I'm Jordan Karp. I am professor and chair for the Department of Psychiatry at the University of Arizona College of Medicine in Tucson and I'm also a card-carrying geriatric psychiatrist and I want to welcome and commend you all for coming to this clinical update in late-life mental health in the last afternoon of the meeting. So kudos to you all for sticking in there. I promise that this will be an entertaining and educational and well-spent next hour and a half and we're really grateful that you've decided to spend it with us. We have assembled three, plus me, experts in late-life depression who will be speaking about best approaches to treatment, predictors of recurrence, intersection of dementia and depression, and best practices for getting and keeping your patients well. Our first speaker is Eric Lenz and I've asked all the speakers to tell me the scientific accomplishment they're most proud of as well as what they think is the biggest unmet need in geriatric psychiatry so I will share that about each of these speakers. But our first speaker is Eric Lenz who is a geriatric psychiatrist. He is professor and chair for the Department of Psychiatry at Washington University in St. Louis. The scientific accomplishment that he is most proud of is discovering the first evidence-based treatment for preventing real disability and death by COVID which was actually fluvoxamine and he thinks that one of the biggest unmet needs for geriatric psychiatry and late-life mental health is advances in precision medicine. So without further ado I'm going to invite Dr. Lenz to come up and teach us. Thank you, Jordan, and thanks everyone for attending. Thank you. These are my disclosures. I'm going to start with this thought here because some of you have been around for a while and I've now been around for a while and so I can look generationally, look back at generation and now and say, my god, clinical complexity, meaning the complexity of the everyday patient encounters we have with our patients, it's gone up and in fact it's gone up a lot in that time. What's going on? Well, many antidepressants are now available. You can't count them on the finger of one or two hands anymore and that includes augmentation and interventional choices. But importantly many of these are really complex to give and then in older adults advanced age, medical complexity, polypharmacy, and nowadays self-medication are the norm. What do I mean by that? Let me put this in the context of aging. You hear that people are living longer. It's not, that's not totally accurate just to say people are living longer. What you can see from these demographic figures and projections is that very old people are living longer and what you can see is that the largest increases now and more to come are in people age 75 and up. People living in spite of having high rates of medical problems that a generation ago they may not have survived. How does this play out in our clinical encounters in geriatrics? Let me go back to 1994. That's when I began, I guess, a career in psychiatry starting a residency at the time. This is what geriatric psychiatry, this is what outpatient late-life depression looked like. I'm going to read it for you. Sixty-five-year-old woman presenting for depression care. She's never had mental health care. She takes no psychiatric medicines and she takes three medications total for arthritis, hypertension, and coronary artery disease. Seems quaint. This is nowadays. 78 year old woman presenting for depression care. She has heart failure, stage 3 renal disease, diabetes, hypertension, has been hospitalized five times in the last year, most recent from complications of uterine cancer surgery. She's had a stroke. She has cognitive imbalance problems. She takes duloxetine plus bupropion and she previously took venlafaxine, escitalpram, and mirtazapine. By this time my head is swimming when the resident's presenting to me. She takes 25 other medications, six of which are CNS active, plus she takes several supplements including melatonin. She drinks daily and uses gummies at night to sleep. Sound familiar? With so many, and going back to the treatment options, with so many treatments available it raises the question of which one to choose. And I don't know about you, but have you ever, I have, have you ever looked at a patient's medication list and scratch your head saying how do they get there with that treatment? So what I'm proposing today is an alternative, an evidence-based treatment algorithm, namely one that considers the best available data in order to maximize benefits and minimize risks when you're going through first, second, and later line strategies in late-life depression. And the good news is we now have high-quality data to make an algorithm, and that's based on a generation's worth of research. But first and foremost, I'm preaching to the choir here, but you got to know your drugs. And this is something that we have to keep reminding ourselves. This is the expert knowledge that we have as psychiatrists. We're the experts who need to know these drugs well. And as an example, here's a side-by-side comparison of amitriptyline and desipramine, both called SNRIs, serotonin norepinephrine reuptake inhibitors, but with very different profiles in terms of their side effects, their drug interactions, their off-target pharmacodynamics, a term that I did not even know of when I was a resident, their active metabolites, and their toxicity. And as a result, we have a winner based on, among, if you were going to choose between two SNRIs, we have a winner based on our knowledge of these drugs. Nowadays, a graduating psychiatry resident needs this level of working knowledge of all these issues for each of the hundred-plus drugs in our armamentarium. So I said that it's taken a generation, it's been a long road to get to evidence-based care for late-life depression. This was the beginning of that road. This was research done painstakingly, clinical trials in the late 90s and early aughts by our colleagues, led by our colleagues when both were at the University of Pittsburgh. On the left, Ben Mossant published a clinical trial, a randomized trial, that was the first demonstration that SSRIs, which were new at the time, at least at the time they started the trial, worked as well as tricyclics. For those of you who have long memories, you may remember that this was a controversial question for a while. And then on the right is one of the trials that really definitively showed that maintenance of an SSRI in older adults prevents recurrence of depression, reminding us that one of the best pieces of evidence about these medicines' benefits is preventing recurrence. So that's first-line treatment, SSRIs, right? Because they're easy to use, safe, well-tolerated. We've only answered the question of what's second-line treatment more recently. What I'm going to do is walk you through, I'm going to read the title, which is that SNRIs, again serotonin norepinephrine reuptake inhibitors, are good second-line treatments, unless you've already tried an SNRI. And I'm going to walk you through the data here showing that. This is protocol, 500 older adults all receiving protocolized treatment for major depression. That is, they all received the same protocol of venlafaxine, flexibly dosed up to a maximum dose of 300 milligrams per day. The reason you see five bars here is they were broken out, those 500 older adults, by what their prior trials were. That is, did they have any prior adequate trials of an antidepressant? And if so, how many and which kind? So what you see on the far left is for those who we would call treatment naive, right? They had had no prior adequate trials of any antidepressant, really high remission rate, 65%. Right next to that, if they had had one and only one prior adequate trial and it was not an SNRI, you still see a very sizable remission rate with a venlafaxine, the SNRI, at almost 50%. But then let's go to the far right. If they had had two prior trials and one was an SNRI, then you have a very low remission rate trying out another SNRI, venlafaxine, of below 20%. Okay, so again, SNRIs, high remission rate as either first or second line treatment if they've never tried one before, but a low remission rate after that. And so now we, from that, we can start to put together a treatment algorithm. Start with SSRIs, mainly because of ease of use, safety and tolerability. Use simple treatments like escitalopram and sertraline that don't have drug-drug interactions and off-target effects. Same thing with the SNRIs. And then for a second line, try an SNRI. But then what about third line and beyond, otherwise known nowadays as TRD or treatment-resistant depression? Well, we started to answer that by looking at augmentation for treatment-resistant late-life depression in this first-in-kind clinical trial that we published back in 2015. This was a really, like, classic placebo-controlled study of erypiprazole augmentation for older adults who had a major depression that persisted in spite of that thorough trial with venlafaxine for treatment-resistant. What you can see from the figures here are standard efficacy data. On the left, greater reduction in depressive symptoms. On the right, higher remission rate compared to placebo, thus demonstrating efficacy. And then although not shown here, we also characterized the safety of erypiprazole and found that in general, in spite of being an antipsychotic, this appeared to be a safe and well-tolerated option for older adults. So augmentation does work in older adults. But that study didn't answer really the key question, which is, should we augment? Because after all, you can always switch treatment, right? If you have a patient on a medication, you've optimized the dose, and they're still depressed, you could always switch it. And the question is, by augmenting, do you have more medications, more benefits, or do you have more medications, more problems? So back to the clinical trial drawing board, as it were, and this is data that we just published in this past year in the New England Journal of Medicine. And I do want to thank my colleagues on this, including Dr. Karp, who's the senior author of that paper. I'm going to walk you through those findings now. This study, which we called Optimum, was a study where we randomized people with treatment-resistant depression, so non-responder to at least two adequate antidepressant trials, where age 60 or up, to either aripiprazole augmentation, or bupropion augmentation, or a switch to bupropion. Those three treatment choices were made because of a consensus from a poll of APA member psychiatrists who suggested this. If they did not remit in that first phase, or had already tried one of those treatment options and remitted, they went into the second step, or second phase, where we tried what we called some oldies but goodies, augmentation with lithium, or switch to the tricyclic nortriptyline. I'm going to show you the results now. These are, what you see in the red boxes, are the sample sizes of each cell. So a little, about 200 plus in each arm, which allows us to have some confidence about these findings. We actually used an outcome measure called psychological well-being, which was chosen by our patient stakeholders as a primary outcome, measuring aspects like positive affect and life satisfaction. And to give you a sense of the data, a standard deviation in psychological well-being is 10. Okay, so if treatment was going to increase that by 10, that would be a really huge effect size. So what you see is a smaller than that, 4.8, but still a substantial increase in well-being in people who received erypiprazole augmentation, a similar one with bupropion augmentation, and a smaller improvement or change in psychological well-being with bupropion switch. So from this primary outcome, we were showing augmentation approaches, particularly erypiprazole augmentation, beating switching. I think those of us clinicians are usually used to looking at remission rates, and so I'm going to show you those here. 29% with erypiprazole, 28% with bupropion augmentation, versus only 19% with bupropion switch. So again, the conclusion from both of those effectiveness outcomes, augmentation beats switching. Okay, but what about risks? I showed you the greater benefits. What about the greater risks? It's hard to compare risks in clinical trials because any single bad outcome probably is unlikely, but there is one risk that we can look at that's common in older adults, and that's falls as a risk of depression treatment. It's important because falls are common and serious in older adults, and it's important in antidepressants because it's plausible. Antidepressants can cause orthostasis, dizziness, reduce reaction time, and changes in balance and gait. And a study like this is somewhat ideal, a head-to- head comparison that can find a fall-prone medication based on having a higher fall rate. So at each study visit, at each follow-up visit every two weeks, we asked about falls since the last visit. I'm going to show you the fall rates now from those three arms. So this is a rate per 10 weeks of treatment. So you see with erypiprazole augmentation, 0.33. In other words, one out of three patients in 10 weeks of treatment. Does that seem high, low to you people? High. Yeah, me too, right? We usually, as our geriatrician colleagues, usually report to us a rate of falls in older adults one out of three in a year. This is only 10 weeks. So who wants to guess, higher or lower with augmentation with bupropion? All right, some of you read it, but most of you didn't read the article. Higher, actually, 0.55. Relatively speaking, 67% higher. And then sort of an in-between with switch to bupropion. And this was a significant difference. So remember how I showed you augmentation in general is more effective than switch. Among those augmentation approaches, however, erypiprazole had the lower fall risk and therefore came out ahead in terms of safety. Then recall I said there was a step two that, although it had lower sample sizes, still had over a hundred per arm. We didn't find a whole lot of difference between the two treatment arms there. So you see about a three-point increase in psychological well-being and a 19% remission rate with lithium and sort of similar with nortriptyline switch. In other words, those oldies were not such goodies after all in this. But what that allows us to do is really get somewhere with an evidence-based algorithm now with multiple steps. And this is the the algorithm that we propose. Again, start with an SSRI. Again, we're talking about a treatment-naive person, right? Certainly if they had already tried an SSRI, then you move further down the algorithm. But start with an SSRI. Start one that's easy to use. And the chances of remission are rather high. Now I'm guessing none of us in this room very often treat treatment-naive people, but we probably work with primary care doctors and others in models like collaborative care. And so this is important to know. Second line, SNRI. Preferring venlafaxine, desvenlafaxine, or duloxetine because of favorable profiles. Still a pretty good chance of remission. Third, augmentation. After two trials, augmentation. Our data suggests prefer aripiprazole, realizing that you wouldn't always use that drug. You can see the remission chances going lower, but still a significant chance of remission. And then after that, we think it's probably time for neuromodulation or ketamine. All right. I hope I kept within my time and ready to move on to our next speaker. We're trying to do some rapid-fire talks here because we realize it's late in the meeting and we want to keep you all entertained and keep things moving. So we will have time for questions at the end, so please, that will encourage you to stick around to the end. So our next speaker is my good friend Meryl Butters, who is a neuropsychologist and professor of psychiatry at the University of Pittsburgh. Her research focuses on factors that influence cognitive functioning in older adults, especially the pathophysiologic mechanisms that explain the varied long-term cognitive outcomes of mood disorders. And she told me that the scientific discovery she's most proud of is showing that impaired cognitive function in older adults who remit from late-life depression generally does not improve upon remission, and that leads to the discrediting the still widely taught concept of pseudodementia. So Dr. Butters, please come on up and teach us. Thank you, Jordan. Thank you for including me. This is really a very exciting panel to participate in, and I want to thank the audience for sticking around to almost the bitter end of your conference. I think we're in good shape. Is that OK? Perfect. OK. I just want to make sure that the pointer is on, which it's not. You might not have a pointer. The thing right in front of you. Cursor. Where's that? Well, not over there. There was a way to do it on the screen, but that's OK. It'll be OK. OK. So the title of my talk is Mood Matters, Depression and Risk of Dementia, because that is what I study. Here are my disclosures. I don't have any other than NIH grant funding. Before I get to the meat of my talk, though, I want to actually sidetrack for just a moment. Whenever I give a talk on this topic, I always get the same question, so I'm going to try to head it off, which is, when you talk about late-life depression, who are you talking about? Are you talking about people who have been depressed before, and are depressed again? Are you talking about people with new-onset late-life depression? So I want to head this off with this slide, and just say that late-life depression, in research, usually there are people with a major depressive episode, and someone who's usually over about age 60. It may be a recurrence in some people who are vulnerable to depression. Most of those people had early-onset depression, meaning their first episode was years ago. It also, though, may be a psychological response to an early, mild cognitive loss due to a pathologic process in the brain. And most of those people are late-onset, meaning this is their first episode. Maybe it's their second episode, but their first episode was later in life, and it's really related to a reaction that's turned into a major depression. It also may be, oftentimes we think, the leading neurobiologically-driven symptom of a neurodegenerative process. Almost all the time, these are late-onset cases. So for example, if you're developing Alzheimer's disease, or you've had some strokes, and an area that's important for mood regulation gets hit, you may develop an episode of major depression. But my main point here is that regardless of the subtype or phenotype I've just spoken about, the clinical, cognitive, and neuroimaging presentations are usually not distinctive. So inclusion criteria and research studies that I'm going to be talking about in the field in general are usually very broad, because we suspect that regardless of the etiology, major depression, especially difficult-to-treat major depression, can be neurotoxic and can contribute to cognitive decline and neuroprogressive disorders. So hopefully I've cleared that up, so now we can move on with the meat of my presentation. So this is what I'm going to talk about. First, I'll talk about the neuropsychology or cognition of late-life depression and the neuropathology of late-life depression. Then I'll talk about risk of future dementia, and pathways and mechanisms linking depression to mild cognitive impairment and dementia, and then some recent approaches to kind of lighten things up, some recent approaches to examining the interventions to preserve cognitive function in depression. So let's talk about the cognitive features. Cognitive impairment is broad-based, substantial, and highly prevalent. About 50% of people with late-life depression have significant cognitive impairment, and short of dementia. I'm not talking about people who have dementia and major depression. I'm talking about people who present with depression. When you actually test them, 50% fall in the range of mild cognitive impairment, meaning that they perform more than a standard deviation below the mean on multiple cognitive tests. And this impairment, as Jordan mentioned, actually persists after remission. I'm going to show you some of that data in just a minute. Meaning that pseudo-dementia, the concept of pseudo-dementia that we were all trained in, is actually pretty rare. And also, there's a substantial risk, but it's double, of progressive cognitive decline, even among those without initial impairment, even among depressed people who present cognitively normal, are at double the risk of developing dementia in the ensuing years. So first, I'm going to talk about these first two, the impairment being broad-based and persisting. This is a study, there have been about 10 or 15 studies now over the last 20 years that have led to those conclusions. This is by far the largest of those studies, which is why I'm going to show it in particular, but they all pretty much back one another up. And they've been done by a variety of groups. This one happened to have been done by our group and was particularly large, and is one of the later studies, which is why I want to use it to make the point. This was a large study we did at the University of Pittsburgh that had three groups of depressed patients. So can you see the cursor here on the screen? No, so there's not enough of a cursor, okay. We had a group of never-depressed participants, a group of participants who had recently been depressed and just been treated to euthymia, so they now had normal mood, but they had recently had an episode of depression. And we had a group of 120 currently depressed people. So basically there's a group of controls who've never been depressed and then two depressed groups, one currently depressed, one currently euthymic. And we gave them a battery, large battery of neuropsychological tests, and there in the panel on the right, each, I wish I had a pointer, but each graph represents a different cognitive domain. So the first one on the top left is general cognition, and then we have delayed memory, executive function, attention and processing speed, and then the bottom two is verbal ability and visuospatial ability. And within each cognitive domain, we gave multiple tests, and that's what all the different sets of bars are. They're different individual tests that fall in that cognitive domain. And a participant's performance is represented in the bars. Black bars are the never depressed group, the light gray bars are the now euthymic but recently depressed group, and the medium gray bars are the currently depressed group. And the point here is this. All of the tests that I have circled in red here, in all of these tests, there's a significant difference between the never depressed normal control group and both depressed groups. And the first point I want to make is what you'll notice is there are tests in every domain, and in fact, multiple tests, in particular in delayed memory, executive functioning and attention and processing speed. They're highly impaired in people with depression. And there's even one verbal test and one visuospatial test, which also the depressed patients were impaired on. So the point here is this is kind of trying to get home the point that the cognitive impairment related to depression in late life is very broad based. It covers almost all domains, some more than others, but really all of them. The other point I want to make is that in each one of these tests circled in red here, the two depressed groups, meaning the one that was recently depressed but is now euthymic, and the one that is currently depressed, both performed the same as one another. There was no statistical difference in their performance and worse than the controls. So the point is that whether people were remitted and euthymic or they were still currently depressed made no difference in their performance. It was still worse than control. So this is really good evidence that the impairment that presents itself or the people experience when they're depressed generally does not improve once their mood improves. And then finally, there are just two tests in this whole large battery, one verbal and one visuospatial, clock drawing and a naming test, in which actually the two depressed groups differed and the ones who were currently depressed performed worse than the ones who were euthymic. But that's it, two out of 20-something tests in which that's the case. The vast majority, it's the two depressed groups that performed virtually the same as one another relative to the never depressed people. So that's the evidence that cognition is broadly affected and that impairment does not usually improve once mood improves. I now wanna talk a bit about, so if we have all this cognitive impairment, there's probably something going on in the brain that's causing it, right? Separate from their mood disorder. And I wanna talk a bit about the neuropathology of late-life depression, but I'm not gonna talk a lot about it. Just this is my only slide, really. There's evidence, there's a substantial evidence, a lot of evidence collected over the last 20 years or so, that there's a lot of cerebrovascular disease and Alzheimer's disease pathology that coexists in people who have major depression in late life. There are also a lot of structural brain abnormalities. In particular, the people have smaller prefrontal cortex, basal ganglia structures, and hippocampi. And these reduced sizes, we don't know whether they're shrunk or whether people were born that way, we can get into a chicken and egg debate, but these smaller brain structures are actually often associated with clinically relevant features, aside from their cognitive impairment. So this is just an example and there are many more, but for example, hippocampal volume is related to the time spent depressed over a course of a lifetime, so the people who've spent more time depressed have smaller hippocampi. Another example is from our new Optimum Neuro study, which is an add-on study to the Optimum study Eric just talked about a few minutes ago in treatment-resistant late-life depression. We're just now starting to look at the results, but I'll talk more about it in just a minute, but our earliest Optimum Neuro finding suggests that brain structure, in particular the anterior cingulate, is associated with treatment resistance. So my point is that many of these structural abnormalities actually have clinical significance. So, now I wanna get back to talking about the depression and the risk for future dementia. When I first started in this field 25 years ago, there was a kind of a hint. People had done some retrospective analyses of medical charts and there was a hint that people with late-life depression were at increased risk for dementia, but no one really knew. And over the last 20 or 25 years, there's been a lot of work in this area. And this is a meta-analysis that our group did. This was a follow-up to another meta-analysis someone had done a few years before, and I think there's been one since. They all show the same thing. We gathered together all the studies, the large epidemiologic studies or large studies of community-dwelling older adults, and there are a lot of them now, that have collected data on folks in the community, both cognitive data and mood data, at multiple time points in a longitudinal manner. And we looked at the results so that you could see people's mood at one time point, and then you could see their dementia rates at a later time point. And in fact, it turns out that the best, that almost all of the studies show increased risk for dementia among people who've had a depressive episode, actually not just in late life, but at any time in life. So a depressive episode at any time in life basically doubles your risk of developing dementia when you're older. And again, this has been replicated again and again now. So, if people have, if there's broad-based cognitive impairment that doesn't improve and often declines, and often progresses so that people develop dementia, what are the pathways and mechanisms that link depression to mild cognitive impairment and dementia? It's an important question because that's what's going to lead to targeted treatments. If we understand the mechanisms, we can know what to target in order to prevent or manage the dementia risk that people with major depression have. So I'm gonna talk now a bit about what some of these pathways are. So the relationship between the prevalent cognitive impairment, cerebrovascular disease, Alzheimer's disease pathology, and other structural abnormalities in the brain, and the increased risk for dementia has really been difficult for researchers to reconcile because there's kind of a lot going on when you think about it. The big picture consists of, likely consists of multiple phenotypes of course, of cognitive course in depression characterized by different pathophysiologic processes with different long-term trajectories and outcomes. And the challenge for researchers in this area is to identify the phenotypes in their associated markers, identify their trajectories and the underlying mechanisms all in order to identify targets for intervention, right? So I don't have time to actually go through this slide. If someone asks me in the Q&A, I'll be happy to talk about it, but these are some kind of prototypical phenotypes that we believe exist in late-life depression. I'm gonna skip over it for now because I don't have time. And I wanna say that the hypothesized pathways basically are this. Late-life depression's associated, we believe, with neurotoxic processes. For a long time, we thought that people with depression produced more beta-amyloid, which is one of the really bad proteins associated with Alzheimer's disease. That's here because it's still talked about and written about, but there've been two very recent studies, one by Scott Mackin at UCSF and one by us in Pittsburgh that have now showed us that actually depression's not associated with increased amyloid. So it's not causing, depression's not causing people to collect more amyloid leading to Alzheimer's disease. We can kind of take that off the table. But depressed people do produce more glucocorticoid and have inflammation. And a more recent finding, that's also in red, is our colleague, Brenna Denise at University of Connecticut has been examining molecular senescence, which I'll talk more about in a minute, in late-life depression. And all of these, or some combination of these, plus maybe things that we haven't measured yet, we think serve to lower brain reserve, increase the risk of expressing cognitive impairment and crossing the threshold of clinical dementia. And I'm gonna show this in a picture now, which may make it a little easier to grasp. So people who develop depression, if you look way over on the left, we know that there's HPA axis dysfunction occurs in major depression, which leads to increase in glucocorticoid output. And we think that's what's driving the reduced hippocampal volume, the smaller hippocampi in people with depression. There are a lot of glucocorticoid receptors in the hippocampus. We think that all the overproduction basically wears them out. They become apoptotic and die. And therefore, the hippocampus shrinks. Depression's also associated with chronic inflammation, like I mentioned, which activates the endothelial lining of blood vessels, leading to vascular disease, cerebrovascular disease in this case. And cerebrovascular disease is a predilection for the frontal striatal area underlying the frontal lobes, leading to frontal striatal ischemia, and therefore, executive impairment. And then as I said, our colleague, Renaud Denise has been studying this concept of molecular brain aging, which really are molecular processes involved in immunoflammatory pathways related to cell damage and cell health, and to vascular health, leading basically to premature brain aging is what he's finding. And we think all of these, the hippocampal atrophy, the frontal striatal ischemia, and the accelerated brain aging all lead to a reduction in brain reserve. Now, brain reserve is this concept that we all have more circuits than we need to function. That's why you can have a concussion earlier in life and fully recover and go on and have a normal life. But your brain reserve is likely lowered, meaning the excess, excess circuitry gets reduced. And we think the same thing's happening in depression. Because of all these neurotoxic processes taking place, it probably leads to a reduction in brain reserve, which is not really measurable before old age. But what happens is, as you get older, if you're developing Alzheimer's disease, and remember, we don't know what causes Alzheimer's disease and it's the most common form of dementia. It accounts for 70% of dementias. If you're getting Alzheimer's disease and you collect the AD pathology in your brain, if you have reduced brain reserve, it will reduce the amount of time to a clinical dementia diagnosis. So that's the mechanism by which we think depression actually leads to this increase in dementia. It's really by lowering brain reserve because of neurotoxic processes that occur. I'm gonna skip over this, which is really just another example of how brain reserve works. So just in summary, late-life depression is common, heterogeneous, and complicated, and frequently accompanied by persistent cognitive impairment that frequently progresses. Pathways and mechanisms linking depression to increased risk for dementia likely involve multiple biologic pathways, including inflammation, glucocorticoid overproduction, leading to cerebrovascular injury, and hippocampal atrophy, as well as poor cell health and molecular senescence, or accelerated brain aging, which reduce brain or cognitive reserve, increasing risk for dementia. And multi-method approaches that measure multiple candidate neurotoxic processes simultaneously may be the best way to disambiguate the pathologic processes in order to confirm the mechanisms of decline, and therefore identify intervention targets because that's really what we need, are intervention targets. And then finally, there is a new frontier, which I'll mention briefly, which is that there are now a number of novel interventions. Even though we haven't identified all the targets yet, there are now novel interventions being studied to improve reserve and cognitive function and forestall cognitive decline in people with depression. So this is an example of a study that uses the multi-method approach. This is what we call our optimum neuro study, where we examined a subset of the people in the optimum study that Eric described, the study of treatment-resistant late-life depression. And this study is just wrapping up now. In fact, our study ends in July, and we're just now starting to look at the data. And it's based on the premise that patients with treatment-resistant late-life depression represent one of the highest risk groups for progression to dementia. And we're trying to answer two questions with this study. One is how, meaning through which neural circuits and biomarkers does treatment-resistant late-life depression accelerate cognitive decline and lead to dementia? And two, does successful late-life depression treatment mitigate that risk? And in this study, we've assessed about 500 treatment-resistant patients. It's a huge study across five sites. Patients are at mean age is about 72. We've collected MRI, blood-based biomarkers, and cognitive data at baseline, six and 24 months in all these treatment-resistant patients. And we've also adjudicated cognitive diagnoses on everyone. So we've figured out whether each and every person, whether they're cognitively normal, have mild cognitive impairment, or dementia. And in the very early results, which we've just started looking at now, we have a paper in preparation, we're finding that brain structure and function actually are related to cognitive function, which should be the case. It's nothing new there. But it's reaffirming that we're finding it. We're also finding that worse brain structure and cognitive function is associated with ongoing treatment resistance to antidepressants. And stay tuned for more, I think, in the next four to six months, we'll have a lot more coming from this study. And then the final thing I was gonna talk about are, okay, our recent approaches to examining interventions to preserve cognitive functioning in depression. And I'm not gonna go through them. I won't go through the findings. Just so people are aware, there have been studies of the effect of, the MTLD3 study was done by Chip Reynolds in Pittsburgh and looked at whether or not Dinepazil can preserve cognitive functioning in people with late-life depression. We've had several studies now going on, looking at whether physical activity, either augmented, either as a pharmacotherapy augmentation, or on its own, can forestall cognitive decline. Sarah Morimoto at University of Utah is studying a cognitive remediation protocol to see whether that can both improve mood and forestall decline. A large study at University of Toronto by our colleagues Tariq Raji and Ben Molson have just found that transcranial direct current stimulation can actually forestall decline in both executive functioning and memory in people with late-life depression. And the last two studies, the one I'm not gonna talk about, but the other one is another study of physical activity that's ongoing at University of Pittsburgh by Dr. Swati Gujral, trying to see if physical activity can forestall decline in people with late-life depression. And that is it. So thank you for your attention. Thank you. Thank you, Dr. Butter. Let's give Dr. Butter another round of applause. That was... Thank you. Thank you. Thank you. Thank you. She did her whole career of 25 years of doing this in 20 minutes, so amazing. Again, I wanna thank you all for hanging in there with us. Two more speakers. We're gonna keep things moving and then we will have time for questions for sure. So, our third speaker is Dr. Olu Agilore. He is professor of psychiatry at the University of Illinois and director of the Center for Depression and Resilience. His research is at the intersection of neuroimaging and digital biomarkers to better track and treat mood and anxiety disorders. And he told me that he considers the biggest unmet healthcare need in geriatric psychiatry is building upon what Dr. Butters just taught us about preventing or treating cognitive decline. So, please come on up, Dr. Agilore. Thank you. Great. Thank you, Jordan, for that introduction, and thank you for inviting me to be a part of this panel. I'm really glad to see all of you here. I thought we were going to talk to about five people, given that this is the last day and close to the last session. So today I'm going to talk about the REMBRANDT study, which stands for Recurrence Markers, Cognitive Burden, and Neurobiological Homeostasis in Late-Life Depression. This is a multi-site study that I'm doing with my friends and colleagues at the University of Pittsburgh, led by Carmen Andrescu, and Vanderbilt University, led by Warren Taylor. Here are my disclosures. Everything that I'm going to talk about was funded by NIMH. So the motivation of the REMBRANDT study is the fact that we know that late-life depression is associated with a great deal of disability, and as you heard from Dr. Butters, it's associated with cognitive decline and dementia. It's also associated with an increase in all-cause mortality. And in addition to being very difficult to treat, we see very high rates of recurrence in late-life depression, up to 43% within a two-year period. And some of the clinical risk factors that we know that are associated with recurrence include things like depression history, so how many previous episodes did your patient have, or how severe were those episodes, as well as residual symptoms like increased anxiety or insomnia being associated with a higher risk of recurrence. Sometimes we can see persistent problems like negative affect or rumination, which may be associated to the cognitive deficits that Dr. Butters talked about. That is also associated with a higher risk of recurrence. We also know that there are some predisposing factors. Stressful life events, we know, can precipitate a recurrence in our patients, but there are also protective factors, things like increased social support and physical activity. In addition to these clinical risk factors, we're interested in seeing what might be some underlying neurobiological risk factors associated with recurrence. And for that, we look towards functional magnetic resonance imaging, particularly resting-state fMRI, where we've seen alterations in functional networks that persist into the remitted state, similar to the cognitive problems that you saw persisting even in the euthymic state for older adults with depression. Some of the things that have been shown are less connectivity between the default mode network, which is associated with brooding, rumination, self-reflection, as well as less connectivity within the central executive network during cognitive tasks. And the central executive network has been strongly associated with executive function, cognitive function, and so we see less connectivity in these networks associated with a higher risk of recurrence. And then we also see increased activity and connectivity in the salience network that seems to be correlated with the number of prior depressive episodes. In all of these networks, we see that stress reactivity, which can also be a risk factor for recurrence, is associated with alterations in all these three networks. And we think that this stress reactivity is related to affective instability. And it turns out that all of these clinical neurobiological risk factors for recurrence are also associated with an increased risk of cognitive impairment in the context of late-life depression. So the specific aims of the Rembrandt study is to look at what might be some of these neurobiological risk factors associated with recurrence within a two-year period, and then to see if that in turn is related to cognitive decline in these same participants. And then we also are doing some extensive assessments to look at whether we can predict when recurrence may occur using some of the data that we're collecting that I'll talk about in the next couple slides. Here is our overall model linking these three aims where we're looking at the relationship between alterations in these functional networks, how those may be in turn related to cognitive decline, destabilized by external factors like stressful life events, and how all of that can lead to a worsening of symptoms. And then with the cognitive decline piece, we're not only interested in seeing if there are state shifts in cognitive performance, but whether variability in cognitive performance might be a salient signal for increasing risk of recurrence. So to do this across all three sites of our study, we have two phases. We have an initial treatment phase where participants can come into our study already depressed, and then we treat them to the point of remission. And then once they reach remission, then they enter into the longitudinal phase of the study where we're following them for two years. And every eight months, we get multimodal neuroimaging scans. We do extensive ecological momentary assessment, asking about mood, energy level, social activity. We also have them wear a Fitbit during this time. And then they also do mobile cognitive assessment, which I'll talk about. This first phase, the initial treatment phase, was informed by the work that you heard about from Dr. Lenz, where we use a treatment algorithm stepwise, very similar to what you just heard earlier today. And about 63% of our patients that entered into the longitudinal phase of our study in remission reached remission using this treatment algorithm. We also have an extensive neuropsychological battery developed by Dr. Butters to look at things like executive function, memory processing speed across a whole range of domains. And then we're also doing this ecological or mobile cognitive assessment using an app called the Ambulatory Research in Cognition, developed by Jason Hasselstab at Washington University. And this is a on-device smartphone-based cognitive assessment tool that looks at different domains like processing speed, memory, and working memory. And the ability of, or what we can get out of the Ambulatory Research in Cognition app is to look at these fluctuations in cognitive performance that might not be obvious when we use a standard neuropsychological battery. When looking at our imaging protocol, we have a multimodal neuroimaging protocol where we're doing task-based fMRI using the multisource interference task, which is designed to induce a stressful-like situation in the scanner. We also have a resting state scan, a diffusion imaging scan, and structural scan. Let me highlight some of our preliminary findings to date. We have 171 remitted participants in our study and 85 never-depressed controls enrolled. We have over 500 scans that have been collected over the two-month study period, as well as 447 ecological momentary assessments and mobile cognitive assessments over that two-year period. I mentioned that we had about a 63% remission rate for the initial treatment phase. And then during the longitudinal phase, we have about a 42% relapse rate, which is exactly what we expected. Some of our very preliminary findings is that we were able to replicate some of the work that's been published by other folks, showing that things like age of onset or episode severity as indexed by antidepressant treatment intensity is a significant predictor of recurrence. Medical comorbidities like fatigue or high VMI has been associated as a predictor of recurrence. We see poor social support or an increase in life stressors, as predicted, is associated with recurrence. And then we also see some measures of disability that are associated with recurrence, both overall disability as well as specific domains of disability around self-care and interpersonal interactions. I'm going to talk in more detail about neuroimaging, but some of our initial findings suggest that white matter hyperintensity burden is associated with recurrence. And this also might be reflective of the cognitive deficits that you heard about from Dr. Butters. And then what's really interesting and might be a point of intervention, per what you've just heard, is that activity seems to be differentiating who remits, stays remitted, and who relapses. So basically, the lower your step count, the lower your physical activity, the more likely you are to have a relapse. So I'm just going to zero in on this model and focus on network instability and highlight some preliminary findings from our resting state functional imaging, where we looked at instability in functional networks by looking at something called dynamic functional network connectivity. This analysis was done in our baseline sample. We had 40 folks that were never depressed, 50 that stayed remitted throughout the two-year period, and 33 of our participants that had a relapse at any time. Here are the subject characteristics. There are no real differences on age. Both the remitted and the folks that go on to have a relapse did slightly worse on various cognitive assessments. When we did the resting state analysis, we did something called coactivation pattern analysis, which basically looks at what brain states exist during the resting state scan over time, and how often do people stay in these states over time. And we can look at transition between states or the tendency for people to stay in a state once they're in that state, and that's a measure of network stability. We got three networks out of this analysis, basically the same networks that I told you about before. The default mode network that's shown in blue, that's CAP2. We have the salience network shown in red, that's CAP3 or coactivation pattern, sorry, coactivation pattern 1. And then the central executive network is in green, that's coactivation pattern 3. And when we look at how stable are these networks over time in our participants, we see a pattern that those who stay remitted and those who have a relapse had lower network stability of the salience network compared to their never-depressed counterparts. When looking at the network stability of the default mode network, we see a pattern where the relapsers had worse network stability compared to the remitters, and the remitters had worse network stability compared to those who were never depressed. And then finally looking at the central executive network, we see a very similar pattern where there seems to be an effect of having had depression at all on the network stability such that both the people who stay remitted and those who have a relapse had lower network stability compared to the never-depressed controls. We did a survivor analysis looking at time to relapse based on network stability, and overall there was a pattern that lower network stability in the default mode network seemed to be predictive of time to relapse, but it wasn't quite significant because of our small sample size. I also looked at whether these network stability metrics are associated with some of the persistent cognitive deficits that we see that persist in the euthymic state like rumination, and we see that in the never-depressed controls and in those that stay remitted, there was a significant association between network stability of the central executive network and rumination such that the more stable that network is, the less they were ruminating, but we did not see that pattern in those that relapsed. Similarly, we see an association between salience network stability and strew performance in those that were never depressed and those that stay remitted, but we did not see that pattern in those that relapsed. So some interesting associations between some of these persistent clinical features that are associated with recurrence and measures of functional network stability. So I just want to end by referencing a couple papers. This one was published in the American Journal of Geriatric Psychiatry that lays out the theoretical framework for the Rembrandt study, and then we have a protocol paper out in the Journal of Mood and Anxiety Disorders that describes the protocol. And I just want to conclude by saying that we can see that late-life depression recurrence is associated with a number of risk factors that have associated neurobiological correlates, and we hope that by better understanding these factors, we can come up with tailored interventions that will help our patients stay in the remitted state. So with that, I'd like to thank my co-PIs, Warren and Carmen, and the entire Rembrandt study team, and thank you for your attention. Okay, we have one more talk, and you guys are hanging in there, so I'm going to encourage everybody to stand up and just stretch for a minute. You all deserve it. We'll help you concentrate a little bit more. It's been a long day. Say hello to your neighbor if you're sitting next to somebody you don't know. That's great to see. Are those new? Yeah. Okay. Are we having another DSMV meeting? Let's get back to work. My talk is trying to meet the challenge of putting this all together, and I hope that what I'll share is practical and useful for you in your care of older adults with depression. This is my disclosure slide, and this is what I'll talk about today, and my talk's only at the most 15 minutes, and then we'll have time. We're ahead of time. We have time for questions and answers. I'd like to start by talking about four concepts, so clinical inertia, ageism, homeostasis, and homeostenosis. Then I'll move on to the geriatric 5Ms that you must know about if you're taking care of older adults, some clinical pearls, and talk about some moderators that matter when you're taking care of late-life depression, and then some tips for successful treatment of late-life depression, and responding to Dr. Ron Winchell, who's our moderator, and encouraged me to include something about ECT and late life. I included some practical things to share with your patients, especially about cognitive concerns of using ECT in older adults. Let's start with this question. What is the point? Because getting old is depressing. Isn't depression part of getting older? I would say the fact that I asked this question at all speaks to this concept of clinical inertia, maybe therapeutic nihilism. Let's talk about what is clinical inertia in late-life depression treatment? I'd say it's not establishing the optimal dose that you know is going to help your patients get well, or not changing the treatment when people are not improving or there's residual symptoms. And why does it happen? I think the big thing to remember is that we accept that better is good enough, and it's often due to time limitations and both implicit and explicit agents and bias. If you take one thing from my talk today, I hope it's that you appreciate that clinical inertia or therapeutic nihilism is one of the biggest risks to the effective treatment of late-life depression in older adults who have access to care, because the majority of older adults don't have access to high-quality mental health care. And compared to treating other conditions like diabetes, hypertension, pain, cancer, treating depression reduces something that we can call bothersomeness. That's a funny word, but it means something. These other conditions become more bothersome. They have more disability if they are confounded by depression. So treating late-life depression may be the most effective way to lower costs, to improve late-life quality of life, and to reduce all-cause mortality, both by suicide and other medical conditions. Well, I hope that you or your family never look like this guy when you go to see a health care provider. And this is a poster from the World Health Organization's Global Campaign to Combat Ageism. It's very cool, and I encourage you to check it out on the World Health Organization's website. But it's useful for us to define what ageism is. We talk about stigma a lot in psychiatry. There's been other talks about stigma at the APA. I don't think we talk a lot about the stigma of ageism or the stigma of body shape. I think those are maybe two of the sort of still acceptable stigmas that exist in our society today. But ageism refers to the stereotype. So it's how we think, prejudice, how we feel, and discrimination, so how we actually act. There are implicit ageist behaviors, so talking down to patients using elder speak, like, oh, honey, or oh, sweetie, you shouldn't talk to an older patient that way. Not including them in medical decision-making, and maybe a lack of patience. Explicit ageism is something that we really need to be concerned about. So it is prioritizing the care of younger people over the care of older adults. Well, I'm interested in clinicians' attitudes about older adult patients, and to prepare for this talk, I found this article called Attitudes to Aging Amongst Healthcare Professionals, a Qualitative Systematic Review, and I put it in this computer program that creates word clouds, and it made this word cloud for me, and these are some of the words that came up. Rejecting, impatient, complex, nuisance, dehumanizing, disempowering, unwanted, neglect, vulnerable, unworthy, dissatisfied, helplessness, nihilism. We don't always hear this when taking care of other populations. But I wanted to do a deeper dive into my own feelings about working with older adults. I'm a geriatric psychiatrist. I love working with old people. And so I took the Project Implicit test for ageism, and if you don't know about Project Implicit, you should check it out. It's a Harvard program. You can test your implicit bias for race, gender, class, all kinds of things. I did it for ageism, and it told me that about 75% of the other respondents had either a strong, moderate, or slight preference for older adults compared to younger adults, and I also had an automatic slight preference for younger people over older people. So this is something that I was not aware of. I thought, oh, I'm perfect in this regard, but I still have work to do, and I think that all of us in the room have work to do when we're caring for older adults, because it does affect our sense of inertia and therapeutic nihilism. So let's move on to these concepts of hemostasis, homeodynamics, and homeostenosis in late-life depression, and in many ways, this is the bread and butter of geriatric psychiatry, and this really builds upon what Olu and Merrill and Eric have been teaching us. I'm just trying to maybe make it a bit more practical, but they are advancing the science, and then part of the rest of our jobs is to help to disseminate it and get it into the clinic. But I'm sure that everybody here is familiar with the concept of homeostasis. It's the maintenance of stability of an organism or a system in the face of change. You may not be as familiar with this concept of homeostenosis, which is the constriction of an aging organism's ability to effectively respond to stress. Think about spinal stenosis. It's a constriction of the spinal canal. So preserving functional reserve, and Merrill spoke about brain reserve, which is different than brain as an organ. I mean, we all have physiological reserve, and then we have functional reserve. And so here is an old man. The B is biological, the P is psychosocial, and the S is social, and he is intact. He's doing great. He has all his medical problems controlled. He is not depressed. He is resilient. He is wise. He has a good social network, but he has a hip fracture. So his biological reserve has taken a hit, but he's not depressed, as I said. He has a good sense of humor. He is looking at this with optimism that he's going to get better, and he has an intact social network. So there's really no impact on his overall functional reserve. He's going to make it. He is not moving towards frailty. But say this old man has a hip fracture. He is depressed, and he stops socializing. Well, there are big hits on his functional reserve, which then takes a toll on his physiologic reserve, and he is more likely to become frail, ill, and die early. I hope that people here have heard about the Geriatrics 5M. So raise your hands if you have. If you haven't, I encourage you to look at this article from Tinetti, et al., in JAGS in 2017, Mobility, Mind, Medications, Multicomplexity, and What Matters More. and what matters most are how we should approach our care with older adults in geriatric medicine and geriatric psychiatry. I'm just going to focus on multi-complexity, which is going to build a bit on what Dr. Lenz was speaking about, and I hope that you'll consider how this may continue this idea of homeostenosis and functional reserve. So multi-complexity means being not just a psychiatrist, but you also have to behave as an internist or a family medicine doctor. So helping our older adults and their families manage a variety of health conditions. We also have to be a social worker. So assessing the living conditions that are impacted by age, health, and social context. So how do you do this? When you are working with an older adult to assess their multi-complexity, you want to be sure to ask about pain, loneliness, diabetes, cognition, driving, and finances. And I share this very complicated anecdote that Dr. Lenz brought up in his talk, which made you all giggle, but it's true, right? This is the common patient that we treat in the clinic. These patients are ill and complicated. And I would say that probably you're familiar with this curve. We used to call it the Kupfer curve because David Kupfer was the first to publish it. So it describes the acute continuation and maintenance treatment of depression and then the five R's. So response, remission, relapse, recovery, and recurrence. We can get older adults well, as Dr. Lenz shared with us, but this red squiggly line that I added over the continuation and maintenance phases of treatment illustrates the brittle response that many older adults have during their treatment for depression. I think it's because of multi-complexity. We can get people well, we can keep people well, but they need some more TLC and attention, and we need to address the multi-complexity to keep them well. And much of my work, much of my career has been identifying moderators and predictors of either non-response or a brittle response. So making sure that diabetes is effectively treated because diabetes, depression, and dementia are a toxic triad. Making sure that if patients have sleep apnea, their sleep apnea is effectively treated. And if patients have executive dysfunction, as both Dr. Butters and both Dr. Aguilore spoke to, being aware that we can get them well, but they may be at increased risk of recurrence. So CARP's six tips for successful treatment of late-life depression. Clarify if it's a single episode or recurrent form of the disease, because this guides how long patients should be treated, and some language that I use because patients don't want to be on an antidepressant for the rest of their life. They want to know that you have a plan. So I will, this is straight from my clinic. I consider depression treatment in six-month chunks of time. And at that time, we'll reevaluate the potential risks versus benefits of staying on or stopping the medicine. Charter a course, instill confidence, and set expectations. I hate to say it, but I do think there's a little too much shared decision-making with all of our patients. Our patients don't know what they should be asking for. If we are following an algorithmic, measurement-based approach to treatment, we should know, based on the evidence, what we should recommend and what should be coming next. And the placebo effect is an important part of what we provide. So showing that you are an expert and are confident in your decisions is important for good outcomes. So I'll say, let's consider treatment as an experiment. If what I'm prescribing doesn't work, I have a plan for what we're going to do next. If you have medical assistants or nurses, leverage them for an early check-in. Have them contact the patient in one to two weeks. 40% of people never fill their antidepressant prescription. People are troubled by early treatment emergent side effects. Many people don't have MAs or nurses. So just doing a quick phone call is really meaningful for patients. Engage family supports, especially if there's problems with cognition, because if families are not on board, especially in late-life depression treatment, treatment will be sabotaged. Again, assure that obstructive sleep apnea and diabetes are well-controlled. And I know that this is a pet peeve or a passion project of Dr. Lin's, is reducing nuisance medications and certainly screening for substance abuse. I will share, we've been speaking about the Optimum Study throughout this presentation today. We had a patient at the Pittsburgh site where I was the site PI, who we didn't know was misusing alcohol, and we didn't know he was taking more Xanax than was prescribed. He was, I think, the only death in the study, and he had a catastrophic fall down the steps with a head injury and numerous fractures because he was taking these two substances and we didn't know about it. And it changed our approach to safer management of patients throughout the study. So Dr. Lin's shared a version of this that if we start with an SSRI, an SNRI, augment with aripiprazole if we're concerned about fall risk, maybe using TMS or ketamine or S-ketamine, we can get a substantial number of patients well. But what about the 10 to 15, maybe 20 percent that we can't get well? First of all, I would say we need to revisit and clarify the diagnosis, re-evaluate cognitive status, social determinants of health, supports in residential situation, but again, you need to revisit the cognitive status because that's one of the special things about being a nuanced or sophisticated clinician working with older adults is understanding that neurodegeneration happens and often it presents with emotional and psychiatric symptoms even before we see cognitive decline. And finally, you could refer to an interventional colleague with the consultation question, please evaluate for difficult to treat depression and possible use of ECT or TMS or ketamine. So I'm just going to very briefly touch on the use of ECT in older adults. It works. It is safe. ECT has higher rates of response in people who are older compared to people who are younger and unilateral ultra-brief ECT has the lowest amount of cognitive side effects. So this is from the PRIDE study phase one. About 70 percent of patients were responders. You see a steeper trajectory that continues out to the 14th ECT treatment visit and by week three, about 75 percent of the sample had responded. So perhaps the biggest concern with ECT in older adults is the worries about cognitive side effects, which are actually quite mild when using ultra-brief unilateral ECT and the fact that it only works during the index treatment or if it's being used as maintenance treatment. But my colleague says this better than I could. So I have a podcast for the American Journal of Geriatric Psychiatry and I interviewed Vaughn McCall, who is an expert in ECT and I just love the way he describes concerns about cognitive problems for his patients. So I'm going to share this with you. People sometimes wonder about, well, is it still good for catatonia and we don't know for sure quite yet, but outside of catatonic presentations, I think high dose ultra-brief right unilateral ECTs is terrific. One thing I would say about how I advise my patients regarding the cognitive side effects of ECT is if we can use this low touch or light touch technique of the ultra-brief right unilateral, I'll tell the patients that there is a risk that they may have trouble remembering and maybe will even lose forever recent memories of the last couple some weeks, maybe even the last three or four weeks. I don't think it goes much further back than that and that they might not remember much of anything that happened during ECT itself such that if I were to interview them a year from now and quiz them about events around and about the time of the ECT course, they may have a very sketchy memory about it. On the other hand, presuming that I'm talking to an older person who may be decades into their, let's say, their marriage, I'll say you're not going to forget who your children were, you're not going to forget who your parents were, you're not going to forget what your life's work was, you're not going to forget getting married, you're not going to forget the vacation you took to Italy five years ago, but since Jordan, you and I are now speaking right after New Year's, I'll say, but you may forget Christmas or you may forget New Year's, maybe even parts of Thanksgiving, who knows, but that's probably about it. When you're quite frank and blunt about it that way, because I think those are reasonable expectations of the cognitive effects, my experience has been patients will say, you know, if I have an 80 plus percent chance of being myself again and I have to sacrifice some parts of my memory over the last number of weeks, maybe a month, that's a fair trade. I'm willing to make that trade. So I, as I've gone through my career, I felt less need to apologize for the cognitive side effects because the patients don't seem to want an apology from me. They just want to feel better. And the cognitive side effects, the way that ECT is done nowadays, from the patient's point of view, seems like a fair trade. I think that that's wise words from him and a really patient-centric kind way to describe that you may lose a little bit of memory during the period right before ECT, but the potential benefits and the chance that there's a 70 to 80 percent chance that you might get well outweigh those concerns. So I'm going to let you read this to yourselves, this top paragraph, because this is why we do this work. And I'll leave you with this comment or question or challenge. What can you do in your own practice to minimize ageism, clinical inertia, and support functional reserve when you're taking care of older adults with depression? So with that, I want to thank you for your attention. Again, you all are amazing for hanging in there with us. And we have about 10 minutes and would welcome your questions. We're going to alternate between live audience and people online. Thank you all very much. What do you do given the need to augment or the successful strategy of using atypicals for augmentation in late-life depression when you also have a patient with dementia? Not psychosis, you know, what do you do about the black box, warning which atypicals are better than others? I know ibuprofazol is recommended, but can you use those medications in those patients? Eric, why don't you take this? Yeah, and for those who don't know, the black box warning is based on many meta-analysis of old acute placebo-controlled clinical trials back when the pharmaceutical companies were trying to get atypicals approved for the treatment of agitation and dementia. The drugs worked, but the FDA found a somewhat higher, I think about a 1.5% or so higher mortality rate compared to placebo. And so that black box warning does not apply to people without dementia, but you're bringing up the issue of what about treating depression in dementia? I think the bottom line is we still don't really understand what was the cause of that elevated mortality. I like to think that it may have been caused by the fact that if you're upping within a short clinical trial, if you're upping that dose more and more to try to get agitation controlled, you might be heavily dosing someone and causing sedation, falls, etc. But there may be also, as you said, some sort of innately toxic effect of antipsychotics in older adults that we don't really understand. So I warn people about that, and I say, you know, we'll prescribe it as gingerly as possible, but this is that black box warning. But I wouldn't avoid using atypicals across the board in dementia, whether for depression or agitation, because of that. I just had a follow-up point about some work that Helen Kales published looking at different rates of mortality using a VA sample and showed that it seemed to be associated with the amount of D2 blockade that the antipsychotic has, and they saw the least sort of mortality rates with those that were prescribed quetiapine. I think an important thing is this is where shared decision-making and informed consent is important, because we do know that they work, not a lot of other options. So having that discussion and documenting it is probably the best thing you can do for your patient and to protect yourself. Hi. I'm a psychiatrist from North Estonian Medical Center neuropsychiatric clinic, and my question was about those brain networks that we talked about. It was really interesting. I was thinking about the effective instability which we have in so many ADHD patients and also borderlines and et cetera. Are they in a bigger risk for developing dementia therefore? That's one of the questions. Maybe we should take that question first. So Olu and Meryl, do you want to? There's literally no research on it. You also said ADHD, right? So I do know there's a study that there's a grant application, a colleague of mine is writing right now to study ADHD, and that's because, you know, now that people are diagnosed more frequently, we are actually now starting to see in clinic people coming in saying, I think I have ADHD, but someone also thinks that they're experiencing cognitive decline, and we have no data to tell us what normal cognitive aging, normal cognitive aging looks like in somebody who starts out with some weakness in executive functioning, like lifelong. And so what ends up happening is a lot of these patients get diagnosed with frontal temporal dementia, when in fact it may be normal aging, you know, where everyone experiences some mild decline in executive function, but if you already start out so low, you look demented earlier. I just had this kind of patients, and I was debating with my neuroclinical psychologist whether that's a person that has the lifelong as an artist, you know, lifelong like that, or is it now frontal temporal dementia? And I can tell you in our clinic what we end up doing is we see people, and we often can't tell, they're impaired, but we can't tell, and so we actually say we want them to come back in 18 months, and we'll use that initial assessment as a baseline, then we'll assess whether or not they're declining at a faster rate than we would consider normal, because by 18 months later, a dementia should declare itself. But there's really, we have no data, and no one has data on this yet, so that's, I think, due for some serious research, because ADHD now, I mean, I don't know that it's more prevalent, but it's obviously quite more diagnosed quite more often, and we just know nothing about what aging with ADHD looks like. In terms of personality disorders, there's just, there's no data either. But people living with high levels of stress or SMI, high levels of chronic anxiety, these are all just high stress states, right? And high stress states drive up glucocorticoids, which are toxic for the hippocampus, because they're enriched in glucocorticoid receptors. It increases inflammation and increases vascular disease, so it speaks to the need for worldwide prevention and treatment for all psychiatric conditions to protect our blood vessels, our heart, and our brain. And then another question was about pseudo-dementia, because I'm still, like, I don't know, clinged to the fact, especially in those patients that come in are really very depressed, and they present like dementias, and after ECTs, they're just, like, so good. So this is what I think that you talked about, how actually the cognitive decline in the long run stays the same, but clinically sometimes, you know, you see, like, an A and a B, and I was wondering, do they really then, also those patients that go, like, boop, like this, do they still have this cognitive deficit, although they seem clinically back to normal, like the family says? So that's why, actually, I say that pseudo-dementia is basically rare. I don't say it doesn't exist. That's because patients who are so depressed that they're catatonic often respond exactly as you're saying. So there are some. It's just that it's not the majority, and there's certainly not the outpatients who are walking around, but there certainly are people, like you're saying, who are just deeply depressed and really don't have much cognition happening at all, who, once you get them well, you know, recover. Okay. Thank you. Now let's take Dr. Winchell. Dr. Winchell? Speaking as an aging person with ADHD, you have my email address, so feel free to stay in contact and follow me. Two very quick questions. One, what can we say now about the utility, potentially, of lithium to help offset dementia? Because sometimes I will preserve that as a choice of drug I might have stopped in an elderly patient. Do we have a consensus on how useful it is or is not? And the other question, Dr. Butters, is how do we measure brain reserve? Maybe Dr. Lenz could speak first to lithium. For lithium, there is a study by Ari Gildinger at PID that's trying to answer that question. Probably not definitively, because it's not a huge sample size, but if those findings, which I think should come out within the next year, if those are promising... He's breaking the blind this summer. Okay. It's ending in July, so we'll know. I'll volunteer for that one, too. And if the findings are promising, sorry to say, it's going to require a subsequent larger clinical trial to confirm it. But yeah, there are studies, small studies, epidemiologic studies, suggesting of a dementia prevention effect of lithium. Well, that's what Dr. Gildinger is trying to determine, and I think he's looking for like 0.3 to 0.6 nanograms per deciliter in the blood. But there is epidemiological work. I think it's from Denmark or the Norway, and so they looked at geographic areas within the country that had different levels of lithium in the groundwater, and they found that one area had a higher concentration. So these are micro doses, but this one area had lower prevalence of dementia among the patients who drank that water. So there is compelling evidence from both large scale epidemiologic surveys as well as clinical work. What was the second question, Dr. Winchell? How do you measure brain reserve? I'm wondering if my colleague, Olu. So there are a lot of, there's cognitive reserve and there's brain reserve, and they're two different things. Okay. Brain reserve, we're literally talking about sort of excess circuits, having more circuits than you need. There are brain imaging, there are some brain imaging algorithms being developed to be able to actually measure it with MRI, am I right? Yeah. So there's some approaches where you can take the neuroimaging data and generate a network model of the brain and then look at the sort of network capacity of the brain in terms of efficiency of handling information or the way the actual brain is structured as a network that might be a proxy for brain reserve. Oh, and by the way, I believe Brexpripazole was just approved without the black box warning for psychosis and dementia. Only for psychosis, not for agitation. Oh, right. Distinction. Yeah. It's an important distinction. That's how you can, when you prescribe it, you have to write it that way to protect yourself. So we have, let's take one question from online and then I think we're going to, we're going to call it to an end to be respectful of people's time, but we will stick around and are glad to answer any questions of people who would like to speak with us. So I'm going to take this one. Yeah. So one of the audience members asked, what options are there outside of Lifestyle to manage neuroinflammation in this population? Neuroinflammation? I guess I would assume that the questioner is saying, what evidence-based options are there? And I'm not clear that there are any. I think there's a lot of promising options, but I don't know about evidence-based approaches to neuroinflammation. I'm not aware of any either. Okay. So we're sorry to the online questioner that we don't have any answers. More research is needed. More research is needed. Say the researchers. With that, please give our speakers another round of applause. Thank you.

late-life mental health

depression

cognitive decline

geriatric psychiatry

treatment strategies

neurobiological markers

polypharmacy

antidepressants

cognitive impairment

pseudodementia

cerebrovascular disease

REMBRANDT study

resting-state fMRI