NP Notes: Overview of Major Depressive Disorder (MDD Episode 1)

Craig Chepke, MD, DFAPA: Hello and welcome to the Great Exchanges in Mood Disorders podcast. I'm your host, Craig Chepke. I'm the medical director of Excel Psychiatric Associates in Huntersville, North Carolina, and I'm also the scientific director of Psych Congress. I want to welcome my colleague, Kristian Dambrino. Kristian, tell us a little more about yourself.

Kristian Dambrino, MSN, APRN, PMHN: It's good to be here with you today. I am a psychiatric nurse practitioner working in Nashville, Tennessee. I'm actually doing this in between seeing patients today. So, and I know Dr. Chepke, you work the same way, but I've been really—a lot of my background is in community mental health. I also do some speaking and teaching as well. I’m just really excited to talk about this topic today.

Craig Chepke, MD, DFAPA : Well, it is an incredibly prevalent one and for us in practice, probably one of the most prevalent conditions that we see unless you're in community mental health. So, let's talk a little bit about just an overview today of symptoms, diagnosis, etiology. Tell us a little bit about the incidence and prevalence. I know it's very common, but do you know the numbers?

Kristian Dambrino, MSN, APRN, PMHNP: I don't know the numbers because I don't have a PowerPoint in front of me right now, but it is the leading cause of disability in the United States. And so, this is something that we're seeing a lot more of today. I know I see more of it in my practice. I opened my practice up about a year ago, and I think that's—when people ask me, what are you predominantly treating? It is depression and a lot of difficult-to-treat depression as well. So, we are seeing more of it. I'm seeing a lot more of it in clinical practice. What would you say those numbers are?

Craig Chepke, MD, DFAPA: So, that's the thing, is— that's exactly the answer that a clinician gives because I don't know the numbers off the top of my head either. We put those up on PowerPoints, like you said, but it's something that we see so often. And, again, it's the biggest cause of disability worldwide by the World Health Organization. I know, personally, I write more FMLA paperwork for MDD than every other diagnosis put together. So, yeah, the numbers, one that sticks out at least is that in last year, I believe, that 21 million people experienced symptoms of a major depressive episode. But, in terms of percentages, I don't know. I don't tend to think that way as a clinician. So, those don't usually spark in my head. They can change over time. You change the criteria, and they change. And we saw that with schizophrenia a number of years ago, the prevalence dropped because they changed the way that they were reporting it. And so, I think just leaving it that it is one of the most common conditions that any psychiatric provider is going to see is a way to really think about it.

Kristian Dambrino, MSN, APRN, PMHNP: Right. And another thing you and I talk about a lot—because we just did a presentation in Boston, actually went back to see the city again because the conference was so busy—but what we talked a lot about is how depression does not look the same in everyone. So, even if we think about how those statistics are calculated and how different that is person to person. In fact, I just had a conversation with someone who's been struggling with depression, and you have to rule out other mood disorders as well. Is it unipolar depression? Is it on more of a bipolar spectrum? And so, it's not as—and I always say to my patients, there are layers to people. So, even in that first psychiatric evaluation, that's one hour out of a whole life. And so, really understanding depression at the individual level is so important.

Craig Chepke, MD, DFAPA: I mean, there's nine symptoms per the DSM that you can draw from. You have to meet five out of those, and at least one has to be either number one or number two, which is either a depressed mood or a decreased or diminishment in the interest, which we may also define that as anhedonia. But then, the other seven symptoms, you can have just four others of those. So, that leaves a huge breadth. There's 227 different combinations of symptoms. So, it really doesn't make sense to think of it as one thing. It's what is it for this one person?

Kristian Dambrino, MSN, APRN, PMHNP: Right. And that's even why, when we think about the PHQ-9 and these standardized validated t ools that we use to measure—and you and I have talked a lot about this too, and among my colleagues, the difference between a clinical improvement versus a functional improvement. We have those validated instruments to measure that. But also, what does this look like in a person's day-to-day life? And you just said that—the amount of different combinations. And it makes sense, especially with what I see in clinical practice that there are that many different combinations.

Craig Chepke, MD, DFAPA: Well, yeah, and it's the result of so many different things put together. I mean, biological factors, genetic factors that we inherit from our family. It's a relatively heritable condition, not the most heritable among psychiatric conditions, but fairly heritable. And then, how does that environment play into the genetic biological factors and then epigenetic factors as well? And then, the psychosocial factors. So, it's this soup of a lot of different factors going in together. And so, of course, it's going to be highly different between one individual to another.

Kristian Dambrino, MSN, APRN, PMHNP: Right. And that really impacts how we prescribe. And so, as my role as a prescriber, the medications that I'm going to choose—and I know we're going to talk about that today with mechanism of action, really understanding how different depression is, is going to impact what I choose as a medication. I was just speaking with someone who was on a medication that would treat depression but maybe has, is more likely to have stimulating effects. And this person struggles with comorbid anxiety. And so, a medication like that can also trigger anxiety. And so, that's very important as a clinician for me to understand the different ways that depression shows up in a person and what medications I choose are going to really impact that.

Craig Chepke, MD, DFAPA: Yeah, great points. And it's all kind of leading us, several different lines of conversation too. Talk about the etiology of MDD in terms of the neurotransmitters. Our understanding has changed recently, hasn't it?

Kristian Dambrino, MSN, APRN, PMHNP: Right, it has. I was actually, before this podcast—because we are kind of talking about some detailed information. I love to look at in terms of how far we've come. What were we using at the end of the 1800s for depression? Were we using anything then and how that's evolved? We talk about, the monoamine hypothesis is what we typically discuss in psychiatry. And that we really, for a long time, thought that serotonin, norepinephrine, dopamine, re-uptake inhibition is kind of the thought behind how those medication works for a long time. What I love too, and I find very ironic, is the serendipity of the evolution of psychotropics. And so, we worked—I learned in my graduate education, and I'm sure that you did in your education as well. We really, it's prudent not to prescribe based on a side effect profile. Yet, that is where we have kind of gotten this hypothesis, which is really ironic to me is that we, in the 1950s, a VMAT-2 inhibitor was what we saw in patients being treated for hypertension. That, in some of those patients they developed depressive symptoms. And so, that was kind of the evolution of that. And then, also the use of medications for terminal tuberculosis in patients in New York resulted in improvement in mood, so much so that the Associated Press put out there they're really excited about it. And they were saying people were dancing through the halls though they had holes in their lungs. And so, that was kind of the birth of what we think or what we have thought and has changed, but the thought behind how neurotransmitters work in depression.

Craig Chepke, MD, DFAPA: Right. So, those early theories, both directions back in the ‘50s, “Monoamines up, and depression better; monoamines down, depression worse” kind of has prevailed for decades upon decades. And there've been some successes there. We can't say that that is completely dead. We don't want to throw away the monoamine hypothesis. It's served many people well. Probably a lot of those, though, unfortunately, are those that are treated in primary care before they get to us in psychiatry. Because once they get to us, then usually the monoamine hypothesis has generally failed those individuals. But that's kind of the traditional view. What's our more modern uptake?

Kristian Dambrino, MSN, APRN, PMHNP: Well, now we're starting to look at different hypotheses underlying depression, which is exciting for me because I can't tell you how many times I see patients and they ask me, “Why would you recommend this treatment? Tell me how it works.” Now, not everybody does that. But some people will kind of maybe go to TikTok or, well, they go to the information that's available. And I tell my patients, bring whatever you have to me because that's part of patient education. It's all important. But a lot of times people say, “Well, why are you choosing that? Tell me how that would help my depression.” Now, we're thinking about the neuroplasticity hypothesis of depression, for example. My favorite example of neuroplasticity or the brain's ability to form new connections, I always like thinking about language learning later in life, mainly because I started learning French only recently. And you know. I talk to you about that all the time. But I love that. That gives me hope as someone who's passionate about education that I can—my brain can form new connections even later in life. And that is a part of—in depression, when people are struggling like that, that ability for the brain to form new connections is impaired. And so, that's sort of underlying the neuroplasticity hypothesis. And then, we're looking at more glutamatergic treatments now.

Craig Chepke, MD, DFAPA: Exactly.

Kristian Dambrino, MSN, APRN, PMHNP: So, treatments that will target NMDA receptors. And I know you and I just talked about that. Gosh, it feels like it was yesterday, but time has flown. But we talked about how detailed that is. So when I'm talking to clinicians and especially patients and trying to explain the complexity of—and it makes sense. If we're complex humans, of course our brain chemistry is going to be complex. And so, of course we're going to have more hypotheses to explain depression.

Craig Chepke, MD, DFAPA: Right. And so, I mentioned how the people that we generally see, the monoamine hypothesis has failed them. Often, antidepressants have failed them. I always make a point to say we should never say that a patient has failed a medication or a line of medications, even though that's common parlance, because that's blaming the victim, in my opinion. The patient didn't fail the medications. The medications failed the patient. And so, when someone has been on two, I prefer to say unsuccessful trials of monoaminergic antidepressants, the first-line treatments, SSRIs, SNRIs, NDRIs, et cetera, that is what we define as treatment-resistant depression, TRD. Tell us a little bit about how TRD differs from MDD, Kristian.

Kristian Dambrino, MSN, APRN, PMHNP: Well, primarily in the literature we define treatment-resistant depression or TRD—and you're right, we do, the terminology around that has changed, too. We are now saying more like difficult-to-treat depression, challenging-to-treat depression. And I do think that has to do with instilling some hope in our patients because that terminology can be difficult to hear, but in the literature, it is typically referred to as someone who has failed two or more antidepressant trials.

Craig Chepke, MD, DFAPA: Eh. Try again.

Kristian Dambrino, MSN, APRN, PMHNP: Well, it can be four as well.

Craig Chepke, MD, DFAPA: You said, “someone who has failed.” “Someone who has been failed by”—

Kristian Dambrino, MSN, APRN, PMHNP: You're right. You're right. And I said that—

Craig Chepke, MD, DFAPA: It's hard though, isn't it? Because it's so ingrained in us. We get it in our trainings when we talk with colleagues. Every prior auth that you ever do asks, “How many medications has the patient failed?” It is so ingrained. And it's intended to be a neutral term, but I just think of it from an individual with limited experience. What if they overheard us talking about, “Oh yeah, I'm about to see Mrs. Johnson. She's failed a couple of antidepressants.” If she overheard that, her brain with depression would think, “I knew it. My nurse practitioner, my physician, they think I'm a failure, too. Just like I've been thinking. I was right all along. That little voice in my head telling me I'm a failure.” But they perceive things that are neutral or it could be even things are positive in other circumstances as negative potentially. So, it's very difficult to stamp out. And so, it takes a lot of practice. I've been doing it for years, making sure that I've eliminated it. But I just wanted to—see, that was actually a great demonstration of just how hard it is for us to not use that terminology.

Kristian Dambrino, MSN, APRN, PMHNP: It was. You're right. So, I'm finishing up my Doctor of Nursing practice program, too. And what terminology is appropriate to use or therapeutic to use across when we're talking about access to care, and that changes all the time. And it's really good. You're right, that piece about it being ingrained. After I prefaced in that way, that I would go to that. It's a really good point. But, right. So, it's two or more trials of an antidepressant that have not been effective. That’s right. And so, and the thing that's really striking as well is we talk a lot about the STAR*D trial. Now, there were imperfections in the design of the trial, but it was really the largest multicenter trial that we had at that point that sort of tried to mimic real-world practice. And to me, what I never, I think about this when I'm seeing my patients, that 60%, roughly 60% of patients in that first phase, which was an SSRI, did not remit.

Kristian Dambrino, MSN, APRN, PMHNP: And, really, that's pretty profound to think about. When I'm thinking about medications, I'm choosing and also just discussing realistically and, like you said, helping because there's a lot of guilt in depression. A lot of these patients come to me and if they have not had success on the medication regimen, they feel guilt. They do take that responsibility. They think that there's something wrong with them. And it really is—it moves me because they will get emotional talking about it. If they feel comfortable, ideally safe enough to express that emotion, they will start crying in the appointment. And they'll say, “I just—I feel like there's something wrong with me.” And it is—I think that's why we are seeing the discussion around depression changing so much, which is wonderful. That we’re not, that the language is not placing responsibility on the patient.

Craig Chepke, MD, DFAPA: Yeah, and so, you brought up STAR*D, and that's one way in which we got the definition of TRD that we're currently using. And also, I like monoamine-resistant depression or monoamine reuptake resistant depression, something like that, because that's usually what we're more referring to. But walk us through why two antidepressants? How did they get, extrapolate that from STAR*D with successive treatments?

Kristian Dambrino, MSN, APRN, PMHNP: So, the way the trial is set up is that patients or participants were put on an SSRI to begin with. And that was citalopram, correct?

Craig Chepke, MD, DFAPA: Yep.

Kristian Dambrino, MSN, APRN, PMHNP: Okay. So they were put on citalopram in the first trial. If they didn't respond to that or if they did not have a successful response in the trial, they were then put on another medication. And then, with each, it was a stepwise treatment, the way that the trial was set up. So, they would either be put on the medication as adjunct or maybe CBT as adjunct. And the design of the trial was meant to mimic real-world practice. But, are you asking specifically how the trial, why did we get two?

Craig Chepke, MD, DFAPA: Exactly. Why'd they cut it off at two? Why not one, why not three? Why not four?

Kristian Dambrino, MSN, APRN, PMHNP: I actually don’t—I actually have forgotten that information.

Craig Chepke, MD, DFAPA: Yeah, so what it is, is that if you look at those remission rates, like you mentioned. That going from step one to step two, that was a little bit of a decrease in the remission rates. But, it was from step two to step three that there was a precipitous drop off.

Kristian Dambrino, MSN, APRN, PMHNP: Right.

Craig Chepke, MD, DFAPA: That it went from the mid to high twenties down to about 14%. So, it was over 50% reduction in the remission rates and down to 14 and 13%. And so, that's why, because you get really diminishing returns as sharp drop off of the remission rates after step two. And then, also with each, its successive step though, increasing rates of intolerance due to adverse reactions. So, there's diminishing returns in terms of efficacy, but definitely a lot more intolerability. And that's why they put the cutoff at two because you're not getting much more bang for your buck. If you continue to switch, continue to add amongst the traditional treatments that we had in the past, you're really not getting more efficacy for the patient. So, it's a really critical juncture when someone's been on two antidepressants unsuccessfully, what do we do? So, I usually talk about it like that they're standing on the edge of a cliff. And we as providers have the opportunity to reach in and pull 'em back from that cliff. Or if we continue to do the same thing that they've been unsuccessful with over and over again, in effect, it's like shoving 'em off of that cliff.

Kristian Dambrino, MSN, APRN, PMHNP: Right.

Craig Chepke, MD, DFAPA: And so, we've got to really be aggressive after those two antidepressants in that same depressive episode or else our patients are probably not going to get better, I believe.

Kristian Dambrino, MSN, APRN, PMHNP: I have a question for you actually for clarification, because you're talking about two antidepressant trials with vagus nerve stimulation. And I know we may talk about this later. But, vagus nerve stimulation, when that was FDA approved, the way that they were talking about at that time, and I want to say it was in 2005, well, I think it was 2005 because that was also the same year that I won Miss Mississippi, so it's easy to remember. But, in 2005, they said they were referring to treatment-resistant depression as four failed trials. Is that correct, or do you remember that information? And why was that? Why was it four? I mean, I can posit kind of why that would be. But, why do you think that was?

Craig Chepke, MD, DFAPA: Well, a couple answers to that one. One is that there is no one universally accepted diagnosis or stipulation for what is TRD. Mostly, the consensus has aligned with two trials. That's the definition that the US FDA has accepted. But there are other groups and other lines of thought, which reasonably so. We'll talk about different numbers of trials stipulating what agents have to be tried, does it have to be from different classes, same class, so on and so forth. And also, so that's one answer. And another is just that for a surgical intervention like VNS, then there should be a higher bar. It's not just another medication, it's a surgical intervention that has a greater degree of potential risk and harm to the patient. And so, therefore, I wouldn't want to jump to VNS too soon. I don't want to wait too late either. But I think four, for that, for those purposes, is a reasonable balance between not waiting too long, but making sure that they are getting treatment with something efficacious sooner.

Kristian Dambrino, MSN, APRN, PMHNP:
Yeah. The other question, which is because honestly the topic of depression is, you know, we've talked a lot about how it looks different in everyone. When you're talking about from a population standpoint or a demographic standpoint, age is what I'm thinking of. When you're working with adolescents versus maybe someone who is in their sixties or older, how do you approach the assessment and treatment of depression differently? Or do you? I'm curious. I think every clinician is also, as we talk about heterogeneity in depression, there's heterogeneity in clinicians as well. And so, I think that's why I have so much empathy for patients in seeking care and knowing where to go. But for you, how do you approach that? Or do you approach that differently depending on who you're working with?

Craig Chepke, MD, DFAPA: Well, it's still very individualized. Maybe a couple things I might pull out, and we're a little short on time, but I'll make it kind of high level, is that someone later in life, is it that they have—they had major depressive episodes throughout their life, and this is yet another one, or is it a new onset? Because if it's a new onset of someone who's later in life, at, say, 60, 70 years old, that's going to trigger a different thought process. I might be thinking, okay, if this is their first major depressive episode, is this something like a prodromal phase for a neurodegenerative disorder, Parkinson's disease, Alzheimer's disease, et cetera? Whereas obviously I'd be less likely to think that for a younger adult or obviously for an adolescent. So, that's one thing I would think about. If they've had it throughout, then probably they've been on a lot of different treatments, and I want to take into account what have they tried, what worked, what didn't work, what were the good things, what were the bad things about the medications?

Craig Chepke, MD, DFAPA: Someone earlier in life, they’re less—again, you mentioned earlier, we have to rule out bipolar disorder. And so, someone earlier in life, well, they're less likely to have had a manic episode than someone later in life. So, if someone is coming in with a history of major depressive disorder at age 65, 75, and they've never been found to have a manic episode, less likely that they're going to have bipolar disorder. Now, it's possible it's been missed for all those years and decades. I have seen that before where it was very clear that the individual who in their 60s or so actually had bipolar disorder, just no one ever diagnosed it—lack of access to care, or stigma, things like that. But, more often, bipolar would've declared itself by then. But in an adolescent, probably not. And you can't diagnose a manic episode that hasn't happened yet. So, being very cautious and, therefore, educating the individual and their family about the potential risks and obviously the boxed warning for all medications with antidepressant efficacy. So, those would be a couple of the things I would highlight. But we could go into a ton of different things, but I think we're going to have to wrap this up here for time purposes, unfortunately. So, thank you for joining me today, Kristian. And thank you for our audience and look forward to seeing you on a future episode of the Great Exchanges in Mood Disorders.

Kristian Dambrino, MSN, APRN, PMHNP: Awesome. Thank you so much.