Closing Arguements

Debate Transcript:

Charles Raison: All right. Hi everyone. Thank you for joining us for the closing arguments of our Great Debates in this  Psychiatry series. All right, Vlad, Greg, this is your last chance to change our viewers’ minds. Give us your best closing argument on why the monoamine or the non-monoamine strategy is an optimal approach for treating major depressive disorder. And Vlad, we're going to start with you. So go ahead. You can begin.

Vladimir Maletic: I wish I could disagree more with Greg, but I really can't. I think the approach that he is suggesting is a very valid approach, and that is that in the future we will probably be combining monoamine-modulating treatments with antidepressants of a different class. It just happened that today the emphasis was on glutamate- and GABA-modulating treatments. There are kappa-opioid treatments on the rise, and there are calcium channel-modulating treatments on the horizon. So as heterogeneous major depressive disorder, as large a tent as it is, I think there is room for all of these mechanisms of action.

But when it comes to certain kind of symptom domains, and I'm talking primarily suicidal ideation, I'm talking about anhedonia, when it comes to sleep disturbance, when it comes to neuroinflammation. I would say if we look at, not necessarily quantity, because there's not been as much research in and GABA- and glutamate-modulating agents, but if we look at consistency of the data, data very consistently suggests that there is improvement in all these symptom domains with novel agents.

Is there some data supporting use of monoamines? Absolutely so. But if we look at it, those data are not the rule. They're exceptions. There are a couple of agents amongst monoamine-modulating antidepressants that enhance cognition, but it is not typical. There are a couple of agents that do not generate emotional blunting, not typical. There are some agents that are antidepressants that work through monoamines that modulate inflammation, but it is equivocal.

So what I would say is monoamine-modulating agents are here to stay. They do have a historical value. But in terms of putting things in perspective, let us say that monoamine-modulating agents may be akin to steam engines. They're very reliable. They're a little bit slow, and they do pollute the environment. On the other hand, when it comes to GABA- and glutamate-modulating agents, they're more akin to magnetic levitation railways. They're really fast, they're very reliable, and they don't pollute environment, as in the balance between efficacy, rapidity and adverse reaction burden, really favors them.

And when we're talking about adverse reaction burden with glutamatergic agents, with NMDA-modulating agents, robust data on esketamine, between 85% and 90% to adverse reactions resolved within 2 hours, 97% resolve the same day of treatment. When it comes to GABAA-positive allosteric modulators, they're only used 2 weeks at a time; 70% of the patients will need 2 treatments in a year. The rest of the time no medicine, no adverse reaction. So it is a very different cost-benefit analysis than we are accustomed to with monoamine-modulating antidepressants.

Charles Raison: Okay. Thanks Vlad. Okay, Greg, your closing argument. Go ahead.

Greg Mattingly: Vlad, once again, a fantastic discussion, but once again, I think you've looked at one side of the coin and not the other. So when we take a look, monoamine antidepressants are not all within one class. We have monoamine antidepressants, as you noted, that are the only antidepressants, vortioxetine, that's been shown prone to improve processing speed and has that as a part of its package insert for the FDA. Not just here in the United States, but globally around the world, I've been a part of studies looking at the role of vortioxetine for reward, motivation, drive; for making it to work and showing up to work, but being more efficient at work, so being more present. So improving presenteeism, I get more accomplished when I'm at work. So we improve processing speed. We improved anhedonia. We improved motivation and drive with vortioxetine in global studies around the world.

We also have monoamine antidepressants that have a very different profile for our patients. Some of those are also approved for neuropathic pain. When we think about the role of duloxetine for helping not just depression, but those patients struggling with comorbid pain. We have monoamine antidepressants that are also approved for treatment of patients that have obsessionality, obsessive compulsive symptoms as a part of their depression. And we have monoamine antidepressants that have been shown to help with sleep, such as mirtazepine.

 So what I would say is, this is not a one-size-fit-all. We have a really exciting group of monoamine modulators on the horizon—the psychedelics, which modulate serotonin 2A, they have very fast onset in the course of a session in your office. They begin working quick enough that a therapist can do guided psychotherapy in the day that they're administered to improve the outcomes of patients by the time they leave your office.

So while it's an exciting world to look at multiple mechanisms, mechanisms that go through neurogenesis, neural growth factors, GABA, glutamate, the opioid system, the inflammatory system, we know that monoamines are going to be the hallmark at the forefront. They're going to do the heavy lifting. They're going to carry the burden of disease when it talks about caring for patients within our country that have depression.

I would also highlight something that Vlad I think may have skipped over. We only have two antidepressants that have been shown to be effective in children. Both of those are monoamine antidepressants. When we look at the literature of the non-monoamine treatments, Vlad did say something that's really important. Quite often that research is very limited. So if we look at the studies of IV ketamine, first of all, not FDA approved, and second of all, the number of people in many of those studies, 20, 30, 40, 60 people in a trial.

So when we look at these analogs, remember that the wealth of data, the largest group of data documenting the improvement of patients, is with our monoamine strategies. Remember that monoamines are not one-size-fit-all, various ways to approach the monoamine system: being a serotonin 1A agonist, being a receptor partial agonist, using one of these monoamine strategies such as the atypical antipsychotics for adjunctive treatment on top of another antidepressant for augmentation strategies. And then the exciting new role of the psychedelic class that'll modulate serotonin 2A, with a very rapid onset of improvement for our patients struggling with depression.
Thank everyone for joining Vlad and I, it's an exciting time to be in our field, in the mental health field, with the tools that are coming for our patients.

Charles Raison:
All right. Well, folks, there you have it. Vlad, Greg, thank you so much for just an informative, lively debate. It was just an honor and a pleasure to listen to you two discuss these things and have some fun kind of going at each other and really helping educate us in the process. All right, so thanks folks. Thanks everybody for joining us. Be sure to tell us who you think won this debate by answering the poll question you see on your screen, and we'll see you next time.