NP Notes: Treatment Approaches for Major Depressive Disorder (MDD Episode 3)

Craig Chepke, MD, DFAPA: Hello and welcome to another episode of Great Exchanges in the Mood Disorder podcast. I'm your host, Craig Chepke. I'm the Medical Director of Excel Psychiatric Associates and the Scientific Director of Psych Congress. And joining me is my colleague and friend Kristian Dambrino. Kristian, tell us about yourself.

Kristian Dambrino, MSN, APRN, PMHNP: Hey, it's awesome to be here with you today. I am a psychiatric nurse practitioner in Nashville, Tennessee. I own my own clinical practice. And so, I've been practicing in Nashville for about seven or eight years with mostly a background in community mental health. But find myself seeing a lot of depression in my practice and certainly difficult-to-treat depression as well.

Craig Chepke, MD, DFAPA: Yes, absolutely. By the time someone makes it to a psychiatric provider almost then by definition it's difficult-to-treat depression, whether because of the severity of the symptoms, the chronicity of the symptoms, or just the difficulty in finding appropriate treatments. And that's what we're going to focus on today is treatment of major depressive disorder. And, of course, we'll get into some of the difficult-to-treat depression a little bit later on. But let's start off with just a broad overview of what types of pharmacotherapies are there for major depressive disorder, Kristian?

Kristian Dambrino, MSN, APRN, PMHNP: So, we typically think of, or at least for a long time, we were really working with medications that addressed monoamine system. And so, the monoamine hypothesis for a long time, we kind of—even when this was all that was available, I remember learning about this. And the professor would always say, this is an oversimplification, but this comes from the idea that there is a lack of monoamines in the synapse. And I knew learning that, I knew this is not explaining the whole story. There's no way. And I think we really have learned that because now we have more than just SSRIs, SNRIs, tricyclic antidepressants, MAOI medications. We now are looking at atypical antidepressants and medications that impact the glutamatergic system. So, we have more options. We'll talk a little bit, I know, today about ECT and TMS, and we also have nonpharmacological interventions as well. And I think collaborative care is always best for our patients. So, we have different ways we can work with patients who have depression. And that's really good because for people, depression looks different in everyone.

Craig Chepke, MD, DFAPA: Yeah, absolutely. So, SSRIs, serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, SNRIs. Do you use many tricyclic antidepressants?

Kristian Dambrino, MSN, APRN, PMHNP: I actually do. I actually do. I was reading, before this discussion I always go into, anytime I meet with you, I'm going into the literature. Because I know, I know you're going to throw me some curve balls and, which is so good. It, it's so awesome for learning. But I was actually this weekend reading about that earlier response is a predictor of remission. And so, I was reading about, I was looking at a systematic review and a meta-analysis that was looking at early response with mirtazapine and tricyclics. And so, I do use quite a bit of that now. I use those for depression but also for OCD as well. And I've had some success with my patients.

Craig Chepke, MD, DFAPA: Yeah, I'd say I probably use more tricyclic antidepressants than I do SSRIs because by the time someone's made it to me, what's the point of trying yet another SSRI, if there are even any left that they haven't tried. I have so many patients who come to see me and on their intake paperwork, I have a checklist of almost 200 psychiatric medications, virtually everything that's ever been approved. And the number of individuals who would check off either five out of five or all six out of six SSRIs that are approved in the US just baffles me. And so, it baffles me because I don't understand why after someone's been on three, four SSRIs, do you really think the fifth or sixth is going to make a big difference? STAR*D, as we know, taught us, not really. But tricyclics, on the other hand, are extremely differentiated pharmacodynamically. And I think that's why we keep switching SSRIs because it can work with tricyclics because one tricyclic is so different from other tricyclics.

Craig Chepke, MD, DFAPA: In terms of the serotonin, norepinephrine reuptake inhibition, the direct receptor binding, it makes sense to switch there between one to another to another. But it really doesn't, in my opinion, clinically, at least with SSRIs or SNRIs, much more alike than different. But I really—now, there are drawbacks obviously to tricyclics in terms of many different adverse effects, but they're very potent medications. And I think studying those for our audiences was something that can really enrich your clinical practice. You know, make sure you know how to use those tools and what each one is and what it does and the side effect profile. But when you use the right way, I found some very good results with many patients that have difficult-to-treat depression.

Kristian Dambrino, MSN, APRN, PMHNP: Right. It's so interesting, too. I know you and I always talk about—we talked about this in a previous discussion as well—just the timeline of how medications for depression has evolved. And for tricyclics, that was, I believe the first one was FDA approved at the end of the 1950s. And it was imipramine, and it was chemically sort of similar or thought to be similar with chlorpromazine, which is so interesting. But, of course, at that time, the medication was not in the trials. They saw that it wasn't effective for psychosis, but there was a benefit for depression. And I always think that's such an interesting thing about medications that we have because what we know about them was discovered sort of serendipitously. And so, that's another thing when you bring up tricyclics—and we've talked about that with many different classes of medicines—but those preceded SSRIs and SNRIs, which were more like the late ‘70s and early ‘80s. And so, it's interesting to see kind of how far we've come because really the first glutamatergic agents were FDA approved between 2019, 2022. So, that's really, I mean, how long we've been kind of working with the monoamine hypothesis. And then, finally—and we've known about it. We've known about it way before then, the first clinical trial that looked at—and I'd love to hear you talk more about that, too—but in 2000, when we sort of saw, we saw ketamine be effective for depression, we've come a long way. And that was, if you think about that, 19 years later, that that FDA approval for those medications happened.

Craig Chepke, MD, DFAPA: Well, one thing that I kind of pull out of that that I want to highlight is that there's so many medications psychiatrically were found serendipitously. They were being tested for one thing, but they were found to be useful for others. It really shows us, pay attention to your patients holistically. Don't just go in with a one-track mindset of, “Okay, I'm going to give this medication for this indication and it's only going to affect that.” It could have effects that are something that we would not have predicted, but may be able to be replicated of, “Oh wow, this isn't what I thought would happen with this medication, but it's also showing some benefits in this area” or “It's not really working for them for this, but it's working for them for that.” Being mindful clinicians and really paying attention, which is hard. We've got our EMRs, we're typing away sometimes, or we're thinking about other things. But, really paying attention. That's what I love about those stories is that it's savvy clinicians and not all of them psychiatrically minded. Chlorpromazine was first discovered to have psychiatric effects by an anesthesiologist because he was paying attention that, “Wow, this isn't just sedating them. It's doing something different. I need to talk to my psych colleagues about this.” I love those stories.

Kristian Dambrino, MSN, APRN, PMHNP: Right. It's fascinating, too. If you look at the literature, what I love about a literature review is they'll often kind of put in quotes from the clinicians who are studying that with their patients. To your point about that holistic assessment, they'll put in, and I love the writing back then, too. It's so beautiful and literary.

Craig Chepke, MD, DFAPA: Yeah.

Kristian Dambrino, MSN, APRN, PMHNP: So, I love seeing that in the literature, just that account of a description of what they saw in a clinical setting. It's really inspiring.

Craig Chepke, MD, DFAPA: Yeah. So, let's turn now from medications to some other aspects of treating major depressive disorder, because it’s not just about meds. You know, talk us through psychotherapy and lifestyle modifications. How should we be utilizing those?

Kristian Dambrino, MSN, APRN, PMHNP: So, I have—usually when I'm establishing care with a client and they ask me, “What does treatment look like?” Sometimes, they don't even know. They say, “Well, do you provide therapy?” And I have to clarify sometimes, “Well, I can.” I do believe, as a prescriber, I always believe in continued education. If I need additional training or if I'm not as experienced in something, which for therapy, you go through additional training for that. So, I'll kind of educate the client on, “Here's what we're looking at.” I really want clients to be involved in therapy and medication management together. I see that really be helpful, particularly with depression. And the therapeutic relationship both with a prescriber and a therapist works best when that trust is there and that therapeutic alliance. So, I always explain that to my clients, too. You can have someone who's extensively trained in a modality and if you can't connect with another human being, it's not going to be as impactful, which I think is really unique about our specialty.

Kristian Dambrino, MSN, APRN, PMHNP: And the other piece of that is there are different modalities within psychotherapy. And so, it's really important for me as a prescriber to understand what does that modality entail? If I have someone who has high anxiety and maybe they tend to have more perfectionistic tendencies, perhaps CBT might be a little bit difficult for that patient. If I have someone who's working through attachment and they want to understand themselves better, internal family systems might be an interesting modality to see, “Okay, in real time today, what parts of myself are showing up in these interactions or professionally?” So, therapy is so interesting. It's so important for us, even if we don't have—I did have actually, in my graduate training, I did have four of my own psychotherapy clients. And let me tell you, I have so much respect for my psychotherapist colleagues during that time. I just remember thinking, okay, so this is really, it's more than—therapy is more than just catharsis. It's more than just, “We're talking through something.” There's so much to that and I think it's important for us to understand that as prescribers.

Craig Chepke, MD, DFAPA: Yeah, and so, there is research to back up what you said about relating to individuals. That the best predictor of success in psychotherapy is the relationship between the patient and the therapist, but also important what modality, too. So, you want to optimize both. Someone who the individual is able to connect with and have that type of trust, but also making sure that we're optimizing both aspects of the modality as well and finding the two in the same person. That's what we're reaching for always. And then, lifestyle, incredibly important with diet. Garbage in, garbage out is high. I like to talk to patients. If you're eating things that are not healthy, you're not going to feel healthy physically or mentally. You add exercise, a lot of ways I try to pitch that sometimes. Could be that, well, if the person's really focused on medications, medications, well, the exercise will help you to pump your blood and move the medication through your body better.

Craig Chepke, MD, DFAPA: But also, exercise we know is also something that is a powerful stimulator of BDNF, brain-derived neurotrophic factor, which is a key mediator of neuroplasticity, which is one of the leading modern hypotheses of major depressive disorder, that there's dysfunction in the individual with depression and we want to stimulate neuroplasticity to induce benefits. And then, things like sleep and managing stress, those are all critical aspects to treating depression. And we want to look at it holistically, not just that a pill is going to fix everything. My last analogy I'll give you on this part is that I always talk about that, well, we talked about the bio-psychosocial model a lot. And I kind of change that from a three-legged one to make it a four-legged stool or chair. That there's the biological factors we should address, psychological, and the social. And then, the fourth is physical health and wellness.

Craig Chepke, MD, DFAPA: Now, if all we're focusing on is the pharmacotherapy with medications, well, that biological pole or leg of the chair, well, that could be made out of titanium. But, if the other three legs are made out of balsa wood, it's not a chair I want to sit on. So, what I want to do is address all four of the legs of the chair, make sure it's sturdy and stable, so it's going to support the weight when you sit down on it. And I've used that thousands of times. And that often will really resonate with people of why it's so important to address all of those factors.

Kristian Dambrino, MSN, APRN, PMHNP: Yeah, I love that analogy so much because we really do have to approach things holistically. And I always will tell patients too when I'm speaking to them about that, that I'll kind of say, look, it's easy for me to sit here and make recommendations and, trust me, they're based on evidence. There's a reason I'm making them. And I know that when you are struggling with depression, one, we're trying to treat that on the medication and therapy side of things as well. But I know we're asking—I know it's a tall order. This is not going to happen overnight.

Kristian Dambrino, MSN, APRN, PMHNP: It’s, I guess, a very James Clear Atomic Habits situation, where it's like just a little at a time is what we're looking for. The other thing too, and I have so much empathy, I have empathy for my patients, too. Because I was looking at the literature on physical exercise, and a lot of the evidence supports structured support around that. So, rather than just going to the gym or walking outside or any kind of movement that you incorporate that's unstructured, having a support group or having someone who's more of a coach is helpful in maintaining that. And I was just laughing because I haven't done that in quite some time. I think I'm so busy practicing as a clinician, I haven't had that kind of support. And I was laughing because my former fitness coach reached out and I said, no, we don't have time for that structured support.

Kristian Dambrino, MSN, APRN, PMHNP: But it's interesting what the literature shows. The other thing that's really interesting is in terms of controls. So, clinical trial design, there's always a placebo and there's a control group. I think it's interesting in behavioral modifications or lifestyle modifications, you'll see a waitlist control. Have you seen that in the literature?

Craig Chepke, MD, DFAPA: Oh yeah.

Kristian Dambrino, MSN, APRN, PMHNP: That's really cool to me because the thought behind that is, one, I know we want people to stay in trial, so retention. But also, giving people access to a beneficial treatment, which is really cool. The theory behind that—and maybe you could explain that as well, but that they would be placed on a waitlist and eventually get the treatment and have access to a beneficial treatment.

Craig Chepke, MD, DFAPA: Well, waitlist control I think could be very instructive because that's real world. People wait and wait and wait for appointments with psychiatric specialists. You know, depending on where you are in the country, three months is very good, six months, nine months. I’ve even heard a year in certain places before they can see a psychiatric specialist. So, what is the nontreatment? Now, ideally, it's not just waitlist versus the active intervention. That there could be a, more like a placebo arm to split the difference in there can be—would be the best thing. So, that way, you can compare what would it be like if there was no treatment? What would it be like for everything but the active intervention, which would be the placebo arm and then the active intervention there. So, I think we're going to have to wrap up there because of time, unfortunately. We've got so many things we could talk about. But this has been a great discussion, Kristian, and I really appreciate you joining me here today.

Kristian Dambrino, MSN, APRN, PMHNP: Yeah, I'm really glad to be here with you. Thank you so much.