Nuances in Prescribing Antidepressants

Preston: [00:00:00] Is they target a side effect and their whole thing is like, "A little bit less sexual side effects." And then we go to APA and there's an entire bus- Boom. ... that says Vraylar. And it's like, "Limit your patients' sexual side effects because we, the company Vraylar sponsored-" Allegedly. "... one study of 300 patients where we showed with a significant enough p-value that there was lower sexual side effects.

And make sure you prescribe it now before," "before these studies get repeated." So

Margaret: Hello, guys, and welcome back to How to Be Patient. I'm Margaret. I'm not very patient, and I have Preston over here. Preston, how patient are you feeling today? 

Preston: I'm, you know, I'm moderately patient. I'm, not the most patient But patient enough 

Margaret: Medium. That's, like a natural thing I'm 

Preston: Preston 

Margaret: and I'm 

Preston: Patient Enough.

Margaret: The rejected first name. That's what our Patreon should be called, [00:01:00] is just like- ... How to Be Patient Enough, like pa- parenthetically. 

Preston: Yeah. It all has an implied enough . 

Margaret: Today we are doing an episode on depression prescribing, and you guys were great on our little Instagram page which is howtobepatientpod, right?

Or is it howtobepatient? 

Preston: I think it's just howtobepatient now. Howtobepatient 

Margaret: on Instagram. I like to put question boxes up there. You guys had a lot of questions on when depression's not so clear cut or when prescribing is not so clear cut. So maybe you tried a couple SSRIs, maybe there's some other stuff going on.

How do we think about it? Our hope for this episode is using a number of your questions but will go through some slightly trickier scenarios and kind of also talk about, like, when do you, especially for our non- psych listeners, when is a psychiatrist really kinda needing to get involved? How do we start to think about this?

And maybe you have a patient on a wait list for us, how would we start things off? but before we get into that, I thought we could just do instead an icebreaker. Just an old fashioned catch-up for our listeners. Preston, you had [00:02:00] a big week this week. 

Preston: Oh, I did. Yeah. 

Margaret: Media-wise. 

Preston: So today was ... Or the fifth of August whenever this comes out, we're recording on the seventh, was like the Figs back to school campaign launch.

And I was a part of it. So I don't know if it's still up, but if you go to the Figs website you'll see me on their little banner. may- maybe I was in your email. I'm leaning forward wearing a pair of, blue scrubs smiling. really smiling. They told me- It was a- For most of the photos that we did they said, "Smile with your eyes."

Smiles. We- we don't want the big cheese-ing - Pyra ... kind of thing. And they were g- and th- and then they try to get me to laugh and do other stuff to, you know, g- get that candid look. So I figured, okay, what's gonna come through will be, like, the reserved Preston smile to his eyes. You know, maybe stoic, a little pensive, a little mysterious.

And then the actual photos that came out were, like, the biggest, yeah. my facial [00:03:00] muscles were in full activation, like the largest cheese-ing you'd ever seen and I was like, "If you guys-- If that's what you wanted, I can supply-" You're like, "This is 

Margaret: AI" "...the cheese," you know? "

Preston: This is AI." So yeah, you will see me smiling big.

Margaret: How did it feel to ha- 'Cause I know you've done stuff with Figs before. How did it feel though to do this as, I think this is your first, maybe not your first one, but, full commercial production? Like- 

Preston: Yeah. This is the first one with dialogue. I have, like- ... one line. I say, "And them I'm getting a muffin.

Actually, we're all getting muffins." Which I wrote that line. You 

Margaret: nailed that line. 

Preston: Yeah. They told me, "What's, a way you cope when you're stressed out on call?" And I go, "Oh, I, I run my list together.” I say, “Then we're gonna see the patient ED then we're gonna go back up and see this consult, and then I'm getting a muffin."

and they were like, "That's funny." I was like, "Thank you." 

Margaret: Yeah, that's what I do. 

Preston: And I usually give my med students muffins too. So then yeah, like I put that all together. and I'm s- I'm [00:04:00] sad this didn't make it into the final cut but they wanted a shot of me eating a muffin in the break room and on the shot list there was just like a single block that said Preston eats muffin.

And it became like a meme for the day. They were like, "Are we at Preston eats muffin yet?" And they would be like five-"We're five out till Preston eats muffin," and I was like oh God how many muffins am I gonna eat? I'm like I told you guys I liked muffins but I don't know about this. 

Margaret: It got caught. Put it somewhere--put your bonus clip somewhere.

Yeah. You know release the background footage. 

Preston: Release the muffin footed muffin gate. Yeah. Release the Muffin 

Margaret: Man.You 

Preston: do not have- So so it's been a fun week though people that haven't known or seen in awhile are texting me like" You're one you're on my figs email Like what's up?" Hey yes its me.

Margaret: Bad dude It big time Your big time now Youve been big time We know that But this is actually This high production Big Time 

Preston: Mm-hmm.. .yeah feels good High productions Fun How's [00:05:00] life with you?. 

Margaret: How's life with me Just doing New England summer stuff Uuh trying to figure out what my job will be next year Ive got a strong lead on something in the Eating Disorder space That Im pretty excited about For My first attending job probably In new england And done A little bit Of private practice Sothings confirmed YetBut Ifeel There are a couple places where I'm, like, already connected to in terms of, working with them clinically, and so I feel after some conversations that, it seems likely that if I want the job, I can maybe have it probably.

You know, nothing's ever certain. It has to be approved by department and stuff like that. but so I'm excited about that 'cause I feel like normally it would be like you're stressing out between September to December or January or February to, nail down what you're gonna do next. And if the first thing I-- it's not the first thing.

I'll [00:06:00] look into some other things too, but, if it's just oh, and then this is gonna seamlessly transition into, kind of 50% private practice, 50% clinical, in a s- hospital system and eating disorders, that would be amazing. That would be so great if it was just, if it was that easy.

Preston: So y- you see yourself staying in New England? 

Margaret: I think f- I think that's my hope for the time being. I've always said I'll probably end up back in St. Louis eventually 'cause I just... My family's there. But I, love Boston, and I like being in an academic city as well, and, the nerdy part of me likes that there's so many bookstores like, just, the little communities I have here from the last, five, five years.

so for the time being, I wanna stay. 

Preston: Yeah. it, I think it's, it eases the transition into being an attending. You're not- 

Margaret: Yeah ... 

Preston: taking on a new role in a new city. You know what's funny? Somebody told me, I haven't verified this, that there are, have been [00:07:00] more 100 degree days in Boston and New York than in Texas this summer.

Margaret: Really? 

Preston: And I said, "No way." And I think it's true. The thing is though, we'll be, at 98, 97 degrees, and then I look at the forecast and it's 97, 97, 97, 97, 97. And then I'll see the hundred degree d-... Hundred degree day in New York and then the following day is like high of 83. 73. Yeah.Then I'm like okay Let's all calm down, you know?

Ba- base rate fallacy is, creeping 

Margaret: in here a little bit The humidity out here is not as much as Texas, but I'm think- I'm comparing to Missouri and St. Louis where it would be like-- I remember, after my first year of med school everyone did, a research internship at Wash U., and I remember walking the 10 minutes from my apartment to, the lab I was in and that it would just, You would get into the lab- It's sweat for everything ... oh, it's just sweat. Whereas, here I'm like, "I wore this outside today and it's, 85." I'm not... so yeah. But I am seeing announcements right now, it's August right now, that will release this in [00:08:00] a few weeks. But there's I follow, the Boston Instagram pages and it's this week it's "Oh, this is the last sunset after 8:00 PM until next May"

Just bro, like can we not talk about this right now?" That'll be your life soon. 

Preston: Yeah. You guys go through that winter is coming every- Yeah Every August. Yeah, real Game of Thrones stuff. 

Margaret: So speaking of depression, yeah. 

Preston: Yes. Speaking of impending, impending depression. 

Margaret: this is a great transition for us to talk about what we're gonna cover in our episode today which is prescribing for depression and kind of getting into some of these more nuanced, I think, like thinking patterns around how, what and when do we prescribe.

And so one thing I want us to start on just for a couple minutes before we get into some more, like specific scenarios that we're gonna talk about is I'm curious Preston what you think [00:09:00] if you think back and if, I think back to myself like intern year or as a med student or you think of our friends who are, like doing the majority of psychiatric prescribing so in internal medicine and pediatrics most prescriptions for antidepressants come from primary care because there's just not enough of us.

Are there any things that come to mind that you feel have changed in your prescribing patterns or things that you see coming out of primary care that looks different than what it looks like when psychiatry is prescribing antidepressants? 

Preston: So I see on the, primary care prescriber side, I see most people have usually one or two maybe SSRIs that they're comfortable with and that if anyone they see kinda falls into the depression anxiety bucket where they know SSRI is the right answer They’re like, "This is the one I can start.

I feel good with the dosing on this one and I can kinda walk it up". And I think that-that's very similar to how I was an intern. I'd have like my one either like usually Zoloft or [00:10:00] Lexapro. I'm like, okay I'm comfortable with these and like these are the ones I wanna use. And then if someone has problems then you try maybe a different class or you just move on within the classes but you're not thinking necessarily like the nuances between the drugs Now that I have a couple years under my belt, I think I'm starting to kind of see in between the matrix as to like how people in general respond to these types of medications.

And there's stuff that shows up in the data and then there's stuff that just anecdotally you hear over and over again that may not be like measured on a PHQ9 detected on a PHQ9 or GAD 7 but you're like this person is like heavily anxious doesn't have a lot of anhedonic features Like I feel like they're just gonna be more of like Lexapro person than something like Prozac from like out the gate or something whereas someone has a more melancholic or anhedonic depression rather than an anxious depression maybe using something a little bit more catecholamine heavy or a little bit more [00:11:00] boosting because I don't think it's going to worsen their anxiety Or don't need much anxiety to make worse So what-- Right

I've been able to apply I think more my psychopharm knowledge and then actually s-start to get some wins - 

Margaret: Yeah. 

Preston: yeah With those peeling out so That's probably biggest difference for me 

Margaret: I totally agree with you. I think the other thing shoutout to my sister-in-law who's primary care doctor and every once in a while when she's in this situation She does curbside me and without breaking HIPAA she does curbside me and say "Is this q- Is this medicine a good fit?

Is this..." They're on the waitlist for psychiatry I think one of the things I notice especially, I feel like in child and working in residential I feel like I'm just talking to a lot more prescribers because like child psych is so collateral heavy But I think one thing that is a big overall concept and we'll talk about this more is What is an adequate trial which We love hammer on this all day long In Psych but I think it actually is super important part of outpatient prescribing Which is if someone [00:12:00] starts on sertraline at fifty and go by fifty every week until they are two hundred in four weeks And they don't tolerate it because side effects Is that a good trial?

Is that truly a medicine that doesn't fit? Or if they were at fifty for year and then You go up by a hundred in two weeks Suddenly its not Their irritable and insomnia More GI stuff Before Sertraline was really helpful Does that rule our sertraline The pacing Of Starting medicines Then do consider A Good Dose For Depression Comorbid Depression Anxiety Are we helping depression Not Anxiety If Medicine Was Helpful before Do change Reasoning Level Detail Other Thing Two Quick Things These last two Go together Staying Evidence Based Obvious One[00:13:00] 

Thing Notice I see more people per, referred to me and this was an adult too where like adjunct with a second generation antipsychotic I feel like is much faster in some primary care settings And I don't think most psychiatrists nec- necessarily go to that as frequently. I think that, often it's like hard to tell and you don't have enough time in a primary care visit to dig down into all these questions we're talking about.

And so if something's sort of working adding something else on makes sense and in psy-- In, specialty in psychiatry that sometimes makes a lot of sense too But I think I see in particular a lot of like Abilify being added on or like Vraylar stuff like that And it's not that's never what we would do but I think it happens It's related to kind of this like what's a good trial and why are we making this change?

And then avoiding polypharmacy So I think those are a couple things I tend to see [00:14:00] that I will talk about which we will talk about right in a second when we get back from our break

I realized there was one more thing I didn't say that was related to the evidence part, which is knowing where to find evidence-based guidance when psychiatry is Avoiding your calls or dodging your patient, which again is not purposeful We, 

Preston: never do that. We've never done that We 

Margaret: don't-- We're not trying to do it 

Preston: Yeah.

So if the impossible happens, this is where to go 

Margaret: Yeah. in the notes section of this episode, one I put what the APA recommends, which is the most recent guideline from the VA and Department of Defense depression treatment guidelines. We've talked about this ad nauseam. A lot of times there's good funding through the VA to do good research, and therefore good clinical guidelines.

There's also one that is meant for primary care doctors and pediatricians in the notes that is from the American College of Physicians on Depression. And then we'll get into [00:15:00] this a little bit, but I linked a paper for mechanism of weight change in antidepressants and like how much weight changes based on each class, and then as well as one of the resources I like for pregnancy, perinatal, and breastfeeding.

So those are all in the notes. Just that is to end that point of where do you actually go if you're not sure? 'Cause I mean, we do that. if, we're truly like out here floating in the waves and like we're really th- I'm really thinking about Raylar or using like EMSAM, which is an MOAI patch, which we'll talk about, I'm not doing this just like totally off the cuff at this point in my career.

And I -- Preston, you may be better than I am, but I would hazard to say you're also double-checking with some of these newer meds or ones you're not as familiar with. 

Preston: Yeah, I am double-checking. If I wasn't, I don't know if I'd use the phrase "better". Like we're just doing it live. It'd be more willing, yeah. 

Margaret: okay.

Are you ready for our first clinical vignette? 

Preston: I am. Let's do it. 

Margaret: So what I'm gonna do is I'm gonna read them, and then I'm gonna say the [00:16:00] like -- And we're gonna talk about a little bit, and then I'm gonna say like what we're trying to get at, and we'll finish talking about it, and then we'll move on so- Okay

prime—we're in primary care in some fashion, right? We're not in psychiatry group. Thank you. There. We're in primary care world. So I want you to imagine you have 20 patients that you're late for right now because they overbooked you. Mm-hmm. Twenty patients. And also something just got denied for your patient who really needs that medicine.

Ah. Prior authorization. Ah. So this, is the- Ugh. I'm angry. I'm busy ... we're in the Doctor Orange mindset. The Dr. Orange mindset's right here. Oh, okay. Okay. so- 

Preston: There ... 

Margaret: thirty-five-year-old with 10 months of depression symptoms, had a trial of sertraline or Zoloft up to 150 mil-milligrams daily for three months, was six weeks at this dose.

You know, it's the most bothersome symptoms of his depression are constant feeling of low energy, overeating, and low motivation. No prior history of anxiety or sleep disruption. Question, Preston: Do you add on to the sertraline, AKA use an adjunct or new agent, or do you switch from the sertraline? Tell me your thought process.

Okay. 

Preston: I would try [00:17:00] adjunting first. 

Margaret: Okay. Can you tell me your reasoning? 

Preston: Yeah. So I, at the very least, know that he's tolerating the sertraline. 

Margaret: Mm-hmm. 

Preston: So the adjunct could be helpful In that regard, I think on a test question though, it would be the right answer would be to switch to a different class because he's, if he's reporting that he's having no impact on his depressive symptoms, then we would need to try another medication before we then, adjunct.

Margaret: Right. So why would you not do that in real life? 

Preston: because I think logistically, some people struggle with the taper and then I also Maybe this is my own, like skepticism but... And I guess I'm making up stuff that's not even in this. Sometimes people report seeing no change in their depressive symptoms but either through collateral or through like my own observations or their PHQ-9s, I notice like subtle differences.

[00:18:00] Mm-hmm. So but that would, be still to say then, it changes the paradigm of you know, "Oh, I actually think that he's receiving like a partial benefit," which- Yeah ... would then justify augmentation so.. 

Margaret: What-- and if he was saying like let's say he, he was saying maybe and his wife was saying, "I've definitely noticed" then you can all agree that it actually is sort of helping?

Preston: Yeah. 

Margaret: Besides like maybe going up on it or something which you could argue there wouldn't necessarily be benefit per FDA but maybe anecdotally some people just benefit from a higher dose. If you were thinking of adjuncting when you knew the sertraline was working what is the adjunct in your mind? 

Preston: usually probably do either two and a half or five milligrams of Abilify.

Margaret: Okay. 

Preston: Usually my go-to adjunct. If he's having trouble sleeping then probably 50 of Seroquel. He does mention that he's overeating though and even as low as 50 of Seroquel I can see people really stimulate their appetite so- 

Margaret: Yeah ... I'd probably just go with Abilify. Well and [00:19:00] he's got low energy - Yeah

poor motivation, overeating so yeah. I mean, I do think if -- So my answer to this would be s- not adjuncting and would be s- like taper it cross tapering which I don't know how often in primary care they're doing cross tapering. I think like relatively frequently. And so if it's like truly I'm not noticing anything, the measures aren't noticing anything, he's not noticing anything and he's been on this for three months.

He's now like in 10 months of depression, presumably disruptive to function, I think I would maybe be sort of aggressive in a cross taper and I would think about based on these symptoms, and obviously this is easier for me than Preston because I wrote the question, it would be a trial of Wellbutrin.

or even an adjunct with Wellbutrin would be an intriguing one to cross taper with given the like overeating, low motivation, low energy and then no history of sleep and no anxiety history. So the, I guess the purpose that I'm, trying to make with this question is let's presume that [00:20:00] this question stem or this vignette is enough that it-- he's truly not really getting any benefit and you're not seeing a difference.

I think that adding on, and I think actually we feel pulled in the clinical situation both in psych and primary care to Add on rather than go through the, kind of painful process of, cross tapering. But that it would be more evidence-based and I think more clinically relevant to in this situation on its face not stay on a medic- because then what happens, and we see this all the time in psych is, you maybe get benefit and someone doesn't really notice, and they end up on, four medicines and are like, "I don't really think anything's helping."

We have polypharm, we've gained weight, and we've kind of chipped away at the trust in the scientific process that is still hopefully what we're doing in psych a little bit. Other thoughts on this? Like you said, Abilify. Are there things that if I put different symptoms in the depression stem outside of, let's say he is sleeping through the night, but are there any reasons why you'd be like, "Not Abilify as an adjunct," if we were gonna adjunct?

Like [00:21:00] any symptoms in the depression you might see? 

Preston: specific like d- depressive symptoms that would keep me from adding on Abilify? 

Margaret: Yeah. Or just like parts of his overall mood picture. So, let's say he's sleeping so he's not like frankly manic in front of us and he doesn't have bipolar to our knowledge.

I'm thinking of, things with Abilify... I, I-- like I don't mean to make you guess. So I guess I would just be thinking of if you have someone who's already kind of twitchy and restless, Yeah ... I don't love using Abilify for the akathisia. 

Preston: Is it more likely to cause akathisia in people that are twitchy at baseline 

Margaret: I mean, I feel like I've anec- clinically speaking, anecdotally noted it more in like slightly more anxious people, slightly more like motoric kind of people which he's frankly not in my stem.

Mm-hmm. Like he's low motivation and kinda slowed down. But that's just one I've seen it-- I feel like I see it every single time someone's on Abilify is like, apropos nothing. m- without me even asking about symptoms they're like, "I feel like I need to run around in bed." [00:22:00] and I th- 

Preston: Yeah ... 

Margaret: I think maybe it happens more in kids but I think adults- I would say it happens 

Preston: probably like somewhere between 10% and 20% of the time for me.

Margaret: Yeah. Yeah. So I mean point being like why use that one if there's like a higher likelihood? And I f- I think that one does definitely have much more of that than others. And that Abilify in terms of adjuncts right? I would still ... And this something that they don't do as much in primary care except for some of our very excellent primary care colleagues is like Abilify is still an SGA so you need to be doing the like lab and weight monitoring and then AIMS.

Preston: Mm-hmm. Wh- which can feel like a lot for a primary care doctor. Yep. 

Margaret: Yeah. And are you used to doing like an AIMS exam or like looking for monitoring at baseline the kind of symptoms of like motoric change? I also think that's kind of a complex conversation to have around like long term risk of like tardive 

Preston: dyskinesia.

yeah. And, that's, tough to feel like you're in charge of that if you're managing that among [00:23:00] 20 other patients. 20 other, 

Margaret: yeah. Yeah. 

Preston: So let's say you-- We go through with the cross taper and we're switching from sertraline to wellbutrin what i- what does your cross taper look like? 

Margaret: So they're on 150.

I think the first question I would ask would be like how quick did they get up there? he's been there for six weeks. Have there been any side, effects because we know that like especially with a medication like sertraline that has a relatively short half life coming down off of it too quickly it has no-- It doesn't-- It's not like Prozac where it has its own built in kind of tail or taper.

And so if they noticed --like we think about the delta in terms of changes quickly for side effect. So if s- I tend to think if someone's gone from like 50 to 100 and they did have a kinda gnarly week of side effects with nausea going up. I tend to think that they'll have gnarly effects coming down.

and so that would determine my pacing a little bit. But I would say I probably would go down by 50 every , [00:24:00] depending on how dire it is, every like week to two weeks. I'm a little bit currently biased by the fact that I'm working in a residential setting and so we like are doing things a little bit faster.

But in outpatient I would say like Coming down 

Preston: by 50 every two weeks It's pretty close to how I think I would do it too. 

Margaret: Yeah. 

Preston: I, also try to think about the convenience of a cross taper for a patient so... So- 

Margaret: I, would start the Wellbutrin like then 

Preston: You could just start it right away. Yep. Yeah. I'd be like you can start this Wellbutrin as soon as you pick it up from the pharmacy and then are you taking the like 150 capsules?

Okay, great. I'm gonna prescribe you 100 milligram tablet. 

Margaret: Mm-hmm. 

Preston: I want you to just right now we're gonna drop you to 100. 

Margaret: Yeah. 

Preston: So we could drop you to 100 today, we'll start the Wellbutrin tomorrow, and then in a week take half a tablet, a week after that stop the sertraline. That's probably how I would do it.

Margaret: Yeah. Yeah, I agree Then to go up on Wellbutrin, but since the Wellbutrin is not ... So our listeners at home who are less doing this, Wellbutrin is not really serotonergic [00:25:00] directly and so we have less of a concern about being on it and Zoloft especially at these like starting at a low dose and Zoloft being on a relatively like medium dose here, in terms of the taper 

Preston: The exception would be if they were on fluoxetine.

So Wellbutrin and fluoxetine are both CYP2D6, metabolites whereas, if I remember right, sertraline is a CYP3A4. So because fluoxetine's such a potent inhibitor of 2D6, it can sometimes effectively, either increase by 1.5 or 2X the dose of like something like a billifier- Yeah ... w- Wellbutrin. So it could be a reason to just start it slower.

Margaret: Yeah. What do you think you would start at? let's say they were on Prozac, like what do you think you would start the Wellbutrin at? 

Preston: Probably 

Margaret: 75. Or would you go 

Preston: down earlier? For, for an adult, a 35-year-old adult who's very dep- who has this melancholic depression and fluoxetine's not in the picture, I would start at probably 150.

Right. [00:26:00] And then for if he's on fluoxetine, just start at 75. 

Margaret: Start at 75, okay. Yeah. That's a good point. I always-- I struggle to remember sometimes the particular CYP inhibitors related to this and one we didn't talk about, I mean, do you have any experience? One person asked in an Instagram Questions about Auvelity, so which is dextromethorphan and bupropion combination, but it's metabolically very interesting 'cause the bupropion is not acting as like an active element in the way we normally think of.

Have you read into this- Mm-hmm ... or prescribed it? 

Preston: Yeah. I have prescribed bootleg Auvelity. Nice. 

Margaret: This is not a medical recommendation to bootleg anything. 

Preston: yeah, so, so here- Legally ... here what, what happens with Auvelity guys. So, so it's dextromethorphan and wellbutrin, and the dosing is super weird. I think it's 56 milligrams of Wellbutrin or something and like 72 dextromethorphan.

I don't know. So I'm like, "What are we..." what the heck? And the reason why they pick those weird dosing isn't because it's like more pharmacologically optimized. [00:27:00] It's just so that they can argue that it's a totally new medication or like- Yeah ... a new drug. Allegedly. So what you could do instead- ... is just prescribe- 

Margaret: Just adding in legal terms 

Preston: here presencing it.

dextromethorphan. Yeah. 

Margaret: Allegedly, we don't know Auvelity. 

Preston: Yeah. W-what is this? It's like, object permanence with a kid. They're like, "Peekaboo" And we're like, "Whoa." Whoa. 

Margaret: I'm trying not to get sued for this podcast. 

Preston: Yes. Compressibility. 

Margaret: Well, the, so the bupropion part, or the Wellbutrin part, I found this fascinating when I learned it.

I actually have not prescribed this for anyone. Also, I'm like working in peds now, so... And it's like relatively new so prior auth and da and insurance and blah, blah, blah, blah, blah. Okay, you correct me if I'm wrong. My understanding is that the Wellbutrin acts by inhibiting the CYR2D6 Which then makes it so that you have, the dextromethorphan for longer in the like body and active because otherwise we like metabolize it super quickly and [00:28:00] that is kind of acting to modulate...

And I looked on the web- like the website and the package insert. We don't actually know the exact mechanism but its modulation of NMDA glutamate is why we think this works. So it's, a novel mechanism relatively to other antidepressants. 

Preston: Yes. So part of the draw to ketamine which is also an NMDA antagonist like said dextromethorphan - Ketamine mentions

Margaret: We hear that you guys want an episode on ketamine 

Preston: It's how fast it can act which is like Evelody's whole thing It's like "Can lift depression symptoms in two weeks." So as far as the like acute benefit Wellbutrin is operating as a like a metabolite inhibitor that keeps the dextromethorphan at a higher level Like that's the initial antidepressant action However like you can't discount that Wellbutrin has its own antidepressant effects that will kick in over time 

Margaret: Yeah But at a dose that's not particularly [00:29:00] Notable.

Not that it doesn't do anything, but like we don't tend to prescribe 56 milligrams of Wellbutrin 

Preston: Let me-- let's check the Wellbutrin dose novality. Watch it be actually, yeah, 56 

Margaret: It's -- Yeah, it's low 

Preston: Yeah. Oh, it's four... It's not even that, it's forty-five. 

Margaret: Yeah. Yeah. Yeah, you right So I think it's agree in the same way that like can twenty five of sertraline do something?

Yes, but- 

Preston: Mm-hmm. But it's not the, the primary means of, antidepressant 

Margaret: Yes. And then because we still have three more vignettes, I'm just gonna name drop a couple others that people ask for. Trintellix or vortioxetine, relatively newer serotonergic modulation. Someone asked for us to go through every, receptor.

I'm not gonna do that because this is a clinical episode. Preston, if you want us to take us through a receptor through ... Not today. If we wanna do a full on receptor episode, we will. And I actually wouldn't mind that for my board prep. But regardless, it is serotonergic modulating. It is slightly different than other [00:30:00] serotonergic modulation in SSRIs that we have.

and then we have Vraylar, cariprazine which is essential D2 partial agonist. This is for the commenter. Five HT1A partial agonist, five HT2A antagonist and has more similar side effects to like atypical antipsychotics maybe you think of Abilify. Not exactly the same, but people ask about those. I haven't prescribed them that often yet because we still run into insurance issues.

But they-- I have a few patients on them and they've found them helpful. There is a saying that I attribute to hearing for the first time on David Puder's podcast Psychiatry and Psychotherapy which is alleg-... well this isn't alleged but "You better use new medications in psych before five years pass while they're still more effective than all" "the other ones in psych though."

You know? Before someone else studies them and they look about the same. Theoretically Vraylar has less weight gain and less s- sexual side effects than other atypicals or typical-esque meds. That's kind of [00:31:00] my run through of those three. Do you have anything to add to that Preston? 

Preston: Honestly no. This is how these meds are presented to us as psychiatrists.

We, the, we go through and we look at the receptors and say, okay it hits a lot of the same things as I would expect for any other antipsychotic. Maybe this five HT1A agonism is a little bit different so might, you know act a little bit similar to Buspar or something. 

Margaret: Yeah 

Preston: But then this is what happens.

They target a side effect and their whole thing is like a little bit lesser- huh ... sexual side effects. And then we go to APA and there's an entire bus- Boom. ...that says Vraylar. And it's limit your patient's sexual side effects because we, the company Vraylar sponsored one study Of 300 patients where we showed with a significant enough p-value that there's lower sexual side effects and make sure you prescribe it now before, Before these studies get repeated.

So [00:32:00] like this is why we have this like level of skepticism but also when patients come to us and we inherit them and they're doing well on the medicines, we're not gonna stop them. 

Margaret: Yeah. I think it just takes time clinically also for the field too. Like we know that there's a financial reason why places seek particular indications or particular studies.

Like the studies are valid, but they're also certainly designed in a certain way often to get an outcome that can be profitable. again, the studies are often valid, but I mean, you can say this for some indications, like it costs a lot of money let's say. So like getting something approved for like pediatric psych and the benefits like the FDA gives places for doing that is a super intriguing thing in terms of how long someone gets to keep a patent on a medication and they can't make a generic.

And so there's just a lot of ins and outs of like how these studies get funded and how indications both on side effects and treatment happen. That is not always... You [00:33:00] know, be evidence based. And we know the limitations in psych of How, does it really mean that you can't treat a kid with OCD with sertraline just 'cause there's not like an FD- FDA indication to treat pediatric - Mm-hmm

OCD with, sertraline? Not necessarily. So point of that being it's really a grab bag. But you were gonna say something, Preston? 

Preston: No, I think, you summed it up well. I ... S- be evidence based and know that there are limits to evidence too. 

Margaret: Yes. One other part for this vignette that we're not gonna go into that we can … If you guys are that interested, we can do more of a full episode on this, but other classes, so like MAois, TCAs.

We're not really gonna talk about SNRIs. I feel like SNRIs I mainly think about for like pain comorbid and then like activation. We'll get in, we'll get into that maybe a little bit in one of the following vignettes. But I do think if you have someone who has really real treatment resistant depression using an MAOI can be really helpful.

usually [00:34:00] most of the one we think about is the EMSAM patch which is selegiline because it has less of the issue with having to worry that much about food intake and the like hypertensive emergency stuff happening if you like have too much- 

Preston: Tyramine .. tyramine? 

Margaret: Tyramine. 

Preston: Mm-hmm … 

Margaret: but I've never prescribed selegiline.

I'm trying. I need to. They-- In re- in psych residency I feel like at least out here they're like, "Have you prescribed an MAOi yet?" And I'm like, "I haven't found someone yet to prescribe one." But they 

Preston: can't- Who will take my MAoi? 

Margaret: They're a different mechanism. You may have more experience working with the population you work with than I do.

Preston: So I have not described an MAOI, but I have gone to tricyclics on a couple- Okay ... of my patients and found that to be pretty beneficial. Yeah. Mostly amitriptyline. Mm-hmm. 

Margaret: Yeah. And in some ways sometimes primary care is more comfortable with some of the tricyclics because I feel like there's They're not more comfortable, but like I feel like I see Doc Lapin I think that all of the super old primary care 

Preston: docs are 'cause that's like all they 

Margaret: had Shout out to my dad.[00:35:00] 

Yeah. 

Preston: And they're like, "Oh, I know this one." 

Margaret: Yeah. I think that sometimes for sleep stuff it comes up and again most, people are not seeing us for a while if they see us at all or they're just like not comfortable talking to shrinks. Like I love our work, but you know, sometimes we're not the, the easiest people to talk to compared to your primary care doctor who's known you for 10 years or 20 years.

but I think TCAs for sleep and then more in the anxiety world I think of like clomipramine as like a useful OCD medicine. but then yeah treatment resistant depression if you're not super worried about suicidality and overdose concern just because TCA overdose can be pretty severe in terms of like morbidity and mortality.

Preston: Yeah. So if, if-- That is a great point. If somebody h- has any history of a suicide attempt, TCA's off the table, in, in my practice. Like the, the strongest predictor of another suicide attempt is an, is a previous one and [00:36:00] like amitriptyline is something that like will genuinely kill you if you overdose on even like your, you know, 30 pills.

I think ... I did the math on it one time and I think it's like anything over like a gram is like lethal which mean- 10, 15 pills? So you know if a standard 30 day supply will stop your heart pretty easily. 

Margaret: Right. Which is it's always an interesting conversation in psych for this 'cause someone could just go get Tylenol.

But we are always thinking about reducing-- Like increasing the number of steps that someone has access to in terms of things that are lethal to them which is why part of the reason why like not having a gun in the home is helpful for preventing suicide right? Like I feel like just sometimes you're like,"Well they could go get this."

And it's yeah they, could but they don't have to pick it up every day and look at-- Have, the thought cross their mind especially if they're already someone who struggles with suicidal thoughts. [00:37:00] 

Preston: Mm-hmm. And, I would say like the difference between like a bottle of amitriptyline and a bottle of Tylenol is the difference between a loaded gun and a gun that you have in a safe with a trigger lock on it.

You know if you down a bottle of Tylenol you'll probably feel sick and your LFTs might go up. But if you down like four or five of them like yeah you could into liver failure. But a single 30 day supply impulsively taken of Amitrypteline is like- 

Margaret: Yeah that's true ...

Preston: having a loaded gun so the- That's a 

Margaret: good metaphor ...

Preston: they do-- you're right like you could just go do anything else however the, the action to consequence ratio is much different.

Margaret: Yeah decreasing the how potent the morbidity or mortality is. great! Okay We are gonna take a quick break and then we're gonna come back and do a few more vignettes but more quickly this time. But I feel like that was kind of a that was a hefty one vignette in terms of thinking through it but I also think it was maybe the most useful.

Preston: Yeah it was good. I feel like kinda dumb.You try to present literally the most like cut and dry [00:38:00] like- This is situation where the med's not working and it's like melancholic depression. And I was like "I 

Margaret: think I'll keep it" Fuck it we ball. 

Preston: So yeah like you know let's do some more vignettes because that's there needs to be some redemption over here.

Margaret: We will be right back.

Okay, we are back for the Preston's redemption round. It's like him you're like on the rocky stairs like you're running up you've got your hood on and you're gonna Da You're gonna crush these vignettes da This next vignette is- Okay ... small and I think you'll like it better because it's a little bit more of a mechanism question the c-- it's only one sentence which is "The medicine is really working and has been for a year and half for moderate to severe depression symptoms but the weight gain has been bad They are on Prozac" So before we talk about Prozac my first question for you [00:39:00] is why the hell do our medications impact weight so much?

So outside of let's include in this like Abilify The TCAs the SSRIs give me your best guess 

Preston: So there's a couple things Part of it is appetite driven The other part of it may be actual like physiologic changes in metabolism My understanding, for SSRIs particularly is that it's mostly via appetite.

Increasing levels of serotonin can increase cravings specifically for carbs- Mm-hmm ... I think. 

Margaret: for Prozac- What-- You're knocking this one out of the park. 

Preston: Oh, thank you. For, for Prozac specifically, it actually has a decent amount of, histaminergic, Mm-hmm ... activation which at first is usually masked by its norepinephrine activity which is why it seems activating at first.

But as people kind of adjust to the norepinephrine part of it, the histamine takes over. It can be more sedating and also more appetite stimulating. [00:40:00] So that's one reason why for Prozac. For the antipsychotics all the reasons mentioned above. Olanzapine is very histaminergic. bilify less so. But there's something with like the D2 or D3 receptor that some of these will hit that may actually -- And it's called like the X factor.

Don't know why necessarily but may change how your liver either runs gluconeogenesis, metabolizes lipids, transfers ketones and it's kinda that part's like a black box but we do see it change people's basal metabolic rate. 

Margaret: Yeah. Which I found fascinating and I learned from my co-fellows, a couple weeks ago when we were on consults.

But yes, there's like emerging data that it is something kind of peripheral not just through central through appetite or anything like that, in terms of the weight and metabolic impacts especially for the antipsychotics. you hit the nail on the head in terms of [00:41:00] appetite regulation with the serotonergic impacts and then the histori- histaminergic slash cholinergic stuff, for weight gain.

in particular ones we think about for weight gain. So the paper that I put in the notes for the show has a couple interesting charts that talk... They like-- they have a really great chart that like has each one and then the mechanisms and ha-has some shared mechanisms. So for those- Oh cool ....people who like to nerd out you can look at that chart for the shared mechanisms between different classes.

And then it has also a list that doesn't include the antipsychotics but has like what studies have been done and like low, so either zero to weight loss I don't disagree with you, Preston, 'cause I feel like I've seen the same thing on Prozac and there's probably deeper reading to be done on this. But Prozac was actually on the relatively, like low for risk for drug induced weight gain 

Preston: And it, is 

Margaret: it is?

Okay ... 

Preston: I still agree with that. 

Margaret: Okay. 

Preston: it's just that people go from being like, "Oh my, like I don't have-- I have like less of an appetite." Or, totally fine- Oh, I see what you're saying ...to like ... And then when [00:42:00] they do gain weight, it's three pounds. 

Margaret: Right, right. 

Preston: Three or four 

Margaret: pounds. that's also like I feel like an important note fo- so for this general thing of like weight gain and working it up from a psych perspective is was someone super depressed and one of their depression symptoms, like you're saying, was like low appetite instead of increased appetite?

And then we treat the depression and now they do have an appetite again and is that the, is the weight gain healthy, weight gain da, Mm-hmm. The other thing is obviously Wellbutrin, as we mentioned, is associated with no wei- weight gain and some weight loss. and then other low weight gain risk cla- in the class like vortioxetine is, SNRIs is venlafaxine and desvenlafaxine.

Preston: Mm-hmm. And then on the high end would be like Paxil. 

Margaret: Yeah. So pa- Paroxetine ... Paxil We're not really talking about MAois but like phenelzine nor triptoline The TCAs are pretty high because they, the histaminergic and cholinergic effects are weight inducing Generally [00:43:00] speaking for psych if a medicine makes you at all a little bit tired There's probably something histaminergic going on therefore It probably has some weight impacts And then the other one that I always didn't know off the top Of my head was citalopram and then mirtazapine which we talk about and it's in like sketchy So I feel like most people know that one But I don't really associate Citalopram with weight gain but now I will And then in the mi- middle were Lexapro duloxetine and sertraline 

Preston: I also did not know that about Citalopram That's not one I prescribe too often Though when I have used it its been relatively good 

Margaret: yeah People respond 

Preston: well to it 

Margaret: the only other thing I would say is like I think one situation that can be more complicated Like it's If a med is kind of working but not really Or and the net weight gain Is definite You have an easier path forward But I think something that happens Equally as commonly if not More in the gray area is like I think this Medicine was really helpful Its cha- turned My life around In over the last year and half And this Weight gain seems [00:44:00] Kind of definitely related To it What do we do now?

'Cause I-- and let's say the patient's "I don't really wanna change the med but I'm open to it." And so you're really the one who's working through the ambivalence with them 

Preston: This is—and this is a patient took it f- took it for depression right? This is their pre-depression episode. So assuming that this is their first medication, I'm kinda creating a scenario here, you can offer to just taper off the medicine knowing that they're in remission and were the depressive symptoms to come back they can restart that medication.

Margaret: Yeah. 

Preston: and that sometimes can be a clean way forward for the weight gain. I n- I need to have the paper in front of me before I quote the data but I do know like there's about let's say, I think there's like a forty percent risk of relapse of depression if you don't take your medication - That sounds right

and then there's like a twenty to thirty percent relapse risk staying on the medication. So and that's very significant over like population. So we know w-we buy ourself like a ten percent [00:45:00] better chance or arguably twenty-five percent better chance of like relative risk reduction in relapse by staying on the medication.

Margaret: Right. 

Preston: However, i- But if you relapse multiple times then it's much higher again without medication. So if someone has relapsed twice into depression I would recommend staying on the medica-medication regardless but like the neurologists say for epilepsy, you know everybody gets one free seizure, everybody gets one free depressive episode.

You came out of it Let's trial going off the medicine and then maybe we can have our cake and not eat it too since we're trying to avoid the weight gain. 

Margaret: Yeah. No I think that's a great point and a point also that's when what else was going leading up to this depressive episode Do you have a history of kind of depression that just you know Your family didn't really believe in that whole mental health hoo hah and like you actually maybe had multiple depressed episodes before you were ever [00:46:00] treated and Or have you been working on CBT or other therapy and made Like lifestyle changes with exercise or sleep or whatever substance use.

So I think that's a great point Is like you don't have to stay on an antidepressant forever 

Preston: And you don't have to add another medicine to try to cancel it yeah. 

Margaret: And I think the other thing I would say would be like The cross taper to one that is more weight neutral You could and I've seen some people do A little bit of Wellbutrin To help With it or to lower the dose of the s Whatever medicine that you're on Also Help reduce the appetite stuff

I think that's a- that's actually mostly it. And then obviously when we talk about like atypical antipsychotics for other things or for like mood stabilizing, there's always a conversation that we should be having or at least thinking about around like metformin kind of prophylactically and eventually GLP-1s will be probably part of that in the antipsychotic class but not yet.[00:47:00] 

There are some people who are probably already there who are like prescribing antipsychotics every day but for a lot of us not yet 

Preston: So I just finished my third year. I'm actually still doing outpatient military medicine right now. Every time I started olanzapine outpatient, I attempted to start it with metformin.

Margaret: Period. And that's evidence 

Preston: based. And I say I attempted because Yeah. Metformin sucks ... there were times where the patient really wanted to stay on olanzapine but was hesitant about metformin either a family member or they had like past experience with it that were negative. 

Margaret: Yeah. 

Preston: And it's tough because th-, you know, the patients say "Oh," "I can just focus on eating healthy and have these lifestyle modifications."

Like "I want to exercise more" And I'm kinda like Olanzapine is like It's a hard one . 

Margaret: yeah It's tough She's doin stuff to your liver 

Preston: girl.it's gonna be an uphill battle t-like— I, do wish we could have our We would try stronger options And I guess what I'm [00:48:00] alluding to is, GLP-1s. I-- 

Margaret: Yeah ... 

Preston: I would be okay seeing a future where there...

And this is Preston's opinion, just to clarify that everybody, this is Preston's opinion, where we have long-acting injectables that are paired with GLP-1s. 

Margaret: Yeah. 

Preston: I think- Yeah ... I think that the number one reason that people who are stable on their antipsychotics stop them long term is due to the weight gain.

So it could be a huge boon to compliance. 

Margaret: And if it's not weight gain, it's, anagnosia. So, I agree with you. 

Preston: Yeah. 

Margaret: I think ideal world 

Preston: would be- Yeah, exactly. The thing is, it's just more effective than metformin at weight loss, and you see there's s- there's a combo med right now. Have you seen that one with semaglutide?

Mm-hmm. 

Margaret: Yeah. 

Preston: It, doesn't make a difference. 

Margaret: Yeah. I mean, it's similar. I mean, I feel like it's already easy to forget that, before GLP-1s, a lot of, weight loss medications were not, are not that effective. it's interesting 'cause, already we've forgotten that, a lot of them were [00:49:00] not...

s- there's a lot of history of those other ones not working. Yeah. And now you guys just have to wait a couple years for the how to be patient long- acting GLP-1 antipsychotic injectable. No, I'm kidding. But, like- Sponsored ... when you look at morbidity and mortality around, SMI or severe mental illness, for our listeners who aren't in the space, there is, a 20 to 30 year morality gap, and much of that is attributed to, cardiovascular risk.

So yeah, it's huge. Which is not just our meds, but our meds are certainly a part of it . 

Preston: No. A- and so the, the proof is in the stats too. So I'm, Googling this live right now, but I remember seeing it earlier. For the, first time, I think maybe ever, the obesity rate in America is now declining.

So for the last three years, it's gone from 39%, I think down to 37%. So really it's like moving the other direction, which is to show how much these medicines are making a difference. And I did, recall this from earlier. About 10% of [00:50:00] Americans are on a GLP-1. 

Margaret: No. 

Preston: And 60 to 70% of those are patients with diabetes or, like, where it's medically indicated for, obesity related weight loss.

But then 30% are taking it for arguably non-medically indicated reasons. you can... Feel like I don't, wanna give people too many tips. I guess this mostly healthcare people listening to this, but, you can go buy Reddit True Tide on- Please don't 

Margaret: do that .... 

Preston: a website. We're podcasts, 

Margaret: let's - 

Preston: Okay.

Okay, never mind. You 

Margaret: can't buy Reddit True Tide. Save it for Patreon Preston. Well they know what they need to know What about we had an ad cut in that's like being sponsored by Please... No, just kidding. The point 

Preston: being these are effective medications that I think we should be using 

Margaret: with antipsychotics.

They're very important medicines. Yeah. They're very, important medicines and it'll be interesting to continue to watch the data around, other kind of impacts or uses for them in psychiatry and substance use. Okay, I have w- I have two more slightly [00:51:00] faster, hopefully, vignettes. If you want the other two vignettes, they're gonna be on the Patreon because we run long on this.

and so please come support us in the one way that helps us not have to try to figure out how to sell a GLP-1 to you guys by supporting us on Patreon. But we are gonna take a quick break and then jump into- Yeah. No, 

Preston: we promise you right now we will never grift, but we will promote our Patreon. 

Margaret: The Patreon's the grift.

That's ... 

Preston: Yeah. The grift 

Margaret: being having a good time together, okay? Yeah. And learning more clinical information. 

Preston: The grift being Preston lowering his already pretty low social inhibitions- .. on this podcast. 

Margaret: Well, and the other two vignettes I have are for sexual function and then pregnancy and breastfeeding.

So, you know- 

Sexual function goes on the Patreon. Not really. You should feel more empowered to talk about that in visits. But we will see you on the Patreon side after this break. You can catch the next part of this on Patreon. 

Preston: It's patreon.com/happypatientpod. Okay. Well, we're back to the real world. If you [00:52:00] missed that, we were, we had a great conversation about pregnancy and- 

Margaret: Perinatal, sexual side effects

what not 

Preston: to do. Yeah 

Margaret: Preston's beef with some famous psychiatrists and my active disinvolvement. That's not a word, but from your beef. 

Preston: We'll, see. Beef is beef, you know? 

Margaret: Okay, Arby's.

Preston: So, thanks y'all for going through this very clinical and, I think, helpful episode for us. I think it's nice for us to, put our, like, actual psychiatrist hats on every once in a while and really, get into the, depths of what we do every day. S- so yeah, I, enjoyed going through these vignettes.

I really redeemed myself in the Patreon side. Guys, it was incredible. Thanks again for all your comments on Spotify, on YouTube following up with us answering the questions on the Instagram 

Margaret: polls- 

Preston: Seriously Margaret 

Margaret: does It helps us make the episodes [00:53:00] more useful to 

Preston: you A- and it makes it feel more interactive.

So we're just, like always, we're very grateful for y'all as an audience, and, you make us doing this very worth it. If you're new to the pod and you wanna find other ways you can interact with us, I'm @itspresro on Instagram and TikTok. I also have the full videos of the podcast on my YouTube.

Margaret's @badarteveryday. She's also on Instagram, TikTok, and Substack where she's doing the 75 Grow, I think, right now. 

Margaret: My habit change, yes. I think we'll still be in it when this comes out. Yeah. It'll be near the end. So 

Preston: yeah, if basically if you want good, consistent, like Poetry, whimsy, the opportunity to kind of build some fun structure into your life with different challenges that are gonna rotate seasonally.

I think Margaret's a great follow for all those things. 

Margaret: Thank you, Preston. 

Preston: We're your hosts, Margaret Duncan and Preston Roche. Our executive producers are me, Preston Roach, [00:54:00] Margaret Duncan, Will Flannery, Kristin Flanary, Aron Korney, Rob Goldman, and Shahnti Brooke. I'm actually-- I'm doing this on the fly.

Boom. I normally read this off. Our editor and engineer is Jason Portizzo. Our music is by Omer Ben-Zvi. To learn more about our program disclaimer and ethics policy, submission verification, licensing terms, go to howtobepatientpod.com or reach out to us at howtobepatient@human-content.com with any questions or concerns.

How to Be Patient is a Human content production

Thank you for watching. If you wanna see more of us or if you wanna see... This is Lilac. She's my cat. She's gonna be waving her hand at one of the floating boxes, which will lead to more episodes. Lilac, point to the [00:55:00] other episodes. Lilac doesn't know what the internet is, but I swear they're there. They pr- they probably exist for real.

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