Round 1: Does speed matter?

In the first round, Dr Maletic and Dr Chepke will debate whether major depressive disorder (MDD) is a brain disorder or a whole-body disorder. Both experts will present their opening arguments in a clear and concise manner, drawing on the latest research and their own experiences  in the field.

Debate Transcript:

Charles Raison: So having said all that, let's jump right into round 1 and begin by addressing our first debate topic, which is the question of whether the speed at which antidepressant agents work is relevant and, if so, how relevant is it? So Dr Maletic, you're up first. Why don't you go ahead and start with your opening argument?

Dr Vladimir Maletic: Well again, thank you very much for your question, Chuck. When it comes to comparison in speed between non-monoamine-modulating antidepressants and monoamine-modulating depressants, it's pretty much like dial-up internet versus optic fiber. There is remarkable, clear, replicable difference in onset of action. So when it comes to glutamate-modulating agents, and I would talk about IV ketamine and I would talk about intranasal esketamine adjunctive treatment because those have been investigated more. In addition to that, when it comes to neurosteroids, brexanolone has been investigated in peripartum depression as a 60-hour infusion, and the outcomes are very similar and indicative and important difference. So when it comes to NMDA antagonist, glutamate-modulating agents, we see response and a very clear response within a matter of minutes to hours. When it comes to response to brexanolone in peripartum depression, again, it was just a few days and there was a clear response.

When it comes to monoamine-modulating agents, if our patients are in the lucky two-thirds to ever have a response or remission, it's going to be weeks. So it is very clear that there is a difference. Now, in my mind, why would rapidity of the response matter? Well, rapidity of the response is reduction in suffering. So we're dealing with depressed people, they're suffering, their loved ones and families are suffering. There is a reduction in quality of life. There is a substantial reduction in functioning and productivity in these individuals. So of course speed matters, but there's a cardinal symptom of depression where the contrast is even sharper. And that contrast has to do with reduction in suicidal ideation. So there are studies with IV ketamine and then this is very clear cut. This is monotherapy IV ketamine. One published in 2018 and Jennifer Phillips 2020 study showing clear rapid reduction in suicidal ideation day 1.

So how can one argue that that is really not an important facet of the activity of these agents? And frankly, there is hypothetical implication. I'm saying hypothetical because when it comes to mechanism of action of all these medicines, it's not 100% clear how they work. But it is very reasonable to assume that if we are proximal to the cause of a major depressive disorder in individual, that we're going to see a more rapid response. If that is the case, both neurosteroids and glutamate appear to be much more proximal to the cause. When it comes to monoamine-modulating antidepressants, gosh, if we look at a preclinical studies, so microdialysis studies, we will observe a response within 60 minutes in rodents after intraperitoneal injection in a sense that there will be increased monoamine concentration at the prefrontal cortex. So increase in monoamines at 60 minutes. Onset of action of monoamine-modulating antidepressants is weeks. It tells us it's a downstream effect. We are distal from the cause of whatever underpins major depressive symptoms. I would say with monoamines we're distal. With glutamate and GABA A-modulating agents, we're very close.

Charles Raison: Good. All right. Dr Mattingly, your opening argument please.

Dr Greg Mattingly: So Chuck, Vlad, two of my very best friends and colleagues. Vlad, I'll have to say it seems like somehow you forgot the past 50 years. The past 50 years, the historic role of the monoamine antidepressants, as Chuck was saying, have saved millions of lives around the world, have decreased the suffering and burden of depression and the historical nature of SSRIs, SNRIs, NDRIs, monoamine oxidase inhibitors, TCAs, and now what we call the multimodal monoamine-modulating antidepressants. We know that not only have those medicines helped to improve the burden of depression and helped prevent suicides for decades around the world, we know that these medicines by guidelines, not just here in the United States, but our guidelines by our Canadian colleagues, our European colleagues, our Australian colleagues where I just returned. The monoamine-modulating antidepressants are still considered the first-line gold standard treatment for patients struggling with depression.

So, we have a historical precedence of 50-plus years, millions of patients who've been improved with these agents, and a variety of different multimodal agents that have now come out modulating monoamines. I think one of the mistakes that Dr Maletic may have made, and I see this happen quite often with colleagues, is they lump all of the monoamine antidepressants into one basket. We know that's not the case. We know that we have monoamine medicines that target transporters, reuptake transporters, serotonin, norepinephrine, dopamine. We know we have monoamine antidepressants that modulate the receptors themselves, that target specific monoamine receptors: serotonin-1A, serotonin 2, serotonin 7. We know beyond that, Chuck, a group that you've been involved with. We have a group of medicines that we call psychedelics that modulate the serotonin-2A receptor that have very fast onset in their mechanism of action.

And then finally, we have a group of medicines that we now classify as the atypical antipsychotics that all been approved for adjunctive treatment of depression on top of an antidepressant or monoamine antidepressant when those monoamine antidepressants by themselves have not gotten the job done. Even if we dive into the world of the GABA glutamate medications, of which I've been a part of a lot of the research, we know that those medications are quite often reserved, if not exclusively reserved, for people that have treatment-resistant depression, where monoamine antidepressants haven't been successful. And quite often in those indications such as with esketamine, the indication for treatment-resistant depression, even there while using esketamine, is mandated to also include a monoamine antidepressant. So whereas no one size fits all, the historical nature of the monoamine antidepressants, their guideline precedent, their foundational precedent said that these are still our first-line agents when we come to treating depression.

Charles Raison: Interesting. And Vlad, Greg makes a really interesting point. I mean, psychedelics clearly operate by the serotonin system and they seem to produce almost their entire effect within a day. So that brings up the sort of question about the distal nature of things. It's complex, isn't it?

Vladimir Maletic: It is. And I really appreciate Greg's admiration of history and I appreciate your comment of psychedelics. And I agree with you, monoamine-modulating antidepressants do belong in history. So they have had relevance in the past, but we're in a period of transition and we're transitioning to something that is completely new. In terms of treatment guidelines, I also agree about historical context of treatment guidelines and that APA guidelines are probably a very good museum exhibit right now. They are from 2010, based on the data that was generated for the most part in the last century. So I think what we are dealing with is a gap. A gap in implementation of the more recent knowledge. And in terms of many of these medications, well esketamine being the prime example, yes they are approved for treatment-resistant depression, but I would say that that is not a pharmacological and neurobiological phenomenon. That is a commercialization phenomenon. It doesn't mean that these agents would not work earlier or just as well in individuals who are having their first or second episodes.

Now, they have not been extensively studied in that context, but in few scenarios where they have been used, it didn't in any way diminish their effect. When it comes to combination with antidepressants, sure, esketamine is approved as adjunctive treatment. On the other hand, let's look at the studies. The difference between esketamine and added to an antidepressant—and this is newly started antidepressant—and placebo added to antidepressant is present day 1. Do we really believe that monoamine-modulating antidepressant made a big difference day 1? No, it’s probably mostly placebo, non-specific effect. Is it true that if they’re working alone, they will not work so well? No, not really, because NMH has done multiple studies with ketamine, whether it's monotherapy and it is just as fast and it is just as effective.

Brexanolone studies in peripartum depression included large number of subjects who were not on antidepressant. Was there a difference between the ones who were and the one? No. Zuranolone early studies included patients who were on antidepressants and the ones who were not. Again, no differentiating factor there. Presence of antidepressant did not appear to add or subtract much from the response to the novel either glutamate- or GABA-modulating agent. So I would say yes, we are in a period of transition. It is a historical period, but I think that monoamine-modulating agents, while they will still have a role, their role is more noticeable in the rearview mirror than in the windshield of psychopharmacologic future.

Charles Raison: Wow, Vlad, that is poetic. That's awesome. Okay, Greg, the rebuttal is yours. You want to reverse the mirror and the windshield or how do you want to think about this?

Greg Mattingly: Oh, Vlad is a good friend, but he's also very crafty.

Charles Raison: He is. He's very crafty. You got to watch,

Greg Mattingly: He's obviously admitting where the literature stands. Yes, not only does historical precedent recommend monamine antidepressants, but a recent article published in JAMA within the very past year, Vlad, that I know you're aware of, by our good friends at Mass General, Mauricio Favia and colleagues. They say that based on all of the current evidence, monoamine antidepressants should be your first-line treatment. Atypical antipsychotics in that article published in JAMA were listed as the second-line treatment on top of an antidepressant and third-line, finally, we got to the novel glutamate GABA medicines. So even in that most recent guideline piece where they said, what would Star*D look like now if we did it in our current day with our current tools, monoamine antidepressants were first, Atypical adjunctive treatment is what they said is the evidence shows us should be second, and only moving to these more novel GABA glutamate strategies for people with those two strategies had not improved.

When we talk about rapidity of action, we know that some of our classic monoamines did take a while to have onset. We know that atypical augmentation quite often works quicker than that. Quite often we see improvement within a week. Something that clinically every clinician has used, and especially if you're a clinician taking care of older patients, it's augmentation with stimulant medications. And remember, stimulants are once again working through dopamine, working through norepinephrine, monoamines, and we see improvement by the very next day when we come back to see our patients when it comes to energy, apathy, alertness, arousal, core aspects that we use these medicines for adjunctive treatment. And then finally, an exciting monoamine area is the psychedelics. We talked about it before, but the psychedelics which work through 2A, we see improvement in hours within clinics. Guided assisted therapy where a therapist can already see somebody improving within hours of doing this treatment so that you can augment it in a single one-day session. A serotonin-2A medicine with psychotherapy for improvement of depression.

Charles Raison: Okay, so Vlad, this is your closing argument.

Dr Vladimir Maletic: Yeah, I can't disagree with Greg. Yes, psychedelics do work quickly. They are serotonin-2A agonists. On the other hand, 70% to 75% of serotonin-2A receptors in the prefrontal cortex are on glutamatergic pyramidal neurons. So we have found a way of more rapidly modulating glutamate. And yes, it works fast, but I think it works fast because it works through glutamate. In terms of stimulants, yes, stimulants will provide, as adjunctive treatments, relief and major depressive disorder for certain symptom domains. There's no arguing with that. What about a sustained effect? Their effect dissipates very rapidly. In terms of what we know about NMDA-modulating agents, there are studies with esketamine that have gone on now for 4 years. We do have cohorts which have been studied for 30 months; 30 months out we see no evidence of deterioration of the effect.

Now the part that is intriguing, these medicines were not given every day, and still we do not see, compared to baseline, any deterioration of effect. What happens with antidepressants, if you try to give them intermittently, they'll lose effect very, very rapidly. In terms of GABA A-modulating neurosteroids, talking about zuranolone, we have 2 weeks of treatment and that is repeated if necessary. Seventy percent of the patients in the studies needed 2 2-week periods in a year. What would happen if we treated somebody with monoamine-modulating antidepressants for 2 weeks and stopped? They'd be depressed very, very quickly, right?

So I would say yes, preponderance of evidence, which influences guidelines, and I'm not arguing that point, supports the use of monoamine-modulating antidepressants. Why? This is a volume question. There has not been enough time to generate literature about non-monoamine-modulating antidepressants. So what we're doing, we are actually summarizing and rehashing the past, but that does not necessarily influence the argument that novel GABA A and glutamate receptor-modulating treatments are not just, if not more, effective. Unfortunately, we don't have studies in patients in early course of depression where we're using monoamine-modulating agents versus non-monoamine-modulating glutamate-  GABA-modulating agents to see how they compare head to head. We really don't have those studies. But if we did and if we're looking at the onset of action in first 2 weeks, I don't think it would be much of a competition.

Charles Raison: All right, Greg, your closing statement.

Greg Mattingly: So let me agree with Vlad on a couple of things, and Chuck, I think you would chime in here as well. It's an exciting time to be in mental health research.

Charles Raison: Oh yes.

Greg Mattingly: It's a very exciting time. We know some of the limitations of some of our standard monoamine antidepressants are becoming a thing of the past. Researching various receptor subtypes of those monoamines, looking at how to touch those receptor subtypes either by themselves or in conjunction with other receptor subtypes to improve onset, to improve outcomes, to overcome residual symptoms in our patients where some of our standard reuptake inhibitors just hadn't got the job done. So I would say for all of us, the role of monoamines can't be forgotten when it comes to treatment of depression. But it's an exciting time when we look at holistic treatment using all of these mechanisms for our patients.

Charles Raison: All right. Well, thank you both. You guys are so articulate and made so many good points and you can see why it's a great debate because there are valid arguments on both sides and there are ways of trying to combine these different viewpoints in ways that I think are going to be really useful. Okay, so this concludes round 1 of our Great Debates series. Now be sure to tell us who you think won this round by answering the poll question you see on your screen. And be sure to join us next time for round 2, where we will be discussing the role that clinical manifestations play in determining treatment approach.