Hello everyone and welcome. I'm Dr. Rob Cotez, Associate Professor at Emory University School of Medicine and Director of the Clinical and Research Program for Psychosis at Grady Health System. I also serve as SMI Advisor Physician Expert. I'm so pleased that you're joining us for today's SMI Advisor webinar, Elder Depression Treatment Indications and Psychopharmacology for Optimum Outcomes. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you to get the answers you need to care for your patients. Now, I'd like to introduce you to the faculty for today's webinar, Dr. Michael Rice. Dr. Rice is considered a national international expert on psychiatric mental health education, service delivery, and policy. He is currently a Professor Emeritus at the College of Nursing Anschutz Medical Center, University of Colorado. He served as a member of the Advisory Board to the Colorado Center for Nursing Excellence. He continues to provide consultation on targeted projects, mentor faculty on manuscripts publishing, development of research projects, and also with his own publishing efforts. He has worked in every direct care role in psychiatric mental health nursing, from a student nursing tech to Assistant Medical Director of a community mental health hospital. He continues to be board-certified in advanced practice psychiatric nursing, working with suicidal non-VA veterans in PCORI-funded research. Dr. Rice, I'd like to thank you so much for leading today's webinar, and I'll turn it over to you. Thank you very much. I'd like to thank everyone for inviting me here to do the lecture today, and I'm really honored. Hope that everyone finds that it's beneficial and useful. I will disclose that I have no financial relationships or conflicts of interest to report of any nature at this point in time. The learning objectives for today, as you see listed, upon completion of the activity, participants will be able to, one, explain how to screen for appropriate use of antidepressants in the elderly, two, to discuss appropriate antidepressant dosing associated with age, liver, and renal functioning, and three, determine the routine behavioral and laboratory follow-up and monitoring needed for maintaining antidepressants for the elderly. Now, elder depression really has a huge prevalence. By 2030, older adults over age 65 will make up more than 20% of the U.S. population. But depression is not a normal part of aging. The point prevalence for major depression is 4.6 to 9.3% in patients over 75 and just increases about 25%, 27% in those over 85. So as we see, it's just an ever-increasing incident the older one gets, but it is not a normal part. The symptoms are complicated because we often look at impaired cognition, which does double every five years after the age of 70, and depression can really complicate that. Now one of the big questions clinically that we always look at is the issue of depression versus dementia and what's the comorbidity of that. Well, the data shows that 52% of cases have their first depressive onset at age 60 or older. It affects up to 50% of the people with dementia, so we often have comorbidities of different etiologies at the same time. The neuropsychiatric symptoms of any dementia include depression, psychosis, agitation, hepatitis, sleep disturbances, and just inhibition, which makes it really difficult at times to sort through what is the cause of what we're looking at. But we'll give you some instruments later on to look at how to sort that out. The symptoms can be severe and lead to excess morbidity and mortality, unfortunately. Now, there is a relationship between depression with physical illnesses, and this is from translational psychiatry. I've got the reference here so you can look at it. But essentially, what it reflects is the new research that we're seeing that the cytokines and cytokine involvement, often associated with physical illnesses, causes a direct relationship in depression and many of the illnesses. So things that you see like cardiovascular, coronary artery disease, dementia disorders of all kinds, autoimmune diseases, and endocrine diseases, leave us with one common understanding, and that is that it's physically impossible to have a physical disease as an elder with elevated cytokines that are separate from, or inflammatory factors that are separate from, causing depression. It just simply cannot happen. Now that leads us to antidepressant use. The depression in dementia really accelerates cognitive decline. So the faster someone goes with dementia, the greater the level of depression. Think of it as a linear relationship going up. Yet, meta-analysis really consistently shows that 50% of all of these elders respond to antidepressants. So they become an essential tool in our armamentarium. At the same time, there really is an inappropriate use of antidepressants within the elderly population. We'll talk about that and what really results in inappropriate medication use. But, and here's the risk, is that when they're used inappropriately, depression and dementia risk increases. That means that selecting the right antidepressant really becomes a critical task. Now, in inappropriate antidepressants, there's a series of mythologies about that that I want to just dispel at the beginning. One, most elderly are depressed, demented, or dependent on someone else. That's not true. Older adults just by nature complain and are negative. Older adults have rather rigid personalities. Dementia is normal for aging and disability is inevitable. That is just simply not true. Any cognitive impairment and memory loss is Alzheimer's. Genetics alone really determine their susceptibility to this. They can determine if their parents were that they will be. Probably the most critical thing here is that adult age, normal adult pharmacology and psychopharmacology doses are applicable to elders. That is untrue. And then the final one, and one of my pet peeves is that psychiatric medication will control behaviors. So the critical thing becomes about who are we really treating here and what? So when we look at elders in antidepressants, depressive symptoms and impaired cognition really doubles every five years after the age of 70. Inappropriate antidepressants are associated with increased dementia. 50% of all of these elders do respond to antidepressants and inappropriate medications associated really with our myths about controlling behaviors and effects only the brain blatantly through us we'll see. Now the problems with identifying addressed elders is really where we need to begin. One, excuse me, they are less likely to verbally express their mood. That is true. And many of them are less able to recognize depressive symptoms because of the change in depressive symptoms as one ages. Many of them, because of the problems of self-control will not admit cognitive affective symptoms. And they don't report a decline in sexual functioning. Most certainly in some of my patients in the past, one of the most eye-opening experiences was to have them complain to me about their sexual activity and sexual function, particularly amongst couples who've been married for a long time. And it's something we just need to kind of wrap our heads around in terms of their identity and who they are as human beings. There are some neurophysiological changes that make medication very difficult. And this is critical for you all to understand. One, there's reduced white matter connectivity between the hemispheres with the more frequently individuals have depressive episodes. So they actually lose some of the cognitive connective matter with depression. That the alterations in cognitive dysfunction are really associated with geriatric depression. That there is a significant age-related decline in serotonin receptor binding. And this has been shown over and over and over with scans. And as well as dopamine receptor reductions, et cetera. An analysis of 29 patent spec scans demonstrates reduced serotonin activity and reduced serotonin orders, which becomes critical primarily when we select and look for our understanding of the medication. Now, here's the evidence to make sure that we're clear on the evidential stuff. There are age-related changes in dopamine synthesis, dopamine binding sites, a decrease in D1 and D2 receptors, and a significant decline in dopamine receptors D2 and D3. So the message here is that antidepressants that really work through the dopamine mechanism system have less effective diversity. One of the big things these days, and it's particularly difficult because we don't have the depth of studies on elders that we do for the normal aging population. There have been four studies that have investigated depression involving specifically potentially inappropriate medications. And those studies show that under use of antidepressants in African-Americans is associated with increased mortality. That is similar to the fact that anyone who has a depression and is not treated appropriately has an increased mortality. The trajectories of late life depression are comparable by race. There is some variation risk estimate, but with such less studied factors, such as the region or area of birth. There are regions and areas where people are exposed to significantly more stress that have higher rate of depression, but basically they are comparable by race. The antidepressants odds ratios in terms of use are 0.42 for African-Americans and 0.49 for Hispanic when compared to Caucasians. So essentially they're much reduced in terms of the recognition of depression in people with different ethnic and minority backgrounds. Now, we do know that there is some evidence that the blood-brain barrier, which is always critical in terms of administering medication, changes with age. The lipophilic agents really are markedly reduced. The levels of neurotransmitters, acetylcholine, HBH, serotonin, and dopamine are all decreased due to the choline-acetyltransferase and choline-esterase activities, which increase. So in other words, they not only have fewer receptors, they have higher levels of esterase activities that actually decrease the functional chemicals in the brain. Tryptophan hydrolase is not affected and monoamine oxidase A increased. My message on this for y'all is that we need to be cautious not to be too heavy-handed in terms of the medications because they aren't going to be absorbed, which means that we're going to have more external side effects. They're not going to be as effective at the higher levels, particularly because of these changes. Now, that's associated particularly externally by other functions, and we need to be cognizant that the hepatic function also declines with age. It's a significant amount of variability dependent on the groups of liver functioning and older adults. Particularly, we look at changes in hepatic sinusoids have been identified as contributing to this. So individuals with larger sinusoids actually have less capacity to metabolize. And so generally, the safest bet is that there's a reduction in capacity to metabolize these medications into their free and active agents. It's also affected by renal function. There's a progressive decline in renal clearance at age 30 to 97 to 80, which is about a third less than what we see routinely. There's a decline in renal function that's associated with coexisting cardiovascular diseases and risk factors, which most certainly affects the clearance, and decreased Doug clearance may result from a natural decline in renal function, even in the absence of renal disease. Now, this becomes critical when we start the new PREA screening workshop, which we'll talk about in some detail. So in summary, the physiologic changes of elder is that depression is comparable by race, but variations are associated with region of birth. The neural alterations in cognitive are associated with cognitive dysfunction and geriatric depression. In the very old days, we used to call this pseudodementia, but it's really inherent in reduction of disease. Age related decline of neurotransmitters are decreased in serotonin and dopamine systems, the reduction in the liver's capacity to metabolize, and it decreases renal clearance, which is natural as a function of age. Now, this doesn't mean that individuals that are elders are more fragile. It means that they don't metabolize and use drugs in the same ways that aren't as effective as using, as those people say, under 60 or 65. Now, that behooves us to take a good drug and alcohol history when we start to screen for this. Now, when we start looking at the data, particularly around mortality, polypharmacy accounts for the majority of atherogenic morbidity. In other words, we caused it because we've over-treated them. The sad part of it is when we start to look at, particularly for depression, people are often either over-treated for depression or under-treated for depression. Finding that good middle ground takes some effort and some work. Now, that's because there are, as remember back to the earlier slides, there are, and here are the most common ones, chronic diseases that put them at risk, diabetes, heart disease, heart failure, COPD. I cannot tell you how many people, and it makes sense physiologically, that if you're not delivering glucose to the brain because you have diabetes, you just simply can't turn the neurochemical for it. So, it's really critical that some of these conditions be as managed and controlled as we possibly can. Most certainly, myocardial infarcts have an effect, dementia, stroke, Parkinson's disease, cerebrovascular disease, big factors that affect the response to and presentation of depression. The other factors involved are things that we generally don't think about. One is thyroid disease. Just because someone has a normal thyroid lab, and hopefully people are doing 3T3s and 3T4s on thyroids to determine the breakdown, is something we need to watch. Hypercalcemia, B12 and folate, we'll talk about B12 and folate in a little bit, any form of malignancy, and most certainly because of the inflammatory factors in chronic pain and disability. Now, in general, what we always want to assess, and you want to make sure that we assess suicide risk. We think oftentimes because they're not out or mobile or don't have those things that we shouldn't, and that really should include not just a suicide risk, but a harm risk strategy. There's more than one elder that's so depressed, they can't kill themselves, but they can't kill themselves, but they involve themselves in excessive alcohol consumption. Identifying any comorbid psychiatric or medical illnesses that we talked about. Most certainly, while it's not diagnostic, identifying personal family history of mood disorders is important. Next, reviewing their current medications, allergies, and substance abuse. I keep going back to substance abuse. One of the big problems we have with elders, particularly in ICU, is if you do consults in that environment, you find out that they begin to go through withdrawal, their vital signs get all out of whack, and no one really knew that they had an alcohol dependency. Additionally, review the contextual and current stressors in life situations that they're in. Sometimes moving out of a house into an assisted living where they've lived for 40, 50 years, levels of functioning or disability, the ability to drive safely and get around, all really have major, major impacts on mental health and mental health consideration. Look at the support family system, the family situation, and their personal strength as well. It's great that they have children oftentimes who are very supportive, but if the children live half a country away, it becomes very difficult. Most certainly, reviewing the results from the mini mental status exam and other tests for cognitive function is helpful. Now, when we look through the science and the literature, what we find is these are the best rating scales that we have for elder depression. As you see, it's a rather long list, depression inventory, symptom inventory, CSD, which is a little bit long, hospital and anxiety, depression, mood disorders, geriatric depression scales, PH9, or PROMIS depression scale. Some people may say, well, but the PHQ-9 is just a cutoff for medication. Yes, but PHQ-9 is so widely used that it's got such a huge database. It's actually been included in NIH PROMIS scale, so it's really worthwhile. Finally, the dementia Cornell scale for depression. Now, without neurocognitive problems, which may be the case, those with dementia have similar symptoms of depression and anxiety at 1, 6, and 12 months. When we serially look at it, we see that depression doesn't change. The PHQ-9 and the Hamilton depression scale for rating really become some of the better tools for detecting just pure depression. The HAM-D6 is, interestingly enough, starting to emerge as being superior over TAMD12 in randomized controlled trials. But all forms of the geriatric depression scale detects depression among the elderly with higher sensitivity and specificity. It's better for the short forms, such as the 15 and 10, when compared to the 30, which sort of makes sense. People lose interest. And so, moving some of the research instruments into diagnostic tables really works. And most certainly, the geriatric depression scale seems to be one of the preferred ones, although the others that were listed have been used in the research literature. Now, when we look at antidepressant labs, we need to look at a pre-lab workup. It's not just something that we can just throw in, because with the changes in cardiac, renal, and liver functions, we need to really start looking at what are the basics. And always, it's got to be specific to the medication. All right? So, an example, if you're going to use tricyclic antidepressants, there's almost a mandatory EKG prior to that workup. But in general, they are complete blood count, CBC, basic metabolic panel, prolytes, particularly noting serum sodium levels. And this will become important when we talk about SSRIs. A comprehensive metabolic panel, a lipid panel, thyroid function, expanding the TSH, which I understand is 2 percent to T4 and pre-T4, which are the pre-breakdowns for the functional elements of the thyroid. Do grab a B12, particularly because so many elders have depressed B12, and an A1c. Now, we have to match these to antidepressant use, as I just mentioned. These are the baselines, but that also should include a urine analysis, but it needs to be done probably if they're on antidepressants once every three months, and the thyroid needs to be done once every six months. Given that there's increasing concern about both in the SSRIs as well as the parasyte glycogen. I would encourage people to do a baseline EKG given the rate of cardiac events associated with medication. So here's the workup. Polypharmacy and substance abuse are often not evaluated and should be. Make sure you look for chronic diseases. The dementia Cornell scale for depression and dementia is really best for those without neurocognitive problems. The diagnostics are more accurate for the shorter forms of the geriatric depression scale. Most certainly, you must be matched to the antidepressants being used and baseline CBC, CMP, UA, T4, T3, and baseline EKG given the rates of cardiac events. Now, if there's one rule with elders, I encourage, and that's slow and patient. So the starting dose generally should be one third to one half. That prescribed for a normal, healthy adult. And we'll go into some of the details on that quite specifically. The general rule is please start low and go slow. Now, while we often talk about our impatience with antidepressants, you know, they're not miracle drugs and they don't just suddenly boom work, but you really increase it tolerated at two to four week intervals. And I strongly encourage the latter, four week intervals, just because of the metabolic issue. You do monitor in all of these for increased depression, agitation, anxiety, and suicide rates, especially in the early stages of treatment. What is critical here is that we not miss extra pyramidal side effects that individuals think attribute not to the medications, but to someone else externally. Oftentimes what I, what I tell people is that if they start to feel agitated or anxious, internal anxiety, to be sure and let me know, and then I go back and I will check physically for EPS. Antidepressant trials in elders should be at least, at least 68 weeks, given the lower doses in these lower rates of absorption. And the continuation of treatment really should be a minimum of 12 months. There is a great deal of debate about whether treatment medications should be titrated down. Generally, anything less than 12 months is exposing and waste of time for people. Now, antidepressants in general have a series of adverse events, and I'm not talking side effects. These are adverse events, cardiovascular problems, metabolic problems, central nervous system events, osteoporosis, big falls and big fractures. This all links back to that initial workup where we look at things like calcium levels and cardiac functioning, et cetera, so that we know where we start with, because these are adverse events in consequence, but it's an increase over what you see in the general population, largely because of the high level of liver functioning and renal clearance. In addition, it is associated with increased suicidal risk. Now this really, again, has to do with an induction of external side effects for people with the elderly. All potentially inappropriate medication antidepressants have been associated with dementia were non-selective monoamine uptake inhibitors. In other words, all of the inappropriate medications really were not MAO reuptake inhibitors. They were the medications that we routinely and usually use. Potentially, the intake of drugs with anticholinergic effect appears to be at an increased risk for dementia. That's largely because anticholinergic activity is really associated with learning and memory retention. By having anticholinergic side effects, we're going to actually decrease that, much as we do in children. Anticholinergic activity is one of the big things we watch for children when we treat them, and the same is true for elders. Elder exoprimal side effects, they really originate within hours or a few days of starting antidepressants, potentially appropriate medication, but they include Parkinsonism, anesthesia, and dystonia. It is not normal for an elder on medications and should not be accepted if they shuffle along. They can't lift their feet and move. That is an exoprimal side effect. I strongly encourage people to go in when they do this and look for smooth and long bone muscle twitches and look for those side effects. Physically examine them. If we look, there are some medications that are much worse than others, believe it or not. Baroxetine, Paxil, has a hazard risk ratio of eight times PPS over others. Imipramine has a hazard ratio of 8.3 times and surprisingly, floxetine, which has a hazard ratio of 8.2 times. In studies, these are the ones that have the greatest risk for generating exoprimal side effects. That most certainly is affected by age. Smoking, which really speeds up the liver, will chew up the medications a little faster. People oftentimes give it an increased dose, but it triggers that. Any kind of essential or tremor history and a history of taking any kind of antipsychotic, this includes second generation antipsychotics. While there are lots of markers that will tell you that second generation, third generation antipsychotics don't have exoprimal side effects because they work, I will stand here and tell you that's untrue. I've seen it based on people and it's totally associated with the duration of use. Those are additional risk factors for drug-induced PPS as well. Now, in terms of some general guidelines for using antidepressants, this is what I recommend. One, start low and go very slow. You increase only as tolerated at two to four week intervals. Most certainly, I encourage more than four week intervals. Monitor for increases in depression, agitation, or anxiety, and suicide risk. Those are the most immediate kind of events that occur. Exoprimal symptoms originate within hours or days and include Parkinson's, asthma, acustic, and dysphonia. You'll usually see this within the first week or so of treatment. That's really the critical window. After that, they can adapt a little bit, but it's always worth keeping monitoring for. Antidepressants are associated with an increased risk of adverse events just because their elders would change metabolic function, such as cardiovascular, metabolic, PNS, osteoporosis, falls, and fractures. All potentially inappropriate antidepressants are associated with increased dementia, or non-selective monoamine uptake inhibitors, and those that had anticholinergic effects. We'll talk about those. Particularly, the tricyclic antidepressants have a significant amount of anticholinergic effects. Now, antidepressant selection. When we look at antidepressant selection, there's people often look at one side of this whole prescribing point, not the other. What it must be is it must be a primary mechanism of action that targets the symptom. In example, anxiety must be something which is particularly hard to know, but it must be one of the approved target symptoms to get. Second, look at a beneficial side effect profile. We'll talk about some medications that people use excessively and found successful, but the best side effect profile with the lowest risk of drug-drug interaction. What we often forget is that we'll prescribe a medication and then not look at what is the beneficial side effect profile. We'll look at just what side effect profile is. Now, please note, short-term studies show a reduction in risk with antidepressants compared to placebo for age 65 and older. In other words, antidepressants really do better than placebo and are effective in elders, particularly over the age of 65. There is a place for these medications. Cautious though we may be. Now, what is the evidence that they're effective? What's the evidence? You know, unfortunately, there are clinical trials for antidepressants in the elderly are really underrepresented, particularly controlled trials. It's just they're probably less than a handful out there. And unfortunately, the long-term effects are very confusing when you look at these studies, as well as the emergence and or treatment in dementia, which is really central to providing care. All right. So you want to make sure you remember if there's an inappropriate dementia response, it's probably associated with antidepressants. And so those are critical kind of things to balance and use. Now, overall, the data is really good. The efficacy of antidepressants is not related to selectivity or potency for norepinephrine, dopamine, or 5-H serotonin-based blockage, but their relative profiles of side effects and individual tolerance are the critical factor in terms of making them effective. It's back to monitoring for those side effects and monitoring for the adverse events. Now, a meta-analysis does reveal that nitrazepam, escitalopram, venlafaxine, and SIRK-C are more effective and acceptable than the following, fluoxetine, fluoxetine, fluvoxamine, fluvoxamine, and paroxetine. And as we just saw, those are the ones that literally actually increase your hazard respiratory dose. So you're better off using some of these others, in part because they have a higher dose range that you can manipulate, and the side effects are better. The problem is that less than 1% of all clinical trials generally have been done with treatment-assisted patients. So when we get someone who doesn't respond to them, then we start to have real problems. Anxiety. Treating elder anxiety is particularly difficult because it doesn't respond well to most antidepressant treatments. But one thing to look at is vitamin B12 and folate deficiency. It actually increases the risk of depression. Moreover, this deficiency has been linked to poor antidepressant response. We'll talk a little bit about one medication called Deplin that is really effective in these cases. The one caution I have on Deplin is that you must be initiated and be patient because the absorption rates take a while, particularly with the metabolic issues we talked about, to start to become effective and turn this around. Let's look at certain classes here. Amitriptyline. These are tricyclic antidepressants. Amitriptyline, chloramepramine, disepramine, imepramine, mayotriptyline, nortriptyline, protriptyline, and triametramine. These have a class of potent reuptake blockers of norepinephrine and serotonin. But they also block the alpha-1, alpha-2, beta-1, beta-2, and muscarinic receptors as well. That means that we have some major problems. Disepramine blocks the reuptake of norepinephrine. Amitriptyline, primarily by 5-HT, and various degrees of side effects primarily are cardiac and anti-cholinergic. Now, amoxetine really causes more extramural side effects. Now, in thinking about these, there are several things to look at. One is, if you get into a problem and wonder if there are side effects associated with it, primarily cardiac and anti-cholinergic, you cannot measure the primary drug alone. You also must measure its metabolites, because measuring the metabolites really is what, and adding the two together, gives you the LD50, the toxic dose, and particularly the dose that causes cardiac and anti-cholinergic kind of side effects. Amoxetine not only causes EPS, but has a significant amount of sedation and endocrine changes associated with it. It is oftentimes one of the more preferred ones, particularly for people that don't want to be heavy-handed with the primary and secondary antipsychotic, first and second generation. Now, my general rule of thumb, to be honest with all of you, is that tricyclic antidepressants are not recommended as the first line. These are side effects, such as hypertension, cardiac conduction abnormalities, and anti-cholinergic side effects are so common. They are inherent in the medication. These are, as a class, anti-cholinergic, and they have all the things that we fear, postural hypertension leading to falls, cardiac conduction, abnormalities in terms of moving out to first degree heart block, and the anti-cholinergic side effects, increasing dementia, are all the things that we really don't like to do. I know they're very popular, and I hear of a lot of people that use a small dose, like 10 milligrams of imitripoline to help for sedation, but it really creates more problems than it's beneficial. Second, when used as a second line agent, an EKG, postural blood pressures, should be obtained before you start and monitor them, if you use them. And blood level monitoring is highly recommended because the liver functions, as I said before, you must add the primary and the secondary metabolites. If you go to that and decide to use it, rather than disipramine, imitripoline, go with nortripoline and disipramine because they have a lower anti-cholinergic subversion than the other primary side effects. In general, what you're going to see is this range of side effects. If you want the old adage, hot as a fox, red as a bee, mad as a hatter, because of the vasodilation, dry mouth, blurred vision, particularly indirect form of glaucoma, fatigue, disorientation, drowsiness, urinary retention, low blood pressure, nausea, dry eyes, dizziness, headache, seizure, particularly constipation. Constipation is a given for these medications because they kind of have a suck the water in because of the hypertension kind of thing, the reaction to it, sexual dysfunction, and most certainly weight gain. They are highly lipophilic and lipophilic to positive. The adverse events are angle closure leading to glaucoma. They will have an enlarged prostate. They will have urinary retention, cardiac problems, thyroid problems, and the blood sugar needs to be monitored more aggressively if they're on. And an overdose. Interestingly enough, tricycline and antidepressants are the highest cause of drug-related death after alcohol and drug companies and heroin. It is the fourth highest cause of overdose seen in ER. Seventy, 80% of overdose do not reach the hospital alive. Now, just a word of caution here. Like I said, remember I said that we're both a victim of our own judgment and the healthcare system. Ten milligrams of amitriptyline is very good for sedation. I will not debate that. But the problem is because we often end up giving people one-month and three-month scripts. Three months is well over the elderly, about lethal dose 50, particularly because people recalculate the metabolites on it. So it is just literally a killer. It's one of the reasons I think that psychiatry in general kind of gripped it away from them in the early days, particularly for when SSRIs came out. The lethal dose is close. Therapeutic dose is close. The lethal dose, three to five times the therapeutic dose, makes them lethal. And because patients, as I said, are often given a 90-day supply, they have more than enough to kill themselves. And when trisect antidepressants were first initiated, we used to see these people every two weeks, but we do not give them more than a two-week dose because that starts to become lethal. It has decreased to less than 10% of all antidepressant prescriptions written in the U.S. So I think it's these adverse events and adverse consequences that oftentimes have led people to commit these dangers. There are heterocyclic antidepressants. Amoxifen, Ascendin, which is, again, if people start to have a little bit of a psychotic when they take these medications, it's oftentimes good. Trazodone. Trazodone is a wonderful, wonderful medication, particularly at low doses for sleep. But the problem is that it has massive postural hypertension issues and luteumil. And I personally have never been able to use luteumil effectively, mostly because it solves all problems because it totally sedates people. People go to sleep quite quickly with that. But it's closely related to Trazodone. But it has been an option. Remember that prior cautions on the use of this medication. Now, oh, I'm sorry, wrong direction. Now, Trazodone Denterol is really a major departure with less risk of toxicity. It has low anticholinergic effects. But as I said, it's very sedating. It's a strong antihistamine effect in the adrenergic blockage. So it has a lot of postural hypertension. So it's going to increase their risk for falls. All right. And particularly in the early morning, they'll complain about having a drug hangover, feel slightly drugged. That's when it's probably at its worst. Moderate serotonin reuptake inhibitor blocker. But the side effects are serious. Dizziness, sedation, cognitive slowing are common. I always throw in privacy from here simply because it's there and uncomfortable. My general recommendation for the dose is very, very small. All right. And it's excellent agent for sleep, but in the very low dose form, 25 to 50 milligrams or more. Here the SSRIs, most of us are familiar with. Citalopram, escitalopram, fluoxetine, fluoxetine, paroxetine, sertraline, ritalix, the new one kind of on the block. The side effects of this, you can get EPS with these largely because they back up through the dopaminergic form. They feel agitated, shaky or anxious. They feel nauseous, get dizziness and blurred vision, low sex drive. It will totally can wash it off. Sometimes it doesn't. I've not been able to really figure out any kind of algorithm or patients do or don't fit low sex drive and sexual difficulty. In men particularly, it can block getting or maintaining an erection. But just because it's an SSRI doesn't mean that you cannot get exopram or cytokine. Are they harmless? No. The research literature shows that with SSRIs, they have an increased risk of falls, largely because you start to deplete sodium through renal excretion. That's why you do the renal and urine UAs because it's really very sodium depleting. Just like the children, you really need to monitor renal sodium. Now, what we've also found is that at milligrams or 40 milligrams or above, citalopram will have prolonged QT. So that's why you've got to grab cardiac EKG and begin to continue to look at it, monitor that. Ventilifaxib. Box both serotonin and norepinephrine reuptake. 40 respond in rate in patients that are refractory to other antidepressants. Monitor BP, discontinue. I really encourage people to discontinue this low if you don't have EPS withdrawal. The withdrawal is the strongest with Paxil, but you do see it with it. Nausea is coming. And an old NIH director at one point in time had a post that you can really accommodate the nausea in starting up these medications by having a cup of yogurt in the morning. It's just a clinical pearl because most of the serotonin receptors in the human body are GI tract. But it settles it down. And I've really never had anybody not take any of these medications because of nausea. A cup of yogurt can really help. Sweating can be a problem. Sometimes with the blood pressure going up and down and some sexual dysfunction. I found ventilifaxib to be particularly effective for individuals that have some kind of alcohol history. It just seems to be metabolized more and work more effectively if they've got alcoholism in their alcohol history in their form. This ventilifaxib for STIQ is spasomotor symptoms. It does work with fibromyalgia to reduce a lot of the pain. So you see a decrease in the inflammatory factors. It is also seemingly a little bit better for general anxiety disorders as well as social anxiety, post-panic disorder, and anxiety associated with PTSD. And there is some good emerging literature on premenstrual dysphoria disorder as well. Phyloxetine, Cymbalta, is one of the probably most prescribed and most important. Because it has a beneficial side effect, which we'll talk about in a second, it is a serotonin, most potent serotonin reuptake inhibitor. It does have some norepinephrine, slightly less than the serotonin. And it has the least potent dopamine effect, particularly for higher doses and for people that may suspect already have some kind of tremors. It is, for the elders, particularly superior to SSRI. And here is the number one reason. It's that it's used to stimulate appetite, which can be beneficial. I mean, people want to eat on this medication. I've had patients come in and say, I don't want just a slice of cake. I want the whole cake. And for elders who oftentimes decrease their appetite or food intake, it can be beneficial, but it needs to be monitored. That's why the 1-AC's become so critical. Nifazodone. Nifazodone was a wonderful drug, but there were some problems with it. And all the patients who were given, as you see here, there are 109 cases of serious liver toxicity, 23 cases of liver failure. And unfortunately, it just seemed to be somewhat random. It popped up. The symptoms were from a few weeks to two years at length. Most often occurred in the first four months. The baseline and continuous monitoring of LFTs is not required, but you really should discuss it with the patient. I've largely, because of this, drifted away from Nifazodone, even though I really love how it works, particularly with some of the elder patients. Largely because of this, it's just simply not worth the risk. They already have decreased metabolic issues with the liver. And so I've drifted away from it, but there are people that still use it. Bupropion. Well, Bupropion is the first heterocyclic ever. It is available in immediate release. I will tell you that I don't approve of the immediate release because in some of the research, there's suggestions that the immediate release is associated with those rare cases of seizures associated with seizures. It also can be used BID with sustained release. My BID use of this really has to do with early in the morning and four or five in the afternoon. I will not give it to people after five o'clock because they seem to have difficulty sleeping. Once daily XL form is available, it works well. The blood level is the lowest for efficacy, but it's also quite expensive. It's just enough dopamine blockade to synergize with partial norepinephrine blockade. And so it really increases both dopamine and norepinephrine. It's really a very good medication if people need to be energized a little bit. You've got to watch that afternoon, bedtime dosage. Its side effects, however, can include agitation, dry mouth, constipation, headache, migraine, nausea, vomiting. The nausea, vomiting, particularly for elders, is a little bit more concerning. The average person loses over the first two or three months about 20 pounds using Wellbutrin. You've got to be very cautious about that. However, it has four times the risk of seizures over other antidepressants with the exception of Trifecta. Extended release increases tolerance and effectiveness. So I really encourage all of the slow release and long-term medication. It can cause some odd side effects. You've most certainly got to watch. Edema, the feet and hands, respiratory problems, rashes or hives. And this may have something to do with the coloration. There's some dyes, particularly in brand name, that makes it unique, but it's also a lot of people have difficulty. Mania, nervousness, irritability, insomnia. Most certainly when that happens, what you want to do is protect yourself from those side effects. Restlessness, coordination problems, changes in sex drives. I've never seen changes in Wellbutrin-caused impotence interfere with the menstrual cycle, but it does exist in the literature, so it's something to watch for. I have seen difficulty urinating. That and this medication, bupropion and effects are notorious for these kinds of things. There are some reports of chronic sore throats and infections that won't heal. So they're most certainly worth monitoring. Deflin. Deflin is, as we talked about, the B12 kind of instrument, comes in 7.5 milligrams, 15 milligrams. Typical supplement is 1,000 micrograms, so you've got to dot that up. And particularly if they're on any kind of anti-inflammatory, they impair folate absorption. But folic acid, it really is associated with enhanced fentonin or cephalic metabolism, which does allow it, so you've got to be cautious on that. And fluoxetine is the non-competitive inhibition of the transport of it, particularly in the intestine. So those are all things to be aware of. Deflin takes a long time. My experience is it takes a long time. It's not going to be a miracle thing. You've got to waste at least four to six weeks before you start adjusting the doses around. Interactions with deflin, most certainly you see in inflammatory drugs, NSAID, smoking and alcohol, sulfazine, inhibits absorption, metformin, warfarin impairs. So there's several things that are impairing absorption. Here's a table that I put in the handout with normal starting dose for adults, and then the recommended dose, which is basically 50% of the adult dose, at least. And then the maximum daily dosage that you can go to for each individual. So in summary, what I would say is that when you're treating antidepressants, exclude the medical causes for the symptoms, and consider seriously behavioral non-pharmacologic therapies, and monitor if you give them for change in hyponatremia, falls, GI bleeds, ADHD. Most certainly look at the risk versus the benefit analysis to improve the quality of their life, particularly as they get older. And if there's no improvement in literally eight to 10 weeks, and I would give it a full 10 weeks, change treatment and then cross targeting down. Sudden cessation really causes withdrawal syndromes, particularly for paroxetine and benzofaxone. If you look at the drug information in paroxetine, half-life is only 21 hours. It doesn't last a full 24 hours. And I've had patients complain of that until they get the dose levels up. They begin to cry and weep every morning. So it's something to worry about. If there's some improvement, but it's not optimal, consider augmentation with B and folate supplements. Monitor for the emergence of their clone syndrome always with anything. Now, the general treatment goals are SSRIs, SNRIs, metrazotamines, or plevamide are all relatively safe in the elder with similar effectiveness. Fluoxetine has a long half-life, but it has greater drug use. I'm a real fan of fluoxetine largely because if they have memory problems and they forget a dose, if they're home-based and they're home-based and they forget a dose, it's not that big of a deal that can be caught up on. But you got to monitor for often. Fluoxetine and most PCAs have greater anticoagulant effects and can be problematic. Thank you very much. Appreciate your tolerance for me. Dr. Rice, thank you so much. That was a really terrific presentation. I learned a lot. Before we shift into the Q&A, I just want to take a moment to let everybody know that SMI Advisor is now available from your mobile device. So use the SMI Advisor app to access resources, education, and upcoming events, complete mental health rating scales, and even submit questions directly to our team of SMI experts. Download the app at smiadvisor.org app. So now on to the Q&A. We will do two questions. One of the questions that came in from the audience was, should we treat depression that is comorbid with cognitive decline the same as we would treat depression with intact cognition? Oh, thank you for asking that incredibly relevant but massively hard question to ask. I think the answer is no. And here's what I would suggest, is that if you're looking at cognitive impairment per se, you must be sure that it's not associated with any of the medical basis of that. If it's not associated with any kind of cerebrovascular or cardiac kind of events, even something like COPD, then yes, you should treat them the same. But just an example, I've had patients with COPD that need to be on continuous oxygen. The second need to be on continuous oxygen, the second it drops off, it droops to the side or something like that, they become floridly cognitively impaired. And so really optimizing the COPD treatment first, and then looking at the depression and seeing what the residual is. But it's a very critical question. Thank you for asking that. It's very, very relevant. And unfortunately, it's got to be a two-step process. What is the source of cognitive impairment? Now, as I said earlier, if there's no basis, metabolic or physiologic basis for it, then I would say yes, treat it just the same as you do other depression, perhaps with one of the more stimulating kind of agents like the Fexer to see if that picks up the cognition a little bit. But the critical thing would be first, be sure that it's not due to some kind of underlying medical. Great question. Thank you, Dr. Rice. Another question is, do you have any clinical tips for discussing antidepressant medications with elders who may be reluctant to try them? I mean, perhaps it's the first depressive episode they've had, and they may be a little reluctant to talk about it or stoic. Do you have any sort of clinical tips in that discussion? You know, that also is a great question, because sometimes, particularly with elders, you get this pull yourself up by your bootstraps kind of philosophy. And I think that's where motivational interviewing really comes in, and you talk with people about that, and then educate them. And I always try to educate them about what both the causes are as they age, as well as any changes they've had in their life or anything, that most certainly things are not permanent, and most certainly we start very low and go slow. And that's particularly true with anybody with kind of a generalized anxiety kind of stuff about it. There are some psychotherapeutic strategies involved in that, almost paradoxical, but I'm going to go so low, I don't expect it to actually work, and then give them a month. And invariably, they will have some positive gains, at which point say, well, let's bump up a little. We've got to be really cautious. I don't, I'm not sure this is going to be that effective, but let's give it a try. So it's really kind of just motivating them to this, and then that's where I think the slow, low and slow strategy comes in to be most beneficial. But yes, discussing, there are some people that you will not be able to convince to do it, you know, unless they have, and then we get into guardianship and other kinds of issues. But generally, that's the strategy I want. I usually, I'm a big fan of motivational interviewing. All right, terrific. That's a really, really helpful perspective. So we'll have to wrap up the Q&A now. And again, Dr. Rice, thank you so much. So on to the next slide. If you have follow-up questions about this or any topic related to evidence-based care for SMI, our clinical experts are now available for online consultations. Any mental health clinician can submit a question and receive a response from one of our SMI advisors, experts. Consultations are free and confidential. SMI Advisor is just one of the many SAMHSA initiatives that are designed to help clinicians implement evidence-based care. We'd encourage you to explore the resources available on the Mental Health Addiction and Prevention TTCs, as well as the National Center of Excellence for Eating Disorders and the Suicide Prevention Resource Center. These initiatives cover a broad range of topics from school-based mental health through the opioid epidemic. And thank you so much for joining us. And until next time, take care. Thank you.

Elder Depression Treatment

Psychopharmacology

SMI Advisor Program

Dr. Rob Cotay

Dr. Michael Rice

Antidepressant Use in Elderly

Adverse Events in Elderly

Antidepressant Classes

Depression and Physical Illnesses

Evidence-Based Care