Round 2: Which clinical manifestations determines your approach?

In the second round, our speakers  will debate whether MDD is a neurotransmitter or neural network disorder, addressing specific issues related to the diagnosis and treatment of MDD. This will be an opportunity for the experts to strengthen their arguments and clarify their positions on key issues.

Debate Transcript:

Charles Raison: So for this round, we're going to start with Dr Maletic again. So Vlad, you are on for your opening argument.

Charles Raison: So for this round, we're going to start with Dr Maletic again. So Vlad, you are on for your opening argument.

Vladimir Maletic: Thank you very much, Chuck. Of course, there are some symptom domains in major depressive disorder which are crucial from the perspective of functioning. And one of those symptom domains includes cognition. Another one includes anhedonia. And the third very important symptom domain includes suicidal ideation. So let's see what's going on with the monoamine-modulating antidepressants. There are studies looking at the processing speed using digit symbol substitution tests, evaluating a number of different monoamine-modulating agents. As Greg has pointed out, they do have different mechanisms of action; that is absolutely a valid argument. And none but 1 actually seemed to enhance cognition. As a matter of fact, most of them were detrimental when it comes to cognition.

Now, I must admit, when it comes to glutamate-modulating agents, data supporting improvement in cognition are relatively sparse. So there are only, I tried to find controlled studies, there are only 2 or 3 studies that indicate that using good neurocognitive batteries, we can actually appreciate improvement in cognition with NMDA antagonists. There is really not much data about neurosteroids and improvement in cognition. I also have to admit that when it comes to NMDA antagonist, in the first 2 hours, there may be actually decline in cognition. Looking from the safety perspective, cognitive decline is not noticeable 2 hours later, and it's not noticeable the next day. But again, we do have 2 studies actually looking at a more long-term effect in improvement in cognition with these glutamatergic agents.

When it comes to anhedonia, data are not as robust as we would like it to be. But indeed, there are clearly studies with IV ketamine showing improvement in anhedonia. So it is very consistent finding. Again, not many studies, but few that exist show improvement in anhedonia. I would say the most robust argument is when it comes to suicidal ideation. So we do have studies with intravenous ketamine, these are NIMH studies, where patients have actually been very gradually titrated off their monoamine-modulating antidepressants. So these are not adjunctive treatments. This is just plain IV ketamine. And the outcome is that there is a rapid reduction in suicidal ideation that is noticeable day 1. So it is something that is without a doubt. Again, we don't have as much data when it comes to modulation of GABA-A receptors.

But I do want to remind you that there is no monoamine antidepressant that does not have a suicidality warning associated with it. So we are reminded that in patients, either late adolescence and early adulthood, younger than age 24, there is an increased risk of suicidal thoughts and behaviors. Again, this is in contrast with medications such as ketamine and NMDA-modulating agents. Now, Greg can make a very valid argument and say, look, this warning is associated with esketamine. And indeed it is, but for historical reasons. It is not because it has been there in the studies, it is because it is a class warning.

So I would say that in certain domains such as cognition, such as psychomotor retardation, anhedonia, and particularly suicidal ideation, there is clear class differentiation between these two families of agents.

Charles Raison: And with you suggesting that non-monoaminergic agents are superior across those categories in general-

Vladimir Maletic: I would say they have more consistent data. Because when it comes to monoamine-modulating agents in anhedonia, again, a pair of notable exceptions. And when it comes to cognition, same. Exceptions, but as a rule, they don't help cognition, they interfere with cognition. And when it comes to anhedonia, they really don't help much with anhedonia, they actually may make it ... well, at least emotional numbing, flattening tends to accompany most of monoamine-modulating agents. Again, there are a pair of exceptions in this scenario, but as a rule, not very helpful.

Charles Raison: Okay. Greg, your opening statement.

Greg Mattingly: Certainly. So Vlad, once again, articulate as always, but I think he forgot half of the argument. The exceptions that do improve cognition are in the monoamine class. The only antidepressant that has in its package label that it improves processing speed. I was a part of those trials. We have somebody sit down and we measure them over the course of their treatment of depression. And we say over 90 seconds, how many problems can you do? The only agent that has that in its package insert is a monoamine antidepressant, vortioxetine. So by hitting specific monoamine receptors, by being a multimodal agent, vortioxetine was able to improve processing speed, working memory, digit symbol substitution, in adults and older adults struggling with depression.

Beyond vortioxetine, 2 other monoamine antidepressants have been shown to at least have some improvement in cognition. The next one would be duloxetine, which has been shown on several studies to help with various aspects of memory and memory retrieval. And then among the SSRIs, the one that seems to have the best benefit would be sertraline. Because a metabolite of sertraline, D-sertraline, actually has dopamine reuptake properties. As Vlad now, I've written a review article about this that was published in postgraduate medicine, where we ranked medicines based on their ability to improve cognition and depression. At the top was vortioxetine. After that came, duloxetine. After that, you may think about bupropion, you may think about stimulant augmentation. Nowhere on that list did we see GABA glutamate.

Now, when we think about the GABA glutamate drugs, as Dr Maletic knows, they all have warnings about cognition. This new group of GABAergic medications are sedating, they have to be given at night. They're going to have warnings about be careful with cognition. For anyone who's used esketamine, we know that we have to watch people during the treatment course of those 2 hours because of concerns about cognition. But we also know they can't drive on the day they've had a treatment because of concerns about cognition. So when we look at the place to go where the data shows us that we have improvements in cognition, it's our multimodal, vortioxetine. It would be duloxetine because it affects the serotonin and norepinephrine. It would be sertraline because of its metabolites effects on dopamine.

Two other areas that Dr Maletic brought up that I think are really important when we think about holistic improvement of depression—the next would be anhedonia. Anhedonia feeds into reward, motivation, and drive. And we know one of the biggest issues right now when it comes to depression is depression isn't just feeling sad, but depression can be disabling. It can rob us of our reward, our motivation, our drive. And this term called anhedonia, do I experience pleasure? We know it's a key predictor of reward, motivation, and drive. Once again, we have an agent that's been shown in multiple studies done around the world to actually help with anhedonia in patients struggling with depression, and that would be vortioxetine. Vortioxetine has been shown on studies with various depression scales specifically targeting anhedonia, reward, motivation, persistence with a difficult task, to move the needle in those patients where reward, motivation, and drive has been damaged by their depression.

Finally, when we talk about suicidality, suicidality is something we always have to keep in mind when treating depression. And what we know is, from nationwide studies across the United States, across Europe, across Australia, that as we use more monoamine antidepressants, we tend to decrease suicide rates. Unfortunately, in communities that have underserved mental health, where they have decreased access to monoamine antidepressants, we see suicide rates spike. So in my own community here in Missouri, Chuck, if we go outside of St. Louis and go to rural communities where they're underserved from a mental health perspective, they have lower use of antidepressants, we see higher rates of things like teenage suicide.

So I think Vlad's 100% right, cognition is vitally important. Anhedonia with reward, motivation, and drive, that's two places where vortioxetine in particular stands alone among our antidepressants. And then moving the needle for our patients that are struggling with suicidal thoughts, which we know from a nationwide perspective that treatment of depression with these classic antidepressants has been a benefit to our patients.

Charles Raison: Okay. Vlad, you get you the first rebuttal.

Vladimir Maletic: I think that Greg is making a great point, I agree with everything that he has said. But I think there is a keyword there, and that keyword is exception. So when it comes to impact on anhedonia, when it comes to impact on cognition, vortioxetine is an exception, not a rule. And we're debating antidepressant classes, not single agents. Yes, it is one of the 20+ that does confer these benefits. How about the remaining 19+ or 20+ that don't?

So when it comes to anhedonia, I'm not aware of any study that has looked at the impact of ketamine on anhedonia that has not found a benefit. On the other hand, we can't also ... when it comes to esketamine, we can't say that it doesn't have an impact on anhedonia, because there are no data. So absence of evidence is not evidence of absence. It also does not confirm that it does have an anhedonia effect. But again, based on ketamine data and based that it's a very similar mechanism of action, I would postulate that that would be the case.

When it comes to cognition and glutamatergic agents, yes, the warning is there. But impairment in cognition, please keep in mind, 2 hours; 85% of the patients have no cognitive issues after 2 hours, and none of them have cognitive issues the next day. And there are data in the long-term looking using neurocognitive battery, what happens with cognition? And cognition gets better. So when it comes to suicidality, yes, I would agree with Greg. He's making an excellent point. We have to differentiate between the class warning and real life.

And I would agree with Greg that monoamine-modulating antidepressants are helpful when it comes to suicidal ideation, long term. But on the other hand, if patients are really struggling with intent, do any of them have indication for suicidal ideation with intent? On the other hand, esketamine is indicated for MDSI. This is for patients who are depressed, struggling with suicidal intent. And it's a major depressive episode. This is not TRD. In the studies. It didn't reduce suicidal ideation robustly in the short term, but it did reduce depressive symptomatology in those individuals.

And by the way, I like that Greg likes to stick to the evidence and indication. That's the only antidepressant that is indicated for major depressant episode with suicidal ideation.

Charles Raison: Okay, Greg. Your chance to rebut the good Dr Maletic here.

Greg Mattingly: Vlad makes many key points that are obvious, that are important for our patients. Let’s visit one of his points. Esketamine, the major depression with suicidal ideation study. That study ... I've done many of the esketamine studies. As Vlad knows, it didn't improve suicidal ideation. In that study, patients had to be hospitalized to keep them safe, to make sure they didn't attempt suicide. We know that study also allowed monoamine antidepressants and other augmentation strategies. And even with that, we were able to show we improved depression, but we weren't able to show that we actually moved the needle on suicidal ideation.

When we come back and step back and think about one of the agents that Vlad did note is an exception to the rule, it would be vortioxetine. Vortioxetine, when we talk about its effects in the brain, it's a very interesting molecule. The original patent for vortioxetine said that by stimulating serotonin 1A and blocking serotonin 3, we do something novel we've never seen in the brain with other antidepressants. We raise acetylcholine. We raise acetylcholine in the prefrontal cortex and the hippocampus. That's what led to the studies looking at the cognitive improvement associated with vortioxetine.

So remembering a monoamine strategy is not a one-size-fit-all strategy. Vortioxetine is very different than bupropion, which is very different than an SSRI, which is entirely different than a psychedelic or an atypical antipsychotic. When we take a look at some of the other roles when we think about our monoamine antidepressants, when we look at anhedonia, some antidepressants do have baggage there. I agree with Vlad. That's a place where you want to know your literature. So unopposed increases of serotonin by themselves may not always help with emotional blunting, but we have agents that we know do help with anhedonia. We know that agents that modulate dopamine, another monoamine, tend to help with anhedonia.

Vortioxetine, as Vlad knows, has been widely studied in many studies. I've been a part of a study called the RELIEVE Study, which was a global study looking at real-world clinic populations such as ours. Complex, comorbid, difficult patients that had things like obesity, diabetes, cardiopulmonary disease, comorbid other psychiatric conditions. And we were able to show that we moved the needle on function, disability days, presenteeism, showing up to work and being motivated to be at work. Quality of life, where I looked forward to my life, because I didn't feel like there were holes in my life.

So when we think about the role of monoamine antidepressants, once again, it's not a one-size-fits-all. We have a variety of treatment options. And the exciting part of what we're doing right now is all of the different ways that we can modulate this monoamine system within our neural networks.

Charles Raison: Yep. Very well said. Very well said, Greg. Okay. Vlad, it's your closing argument. Want to summarize the-

Vladimir Maletic: It's going to be very short. Again, I think that Greg's response is very thoughtful. It is very studied, it's very eloquent. I would just remind that, again, the best example of monoamine modulation enhancing cognition and enhancing ... well, improving symptoms of anhedonia, is vortioxetine. And I agree with Greg that it is presumed to be related to serotonin 1A modulation and serotonin 3 receptor antagonism. He did point out that there is increase in cholinergic transmission as a consequence.

There is something that Greg did not highlight—there's also increase in glutamate transmission. And how was increase in glutamate and acetylcholine transmission achieved? Well, it's pretty easy and, frankly, fairly obvious. The only location of serotonin 3 receptors in the prefrontal cortex is on GABA interneuron. So we're actually modulating GABA interneuron. We are decreasing GABAergic transmission and therefore increasing glutamate and cholinergic transmission. And that is the most notable exception. And it is downstream. What it does is increase glutamate, increase acetylcholine.

What I'm saying, there are shortcuts. We don't have to walk around the block to get to our back door. Glutamatergic interventions may be able to do so even without modulation of monoamines. And frankly, most of the agents that modulate monoamines do not show benefit when it comes to cognition. And frankly, don't show benefit when it comes to anhedonia.

Charles Raison: Well said. Okay, Greg. He's suggesting that at the end of the day, the monoamines are just roundabout ways to get to this more direct GABA glutamate stimulation.

Greg Mattingly: I would 100% agree with Dr Maletic that our neural networks are interconnected. This is not a one system works alone, it's all of our systems working in concert. But we have historical data going back 50 years that modulating monoamines can improve the symptoms of depression. We now have really exciting data that by hitting specific receptor subtypes for monoamines, we can improve specific symptoms of depression. We can move the needle on cognition with processing speed. It's now a part of the package insert for vortioxetine. We can move the needle with atypical antipsychotic augmentation, which isn't raising the level of chemicals. We're directly hitting those receptors from day 1 to help people with residual, or what I think of as stubborn, depression.

We can move the needle hopefully in the future, Chuck, with a group that I know you're very excited with, the psychedelics that modulate serotonin 2A. They have a rapid response on our depression. So systems aren't isolated, they work in combination. But we know that around the world, the first-line agents that are recommended is the monoamine treatment agents, where we have a variety of treatment options to meet the needs of your patients.

Charles Raison: All right. Well, thank you both. This whole debate really highlights these really key issues. One issue that I heard, at least, listening to this is that from what Vlad was saying, that the monoamines may be indirect ways of targeting more basic GABA glutamate-type processes. But of course, indirect ways are not always the worst ways. And I heard Dr Mattingly say that there may be much good gold to be mined still, amongst the monoamine neurotransmitters as we better understand how to tailor more specific ways of targeting specific monoamine transporters and receptors. So you can see the complexities here, but what a fascinating differentiation on one level. And yet on the other level, as both of our debaters have indicated, these systems are all interrelated. And at the end of the day, we are likely doing similar things, just coming at them from different entry points.

So this concludes round 2 of our Great Debate series. Be sure to tell us, please, who you think won this round by answering the poll question you see on your screen. And don't forget to join us next time for our very final round, where we'll be discussing inflammatory biomarkers, something that's near and dear to my heart, and their role in the treatment strategy for major depressive disorder patients.