NP Notes: Early Use of Adjunctives for Treatment-Resistant Depression (MDD Episode 6)

Craig Chepke, MD, DFAPA: Hello and welcome to the Great Exchanges in Mood Disorder podcast. I'm your host, Craig Chepke. I'm the Medical Director of Excel Psychiatric Associates in Huntersville, North Carolina and the Scientific Director of Psych Congress. And with me is my friend and colleague, Ander Penn. Andrew, tell us a little bit about your practice.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Hey, thanks for having me, Craig. I'm a psychiatric nurse practitioner by training. I'm a clinical professor at UCSF where I divide my time between teaching psychopharmacology, treating veterans at the San Francisco VA, and also conducting research on rapidly acting antidepressants, particularly psilocybin as a means of treating depression rapidly.  

Craig Chepke, MD, DFAPA: So, Andrew, I know you have a lot of experience as a clinician and also as a researcher in treatment-resistant depression, so that's what I want to focus on today. And with anything in medicine, we always, almost always, start with monotherapy and then we have to figure out if someone isn't getting better, what do we do next? So, what types of adjunctive treatment options are available specifically for treatment-resistant depression?  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Yeah, so in TRD, historically the strategy was always augmentation. So, when I trained a million years ago, we talked about using lithium as a means of augmenting and then the atypical antipsychotics, or dopamine-modulating drugs, like aripiprazole, brexpiprazole, started being approved for adjunctive treatment but not as monotherapies. And then what's been interesting in recent years is the arrival of, or I mean ketamine's not an arrival, it's been around for a long time, but ketamine and then more recently esketamine Spravato, have been things that have provide the potential of a rapidly acting treatment and even as a monotherapy, of course, Spravato recently got an updated indication for monotherapy. So there are more options now. And then there are procedural treatments. So, we have RTMS, we have ECT, those are all options as well for treatment-resistant depression. And then some more traditional things like wellness practices and psychotherapy as well.  

Craig Chepke, MD, DFAPA: Yes. So, in terms of FDA-approved pharmacotherapies, esketamine as monotherapy or as in conjunction with antidepressant, then technically the alanine fluoxetine combination is kind of augmentation, but it's only with the one specific antidepressant. But these are both relatively recent. And so as you went through a fair number of different pharmacotherapies, there's still a lot of others too because we had to make do with whatever we can get to work for someone. And so there are so many different technically off-label pharmacotherapies, but I love the other interventions that you're talking, that you brought up, things like the TMS for one, but wellness practices, I think that's one that is all too often overlooked in our practices. And what do you think about, tell us about what wellness practices you try to coach with your patients with TRD through?  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Well, I always go to our colleagues’ work, Rakesh and Saundra Jain did such fantastic work with bundling these into this Wild Five model. So, it's meditation, exercise, diet, sleep, and social connection. Those are the five things. And really helping patients identify opportunities to just maybe add a little bit onto what they're already doing. Because one of the worst things to hear when you have depression is you should do a whole bunch of things that you're not doing right now.  

Craig Chepke, MD, DFAPA: Exactly.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: And so you can have one more thing to feel badly about that you're not doing. That's not helpful. So when I talk about exercise, a lot of people think, oh, you want me to join a gym or something? I say, no, I want you to put your shoes on and walk out of your house for 15 minutes and then turn around and walk back. So you just got 30 minutes of moderate exercise, that wasn't too bad, was it? Or do what I did, get a dog. Then you'll have lots of walks at strange hours of the night as well. He wants to go out. And thinking about meditation doesn't need to mean sitting on a cushion for an hour. It could mean going in your backyard on a warm day and closing your eyes for five minutes and just listening to whatever's happening around you. Making these attainable goals that are attainable and also enjoyable. 

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Because one of the horrible things about depression is that it separates us from the reinforcement of pleasure, that anhedonia. I don't usually teach patients technical jargon unless it's really useful, but that's a term I will explain to people because a lot of times people have this ‘aha’ moment of like, oh, I know what you're talking about. I didn't know that had a name. And I say like a hedonist, right? Pleasure. When we put an ‘a’ in front of things in medical terminology, it means without, so without pleasure. And people can really relate to that. And so the hard thing about that is that pleasure is often the driver for repeat behaviors. When we go out to a restaurant and we have a nice dish, we go back to that restaurant and think: ‘You know what? I'm going to have that same thing again cause it was so good last time.’ Because we have that signal of pleasure. But when people have depression, you take that out and everything is kind of blah, and so why would you want to do that thing again? So, you have to sometimes incrementally introduce things that are enjoyable and rewarding back into their lives, especially if they’re lifestyle things, so that they don't feel like a chore or another opportunity to feel like they failed.  

Craig Chepke, MD, DFAPA: Yeah, I think that's the real brilliance of the Wild Five program is that it gives you a protocol to make it easy and it's not overwhelming. Instead of saying, well, because we know that many people with TRD do have the obesity type two diabetes, so on and so forth, possibly in part because of the medications, but also possibly in part because the illness of major depressive disorder comes with certain liabilities genetically that predisposed towards those conditions. And so, you tell them, ‘Oh, go out and diet.’ Well, meanwhile, Wild Five says, just write down what you eat, keep a log of what you eat. Then it relies on the individual, which people naturally say, ‘Oh my gosh, this is what I'm eating? Maybe I should eat better than this.’ But you're not forcing it on them. You're just giving them a small, simple little task to do on a daily basis, and then they can grow into the other aspects of it. And it's not too overwhelming. And sometimes I'll say that, okay, well you can't do 30 minutes of exercise a day? Just walk to your mailbox, check the mail and walk back.  

Craig Chepke, MD, DFAPA: Tomorrow, do it and then do it a second time, and then do it three times, and then build up. If you do 30 seconds of exercise, that's mathematically, infinitely better than zero minutes of exercise. So I just want you to start somewhere. Just don't do nothing because nothing is what got you into my office. Something like that.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Yeah, yeah. I talk about the positive snowball effect that like, okay, your house is a mess. Don't clean your whole house, clean your bathroom sink.  

Just start there, and then maybe while you've got the cleaning supplies out….You know what? I'm going to clean the toilet out too. Okay, great. And now I'm going to do the bathtub. And you've got momentum going because one of the things that's horrible about depression is the inertia that happens. And there's just so much, so much, depression introduces so much resistance to being able to do things that we would normally do. And so anytime you have the opportunity to get a little bit of momentum going, that's great. So, you're out for that 10-, 15-minute walk and you decide, you know what? I'm going to grab a coffee in my local coffee shop and sit in the sunny window for 15 minutes and drink my coffee. Great. You're getting some social engagement. You're out there in the world and not staying in bed, and maybe that's enjoyable. So then the next day you do it again, or later in the week you do it again.  

Craig Chepke, MD, DFAPA: I love discussing, when thinking about the whole person, I think that's so important. But I do want to turn back to pharmacotherapies a little bit because I'm sure you see the same thing I do: That people come into your office with TRD and they've been on five, eight different monotherapies, and there's no one definition of TRD. One of the most commonly accepted definitions is two unsuccessful trials of antidepressants, which largely follows from the STAR*D trial. But often people who qualify for that or some people who qualify for any TRD diagnosis you can think of still aren't getting, are still getting monotherapies. So how do we bring up the use of adjunct treatments earlier in the discussion?  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: I go back to the initial assessment and treatment plan. So when we're doing an assessment, if I do come to the conclusion that they are dealing with depression and we talk about treatment options, usually I'm going to start with a monotherapy. I mean, I'm assuming this person isn't treatment-resistant at this point. And there's also a little nuanced language thing that I always tell my students, but don't tell patients that they failed a medication, say the medication failed them. Right? Because when you have depression, you feel rotten enough as it is. You don't need to feel like you failed another thing, right? 

Craig Chepke, MD, DFAPA: Even though that's not what we're meaning, it's medical jargon to us, in the mind of a depressed person they’re going to see, ‘I knew it. My doctor, my nurse practitioner, they think I'm a failure too. I heard them say it.’ 

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Yeah, exactly.  

Craig Chepke, MD, DFAPA: We can't do that to people.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: So we have to say, it's the medication, it's our treatments that failed you. This didn't work. I'll set the stage that ideally we want to use the simplest treatment plan that we can get away with. In my book, that's one medication. For example, I will optimize medication before I'll add on an adjunct medication. So it kind of drives me up the wall when I inherit a patient, I see that they're on three different antidepressants at the lowest possible dose, and I think, what were you doing here? And I would much rather see somebody on a high dose of a single medication that is working than a bunch of adjunctives if they don't need it. Now, there may be reasons why somebody stopped at a lower dose, maybe they couldn't tolerate a higher dose, and that was why they went to an adjunctive. So, there can be reasons for that, but sometimes I see this sort of style of doing a pinch of this and a pinch of that, and I would much rather keep it simple to one medication. 

And my usual strategy is if somebody comes in, they're having a partial response to a single medication, I check in about side effects. And I say, if the side effects are within reason and there's still safe range to go up, I'll say, you know, what I'd like to do is actually optimize this medication before we think about adding anything else. But even before that, I'll have the conversation with patients to say, look, I want to make this as simple as possible, and that means ideally using one medication. But sometimes depression, like hypertension, requires more than one medication. Sometimes you got to approach this from two different angles, like in hypertension, we might use a beta blocker and an ACE inhibitor. Totally different mechanisms of action, but both having the final outcome of reducing your blood pressure. And so sometimes in depression, we need to do that as well.  

We might take a serotonergic and a glutamatergic approach. Or we might, a classic would be an SSRI plus bupropion. So we're going at this from norepinephrine and serotonin. So, I at least sow the seed that we might need to do this at some point down the road. That's not my goal. That's not where I start. But I just put that idea out there into the conversation so that if some point later on down the road I can reference that and I say, you know, remember when we first met I said, I'd really like to do this as one medication, but I think at this point it would make sense to add this second medication and here's why. And a lot of times it's important as clinicians to explain why we're choosing that other second medication. Because to us as clinicians, we think about SSRI or an NRI, and we see those different mechanisms of action. If you go and Google those things, they're both going to say antidepressant. And so your patient might think, well, I'm already on one antidepressant. Why do I need a second one? Whereas we're going to think, well, those have two different mechanisms of action. So it's important to explain that to patients that we're taking this from two different angles.  

Craig Chepke, MD, DFAPA: And I similarly use that medical model of hypertension, diabetes, COPD, asthma, especially if the individual has one of those illnesses that are very commonly treated with polytherapy. And if they're getting polytherapy, then that makes it so much easier for them to understand. But as you very wisely pointed out those other fields for, it doesn't just say they're all antihypertensives. It says beta blocker, ACE inhibitor, ARB, diuretics, so on and so forth. And for us, it just says antidepressant. And so we have to take that extra educational step of, yeah, well, they're all antidepressants. The FDA just doesn't name them by the mechanism, and here's what the difference in the mechanism is. But ultimately the best is if you can get and what—serotonin, norepinephrine, dopamine, they're different, they're still monoamines. And so, I love the serotonin glutamate combination that you brought up cause that is truly a fundamentally different mechanism of action.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: It is.  

Craig Chepke, MD, DFAPA: And the further away the MOAs are of two different medications, the more rational to me that polypharmacy is. Even similarly, I'd rather use, instead of two re-uptake inhibitors, I'd rather use a re-uptake inhibitor and something that has direct receptor binding because you're getting more differences. The more difference to me, the better the outcomes, in general, for most people. 

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Yeah, no, agreed. And part of this is in our training, because a lot of our training in psychopharmacology was disease-state organized. This week we're going to talk about antidepressants, and so we tend to cognitively lump them all together. In recent years, I've changed the way I teach my class more, kind of like the way that Nassir Ghaemi has organized his textbook, which is by mechanism of action. And it feels a little more technical at first to see this week is about monoamine reuptake or monoamine transporter inhibition. That sounds very daunting. But it really, once…what I've found with my students is once they understand the mechanism of action, it's a lot easier for them to then integrate newer medications into their thinking because they're not thinking…This became really clear with adjunctive use of dopamine-blocking drugs for depression. Because even patients would say, well, I don't have psychosis. Why are you prescribing aripiprazole? And even students would say, was that only for psychosis? Is that for depression with psychotic features? 

And if you understand the mechanism of action of partial agonism of dopamine, then it starts to make more sense why that class of medications might be useful for a mood disorder even irrespective of psychosis.  

Craig Chepke, MD, DFAPA: Yeah, absolutely. And also, just wanted to circle back to and highlight for the audience the method of bringing it up at the first visit, that there could be adjunctive options are on the table, because that really normalizes it. The term treatment-resistant depression. I hate that. It's not that you’re treatment-resistant, it makes it sound like it's a terminal illness and it's not.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: It does.  

Craig Chepke, MD, DFAPA: It's just resistant to the medications you've been given so far. And if they're all monoamine-based, well maybe you have monoamine-resistant depression or something like that. So I think that's just a nice way to put it to the very beginning of this is totally normal if you do end up requiring multiple medications, and then you can circle back on that later in treatments. I think that's a fantastic way to do it. Well, I think we're about out of time for today's episode, Andrew, but thank you for joining us today.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Thanks for having me, Craig. It's always good chatting with you.  

Craig Chepke, MD, DFAPA: Always. And thank you for our audience to joining us for this episode of The Great Exchanges of Mood Disorders Podcast.