Addressing Unresolved Symptoms of Major Depressive Disorder

Join us to watch speaker Brooke Kempf cover how dysfunction of the three major monoamines (norepinephrine, serotonin, and dopamine) plays a role in MDD pathophysiology, focusing on norepinephrine. The presenter will describe the unresolved symptoms and their impact on patients with MDD.

Shivani Kapadia, PharmD:  Hello. Thank you for joining our webinar today with Ms. Brooke Kempf. Ms. Brooke Kempf is a psychiatric mental health nurse practitioner at the Hamilton Center in Terre Haute, Indiana, where she provides patient evaluations, diagnoses, and medical management for mental illnesses. 

Over her 28 years at Hamilton Center, Ms. Kempf has held a variety of positions, including inpatient and outpatient services, chief nursing officer, and currently works as the hospitalist for their psychiatric inpatient unit. She is also an adjunct faculty member and a clinical coordinator for IUPUI's psychiatric mental health nurse practitioner program.

She's passionate about providing education to others. Ms. Kempf was a recent recipient of the DAISY Award for Extraordinary Nurses by the Daisy Foundation. The award honors nurses who are professional, dedicated, clinically skillful, sensitive, comforting, genuine, courageous, and most of all, compassionate. I'm pleased to introduce Ms. Brooke Kempf.

Brooke Kempf, MSN, PMHNP-BC:  Thank you, and thank you to everyone out there for joining us today in addressing unresolved symptoms of major depressive disorder, or MDD. Just as a reminder, today's program is brought to you by Otsuka Pharmaceuticals and Lundbeck. I am a paid presenter on behalf of Otsuka and Lundbeck, and I do get paid to give you this presentation today.

My name is Brooke Kempf. I'm a psychiatric mental health nurse practitioner at the Hamilton Center, which is a community mental health center located in Terre Haute, Indiana. In addition to doing clinical work here at our community mental health center, I also teach for Indiana University and their psychiatric nurse practitioner program.

But again, today I am very, very happy to be here to talk to you about those unresolved needs in major depressive disorder on behalf of Otsuka and Lundbeck. Just for your information, here are my disclosures against advisory boards and the speaker bureaus that I do speak for.

So let's jump right into what we want to focus on today. We're going to try and understand why it is that so many of our patients with major depressive disorder continue to experience unresolved symptoms following first-line treatment. We also want to understand why, even though we know serotonin and dopamine are important monoamines, let's not forget about norepinephrine, and norepinephrine dysregulation also attributing to those unresolved symptoms of major depressive disorder.

We're going to discuss the role of three classes of noradrenergic receptors on neuronal activity and learn how adjunctive, atypical antipsychotics, or you will hear us refer to as AAPs in this program, may improve MDD symptoms by addressing dysregulation of the norepinephrine system in addition to dopamine and serotonin.

So what we know from STAR*D trials, and I will try and say I don't want to emphasize the “as you know,” or “as you might remember,” because STAR*D has been around for a while. There may be some of you that aren't quite as familiar with this study, but what we learned from STAR*D were that individuals that had first-line treatment of major depressive disorder, what you'll see here, two out of three patients after that first-line treatment continued to have unresolved symptoms following treatment.

What you'll also notice, so you'll see there, our goal for treatment of major depressive disorder is always to treat to remission. We should always be chasing that as our ultimate goal with major depressive disorder. We cannot get comfortable with residual symptoms being around. It's not good for our patients and it should not be what our ultimate goal is.

What you'll see after first-line treatment, only 33% of individuals actually achieving remission. And then if you look at the majority then of patients experiencing mild, moderate, severe, and very severe symptoms, actually about 40% of those, their symptoms are moderate, severe, or very severe. So we're not talking about just some lingering symptoms continuing. We still have 39% of those experiencing moderate and severe symptoms.

That is not acceptable within our career. If we were treating any other medical kind of diagnosis, we would not be okay with a little bit of infection lingering around. We would not be okay with a little bit of cancer lingering around. Therefore, we do not want to continue to be okay with a little bit of depression lingering around.

When we talk about unresolved symptoms, what is it that we might be referring to? What you see here when we're looking at a three-year follow-up study, looking at what types of symptoms continue to be present after antidepressant therapy, you'll see listed here in multiple different colors everything from cognitive problems. It doesn't really differentiate between depressed mood and diminished interest, but that's listed here. Lack of energy, sleeping problems, feelings of guilt, worthlessness, eating problems, psychomotor problems, and suicidal ideations or death ideations.

What is interesting, if we look even a little bit further here, we'll notice that the top symptoms that continue to linger are cognitive problems, lack of energy, sleep problems. Think about what a continued vicious cycle that can be. If you have your symptoms, you've gone into your provider, you're requesting treatment for your depression, but you still can't think really straight, well then at night, you're not sleeping well. So of course you're going to have lack of energy the next day.

And then again, when you don't sleep well, you have more cognitive problems. So think of that vicious cycle of not only those separate symptoms lingering, but how they're all going to attribute to each other and think about how that affects somebody's outcomes. That can lead to poor functional outcomes, more chronic depressive episodes. Think about if you are tired and you're not thinking well, you can't make decisions as well as you used to. That's going to impair your work, and think about how that could then cause economic burden on you. You're not able to work like you used to. Maybe you're missing days, maybe even losing a job because of some of your symptoms.

Well then that can also lead to relationship problems. They can happen in any order, I know, but if we think about how just identifying those specific symptoms and how those can impact a patient's day-to-day functioning, those are not the outcomes that we want for our patients.

So let's talk about monoaminergic dysregulation in major depressive disorder and take a closer look, particularly at norepinephrine. What we want to do is we want to understand each one of these monoamines. We are somewhat familiar with serotonin and its role in depression. What you'll notice here are some specific symptoms related to serotonin and its dysfunction.

When you have a dysfunction of dopamine, there you'll see a couple of the symptoms related to dopamine dysfunction, but you'll also see the overlap of things like mood and impulsivity that can occur with both of these. We'll take a little bit deeper dive into those and talk about what we want to really hone in, on matching symptoms to the monoamine. Because that helps us make better decision-making when it comes to choosing medications for our patients. If we can try to understand where some of those symptoms might be coming from, we're able to make a better decision when it comes to choosing a treatment option with our patient in mind.

So let's first look at serotonin dysfunction. So you'll notice here the serotonin starting from the raphe nuclei going pretty much throughout the brain. So we're talking about all these different areas that are involved with serotonin, but what happens when there's dysfunction? What type of symptoms do we see in regards to mental health problems or major depressive disorder? Anxiety, mood problems, aggression.

If you look at the specific receptors, you'll see there 5-HT1A, a lot of our medications are targeted to that serotonin 1A receptor. But you'll see there are a lot of other serotonin receptors that we need to be thinking about whenever we're looking at the context of treatment. But keep in mind these specific symptoms that can be correlated with serotonin.

Let's move on then. Our next one is dopamine and the dopaminergic system dysfunction. So if you look at dopamine and where it is going throughout the brain and we think about what symptoms are specifically correlating with dopamine dysfunction, pessimistic thoughts, sadness anhedonia, impulsivity, reckless behavior. You'll see the five different dopamine receptors divided down here, but you'll notice the target going to D2 and D3, a lot of medications targeting those receptors. But again, just keeping in mind some of the symptoms that are associated with dopamine dysfunction.

Moving on then, looking at a whole picture, again, correlating and seeing the overlap in some of those symptoms. What are we missing? What are we wanting to talk about a little bit further? Norepinephrine. When we look at the noradrenergic system dysfunction, it can also contribute to unresolved symptoms of major depressive disorder, and you can see how it's going to overlap with some symptoms with both serotonin and dopamine.

But then we have those that are specifically related to norepinephrine. Think about what we said, those lingering symptoms of depression even after first-line treatment. Think about where that correlates with energy, concentration, agitation. So again, when we're targeting treatment options, we want to think about where that dysfunction could correlate.

Whenever we look at norepinephrine, norepinephrine is one of the major monoamines that may be related to wakefulness, energy levels, attention, behavior-related agitation, irritability, aggression, fear. We know a little bit about norepinephrine and that fight-or-flight response. So what you'll see here listed on this graph are the norepinephrine concentrations during different level of behavioral states. Being very low during sleep, minimal interaction with the environment.

But you'll notice as the alertness increases, you can see how the levels of norepinephrine do. You have the relaxed interaction, you're kind of quiet, you're awake but not really interacting. But then notice how norepinephrine levels going up, actively awake, significantly interacting with the environment, and then to the extreme, that fight-or-flight response.

So let's again look at some specific symptoms of when it comes to noradrenergic system dysfunction. Low energy, concentration difficulties, somnolence, agitation, irritability, insomnia. What you'll notice here are the alpha-1, alpha-2, and beta receptors. We're going to dive a little bit deeper and look how these correlate with those symptoms and symptom management and also target of some medications.

So let's talk about dysregulation of noradrenergic system associated in a wide variety of psychiatric symptoms, not just major depressive disorder. Let's look first at what might be associated with low levels of norepinephrine. So low levels causing somnolence, that difficulty concentrating, low energy. And then we have the opposite end of the spectrum when there are high levels of norepinephrine, agitation, insomnia, hyper arousal. So thinking about how the adrenal receptors can modulate symptoms, we want to a balance of this rather than dysregulation. We want a balance. Not too much, not too little.

So let's talk about the localization. When it comes to norepinephrine, think about that whole fight-or-flight response. The way that we were made, the role that norepinephrine plays in that autonomic nervous system along with our central nervous system. It doesn't just concentrate in the brain. You think about different areas of the body, the lungs, the heart. Let's look at how these are expressed in different areas.

So we'll see that when it comes to norepinephrine, adrenal receptors, they're broken down into alpha-1, alpha-2, and beta receptors. You'll see they have further subclasses going into a1A, a1B, a1D, and furthermore. Let's first look here at the alpha-1 receptors. These are mainly postsynaptic and they are excitatory. I always think about my finger, the number one, pushing a button, causing a reaction. So I'm thinking excitatory, causing something to happen.

Whenever we look at alpha-2, these can be both presynaptic and postsynaptic, but they're more inhibitory. I always use my two and the peace sign. A little bit more peaceful, inhibitory. That's just how I correlate these within my brain. But remember, they can function as auto receptors to inhibit norepinephrine release. Rather than excitatory, these could inhibit the release. So those are the differences between alpha-1 and alpha-2.

Thinking about that response in fight-or-flight, sometimes we need our lungs to relax so we can get better breath, but then also maybe we need our heart rate to get up so that we're ready to respond to what's dangerous. So there's different reasoning behind some of this and the way that our brain works with our body and these receptors. When it comes to the beta receptors, these are predominantly post-synaptic and typically excitatory.

Taking again another deeper dive into this and looking at the impact of alpha adrenoceptor antagonism. This can depend on the level of norepinephrine activity. So if we talk about alpha-1, whenever it comes to alpha-1, it is not engaged when there are low levels of norepinephrine. What is engaged are alpha-2. So when you think about selective alpha-2 adrenoceptor antagonism, what that's going to do is work to increase norepinephrine levels.

How does that work? How is it if we're antagonizing something and blocking it, how does that increase levels? Well, remember this is more inhibitory, so it is stopping that release of norepinephrine. So if we are to block that inhibitory response, then our levels can actually go up.

What about on the other side of things? When norepinephrine activity is hyperactive, that is when alpha-1 receptors are engaged, and our alpha-2, they're desensitized due to prolonged exposure. So if you have selective alpha-1 adrenoceptor antagonism and you're blocking that excitatory, then what that can actually do is block the action of excessive levels of norepinephrine.

So you can see by blocking both in these, the antagonism, whether it be alpha-2 receptors or alpha-1, you could obtain a balance of norepinephrine based on if it is too low or if it is too high.

So where does that fall within our treatment considerations? Why do we need to know about that and how we are choosing medications? Let's look a little bit closer at this meta-analysis, looking at efficacy of second-line treatments for major depressive disorder. So as providers, we have a patient we have started on first-line medication and they come to you and they're like, "You know what? You gave me this medication. I'm not responding. What do I do?"

Some individuals may think that, well, I need to increase the dose. Maybe the dose is not high enough. Remember what this is saying to an individual that is not having a response. There's initial non-response. Studies suggest in that case, dose escalation after initial response may not be particularly effective.

What about switching? Okay, my first medicine didn't work. It was an antidepressant therapy that I chose. It didn't work. What about I choose a different antidepressant? Studies have shown similar efficacy between switching antidepressant therapies and continuing with the current. So whether you continue or you switch, the efficacy seems to be similar.

If we look at combining antidepressant therapies, we're looking at the evidence supports improvement over monotherapy. So we're looking at augmenting with antidepressant therapies. Data suggests that switching antidepressant therapies is frequently ineffective, whereas combining antidepressant therapies with different monoamine profiles may be more effective. So when you're augmenting rather than switching or increasing the dose, you're again, remember each one of those have, those monoamines having specific areas that are related to each of those symptoms of depression. If we can use adjunctively those treatments, we can target in on those monoamines more effectively.

So where are our practice guidelines and what do they recommend? What you'll see are the different types of adjunctive treatment we have considered using as providers. We have antipsychotics, mood stabilizers, benzodiazepines, psychotherapies. And then these are our bodies of evidence here looking at APA, NICE, BAP. We're looking at the different individuals that are going to give us recommendations. And what you'll notice, top line there, the antipsychotics, four out of five of these bodies recommended this with substantial evidence to show that these would be effective in your treatment.

Whereas the other mood stabilizers, benzodiazepines, now what you do see, psychotherapy, it did have three out of the five also. So again, looking though at this evidence, substantial, moderate, low evidence or none, antipsychotics do, across the board here, support it with more substantial evidence.

What about response and remission rates? Again, response is good, but our goal is to get individuals to remission. So response and remission rates of augmentation with atypical antipsychotics, antidepressant therapies, monotherapy and augmenting with DNRIs. So patients, this is a 12-week follow-up of randomized control of over 1500 patients with major depressive disorder. Patients with unresolved symptoms were separated into three treatment groups. They were either switched to a DNRI, they augmented their antidepressant therapy with a DNRI, or they augmented their antidepressant therapy with an atypical antipsychotic, or AAP.

What you'll see with the response rates and the remissions rates, augmentation with an AAP was superior in response and remission rates compared to the other two groups. In this meta-analysis of 11 randomized control trials consisting of over 3000 patients with major depressive disorder, AAP augmentation showed superior efficacy compared to monotherapy, and the effect size was actually positive correlated with the severity of treatment-resistant depression.

So you'll see there everything from non-treatment resistant down to two to four trials of antidepressant therapies, and you'll see that that severity of treatment was positively correlated with the AAPs.

So let's look at the impacts of the alpha adrenoceptor antagonism and depending again on the levels of norepinephrine activity. So again, during times of hypoactive norepinephrine activity, the alpha-2 receptors are engaged, this time, going into a little bit further, another subclass of the alpha-2 receptor, alpha-2C has high affinity during times of hypoactive norepinephrine levels. Again, because alpha-2 being more inhibitory, when you are antagonizing that, you could then increase norepinephrine levels.

Again on the vice versa side, going a little bit further in the subclass, alpha-1B is engaged whenever there are hyperactive levels of norepinephrine and antagonizing alpha-1B could actually block the action of excessive norepinephrine levels and decrease that. So again, targeting in on these receptors with antagonism to get a balance of your norepinephrine.

When it comes to choosing a medication option, what's really important for us as providers to know are the mechanisms of actions of each medication. And what you'll see is each one of these medications have different binding affinities to different receptors. It's important for us to know that binding affinity when we're really trying to target in on symptoms.

You'll see across the board here, these are the affinity profiles of AAPs, and you'll notice each one of those are different. So even though we may say there are atypical antipsychotics we can use adjunctively for the treatment of major depressive disorder, particularly for individuals that have not responded well to first-line therapies, not one medication fits all. Each medication is different in one way or another. Important for us to learn how each of those work differently.

How do we consider augmentation with atypical antipsychotics? Of course, there are going to be advantages and disadvantages. So what could the potential advantages be? They can maintain the therapeutic benefit of first-line agents. So if you're getting a response but not enough, we're getting a response but we're not getting to remission, we can add an atypical antipsychotic and continue to get the benefit that we had from that initial antidepressant therapy and hopefully improve that even further.

We can enhance the antidepressant effect, hopefully increasing remission rates. We can avoid withdrawal symptoms due to switching. So if you start one medication, you switch over to another, you may have withdrawal symptoms during that time of cross titration or stopping and starting. And whenever it comes to counteracting antidepressant therapy side effects, sometimes during that switch, you're also dealing with side effects. And then also maybe this can help with some of the side effects that patients are experiencing during that time.

Certain AAPs target three MDD-related monoamines. So remember we talked about dopamine, serotonin, norepinephrine, three monoamines that all can work together somehow, specifically targeting individual symptoms of major depressive disorder. In utilizing an antidepressant therapy augmented by an atypical antipsychotic, you can address all three monoamines.

Atypical antipsychotics act synergistically with reuptake inhibitors. When it comes to potential disadvantages, these are atypical antipsychotics. That's going to add another pill. If individuals are concerned about pill burden, they don't like the idea of, “Ugh, I don't want to take another pill every day.”

We also have to be concerned possibly about other potential side effects. All medications have side effects, and we're talking about newer and different side effects when we're talking about adding an atypical antipsychotic, something for us to continue to educate our patients on, talking about potential risk and benefits.

There's also a huge stigma related not only to mental health problems, hard enough to ask for help with major depressive disorder, let alone when you offer your patient an antipsychotic medication, they might kick back and say, "Why do I need an antipsychotic? Do you feel that I'm psychotic? Do you feel that there's more wrong with me than I even thought?"

There's this stigma, even that name sounds a little bit scary to patients. So we need to approach that carefully and educate them on how we're using this as an adjunctive treatment. When it comes to the importance of monoamine neurotransmitter systems in unresolved symptoms of major depressive disorder, serotonin and dopamine have established roles in MDD symptomatology. When it comes to several common unresolved symptoms in MDD, they can also be associated with norepinephrine and norepinephrine’s dysfunction.

Some studies reported that augmenting with AAPs was actually more effective than monotherapy, more effective than switching antidepressant therapies, or combining antidepressant therapies. Some AAPs target multiple monoamine receptors.

So in summary, following first-line treatment, many patients with major depressive disorder continue to experience unresolved symptoms. Symptoms of major depressive disorder may be related to hypo or hyperactive norepinephrine systems. Antagonism at alpha adrenoceptors may help regulate norepinephrine levels in appropriate ranges.

Norepinephrine signaling is mediated by three classes of noradrenergic receptors that differentially modulate neuronal activity. Augmentation with AAPs may target several monoamine neurotransmitter systems and improve symptoms related to monoamine dysregulation.

And that concludes our program today. I want to thank everybody for taking your time to wanting to learn more about these unresolved symptoms of major depressive disorder.

October 2023    01US23EUP0075