Psychiatry & Psychotherapy Podcast - Psychotic Depression with Dr. Cummings

Episode Date: December 22, 2023

The underreporting of psychotic symptoms by patients in depression is a significant concern, frequently driven by the fear of consequences like hospitalization or the stigma of embarrassment.  We'll discuss the history, the differential to consider when thinking of psychotic depression, mechanisms, and treatment. Notably, individuals with psychotic depression face a suicide rate double that of their non-psychotic counterparts. A recent cohort study by Paljärvi in 2023 revealed a stark contrast: deaths due to suicide were 2.6% in the psychotic depression cohort, compared to 1% in the non-psychotic group. Alarmingly, most suicides occurred within the first two years following diagnosis. People who suffer from psychotic depression often do not report their psychotic symptoms, leading to inadequate response to normal depression treatments. With 6-25% of individuals with major depressive disorder (MDD) exhibiting psychotic features, it is imperative to understand and address these unique challenges. Join us as we unravel the complexities of this underrecognized aspect of mental health. By listening to this episode, you can earn 1.25 Psychiatry CME Credits. Link to blog. Link to YouTube video.

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 Psychiatrypodcast.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, catatonia. 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 at. 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. 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 clock, which someone with

delirium will have a hard time doing. As well with psychotic depression, they may have a substance-induced psychosis. And we'll be talking about methamphetamines, how they can look psychotic depressed as well. Subsequently, we're going to be throughout the episode talking about things like BDNF, the HPA axis, how that relates, and we're going to get into the treatment. And just to kind of Q-U-N, you know, normal treatment might start with an antidepressant and 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 in 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, change 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 psychotherapy, very pertinent for psychotic depression, especially to build that therapeutic clients 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. I am joined today with Dr. 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 underreported often by patients

due to fear of potential consequences, reporting symptoms, you know, will they be hospitalized, will there 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 6 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 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 6% 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 the history of it. I always like to hear your take on the history of it and um okay one of the yeah indeed one of the problems with research in this area has been that the shield's definition of psychotic depression has changed over time uh if you go back prior to dsm three psychotic depression was a term used to describe people whose illness included melancholia, withdrawal, and deterioration and functioned 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 to bed, and if they weren't actively treated, were at risk

of dying due to not eating, 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 DSM-3, 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 in mild, moderate, or severe depression. And 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, in addition to their vulnerability to becoming depressed. 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, 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, 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 of course who are bipolar can be psychotic. even anxiety disorders are 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 to some extent, that's supported by the fact that in broad population surveys, mostly again in Scandinavia because they have birth to death, you know, 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 will say yes that they have had men hallucinated visually or auditorily or not only they've had a, probling,

persecutory 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 not impacted by the psychotic symptom. And usually they're transient. So I think we're moving towards seeing psychosis as a dimension or subcomponent

that may be there in a variety of businesses, but certainly true in major depressive disorder. And indeed, DSM-5 permits a diagnosis of psychosis in the context of things like dysphymic disorder or what was termed in the research diagnostic criteria, minor depressive disorder. So, again, showing 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 and as the 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 impatient, right? It's like depression with psychotic features, one category, borderline per se disorder

with sub-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, than we've tended to think of them. It certainly is true. I think the more severe the illness, the more likely it becomes that the person will have persisting psychotic symptoms. But I've had, I've crossed a few patients over time who confided after they got to know me that, yes, they have had a persisting 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 it used to be. Okay. 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, like the psychotic symptoms may be more in line with the trauma, right? Yes. They're often, in the case of PTSD and maybe a spillover of 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 association, or if there's a residual suspiciousness

or unreasonable attitude about a circumstance or situation, how much is that sort of stretching the boundary of not being reality-based? is that as part, 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 attendance, to misperceive something all the way to fully evolve, multimodal, hallucinatory experiences,

which I've seen 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, you know, the people had changed to different people, the surroundings had changed to a different place. So it was a substantial departure from reality.

It sounds like a dream, a nightmare, because I know in PTSD nightmares are not a direct copy of the actual trauma over and over again. Nightmares will be slight variations of the trauma. One of the sign of malingering is that it's always an exact copy of the trauma, according to my malingering textbook, correct if I'm wrong?

Now, that is accurate. Malingerers want to sell the story, and we'll say that it's always the same, whereas people who actually experience flashbacks or psychotic symptoms, they morph over time, 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-incongruent, psychotic signs and symptoms. As you know, I guess, or as you know, mood-congruent simply 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 children around psychotic symptoms as well. I think one of the other things that tap into the field is in DSM-5, there's a recognition that the person may have a 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 hypomanic or manic. I think that reflects that we're also learning that there's not as sharp a break between major depressive disorder

and perhaps bipolar spectrum illness as we once thought there was. There is some crossover, which, going all the way back to the basics, to genematics when people who looked at the vulnerability genes for major depression and the vulnerability genes for bipolar mood disorder on the fair number of the low

side that have been identified overlap. So in some ways it would be kind of silly to think that the Chinatypic illness is going to be entirely separated from each other. Right. So, okay, so let's talk about, let's go a little bit deeper into the mood, congruent, psychotic

features first mood and congruent because I think like actually talking about what they might be might be helpful so like the mood congruent with depression so might be like personal inadequacy guilt I have some disease I'm close to death or I'm dead there may be some nihilistic peace my organs are turning to dust so I'm cursed I deserve punishment Yeah. For example, I had one individual I interviewed recently. He's 23. And he believes he was responsible for World War II, which of course, in the U.S.'s entry 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. Yes. So that's mood congruent.

mood incongruent may be 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, start, like, go ahead. You tell me what some common art that you've seen. Oh, yes. Well, we have several people who believe that they are some form of deity.

We have some people also who, indeed, as you allude to, believe that they're either incredibly wealthy and own everything or they're in some way, 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's just a deflated narcissist who's now depressed for someone who's like having a psychotic symptom that seems grandiose, or some of the, you know, these hypomanic defenses are in that, you know? 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 disprove to anybody who was not able to test reality. And in fact, I've had very depressed patients tell 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 insight into that they're not a billionaire? No, no, no, no. They'll turn them right around and say, no, but I really am a billionaire.

I just don't happen to have any money right now. the money is somewhere else or someone or someone else's control or it's being inappropriately taken from them some projective defenses there in terms of somebody else has made all of this happen 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 idealized self that they had created. And then whereas psychosis is like, yeah, like you're saying, they have very little insight into the reality in a psychotic event.

Yeah. One of the things that research has established about mood incongruent delusions in particular is that that's often a tip-off that you may not be looking at major depressive disorder, you may be looking at somebody who's bipolar. About, somewhere between a third and a half of the people who have mood-incongruent delusions at some point later go on to have a hypomanic or manic episode. And indeed, one of the things to watch out for is people who, who start having depressive episodes early in life,

recurrent episodes, and who may have mood incongruent features in their depression, you may be looking at a budding bipolar patient who just hasn't had their first hypomanic or manic episode yet. That's good. Okay, so that's a good clinical pearl. If you see someone with mood incongruent, so they're depressed, the depression has been maybe progressive,

but now they're having mood and congruent psychotic symptoms. Like 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 an undiscovered bipolar patient. The other clue in that chronologically is if you put them on antidepressant, 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 a little overactive maybe a little hypersexual

you may be the antidepressant may be moving them toward their first hyponamic romantic episode yeah like when you say

hypersexual what kind of symptoms would you be seen or what kind of behaviors would be seen you be seen somebody who is normally not that social begins overtly flirting with a lot of people somebody who maybe has had a steady girlfriend or boyfriend suddenly starts being interested

in going out with multiple people and other you know with related areas of impulsive people who've normally been fairly thrifty, starts spending money impulsively, that kind of thing. 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, 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? when the mood is rather than being consistently depressed, the person's mood is very labile and very responsive to social interaction. One of the characteristics in major depressive disorder is as the person's depression worsens, they become essentially less and less mood reactive. At the severest end of major depressive disorder, the person is largely unresponsive to any events in terms of feeling better or having any hedonic capability.

With a borderline individual, their mood depends on what happened in the last few minutes. these are the people who may be 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. I tend to think of borderline personality disorder, indeed as a mood disorder, but as one characterized by mood liability and mood intensity rather than a consistent elevation or consistent depression of mood.

Yes, with borderline for size where I also 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. Social veneer, but they'll have these quasi-psychotic episodes that are kind of dissociative in quality. Can you give any sort of like details on what kind of psychotic episodes they might have? Usually they are time limited and usually they are focused on a misinterpretation

of an interaction with another specific person. They may become paranoid about, you know, a particular person, transiently, oh, that person is plotting to get me, they're out to harm me. But when you talk with them about it, at the core of it, there usually is some real conflict, but they've distorted it beyond all recognition. That may become jumbled up with dissociative elements as well, so that I had one borderline patient who, when she was really distressed and would have a psychotic break, she believed that her coworkers 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, oh, that's not true. That's silly. Okay. You can see where this is complex, because it's like you have to have the big picture with borderline personality disorder. 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 does not suddenly look well. It often takes them weeks or months to appear well.

And that's one of the differences in psychotic depression. They don't, pharmacologically, they don't typically respond to antidepressant treatment alone. I think the response rate for antidepressants in the psychotically depressed is down in the 20 to 30% range, very low. If you add an antipsychotic to that, you'll get response rates that are more typical of what you see with antidepressants in general. you'll get a response rate up around two-thirds. Yeah, so you're saying just an antidepressant does not treat someone with depression with psychosis very well. Typically, no. The treatments basically fall into two camps.

You have an antidepressant with an antipsychotic or in the most severe cases you have ECT. There has been some work done with looking at transcranial magnetic stimulation. 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 Eck Strand at all. It's from the department in Sweden. and at Lund University. And this was a study of 186 inpatients who did not have a primary psychotic disorder,

meaning they didn't have primarily like 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% went into 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, indeed, had they had a larger sample, they would have achieved statistical significance rather than,

I don't know, most people would interpret that as a statistical trend toward 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 away the most effective treatment we have. No. 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, an and at all, 2003. 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, you know, the advantage of ketamine and es ketamine is both are very rapidly effective in treating depression and in reversing suicidal, suicidality. Ketamine and escutamine, though, were both dissociative, well, anesthetics, basically. and to an extent they are psychotomimetic, that is, they induce psychotic symptoms at Ritom. One of the limitations with ketamine has been that, you know, the initial antidepressant response tends to wear off over several days to about a week. But if you keep giving people ketamine repeatedly, the length or the duration of the benefit gets shorter and shorter.

and the degree of dissociative and psychotic symptoms gets bigger on 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 es ketamine have limitations in terms of ongoing treatment. I think one of the thoughts that I had in reading this 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, 1.2, which is a very strong dissociative experience at that dose.

It's a full dissociation, usually. Oh, I know what I was going to say about that first study, though. 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 with psychosis 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. It certainly is 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 that in some cases at least, or at least in some samples, that these people may have had numerous subclinical episodes of depression or dysphoria before they finally blossomed into a, you know, a fully-evolved major depressive episode at an older age with the longer duration of perhaps subclinical depression incurring some degree of tremor resistance in them. our understanding of the premier resistance and depression has focused largely on the hypothalamic pituitary axis those people who have chronically elevated cortisol

tend to be those who are resistant to antidepressant medications as illustrated by the fact that if you give them Mephiphristone at 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 ECT. Now, unfortunately, you can't continue to get people

with your personal because you'll put them into ad-soviet prices. But it does suggest that if you block their cortisol, they suddenly regain their responsiveness to antidepressant medications. Again, an inevitable HPA axis as tending to be perhaps the source of, at least one source of three more 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 HPA access. Is there any other things that kind of come to your mind as potential mechanisms of depression with psychosis? Yeah, if you look at, well, if you start with the very basics, then in terms of frontotemporal metabolism and people with major depressive disorder, there's about a 20 to 40% decline in glucose uptake and utilization in the frontotemporal areas. There is a loss of dendritic arborization. The dendritic trees on their neurons do look like a blue. and wintertime rather than spring.

We've lost these spines and the connections. It's easy to imagine that loss of intermarital connections, if it becomes severe enough, can start to lead to outright dysfunction and errors in both processing of sensory information and errors in terms of reality testing. So it's very likely that the sort of atrophic changes may underlies 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 have actual brain changes? Yes.

Yes, they exhibit a thinner cortex, loss of dendritic arborization, decreased metabolic rates. You know, and to go back to our, understanding of major depression. In the 1950s, we simplistically thought that, oh, people are depressed because they have a deficit in mono-means, serotonin, morphine, dopamine. I think our view of this has evolved to say, no, they have a primary problem with their

frontal control over limbic structures, and the abnormalities we're seeing in their their modulatory molecules is more in effect than a cause. 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 now we recommend that if somebody's had recurring episodes of depression, maybe they should stay on an antidepressant rather than being tapered off.

It used to be that every time somebody would recover from a major depressive episode, they'd get tapered off their antidepressant, and that certainly still makes sense for somebody. who's had a single episode, but if somebody's up to their third episode of major depression, they may need ongoing treatment. Yeah, or, and usually multiple types of treatment, exercise, diet, therapy. Yeah, exercise, diet, cognitive behavioral therapy, other therapies. And in fact, that's one of the areas for cognitive behavioral therapy has an advantage and that, you know, when you stop taking a 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 in that sense, they get an added benefit. Yeah, I think, 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 Huntington's, Parkinson's have much higher rates of depression.

Strokes have much higher rates of depression. And so there's this sort of crossover there. And yeah, anything else you want to say on this before we move back to psychotic? Yeah, just that the, you know, the tronto temporal area of the brain, we tend to think of the limbic system in terms of mood,

but 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. 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 asking people if they have feelings of hopelessness and hopelessness. That's how that's a relevant, clinical question. Okay. Coming back to the psychotic depression question, Are there unique brain changes findings with psychotic depression that are not in other types of depression? There seems to be in psychotic depression.

There are a limited number of pet studies that have tried to look at this, and there appears to be a greater disturbance or decrease, and the metabolism for the, particularly the dominant temporal lobe in psychotic depression. And in some ways that makes sense. In primary psychotic illnesses, we think that, in particular, the non-dominant temporal lobe is often the source or positive psychotic symptoms such as delusional 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 almercs in major depressive disorder is that there is a huge falloff in brain-derived neurotrophic factor. neurons 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 greal cells to do everything except transmit information. And in major depressive disorder, there is a dysfunction of those support networks. so that things like brain-derived neurotrophic factor, glial cell derived neurotrophic factor, and endothelial-derived neurotrophic factor all declines steeply 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 a corresponding rise in neurotrophic factors and essentially a sprouting of new dendritic spines and a reconnection and an uptick and metabolic rate. So it literally is a case of having depressed metabolism, well as a depressed mood. Yeah.

We also know exercise increases BDNF. Yes. Specifically vigorous exercise. Yeah. Yeah, specifically aerobic exercise, things that get your heart rate up, make you breathe 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. All the I think is now, in addition to the post-mortem studies, they're also able to using magnetic resonance spectroscopy. You can actually see the changes in people who are living. So it's a lot of post-mortemal artifact of some sort. I wonder what you think about, you talked briefly about TMS.

I'm actually about to do a big TMS episode. What do you think of like the Saint Protocol for this type of patient, for the psychotic depressed patient, Staint Protocol in general? You know what I'm talking about coming out of Stanford? Yeah. I think the St. Protocol is reasonable. I don't think we're using TMS as widely, perhaps, as we're,

trude as an augmenting strategy for either antidepressants or in some cases as a standalone 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's who are psychotically depressed. It may still be a very useful adjunctower where I haven't seen any data to make up my mind about. Okay. Okay, so we've talked about mechanism,

anything else you want to tie into the mechanism? Just that basically, the more we can do to once 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 depressive disorder is that every time somebody has an episode, psychotic or not, it makes the next one more probable. Yeah, yeah, okay. We talked about differential. One differential, I think that's important to put out there, is delirium.

because you can have a consult for depression in the hospital, like, oh, this person's really depressed, they're not talking, they have all these, you know, awful things that they believe about themselves, and there can be an aspect of psychosis, like, oh, they, you know, 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, you know, they have this waxing and waning, ability to focus and concentrate.

One minute they're 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 an upper respiratory tract infection. So they're in the hospital for something else sometimes, like post hip fracture repair. So yeah, tell me about delirium and how it could look like psychotic depression. Okay. Well, one of the truisms about major depressive disorder is it typically has a long prodromal period and is very rarely abrupt an onset, whereas delirium represents essentially a loss of the brain's normal physiologic state. It's been insulted by a major insult, either inflammatory or metabolic and brain function.

abruptly deteriorates. As you point out, a fluctuating level of arousal. The person may be alert and lucid at one moment, and the next, they're confused and disoriented and not making much sense, and then they'll come back, and it's something that we need to keep on a very high on an index of suspicion, particularly in hospital settings. When they've done surveys specifically looking for delirium in hospital. in hospitals, they find that the rate in-patients is right around 40%. Because people indeed, 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 delirious are just quietly delirious for a day or two, and then they get better. I don't know. There are people, though, that don't get better because their delirium is being driven by them,

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 exam and, if possible, observe the person over time. So I would say there's a saying if you're consulting on a patient in the hospital, delirium until proven otherwise. You know, 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, 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 and 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 him like no this is delirium yes 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 legion. Certainly in an acute care hospital, the vast majority, probably the most common is post-surgical delirium, which in most cases is a response to the anesthesia. Those are those people get missed because they get better fairly quickly. But if you actually examine them right after they come out of recovery, they're often having things like hallucination. Indeed, I talked with one patient who, he sounded on superficially okay until he started doing a mental status exam, and he couldn't quite spell world, either forward or backward.

He couldn't really count backwards. and while we were talking, he keeps looking out the winter and asking, well, what are you looking at? Because as far as I was aware, there wasn't anything outside the special. And he said, well, no, there's a large taradactyl that keeps circling the building. Okay, now. Okay, here's a recent one for me.

This was a family case. It's not a patient case. You know, a person, 60 years old, gets admitted to the hospital. They've had a chronic fully, so they're having some issue with urinations. 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 Lone B.

hold 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 anitis of infection until you get that catheter out they're going to stay infected treat them from the UTI and and the next thing I'm hearing is that the psychiatrist on wants to do ECT and I'm like uh was this person depressed was this person depressed before they went in the hospital like a month 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 that 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. As a jumping to ECT, that would be my sense. Yeah, certainly in an elderly person in the hospital who becomes delirious, always check the lungs and the bladder. Those are the two most likely sources of women infection 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 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, some diverticulitis maybe or some sort of bladder infection, you know, 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, 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 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, oh, it's a mental disorder. No, it's a delirium until proven otherwise. Yep. Okay, so differential, we talked about borderline personality disorder. We talked about delirium. We talked a little bit about bipolar, especially if they have a typical features. I don't know if there's any, I think that the, you know, hearing the family history, is there a family history of 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 diagnoses depend more than, almost 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 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 because they've been using massive amounts of methamphetamine which did a nice job of producing a dopamine deposition state, which looks psychotic depression. You know, okay, so how these patients usually look impatient to me is they're 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 in residence, 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 you know no give them a break and come back later and gather your interview in pieces yeah any other like what is the psychotic symptoms unique to meth that you might be seen that would differentiate

It tends to induce most often a persecutory delusional system. They may or may not hallucinate, but they are very often quite paranoid initially. You know, one of the effects of increased dopamine in the brain is to make the person hypervigilant. And typically, if they're a heavy user, that will spill over into overt paranoia. usually not a very well-formed or elaborated delusional system. It's more like, well, things are dangerous. People might be out 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. it's a more free-floating global paranoia often, as you pointed out, associated with irritability. Do you find that they're paranoid crashing off meth? Because 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 describe that difference? Well, yeah, most people who use methamphetamine acutely, they look, if anything, somewhat manic and paranoid.

And they're, you know, they're agitated, they're hyperlorable. They exhibit essentially flight of ideas, persecutory ideation. They're very prone to becoming violent. If they are a chronic user, they may induce... essentially a settled psychosis that may take a while to resolve. You know, we are, I work in a forensic setting where we often get them a few months after their last meth use. By the time we get them, they appear most often dysphoric, still have abnormal sleep, although they are now sleeping,

and they may have persistent psychotic symptoms, usually this sort of. of free-floating, paranoia, and sometimes occasionally hallucination, but not very often. Those people often will go on to recover completely once they're off the methyl lymphogen long enough, albeit they usually also get treated with some antipsychotic medication along the way to dampen the symptoms. My countertrans, what I feel from someone who's like day four, day five is, often like a just lack of joy, lack of pleasure. Yeah.

Well, 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 pleasureless, but then they'll have this sort of vague, vague psychosis. anger maybe so that's one the other thing i would i would want to differentiate is like

schizophrenia with depression because sometimes it's it's the negative symptoms versus maybe the antipsychotics are very blunting can you speak to that one of the things people are sometimes not careful enough about with antipsychotics is to be sure we're not pushing the drug beyond the drugs point of utility um that is to concentrations that are beyond the drug's therapeutic range, because you can, in particular with the more potent dopamine antagonists, and do something that is very much like a dopamine depletion state where the person is anergic, anhydamic, they look very negative, withdrawn, and it's essentially excessive dopamine blockade. We use the antipsychotics in 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 psychosis any better or faster. That was a rapid neural lupitization was at one point in psychiatry of theory. When they finally got a large-scale study done, comparing

very early high-dose neurolaptics versus just starting at a typical therapeutic dose, absolutely no difference in the response rate of the psychosis or the time course of the response. So that

was a theory that's been a long since debunked. People sometimes conflate acute control of agitation with treatment of psychosis. they're not the same thing. You can treat agitation with an antipsychotic, that is particularly ones that are also anti-histamineic.

You can make people sleep, but you're not going to make them less psychotic faster by giving them more and more antipsychotic to the point that you're overdosing them on the antipsychotic. Indeed, you can induce this sort of dopamine depletion state where they will look very negative, very withdrawn. Yeah. Flat face, you know, just like someone with Parkinson's, they'll be less reactive in their face,

their emotionality. And so it's the time course, right? It's for someone with that, you would get, you would have to get collateral. You would have to, you 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 of plasma concentrations. The last thing is we now have a fairly good understanding of

the antipsychotic effects of dopamine antagonists and their relative concentration range. And for example, if you were treating somebody, say with, the olanzapine, xypregs, there is no point in pushing the drug above 150 nanograms per milliliter. At 150 nanograms per milliliter, the receptor occupancy of elanzapes are around 83%. If you wanted to push that up to 85%, because the receptor occupancy curve has become so flat

by 150 nanograms per mole, you'd have to give a person, you'd have to get them up to around 400 nanograms per milliliter to get from 83 to 85% receptor off. 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 haloperidol or flu-phenazine, how a peridol essentially saturates the D2 receptors at about 18 nanograms per

melal liter. So the phenazine gets there by about four nanograms per milliliter. Well, there's no point going further because you can't occupy more than 100% of something, but you can produce adverse effects in other systems. Good, yeah. And also for those who are interested, episode 127, Jonathan Meyer came on and talked about antipsychotic plasma levels. He has a nice book on this as well. In the website, we cite the Dr. Cummings and at the Padden State Hospital, their blood levels that they're looking for for each antipsychotic.

Go ahead, Dr. Cummys. 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 that I've seen. yeah so um so okay so schizophrenia you know are are we overtreating with an antipsychotic that's part of the differential i always i always think it's wise as psychiatrists to think are we doing this to the patient you know and and and to kind of have the humility to consider and look at the time course right the time course will tell you if 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, more depressed. It's like, okay, maybe we did that. 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 the patient. It may just incur further adverse faults.

Now, depression is quite common in schizophrenia, they estimate probably about 30 to 40% those schizophrenia, at least experience dysphoria, if not outright, depression at some point during their illness. Well, understandably, 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,

at irisks or suicide because, well, certainly not a good thing to have your mind begin to do bad things and 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. I think the only thing I would add is when people are talking with somebody who they suspect has developed major depression, it is prudent 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 in their 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. It's not like most of the public doesn't know what that word means. and if I've gotten, if you ask specific questions, you'll get specific answers. Okay, you said blame yourself for something, right? 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 their outlook on the world is bleak, negative, compared to that same person in a euthymic 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 in 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 treatment response and alters the prognosis. Yep. So, okay, treatment algorithm.

First, you know, if you think someone is psychotic depressed, my first line would be like an SSRI and an antipsychotic, 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 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.

Yeah, if they've reached the point where they are hospitalized, we're going to be proceeding fairly quickly to ECT if they fail an antidepressant slash antidepressant, slash antipsychotic adequate trial, which usually means six weeks at therapeutic tosis, or if they're continuing to worsen despite the treatment. Now, if they are outpatient, I may try them on more than one antidepressant slash antipsychotic, give them two trials before proceed at ECT, depending indeed, again, on how severe the depression is, how much risk they're incurred. but I would not put off

Procedo DCT for a long period of time I've come across patients who've been on four or five, six, seven trials of antidepressants with or without antipsotic and no one's ever thought to move it beyond that. And that's not doing the patient any favors because the longer we let

illnesses like major depression smolder, the worst of prognosis for achieving a full remission becomes. Yep. Yeah. Okay. So depending on the level of severity, like if they're hospitalized, would you wait six weeks first move to 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, essentially after their review of their history, that they've had at least one adequate therapeutic trial, and anti-depressant and antipsychotic, and they're still ill enough to require hospitalization. That may be the case where, if there are no contraindications,

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. Yes. 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, um, This kind of immobility stupor. 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. And just make it a routine part of your workup because we miss a lot of catatonia in hospital settings. Yeah, so in the Bush-Francis Catatonia scale, you're rating them from zero to three on things like immobility, stupor, number two. two is mutism, number three, staring, number four, posturing, uh, 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 of the different aspects.

Because it's, it's, it, it amazes me how often catatonia is missed. And it's mostly 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 they may need a lot of laurazepam, and laurazepam itself may be enough. They may not need ECT, right? If they get complete resolution from the catatonia, from laurazepam, how long do they need to be on that dose of lorazepam? 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. They could be on like 12 milligrams of lorazepam per day, every day for a month, right?

And then you go down to 11. Yeah. Well, one of the, you know, fortunately, one of the causes of catatonia is benzodiazepine withdrawal. So people have to be very careful about the rate at which they reduce the benzobazapine. If they go too quickly, they'll just reinduce the catatomia. The other thing I always want to be sure people do correctly is if you're going to do a little raise a pound challenge, I test to see if the person's,

responsive to abenzoidine, it should be given IM or IV an oral dose of orizapam will typically modic you

a high enough peak to get a response from the catatomic person. So you give the IM 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. You know, that was always, it was always like my funnest event to do when I was...

Oh yeah, because 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, if it worked, start escalating the dose of lorazepam,

Yeah. And those, yeah, get them on a high enough dose that actually like gets them out of the catatonia. Okay. All right, anything else you want to talk about today or anything coming to your mind that you want to share about psychotic depression? No, I think we have pretty much covered it. It's been fun. I think 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 great day.