Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk, Episode 83 I'm your co host, Dr. Kane. Speaker 1 00:35 I'm Dr. Schuman, and I'm Dr. Patel, and today I'm really excited to bring another kind of mental health focused topic. So we're gonna talk about flow and fluoxetine, evaluating antidepressant selection and chronic kidney disease. Dr. Sean Kane 00:47 And really the impetus for this episode actually came from a patient that I had in the ICU probably about a year ago, maybe a little bit longer than that. So I'm gonna kind of present that case as kind of a starting point for what is the clinical conundrum or scenario associated with using antidepressants in patients with CKD or even ESRD in stage renal disease. Speaker 1 01:07 So then we'll kind of look at the importance of accurately recognizing symptoms in patients with CKD, look at the limited available evidence regarding treatment in that population, and then maybe go and discuss some of the guidelines and determine what are some of the better treatment options we have in light of that evidence. Dr. Sean Kane 01:22 So we'll kick it off with a 60 year old male who was admitted to the ICU following a multi system trauma with massive hemorrhage following a very severe car accident. So this particular patient was in the hospital at this point for probably about three weeks. His hospital stay was complicated by a number of surgeries, respiratory failure, requiring tracheostomy and prolonged ventilator support, a number of infections, requiring, again, prolonged courses of antibiotic therapy. And then finally, his hospital course was complicated by acute kidney injury, eventually resulting in his need for longer term hemodialysis support, because his renal function didn't recover. Now, in this scenario, most likely this is a patient who had acute kidney injury because of hypotension, blood loss, and that progressed to a form of intrinsic acute kidney injury called atn, or acute tubular necrosis. That's where the cells in the kidney die because they don't get enough blood and oxygen. So for this patient, he's essentially anuric. We don't expect his renal function to get better anytime soon. It may recover, but it's unlikely it will recover. So in the most likely scenario, this is a patient who will be a lifelong hemodialysis patient. Now, at week three of his hospital stay, it was noticed, both by his family and nursing staff that the patient seemed to have a more depressed mood or affect. He was really not interested in participating in his own care, in terms of basic physical therapy that we can do in critically ill patients, all the way to kind of interacting with his family and then kind of expressing a desire to kind of not go on feeling very depressed about his situation. He didn't have a past medical history of depression. And really, at this point, the question came up on rounds of, what is the best option for this patient in terms of, we want to do something to treat his depression, to help his affect, to help his mood, what medication could we use in this patient to help him get better? Knowing that most antidepressants will take many weeks to kick in. In terms of efficacy, maybe we can get the ball started now, knowing that he won't be in the ICU in six to eight weeks, for us to really see that benefit anyway, but we have to start at some point. Speaker 1 03:31 That's a great clinical question, clinical conundrum there. So Dr. Patel, how common, though, is this kind of scenario here where we've got a patient with a limited renal function, and we need to look at an antidepressant? Dr. Khyati Patel 03:41 I'm gonna say that magnitude a problem is fairly common. We're looking at 6.7% of adults in the United States there experience one episode of major depressive disorder in the past year, and that's according to the 2016 data. And this number is a little different according to gender, as we know, slightly higher in adult female patient, 8.5% versus male patient, it's about 4.8% but, you know, regardless of if it's chronic kidney disease and depression, I'm just gonna come out and say, from my clinic experience, that any kind of long term condition patient has, you know, aka diabetes, depression, kind of comes along with that, you know, It could be. And we're going to probably talk about the inner pathophysiology and true chemical differences that are happening inside the body, but it's the taking care of the disease burden and the prognosis related burden that patient feels of am I ever going to come out of this? You know, am I ever going to go back to doing things that I used to do and things like that? Speaker 1 04:40 So Dr. Kane, I believe there's even a term that's used in kind of the intensive care setting to describe this kind of a situation. Dr. Sean Kane 04:47 There is. So it's kind of a newer term called pics. It's post Intensive Care Unit syndrome, and it's kind of this constellation that can encompass physical, cognitive or psychiatric or mental health conditions arising from your. Critical Illness. It's fairly new, and we don't have a lot of kind of incidence numbers, but in terms of the psychiatric component, somewhere between five and 25% of critically ill patients will experience a psychiatric condition resulting from the critical illness. This could be anxiety, PTSD or depression, or a combination of many of those. Right? Speaker 1 05:19 I know that depression is the most common psychiatric comorbidity in patients with end stage renal disease undergoing dialysis. Rates as high as 18% in some studies, and again, I'm trying to mostly use the term major depressive disorder versus a general depression. We'll kind of get into some of the nuances later. So as far as looking at why the higher rate in somebody with end stage renal disease or CKD, a lot of it is subjective, as Dr. Patel alluded to, you've got, again, just the ideas of chronic conditions that lead to an overall burden, a lot of frustration. There's also a number of physiologic changes, uremia, the waste products build up, fatigue, weight loss, sluggishness, insomnia, all of these symptoms occur again that your uremic syndrome. Uremic symptoms mimic a lot of the non specific mental changes in somebody with depression, and so they can even look like major depressed disorder, although they may not meet all the symptoms. And because of that, it really is important to do a couple things. One is to use a rating scale to identify symptoms. Some of the ones, common ones, the MADRS, the Beck Depression Inventory, the PHQ nine, another fairly common one used in clinic, but then also the the interview, so really, sitting down with the patient, doing a good, focused clinical interview to talk about what's going on before again, you make a diagnosis of MDD or major depressive Dr. Sean Kane 06:36 disorder, and again, going back to the ICU side of things, hopefully The listeners can appreciate why some patients, especially in a critical care setting or just in a hospitalized setting, may have some of these depression type symptoms based on the fact that they can't go home. They're stuck in a hospital bed. This particular patient can't speak because he has tracheostomy and he's receiving mechanical ventilation. You know, everything is turned on its head when you're critically ill or just in this chronic illness phase, and clearly that's going to contribute to your ability to cope with, you know, your depression and things like that. Speaker 1 07:11 One other thing I know is that just in looking at the link between the two is there may be some physiologic changes. So Dr. Patel, and in brief, I know when we talk through diabetes and depression, we look at that inflammation as a link between diabetes and depression. Well, some inflammatory mediators seem to be elevated in kidney disease too. And so again, we have that link where maybe it's also that you're more likely to have depression with CKD or CKD with depression, vice versa. So that's an important thing to recognize, too, as we're looking at the overall assessment of the patient. Dr. Sean Kane 07:43 So kind of, going back to our patient case, you know, kind of the knee jerk reaction is okay. We have a depressed patient, we will give them our favorite SSRI. Wipe our hands with it. We're done, right? And in this particular patient, I personally didn't really appreciate all of the nuances associated with renal impairment and selecting an antidepressant. And I think that as you start going down this rabbit hole of, you know, what are some of the things to think about with that renal impairment, you start knocking out some of the agents that you might prefer to use, or you might be dosing them differently, or considering a different adverse effect profile just because of that renal impairment. Dr. Khyati Patel 08:20 And I mean, we're talking about CKD. So there are different stages of CKD right there. Early stages of CKD, they may not be on hemodialysis. Late stages, you know, they might be on hemodialysis. So the we have to consider the clearance of the drugs, you know, whether we dose it before they're hooked out on the chair, or would it be the dosing after? So all these nuances are very important to Kevin. Speaker 1 08:41 That's Dr. Patel. That's a great point. What has made some of the studies difficult again, is classifying where CKD is set at such a heterogeneous description because of all those stages you mentioned, versus end stage renal disease, you've kind of got dialysis there. You're doing it, you you know, there's not as much change in the renal function. And so that population, they can kind of capture a little bit more consistently in studies. But as far as CKD, Dr. Patel, what? What are some of those stages? How do we, how do we kind of compare somebody based on renal function? Again, because we'll be talking about some of these definitions throughout the rest of our talk, Dr. Khyati Patel 09:13 sure, and I think these stages are defined based on the EGFR, and they are coming from the KDIGO guidelines. So we can start from stage three, where the EGFR is between 45 to 59 we can go to stage 3b where it's slightly lower to 30 to 44 and then stage four will be where EGFR is 15 to 29 and anything below 15 will be considered stage five. Dr. Sean Kane 09:38 CKD, you know, classically when we think about renal adjustment for many medications, typically, not always, but typically, they're thinking about a creatinine clearance of about 30 or an EGFR about 30, which would put you in the stage four or stage five camp, right? Dr. Khyati Patel 09:52 Yeah. And they're a handful of medication that says, you know, dose adjust below 60. But most of them, like Dr. Chan, you said. They're below 30 is where adjustments or contraindications for renal dosing start, Speaker 1 10:06 and then obviously end stage renal disease, initiation of dialysis or transplantation due to kidney disease, again, other than an acute kidney injury, would be your end stage description. So one other thing that comes up is, again, in looking at why don't we just start everyone with depression on you said your antidepressant, or SSRI du jour, is that about a lot of patients actually aren't interested in the regimen. There was a study that was very surprising. They found that 91% of individuals that were offered in antidepressant refused to even be placed on the one that was recommended by their provider. A lot of them said, you'll know my depressive symptoms are external things like chronic illness or the dialysis itself. These are going to go away. I don't want to really be on a medication. And so this gets into this old topic of exogenous depression, something based on external circumstances, adjustment to life circumstances, versus endogenous based upon changes in neurotransmitters. That's way beyond our scope here, but it is something to note, is that there are differing levels, again, of somebody who feels sad versus what we call a clinical or major depression. And again, going back to, as I stated before, the importance of being careful how you screen for it. So we should really, if we're going to be doing it in a clinical sense, be using one of these validated rating scales, PHQ, nine, while it's not the gold standard in clinical trials, that's the patient health questionnaire. It's pretty easy to do. It's, you know, a numbering system. It's nine questions. Anyone can give it without a whole lot of training, and that can give you an idea to screen for and assess for changes in depression. Dr. Sean Kane 11:38 And I really want to highlight, again, we're not going to go too deep into it, but the exogenous versus endogenous type of depression, really, the clinical question we have here is that this patient did not have a past medical history or potentially a disposition to getting depression. This is something new for the patient, right? So presumably, his depression is primarily mediated by his critical illness and his current circumstances. So really, the question isn't, does an SSRI, for example, treat depression? The question is, does an SSRI actually treat his kind of depression that is caused by his circumstances, as opposed to a neurotransmitter problem that he may have? And that distinction is really tricky, and we've actually done studies specifically in patient groups that may be depressed because of their chronic condition, heart failure or post in my patients, for example. And that's actually a very different patient population than someone who has baseline depression, not caused by one specific factor, in general. Speaker 1 12:33 And I think one of the things to consider is, again, why is, you know, there's, there may be a discomfort with prescribing antidepressants in this population, because we don't have a lot of the data. Again, antidepressants are not the only way to go. Psychotherapy. Counseling becomes a wonderful option too, but I think there's a hesitation to use the medication sometimes because we don't have that data in the in the studies where you look for major depressive disorder management, most of the studies, just like with many other diseases we've covered throughout these podcasts, they look for the ideal patient. Well, if you have kidney disease or liver disease, you can't be in the study. And so we take perfect world data and then take it to a real world population, and all of a sudden realize that it may not, it may be, not be apples and apples there. And what do we do? Dr. Sean Kane 13:19 And a lack of data, especially lack of clinical data, we're kind of forced to consider some of the more basic sciences type data that we have available to us. So it could be something as simple as well. Most CNS type drugs have to penetrate into the CNS to have their effect. Therefore, that CNS penetration requires them to be lipophilic, and if they're lipophilic, typically they're going to have a big volume of distribution, which means that they're not going to be in the blood for dialysis to pull them off. So in terms of elimination of the drug, it's unlikely that most depression type drugs are going to be eliminated with Speaker 1 13:53 dialysis correct. Then you also have the idea about pH changes, so within the gut that enter the whole system, that occur that may affect bioavailability. And we look at different drugs that are maybe delayed release, or enteric coded antidepressants. And does that change how much absorption and how much of it just goes right through the body without without essentially getting to them. And then Dr. Khyati Patel 14:12 we're looking at the molecule size as well, kind of similar to the lipophilicity. And you know, if they're bigger molecules, they're not going to be easily removable by dialysis. So are we looking at smaller molecule drugs or bigger molecule drugs, vice versa, looking at efficacy versus safety? Speaker 1 14:28 And one other thing that doesn't come up a lot is that we learned that SSRIs antidepressants aren't perfect. We know part of how we know about serotonin is we know that it affects platelets. Some of the early studies when they looked at depression, they looked at serotonin and platelets, and so if you have medications that affect serotonin, there's potentially concern for bleed, and obviously we have anemia due to chronic disease and other hematologic abnormalities in somebody with kidney disease. Is there a concern then that the antidepressant itself could maybe worsen some of those outcomes? I think that's something valid. Of the needs to be explored. Dr. Sean Kane 15:01 So we've kind of danced around it about 12 times. It sounds like we don't have a lot of data, but certainly we have some clinical data that we can at least talk about, right? Speaker 1 15:09 And so again, we'll go through some of the main agents. You know, I would encourage the listener that we're going to go through some of the more common antidepressants used in our clinic, in my experience, and those with some of the better data. However, if you looked at some of the resources we'll be providing, there are tables on a whole host of other antidepressants, and I'll encourage the listener to look at that, especially if they have a question about a specific agent. But I think the first one to talk about is going to be citalopram. So this is one, again, there's they did a couple studies as well as, you know, just simply giving somebody a single dose, and that's not quite the same as consistently administering it, but on single dose data of 20 or 40 milligrams, there was really no difference in drug concentration between those with anuria and renal impairment and dialysis compared to a general population. So the authors concluded at that point no dose adjustment needed in kidney disease, even with dialysis. However, how many patients you think they had in there? 1300 How about 13 man? So again, we're taking a lot of faith on a very small population. So I think fortunately, there was a second study that looked at 20 milligrams a day for three months, and then they compared it to this is where it was a little strange, but six sessions of one hour teamwork training every other day, and they talk talked about subjects where they're educated about the kidneys and kidney disease, what dialysis is, what are some other ways you can manage your stress and anxiety? And they found that both groups responded similarly. And so we have a couple different ways we can interpret that Dr. Sean Kane 16:38 study, potentially indicating that this kind of sort of psychotherapy, or just non pharmacologic therapy, may be equivalent to giving an SSRI. But of course, we have to worry about sample size, because if you don't see a difference, you always worry, did you? Were you adequately powered to actually see a difference, right? Speaker 1 16:55 You can kind of say, Well, the good thing is that the SSRI worked and it was safe, so maybe we can use them. The flip side of it, you can also say as well, talking to them about it, psychotherapy worked well. So why not just do that? And so you can kind of come up with your own conclusion based upon that. Dr. Sean Kane 17:10 So we have citalopram, but there's a number of other SSRIs in the market, and fluoxetine was the first one, right? So what data do we have for the oldest SSRI on the market? So this one Speaker 1 17:20 was assessed in two different studies, and it's interesting. It's interesting, because this one has a known active metabolite like norfluoxetine. So the question becomes, then is, if you've got this active metabolite hanging around, does that change the game, as far as concerned for drug accumulation? So in the first study, 16 patients. So again, a small sample size given open label fluoxetine, 20 milligrams. Seven had renal failure with hemodialysis. Nine controls. Six completed in each group. Five out of six in each group saw at least moderate improvement. And the good thing is no difference in drug concentrations. So again, like the other one, they said similar efficacy, similar pharmacokinetic parameters, regardless of kidney function. And the cool thing too, they even noted even the kinetics of the active metabolite were unaffected. And that's nice, too. So we regardless of the active metabolite, it seemed to be that did not change the overall profile of that medication. However, there have also been a couple of case reports. There was one reporting on duodenal ulcer bleed that was blamed on fluoxetine, which didn't seem to remit until fluoxetine was stopped. And so despite some evidence that the medication seemed to be pretty unaffected by presence of kidney disease, do maybe have to be careful at some of those adverse outcomes. And then the flip side, there was another one where fluoxetine was blamed for DVT. So I include that one just to say that we still have to be careful about what kind of conclusions we take from case reports, at least Dr. Sean Kane 18:45 from my perspective, as kind of an outsider to this data, to me, in a study of 16 patients, really it's the certain concentrations that are going to give you probably the best data in terms of, do you rapidly accumulate the parent drug or an active metabolite? I don't put a lot of stock in some of the clinical outcomes of such a small study and with the case reports, of course, we're worried about cause and effect. What else was going on for the patient? Did we definitively prove that the drug caused or did not cause a given problem? That can be really tricky in a case report scenario. Okay, so we've covered citalopram, we've covered fluoxetine. What else is there that we have data for? Speaker 1 19:23 So I think the next one is going to be sertraline, and this one seems to have not the biggest amount of evidence, but the most well designed studies and the most careful studies in individuals with CKD or on dialysis who have major depressive disorder. There were three small studies. Each one showed significant improvement in depressive symptoms. This is one of our go to medications. In my practice, we use sertraline fairly commonly, one of the better tolerated SSRIs. But they you know, as is often the case, what happens when you do a really well designed study and fall on your face, potentially and unfortunately? This was a case. So this one was actually just. Published in JAMA last November. So brand new study sertraline in patients with CKD stages three through five who did not need dialysis and looking for improvement and depressive symptoms. Dr. Khyati Patel 20:12 So I think the distinction over here is that these patients were not on dialysis, Speaker 1 20:15 right, and so we already talked about that's a pretty heterogeneous population already. So is it going to be, then, hard to find consistency in terms of response in that we'll see overall, it was well tolerated. There was a little bit of an increase in nausea, vomiting and diarrhea in the sertraline group, Dr. Sean Kane 20:33 which is something we would see anyway, correct, right? Speaker 1 20:35 But the problem is, at the end of study, no difference from placebo in regard to depressive symptoms at any single point, and they came out as saying, Whoa, this is not what we expected. We expected to maybe see, you know, expected maybe see a little bit of a difference in side effects or concentrations, but certainly expected to see the drug working, because it's well established. Dr. Sean Kane 20:56 And, you know, there's a variety of reasons why they didn't show efficacy. First of all, it's important to note that they didn't see anything unexpected, meaning that in this patient population, they didn't see a massive increase in GI bleeding or some other weird adverse effect that may be attributed to increased sertraline concentrations or something like that. So what are some of the ways that you can kind of pick this apart and say, well, because of these limitations, maybe that's why we didn't observe a difference. Speaker 1 21:22 One of them is the scale these is that the quids, or the quick inventory of depressive symptomatology clinician rated. It's, it's, it is a validated one. But again, it's, it's not the same used in a lot of these other studies. A lot of them used, you know, perhaps the Beck Depression Inventory. Another one that's commonly used is Montgomery-Asberg or the Hamd. Those are our gold standards, a lot of times in clinical trial. So it may have, may have been a difference in the rating scale they were used, as well as the idea about placebo rate. This is one we were just talking about. For some individuals, it's a frustration with dialysis, or in this case, frustration with the worsening kidney disease, the inconvenience of it, all the dietary changes, going to appointments, more and so just sitting down and assessing somebody gives the idea that, hey, somebody cares. Maybe things aren't so bad off. And that would lead to a high placebo rate, potentially. But authors here said, you know, actually, our placebo rate was relatively nominal compared to a lot of other antidepressant sites, so we really don't think placebo rates are problem. Dr. Sean Kane 22:26 Then finally, we look at the sample size. So they had about 200 patients in the trial. So we always worry about a risk of being underpowered when you don't show a difference in two different arms. The authors are pretty firm in saying that they were adequately powered, that if a difference was there, that they would have been able to see it. If there is a difference that truly existed, that they couldn't detect it, would be a clinically insignificant difference. So they're sticking by their guns, about sample size, about placebo rate, and things like that. But of course, some of these are somewhat subjective, and we don't know for sure why we didn't see something in this study, but we've seen efficacy and other stuff, right? Speaker 1 23:01 If you look at some of the editorials with it, one of the things they do say, again, is that difference in the population, that maybe they could have been a little more discriminating in who they enrolled and some of the other factors, what their actual EGFR was to try to capture, again, a more consistent base, kind of like our studies in ESRD, where we have a pretty good idea about when they get dialysis, and what the renal function is that, me, it may just simply be that is, as we do studies, you know, again, I think about traumatic brain injury, different ones is where there's so many different reasons why it happens, and so many different ways in which somebody responds, than any of the studies that are well designed, they seem to fall on their face. And it just seems to be, is when you have a again, a condition that has presents a lot of different ways, the more well designed it is, you seem to maybe see some some false negative results, or at least some negative results that you wouldn't expect. Dr. Khyati Patel 23:53 So we talked about a lot of SSRIs. We have still one gun in our pocket, which is the SNRI, things like duloxetine or venlafaxine. Is there any data for use of those agents in this patient population? Speaker 1 24:04 So again, there's a real lack of data here with these medications. Some of it, I think, is just simply based upon the timeframe. These are newer kids on the market there, so there hasn't been as much time for it. Was one study that looked at 18 patients with renal impairment, six of whom required dialysis, and in the dialysis patients, venlafaxine and its metabolite were clear from the body at about 55% of the usual rate. And what that means then is it's not being cleared as much the drugs going to accumulate. There was also a case report of an 85 year old male with end stage renal disease refused dialysis. He was put on venlafaxine 150 milligrams and noted paranoid ideation that resolves with discontinuation. Now there, you can make a lot of arguments as far as why he had that it's potential, then, that maybe some of the excess noradrenergic activity may have led to a sort of a delirium there or confusional state that could be so it, again, it's not a lot of evidence. I think there's a little bit more. When you the. Company themselves published some some data, or referred to it in the package insert, leading to a wanting to do a dose decrease, because accumulation. That's really all we know is, venlafaxine accumulates more in kidney disease. Perhaps we'll see later, if you adjust the dose, maybe you can overcome that. Dr. Sean Kane 25:16 And I just want to highlight that for a second. So with our SSRIs, for the most part, we didn't see increasing concentrations of at least the parent drug. Some of the metabolites you could see increases with but at least in the SNRI category, and we'll talk about duloxetine later, we actually do see higher levels of the parent drug because of renal impairment, right? Speaker 1 25:34 So it's interesting. Again, as far as you know, from a molecular level, that's something that's that's, again, a bit out of my forte, but it definitely is important to know then looking at these different classes of medications to not, you know, extrapolate too much from one to the other. Dr. Sean Kane 25:51 So SSRI, questionable efficacy. SNRI is not a lot of data. What else do we have? Dr. Khyati Patel 25:57 So I can't forget the power of cognitive behavioral therapy. So do we have any studies looking at psychotherapy or CBT? Speaker 1 26:05 So there's, you know, we already talked about education and mindfulness training, and there are a number of good studies showing both group and individual cognitive behavioral therapy for depression management, the under to work through the individual. About, you know, I said an education piece on when you go through dialysis, this is what it's going to be like. This is you're going to to maybe feel that you're depending upon others a lot more. Your independence, to some extent, may be a little bit limited, and then just talking through it in groups where you can share your experiences and frustrations with others, those things can be highly therapeutic. Dr. Khyati Patel 26:38 So we talked about a lot of individual you know, primary literature looking at individual agents and see what has been there and the what's been the data in the studies. Do we have any organizations that put together the guidelines for use of these agents in this particular patient population? Speaker 1 26:56 So it's a couple years older, but about the best one I found is in 2012 European renal best practice, put out a set of guidelines. And what's really nice is they looked at him across the board, CKD, stage three, a, 3b, four, five. And then also even the talk a little bit about end stage renal disease, and they specify theirs is for management, again, a moderate major depressive disorder. So it's important to make that distinction is, we're, you know, we are requiring a little bit more of a clinical interview and ratings to make that diagnosis, beyond just simply saying, well, somebody feels sad, therefore we'll look at this guide on this is is not meant for that individual. Again, doesn't mean you can't use it, but you really want to sit down and try to make a bit of a hard diagnosis if possible. So the first thing they recommend is active treatment given an absence of a whole ton on data and CBT and non farm, they really do start with antidepressants, and they recommend an adequate trial of eight to 12 weeks of an SSRI. The eight to 12 weeks thing is interesting, because at the beginning of that, we were talking about with your patient, Dr. Kane, and starting them on it. One thing that has been noted is it does appear that the response time may be delayed in individuals with kidney disease, and again, that goes back to not fully knowing all the interplay about some of the physiologic changes that could be contributing. So maybe it is just frustration with it. Maybe it is, you know, these endogenous changes in the body, but we have to counsel somebody on that lag time is maybe we even stay saying, Well, if you don't see anything after four to six weeks, it's not going to work. Maybe we need to be careful and talk about being in this for the long haul, or at least giving it a again, a good eight to 12 weeks. Dr. Sean Kane 28:32 So Dr. Patel, if it doesn't work after eight to 12 weeks, what do you think would be the most appropriate thing to do at that point? Dr. Khyati Patel 28:38 I would say, consider a different treatment, or consider stopping this and switching patient to another agent that we can try right on the patient. Speaker 1 28:47 Factors, again, because we don't have a lot of data on it, is if it isn't working, well, I guess really, in any case, if it's not working, you should continue stopping it. But here, to avoid that, polypharmacy, which we're ready, we're definitely going to see if it's not working, find something else. But don't just keep it on there, just out of fear that, well, what if we get rid of try, you know, try something else, but really push towards avoiding irrational polypharmacy. First thing again, they really recommend starting with an SSRI. The first one, again, to kind of go in some of the order we talked about them, is citalopram. So usual dose 10 to 40 milligrams per the European guidelines, no adjustment needed in CKD stages three through five or end stage renal disease to kind of match up with some of that data we already mentioned. However, this is an interesting point, I believe, Dr. Kane, you looked at some of what up to date says. What did you find there? Dr. Sean Kane 29:36 Yeah, so up to date, which, again, comes from the lexicomp database. They had a statement in there saying that for credit and clearance less than 20 that it's basically not recommended because of a lack of data, and to use caution with it, so they aren't sold on the single digit type studies that we already discussed that basically with a lack of data, there's a concern that you should be more cautious with it, which I think is a reasonable recommendation. Right? Speaker 1 30:00 You always have to be careful. The statement, you know no evidence of benefit is not the same thing of evidence of no benefit, but yes, it does mean that in a lot of these cases, you're somewhat in uncharted waters, and you do have to be careful and do some good monitoring. Dr. Khyati Patel 30:13 And on a sideline, the Use caution phrase, it's basically like, you know them, telling us use your professional judgment. Dr. Sean Kane 30:21 So, so then the brother to citalopram is s citalopram, usual doses 10 to 20. What did they say about E citalopram? Speaker 1 30:28 So again, the European guidelines, no adjustment needed in CKD stage three, four through five, they use Dr. Patel's favorite word use caution. But they did say starting at 10 milligrams, which now that I would start any higher, but being careful about dosing above that. So maybe, maybe you don't push above 20, or if you do, again, use caution. Dr. Sean Kane 30:48 And we see a similar recommendation in the tertiary drug references in terms of be careful at very low creatinine clearances. Dr. Khyati Patel 30:55 Another drug we talked earlier in terms of primary evidence was fluoxetine. So what's the deal over there? Speaker 1 31:01 So again, this one in the studies, the limited, small studies, seem to do very well, no change in terms of the kinetics of fluoxetine or norfluoxetine so European guidelines recommend no adjustment needed, regardless of CKD stage or ESRD up to date, says single dose studies, pharmacokinetics were similar among all levels of renal function. Chronic administration may result in additional accumulation, and it's not removed in dialysis. So they did say to use lower dose or less frequent dosing is not usually necessary. So this is the first one, I think, where everyone seems to be on the same page. They're up to date, and the kind of the European guidelines, this looks to be one. It may accumulate a little bit, but overall, this seems to be probably one of the safer ones, I'd say, to use. Dr. Sean Kane 31:45 So on my checklist for the patient that we started with, this would be a potential option that sounds like, for the most part, you can't get into too much trouble with this, and patients with renal impairment, Speaker 1 31:55 certainly, certainly. So kind of, moving forward, this will be one I would want to probably keep in my toolbox again, usual dose, 20 to 60 milligrams, stay within that range, you know. Again, adjust carefully, but that might be one I think we can use. What about paroxetine? So this, yeah, this is when you have to be careful of with paroxetine, because it does have a lot of anticholinergic risks. It can be it can kind of have a nasty withdrawal with this one. So you do want to be aware of that. But again, especially because the anticholinergic piece of it, sedation, some concern for cognitive function, starting at 10 milligrams, and somebody who has CKD stage three to five versus a usual dose, maybe you're starting at 20 milligrams. Again, above 10 milligrams, use caution. Up to date says in severe impairment, mean plasma concentration four times that a normal function. So I think again here, there's a fair amount of agreement that under ball it a little bit and then just be careful moving up from there. Dr. Sean Kane 32:50 And I'm going to be honest, my my own personal bias is that I'm not a huge paroxetine fan for the reasons that you already said for short half life and adverse effect profile. So I would really have to be sold that this is particularly good in this patient population for me to be convinced to use it. So in my mind, this is another reason to kind of not use it among the patients that have more severe renal impairment, Speaker 1 33:12 correct just just another one, to be careful that you know it's it has some benefits, as far as you know, if you want a sedating one, but we've got a lot of other options there. So then Dr. Sean Kane 33:21 sertraline, Dr. Truman, I know you said that Sertraline is one of your go to agents where you practice. What kind of recommendations do we see on sertraline in the guidelines? Well, the Speaker 1 33:29 first thing to remember is that, again, the new the new study, just came out last November, so it's not reflected in here at all. We'll have to wait and see if anything does update. So this is based on older data, but no adjustment needed in CKD stage three, usual dose is 50 to 200 milligrams. Usually start 2550 mostly 50. And the same thing here they say is, in CKD stage four, start at 50 milligrams. Use caution going above that CKD stage five, or end stage starting at 25 milligrams, and then again, using caution, maybe consider reducing the total maximum dose due to that active metabolite that's kind of renally eliminated it, although it may be less potent. I think, Dr. Kane, you really looked into Dr. Sean Kane 34:10 that hardcore. So to spoil the ending, we did end up picking sertraline for this patient. And I was actually surprised that the guidelines had a statement that said, Use caution. Have has these maximum doses for sertraline. So I looked into it and said, you know, why is it that the guidelines have that recommendation, but tertiary drug references, like up to date don't have that same precaution? So it turns out that the guidelines have this precaution primarily due to the active metabolite, nor sertraline or end does methyl sertraline, and many of these SSRIs will have this more hydrophilic, sip mediated metabolite. Sometimes it is an active metabolite that ends up being renally eliminated. So the parent drug Sertraline is no different in terms of serum drug concentrations, but the active metabolite that is renally eliminated is different, and as I kind of went down the literature path. Pathway, I found out that the actin metabolite of sertraline is way less potent. We're talking 10 to 20 times less potent than the parent compound of sertraline in terms of being serotonin reuptake inhibitor. So at some point you have to say, well, is that clinically meaningful to have this actin metabolite that is a factor of 10 different in terms of its potency. And what was really interesting is I found a study. It wasn't just looking at the in vitro model, but an in vivo model, where it looked at how good was it at actually acting as an SSRI in an actual animal model, and it didn't do anything at all. So either it was so not potent, it didn't do anything, or it couldn't cross into the blood brain barrier and exert its effect anyway. So you kind of have this really complicated picture where, yes, you have an active metabolite, but it's unclear of how potent it is and how clinically relevant that is. And again, in light of having not a lot of data, in the case of circling, we have more than all of the other SSRIs, but we just still don't have a lot of data to help us understand what is the clinical impact Speaker 1 36:00 of that. So to kind of summarize with that one, what we're looking at is, again, if it's CKD stage three, we should be fine at a standard 50 milligram starting dose. We're seeing renal function lowering to starting dose to 25 milligrams. Maybe considering reducing the max dose, maybe you cap it at 100 150 it's not clear. But overall, I think again, this is another one we can probably utilize. And as you mentioned in this patient, it's not unreasonable to use this medication, as long as you're again as always watching the dose. And which is something we should be doing for any patient, regardless of the kidney function, is assessing their response to each dose before we just kind of crank it up. Dr. Khyati Patel 36:37 And as discussed before, if you're worried about the medication not being as efficacious as we saw in the most recent study. Then we talked about, you know, reassessing the response rate within eight to 12 weeks, and if not useful, then we can change them to a different agent. Speaker 1 36:50 Yep. So we talked a little bit about the SNRIs, and this is something that can be considered efficacy studies are lacking. So because of that, you really go off of the manufacturers suggested recommendations in the in their labeling. So venlafaxine usual dose, 75 to 225, milligrams, no adjustment needed in CKD stage three, what they'll say for the European guidelines is consider starting a bit lower, at 37 and a half milligrams rather than 75 maybe limit it to 112.5 Max in CKD, stages four and five and end stage, which, if you do the math, that's pretty much taking everything and chopping it in half and making a 50% reduction, which, lo and behold, is exactly what the package insert says. And so with venlafaxine, it's an interesting one, because we don't have, you know, we're not saying, well, useless, you know, maybe uses a lower starting dose or maybe cap of it, just as a general rule, if it's above stage three, just cut whatever you normally do in half and do that. So I think in the absence of a lot of good data, if we need to use an SNRI, this is something I think we can use. And so for actually, for our patient, from a neuropathic pain standpoint, this is one we may be utilizing down the road for him, because, you know, for other reasons, Gabapentin and others that are so renally restricted and you can't always get the high doses. And this, this may be something that we could consider duoxetine. This is an interesting one. So usually those 40 220 milligrams, no adjustment needed in stage three, see Katie, and then above that, there's, there's a discrepancy. So I think of all the guidances, this is one I noted. You know, the European guidelines will say, consider starting at 40 milligrams, so a little bit of a lower dose, maybe compared to 60 milligrams, if they have stage four and up. But the package insert will actually say, don't even use it if it's less than 30 mils per minute in EGFR. So I think that's a wide discrepancy there. Because of that this is, this would probably not be one that I'd really go to for end stage renal disease or even that worsening renal function. Dr. Sean Kane 38:50 And most likely that recommendation against its use for EGFR less than 30 is going to be because of a lack of data, not necessarily because of perceived harm. We don't know correct. It's just one Speaker 1 39:00 you kind of compare it okay, if it's got lack of data. Of data, and we do have data for these others, maybe that makes it and maybe that tips the scales. So one we didn't talk about before, but I really wanted to include, because of how common it's used, and because it's totally in a different classes. What about Bupropion? We know this is no epi and dopamine, so mechanism different. What about this one? Well, usual dose 150 to 450 milligrams. Recommend just starting at 150 daily, and not going to the twice daily. Right off the bat, if it's CKD states three through five and end stage, nothing, nothing too new. There. Package insert says, Consider reduced dose or frequency, which is pretty vague for a medication that comes in once a day, twice a and three times daily forms. So the parent drug is hepatically metabolized, but is converted into a number of really eliminated metabolites, some of them may have some similar efficacy to it. Again, we're in a little bit of an uncharted maybe it maybe it works. Maybe it does. And with the active metabolites. So caution revised with this one, Dr. Sean Kane 40:04 I think, to summarize, we see a common theme of for the most part, you probably should start at the lowest starting dose and potentially not escalate to the highest maximum dose for these renal patients, certain agents either have better data, or we know don't have accumulation of the parent, drug reactive metabolites and other agents, we either have zero data at all, or we know that they definitely have renal implications, and we just start at a lower dose and we're more cautious. Dr. Khyati Patel 40:31 Yep, and any given point, just like any other patients, you're going to watch for those side effects, you know if there's accumulation, and assess the efficacy at appropriate interval, and otherwise consider substitution or change. Speaker 1 40:43 Yeah, even we use the word we use in a lot of other conditions is de escalation, you know, if, perhaps, if there is a thought that a lot of it is situational, and the individual is responding, you know, maybe it's not, if you believe that a medication is not part of the response, but the individual is simply, you know, the debt that either their renal function is improving or their outlook on the whole situation is if we maybe we can consider bringing down the medication, as you would in any other condition, but just do it very carefully. Dr. Khyati Patel 41:12 So, Dr. Kane, you said that for the patient we brought up as our clinical case, were put on the central lean 50 milligram. What happened thereafter? Dr. Sean Kane 41:21 Yep, so we picked 50 milligrams of Zoloft or sertraline. And really the rationale there was we wanted to pick an SSRI because of the lack of data with SNRIs the renal implications with both of the main SNRIs that we talked about. So we wanted to pick that SSRI and of the SSRIs that were available that seemed to have kind of the least scary issues in terms of renal implications with it. So that particular one was picked, not knowing about the JAMA article, but again, that JAMA article was a non dialysis patient, so it potentially wouldn't have applied anyway. This is a very unique circumstance of critically ill, new onset hemodialysis patient. Just the circumstances of the clinical condition are extremely unique in terms of another rationale to pick sertraline. Part of it was actually logistics. So generally speaking, we hate to add chronic medications in an ICU setting, because we're never there in a month to monitor therapy, adjust doses and things like that. And I was very worried that if I picked a VIN lefaxine, for example, and the patient started having side effects that wherever he ended up at, presumably an LTCH or a longer term care facility, that they may not connect the fact that his renal impairment had implications with his dosing of his venlafaxine. And I was very worried about that, so I wanted to pick the agent that would be at least risk for having these renal problems and potentially having someone not recognize that link between the two. So unfortunately, like most things in critical care, I get to see the patients when they're really, really sick, and generally, I don't get to see them when they get better. Which is the goal? Typically, the goal agreed. So in this particular patient, he did get transferred out to a long term acute care hospital or an LTCH for ventilator weaning, for for acute rehab of his deconditioning by being in an ICU for three weeks. I don't know what happened to him. I hope that he did well, but it's one of those things that you kind of set it and then pass it off to the next healthcare provider to kind of continue that care, hopefully thinking about psychotherapy and things like that to help the patient along his Dr. Khyati Patel 43:21 path, but I bet you got a really good night's sleep that night, considering that you started him on a very evidence based therapy that was very individualized for him, Dr. Sean Kane 43:30 I still feel good about my sertraline recommendation. So to summarize, in terms of depression, we see a lot of depression in the CKD ESRD patient population. We do know that the depression may be a response to the stressors associated with being dialysis dependent or having chronic kidney disease, but it could also be somewhat due to the physiologic changes of having uremia and things Dr. Khyati Patel 43:50 like that. And as we discussed some of the study, you can appreciate that. You know, we don't have a whole lot of data, especially with the larger patient population, and so we're looking at the effect of the impaired renal function or antidepressant serum concentration, we have to take those with grain of salt. Speaker 1 44:08 So if we do decide again, if we do decide to go the route of an antidepressant, SSRI, fluoxetine does not really require any dose adjustment, even in end stage renal disease, we talked that sertraline seems to have again, with the exception of that newer study of account, which probably will need to be discussed further, you can use that medication. You may want to start with a little bit of a lower dose, maybe down to 25 milligrams instead or and be cautious raising the dose. But certainly, and can certainly be used as well of the SNRIs venlafaxine lacks a lot of efficacy studies beyond what the manufacturer describes in their package insert, but can be used with probably a 50% dose reduction to account for that drug accumulation. Duoxetine is all well and good till you get below 30% EGFR, and at that point, you probably want to use caution and as from package insert standpoint, recommend really not using it at all and don't. Dr. Khyati Patel 45:00 Forget about the behavioral therapy, the psychotherapy. We call it, you know, a lot of the depressive symptoms may be in response of the the outside stress of, you know, being on dialysis, multiple medical appointments and stuff, and so that obviously is going to impact the quality of life. And what psychotherapy can do is help patient adjust with this burden that is extra than what it was before. Totally Well, I think Dr. Sean Kane 45:24 that wraps it up nicely. If you want to see some of the references, including those European guidelines just for depression and CKD, those are linked up in the show notes, and you can access those at HelixTalk.com again. This is episode 83 so we have references there. We love the iTunes reviews and ratings, so keep those coming with that. I'm Dr. Kane, Unknown Speaker 45:42 I'm Dr. Schuman, and I'm Dr Dr. Khyati Patel 45:43 Patel, and as always, study hard. Narrator - Dr. Abel 45:47 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 45:58 to suggest an episode or contact us or online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.