Good afternoon, everyone, and thank you all for staying for the nine-hour course. And I'm going to take you to the end of the course, and I will be doing the talk on behavioral and psychological symptoms of dementia. And I'll also have 15 minutes or so to wrap up and answer any further questions that you have. Next slide, please. For disclosures, as you all know, brecprepazole, that is Regzolte, is the only FDA-approved medication for the management of agitation among individuals with dementia due to Alzheimer's disease. As I had pointed out in my previous presentations, it is not approved, Regzolte is not approved for the use of treatment of psychosis in dementia, it is only approved for the treatment of agitation among individuals with Alzheimer's disease. All other medications that I'm going to discuss today are off-label in their use for treatment of BPSD. I have no conflicts of interest to disclose for this presentation. Next slide, please. So the objectives are very straightforward. For the last talk, we are going to look at the epidemiology of behavioral and psychological symptoms of dementia. We're going to talk a little bit about the neurobiology and the evidence-based assessment of individuals with BPSD, then we'll talk about the management of BPSD, and then talk a little bit about the controversies in the management of individuals with BPSD, mainly to do with the risk of cerebrovascular adverse events and death when these individuals are treated with antipsychotic medications. Next slide, please. So the best definition of behavioral and psychological symptoms of dementia, or neuropsychiatric symptoms of dementia, was I got from a paper by Ashok Bharucha and colleagues, which was published in 2002 from CNS Spectrums. The investigators indicated that BPSD are a group of heterogeneous range of psychological reactions, psychiatric symptoms, and behaviors that may be unsafe, disruptive, and impair the care of a patient with dementia in a given environment. So it's a constellation of different symptoms that are grouped into the behavioral and psychological symptoms of dementia. Next slide, please. So when you look at the prevalence of BPSD, as you can clearly see, BPSD is very common. It is inbuilt into the natural history of the progression of the neurocognitive disorders or dementias. In the community, 65% of individuals have at least one disruptive behavior. 40% of individuals with dementia who are living in the community have three or more disruptive behaviors. When you go to the nursing homes where the individuals have more severe cognitive impairment, they are older, they're more frail, the number of the prevalence of behavioral and psychological symptoms increase significantly. So at least 90% of these individuals present with at least one disruptive behavior and 45% have at least four disruptive behaviors. What we know is that these behaviors are often chronic with different symptoms emerging as the illness progresses. So that is why there is no one medication or medication group that is effective for all of the different behavioral and psychological symptoms of dementia. What we also know, psychomotor agitation is the most persistent but not necessarily the most common behavioral and psychological symptoms of dementia, and I'll talk about the most common one in the next few slides. Next slide, please. So how can you classify behavioral and psychological symptoms of dementia? You can do it phenomenologically. That means just based on the type of behavior the patient is exhibiting. So you can call them as affective symptoms. Depression, anxiety, mania, agitation, apathy all come under that affective cluster. You can have the psychotic cluster, which includes delusions and hallucinations. You can have the sleep-wake cycle disturbance cluster where individuals present with sleep-wake cycle disturbance. So they sleep a lot during the daytime and are awake during the nighttime. Or they may be just behavioral with no specific, you know, symptom. There includes agitation, aggression, verbal disruption, and impulsivity. You may classify these behaviors either as primary or secondary. Primary is due to the natural history of the dementing illness with the behaviors emerging as the illness progresses, or secondary due to comorbid or co-occurring medical or psychotic disorders. For example, a patient with dementia may have agitation because the patient is now has a major depressive episode. Or a patient with schizophrenia may develop dementia and the exacerbation of the schizophrenic illness may actually cause behavioral disturbances in the individuals with dementia. So it could be either primary or secondary due to an underlying medical or psychiatric disorder. Next slide, please. So, this is a study that was done in 1996, or the paper was published in 1996, by George Grossberg and Jost, and the investigators looked at 100 autopsy-confirmed individuals with Alzheimer's disease. So, it's the gold standard for the diagnosis of Alzheimer's disease. What the investigators found was that 40 months before the actual diagnosis of dementia is made, that is at zero, people were starting to have psychiatric symptoms, including social withdrawal, depression, disturbance of sleep, anxiety, accusatory behavior, paranoia, and suicidal ideation. And as you can see, from the diagnosis to up to 30 months, patients were having more severe symptoms and greater clustering of symptoms. It usually takes about three to five years after the onset of cognitive decline that the patient is diagnosed with dementia. And as the illness progresses, more and more severe symptoms occur, and there is greater clustering of these symptoms. So, I tell everyone when I see the patients and their family members, and I teach the residents and fellows, I tell them that dementias are neurocognitive disorders. These individuals with dementia have cognitive changes, they have functional changes, and behaviors can emerge at any time during the course of the illness. So, it's not just a cognitive disorder, it's a neurocognitive disorder with behavioral disturbances inbuilt. So, at any time, these behaviors can emerge, but usually as the illness progresses, more severe symptoms tend to occur, and there is greater clustering of these symptoms. Next slide, please. So, this is a table from one of my articles where we listed the different types of behavioral and psychological symptoms in alphabetical order. And as you can clearly see, apathy is the most common behavioral and psychological symptom of dementia. Agitation is the most persistent, but not the most common. Apathy is the most common. Now, apathy starts early on in the illness, and apathy continues throughout the course of the illness. So, it remains there, and it actually gets worse as the illness gets worse. Important point to remember is that apathy does not respond well to antidepressants. So, if you start treating individuals with antidepressants, individuals who have apathy, they will not respond. Available evidence, although limited from meta-analysis, indicates that psychostimulants and cholinesterase inhibitors have better data, not great data, better data in treatment of apathy. There is emerging evidence that TMS is a very good treatment for the treatment of apathy in individuals with dementia. So, again, you have to differentiate between apathy of depression and apathy of dementia. Apathy of depression may respond to more stimulating antidepressants, but apathy of dementia does not respond as well. Next slide, please. So what is the impact of behavioral and psychological symptoms of dementia? It may be the first time that the individual has been diagnosed with dementia. I see a lot of patients who are being seen in the clinic for behavioral symptoms, but nobody has told the family member or the patient that they have a neurocognitive disorder. Nobody has tested their cognition, so they're being actually assessed for a psychiatric illness like depression, psychosis, mood instability, but nobody has given them a diagnosis. So, like I said earlier, when you see an older adult patient, you always have to check cognition, you always have to check function, and you always have to check behaviors because many of these individuals are misdiagnosed as having other psychiatric disorders, whereas the underlying problem is that the patient is now having a dementing illness and their cognition is declining, and thereby they're starting to have these behavioral symptoms. Onset of behavioral symptoms may also indicate the progression of the illness. If you remember the slide from Jost and Grossberg, as the illness progresses, more severe symptoms occur, and there is a clustering of these symptoms. So if there is a sudden onset of psychosis, a sudden onset of mood instability, sudden onset of severe anxiety, that may indicate the progression of the neurocognitive disorder. So make sure that you check for cognition and see if there is a decline. It also causes significant caregiver burden and burnout. If the patient is younger, if the patient is more physically violent, if the patient has more psychotic symptoms, if the patient has sleep-wake cycle disturbances, these are all major risk factors or caregiver burden and burnout. Remember, caregiving in dementia is a career. Individuals with dementia live now 15, 20 years, so the caregivers are burdened with caring for these individuals for a long period of time, and 50% of caregivers of individuals with dementia have depressive symptoms, and half of those individuals have major depressive disorder. Cardiac mortality in caregivers with dementia is very high, so it is important to care for the caregiver. So every time I meet with a patient with dementia, I always ask about caregiver burden and what we can do to alleviate the caregiver burden, because it truly is a remarkable thing that these caregivers are doing. It also indicates, it also can cause these individuals to be placed in skilled nursing facilities or long-term care facilities. Number one reason why individuals with dementia get admitted to long-term care facilities is impairment activities of daily living. Second most common reason why individuals get admitted to skilled nursing facilities is behavioral and psychological symptoms of dementia. Behavioral and psychological symptoms of dementia are extremely expensive. They add to the overall cost of caring for individuals with dementia. One-third of the cost of caring for individuals with dementia is because of behavioral and psychological symptoms. That is about $70 to $100 billion currently, so it's a very expensive illness. So assessment and management of behavioral and psychological symptoms of dementia can really improve the overall care and decrease the cost or the burden of caring for these individuals in our country. Next slide, please. So this is a very simple schematic representation of the neurobiology of behavioral and psychological symptoms of dementia. You have biological, psychological, genetic, and environmental correlates, and they all act together for the individuals to have behavioral and psychological symptoms of dementia. Among the biological correlates, individuals may have neuropathological changes. They can have psychotic symptoms because of frontal, temporal, or limbic cortical abnormalities, both dysfunction and atrophy. Apathy is usually due to the abnormalities in the frontal cortex. Individuals may have polymorphisms of APOE3 and E4, and that may result in depression, anxiety, psychosis, agitation, and sleep disorders. If you remember, I was talking in my psychotic disorders presentation that all those psychotic symptoms in dementia are phenomenologically similar to schizophrenia spectrum disorders, but neurobiologically, they're separate. So that is why these individuals may respond to antidepressants like citalopram and sertraline rather than antipsychotic medications. These individuals may have polymorphisms of serotonin and dopamine receptors that may be resulting in psychosis and aggression. Again, antidepressants may be more beneficial in certain patients when compared to antipsychotic medications. Then there are psychological factors. Certain pre-morbid psychological factors can result in greater behavioral and psychological symptoms when the individual has dementia. One of the common psychological factors is what is called lower pre-morbid agreeableness. These are individuals who have decreased emotional and cognitive flexibility. These individuals can develop agitation and irritability, agitation and apathy when they start dementing. There is evidence that first degree relatives of individuals with dementia can develop behavioral and psychological symptoms when they dement. So there is a genetic predisposition also. There are environmental correlates, especially when there is mismatch expectations or environmental changes which is happening during the care of the individual with dementia. So if the caregiver is not aware of all the care burden and they start caring for an individual with dementia, there may be more expressed emotion. There is hostility, anger expressed and that can actually cause more agitation. I always tell family members and trainees when they are taking care or treating patients with dementia, I tell them that individuals with dementia cannot comprehend or problem solve, but they can feel. So the feeling and the thinking parts of the brain are separate. But the problem is that people feel hostility, people feel anger, people feel negative emotions, but they cannot process that information. So when you are taking care of these individuals, you have to be very careful how you treat them. You have to treat them respectfully. You cannot yell at them. You cannot be negative because that will only worsen the agitation. So as you will see in subsequent slides, non-pharmacological managements are the cornerstone of treating behavioral and psychological symptoms of dementia. Next slide, please. So this is the assessment of any older adult, whether they are demented or not. If you remember the slides from the psychotic disorders presentation or bipolar disorders presentation, it all looks the same because it is basically the same framework that you are using. We do a good history, including information from collateral sources or caregivers. We do a good cognitive assessment, including rating scales to see how impaired the individual is with the dementia. We do a thorough physical examination to rule out secondary causes of behavioral disturbances, medical causes, neurological causes, neurovascular causes. We order investigations to again rule out medical causes. My former boss Craig Nelson used to say that the best anti-psychotic he knows in treating individuals with dementia is Bactrim, which is an antibiotic because urinary tract infection still is highly prevalent in individuals with dementia and can cause severe agitation and can result in up to 25% of these individuals being admitted to inpatient psychiatric units. So if we can treat those symptoms first, patients may become less agitated and may not need admission to the hospital. So do appropriate medical workup. Neuroimaging may be required in certain situations where you suspect that the patient has a neurovascular disease. I had a patient who was being evaluated for gait impairment. And I was like, why would you come and see a psychiatrist, not a neurologist? And the husband was confused. And when I got more history, the patient had gait impairment. The patient had urinary incontinence. The patient had cognitive decline. And I thought that the patient had normal pressure hydrocephalus. I send the patient to the emergency room right across the street. This is when I was working at Yale and they did a CT scan and the radiologist did a wet read and called me and said, hey, you know what the patient has NPH and it is pretty severe. So they admitted her from the emergency room to neurosurgery for shunting process. So you probably will have to do those things, especially if the patient has an atypical symptom or you're getting more information that points to a neurological deficit rather than a psychiatric issue. Standardized rating scales, including cognitive scales, behavioral scales are important in qualifying and quantifying the symptoms. Neuropsychological testing, like I said in both my previous presentations, are important, especially when you get atypical symptoms and you're not exactly able to point to the etiology of why the patient has behavioral symptoms. First, treat the underlying medical and neurological disorders. If the patient has medications or using drugs that can cause severe agitation, remove those first and then, you know, embark upon treating behavioral and psychological symptoms of dementia. Next slide. Next slide, please. Treatments. Most important thing is recognition that behavioral and psychological symptoms are inbuilt into the natural history of the patient. Treatments should always be individualized. So there is no one size fits all. You have to have individualized treatment plan for each patient. CMS, you know, will review your records and see if you've actually had individualized treatment plans for each patient with behavioral disturbances, because otherwise they will cite you for not following what is the regulation. You should always, as pointed out multiple times in my presentations, diagnose and treat underlying medical disorders which can prevent unnecessary use of psychotropic medications. Review neuropsychiatric diagnosis. If the patient has a pre-existing major depressive disorder, bipolar disorder, or schizophrenia, if the person is dementing, it may not necessarily that the patient has behavioral and psychological symptoms of dementia. It may be just that there is an exacerbation of the pre-existing psychiatric disorder. So treat that first before diagnosing the individual with the behavioral and psychological symptoms of dementia. Assess and reverse aggravating factors. If the patient is in pain, if the patient is constipated, if the patient has urinary retention, using a psychotropic medication may actually make the situation worse, not better. So assess and treat those symptoms before you embark upon treating behavioral and psychological symptoms of dementia. Adapt to specific cognitive deficits. Like I said earlier, the thinking part of the brain and feeling part of the brain are separate. The thinking part of the brain is frontal cortex. The feeling part of the brain is the amygdala and the hippocampus. In individuals with dementia, the amygdala and the hippocampus appears to be working fairly well, whereas the frontal cortex is not working well. So when you start shouting at patients, or when you get angry, or when you look disgusted when you're taking care of these individuals, the patient can perceive those things. And what happens is the amygdala starts firing impulses, and if they have a history of trauma or any problematic experiences in the past, the amygdala starts sort of firing and the patient gets more angry and irritable and you're actually making the situation worse. So please try to take care of these patients respectfully, calmly, and that'll actually make the situation much worse. A lot of times I see nursing staff telling the patient with dementia, well, don't you remember? And I always tell them, you know, if they could remember, they shouldn't be admitted or being treated by us. So be gentle, be kind, be helpful in treating those individuals. Review and acknowledge relevant losses or stresses. The majority of these individuals who you are treating have had a change in their function. So they're probably changing the places where they live so that other people can take care of them. And as you all know, after the death of the spouse, the second most stressful event in an older person's life is the change in their living situation. And many of these individuals have that. So sit down, talk to them, ask them what is bothering them. And that may in itself reduce the use of psychotropic medications to treat these behavioral symptoms. Educate caregivers who can be your best friend or your worst enemy. Involve the patient, involve the caregiver in the treatment of these behaviors, because they can help give you clues as to what kinds of treatments work when you're treating these individuals. So it is important to work as a team. And this is a team effort in taking care of these individuals. Next slide, please. Non-pharmacological management. What is the evidence? There is a lot of growing evidence that non-pharmacological treatments are the cornerstone of treating behavioral and psychological symptoms of dementia. I have just put two systematic reviews and one meta-analysis to prove the point. Non-pharmacological management is the cornerstone of treatment of behavioral and psychological symptoms of dementia. Among the non-pharmacological managements, the evidence is that psychoeducation, education of the patient, education of the caregiver, education of professionals, education of providers all improve the care of these individuals and are consistently effective. Cognitive stimulation therapy may be effective. Therapeutic activities may be effective. Specialized dementia care units are not good for all behaviors, but are helpful for wandering behavior. Again, among the non-pharmacological management, psychoeducation is the one that has consistent efficacy. All other non-pharmacological managements may be helpful. What we also know is from the meta-analysis by Bordetti and Asarnam, that non-pharmacological managements have moderate effect size, which is very similar to the atypical antipsychotic medication. There is good evidence that they are effective. They not only treat the behavioral symptom, but they also decrease the caregiver distress. It has a double edge benefit if you use non-pharmacological management. What we also know is that these non-pharmacological managements are good in treating the symptom immediately and their efficacy lasts for up to six months. It is good to have training for the caregiver, training for the professional or the provider who is treating these individuals, and booster sessions to continue to keep these individuals engaged in providing better management for these behavioral and psychological symptoms of dementia. What about pharmacological managements? We should only use non-pharmacological managements in situations where the non-pharmacological management has been tried and the effectiveness or the efficacy has not been great. We can also do it if they're partially effective. You can combine these two modalities to have a synergistic effect. It should always be conceptualized as a process of trial and error. Not one medication or one class is consistently beneficial in treating all behavioral and psychological symptoms of dementia. The medication sometimes may be influenced by the urgency of the situation. We are going to classify these behaviors into emergent and non-emergent behaviors. The emergent behaviors are seen in about 10% of the cases. These are psychiatric emergencies, whereas the non-emergent behaviors are psycho behavioral metaphors, which are seen in 90%. That means these are behaviors that are similar to common psychiatric syndromes like depression, anxiety, irritability, agitation, mood swings. Next slide, please. Emergent behaviors are, as I said, they are psychiatric emergencies and they should be treated as psychiatric emergencies. If a patient is becoming physically aggressive, using a knife to try to hurt the caregiver or hurt themselves, or taking things and throwing where they're extremely agitated, you have to treat the person in an emergency room, call the police, let them come and handle the situation. Don't try to get involved because you and the patient may get hurt. In these situations, these individuals may need to be restrained, both using physical restraints or chemical restraints, that is medications, and may need higher level of care for further treatment. That is only in 10% of the cases. In 90%, the kinds of behaviors you see are non-emergent behaviors. These, as I pointed out, are psycho behavioral metaphors. That means these are symptom clusters that are similar to common psychiatric disorders, like the person appears depressed, you know, is having some depressive symptoms. Antidepressants may be effective. The patients may have hypomania or mania. Mood stabilizers or atypical antipsychotics may be effective. The patient appears to have delusions or may be hallucinating. You may need to use atypical antipsychotic medications. Next slide, please. Prescribing guidelines. I'm sure all of you know this, but I'm just going to highlight them because they're important. You should only select a medication or a medication class that has some evidence for efficacy and the highest likelihood of tolerability and safety. So don't start using, you know, stimulant medications right off the bat, just because you think that the patient has apathy. You have to look at what is the evidence and is it really apathy that you're seeing, or is there something else that is going on? That is why you have to look at the evidence, cluster the symptoms and see the actual diagnosis, and then use a medication class that has most benefits. Sometimes the choice is influenced by a particular side effect of the medication. So, for example, if the patient has delusions and hallucinations, is not eating and sleeping, you may want to use olanzapine or quetiapine because they increase appetite, they improve sleep. If the patient has depressive symptoms, is not eating or sleeping, you may use mirtazapine. If the patient has psychotic symptoms and is eating too much and sleeping too much and gaining weight, then you may use a less sedating antidepressant. You may use ariprazole, you know, or, you know, you may use bregpraprazole. So you may use those medications first rather than olanzapine or quetiapine. If the patient has depressive symptoms and is apathetic and withdrawn, you may use bupropion rather than, you know, mirtazapine. So you may use side effects to help symptoms. Start low, go slow, don't keep on going. So when you, in the end of the presentation, I have a couple of slides on the different medication and doses. You will see the doses are far less than what we would use in younger adults. Avoid injudicious polypharmacy. It is okay to combine a couple of medications based on clear risk-benefit analysis, but don't throw the kitchen sink at the patient because they will, it will then make their symptoms significantly worse. Frequently assess for target symptoms and monitor for adverse effects. So you are doing the risk-benefit analysis, you're going to say, okay, I'm going to target depressive symptoms, or I'm going to target apathy, or I'm going to target mood swings and constantly go back and forth and check whether the symptoms are actually improving. Also monitor for side effects. So you want to make sure that the risk-benefit analysis indicates that the medication you're using is beneficial in helping the individual and not causing more problems. Maintain the medication that you have started at this non-toxic or the sub-toxic level. That means the benefits are outweighing the risks. How long? There is no clear evidence. They say between four and 12 weeks. I usually go for the shorter period of time so that you can reduce the medication burden. So about four weeks is what I use. After appropriate period, about four to 12 weeks, then you can discuss whether you should taper, not stop, taper the medication and see if the patient has a recurrence of symptoms. And evidence indicates that tapering the medication may not necessarily lead to a worsening of symptoms. So you have to assess how the patient is doing. And then you may have multiple different medication trials. Remember the talk on psychotic disorders, you may need multiple different medication trials before the patient actually gets better. So if you're in doubt, ask a colleague to evaluate the patient and see, am I missing something here? Is there something else that could be done to help the individual? But don't throw the kitchen sink at the patient, do judicious assessments, do judicious trials and see how the patient is doing. Another thing I want to point out, if you want to taper the medication, you do the empirical trial and reverse. So the last medication that was started would be the first one that would go. And then you would taper off as needed. And sometimes you can maintain patients on one medication at a very low dose. You just have to play it by ear and see how the patient does. Next slide, please. So I'm going to next talk about different medication classes. So the first one, typical antipsychotics. There are 11 randomized control trials of typical antipsychotics in treating behavioral and psychological symptoms of dementia. They have small sample sizes, they are of short duration, up to 12 weeks, and the outcomes are very modest. These trials looked at 30% improvement in symptoms using these medications versus placebo. And what the investigators found was that they do have modest benefits, that is 59% of patients on medications responded versus 41% of individuals on placebo. Haloperidol, the prototypical drug, prototypical antipsychotic medication had four trials. What the investigators found that these medications were most beneficial for aggression. So in the treatment of behavioral and psychological symptoms of dementia, I use haloperidol only if the patient has emergent agitation and I need to give parenteral drugs. So if I need to give IM or IV, that is the time when I use haloperidol. The only other time I would use haloperidol is if the patient has delirium and not a behavioral and psychological symptom of dementia. And I'm sure that Dr. Wilkins pointed out the efficacy between atypical antipsychotics and haloperidol is the same. Tolerability is also fairly good because you're using these medications for a very short period of time to treat delirium. You are not giving them for months on end, you're only just giving it for days and seeing how the patient is doing. There is no improvement in any of the other symptoms. So like I said, I only use it for treating emergent aggression in individuals with behavioral and psychological symptoms of dementia. What about atypical antipsychotics? There are multiple different meta-analyses. I just picked the one that I think highlights the data. This is by Lon Schneider and colleagues. The investigators found that aripiprazole and respiradone had evidence for treating behavioral and psychological symptoms of dementia. The data was not very strong for olanzapine or quetiapine. The effects were smaller for individuals with less severe dementia, outpatients, and patients who had psychosis, indicating that these medications are to be used in situations where the patient has more severe symptoms and are more agitated. And they're not necessarily always helpful for psychotic symptoms, possibly because of the polymorphisms of the dopamine and serotonin receptors. So antidepressants like sertraline and citalopram may be effective in these individuals. One third of the individuals, as expected, dropped out because of adverse effects. Somnolence was a very common adverse effect in individuals with dementia. Urinary tract infection was a common problem. Extrapyramidal symptoms were more common in individuals with respiradone and olanzapine when compared to quetiapine or aripiprazole. Abnormal gait was more problematic with individuals with respiradone and olanzapine. And the biggest takeaway is that cognitive scores, you know, this is a composite cognitive score, declined when patients are treated with antipsychotic medications. So whenever I start a patient on an antipsychotic medication to treat behavioral and psychological symptoms of dementia, I always tell the patient and their caregivers that there is a chance that the patient's cognitive functioning might decline, and we will, you know, keep a careful watch and monitor the progression of cognitive decline because that is a very real, you know, risk factor when you use these medications. Next slide, please. So this is the CADI dementia trial. I'm sure all of you have heard of it. It is the longest trial of antipsychotic medications to treat behavioral and psychological symptoms of dementia. These were individuals with Alzheimer's disease and psychosis, agitation, or regression. These were outpatient trials. We did not take anybody who was living in an assisted living facility or skilled nursing facility. We compared olanzapine, quetiapine, and respiradone versus placebo. There was a small subset of patients who also received citalopram because, you know, the investigators did not want to use haloperidol as a comparator. But for the CADI dementia trial, that was the article that was published in New England Journal, they just compared the phase one of the trial using these three atypical antipsychotic medication versus placebo. Adipropazol was thought about but was not included because it was just coming into the market at that time. What the investigators found was that the mean time to discontinuation for any reason did not show any benefit for the drug. Whereas mean time to discontinuation, due to lack of efficacy, favored olanzapine and respiradone, whereas quetiapine was only as good as placebo. But individuals who were treated with these three atypical antipsychotic medications had three to five times more risk of adverse effects and drop out because of the adverse effects. And global improvement was not seen with these medications. So yes, these medications may improve some of the symptoms, but they cause significant adverse effects and do not improve global functioning. What the investigators also subsequently found was there was no improvement in quality of life or care needs when you use medication. So it just improves symptoms, does not improve the overall quality of life of the individual. Cognitive functioning. Again, another proof of the pudding that these medications worsen cognition. Cognitive functioning declined with the use of these medications when compared to individuals receiving placebo. Treatment group had higher costs. So it is also more expensive to use medication medications compared to placebo. The biggest takeaway for me is the last point that none of these individuals had cerebrovascular adverse effects or death despite being treated with antipsychotic medications for during the nine month duration of the trial. The good part was that we watched these individuals very carefully. The respiradone cerebrovascular adverse effect data had just come out, so we were very closely watching patients. We were very closely watching our prescribing patterns. So it is not the medications. The medications all cause different problems, but it is our prescribing practices that determines how the patient actually does when you prescribe these medications to individuals. So don't use hefty doses of medications. Don't do injurious polypharmacy. Use moderate doses and for short period of time and the patient will actually do better. Next slide, please. So this is the data for brec prepazole, which is a proof of the treatment of agitation in Alzheimer's disease dementia. There are three randomized control trials. I have put two of them that was reviewed by Dr. Grossberg and colleagues. We have our paper coming out. We are looking at all three trials. Well done. 12-week multi-site, multi-country randomized control trial evaluating brec prepazole, different doses, 0.5 milligrams, 1 milligram, 2 milligrams. And there is a third trial, which also looked up to 3 milligrams of brec prepazole among individuals with Alzheimer's disease and agitation. The investigators found that brec prepazole was beneficial in treating agitation as evaluated by the Cohen Mansfield Agitation Inventory, CMAI, and global impairment of functioning. So the medication was beneficial and they applied to the FDA and the FDA approved the medication earlier this year. So the dosing range for brec prepazole is 0.5 to 2 milligrams. You may use 3 milligram doses in certain patients. The medication was fairly well tolerated with headache, insomnia, dizziness, and urinary tract infection being the more common adverse effect when compared to placebo. We have used it in a few of our patients with some benefit and patients appear to be tolerating the medication well. Only time will tell if they will use this medication more, but the evidence is fairly good for using this medication for the particular indication that is agitation in Alzheimer's disease dementia. Next slide, please. Now, what about pavanserin? Pavanserin also is an atypical antipsychotic. It is approved for the treatment of delusions and hallucinations in individuals with Parkinson's disease. We actually did a systematic review of the evidence. Dr. Srinivasan was the first author on this. We found one well done randomized control trial of nursing home patients. There were 181 participants and Benaprimavansirin was beneficial in treating behavioral and psychological symptoms of dementia, especially individuals who had higher psychotic scores on the neuropsychiatric inventory nursing home scale. So they are beneficial for individuals with more severe psychotic symptoms. They had greater response rates compared to placebo and they were also beneficial in treating delusions and hallucinations in these individuals. What we also found was that the medication is fairly well tolerated. There is only one dose that is 34 milligrams a day. And the common adverse effects with Benaprimavansirin is agitation, aggression, weight loss, QTC prolongation. So please do an EKG before you prescribe this medication. Other adverse effects are peripheral edema, falls is similar to that of placebo and that's it. So it is a fairly well-tolerated medication. So the biggest adverse effects for me are QTC prolongation and weight loss. So patients may lose weight. It is a fairly straightforward medication to use. We have used it in a couple of patients with Parkinson's disease psychosis. And we've also used it in a couple of patients with Alzheimer's disease, dementia and agitation. Again, there is evidence. The company is applying to the FDA. With an indication for the treatment of agitation. So hopefully we will find that out very soon about whether this medication is approved or not. Next slide, please. What about cognitive enhancers? That includes both the cholinesterase group and the memantine group. There is evidence that these medications are beneficial in preventing cognitive decline, thereby the emergence of behavioral and psychological symptoms of dementia. These are medications that you would start first. You will see the algorithm that we have created and we use regularly. That these are medications we start upfront when the patient is diagnosed with a dementing illness. These are not helpful for treating emergent behaviors. So don't give these medications to a patient who is severely agitated or physically aggressive. It's not gonna do anything. I always say these are like brakes on a car. They slow the cognitive decline, thereby they decrease the onset of behavioral symptoms. They're fairly well tolerated. If the patient is having GI symptoms, combining a cholinesterase inhibitor with the memantine can actually reduce the gastrointestinal discomfort in these patients. Next slide, please. What about mood stabilizers? There are two systematic reviews and one meta-analysis looking at mood stabilizers in the treatment of behavioral and psychological symptoms of dementia. And the data is very consistent. Mood stabilizers, especially divalproic, oxcarbazepine and divalproic sodium are not very beneficial. There are five negative trials of divalproic sodium in the treatment of behavioral and psychological symptoms of dementia. So I do not use it unless the patient we have tried different medication trials and nothing is working, so I might use it. The only one positive trial among the anticonvulsant mood stabilizers is a small trial, oxcarbazepine or Tegretol. The problem with Tegretol, as all of you know, that it has significant side effects. It auto-induces its own metabolism. It also is an inducer for metabolism of the other drugs. So be very careful when you use this medication and it can cause sedation in patients. So I rarely use this medication, although this has one randomized control trial that has shown benefit. What about gabapentin? There are no randomized control trials of gabapentin for the treatment of behavioral and psychological symptoms of dementia. There is anecdotal evidence and there are case reports and case studies show some benefit. Again, it's a case-by-case basis. It seems fairly well tolerated, but patients with dementia with Lewy bodies usually don't tolerate this and other medications well. So please don't use it in individuals with dementia with Lewy bodies. Patients may actually have significantly more side effects. But on a case-by-case basis, you can use gabapentin for the treatment of behavioral disturbances, but there is no consistent evidence for anticonvulsants to be beneficial in these individuals. Next slide, please. Antidepressants. I think this is where there is a greater bang for the buck. Two meta-analysis and one systematic review that we did indicated that antidepressants may be beneficial in treating behavioral and psychological symptoms of dementia and are fairly well tolerated. Among the two antidepressants that have the best data are citalopram and sertraline. And when you look at our algorithm for treating non-emergent agitation, antidepressants are at the top of the chain because they have shown to be beneficial and are also well tolerated. What about the other antidepressants? There are quite a few trials which are positive, and there are some trials that are negative, but we do use antidepressants more commonly, again, with sertraline and citalopram being the top of the chain. Next slide, please. What about benzodiazepines? You know, we wrote this paper a few years ago because people were using benzodiazepines to treat agitation and dementia. I personally don't use it because I have found that it actually makes the situation worse. There are five randomized controlled trials. Four trials compared active medications to active medications. One trial compared olanzapine to lorazepam to placebo. That was an emergency room trial giving intramuscular doses of these medications. And the trial showed that benzodiazepines had some benefit, but these were very short-term trials. These are much older trials with very few patients. And as now we know that benzodiazepines increase the risk of cognitive decline, increases the risk of falls, are gateway drugs to other drug use, so I don't use benzodiazepines. Are there situations where I use benzodiazepines? Absolutely. If the patient has acute anxiety and you need something to just calm the patient down, you can use that. If the patient has benzodiazepine withdrawal, you can use benzodiazepines. If the patient has barbiturate withdrawal, you can use benzodiazepines. If you have a patient withdrawing from alcohol, you definitely must use benzodiazepines. If the patient comes to the emergency room, you really don't know why the patient is agitated. The patient cannot take antipsychotic medications because of cardiovascular issues. If you need something to sedate the patient, then you need benzodiazepines. So those are the only few situations that benzodiazepines are used. And based on evidence, I only use lorazepam, and these are very short courses of treatment, and these are not continuation of treatment. So when we see these patients, we tell the patients and their families that there's not gonna be a continuation of these medication prescriptions, and it's a case-by-case basis assessment, and we use benzodiazepines. Next slide, please. What about analgesics? When I was taking care of patients in the nursing home, the charge nurse would call me in the middle of the night and ask me whether I could approve the patient taking some extra Tylenol, extra strength Tylenol, to help them settle down. So I wanted to see, is there evidence to what people are doing? So we decided to do a systematic review of the literature, and we did find there are three unique randomized control trials of six... There are three randomized control trials, six papers based on these randomized control trials, indicating that analgesics do improve behavioral and psychological symptoms of dementia. They don't improve all the symptoms, they just improve general restlessness and agitation. It is probably these patients may be having pain. So the kinds of analgesics are acetaminophen, gabapentin, pre-gabalin, and even opioid medications. So the data that is there is that these medications may be beneficial. And if the patient is in severe pain, then you really have to treat that. Of course, the non-pharmacological managements would come into play first, and then you go up the pain algorithm to see what medications you can use to calm patients down. But there is evidence that analgesics may be beneficial in these individuals. Next slide, please. Then there was a question whether prazosin is beneficial in individuals with behavioral and psychological symptoms of dementia. So we actually did a systematic review that was published last year, and we found one randomized control trial for individuals with Alzheimer's disease, dementia, and behavioral disturbances, indicating that prazosin was beneficial in treating different behavioral and psychological symptoms of dementia in an eight-week trial, but compared to placebo. The dose of prazosin was about 5.7 plus or minus nine milligrams a day. So we do use it in time-to-time when the patients have not responded to other psychotropic medications. Sedation and confusion were the most common side effects, but they are fairly well-tolerated at the dosing range. So if the patient does not respond to any other medication, it is perfectly okay to use prazosin. And as you will see in our algorithm, we have put it there because there is one positive, well-done randomized control trial indicating efficacy. Next slide, please. What about propranolol? So if prazosin was beneficial, how about propranolol? So we published another study looking at propranolol. We found three case series, one case report, and one randomized control trial indicating propranolol is beneficial in treating behavioral and psychological symptoms of dementia and is fairly well-tolerated. If you look at the doses of propranolol that is wide range, it goes from 60 to 560 milligrams. And am I advocating for you to use 560 milligrams? Absolutely not. I have no experience of using propranolol at that high doses. I have used it up to, you know, 100, 120 milligrams with no significant orthostasis or bradycardia. Patients tolerate it well. Probably when they're agitated, the adrenergic drive is there and that keeps up the blood pressure and that keeps them awake. And when you use this medication, it calms down. Are these medications good for emergent agitation? Absolutely not. These are for non-emergent agitation when the patient has not responded to other psychotropic medications. Next slide, please. Cannabinoids. I think that this is where there is greater data coming out. There is a randomized control trial right now being done by my colleagues from the AAGP using cannabinoids for treating behavioral and psychological symptoms of dementia. We actually did a review of the literature and found eight reports. Seven of the eight reports indicated that cannabinoids were beneficial. Five of the reports used dronabinol, two used propranolol, two used dronabinol, two used THC, and one study used nabalone, which is a synthetic cannabinoid. The patients tolerated these medications fairly well. Four of the eight studies showed that there was no significant adverse effects. And these medications improved agitation, aggression, impulsivity, nocturnal restlessness, wandering and poor sleep. Remember, these are not the cannabinoids you get on the street. These are medications that people are using. So these are pharmacy-grade medicines that people are using. When you compare the adverse effects, sedation was the most common adverse effect seen in these studies, followed by delirium, urinary tract infection, and confusion. We are starting to use more of cannabinoids, especially when patients have not responded adequately to other medication trials. Next slide, please. What about transcranial magnetic stimulation? Again, I think this is where it is so exciting that we have new neuromodulation techniques that are being shown to be beneficial, not only for behavioral disturbances of dementia, but also for cognition. We did a systematic review of the literature and found that there were 11 randomized control trials. Three of these trials also studied apathy. Two of them were positive for improving apathy. Seven studies showed that there was significant improvement in behavioral and psychological symptoms of dementia, six using RTMS, and one using direct transcranial stimulation. Four studies showed some benefit, and these studies showed that adverse effects were mild and transient. So we are starting to use TMS for treating both cognitive impairment and behavioral and psychological symptoms of dementia. And I think this is where the field is moving to certain more neuromodulation techniques to improve both cognition and behavioral symptoms of dementia. Next slide, please. What about electroconvulsive therapy? There is a randomized control trial currently underway being done by my colleagues from AAGP looking at ECT for treating behavioral and psychological symptoms of dementia. We actually did a systematic review of the literature and found that there are 20 published reports with 172 individuals with dementia. Majority of them were case reports. They used bilateral, unilateral, bi-temporal ECT. 90% of the patients responded to ECT treatment. Post-dictal confusion or memory impairment was only seen in 15% of these cases. So very well tolerated treatment modality. Let's hope that the RCT shows benefit. We are starting to use ECT more and more for treatment refractory behavioral and psychological symptom of dementia. Could we use it earlier on? Certainly we could use it, but given the bad rap that ECT gets, we have put it for more severe symptoms so that we can use it in those patients who absolutely need it. In my point of view, it is a life-saving treatment in many of these refractory conditions. Next slide, please. What about APA guidelines? So in 2016, APA guidelines came out. It showed everything that we had been working on for the past 15 to 20 years to be true. It said use medications judiciously, use them for short period of time, use them with a good risk-benefit analysis, taper off and discontinue medications they're not effective for about four months. They said, do not use haloperidol unless the patient has delirium, do not use intramuscular medications, reserve them for serious and persistent mental illness like schizophrenia and schizoaffective disorder. And this is the guideline. So everything that we have been studying and saying was put into one document. And we are very thankful that the APA came out with these guidelines, which we now give to everybody when we are prescribing these medications. So this particular slide, I printed and give it to the family so that they can see that what we are doing is really evidence-based. Next slide, please. Now, talking a little bit about the controversies in the treatment of individuals with behavioral and psychological symptoms of dementia. We'll talk about mortality and we'll talk about cerebrovascular adverse effects. As you know, FDA came out with a boxed warning for both atypical and typical antipsychotic medications. They based it on 17 placebo-controlled trials, which had 5,106 patients. 15 of the 17 trials showed numerical increases in mortality 1.6 to 1.7 times. And the death was mainly due to heart failure or sudden death or due to infections. The FDA then included the typical antipsychotics later on. Even Breck proprosol has the atypical antipsychotic warning for death when you use it in individuals with dementia. Next slide, please. So this is the Lon Schneider's meta-analysis, which is an excellent meta-analysis. And if you look at the right-hand column, if you look at the odds ratio, each individual drug does not increase the risk of death when you actually look at it, because it goes through one. The odds ratio goes through one, indicating the risk of death is not statistically significant. But when you pool all the drugs together, you will see that the risk is statistically significant with an odds ratio of 1.54 and a p-value of 0.02. So it is not an individual drug effect, but it's a drug class effect. And so you need to be careful when you prescribe these medications for individuals with dementia. So no one particular drug is better or worse than the other. Next slide, please. What about prescribing practice? Most of the deaths occurred during the first eight to 12 weeks of treatment. It is probably because people are titrating of the medication too fast. So start low, go slow, don't keep on going. The likelihood of harm versus help indicated that every ninth to 25th patient you treat, there would be one death. So that is a very high risk of using these medications. So you have to warn the patient and their families about the particular adverse effect of death and indicate that you will try everything to minimize that risk and only use these medications when other medication trials have failed. What the investigators also found that the risk of death was not due to any particular drug, and it could only be appreciated, as I told before, when the drugs are taken as a group. The subgroup analysis did not show any difference between individuals who had lower versus higher cognitive functioning, patients who had psychosis with Alzheimer's disease, or inpatient versus outpatients. There's no differentiation. The risk was the same for all these individuals. Next slide, please. If you remember, there was a question when I was doing the bipolar disorders lecture on whether the risk for death is only with individuals with dementia or is the risk for everyone. So this is the study that put all the typical antipsychotics into the black box or the boxed warning. And if you look at the evidence that the typical antipsychotics have the same risk of death as the atypical antipsychotic medications, and the risk are highest in the first 40 days and continue up to 180 days. But what is more interesting is that the risk of death is more in individuals without dementia. If you look at adjusted analysis, the odds ratio, the hazard ratio is 1.45 for individuals without dementia, and it's 1.29 for individuals with dementia. So again, indicating that it's not just a drug effect, it is also the age effect. So any antipsychotic medication introduced in an older adult, you have to be very careful. So start low, go slow, do not keep on going. What is also interesting is that in the nursing home, you know, patients had less odds ratio for death compared to people not in the nursing home, possibly because the medications were regulated and medications were being closely followed up with the providers in the nursing home rather than in the outpatient or in people who are living in the community where they or their caregivers are giving the medication. So very interesting finding. Next slide, please. What about risk of cerebrovascular adverse effects? I just put Nathan Harmon's study, which indicated that the risk of cerebrovascular adverse effects, that these include also patients with stroke. The odds ratio, sorry, the combined relative risk for cerebrovascular adverse effects was 2.7. So 2.7 times greater risk of cerebrovascular adverse effects when individuals were treated with the Respiradone or Olanzapine. When you look at the Olanzapine versus Respiradone, more Respiradone treated patients had cerebrovascular adverse effects, 3.3 versus 1.3. And the odds ratio was greater for Respiradone versus Olanzapine. The problem being in this particular, when in the Respiradone trials, there were individuals with mixed dementias and also included. So they had vascular issues going on already. So any individual with mixed dementia or vascular dementia, be very careful when you treat with an antipsychotic medication, because the risk for cerebrovascular events is higher than an individual with pure Alzheimer's disease. So that's another warning I give patients and their families before I prescribe the medication. Next slide, please. So this is an algorithm that we have created and we have used it for the last 12 years for treating behavioral and psychological symptoms of dementia. A good assessment, including rating scales to see the severity of cognitive impairment, individuals with mild to moderate dementia, cholinesterase inhibitors, moderate to severe cholinesterase inhibitors for memantine. We initiate non-pharmacological managements. We symptom cluster. So we make into different clusters. If the patient is depressed or anxious, SISRIs become our first line of medication management. Hypomanic or manic symptoms, we use either carbamazepine. If that is not effective, we use atypical antipsychotics. We may also use divalproic sodium if none of these work. For psychotic symptoms, we use atypical antipsychotics, mainly respiradone and adiproprazole. And now we have started using brepraprazole. For just agitation or aggression, we use SSRIs. We use carbamazepine. We may use divalproic sodium. We may use strazodone. If monotherapy does not work, we use a judicious combination of medications. We always reinforce with non-pharmacological management, and we constantly do the risk-benefit analysis. And if the patient is not improving, I ask a colleague to evaluate the patient to see if I have missed something. And we do that as a team. We discuss that with the patient's caregivers to see if there is any additional points that we can get to help these individuals. Next slide, please. This is the algorithm for treating emergent agitation. Oral medications first. IM medications if the patient refuses. Oral medications, we use respiradone or adiproprazole. And if that doesn't work, we use quetiapine. If that doesn't work, we use olanzapine. We repeat the doses a couple of times. We avoid benzodiazepines because we have found that it actually sedates the patient and makes the patient more agitated. If the patient is refusing oral medications, then we go for IM olanzapine. If the patient does not have good benefit with the IM olanzapine, we use IM haloperidol, and we may have to repeat a couple of doses. We do not give any IM benzodiazepines because, again, patients may be more sedated or may be more confused. Next slide, please. This is the algorithm for non-emergent agitation. As I said earlier, cholinesterase inhibitors for mild to moderate symptoms. We add memantine for moderate to severe symptoms. If the agitation persists, we use SSRI, sertraline, or citalopram. If that fails, we use triazodone. If that fails, we use either breptroprazole, risperidone, or idoproprazole. If those fail, we use quetiapine. If that fails, we use olanzapine. If that fails, we use carbamazepine. Sometimes we may use divalproic sodium. If the carbamazepine trial fails, we use propranolol or prozacin. If those fail, we use cannabinoids. Why lower? Because of acceptability. Because when you say you're using cannabinoids, people have a negative connotation. If the cannabinoids fail, we try TMS. If TMS fails, we try ECT. Why are those lower? Again, because of acceptability. If those monotherapy trials fail, judicious combination of medications along with non-pharmacological management. Next slide, please. So these are the different medication classes and the dosages. Please feel free to use them. We have actually gone through multiple trials to look at these doses, and these are what the trials showed. And we have them printed out so that anybody can use them. Next slide, please. So thank you very much for listening, and I will try to answer all the questions that we have in our chat. So the first one is about technical things. Dr. Rutherford asked that. And the staff can actually explain those. The next question is, is primaprexol a reasonable medication to try for treatment refractory depression? You know, I have not really used that, and I've not seen randomized control trials for treatment refractory depression. Ketamine may be a very good medication, or combination of antidepressants with a stimulant medication. Helen Riverski has a couple of trials looking at that. Citalopram with methylphenidate, or augmenting with lithium or adipropazole is what I usually do. The next question is for paranoia and hallucinations and dementia with Lewy bodies. What medications can be tried? Are cholinesterase inhibitors a good choice? Absolutely. Cholinesterase inhibitors are first line. If patients don't respond to the cholinesterase inhibitors, small doses of quetiapine, small doses of pembenzirin, and even small doses of clozapine may actually be tried. And the next slide is, sorry. The next slide is, do you code somebody with Alzheimer's disease and major depressive disorder as major neurocognitive disorder with behavioral disturbances and MDE? I actually code it as major neurocognitive disorder without behavioral disturbance and separately code for major depressive disorder because major depressive disorder is not a behavioral disturbance and dementia. It is a separate psychiatric diagnosis. The next question is, a lot of times depression and agitation also come from inability to drive, which is tantamount to lack of independence. I had someone who was prevented from driving by family and who insisted on getting a referred for DMV for reinstallment of their license and surprisingly got their license back. With this patient driving again, how often do you think it should be reevaluated? If there is any conflict with driving, if the patient appears to be mildly demented, you certainly can get a repeat driving test. The standards for the DMV is different than that is for the Easterseals. So we find that the DMV is a little easier to pass, but you need to keep in mind that individuals with any kind of cognitive impairment, the risk of having a motor vehicle accident is higher. So we discuss that with the patient. We discuss that with the family and then we give them the options of going to either the DMV or to Easterseals or any other agency that they can do the driving test. Sometimes our occupational therapist may be able to do something about it. And then we discuss together as a family and as a treatment team to do what is best once the results are back. What is the rate of inpatient hospitalization for BPSD and what is the average length of stay? We are actually reviewing that. There is no one consistent data, but the rates of hospitalization for people with severe BPSD or emergent agitation, 10% of these patients have emergent agitation. About half of these individuals get admitted to skilled nursing, get admitted to inpatient psychiatric hospitals. What about the length of stay? Again, very variable. The data is most of these individuals stay between two to three weeks. Earlier involvement of family, earlier involvement of social work is a very good thing and you can reduce the length of stay in these individuals. The next question is, do you have experience with buspirone to prevent sundowning or behavioral agitation and vascular dementia for a patient who cannot tolerate low dose of a typical antipsychotic medication with a history of bowel obstruction, chronic constipation, gives pause to metazapine. In these kinds of individuals, I have used melatonin. I have used cholinesterase inhibitors and they have found to be very beneficial. I have not used buspirone, but again, that is a very interesting thought for using buspirone in a patient. So thank you for that question. The next question is any advice for severely aggressive patients with BPSD and a locked dementia unit? I feel a lot of them end up on valproic acid and or atypical antipsychotic medications and clozapine, but it does not seem to decrease the assaults. ECT is not readily available. For these individuals, I think cannabinoids are a very good addition to medication management. Propranolol and prozacin can also be used in these individuals and combined with the other medications and do modest dosing of these combination medications and that might be beneficial. So I would go for cannabinoids first among these individuals and see how they respond. The next question is, was the cause of death with antipsychotic cerebrovascular accidents or cardiac causes? If you look at the FDA data, majority of the causes of death were cardiovascular, and including sudden death and cardiac arrhythmias and infections. They were not due to cerebrovascular adverse effects. Trazodone dose for agitation. Are you dosing them during the day at low doses? The dose for trazodone is between 50 and 300 milligrams. We dose it in multiple divided doses. So you can do smaller doses during the daytime and higher doses at nighttime. Again, what is the typical dosing? I use between 50 and 200, although you can go up to 300 milligrams in certain patients. And the next slide is, sorry, the next discussion is, Dr. Tempe, do you feel comfortable with sharing your email with us? If you have any further questions, please ask any number of questions. My email is pretty straightforward. It is my first name and last name, rajishtempe at creighton.edu. The next question is, if the dementia is very severe, the patient is in hospice, do memory enhancers still work? Excellent question. These cognitive enhancers do prolong life. So that is a discussion that you have to have with the patient's family members of tapering off and discontinuing the medication. Ideally, these medications should not be given to patients who are severely impaired and are bent-bound because they just maintain basic functioning and really don't improve the quality of life. And Dr. Marciano, thank you for asking that question. Do you use Zofran for Lewy body disease? And the answer is, we can use Zofran for Lewy body disease. And how does Zofran work? They inhibit the receptor and the chemoreceptor trigger zone, the serotonin receptors, and can decrease hallucinations. Have we used it? Absolutely, but the evidence is that it is more beneficial in individuals with Parkinson's disease, dementia, and psychosis. So can you use it in dementia with Lewy bodies? Absolutely, you can. The doses are anywhere between eight and 32 milligrams. And if you ever need the paper, I'm happy to share that with you. So thank you everyone for patiently listening to this very long course and for staying four minutes over. If you have any questions regarding the course, you can let our staff know. And I have given you my email. Please feel free to ask questions and I will route them to my colleagues who have done the various presentations and we can get the answers for you. And I'm glad that we were able to do it and all of you stayed so long to listen to that. And it makes me feel good that people are interested in taking care of older adults with mental health disorders and we cannot do it without all of you. Thank you very much. And I hope all of you have a wonderful evening. ♪♪♪

BPSD

Alzheimer's

brexpiprazole

non-pharmacological

pharmacological

antidepressants

atypical antipsychotics

cognitive stimulation

treatment approaches

caregiver burden

side effects