In this episode, Dr. Adrian Preda speaks with Dr. S. Nassir Ghaemi about the limitations of the DSM framework in diagnosing mood disorders and explores the case for returning to more valid, clinically grounded approaches. They discuss the historical context of manic-depressive illness, the role of mixed states and mood temperaments, and how reframing diagnoses can lead to more effective treatment.

Read Dr. Ghaemi’s full report in Psychiatric News: Validity in Psychiatric Diagnosis: DSM and Mood Conditions

PsychNews Special Report is a production of Psychiatric News, a media platform dedicated to serving as the primary and most trusted source of information for APA members, other psychiatrists and physicians, health professionals, and the public about developments in the field of psychiatry and mental health that impact clinical care and professional practice. Learn more at psychiatryonline.org/journal/pn.

Transcript for Audio

[00:11] Adrian Preda: Welcome to the Psychiatric News Special Report podcast, a monthly podcast produced by Psychiatric News for the APS Medical Minds channel. I'm your host, Dr. Adrian Predap, Editor-in-Chief of Psychiatric News and a Professor of Clinical Psychiatry and Human Behavior at University of California Irvine School of Medicine. Today, I'm delighted to welcome Dr. Nasir Ghami, Professor of Psychiatry and Director of the Mood Disorders Program at Tufts Medical Center.

Dr. Ghaemi is also a lecturer in psychiatry at Harvard Medical School, Cambridge Health Alliance. Dr. Ghaemi is joining us to discuss his recent special report titled Validity in Psychiatric Diagnosis, DSM and Mood Conditions, which explores the conceptual challenges in our current diagnostic framework for mood disorders. Dr. Ghaemi's article offers a critical examination of the DSM approach to mood disorders comparing it with historical perspectives and questioning whether our current diagnostic categories accurately reflect clinical realities. Welcome to the podcast Nasir.

[01:14] S. Nassir Ghaemi: Hi Adrian, thank you for having me.

[01:16] Adrian Preda: Before we dive into the specifics of your special report, I'd like to take a moment to learn more about your journey into psychiatry, what drew you to the field initially, and specifically how did you develop your interest in mood disorders.

[01:29] S. Nassir Ghaemi: Well, I came from a medical family. My father's a neurologist and a neurosurgeon and his father was a family practitioner in the pre-antibiotic era in Iran in the village where there weren't much medical technologies, medicine is in the family, many generations of it, and going to medical school was a natural thing to do. I also had an aunt with schizophrenia, so I had family experience with serious mental illness and both how medications and treatment can help people, but also how little we knew about it. So I wanted to contribute to learning more and to research and knowledge about mental illness. When I went to medical school, I was open to other specialties, especially neurology, but I was very interested in the brain and the mind. I ended up doing psychiatry partly because of the broader aspects to the field as well as well as the family experience.

And once I got in, I realized that there had been many years of research on schizophrenia of a century, but much less on manic depressive illness and more on depression than bipolar illness. So I kind of shifted to bipolar because that seemed to be where I could make the most impact. And it's been a good move for me. I've enjoyed it very much.

[02:44] Adrian Preda: Wow, that's fascinating. Now, I'm curious, were there any particular clinical experiences or research findings that fundamentally shape your thinking about the validity of our current diagnostic system?

[02:58] S. Nassir Ghaemi: Yes, thanks Adrian for asking it. And then of course, that's what we wrote. I wrote about the most here. When I came into psychiatry in the early 1990s, DSM-4 just had just coming out and DSM-3 had been a smashing success for about a decade. And then it was very popular and I, like everyone else, assumed that things were getting better and we were going to progress quickly, diagnostically, for instance. And in the next decade or two, I did a lot of research on bipolar illness. And I concluded, as some people did, that the definition should be broadened, that we should have a broader bipolar spectrum. And there were various reasons for that. But when DSM-5 came along in 2013, nothing happened. There were no major changes. And a lot of that research wasn't really incorporated. So that was 20 years later, after my residency had ended. And I had participated in 20 years of research. And I realized it wasn't making much of a difference because the DSM system really wasn't set up to be responsive to some of that research. And in the meantime, in the prior decade or so, I had been exposed to some European thinking on this topic from colleagues who had meeting conferences like Koukopoulos in Italy. And I was being mentored by Frederick Goodwin, who was the author of the main manic depressive illness textbook about this very broad knowledge of the history of the field. And I learned about this broader concept of manic depressive illness, which had been left behind and they all thought was actually more valid than the DSM 3-4 concept. And when I saw that when DSM wasn't really changing to be more valid, I thought that that's when we really needed to rethink the whole approach we took to diagnosing mood illnesses. So that was probably about 10 years ago.

[04:40] Adrian Preda: But before moving and discussing the specific of manic depressive illness versus our current conceptualization of bipolar and depression, I'm curious about the broader issue of diagnostic validity, which you stopped your special report discussing the important differences between reliability and validity. So could you explain what you mean by validity and why it matters as much as if not more than reliability in psychiatric diagnosis? Yes.

[05:07] S. Nassir Ghaemi: Well, validity is just a kind of a diagnostic scientific term for saying something is correct or accurate or real in some way. It might be biologically real if it's a disease. It might be psychologically real or socially real if it's an actual fact in the mind and the mental world. For instance, trauma reading a PTSD is a construct that has some reality to it.

On the other hand, we've had constructs that were not real. instance, homosexuality was viewed as a mental illness in our field until 1973. These are social constructions that we might believe them for 50 years, but they turn out not to be real mental illnesses. So it doesn't matter so much what our reliability is that we agree on how to define something if what we're defining isn't accurate, correct, or real. And that's why validity matters in the end, much, much more than.

[06:04] Adrian Preda: So in other words, reliability is important. Without reliability, there is no discussion of validity, but it's not sufficient. Reliability does not mean, does not equal validity, and that's a crucial, crucial point.

[06:17] S. Nassir Ghaemi: Yeah, sort of like you have a dictionary term, for instance, you have a unicorn and you can define it really well, but there's no real unicorn in the world. So it doesn't mean it's real just because you can define it.

[06:29] Adrian Preda: Absolutely. So in psychiatry, one of the challenges that we are facing is that we have very little, if any, times, objective indicators of what is the underlying pathophysiology of our diagnostic constructs, right? So with those limitations, then, what is it that can be done to, in fact, improve the validity of psychiatric diagnosis?

[06:52] S. Nassir Ghaemi: Yes, this was always the biggest problem. And I think a big reason why the concept of validity was put aside and DSM-3 onwards focused mainly on reliability was exactly this issue that the question was then, well, how do we get it validity? We don't have a good way of doing it with pathology, laboratory tests like medicine does. In 1970, some of the early researchers that did some of the work that's part of which became part of DSM-3.

I came up with diagnostic validators that were independent lines of evidence separate from the symptoms that could help you say that this construct might be valid. So you have the symptoms and if the symptoms are more specific in this group versus that, that's one thing. So that's one validator symptom specificity. The second construct is the second validator is course of illness. What's the age of onset? Is it episodic versus chronic? Does it get better naturally or not? And that's an old medical concept, course of illness is always part of the ability of any medical illness. Genetics or family history, does it run in families and can you show that in genetic conditions that's relevant, especially like schizophrenia and manic depression. And the fourth was treatment effects and sometimes that's relevant, but it's more nonspecific. So essentially, course and genetics are the most important things. And that's what was used in psychiatric research through much of the late 20th century, that's sort of the standard perspective on this. My view is not that we should change that. I totally agree with that. I'm totally in that tradition. I just think we need to take it seriously and we should apply it. And actually, I think there is a lot of clinical research that's rather good on genetics, course of illness, validating symptom specificity for a good number of illnesses. Schizophrenia, depression being the biggest ones, but there's a few others.

And yes, there's some questionable spots, some things people will disagree on, some things that are unclear. But nonetheless, I think we can have a reasonable agreement on what we think validly describes conditions now and then change it gradually over time. And that's essentially what medicine does in general. But psychiatry has really failed to do for the last 40 years.

[09:06] Adrian Preda: In your article talking about the long span of time, you provide actually a very thorough historical perspective on how mood disorders were conceptualized before and after DSM-3. Could you walk us through how the understanding of depression and mania has evolved, particularly regarding the relationship between unipolar and bipolar presentations?

[09:30] S. Nassir Ghaemi: Yes, yes, it was so different back then. again, luckily, I had some mentors who were in the field in the 1960s and 70s. So they knew and they could tell me about it. But one can read about it too. But basically, Kremlin as we, Emil Kremlin, as we know in 1890s came up with the concept of managed breast illness in contrast to dementia, precox or schizophrenia. And those were two big illnesses, manic depressive illness included most of what we're calling unipolar depression today. And basically it meant recurrent mood episodes of any kind. You could be manic, could be depressive, you could be both, you could be only one, just depressive was the same as just manic. It was all the same. And it's because most of the patients had mixed states. They actually had the manic and depressive symptoms at the same time. It was less common to have them just purely depressed or purely manic. So he didn't differentiate mania and depression diagnostically as being important because people had mixed-aid mostly, but rather just as symptoms, different kinds of symptoms people could have in the same illness. And this later got broken down into the bipolar-unipolar distinction in the 1950s and 60s by other people who did not agree with Kwepplen on this view. And it became codified in DSM-3 because there were some genetics and course research, like we just talked about, that suggested that the people with just depression, the unipolar ones, were different than the people who had mania, the bipolar, in their family history and their course of illness. The claim was bipolar had bipolar family history, unipolars didn't, and that the course of illness of bipolar was earlier and earlier age of onset and it's otherwise different than the unipolar depression. And since then, in the last 40 years, both the genetics and the course of illness show the opposite. They overlap on their genetics. They overlap in their course of illness.

So that's why I think actually if you apply the validity definitions, Kreplin's original concept was more valid. But the bottom, the basic summary is manic depression was a very, very broad illness that included bipolar plus unipolar, the way we define it, most of what we call major depressive disorder. And the DSM construct of bipolar is a very narrow piece of that, very small. And then the rest of that manic depressive construct has been relabeled as major depressive disorder.

[11:50] Adrian Preda: So in other words, and you know, right, you know, there is always this tension in, you know, when we look at psychiatric nosology between the lumpers and the splitters, right? And to explain to our audience what that means, the lumpers is, know, the conceptual formulation that is that we're looking at spectrum type of things, right? Things are actually coming together and there are different aspects of, in essence, the same, the same psychopathological entity versus the splitting approach, which describes discrete entities maybe loosely related to one another.

[12:48] S. Nassir Ghaemi: Yes, that's partially true. I would just say one thing about it. I'm not, I don't think I'm inherently a lumper or a splitter. Whatever the validity data show, if I split, I'll split it. We should lump, we should lump. So I don't think the whole issue of spectrum versus not is actually the core question. But it's true what you just said, except the DSM was also a lumping process because they split manic impressive into two parts.

But then they lumped major depressive disorder with many other kinds of depression that were never viewed as the same as unipolar depression, and they combined it all together. So DSM both lumped and it split at the same time.

[13:26] Adrian Preda: Yeah, I think that's a very useful actually clarification. Great. And you make the point actually to kind of bring that home under the Crepellinia framework. You make that statement in your report and I think it's very the strict gift that a patient with 100 depressive episodes and zero manic episodes, right, would still be diagnosed with many depressive illness, right? convey those points of difference between the Crepellinian formulation and the DSM formulation of the diagnosis.

[13:56] S. Nassir Ghaemi: Exactly, the shift the focus from the episode polarity to the course of the illness. That's how Kruplin did it. Do you have recurrent mood episodes? Any kind, but the recurrence in the long term of these episodes which come and go, that's the hallmark of the diagnosis. It doesn't really matter in this episode what kind of...

[14:17] Adrian Preda: Yeah, very helpful. Now in your article, you emphasize the prevalence and significance of mixed states in Moody's orders. How does the existence of this mixed presentations challenge our current diagnostic paradigm?

[14:33] S. Nassir Ghaemi: Right. So I think that the reason that Kreplin focused on this recurrence and the long-term episodic recurrent courses, the hallmark of the illness, was because you could not focus on the episode polarity as the hallmark. It just wasn't there. There is no polarity. It's mixed. The episodes are mixed most of the time. So if you look at some research, as we described, if I give a ballpark number, about 60 % of all mood episodes are mixed, if you define them mixed broadly.

20% are purely depressed, 20% are purely manic. And that includes all unipolar depression as well as bipolar. So if 60% are mixed, the majority are mixed, you cannot use the distinction between depression and mania to tell whether someone has bipolar versus unipolar depression. This is why we get into the constant clinical conundrum of a patient who has a depression, but we don't know if they've had a mania or hypomania in past. We aren't sure about it or we're looking for it, we're struggling.

And or we have a patient who's depressed and they might be agitated and angry and so on. And they're more less depressed than they are angry. And so what's that? And I would view it as a mixed state. But so the benefit of this, just going back to this Creplenian view is you don't have to engage in any of that effort. It really doesn't matter whether the patient has had a manic or hypomanic episode in the past. If they have recurrent depression, it's still manic illness.

And often you'll find they have a little bit of mania here and there. And in the current system, people will debate whether it matters. Is it two days versus three days versus four days? Should that make a difference? But if you take the crowd planning interview, it doesn't make a difference. So it doesn't really, it's not important to get at those levels of fine distinctions. So I think that's what would change the current system. In the current system, it would just shift our perspective from really trying to emphasize it. Is there a mood episode of mania or hypomania or not?

Or versus depression and shift to just saying, this is a long-term severe episodic recurrent mood illness and it's genetic, it's in the family, that's managed aggressive illness. Let's move on from there.

[16:39] Adrian Preda: Right. So in other words, you know, one of the, these points of, seems like important difference between the Krepelian formulation and the DSM formulation is the centrality. Maybe that's a way to understand it. The centrality of the mixed states. Yes. Which were sort of the core of the Krepelian formulation and they were somehow, you know, distributed in some other categories with a less degree of clarity. And at times maybe these episodes even being mixed in the modern post-DSM formulation of the diagnosis.

[17:10] S. Nassir Ghaemi: Yeah, it's, it's, it's the Krepplinian perspective views mixed states as the central episode polarity. It's the main symptomatic presentation you deal with. It's what you expect to see most of the time in the DSM system because they define major depression so broadly to really legislate away mixed states. A mixed state is something that's kind of peripheral and less common and less important. It's a, it's a major difference.

[17:34] Adrian Preda: Right. Now you also make some other points, important points about the historical nosology of depression. So maybe you can just, know, let's spend some time clarifying the differences between the classical formulation between what used to be classified as neurotic depression versus melancholic depression versus, you know, the higher levels of melancholia according to that formulation that was actually now moving into psychotic, cathartonic type of depression.

[18:02] S. Nassir Ghaemi: Yeah, so there's two different ways in which things were different back then. One is at the overall diagnosis level, manic depression versus neurotic depression versus chronic melancholia. And the other was at the actual episode level, which is, is it mixed or is it pure or is it melancholic for this episode? And so both of those matter. In terms of the overall diagnosis level, the neurotic depression was very different in its course of illness and genetics than manic depressive illness because it was not genetic, unlike manic depressive illness, not very genetic at all. And the course of illness was chronic instead of episodic like manic depression, not necessarily early age of onset, not severe unlike manic depressive illness, usually mild to moderate, and also had some symptoms specificity where there was always this anxiety component along with the depressive symptoms. And you don't have any manic episodes, obviously.

So neurotic depression was actually the most widely diagnosed illness before DSM-3 and the primary indication for psychoanalytic psychotherapy. It's now folded into the MDD concept and a good chunk of people we diagnose in MDD probably would be people we might call on neurotic depression. The other group, chronic involutional melancholia was a concept for DSM-3 and it basically meant people who were chronic like people with neurotic depression, but severe, not mild. That's why they were melancholic, the more severe versions of depression. And anxiety might be there or might not be there, but it wasn't as central to the diagnosis. And it also was not genetic or had any major genetic source. And the course of illness differed because it was middle-age onset or later. So these are the people that we now call late onset depression. And that was always described.

Their depression is chronic and it's not as recurrently episodic as the traditional early onset, unipolar depressions, and not very treatment responsive. ⁓ In the meantime, in the last 40 years, we've realized that they tend to have these patients with white matter abnormalities in the MRI. And the concept of vascular depression, I think, really overlaps with the old concept of involutional melancholia. Again, vascular depression is not a DSM diagnosis, it's just part of the MDD category as well. But I think we could break up MDD into these couple major concepts, neurotic depression, vascular depression, manic depression. And manic depression includes what we call unipolar depression as well as bipolar depression. That's the way I would think.

[20:38] Adrian Preda: Yeah, that's very helpful. you know, maybe a way to understand it and please correct me if I am wrong, but you know, our current concept of MDD, major depressive disorder, which is based on a major depressive episode, right? The major depressive episode could include something that in the in the classical ⁓ classification would have been classified as neurotic depression. And I don't like to use the term of minor depression, but neurotic depression is somewhat minor because there is less of a genetic component and there is less of a biologically driven pathophysiology as opposed to psychosocial components. So the neurotic depression is still in the current classification major depression and also what used to be major depression in your category, the pure depression is also major depression. So that the differentiation that was more granular in the other classification is somewhat lost in our new conceptualization of the major depressive episodes. Is that a way to understand it?

[21:37] S. Nassir Ghaemi: That's correct. There was a lot of debate about this in the 1970s and DSM-3 came in strongly on the lumping together. All these different kinds of depressions, they lumped together into this very broad MDD category.

[21:49] Adrian Preda: Yeah, and something to consider there, right? Because that's always the question, right? When we see our patients with depression is how do we differentiate between the potential responders to psychotherapy versus biological interventions? And it sounds like in the older classification, actually, there will be a way to better differentiate between people who would be probably better candidates for psychosocial interventions, psychotherapies versus that would be the neurotic depression versus people who would be prime candidates for biological interventions, which would be what used to be the pure depression in the past. And right now this differentiation is somewhat lost in our conceptualization of the MDD with the two weeks of the two symptoms and then the additional symptoms, right?

[22:33] S. Nassir Ghaemi: Right. That's one way I came to learning about this, this differentiation. The neurotic depression history is a different history than managed breast illness. It involved more British psychiatry. Sir Martin Roth was one of the main figures. And the reason I got to learning about it was my research on being a clinical researcher in mood illnesses and working on antidepressants and so on.

The debate around when the meta-analysis on antidepressant efficacy and major depressive disorder being very small. But there was a distinction between the mild ones who had zero difference with placebo and the severe ones who had a big difference with placebo. once I realized that, it clicked for me that maybe this is because the mild ones have neurotic depression and the lumping of these diagnoses is making it harder for us to actually see efficacy with a certain drug class or also to know, like you said, when we should use the drugs at all versus psychotherapies. And I think if we reframe our diagnostic thinking, it helps clarify much more clearly how to use our treatments.

[23:40] Adrian Preda: And that's such a great point because the point that you are making here is that in fact this lumping approach might result into unwarranted heterogeneity. Exactly. Right. then in turn could in fact decrease our ability to find an effective intervention. The more heterogeneous the sample is going to be, the more noise that you're going to have compared to the signal that you are looking for. That's a very important point.

[24:04] S. Nassir Ghaemi: Yeah, there's only one thing I want to add to that. And that's true. And there's a lot of noise here. But whether we should have a broad definition or a narrow one, much heterogeneous in some senses, but more homogenous in is really a validity question. We can't prejudge that. We should let the genetics and the correspondence and all that tell us. But I think, you know, there's the validity data support, a broad heterogeneous manic depressive concept, but they don't really support a broad heterogeneous depression concept in a general sense. That's the way I would.

[24:35] Adrian Preda: We should let the data speak. You also discuss the concept of mood temperaments, which you note are often overlooked in the DSM framework. Could you explain what these temperaments are and how they relate to mood disorders?

[24:37] S. Nassir Ghaemi: Yep, exactly.

Yes, this is such an important topic and I have to say, I've been in the field for 30 years now. The last 10 years, I've had a midlife crisis in terms of my thinking about some of these diagnoses. the biggest change was, we've already talked about a lot of it, but clinically the biggest change was the mood temperament concept in the last decade has really changed my clinical practice. But basically the idea is if you have this broad manic depressiveness construct and it doesn't matter what kind of episode you're in, manic or depressive, they're usually mixed. It also doesn't matter what kind of symptoms you have. It doesn't even matter if you're in an episode. So you might never have an episode of any kind, full-blown depression, lasting weeks or whatever, but you have depressive symptoms to a mild degree all the time called dysthymia or manic symptoms to a mild degree all the time called hyperthymia, which is not in the DSM system. Or you have both all the time, back and forth, cyclothymia.

So some of these terms are in DSM, but they're kind of defined as separate disorders. They're not really appreciated to be essentially mild variations of manic depressive illness. So someone can have bipolar presentation or unipolar, lots of recurrent mood episodes. And in between the mood episodes, they're either dysthymic, cyclothymic, or hyperthymic, at least 50 % of the time based on some of our research. No, sometimes, many times they're not. They're just usual, normal thymic, euthymic people.

But a lot of patients just have these mild mood symptoms all the time. And it can get misdiagnosed as something more severe like MDD or the effects get misdiagnosed. They're anxious, they can't concentrate. So they get called GA generalized anxiety disorder or attention deficit disorder. And that the cause of it all, the underlying mood temperament, the depression and the manic symptoms, which make you anxious, which make you not concentrate, isn't diagnosed or treated. And for me, once I started looking for mood temperaments in patients in between their mood episodes, I found that there's a lot of it and that often explains a lot of the actual psychopathology that's bothering them. Sometimes it's not so much the mood episodes, the constant mild mood symptoms and its effects.

[27:04] Adrian Preda: Absolutely. And to bring this home, actually, in your article, you present two cases, right? Could you discuss how these cases demonstrate the limitations of our current diagnostic approach and the clinical implications of re-conceptualizing the disorder? And I'm going to start with the first case. Yes. Right. So that was a 16-year-old male with persistent depression, and he's been previously diagnosed with MDD and major depressive disorder and attention deficit hyperactivity disorder ADHD. He's been tried and he's felt multiple antidepressants, antipsychotics, ketamine and TMS. Right. And he also had a family history of bipolar disorder. So with that history, how did you go about, you know, what was going on assessing and then treatment recommendations?

[27:54] S. Nassir Ghaemi: Right. So this would be a person who people classically these days just call treatment resistant depression. These failed all these antidepressant trials, including as importantly, adequate trials of ketamine, 20 or some treatments of TMS. So I don't view treatment resistant depression as the way to think about these things because once you question the diagnostic construct to begin with, then treatment resistance is not about the drugs. It's more about the diagnostic construct.

So the question really is what's the diagnosis outside of just the depression. And of course the family history tells you the biggest hints as we go to the validators, we got the symptoms, but now we go to genetics and there's the bipolar. Well, if there's bipolar in the family history, the patient should have bipolar illness. If the DSM construct is correct, the ⁓ depressed patients should not have bipolar illness in the family history. I sometimes tell people either the diagnostic definitions we're using are not correct or you don't exist because this shouldn't be a common problem. But that's one thing. And then when I looked at the temperament, the cyclothymia fit his pattern of constant ups and downs. He wasn't just depressed. He would have severe depressive episodes and then he'd be up and down a lot in between. There's a temperament scale we gave him that kind of helped validate that. And so I gave him low dose lithium, starting at 300, gradually going to about 600.

And he had more efficacy with that for his depression, for his suicidality, which of course lithium helps, and all of his other symptoms, anxiety, et cetera, than he had with all those SRIs and antipsychotics and ketamine, et cetera. So it's kind of an interesting story of a ketamine failure who responds to low dose lithium, which I think gets at the issue that it's more about the diagnosis, getting that right, than giving out medications that you just think are more and more powerful.

[29:47] Adrian Preda: And the other point that I think it's worth considering here is that some of those treatments, in fact, if the diagnosis is not correct, could result in not improvement, but worsening of the symptoms. So I just wonder, know, what about stimulants, right? In somebody who is on this, you know, sort of, you know, in this cyclotomic bipolar spectrum, is that not only not helping, but potentially, you know, making things worse.

[30:13] S. Nassir Ghaemi: Yes, because we, know, another big picture, important clinical research concept that I've always worked on myself, important in my work is this view, this observation that antidepressants cause worsening of manic depressive illness over time. If you stay on antidepressants long-term, you have more and more mood episodes over time. In bipolar illness, this has been shown in a number of randomized trials. It may generalize to manic depressive illness. In other words, the people who have milder manic symptoms, but just have some of them or mixed dates and then the antidepressants actually worsen that. And there is some evidence in mixed dates that they can take a currently depressed patient who's mixed and make them more agitated, more mixed, more depressed, more suicidal. And I think that's behind some of the controversy around why sometimes we see some worsening suicide or suicidality with antidepressants. And amphetamines are antidepressants.

They were the original class of antidepressants in the 1930s. They have the same effects in my view. I think that patients like this don't get better partly because all the antidepressants and amphetamines keep the illness active and unstable. Even if you use some drugs that could help like antipsychotics, they don't because they're getting counteracted by the amphetamines and antidepressants. So just as important as diagnosing man-depressive illness, cyclothymia, giving low dose to lithium to this patient was getting him off all the antidepressants, all the amphetamines, getting off all of that so that the lithium had a chance to work.

[31:43] Adrian Preda: In your article, you very thoughtfully challenge some of the very important assumptions that inform our current diagnostic framework for mood disorders. With that, what do you see as the most critical research needed in this area to advance our understanding of mood disorders?

[32:03] S. Nassir Ghaemi: I think, I would say that at one level as a big picture point, I think we need to do clinical research. And I think, unfortunately, we've stopped doing that. I myself had probably about 20 years of NIMH grant funding for clinical research and bipolar illness. And 10 years ago or so, I stopped being able to get it. And that's because NIMH said it would no longer use DSM criteria for most of its research. It was really giving up on clinical research to begin with.

And it was focusing more on biological research definitions, the so-called research domain criteria. You know, and the leaders of NIMH, of DSM, of the NIMH concluded that DSM-5 and its predecessors weren't really productive for research. But the false conclusion, I think, was that clinical research in general is not helpful. The problems with DSM are DSM problems. They're not clinical problems. And I think that a lot of the NIMH leadership being biological researchers made the conclusion that we just shouldn't do clinical work.

I think clinical research should be the central focus of our field, not animal studies, not neuroimaging, and not genetics. We need to be looking at patient populations, at different diagnostic constructs, applying these criteria for research and taking it from there. So I think in general, we should shift our focus to something we're not doing enough of. But specifically, what we should do there, I think is clinical research that looks at mixed states, for instance, I think would be very important. There's not enough randomized studies. There's only two randomized studies of drugs in mixed states because it's been relatively ignored, and clinical research in mood temperaments. think those two categories, we don't have very low, no randomized studies in mood temperaments. It would be really good to have anywhere near the amount of knowledge we have with randomized studies for treatment and for other studies with the DSM categories with these non-DSM ones to help us understand them better. And then hopefully, you know, the DSM approach could shift more to validity than reliability, and we'd have a more accurate and therefore more effective diagnostic system for research and treatment.

[34:15] Adrian Preda: So these are clearly some very important ⁓ institutional and maybe regulatory challenges that we need to consider if we're going to be able to move forward with these very important questions. At the same time, we all know that we train our residents, our medical students on DSM. So there are also some educational challenges, right? Our psychiatrists are now almost exclusively trained using the DSM paradigm. They have little exposure to historical concepts or alternative diagnostic frameworks. There is an emphasis on checklists of symptoms rather than understanding illness patterns and course, which then in turn could result into maybe a superficial diagnosis, right? How can we maybe address, I'm curious about your take on addressing the educational challenges.

[35:09] S. Nassir Ghaemi: That's a very good point. I think that my big picture view would be that obviously people learn the DSM constructs and need to learn them because that's the current standard of care and the mainstream. think we should take the perspective that this should be a minimalist approach to psychiatric education, not a maximalist approach. In other words, that's not all you need to learn. That's not enough. You should say, okay, learn that. That's a minimal thing to learn. You can learn it very quickly and then go beyond that.

So you learn about MDD bipolar, now learn all this history about manic depressive illness, learn about mixed states, learn about mood temperaments. And the same would hold for OCD and schizophrenia and autism and other scenarios where there's just a long history and other ways of thinking about things. And then after you've learned more, you might go back to your DSM criteria and realize that there's these problems with this, that. that doesn't mean you ignore it, but you're just more aware of where the DSM constructs might useful and where they're not so useful. And you use it as a, maybe a baseline knowledge, but you build a lot on that. So I think both for psychiatric residents and also just as importantly, medical students, because these are going to be all the doctors and the other specialties. We should view DSM as just a minimal part of what they need to know. And we should really expand beyond that in terms of the research and the history of the field. Ask them to be willing to think differently, to not just look for a cookbook approach that just lets them do things without having to think about it much, even though makes them reduce their anxiety, but to actually make them think, to make them realize what we don't know as well as what we do know. And then that's the way the field progresses too, because then they can contribute to helping us learn more often in the research or whatever, so that we decrease the sphere of our lack of knowledge and increase our sphere of knowledge.

[37:08] Adrian Preda: Final question. So you are using this alternative maybe diagnostic formulations in your clinical practice. I'm curious, how do patients typically respond to these alternative formulations? Do they find it helpful to understand their symptoms within a broader framework of mood disorders?

[37:26] S. Nassir Ghaemi: Generally they do. It's very common for patients to have already been diagnosed, for instance, with MDD, have maybe not responded to a couple antidepressants. So when you give them an alternative way of thinking about things, they're very grateful for it. And I also always put it in a pragmatic way. say, I'm not saying that this is right and that is wrong, but I'm saying that hasn't worked for you. Let's try this different approach. And if it works, then maybe it's right. And if it doesn't work, okay, maybe it's wrong. But patients do like to have different ways of thinking about things. There is the difficulty sometimes with some diagnoses, attention deficit disorder, ADD being the main one, where in the culture, it's very popular and the patients come in wanting that diagnosis. And then when you're talking to them, for instance, about mood temperaments that might be causing it in this alternate perspective, they're not exposed to that anywhere on TikTok and YouTube or anywhere else. And it's hard for them to understand what you're saying and to really come around and they're thinking to it. so sometimes, you know, I just have repeated meetings and appointments to try to talk things through with people. And sometimes people quite get open to it or are open to it, but sometimes they're just not. And they just want it. They want the mainstream perspective on that. They may want to stimulate whatever. And then we don't really have an agreement and it doesn't work out as well. So it is a little difficult when you're trying to take an alternative approach when there's a lot of cultural, not pressure, but cultural influence for people to not want that. But sometimes it is actually quite helpful because people have already tried the standard approach and they need something different.

[39:08] Adrian Preda: That's such a great answer. but actually, because there is so much that we talked about today and we covered, including this very thoughtful perspective on how patients actually engage, considering this alternative perspective. So I'm going to actually ask you one more question. With everything that we've been talking about, what would be one actionable insight or recommendation that you would like our listeners to take away from today's discussion?

[39:35] S. Nassir Ghaemi: But one kind of, think, important and straightforward insight is that most mood episodes are mixed states. Don't try to divide everyone into pure depression and pure mania. Look at those patients with depression who have a lot of psychomotor excitation, agitation, and anger as mixed, as not purely depressed. And antidepressants are not helpful for that group, probably. And then think of them as this mixed manic-depressive group, and then think about mood stabilizers, maybe dopamine blockers too, as more central to their treatment. that means getting the antidepressants out of the picture completely because they destabilize things and using those other classes. That approach just to the current mood episode would shift how we treat a lot of patients, I think.

[40:20] Adrian Preda: Thank you for the opportunity to discuss these very important issues. I hope our conversation will contribute to ongoing dialogue about how we conceptualize and treat mood disorders.

[40:33] S. Nassir Ghaemi: Thank you, Adrian. I appreciate the chance to talk to you.

[40:38] Adrian Preda: Great. And to our listeners, thank you for joining us for this episode of the Psychiatric News Special Report podcast. If you found this discussion valuable, please subscribe to our podcast, rate and review us on your podcast platform and share this episode with your colleagues on social media. For more in-depth coverage of this topic, be sure to read Dr. Demis' full special report in Psychiatric News. Until next time, this is Dr. Adrian Preda signing off.