Psychotic Depression with Dr. Cummings

[Music] All right, welcome to the podcast. I am joined today with Dr. Michael Cummings. We'll be doing a deep dive on psychotic depression. I want to give a shout out to Kara Jacobson and James Swanson, awesome students who helped me with the write-up that is on psychiatripodcast.com. You know, for every single episode we do a detailed write-up with citations, giving you more information than the actual episode contains. And I wanted to introduce this topic. We kind of jump around a little bit throughout the episode and I wanted to give you kind of a big picture kind of where we're going. Okay, and the first thing we talk about is the history of psychotic depression. We talk about the differential and throughout the episode we're talking about the differential different types of issues that could look like depression with psychosis but may actually have an alternative diagnosis and alternative treatment. For example, in California, you know, how do you differentiate catatonic depression which could have a psychotic, which could have some psychotic symptoms as well from just a psychotic depression. How do you differentiate borderline personality disorder which may have more dissociative psychotic events from psychotic depression? If they're bipolar with psychosis, they could have more mood, incongruent psychotic features, meaning that they look depressed, but some of their psychotic thoughts are very grandiose or very like on a mission with a special purpose so that that could give a hint at more of a bipolar type of illness even if they don't have a history of mania. You know, they may just not have had that first manic episode. We're going to talk about with psychotic depression. Sometimes it's hard to differentiate delirium. In a delirium episode, you can have psychosis. You can be in a hypoactive delirium, you can look depressed, look down. And so we have to look at the history, the fluctuating course, you know, you have to look at the ability to focus concentrate, draw a clock, which someone with delirium will have a hard time doing. As well with psychotic depression, they may have a substance-induced psychosis. We'll be talking about methamphetamines, how they can look psychotic depressed as well. Subsequently, we're going to throughout the episode talking about things like BDNF, the HPA access, how that relates. And we're going to get into the treatment. And just to kind of cue you in, you know, normal treatment might start with an antitripercent and an antipsychotic if they have unipolar psychotic depression. Right. In the outpatient setting, we're going to see maybe if that improves things. You know, if they're so sick to require hospitalization and they're not responding to an SSRI and a second generation antipsychotic, they may need electroconvulsive therapy. You know, determining on different factors in my sort of history of treating these patients, we may consider partial first or partial after ECT. And so, you know, partial hospitalization five days a week, seven hours a day of group therapy. In my mind is considered an option. Many of you will remember my episode 180 with Michael Garrett, where we do a deep dive on psychotherapy for psychosis. Interestingly, we did not get to talk too much about psychotherapy, but there was one study that I came through and preparing the article for this episode in which this one author looked at acceptance, commitment therapy for psychotic depression. And they found that 44% of psychotic depression patients in the ACT group showed clinically significant improvement by discharge greater than two standard deviations changed in the brief psychiatric rating scale compared to 0% in the enhanced treatment as usual group. So, in the enhanced treatment as usual group, 0% of them showed two standard deviations or more change in the brief psychiatric rating scale, whereas in the acceptance, commitment therapy group, about 44% did that's pretty substantial. And so, hopefully there's more research on psychotherapy for psychotic depression in the future. And we will also talk about, of course, there's always a role for exercise and diet, but as the severity increases the likelihood of compliance to these things diminishes. But, you know, psychotherapy, very pertinent for psychotic depression, especially to build that therapeutic alliance so that they get the treatment necessary to get out of this awful state of being. Okay, I'm looking forward to you getting any feedback on the episode. You can always send me a direct message on Instagram. I really appreciate those or on Twitter. You can tweet something about the episode, tag me if you do. And I will appreciate reading that. Let's start the episode. All right, welcome back to the podcast. Michael Cummings, the beloved Dr. Michael Cummings. He is going to break down with me psychotic depression. This is a largely unrecognized and often untreated part of depression. It is under reported often by patients due to fear of potential consequences, reporting symptoms, you know, will they be hospitalized, will they be embarrassment? And so, they will not necessarily report the psychotic symptoms of their that are going on in their depression. It also has a higher suicide rate, about twice that of just normal depression. And these are people that will have different treatment recommendations. And there's actually about six to 25% of people with major depressive disorder that have psychotic illness. So today we're going to be doing a deep dive on it. We're going to be talking about different treatments for it. And so Dr. Cummings, welcome to the podcast. Thank you. Very happy to be back. And as you indeed, as you point out, the estimates of frequency of psychotic depression in the broader context of major depressive disorder is that it lies somewhere between six and 25%. The reason that range is such a broad estimate is most investigators in the field are aware that people under report. And frankly, we don't know where the true number lies in that range or maybe even above it. Yeah. Let's talk about let's talk about the history of it. I always like to hear you're here. You're take on the history of it. And okay. Well, one of the yeah, indeed one of the problems with research in this area has been that the field's definition of psychotic depression has changed over time. If you go back prior to DSM3, psychotic depression was a term used to describe people whose illness included melancholia withdrawal and deterioration of function to the point that they weren't able to carry out the activities of daily living. These were the people who essentially curled up, cooked a bed, and if they weren't actively treated, were at risk of dotting due to not eating and not drinking, they didn't necessarily have first-ranked psychotic symptoms. It was more a statement about the severity of their depression that changed with DSM3, which recognized that yes, there is a possibility for all such things as hallucinations and delusions as part of major depressive disorder coming forward to the present that has been refined to the point that now there's an awareness that in the DSM that psychosis does not reflect the severity of the major depressive disorder in that psychotic symptoms can occur and mild moderate or severe depression. While it does alter the treatment and the prognosis and the suicide risk, currently our understanding suggests that the psychosis is a separate trait that the person may be vulnerable to and additions to their vulnerability to becoming the most. Yeah, I think that's especially important as you look at the age that the research was done, because if you're looking at the DSM2 age of the research, it's more severity, the worst end of the spectrum. You might be also seeing some catatonic patients thrown in there. DSM3, it's really a That's when the requirement for hallucinations, delusions, depressive, stupor was there. And then DSM-4, you have this, it's a severe subtype with delusions, hallucinations, and then with DSM-5, the severity of the depression itself is not as important. And I almost wonder with that, if the DSM-5 potentially captures more of like, the borderline personality disorder with this sort of quasi-psychotic symptoms that sometimes go on with it. Yes, one of the things that has occurred over time is a recognition that psychotic symptoms per se can occur in a wide range of disorders. In addition to the primary psychotic disorders, like schizophrenia, people's porcelain bipolar can be psychotic, even with anxiety disorders or associated occasionally with psychotic symptoms. For example, PTSD with psychosis has been reported and described. And some geneticists think that indeed there may be a heritable vulnerability to psychosis that is somewhat independent of whatever else the person may be vulnerable to in terms of mental illness. And some extent that's supported by the fact that in broad populations are raised mostly, again, in Scandinavia because they have birth to their medical care and registries. About half of the healthy population, if you ask them, have you had any of the following symptoms ever? About half of people say, yes, that they have it, and they're hallucinating visually or outwardly, or they've had a troubling, persicutory thought they couldn't get out of their mind for a few days. And these are people who do not have a mental illness per se, because they ultimately don't, you know, their life is impacted by the psychotic symptom and usually they're transient. I'm sober. I think we're moving towards seeing psychosis as a dimension or a subcomponent in those that may be there in a variety of illnesses, but certainly true in major depressive disorder. And indeed, DSM5 permits diagnosis of psychosis in the context of things like dysphimic disorder or what was termed in the research diagnostic criteria, Lyra depressive disorder. So again, show a dissociation between severity and the presence or absence of psychosis. Yeah, I think that in my own mind, I've always, and maybe this needs to be shifted, but I've always seen depression with psychosis as like the depression gets worse and worse and worse, and then they have the psychotic symptoms come as a severity increases. And I differentiate that in my mind versus someone with borderline personality disorder who can sometimes have these sort of quasi-psychotic episodes, dissociative episodes. And in my mind, those are like the two big categories I see in patient, right? It's like depression with psychotic features, one category, borderline personality disorder with some psychotic features or, yeah. And I'm wondering how you, if you see it like that, if you see it a little bit differently. My view is shifted over time. I'm coming around to the idea that indeed, psychotic symptoms, per se, can occur in a broader range of both severities and in a broader range of illnesses, then we've tended to think of them. It certainly is true. I think we more severe the illness, the more likely it becomes that person will have persisting psychotic symptoms. But I've had a rock cross a few patients over time who confided after they got to know me that, yes, they have had a persistent auditory hallucination or visual hallucination. And these were people who were not that sick. They were not in need of hospitalization. They were functioning. They were going about their business. And to some extent, they had adapted to the presence of the psychotic symptom. So I'm less rigid about the severity, psychosis, relationship, than they used to be. Let's talk a little bit about what the types of psychotic symptoms are. If we're trying to differentiate, for example, someone with PTSD, the psychotic symptoms may be more in line with the trauma, right? Yes. They're often in the case of PTSD and maybe a spill over the dissociation that can occur with a flashback, for example, or the avoidance of certain situations. They get very difficult to distinguish at times from, is this person just having a brief dissociation? If there's a residual suspiciousness or unreasonable attitude about a circumstance or situation, how much is that sort of stretch in the boundary of not being reality-based? Because at his heart, psychosis just means that the person is not accurately engaging in reality testing. They're responding to something as if it were true, when objectively it is not. And that can range, of course, everything from an overvalued idea to an overt delusion or in the case of perceptual disturbance. It can be anything from a tendency to misperceive something all the way to fully evolve, multi-mold, elusive metory experiences, which I've seen in some flashbacks in PTSD patients who, indeed, during the flashback, they were exhibiting multimodal sensory misinterpretation of their environment and, indeed, in talking about it afterward. No, they said, "No, I was back." Where the trauma occurred. And the people had changed to different people. The surroundings had changed to a different place. So it was substantial, substantial, archer from reality. It sounds like a dream, a nightmare, because I know in PTSD nightmares, we're not a direct copy of the actual trauma over and over again. Nightmares will be slight variations of the trauma. One of the signs of malingering is that it's always an exact copy of the trauma, according to my malingering textbook. Yes. Correct. If I'm wrong. Now, that is accurate. Malinger is one of so-l-story. And we'll say that it's always the same, or is people who actually experience on flashbacks or psychotic symptoms, they more showed return, depending on what's happening. The dreams of PTSD also change over time and circumstances. And indeed, in major depression, for a long time, the field has considered mood, congruent and mood and congruent, psychotic signs and symptoms, as you might guess, or as you know, mood congruent, something means the hallucinated experience or the delusional belief is consistent with the signs and symptoms of depression, things like excessive guilt, negative rumination that goes beyond the boundaries of reality, holding beliefs about being guilty for things that the person can't be responsible for. And then the person may have mood and congruent, psychotic symptoms, as well. I think one of the other things that tap into the field is NDSM5. There's a recognition that the person may have major depressive disorder with mixed features, meaning they have some features that would be more consistent with mood elevation, but they don't meet the criteria for being hyper-manic or manic. I think that reflects that we're also learning that there's not as stroke-a-break between major depressive disorder and perhaps bipolar spectrum illness as we once thought there was. There's some crossover, which go on all the way back to the basics to genetics, when people look at the vulnerability genes for major depression and the vulnerability genes for bipolar mood disorder, unlawful. The fair number of the low side that have been identified overlap. In some ways, it would be kind of silly to think that these the tunicypic illness is going to be entirely separated from each other. Right. Let's go a little bit deeper into the mood, congruent, psychotic features, first mood, and congruent. I think actually talking about what they might be might be helpful. The mood, congruent, with depression, might be personal and adequacy, guilt. I have some disease close to death or I'm dead. There may be some nihilistic piece. My organs are turning to dust. So I don't know. I was I deserve punishment. Yeah, I know for example, I had one individual interview recently. He's 23 I and he believes he was responsible for World War II, which of course in the US is entering into World War II was 82 years ago, so he can not be responsible for that. But he believes he is Right, so it's like I created this awful thing, right? Yes. I So it's so that's mood congruent mood incongruent maybe Maybe areas where they are it's almost like they're defending against the depression itself like the depression gets so severe and so horrible that these psychotic symptoms keep them from experiencing the full extent of the nihilistic hell that they start to see the world through. Yes, so they may think like you know, I have a I'm on a special mission or I'm you know, I'm a king or I'm a queen of England You know like you're like start like go ahead. You tell me what some common art that you've got. Yes, talk Well We have several people who believe that they are some form of deity We have some people also who indeed as you alluded to believe that they're either incredibly wealthy and own everything or And they're in some ways all powerful even though they'll turn right around and tell you that Because of their depression. They can't literally can't get out of bed so Things that are incongruent with Indeed a depressed myelistic outlook now when would you say that just a deflated narcissist who's now depressed for someone who's like having a psychotic symptom that Seems grandiose or some of these hypomatic defenses are in that you know I again when it when it reaches the point where it has clearly moved beyond Reality testing that is the person is claiming things the evidence Is ample to would disproved anybody who was Not able to test reality Uh, in fact, I've had Very depressed patients told me that they literally were multi-billionaires And in virtually the same breath acknowledged that they Didn't have any money So what is that is that um Insight into that they're not a billionaire or is that so no no no no no the alternative right around us I know but I really am a billionaire. I just don't happen to have any money right now Okay money somewhere else or someone or someone else's control or it's being inappropriately taken from them um Some projective defenses there in terms of somebody else has made all of this happen hmm Okay, yeah, I would say with the deflated narcissist you're getting also the story Of someone who is narcissistic maybe they inflated Prior to the event prior to the depression and then they go into the depression when they're not matching up to this sort of idealize self that they had created and then um That is psychosis whereas psychosis is like yeah like you're saying They have very little insight into the reality in a psychotic event Yeah Now one of the one of the things that To research has established about mood and congruent delusions in particular is that That often a tip off that you may not be looking at major depressive disorder you may be looking at somebody who's bipolar About I saw in between a third and a half of the people who Have mood and congruent delusions at some point later Go on to have hypomanic or manic episode um Then indeed uh one of the things To watch out for is people who start having depressive opposites early in life recurrent episodes And who may have mood and incongruent features in their depression You may be looking at a budding By older patient who just hasn't had their first type of manic or manic episode yet That's good. Okay, so if so that's a good clinical pearl if you see someone with mood and congruent So they're they're depressed The depression has been maybe progressive but now they're having mood and congruent psychotic symptoms Like I'm just your suspicion for bipolar even if they haven't had a manic episode Goes up Yeah, you put it on your index of suspicion that this may be And I'm discovered by polar patient the other clue in that chronologically is if you put them on that that depressant And they initially appear to get better In terms of depressed mood Energy and adonia But then it goes a little too far and they start to become irritable On the low overactive maybe a little type of sexual um You may be the after depression maybe moving them toward their first hyponomic or manic episode Yeah, what like when you say hypersexual what kind of symptoms would you be seen or what kind of behaviors would be sent you be seen and They somebody who is normally not that social begins Over at leaf flirting with a lot of people um somebody who maybe has had a steady girlfriend or boyfriend suddenly starts being interested in going out with multiple people um And other you know with related areas of impulsivity Uh people have normally been fairly thrifty starts sending in money impulsively that kind of In other words, they're not yet overtly manic or hypomanic but they're doing things that are atypical for that individual Okay, and what When you're just so I'm thinking we're continuing to try to assess The diagnostic categories when would you be more suspecting that this is borderline personality disorder? Uh when the mood is rather than being um insistently depressed Uh the person's mood is very laybile and very responsive to social interaction You know one of one of the characteristics in major depressive disorder Is as the person's depression worsens they become Essentially less and less mood reactive um You know they at the severeest end of Major depressive disorder in the person is largely unresponsive to any Events in terms of feeling better or having any hedonic capability With the borderline individual their mood depends on what happened in the last few minutes Uh These are the people who may be um horribly depressed and elated And that may happen several times between breakfast and lunch Depending on who they've interacted with and how things will Uh I tend to think of Borderline personality disorder indeed as a mood disorder but does one characterized by uh mood liability and mood intensity rather than um A consistent elevation or consistent depression of mood Yes, so with borderline first-size-rassah look at like social veneer right so when they're around certain types of people They can really kind of glue it back together most of the time Yes um Social veneer but they'll have these quasi-psychotic episodes that are Kind of dissociative and quality what can you can you give any sort of like um Details on what kind of psychotic episodes they might have Usually uh usually they are time limited and usually they are focused on a misinterpretation Uh an interaction with the mother specific person That they may become paranoid about You know a particular person transily Oh that person's plotting to get me they're out to harm me And but when you talk with them about it at the core of it There usually is that some real conflict but they've distorted it on beyond all recognition Uh that may become jumbled up with dissociative elements as well so that um I had one borderline patient who When she was really distressed and would have a Psychotic breaks you believed that her co-workers were being controlled by her Mother who had been dead for years And that would last until she calmed down and then she would go out, it's not true. That's silly. - Hmm, okay. You can see where this is complex because it's like you have to have the big picture with borderline personality disorder. - Mm-hmm. - I would also say in my experience of treating these patients inpatient depression with psychosis, it takes longer to treat. They don't have a flight to health on day two and three of their hospitalization. - No, no. The person with major depressive disorder, and does not suddenly look well. It often takes a little weeks or month to appear well. And that's one of the differences in psychotic depression. They don't, from ecologically, they don't typically respond to antidepressant treatment or lung. I think the response rate for antidepressants and the psychotically depressed is down in the 20 to 30% range, very low. If you had an antidecotic to that, you'll get response rates. They're more typical of what you see without a depressants and general, you'll get a response rate up around two thirds. - Yeah, so you're saying just an antidepressant does not treat some depression with psychosis very well. - Typically, no. The treatments basically fall into two camps. You have an antidepressant with an antisacotic or in the most severe cases you have ECT. There has been some work done with looking at transgranate magnetic stimulation, like nerve stimulation. Frankly, for these patients, those treatments have been less than impressive at this point. - What do you think about, okay, so there was a recent, larger study by ECT strand at all because from the department in Sweden and at Lund University. And this was a study of 186 in patients who did not have a primary psychotic disorder meaning they didn't have primarily schizophrenia, but they did have depression. So I think they could have depression with psychosis, okay? And they received either ketamine or ECT. And they found that with ECT, 63% wanted to remission with ketamine 46% went into remission. - Yes. - When looking specifically at the group that had psychotic depression with ECT 79% went into remission with ketamine 50%. - Yes. - The p-value was 0.15. So in the paper, they said this was clinically insignificant. I read it as no, I think it's just a small sample size, but I would definitely, the effect size was significant enough for me to put ECT above ketamine at. ECT for this group had 2.3 effect size, whereas ketamine was 1.4. - Yes. I think how they indeed had a larger sample, they would have achieved statistical significance rather than most people would interpret that as a statistical print or the superiority of ECT, but my own experience has been led for psychotic depression, particularly if it is also a severe depression, ECT is far and away the most effective treatment we have. - There was another study that looked at ketamine versus ECT that looked at outpatients, and they specifically excluded patients with depression with psychosis. And this was a study, anand at all, 2023, you know this, you're familiar with this one. - Yeah. - So I don't think this ketamine is as helpful for this topic that we currently have. - Well, one of the advantage of ketamine and escatamine is both are very rapidly effective in treating depression and in reversing suicidal, suicidality. Cetamine and escatamine that were both dissociative anesthetics basically, and to an extent, they are psychotomatic, that is they induce psychotic symptoms at return. One of the limitations with ketamine has been that, the initial antidepressant response tends to wear off over several days to about a week. But if you keep giving people ketamine repeatedly, the link or the duration of the benefit gets shorter and shorter, and the degree of dissociative and psychotic symptoms gets bigger and bigger, which I think has been a limitation for the use of ketamine as an ongoing treatment. I think for many people, it may be, perhaps not for those with active psychosis, but for many people, it may be an excellent way to sort of get things started in terms of treating their depression, but it has both ketamine and escatamine have limitations in terms of ongoing treatment. - I think one of the thoughts that I had in reading the study was the amount of ketamine that they gave was like 0.5, which I've heard in clinical practice, they go all the way up to like 1.2, which is a very strong dissociative experience at that dose. It's a full dissociation usually. - Oh, I know what I was gonna say about that first study, though. They, the older adults had a higher remission rate with ECT than they compared to the younger group. And I wonder if it's because the older patients who are depressed, it's kind of like that depression was like, it was tends to flare more in the older group in what I would see in the hospital. I don't know if you have any thoughts on that. - And thirdly, it's true. I think the response to major depressive disorder does change over time. Older people, at least in my experience, tend to have more resistant illness. And some of the research I've read suggests than in some cases, at least in some samples that these people may have had numerous subclinical episodes of depression or dysphoria before they finally blossomed into a fully evolved major depressive episode. I don't know over age with the longer duration of perhaps subclinical depression, incurring some degree of trimor resistance in them. Now, our understanding of trimor resistance and depression has focused largely on the hyperphonic butuitary axis. Those people who have a chronically elevated cortisol tend to be those who are resistant to antidepressant medications. As illustrated by the fact that if you give them, if you press them, that 200 milligrams a day for five or six days, you can get a fairly high remission rate in people with depression who have been refractory to multiple antidepressants and to ECT. Unfortunately, you can't continue to give people with your prison, you'll put them into out of some being prices. But it does suggest that if you block their cortisol, they suddenly regain their responsiveness to you. And antidepressant medications, again, pointing to an abnormal HBA axis as tending to be perhaps the source of at least one source of trimor resistance and major depressive disorder. - Yeah, I'm curious if, like, kind of getting into the mechanism a little bit of psychotic depression. Do you see, okay, so we talked about HBA axis. Is there any other things that kind of come to your mind as potential mechanisms of depression with psychosis? - Yeah, if you look at, if you serve with a very basic, then in terms of frontal temporal metabolism and people with major depressive disorder, there's about 20 to 40% decline in glucose uptake and utilization in the frontal temporal areas. There is a loss of dendritic arborization. They're, yeah, they're, well, the dendritic trees on their neurons do look like a bush and wintertime rather than spring. I'm going to toss these patterns and the connections and of course, it's easy to imagine that loss of inter-rural connections, if it becomes severe enough, can lead, certainly to outright dysfunction and errors in both processing of, sensory information and errors in terms of reality testing. So it's very likely that those sort of like trophic changes may underwire some of the psychosis that's observed. I recently saw like this clip on YouTube of someone saying, "We have no idea why depression happens. There's no biomarkers in the brain. And are you telling me Dr. Cummings that there are actually brain changes with depression? Like are you telling me that on autopsy people who died of severe depression had actual brain changes?" Yes. Yes. They exhibited thinner cortex, loss of dendritic arborization, decreased metabolic rates. And to go back to our understanding of major depression in the 1950s, we sympathistically thought that, "Oh, people are depressed because they have a deficit in monomines, serotonin, morpaneiferin dopamine." I think our view of this has evolved to say, "No, they have a primary problem with their structural control over limbic structures." And the abnormalities we're seeing in their their modulatory and all molecules is more in effect than it caused. You know, the modulatory areas are working hard to try to get the thing to work, and it gets further and further from homeostasis. But no, there are real changes in the brain during major depression. And unfortunately, when the person remits for major depression, especially the first episode, those largely recovered. Now if somebody's had recurring episodes of major depression, it gets harder for the brain to get all the way back to baseline, which is why, you know, now we recommend that if somebody's had recurring episodes of depression, maybe they should stand right now to be a person, rather than being tapered off. They used to be that every time somebody would recover from a major depressive episode, they'd get tapered off their attitant presumpt, and that certainly still makes sense for somebody who's had a single episode. There's some of these up to their third episode of major depression. They may need ongoing treatment. Yeah. Or, and usually multiple types of treatment, exercise, diet, therapy. Exercise by cognitive behavioral therapy, other therapies. In fact, that's one of the areas for cognitive behavioral therapy, has an advantage in that, you know, when you stop taking medication, five half-wise, and it's gone. People who learn cognitive behavioral therapy can continue to practice it on their own after they've stopped having sessions. So that's how it's going to get them added. Yeah, I think, um, okay, so in summary, yes, the brain does change with depression. We actually did a really nice dive on this episode. 155 is depression, a chemical imbalance. We talk about all of the things that we know about depression. Being much more, it's much more nuanced than the chemical imbalance theory. There are changes in the brain itself, and we know also people who have brain issues like frontal, temporal, degeneration, depression is much higher. People with different types of diseases like honeytons, Parkinson's, have much higher rates of depression, strokes, and higher rates of depression. And so there's this sort of crossover there. And, um, yeah, anything else you want to say on this before we move back to psychotic? Yeah, just that the, you know, the, the tranto-temporal area of the brain, we tend to think of the limbic system in terms of mood, but, you know, it's highly involved in everything from memory to essentially energy, balance, and manipulation for the human being as a whole, which is why so many things go wrong when somebody becomes depressed. The depression is much broader than simply having a sad mood. In fact, one of my distinctions between sadness and depression is, you know, if you're feeling sad about something, the sadness will typically motivate you to do something about it, change something. People who become depressed become paralyzed by their depression. That's where they often ask people if they have feelings of helplessness and hopelessness. That's how that's a relevant clinical question. Okay, coming back to, um, the psychotic depression question, are, are there unique brain changes, findings with psychotic depression that are not in other types of depression? There's no one's to be in psychotic depression, and there's, there are a limited number of a lot of pet studies that have tried to look at this, and there appears to be a greater disturbance or decrease in the metabolism for the, particularly the dominant temporal lobe, um, in psychotic depression. And in some ways, that makes sense. Now, in primary psychotic illnesses, we think that in particular, the non-dominant temporal lobe is often the source or positive psychotic symptoms, such as delugeal thoughts or hallucinations. And it would make sense that another illness that affects the same area could also produce those sorts of symptoms. Yeah, you sent me a nice article on BDNF, and I'm wondering if you could talk a little bit about BDNF and depression. Yes. One of the all-merics and major depressive disorder is that there is a huge fall off and brain drive neurotrophic factor. Nero-rides are such highly specialized cells that, frankly, they don't do a very good job of even caring for their own metabolism. They depend largely on greeal cells to, um, and do everything except transmit information. And, um, in major depressive disorder, there is a dysfunction of those support networks, so that things like brain drive neurotrophic factor, gleeal cell, derived neurotrophic factor, and into thealial drive neurotrophic factor all declines deeply during a major depressive episode. And indeed, one of the things that you see in response to that is the decrease in metabolic rate and the loss of dendritic arborization that we were referring to. When the person responds to an antidepressant treatment, whether that's ECT or an antidepressant medication or cognitive behavioral therapy, you see it correspondingly rise in neurotrophic factors and a, uh, essentially a sprouting of new dendritic spines and a reconnection, man, and uptick, and metabolic rate. And so it literally is a case of having depressed metabolism as well as a depressed mood. Yeah. We also know exercise increases BDNF. Yes. Specifically vigorous exercise. Yeah. Yes. Specifically aerobic exercise, things to get your heart rate up, making it more rapidly. Yeah. Yeah. So the BDNF is kind of like one of these things that we know is decreased in post-mortem brains of depressed patients. And it's one of those things that changes with treatment, whether it's medications therapy exercise. Yeah. Although I think it is now in addition to the post-mortem studies, they're also able to use a lot of magnetic resonance spectroscopy. You can actually see the changes in people who are living. So it's a lot of post-mortem or artifact of some sort. What do you think about, um, you talked briefly about TMS, I'm actually about to do a big TMS episode. What do you think of like the St. Protocol for this type of patient, for the psychotic depressed patient? St. Protocol in general. You know what I'm talking about coming out of Stanford. Yeah. Intensive. I think, yeah, I think the St. Protocol is a reasonable amount. I don't think we're using TMS as widely, perhaps as we true it as an augmenting strategy for either an antidepressants. Or in some cases, as a stand-alone treatment, most of the data I've seen regarding specifically psychotic depression doesn't suggest that TMS is going to be a highly effective modality for people who are psychotically depressed. It may still be a very useful adjunct, I haven't seen any data to make up my mind about. Okay, so we've talked about mechanism, anything else you want to tie into the mechanism? Just basically the more we can do to want somebody has remitted from depression, there are often a number of lifestyle changes they need to make to help safeguard themselves against future depression because unfortunately one of the truths about major depressors disorders that every child's ability has an episode, psychotic or not, it makes the next one more probable. Yeah. Okay, we talked about differential, one differential I think that's important to put out there is a delirium because you can have a console for depression in the hospital like, oh, this person's really depressed, they're not talking, they have all these awful things that they believe about themselves and there can be an aspect of psychosis like, oh, they're saying, they did these horrible things in the past, some of which are like, you know, completely unreasonable maybe. And then you go see the patient and they have this waxing and waning ability to focus and concentrate one minute to pulling out the lines, maybe the next minute they just look really stuporous. This is a patient with a medical issue as well, maybe they have a urinary tract infection, maybe they have a respiratory tract infection, so they're in the hospital for something else sometimes like post-hyp fracture repair. So yeah, tell me about delirium and how it could look like psychotic depression. Okay, well, one of the trusums about major depressive disorder is it typically has a long pro-droneal period and is very rarely abrupt and on set, whereas delirium represents essentially a loss of the brain's normal physiologic stage. It's been insulted by a major insult either inflammatory or metabolic and brain chulsion abruptly deteriorates, with as you point out a fluctuating level of arousal. The person may be alert and lose it at one moment and the next they're confused and disoriented and not making much tense and then they'll come back and it's something that we need to keep on very high on index of suspicion, particularly in hospital settings, but they've done surveys specifically looking for delirium and hospitals. They find that the rate and impatience is right around 40 percent because people, indeed, had out of, they've come in for an infection, they've come in for a procedure and they get missed as being delirious because the vast majority of people with delirium are just quietly delirious for a day or two and then they get better. There are people who don't get better because their delirium is being driven by an ongoing disturbance or their brain was fragile to begin with, particularly if they're older and maybe at the beginnings of a neurocognitive disorder, it's very easy for those people to become delirious. So it's something we should always be thinking about and it's one of the arguments for always in everybody doing a careful mental status, exhaling them and if possible observe person over time. So I would say there's a saying, if you're consulted on a patient in the hospital, delirium until proven otherwise, have them draw a clock. The clocks will not be normal in someone with delirium. Someone with delirium will never draw a nice clock with the right time. No, if they do that, you're, and if they can do it more than once, then they're not a delirious person. I always, when I would cover for C&L, I would have the residents and medical students always bring me a clock for every patient. I just love to look at them. And sometimes they would, they'd be like, I don't know why this person's clock is so awful. They just have depression. I'm like, let's go talk to them. This is delirium. Yes. This is delirium. Okay, so because think about it, like, would you ever do ECT on someone with delirium? Probably not, right? Probably not because the treatment for delirium is to correct whatever the underlying cause of the delirium is. Unfortunately, the potential causes for delirium are our legion, certainly in acute care hospital, the vast majority, probably the most common is post-certical delirium, which in most cases is a response to the anesthesia. Those are, those people get missed because they get better for all the equipment. But if you actually examine the right after, they come out of recovery. They're often having things like hallucination, and data I talked with one patient who he sounded super fishfully okay until he started doing mental status exam and you couldn't quite spell world either forward or back where he couldn't really count backwards. And while we were talking, he keep looking out the window and asking, well, what are you looking at? Because as far as I was aware, there wasn't anything outside this special. And he said, we know there's a large taradactyl that keeps circling the golden. Okay, here's a, here's a recent one for me. This was a family case, it's not a patient case. You know, so person, 60 years old gets admitted to the hospital. They've had a chronic fully, so they're having some issue with urination, so they have this thing stuck in there for a long time. And they've been acting depressed and psychotic in the hospital, right? So I hear that. And I immediately think, UTI, delirium, check for, you know, and so I tell my friend this, who told me this, and lo and behold, yes, the person does have a UTI. And you know, so I'm like, okay, get that, get that catheter out, right? The catheter is a nitrous of infection. Until you get that catheter out, they're going to stay infected, treat them from the UTI. And the next thing I'm hearing is that the psychiatrist on wants to do ECT. And I'm like, was this person depressed? Was this person depressed before they went into the hospital like a month ago where they had depressed like two weeks before the hospital? Am I missing something here? Is the person catatonic? And I'm just not seeing the full picture, of course, you know, like I can't see this isn't my patient. You know, but let's clear the UTI, let's clear the infection. And let's see if that resolves it. Yeah. As in jumping to ECT, that's, that would be my sense. Yeah, certainly an elderly person in the hospital who becomes delirious, always check the lungs and a bladder. Those are the two most likely sources of the limit detection giving rise to delirium. I think I usually just go from the head all the way down to the feet is the way that I think about it. So in every single organ system, so head, are they having a stroke? Are they having, you know, a really bad sinus infection, something in the face, chest, are they having lung infection, you know, pulmonary embolism, like anything that would cause a big disruption in the chest, usually it's the infection. You know, stomach, are there for some reason? Diverticulitis maybe or some sort of bladder infection, you know, now and then go all the way down to the legs. You know, if they have some like large, you know, let's say they have diabetes and they have some infected toe that's unresolved or necrotic appendage. So yeah, I, with the residents, I would usually just go down the body just a quick way of kind of seeing what's there. And you will be called on these patients if you're a psychiatrist and the team will have missed the medical issue because all they see is this person looks psychotic. Yeah, call, call psychiatry. Yeah, they look psychotic, they're confused, they're often behaviorally disturbed because they're responding to a reality different from everyone else's. And yeah, they think they, oh, it's a mental disorder, mental, it's a delirium. And until we're going to otherwise. Yeah. Okay, so differential, we have, we talked to about borderline personality disorder, we talked about delirium, we talked a little bit about bipolar, if they, especially if they have a typical features, I don't know if there's any, I think, I think the Did the, you know, hearing the family history, is there a family history bipolar? Can you get collateral? Because often if patients are very psychotic, you will not be able to understand the course of the illness until you talk to the family members. What happened first, what happened second, what happened third? - Yes. - Anything you would add to that? - Just that indeed, you know, psychiatric diagnosis depend more than, oh, no, more than anything else on longitudinal history, how is the illness behaved? The other differential I would throw in here for somebody you're just seeing who appears depressed and psychotic is, are they, do they have a substance use disorder? These days I see a lot of people in forensic settings who initially presented as depressed and psychotic, 'cause they've been using massive amounts of methamphetamine, which did a nice job producing a dopamine depletion state, which looks, looks psychotic depression. - You know, okay, so how these patients usually look impatient to me, is there sleeping most of the day or they're angry at the staff? And they'll go from being very angry to like sleeping. And then when you interview them, it's the only patient that I'm like, I tell the medical students and residents, they continue to escalate in their anger. If they've been crashing off meth, so short interviews, please, if they're getting more angry, do not continue to try to talk to them. (laughs) - No, give them a break and come back later and gather your interview and pieces. - Yeah. Any other, like, what is the psychotic symptoms unique to meth that you might be seeing that different? - Oh, chance to induce most often a respiratory delusional system. They may or may not hallucinate, but they are rarely often quite paranoid initially. You know, one of the effects of increased dopamine in the brain is to make the person hyper-vigilant and typically if they're a heavy user that will spill over onto over paranoia. Choose to be not a very, usually not a very well-formed or elaborated delusional system, it's more like, well, things are dangerous. People might be able to get me, but you know, it's kind of quasi vague. It's not a detailed story of, you know, the FBI has been following me for three years and I've been seeing people here and there and it's a more refloting global paranoia often as you point out associated with your ability. - Do you find that they're paranoid crashing off meth? 'Cause usually, okay, so you'll see them in the hospital, in the ER, maybe hopped up on meth, right? And that could look different than like day two, day three, day four in the psychiatric hospitalization. Do you see, can it describe that? - Yeah, I see. Well, yeah, most people who use meth, I mean, acutely, they look, if anything, somewhat manic and paranoid, and they're, you know, they're agitated, they're hyper-triple, they're, they exhibit essentially flight of ideas, first-tutory ideation, they're very prone to becoming violent. If they are a chronic user, they may induce, essentially, acetylpsychosis, they may take a while to resolve. You know, we are, you know, I work in forensic settings where we often get them a few months after their last meth use. By the time we get them, they appear more stuff and dysphoric. Still have abnormal sleep, although they are now sleeping. And they may have persisting psychotic symptoms, usually, this sort of free-slowning paranoia and sometimes occasionally hallucinations have been very often. This week, often, we'll go on to recover completely once they're off the meth and I'm feiting in long enough, albeit they usually also get treated with some anti-psychotic medication along the way to dampen the symptoms. - My counter-trans, my like, what I feel from someone who's like day four, day five is often like just lack of joy, lack of pleasure. - Mm-hmm. - Yeah. - As I said, they're dopamine depleted and if you have no dopamine, you're not going to feel very good. - Yeah. Okay, so we have good, this is really good. Meth induced psychosis differential because they look, they will look pleasurable but then they'll have this sort of vague psychosis anger, maybe, so that's one. The other thing I would want to differentiate is like schizophrenia with depression because sometimes it's the negative symptoms versus maybe the anti-psychotics are very blunting. Can you speak to that? - One of the things people are sometimes not careful enough about without psychotics is to be sure that the amount of pushing will draw beyond the drugs' point of futility. That is to concentrations that are beyond the drugs that are put into range because you can, particularly with the more potent dopamine antagonists, induce something that is very much like a dopamine depletion state where the person is anergic and adermic. They look very negative with drawn and it's essentially excessive dopamine blockade. We use the anti-psychotics and hospital settings for two things. One is acutely to decrease agitation and the other is to treat psychosis. Pushing the drug above its therapeutic range does not treat the psychosis any better or faster. That was a rapid neural uptization, was at one point in psychiatry theory. When they finally got a large scale study done, comparing very early high dose neural uptics versus just starting at a typical therapeutic dose absolutely no different similar response or any psychosis or the time course of the response. So that was a theory that's been long since debunked. People sometimes conflate a acute control of agitation with treatment of psychosis. They're not the same thing. You can treat agitation with an anti-psychotic that is, if you go onto the other also anti-istominic, you can make people sleep, but you're not gonna make them less psychotic faster by giving them more and more anti-psychotic to the point that you're overdosing them on the anti-psychotic. And indeed you can induce this sort of, this dopamine depletion state where they will look very negative, very withdrawn. - Yeah, flat face, just like someone with Parkinson's, they'll be less reactive in their face, their emotionality. And so it's the time course, right? For someone with that, you would have to get collateral, you would have to know when the medication was started. A lot of outpatient care is finding the right dose. - It's also a place to advocate for measurement to apply some concentrations. The next thing is we now have a fairly good understanding of the anti-psychotic effects of dopamine antagonists and their relative concentration range. And for example, if you were treating somebody, say with a landsapine, as I prexel, there is no point in pushing the drug above 115 nanograms per milliliter. Add 150 nanograms per milliliter, the receptor occupancy of a landsapine is around 83%. If you wanted to push that up to 85%, because the receptor occupancy curve has become so flat by 150 nanograms per mill, you'd have to give them up to around 400 nanograms per milliliter to get from 83 to 85% receptor occupancy. So pushing them up to 250 or 300 nanograms per milliliter makes no sense. You're not helping them. All you're doing is increasing their side effect burden. For the more potent dopamine antagonists, like how a paradol or syluphenazine, how a paradol essentially saturates the D2 receptors at about 18 nanograms per milliliter. Syluphenazine gets there by about 4 nanograms per milliliter. Well, there's no point in going further because you can't occupy more than 100% of something. But you can produce adverse effects in other systems. Yeah, and also for those who are interested, episode 127, Jonathan Meyer came on and talked about anti-psychotic plasma levels. He has a nice book on this as well. And in the website, we cite the Dr. Cummings and at the Patent State Hospital, their blood levels that they're looking for for each anti-psychotic. Go ahead, Dr. Cummings, you were going to say something. Yeah, I was just going to indeed also mention that there are books on the same topic. Jonathan's is certainly the most comprehensive lives. Yeah, so, okay, so schizophrenia, you know, are we over-treating with an anti-psychotic? That's part of the differential. I always think it's wise as psychiatrist to think, are we doing this to the patient, you know, and not. Yeah, I'm going to go. And to kind of have the humility to consider and look at the time course, right? The time course will tell you if you are doing it, like, the dose was increased from this dose to a huge dose, this dose, and then the person looked more flat or depressed. It's like, okay, maybe we did that. Yeah. Yeah. Sometimes, as I said, we get carried away in our treatment, not realizing that going beyond the point of futility is not going to help patients, it may just incur further adverse faults. Now, depression is quite common in schizophrenia. The estimate probably about 30 to 40 percent of schizophrenia patients at least experienced dysphoria, if not outright depression at some point during their illness, understandable, schizophrenia is a truly awful illness to have. And indeed, its early suicide rate is actually higher than that of major depressive disorder. It's suspected that a lot of people who have were undergoing their first psychotic break, or at iris, or suicide because it's not a good thing to have your mind begin to do about things that not function very well. Yeah. Very good. Okay. So I think we've talked about most areas of this, and I'm curious if there's any other domains in terms of psychotic depression you wanted to cover before we sort of bring this to a close. I think the only thing I would add is when people are talking with somebody who they suspect has developed major depression, it has pruned clinically to take a close look for specific signs and symptoms of psychosis. If you ask too broadly, the person may not answer because indeed they may be embarrassed by the presence of psychotic symptoms. But as the certain degree of trust begins to evolve, it becomes easier to ask the person about oddities and they're thinking feelings of excessive guilt. Do they blame themselves for things unrealistically? Do they have the experience of seeing or hearing things hallucinating? I don't know why sometimes we're afraid to ask people if they hallucinate, it's not like most of the public doesn't know what that word means. And I've gotten, if you ask specific questions, you'll get specific doubts. Okay, you said blame yourself for something. Are you blaming yourself excessively for something? Okay. And with no insight that you are not responsible for that thing, would you add that? Yeah. Okay. Yes. Yeah. And you wouldn't ask that the way that I said it, of course. But it's like that's what you're thinking as a clinician. What's their level of insight into how responsible they feel? Yeah. Yeah. Because you know, you're basically looking for an excessive loss of ability to test reality. Now, certainly, I think everyone who has major depression, it would be fair to say that they're all looking at the world is bleak, negative compared to that same person on a euthyemic state. But if that becomes severe enough, it can get to the point that indeed it causes the boundary into being unrealistic. And that's an area we should probe. And everyone we meet who is suffering from major depression. I think often the psychotic elements are missed. And it's important not to miss them if they're present because it does alter the dream response and alter the prognosis. Yeah. So, okay. Treatment, treatment algorithm. First, you know, if you think someone is psychotic depressed, my first line would be like an SSRI and an anti-psychotic, you know, second generation probably. If they didn't respond, I would think ECT. Yes. How quickly would you go, are there any other steps that you would do? Of course, I always try to get the people into therapy as well, get them into, you know, exercise. But the severity, if it's a very severe depression, psychosis, my success with getting them to do an exercise routine is pretty low. So, yeah. If they've reached the point where their hospital was, we're going to be proceeding quickly to ECT if they fail an antidepressant slash anti-psychotic adequate trial, which usually means six weeks at therapeutic doses, or if they're continuing to worsen despite the treatment. Now, if they are outpatient, I may try them on more than one anti-depressant slash anti-psychotic, give them two trials before proceed at ECT, depending on how severe the depression was, on which they're in to learn. But I would not put off proceed ODCT for a long period of time, I've come across patients who have been on four or five, six, seven trials of anti-depressant with or without antidepressant, and no one's ever thought to move beyond that. And that's not doing the patient on their figures, because the longer we let illnesses like major depression, smolder, the worse the prognosis or the treatment of full remission becomes. Yep. Yeah. Okay. So, depending on the level of severity, like if they're hospitalized, you know, would you wait six weeks for a smooth ECT? Usually if they're hospitalized, they've already been treated with antidepressants. They may already be on an antidepressant. Yeah. They've already started treatment, and they may be going to ECT fairly quickly, a century after they were reviewed of their history that they've had at least one adequate therapeutic trial, not to underpress an anti-psychotic, and they're still ill enough to require hospitalization. Well, that may be the case where if there are ill-contradentications, they should proceed fairly rapidly to ECT. And then one other thing I think we didn't touch on would be, you know, also if they do look psychotic, if they have depression with psychosis, to definitely consider if they have catatonia as well. Yeah. Because in my experience, catatonia is pretty close in some of those patients, like they're close to developing kind of this catatonic, either how they move or repeating words or, this kind of immobility, stupid. So, yeah, anything else you want to say on that? Yeah, I would encourage people to become familiar with the Bush Francis scale for catatonia. I'm just making a routine part of your work up, because we miss a lot of catatonia in hospital settings. Yeah. So in the in the in the Bush Francis catatonia scale, you're rating them from zero to three on things like immobility, stupid, number two is mutism, number three staring, number four posturing, catalypsy. Yeah. Yeah, the advantage of using a scale like that is it reminds you each and every time to do a thorough job of looking for all the different aspects. Because it's it it it amazes me how often catatonic is missed. And it's also just because people don't look. Yeah, it goes all the way. There's 23 different types of symptoms. Check it out. We did an episode on catatonia. I'm very proud of of note. One of the biggest things I've learned and I'll repeat this over and over again is, you know, they may need a lot of lorazapam. And lorazapam itself may be enough. They may they may not need dct. Right? If they get complete resolution from the catatonia from lorazapam, how long do they need to be on that dose of lorazapam? It will vary, but it may be months. It may be months, right? And then one of the things I learned from Dr. Cummings is you only go down about one milligram per month. - Yes. - And continue to monitor. That is like mind-blowing for outpatient care. Like they could be on like 12 milligrams of lorazapam per day every day for a month, right? And then you go down to 11, okay? - Yeah. Well, one of the, you know, fortunately one of the causes of Calutonia is benzodiazepine will growl. So people have to be very careful about the rate at which they reduce the benzodiazepine or if they go too quickly, they'll just re-induce the Calutonia. The other thing I always wanna be sure people do correctly is if you're going to do a lorazapam challenge, I test to see if the person's responsive to a benzodiazepine, it should be given IAM or IIV. And oral dose of lorazapam will typically monitor you in a high enough peak. They get a response from the catatomic person. - So you give the IAM and then you check back in how many minutes? - About 30 to 45 minutes. - So set your timer. You have to set your timer. And then take the medical students with you. That was always, it was always like my funnest event to do when I was, - Oh yeah, 'cause it's impressive when the person wakes up and looks much more normal than they did. - Yeah, so have the medical students see the before, have them do the scale, right? To get that experience. And then have them go with you after. And then if it worked, start escalating the dose of lorazapam, right? And it was, yeah, get them on a high enough dose and actually like gets them out of the, the catatonia. Okay. All right, anything else you wanna talk about today or anything come into your mind that you wanna share about psychotic depression? - No, I think we have pretty much covered it. - It's been fun. I think our, our diversions into differentials and sort of like things that cluster together will be helpful. I really appreciate you coming on Dr. Cummings. As always. - Okay, thanks. I've enjoyed it. All right, have a good day. [MUSIC]