20% of the DSM labels that we use so where do the other 80 to 90% come from they come from what the DSM 4 leadership has been most explicit about this pragmatic Criterion the pragmatic Criterion means that they make changes based on what they think is best for for the profession that's what I learned in the last few years and I'll explain to you more in the course of this talk let's let's go back to how this all affected mood illnesses um it is important to realize

12:16 that before 1980 before dsm3 we had the concept of manic depressive illness and we had other depressive presentations neurotic depression Melancholia as Michael mentioned and what we did in 1980 was to say that all of those different depressive presentations plus the majority of patients that we called manic depressive should be relabeled major depressive disorder and a very small minority of the manic depressor patients should be labeled bipolar so one very important fact for you to understand that many people don't seem to is that bipolar disorder the way we talk about it is not the same thing

13:01 as manic depressive illness bipolar disorder is not the same thing as manic depressive illness manic compressive illness meant depression or Mania that was recurrent severe and episodic bipolar disorder means depression and Mania that's recurrent severe and episodic the whole difference was in one word a conjunction if you convert or to and you have the difference so if you diagnose somebody today with recurrent depression if they have five depressive episodes that are severe and episodic you'll diagnose them with major depressive disorder right that's all they have well that's what used to be diagnosed as manic depressive illness manic depressive illness did not

13:48 mean Mania and depression it meant Mania or depression the only requirement was that it was episodic and recurrent it didn't matter what the polarity of the episode was now the reason for that which I'll show you in a little while is that kin believed that there was no polarity to the episode it didn't matter if the patient was manic or depressed because patients are not manic or depressed they're both usually they're mixed you can't distinguish the two therefore don't even bother trying that was klin's View and I'll show you some recent research that may indicate that he was right after all um so these were the patients that were called endogenous severe biological depressive patients these severe

14:37 unipolar depressive patients they were considered psychotic in fact in many of the research studies in leonhard studies they were limited to psychotic patients but DSM said oh they could be non- psychotic too and they could even be mild to moderately anxious like and chronically so as the neurotic depression concept was so DSM mixed all sorts of depressions from the mildest and the most chronic ones to the most severe episodic even psychotic ones which nobody had ever considered to be the same and why did they do that because they simply put polarity above everything else if you're depressed you're depressed and that's it end the story if you're Manic and depressed you're a completely different entity now there was some research evidence to

15:22 support that like I said but the interesting thing is that evidence was n as definitive as people think there were these two big studies that I mentioned in 1980 and there's been 30 more years of research since then and one of the most interesting facts is the same researcher zuan is still doing research with the same group with 30 more years of data so it's a lot better data than he had in 1980 and it's showing the reverse you can't distinguish bipolar and unipolar patients often based on their course and on their genetics now it's showing the reverse and so he went to the dsm5 task force and he said you know my data now shows that this bipolar MDD distinction

16:08 isn't so clear-cut we should have a spectrum and they said no we can't do that and my question to them is well why could you do that in 1980 when he had less data and you won't do it in 2014 when he has much better data why if it's just based on the science why not because it's not just based on the science well you can see if you have many many types of illness that are all diagnosed in one category you're going to diagnose a lot of people with that condition MDD I want to give you a sense of some of that genetic research here where when they looked at patients who were bipolar versus MDD what you had in bipolar patients was inheritance of bipolar illness type one or type two but you

16:55 also had a lot of depression un unipolar depression in MDD you had unipolar depression you didn't have bipolar illness the unipolar depression did not distinguish the groups in other words the genetic difference is not in both directions unipolar depression is non-specific genetically it does not run in families of unipolar people it runs just as much in other people bipolars for instance what differentiated the two was a bipolar family history so here's the problem I fa this problem couple times a week with new patients DSM system is entirely based on The View that if we have these two big mood categories and they're based on genetics and course so

17:41 if you have bipolar patients you should have a bipolar family history if you have unipolar patients you should not have bipolar family history but I keep seeing all these unipolar patients with bipolar family histories these patients with recurrent severe episodic depression but they have bipolar illness in their family so there's there's only two possibilities then either that patient does not exist the one who's sitting there in front of my eyes or the DSM system is wrong the only two logical possibilities having unipolar depression with a bipolar family history is like having a squared Circle it's a logical and biological improbability at the very least if you don't want to say impossibility highly improbable the

18:26 whole diagnostic system is based on The View that that kind of thing doesn't happen it's like having an Alzheimer's patient whose cognition gets better we have all these Alzheimer's patients whose cognition improves it's like having you know um well it's it's defined to not happen so if it's happening there must be something wrong with their definitions so MDD is a spectrum it's a broad mix of things there's the neurotic patients there's the classic severe melancholics they're very psycho very anhedonic and then there's this mixed Group which I'm going to talk about and then maybe there are really purely depressed patients but they're not they're not the majority so the secret of DSM is this

19:14 pragmatism concept this concept that why you decide to make a change in the criteria is not primarily based on the science if it was an's research from 30 years more data would lead to changes now towards Spectrum models but nobody wants Spectrum models among the APA and DSM leadership why because they don't want to diagnose more patients why because it's not popular to do that why for various reasons one of which is stigma in the public they're already diagnosing 25% of the population with current DSM definitions they don't want to diagnose more because then they'll be accused of pathologizing and diagnosing too many people and trying to get more power and trying to sell more

20:00 drugs it's unacceptable well why is it acceptable that 100% of the population is diagnosable with physical illnesses at some point in their lives but only 25% would be allowed to be diagnosed with mental illnesses why who said who set the bar at 25 well the the reason they do that is they set up this disorder concept where you have to have functional impairment and severe symptoms to meet diagnostic definitions why what what's the scientific rationale for that do you remember how we used to diagnose headache before the 1950s and 60s you could have a blood pressure of 250 over 150 every day for years on end like Franklin Roosevelt did but if you

20:45 didn't have I'm sorry diagnosis of hypertension if you didn't have headache if you didn't have some symptom from the high blood pressure you were not diagnosed with clinical hypertension you had to have a symptom you had to have functional impairment and severe symptoms it's not enough just to have a high reading on your blood pressure that's pathologizing then of course he got a severe headache and he died five minutes later from the stroke so he was diagnosable 5 minutes before he died and that's the kind of thing that led Physicians to change their definitions of hypertension in the 1950s and 60s away from the requirement for symptoms and functional impairment that's not biologically rational to have

21:31 that kind of requirement well why do we have that requirement for every single psychiatric disorder because we're not basing it on biolog biology and science we're basing it on political economic and social considerations I think that this whole term disorder is useless I try to use it as little as I can it's it's explicitly vague it's meant to be vague it was introduced with dsm3 in 1980 as Michael was saying because they don't want to commit the leadership of the APA and of our profession don't want to commit to anybody saying that anything's a disease or anything's not a disease they don't want to commit to any of that well what are we going to say then we'll call it a disorder and if you want to treat

22:17 it like a disease and give him pills you will and if you don't want to treat it like a disease and not give him pills and give him therapy you will and you're free to do whatever you want well that's nice you're free to do whatever you want but is that the way science functions you can just decide to do whatever you want to I think the law of gravity doesn't exist so I'll just jump off the building I'm free to do what I want to that's not the way science is supposed to function it doesn't mean you have to be totalitarian about it but the evidence needs to be accepted when it's strong enough for something so sometimes we might find that some of these illnesses or diseases people have an allergic reaction to that term disease process kin called it why can't we use that term chrony processin why do we have to say that bipolar illness is not

23:03 a disease or schizophrenia is not a disease does anyone really believe that based on a hundred years of scientific research and why do we why can't we say that some things are not diseases clinical picture zustan building he called it and the Germans called it back then you have a clinical picture this kind of patient population exists we don't know what it is it's probably not a disease but we're not really sure what it is people get sexually traumatized and then they have unstable relationships and they cut themselves we don't know what it is but we see patients like that they used to call it hysteria they had other terms for it we call it borderline but that's not a disease it's a clinical picture which used to be called something else why do

23:50 we think that that's equal in conceptual terms to schizophrenia which is a disease that's existed for hundreds of years and it's always been viewed that way or manic depression which been described pretty well for 200 years the same way and longer I think we're afraid to commit we're afraid to draw conclusions it might have been fine in 1980 when we didn't know much we actually did know a lot then but let's pretend that we didn't know too much but what are we doing all this research for for 30 years 40 years why do we have these research centers like here and like Harvard will I've worked if we're not going to ever draw any conclusions from any of this we're just going to keep calling things disorders for another 40

24:35 years and not and pretend that we don't know anything about him we've Stood Still since 1980 and that's totally unacceptable for a scientific profession science is supposed to be about progress and again some people don't want to admit that but if you're not progressing you know you're not really being helpful there is another aspect to this this pragmatism also reflects postmodernism I won't get into that much now but postmodernism is a cultural ethos that's deep into our culture we are all postmodernists so you don't have to read something about it you're born with it you're it's bred into you just like 500 years ago everybody was very religious right now we're all postmodernists and part of postmodernism

25:20 is a deep skepticism about science and truth and progress and a lot of our DSM leaders in my observation especially the ones who were non-researchers have a very deep skepticism about research and about science the leader of DSM 4 is explicit he says the last people that should be involved in defining DSM criteria are the scientific experts they're the last people they're the ones you should listen to the least because they're the most biased they all just want to expand their own diagnosis because they want power and they want money and they want Prestige that's the postmodernist perspective what nii said everything's about power there's no Truth at all and there's no progress so once you accept all that and

26:05 science becomes just another activity it's not any more important than playing golf you know it's not any more true than anything else than Linguistics than literature then of course you make it up how you like to because there's no truth to it of course you can be pragmatic but if you take science seriously then the whole DSM system is set up opposed to you now ask yourself this question why would genetics and nature and biology and pharmacology follow the definitions of the late 20th century leadership of the American Psychiatric association who Define things a certain way because it's been it's acceptable in our culture and we prefer it this way

26:53 why would genetics follow those definitions so we defined MDD as a certain way based on these social considerations and we Define bipolar a certain way based on those considerations we Define add a certain way based on social considerations we Define temperament disregulation disorder a certain way oppositional defined disorder and so on and so forth well if you do genetic studies of those madeup socioeconomic socially constructed labels if you do genetics of that do you think the genetics are going to be consistent and positive if you do neuroimaging studies do you think they'll be positive if you do pharmacology studies of a specific drug mechanism like say serotone re uptake abiss do you think they'll be consistently strong and positive on labels that you've made up for political

27:40 social and economic reasons not for scientific reasons so this is what has dismayed me the most I've come to the conclusion that the reason we haven't made so much progress in the last 30 or 40 years and biological research most of which is unreplicated and mixed pharmacological research which as we know as we'll talk about some is very weak uh and genetic research which famously has been negative you know in a large sense a lot of non-replication a major reason that we failed is not just because it's complicated people say the mind and the brain are complicated it's not just because of that it's because our DSM system Dooms

28:25 us to failure it prevents us from having any success because our phenotypes are not scientifically valid if your phenotypes are not scientifically valid your genotypes will not be valid and your pharmacological treatments will not work out so it becomes a self-fulfilling prophecy they say there's no truth out there and then they set up a system which prevents you from ever finding out what the truth is if we were to do it differently we might pay attention to the fact that schizophrenia and bipolar have a heritability that's much much higher than anything else including MDD which I know it's not so straightforward to relate heritability to disease processes but it's it's this

29:11 is genetic heritability based on twin studies it's suggestive that we're dealing with something that's more of a disease process we might go back to having 10 diagnoses like the original uh kinian researchers of the 70s suggested instead of 300 and that's plenty you would capture the vast majority of your patients with 10 diagnosis like that we might use a hierarchy Concept in instead of a um comorbidity concept where we say if you have illnesses that cause lots of symptoms you should try to treat those first before you diagnose all these other conditions and treat them and we would treat patients with many fewer medications if we took that approach I don't know why this is

29:56 controversial except again for the fact that it goes against the wishes of the political leadership of our profession for the last few decades but you'd be a very bad physician if a patient came to you with pneumonia and you diagnosed him with fever disorder chill disorder night sweat disorder and gave him a different pill for each one of those symptoms but patients come up come routinely with manic depression and they get an anti-depressant an angiolytic an amphetamine and a neuroleptic for all their different symptoms and they get diagnosed with Gad and add and all these other things so I think that's one way out it's an old idea that was directly rejected by dsm3 but I think that it it makes sense to me now I did want to touch on a few other things in relation to

30:43 diagnosis people have claimed that bipolar is overdiagnosed and this is another rationale for not allowing diagnosis to be based on some of these scientific Spectrum Concepts that some of the research supports one of the most common claims is in children that the diagnosis increased 40 fold but what people don't often note is that it started at 0.01% and it went to 0.4% which is a 40-fold increase that's still below the actual epidemiological prevalence rate of 0.5% this is not to say that some of these kids weren't misdiagnosed but that means that there are plenty kids who have it who aren't diagnosed Because the actual rate is still here or above so to claim the illness is overdiagnosed at

31:30 least on the basis of saying it's diagnosed more than it actually exists isn't true there's no scientific evidence for that and not not in kids we did a small study where we looked at this we published it in 2009 and we compared add patients M major MDD patients and bipolar kids diagnosed by the child psychiatrist researcher that was working with who use DSM criteria so you have obviously you have to accept that level of that that those diagnoses might have been valid and then we looked at the histories of these kids and treatment by other clinicians and as you can see add was diagnosed and everybody who had it and many people who didn't MDD diag was diagnosed and most people had it and some people who didn't bipolar was the only diagnosis that

32:15 wasn't diagnosed in the majority of kids it's useful to have a control group if you're claiming over diagnosis this is actually the only study that has a control group in kids and we found underdiagnosis not overdiagnosis another thing that people don't realize is that bipolar illness in kids means depression it doesn't mean Mania if you follow 10-year-old children for a decade half of them develop manic episodes after having just had depression 10-year-old depressed children MDD kids half of them develop manic episodes by the time they're about 21 if you follow 23-year-old severely depressed young adults 40% of them developed manic episodes by their mid-30s just MDD so

33:04 so-called MDD the point of MDD from the course perspective was that it did not begin in childhood and young adulthood it began in middle adulthood around age 30 was the average age of onset and based on an studies and Paris studies from the 60s and 70s bipolar disorder began average age 19 that's been very consistent for a 100 years onethird of bipolars be start in adolescence that's been described since fall Ray in the mid- 1800s in Paris this is not a new American thing a lot of people say the Americans are diagnosed the British really like to say that in particular but you have an illness that's been defined as starting in adolescence and early young adulthood and then they say that

33:50 unipolar depression is different because the course is different starts later well then how can you have unipo depression in a 10-year-old again if you do and if you have a lot of it and you actually do half the kids are still unipolar 10 years later but if you do then that goes against the distinction between unipolar and bipolar it goes back to the concept that maybe the manic depressive concept is correct that you really can't distinguish these conditions very well based on genetics and course and it also reminds you that therefore this recurrent severe depression in kids may not really be so different from bipolar disorders everyone wants it to be and everyone's all worked up about even in adults this is a Zimmerman's paper we

34:37 had a little debate with him that was published in the British medical journal where Dan Smith and I commented on it in this study they claimed that bipolar was overdiagnosed because only 43% of clinically diagnosed bipolars could be confirmed to have it using the research interviews what they didn't say was that in their own which we reanalyzed the uh bipolar patients were this small bars here there was about 90 of them but uh only onethird of them were actually diagnosed as having it in other words the researchers said these 90 people had bipolar but the clinicians only said onethird of them had

35:22 it so the claim that it's overdiagnosed if you actually look at the the other way around is how many of the bipolars that really had it were overdiagnosed or not diagnosed you don't see that what you see is that there were 30% of the bipolars who had it who were diagnosed with it and 133% of people who didn't have bipolar were diagnosed with it and so really there was twice as much patients who were underdiagnosed as opposed to overdiagnosed twice as many people have bipolar and don't get diagnosed with it as don't have bipolar and get diagnosed with it that's what their own data show so it's not just about looking at what clinicians say and then what they say that's

36:08 reliability a reliability of 50% is Durer Capa values will be about 0.2.3 that's what it is for MDD according to the dsm5 field trials this doesn't show bipolars overdiagnosed if this shows bipolars overdiagnosed then MDD is overdiagnosed too everything's overdiagnosed but I think what's more legitimate is to say what's the validity if you take patients who really have an illness how many of them are diagnosed with it and what you find is that there's a 30% underdiagnosis rate in bipolar illness I think I stated that wrong there's a 30% underdiagnosed 27 out of 90 were not diagnosed 70% were and we found that as well that there's a 40% misdiagnosis rate we've published some

36:53 research we've shown it takes twice as long two to three times as long to get diagnosed if you're bipolar is if you're unipolar to get appropriately diagnosed we publish this repeatedly so there are no data in adults either that show that bipolar disorder is more frequently diagnosed when it's not present than than not diagnosed when it is present the underdiagnosis rate is 30 to 40% so I think it's still a problem but again it goes back to some extent people don't want to diagnose it because they're really caught up on the bipolar label and distinguishing it from MDD and in fact that whole issue distinguishing these two conditions the way DSM 34 and 5 have done it is something that with

37:41 couple of decades more research is questionable I think one of the things that makes it questionable is the research on mixed depression mixed depression has been narrowly defined in the DSM System including the current mixed modifier in dsm5 but broader definitions exist exist which I want to show you I want to especially emphasize for you cucopulos definition of mixed depression which is patients who have depression anhedonia suicidality low interest a lot of the core depression symptoms but it's mixed with psychomotor excitation psychomotor excitation so they're agitated they're Restless they're pacing they're angry they're irritable and they may also have some

38:27 classic manic symptoms like periods of increased libido hypersexuality increased talkativeness racing thoughts now you don't have to have it all the time the way he's thinking about this kind of mixed depression you might have a four-month depressive episode and then for two or three days of it you're hypersexual and talking really fast and running around and then the other 3 months and you know 3 weeks and 5 days you're down well smm says ignore the two days doesn't mean anything well how do you know it doesn't mean anything maybe it means something the other thing is you could be really agitated and angry the whole time and excitable and that's a very different kind of depression than Melancholia

39:13 where you're slowed down and you're not angry or agitated at all at least symptomatically it is maybe diagnostically it's different the other definition that comes from anst is what he calls the bipolarity specifier which is more the the brief two or 3 day period that I mentioned to you of more classic manic symptoms so he did this bridge study which you may have seen that was published where in a large International sample he found that about half of patients with major depressive episodes irrespective of whether they're unipolar or bipolar most of them are unipolar about half the patients with depressive episodes have manic symptoms multiple manic symptoms but very briefly not for four days or a week or 10 days or two weeks but for a day or two or

40:00 three does that not count for anything diagnostically well he looked at some validators in those patients you have much higher rates of family history of bipolar illness and very high rates of anti-press and induced Mania so you have both genetic and treatment validators that it means something it's more like bipolar illness it's not bipolar disorder by DSM definitions but DSM says look if you have one two or three days of mania ignore it doesn't mean a thing who says why there's zero evidence that the 4-day Criterion for hypomania is scientifically legitimate zero there's plenty of evidence that you could argue for a two-day criteria maybe three but two definitely and in fact fact the dsm5

40:46 task force recommended that the hypomania criteria be lowered to two days and it was rejected by the dsm5 leadership the scientific evidence supports it the task force recommended it leadership rejected it why for pragmatic reasons they don't want to diagnose bipolar anymore now this mixed concept is especially relevant I think to this larger issue when we think about the fact that once you start viewing mixed States broadly to include dysphoric mania which is a term we used to define and these kinds of agitated and mixed depressions and the bipolarity specifier that's about 60% of all muda episodes in people with severe mood episodes It's about 60% it's the

41:32 majority it's a minority about 20% that are purely Manic and purely depressed the majority are mixed and this confirms kin's view he had eight mixed States and he had pure depression and pure Mania and he kept emphasizing that most patients are mixed that's why he did not I mean he wasn't unintelligent he could have defined the diagnosis on polarity if he thought that's the way to do it but his rationale was at least it seems to me in rereading him through the lens of this other research his strongest rational was there's no polarity upon which to base your classification it's all mixed or the majority of them are mixed that's not to say you don't have any pure episodes you do but there's infrequent enough that

42:19 it's illogical to base your diagnostic system on what happens in the minority of patients now we shown that this mixed depression is therapeutically important because we did this the first Placebo controlled study with a uh dopamine blocker so-called antic psychotic versus placebo in mixed depression defined the way enx has it as bipolarity specifier in a mixture of bipolar and unipolar patients more unipolar than bipolar and we show that it was effective sidone has been shown to be ineffective in bipolar depression the way DSM defines it we found it effect in mixed depression and that gets it this issue of if you have this very broad heterogeneous depression concept you

43:04 might be dooming your pharmacology research you're not going to see the efficacy when it's more specific to subtypes so it seems a do mean blockers are very helpful for this kind of agitated mixed depression in contrast anti-depressants seem harmful and we have only circumstantial data so far because we haven't been using these definitions to do research Arch but if you look at the Stanley foundation's randomized clinical trial of anti-depressants and bipolar depression treatment emergent Mania happened more if patients had uh even just four a score of four on The Young Mania rating scale meaning this kind of mixed depression a little bit of psychomotor excitation along with depression makes you much more likely to

43:51 get manic on anti-depressants and you not only get manic you get more mixed your already agitated and angry and restless and suicidal and impulsive and then you get the anti-depressant and you're jumping off the the building as one of my good friends did who had a mixed depression and got lots of anti depressant you kill yourself that way that's what Dill saer found in these classic studies of mixed states that mixed states have at least as much if not more depression uh suicide potential as um pure depression when people say people commit suicide because they're energized when they're depressed what do they mean by that how can you be energized when you're depressed depression is a state of

44:36 psychomotor slowing and retardation if you're energized when you're depressed you're not depressed that's a manic symptom mixed with a depression symptom you're mixed so mixed depression is I think a very important clinical issue that's that we need to start thinking about more for me it has really changed changed my practice a lot in the last 5 years uh and I I learned about all this a great deal from copos who was a Greek researcher in Italy for me for decades who just died last year and it became more and more clear as he aged that his experience was right that he he was really bringing it home it's teaching us and now we have access to his database and we're publishing from his patients

45:23 who he followed for four decades and we're showing some of this evidence and it's coming out gradually now mood temperament is the other thing I want to discuss it relates to personality you know you can talk about personality disorders which come from the psychoanalytic tradition but mood temperament is a different way of thinking about personality it's about the original concept which came from cbom and then was popularized by cresmer in the early 20th century cresmer well Kow bom came up with the terms but cresmer really emphasized them the idea that cresmer had was that Damia is a mild version of depression cyia is a mild version of mania and depression hyperthymia is a mild version of mania and schizo thyia is a mild version of schizophrenia and they are all literally

46:10 mild versions of those illnesses that get transmitted in the families of people who have those illnesses and furthermore people who have those illnesses can have these mood temperaments in between their severe episodes or exacerbations and it's been very well shown that schizotypal personality is a genetic gentic variant of schizophrenia and a mild version of it there's emerging research that shows that cyia hyperthymia and Damia are much more common in families of people with bipolar illness than not and we've done research that's shown that half the patients that in our Clinic who have bipolar illness also have cyclothymic temperament most commonly or hyperthymic temperament or dymic temperament these are mild symptoms that are present all the time now if you're cyclothymic or hyperthymic you're going

46:57 to be revved up distracted talking fast Thinking Fast pretty creative energetic productive a workaholic you might have trouble with relationships because you're so revved up and externalizing all the time and since the DSM definition of borderline personality doesn't include sexual abuse and only has self-cutting as one of multiple criteria you easily meet the definition for borderline personality if you have hyperthymic temperament or psychic temperament and then the problem is how can we tell who's got bipolar illness say and Inter in between their cyc thymic and hyperthymic as opposed to having comorbid borderline personality in bipolar or just having borderline well we can tell that I think I just

47:45 mentioning here personality traits is another way of looking at personality that has tons of research behind it does link into the mood temperament concept a bit but it's more dimensional and again it was recommended by the dsm5 task force it actually was approved by the dsm5 leadership supported by them and within a few weeks of the final vote on dsm5 it was rejected by the American Psychiatric association Board of Trustees kind of like the poot Bureau saying no we're not going to take it it's not a scientific decision but the science is really strong for it but it's not going to not in DS sm5 at least as a primary concept we can distinguish I think these mood temperaments from borderline because sexual trauma is at

48:32 least twofold maybe three-fold more common in borderline personality than bipolar illness or the general population and self-cutting is depending on the study at least twofold maybe 50-fold more common in borderline personality than in bipolar illness now the borderline experts often try to downplay sexual trauma and self-cutting these days they just emphasized the mood libility and the stable relationships well every bipolar has mood libility and unstable relationships so that's really not a good way to different differentiate borderline from bipolar and they'll say well some people with borderline personality don't have sexual trauma that's true but the majority of them still do and of course that's a highly underreported and qu and controversial issue about knowing if

49:18 you've had sexual trauma self-cutting is very consistent it's about 70% or so of the Border Lines and much much less in the bipolar so I think that we should emphasize these kinds of diagnostically differentiating validators not just the symptoms not certainly the DSM symptoms again the whole concept of borderline personality grew out of people who had sexual trauma and who were self-mutilating but then those terms aren't used for the diagnostic criteria in the bridge study it was shown that these mood symptoms don't differentiate bipolar and border b line or mixed States and borderline but the non-mood symptoms especially the self-mutilating symptoms and the dissociative symptoms

50:06 did if we started thinking more about hyperthymia and cyia we would maybe also appreciate that many of our patients and their relatives have it and have benefits from it so here's the only picture of Franken Roosevelt in a wheelchair man who I tried to show in in in my biographical description of him had hyperthymic temperament very funny very creative very talkative very high sex drive uh very charismatic very energized low need for Sleep um and that helped him survive polio there's research emerging research that shows that when people have traumatic experiences their likelihood of developing PTSD is lowered if they have hyperthymic temperament premorbidly and also you know his

50:51 personal trauma he got over and I think he my view is that hyperthymic leaders help Nations survive political traumas in his case the worst of the year of the of the century the two worst things the worst depression economically we ever had and of course World War II now a lot of people will diagnose this hyperthymia or cyia as adult ADHD because when patients have manic symptoms they can't focus um and they say people say adult ADHD is really prevalent people like to say that half of the kids continue to have it when their adults well if that's true I wonder why nine prospective studies conducted before the pharmaceutical industry got involved in this field showed that there was a 90%

51:36 decline in ADHD by the time you reach young adulthood the um introduction of stratera at atomoxetine in 2002 is the first FDA indicated drug for adult ADHD led to the marketing of adult ADHD Recent research studies suggest there's more fre of it but still the the earlier studies don't find that I'm going to show you some newer data too the other thing that makes me wonder about this concept that ADHD is purely biological and really persistent is that in the United States there's a good deal of state-to-state differences so ADHD rates are very high in the southern states which are the poorest states in the US and very low in the western states which are usually somewhat wealthier and and people tend to go

52:24 outside more and exercise more and so on so for instance you have literally a three-fold higher rate in some of these Southern States than you do in California this actually mirrors the map for diabetes and heart disease which shows that there are you know generally it's thought of in clinical epidemiologies reflecting environmental factors like diet and exercise that influence behavior that then influences behavioral symptoms it's it's highly suggestive that ADHD just like heart disease has important environmental factors involved and I always wonder why the cardiologists are more behaviorally minded than the child psychiatrists are the child psychiatrist wanted to be purely biological we have this now this

53:11 recently published 33-year outcome study what happens that with kids who have ADH at age8 with a control group followed until they're 41 how many of it how much of it persists and the answer is 20% persists 80% does not so still our best research is that the majority of kids with ADHD do not persist into adulthood with it what's also interesting is that the biggest group that did have problems became antisocial and that there was a good substance abuse rate I suppose those aren't really good things to have as adults if you're taking amphetamines for 20 or 30 years um there was some mood illness as well and some of these kids develop mood

53:57 illnesses as well the substance abuse rates by the way people like to say that substance abuse does not increase with amphetamine use in children that's not true it's not true based on the only randomized data which we have which is the MTA study which actually found higher rates of substance abuse in the kids randomized to amphetamines versus the kids randomized to behavioral therapy at one to three-year outcome so we're going to talk about amphetamin in a second but I just want to make the point that when you start thinking about amphetamines because of adult ADHD you might be making a diagnostic judgment that isn't valid partly because we're misinterpreting mood temperaments perhaps as ADHD and we're also influenced by beliefs about Persistence of ADHD which isn't really well supported

54:45 scientifically now a few words on treatment and then I'll stop I don't like the words we use for drugs I don't like anti psychotic mood stabilizer and anti-depressant they were clinical terms invented in the 1950s and 60s when we didn't know what the biological mechanisms of the drugs were and they're definitely not true anti-depressants don't work for all depression anti psychotics work in non psychotic persons and mood stabilizer doesn't mean anything scientifically meaningful it's a it's just a linguistic term I've I've suggested that maybe we should use biological mechanisms and call the anti-depressants monoman agonists you know like we say SRI I think that's a better way way of talking about them they work better in anxiety than they do in depression anyway we

55:31 could use dopamine blocker for for the antis psychotics we could use second messenger modifiers for lithium and valpro and some of these drugs we call mood stabilizers and gabaergic Agonist for the anxiolytics and I think that would imply fewer assumptions when we talk with ourselves and with our patients I've started talking to my patients this way and it helps I don't have to say yeah you have bipolar depression but I don't want to give you an anti-depressant I say you have bipolar depression for which monom agonists are ineffective it's a much better way of talking I can I don't have to say I'm going to give you a mood stabilizer and then they're afraid I'm going to make him a zombie I say I'm giving you a second messenger modifier to prevent your mood episodes it's much more scientific much

56:18 fewer Mis mistaken assumptions something to think about I proposed this and so far I've had this paper rejected a number of times and it's not published yet so I don't know if it'll ever where I'll get it published but I tend to do it eventually somewhere sometimes it takes a decade all right in terms of treatment I want to make a big picture point the hipocratico to treatment is not is not first Do no harm that's what you probably hear hypocrates never said first Do no harm and none of his students ever said first Do no harm and it is nowhere to be found in the hypocritic writings what is there is as to diseases try to help or at least not harm the term first Do no harm was

57:03 invented in the mid 19th century by a British writer and attributed to hypocrates it was actually never pull it out you guys have hypocrates pull it out at home see if you can find that phrase it's not there and then people say if they want to be fancy they say primum noer they use the Latin which of course proves that hypocrates didn't say because he didn't speak Latin he spoke Greek never said for Do no harm never said premium know no Cherry it's not there and it's that's not the meaning of his approach it's not be conservative and try not to use drugs that hurt people it's actually give drugs that hurt people a whole lot as long as you know you're treating a disease and helping them and if you're not treating a disease don't give them much of anything even drugs that you think are

57:49 safe now that's different than the way we tend to talk about this if you read the hypocritic literature you get a sense of that I won't go into detail I've written a an article on this called hypocracy psychopharmacology which you can download from that website the basic picture which I I put on here is that the hypocracy to treat diseases so a patient comes to you with symptoms your job as a physician clinician first of all this is what you spend your first two years in medical school doing is to find out if the patient has a disease or not then your job is if if you find out they have a disease to look at the scientific literature to see if that disease is treatable this is where the evidence base comes in and so on then you can

58:35 treat them that's all fine this this Arc is fine everyone agrees with that what people don't seem to appreciate is that many times if not most times patients go to doctors with symptoms but have no disease you're not supposed to treat them according to HP atic tradition as two diseases try to help or at least not harm that means if there is no disease you just don't harm you don't treat because there's no disease to treat drugs work for diseases now it's true drugs have symptomatic benefits some of them opiates for pain benzos for anxiety amphetamines for attention isn't it interesting that all those drugs work in normal populations

59:21 for normal pain and attention and anxiety symptomatic drugs are there because they have physiological effects but they aren't treating diseases taleno reduces fever well is it abnormal to have fever is it abor have temperature if I take taleno my temperature will go down from 98.6 to 97 it's not treating a disease so yes it's okay sometimes we give paliative treatments when someone's untreatable but generally speaking we should try to treat them less a shorter amount of time lower dos of drugs and we should also remember thankfully most patients who present with you aren't really sick most patients who come to you are not sick Nature has given them illnesses

1:00:08 which go away on their own so there's a famous saying that um Physicians know and Physicians wives know as well that uh most things get better by the morning that's why you say take two aspirin and call me in the morning it's not because the aspirin works it's because morning works by the time it gets to morning it's done so you know in the case of mood illnesses these are recurrent episodic illness what does episodic mean that means unless they die in the episode they will be cured by Nature how long does the episode last naturally 2 to 4 months 4 to 6 months based on the various studies for Mania

1:00:54 and depression that means if you're seeing a patient who's farther along you can just wait I ask every single patient I see how what's the typical duration of your depression and so frequently they say it's a few weeks a month and they come to me with three weeks of depression and they say the typical duration is a month and I say well great you'll be cured next week no prescription make an appointment for next week see you then we have to give credit to Nature that's the hypocracy nature it's a much more humble attitude than we most Physicians have the old classic saying God heals and the physician dresses the wound that comes from hypocritic

1:01:42 surgical um ideas in the 16th 17th centuries when they realized that wounds heal by just keeping them clean and putting a dressing on it not by continually cleaning it out with your scalpel that makes it worse and worse and worse we don't have that attitude in Psychiatry probably because we don't see the wound that we keep giving people drugs and trying to treat every symptom so that's what the hypocracy now in our drug treatments we have a lot of drugs like anti psychotics in particular do me blockers that are used long-term and I just want to point out that they're based on study designs where only people who respond to the drug can enter the study then they get

1:02:29 randomized to stay on it or come off these are called randomized discontinuation trials or rdts or enrich trials what's interesting is there's almost never been I think I found one but there's almost never been an a randomized discontinuation trial for maintenance treatment of any drug in Psychiatry that ever failed in fact the FDA did an analysis which they're going to publish soon you know that in the acute depression studies with anti-depressants and MDD half the studies failed where they were negative half were positive well in their maintenance studies 15 out of 15 are positive they've never had a negative study because they all use this design same thing with the antis psychotics there's never been a negative study in bipolar illness of any antipsychotic the FDA accepts the design

1:03:15 and I'm I'm trying to convince them not to the one point is look if you never have a negative study how do you have a scientifically valid method remember what Carl poer said Science is based on falsifiability if you can never falsify you can't prove anything either you get things like withdrawal syndromes with this design everybody gets better on O lanzapine then they get randomized to stay on or come off you notice that 80% relaps within two months because they came off a drug which they got better on for a few weeks for severe Mania well does that prove that you need to be on it for years and years and years when you treat somebody in the hospital for 3 weeks a month and and then you stop the drug and they relapse in a month have you proved maintenance

1:04:00 efficac they changed the design they require two months or longer of of acute treatment but still one of the things that's interesting this is based on a paper that Goodwin and I Fred Goodwin and I published if you look at Placebo relapse rates in these maintenance studies if you start out with an initial depressive episode your maintenance relapses into mania the opposite if you start out with a manic episode your maintenance relapse 6 months longer is into depression whereas in the first 6 months you relapse into the same episode that you had before the study started Mania or depression what this I think is showing in these double blind randomized data is that in these maintenance studies if the relapse happens before 6 months it's not a new episode it's the

1:04:46 same episode you had before the study started to really prove maintenance efficacy you need to show prevention after 6 months and that makes sense because there's 100 years of Natural History data that shows that episodes last 3 to six months in bipolar Elms manic depression and the other interesting thing is that the episode that happens is the opposite pole manic depression Mania is Follow by depression depression is Follow by Mania it's not the same pole at least in bipolar realness and uh what you find with the anti psychotics very frequently is that they prevent Mania but they don't prevent depression in some of these studies like a piersol for instance well if that's happening maybe it's just because you are not preventing the maintenance phase of new

1:05:35 episodes another Factor that's relevant to this enriched design I like to use this chocolate vanilla cake analogy suppose you like chocolate cake and then I do a study of chocolate cake and I only include people who like chocolate cake and then I randomize half of them to getting chocolate cake and the other half to getting vanilla cake how do you think it's going to go I don't I don't understand how people can use this design and really take it seriously another suggestion is that if you look at the this design and take Placebo responders which this these uh Andrews and colleagues in this ingenious analysis did they took people who responded to Placebo in MDD not antidepressant and then got randomized to get stay on Placebo or switch to anti-depressant in the maintenance phase

1:06:22 and what they found was that the anti-depressant made them a whole lot worse than staying on Placebo they claim that that means that an depressant actually harm people it could just be another example that this design never fails it invalidly makes whatever you select for seem more effective the one suggestion that supports this is that lithium has both enriched and non-enriched designs and in the enriched design it has an odds ratio of 22 non-enriched that means you inflate the effect size tfold which is huge effect size of 22 is huge my question is what if you have an ineffective drug so that the real effect size is one but you inflate it by 10

1:07:09 you're always going to see a benefit you won't be able to falsify people have been thinking that these drugs just should stay on because you got acute benefit and they use these designs to support that but I'm suggesting to you that the design Minds may not be valid and also the general concept like the happily have ever after fallacy you got better on this drug stay on it and you'll be happy forever is not a medically proven idea there's some examples up here where this doesn't happen with steroids antibiotics propanalol and uh that's all relevant to antis psychotics and anti-depressants I'll just point out that amphetamines are also a problem they can cause Mania as in the study we showed they have

1:07:55 neurotoxic effects in animals in the brain which we reviewed in this paper

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