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Long-Term Antidepressant Treatment: Let's Look at ...
Presentation Q&A
Presentation Q&A
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Well, thank you for such a great presentation, Andy. I always love how data-driven your talks are and they always give us so much to think about. You know, as I'm listening, as I was listening to your talk, you know, so much of the data you presented is, it's not exactly comparing apples and oranges, but it's Fuji apples to Macintosh apples to pink ladies. And it's really hard to compare one agent against another, one approach against another. So, you know, if you were designing a big research study, if you had an unlimited budget, how would you sort out this question of head-to-head comparisons between old and new antidepressants, CBT, TMS, like what would that ideal study look like that would help us really figure out what signal and what's kind of the natural trajectory of these illnesses, if that's possible at all? Yeah. So I think that you could use two strategies to be able to do that. One strategy is that you do what's called a point-of-care study. That means you do not advertise for participants, but you have people who are presenting to care be willing to be randomized to open studies, you know, open treatment. So the participant knows what they're getting, the doc knows what they're getting, and you really look at the long-term outcomes. And you know, it's funny because the researchers use a rather peculiar term, which is called real-world evidence. And I think that if you were able to do a combination of point-of-care entry and randomization with open treatment, with careful follow-up over time, then I think you would get a much clearer picture of how these different interventions compared. We have one question that came in that asks a little bit about how this applies to children and adolescents. And I know you're not a child psychiatrist, but you're also one of the most well-studied people I know. What does the guidance and some of the lessons we learned about today, do those same principles apply to kids? Or should we think about continuation of antidepressants in children and particularly adolescents differently? I'm not sure if I have a good answer to that. I think there's a much smaller literature on continuation for the kids who have early onset depression. The other thing that is incredibly complicated and difficult is that a fairly high proportion of the kids who present with depression will ultimately declare themselves as having bipolar disorder, but they have not yet had their first episode of mania or hypomania. So it makes it even that much more difficult. So I actually don't know. Fair enough. Speaking of kids and thinking a little bit about genetics, should we expect to learn something from, even in adults, their family history around the natural course of these illnesses? I mean, is there an inherited pattern? Do we know that at all? If antidepressants have failed for others in the family, should we expect that in a patient? I think it's something that we've all done clinically. It's the Aunt Tilly effect. If Aunt Tilly responded to that, maybe it's a reasonable choice and decision to give the person the same medication that Aunt Tilly responded to. I don't think that's ever really been tested. I think it would be very difficult to test that hypothesis because you'd have to randomize people to the Aunt Tilly medication versus something else. So is it a reasonable guide for something like that? Probably. Are there any genes that would help or set of genes or network of genes that would help one decide which medication would be better for one person versus another? I don't think so. We had a question, again, thinking about this idea of over the years. When you speak to patients, do you speak with them about this idea that antidepressants lose their efficacy over the years? I mean, is that a correct way of kind of conceptualizing it or is it really just the course of the illness for those who actually stay on the medications? My language has changed with interacting with patients. The first thing is I really do use a shared decision-making model with my patients and usually give them alternatives and try to educate them about what's going on. The second thing is that I present ways to move forward as hypotheses. The third thing is I try to couch the interventions in terms of probabilities. So I'll say to somebody, look, you are in a group of people who respond well to medications and are at low risk of having a problem if you come off of it. However, the data do suggest that if you're okay, if you're really okay for four months, then it lowers the probability that this episode can come back. So let's try to work together to see if it'll keep you well for those at least four months. For other people, I'll say you've had 20 depressions. This is very difficult to treat. You're finally feeling better. What we need to do is always reevaluate the benefits and the risks over time, the side effects versus the benefit that you're feeling, and that it is highly likely that if you continue on this, you will lower the probability that this will come back. It's not perfect. It's not 100%, but it still can be helpful if you continue that over time. It doesn't necessarily mean forever, but it does mean we always have to revisit the benefits and the risks, and you always have the option of thinking about coming off of it gradually and then can watch carefully to see if the symptoms you have reemerge, and then you'd have the option of going back on the meds. Does that make sense, Tristan? Yeah, I think that's a really great framework for helping people understand their risk as part of a group. I think that's something that we often struggle with as clinicians, is how do you take kind of what we could expect from a group of people and translate it down to the individual, but I like the way in which you explained it there. We had a question come in from one of the viewers that asks if you could comment on side effects with remaining on antidepressants for long-term use. Are there changes you would make to dosage, just empirically, just because they've been on it long-term if things are going well? Yeah, so in many ways, my answer to that will be unsatisfactory because it depends, and it depends on what they're taking. It depends on what side effects they have. The general principle is to keep them on the dose that kept them well, generally. The other thing is that I think we have learned that the long-term treatment with the SSRIs can have subtle side effects, and after one to five years of continuous treatment with an SSRI, there's a sort of triad of, I think, underrecognized symptoms that people can have. One is fatigue, and people can just feel tired. The other is a gradual weight gain where people can gain half a pound a month, and over time, that really starts to add up. And the third thing that many of you may have also observed is it's not quite apathy. It's not quite what people describe, but they sort of describe a blunting of positive affect. And I've had patients who, they sort of go to the wedding of their beloved child, and it was okay. They expected more joy, and they didn't really feel it. And there may be a mechanistic reason for this because of the blunting of dopamine that can happen with an SSRI over time. And so some people have turned to using stimulants or dopaminergic agonists, but I think it's something to really watch for over time, at least with the SSRIs. If we were really thinking about that triad as being, do we think of it as a side effect as such that if you were to actually remove the medication, those symptoms would improve? Or do we think about it more as a sequelae that having been on these medications for several years, some people develop this constellation of symptoms which doesn't really resolve, that their brain is wired differently during that time? I think both are possibilities, but I think it's more likely to be a side effect. Because certainly in the old days when we used to switch people from SSRIs to bupropion, some people would say they felt like they woke up. It currently, certainly we've observed that can sometimes happen with vortioxetine, surprisingly. So I do think it's a side effect. Great. Great. We have another question that came in from a viewer that's asking about the role of psychedelics in treatment and what the research is showing there, if there are promise with psychedelics. Yeah, that's a rapidly emerging area where a lot of people have great enthusiasm for the psychedelics with very limited data. And here too, it depends on which psychedelic, depends on what it's for. It depends on the transformative experience that people describe where the psychedelics themselves, psilocybin and things like that, give people an oceanic feeling. It almost dissolves the default mode network and that people feel like it's almost a religious type of understanding of being one with the world. And that helps them tremendously, particularly for people who have PTSD and who also may have a ruminative aspect of their depression where they're mostly thinking about themselves in very, very negative ways. So I think it remains to be seen. I think we need to see more studies that are done rigorously and objectively. And I think we'll find out over time really what's the usefulness or lack thereof of that rather interesting class of drugs. Along the same lines of kind of novel mechanisms or new drugs, we had a question about Brexanilone and asking if there were any identifiable uses outside of postpartum depression. And I guess there's for me a related question of what does the mechanism of action of that medication tell us about possibly new targets for treating depression? Yeah, that's a complicated one. If I remember correctly, I think there might have been one non-postpartum study of Brexanilone and I think it may have been negative, but I can't recall the study. So I'm sorry, I can't pull it out of my head. And there's also some complications in terms of when did people really get it and what was the relationship to their pregnancy. So I don't think we quite know yet. And again, I think we'll learn over time. Is there evidence to suggest, just thinking about where the field is heading more broadly and where the next generation of targets exists? I mean, should we be thinking that more of our treatments are going to be in these, be infusion based or be intranasal that the next generation of targets or small molecule targets is really going to be looking at more invasive delivery as opposed to things that we can kind of easily package into pills? Yeah. And that may happen. I mean, look, the holy grail is to try to identify the pathophysiology of a given individual and match that pathophysiology to an intervention. Right now, we're still flying blind. We can't quite do that. And I think that's going to be the big advances that we'll see in the next five to 10 years. We still don't know what the fundamental pathophysiology is of depression in general. And then we still don't know for any particular person what their own pathophysiology is. So you can have personalized and precision medicine. I firmly believe that we should work to get there. I think it's going to be harder to do than we ever thought. But I think that's going to be very exciting in the next five to 10 years. Well, Andy, once again, thank you for such a great talk and presentation today. I certainly learned a lot. And I want to thank you for joining us here at SMI Advisor.
Video Summary
In this video, Andy, a presenter, discusses the challenges of comparing different treatments for depression. He suggests that a point-of-care study, where participants are randomized to different treatments and followed up over time, would provide valuable real-world evidence. The question of how these findings apply to children and adolescents is also raised, and Andy admits that there is limited research in this area. The idea of considering family history and genetics is explored, with Andy mentioning the "Aunt Tilly effect" where a previous positive response to a medication may guide treatment decisions. Long-term use of antidepressants is discussed, with potential side effects such as fatigue, weight gain, and blunted affect. The use of psychedelics as a treatment for depression is mentioned as a promising area of research, particularly for those with PTSD. The role of Brexanilone, a medication used for postpartum depression, and the future of depression treatment are also touched upon, emphasizing the need for personalized and precision medicine.
Keywords
treatments for depression
real-world evidence
family history and genetics
psychedelics as treatment
personalized medicine
Funding for SMI Adviser was made possible by Grant No. SM080818 from SAMHSA of the U.S. Department of Health and Human Services (HHS). The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement by, SAMHSA/HHS or the U.S. Government.
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