Round 3: Are inflammatory biomarkers sufficient indicators to strategize treatment for patients?

Debate Transcript:

Charles Raison: As has been our custom, once again, we're going to start with Dr Maletic with his opening argument. So Vlad, go ahead.

Vladimir Maletic: Chuck, it's a fascinating and a new aspect of looking at major depressive disorder. And I know you have done some of the pioneer work in this area. So indeed, a significant number of patients suffering from major depressive disorder, does have increased peripheral inflammatory markers. There is a good reason to believe that many of them have also increased central inflammation. And this central inflammation may interfere with glutamatergic transmission as well as monoamine transmission. So, indeed it is something that is remarkable. It's a very interesting question if inflammatory markers will have utility, either as markers of disease, markers of response, which is something that is very different. So when it comes to non-monoaminergic agents, what kind of evidence do we have? Well, mechanistic evidence is very robust. We do know that inflammatory cells, and we're talking about macrophage, we're talking about microglia, do express GABA receptors. We also know that in preclinical studies, if we provoke inflammatory response using lipopolysaccharides, that GABAA-mediated interventions will decrease inflammation. There's really no arguing with it. That are very consistent. There's really nothing in research that would contradict that.

On the other hand, we also have studies using IV ketamine, where with IV ketamine we saw a very nice response in patients who had elevated peripheral inflammatory markers. It's interesting because in the study that is in my mind, looked at interleukin-17. And what they found is that inflammation is a predictor of response and decrease interleukin-17 directly correlated quantitatively with effect size of response. So I would say that NMDA antagonism and GABAA-mediated agonism, which underlie the effect of new glutamatergic agents because they're NMDA antagonist. And more importantly extra-synaptic and NMDA antagonists and some of those NMDA receptors are again on immune cells. GABAergic agents, which work as GABAA-receptor-positive allosteric modulators mechanistically, preclinical science supports their use in patients who have elevated inflammation and there is much more scarce clinical data, I will admit that upfront. But what is there is positive that peripheral inflammatory indicators are marker of response to IV ketamine and also that reduction in inflammatory marker is associated quantitatively with degree of response.

Charles Raison: Yeah. And of course Andy Miller’s group is showing that the depressed people with increased inflammation actually have glutamatergic abnormalities in both the ventral striatum and the anterior cingulate. Yeah, there's a really interesting story there. Greg, your opening statement.

Greg Mattingly: I think the role of inflammation is a fascinating role for our patients and it's something Chuck that I know has been around since all of us were medical students and residents. We've all known the role of the cortisol system, the inflammatory system. We have studies going back 30, 40, 50 years have shown that there's abnormalities there. We know that our patients that are subject to high levels of adverse childhood events, trauma, deprivation, neglect, abuse, have high levels of inflammation. We know that our patients who have struggled with ongoing recurrent depression or mood disorders have high levels of inflammation. We know that lifestyle issues can increase inflammation. Sleep deprivation, poor sleep hygiene, obesity, dyslipidemia, a host of physical issues interact with our biologic systems that increase inflammation, which we know is damaging both for the body and for the brain. My simplistic way when I'm teaching medical students or residents is inflammation—it's bad for the tips of your nerve cells, it tends to frazzle them, fry them, but it's bad for the tips of your blood vessels as well.

So we know there's a bidirectional link between our mental health conditions and our physical health conditions and then the environmental stresses that our patients live in. We've had a number of studies looking at inflammatory biomarkers and saying do they help to predict which antidepressant to use? Specifically targeting some of those symptoms around anxiety, some of those symptoms around sleep. So there are been studies looking at venlafaxine and paroxetine taking a look at the monoamine systems. And taking a look at where are those biomarkers when it comes to inflammation. We know that improvement in sleep and anxiety have both been shown to decrease inflammation. And we know that both sleep and anxiety have been shown to classically respond to our monoamine-modulating antidepressants.

Charles Raison: Okay. Vlad, rebuttal?

Vladimir Maletic: Well, Greg is making a very interesting point in indeed, monoamine modulation may be helpful. There are some data indicating that monoamine modulation may also decrease inflammation. Greg is pointing the impact on sleep. However, while there are monoamine-modulating antidepressants that are not very harmful for sleep, it is not true of the majority of the agents. So majority of serotonin- and norepinephrine-enhancing agents are actually horrible for sleep architecture. As a matter of fact, imipramine is used to treat some of the manifestations of narcolepsy that are based on REM sleep intrusion. Why? Because it's a REM sleep suppressant. So I would say that using anti-inflammatory strategies, I think you have had a role in establishing that some TNF alpha inhibitors such as infliximab may be quite effective in treating treatment-resistant depression. There are data with ketamine showing that indeed it may help inflammation.

And look, what we're forgetting is ketamine is very frequently used to treat neuropathic pain. There is high correlation between its efficacy in treating neuropathic pain and anti-inflammatory effect. And then there is, going to clinical data, there are clinical data that showed that IV ketamine treatment in improvement in depressive symptomatology is also associated with its anti-inflammatory effect, including several preclinical studies that have established that. That in animal models, antidepressant effect and anti-inflammatory effect are linked. So I can't disagree with the body of Greg's argument. What I would say particularly when it comes to sleep... serotonin- norepinephrine-modulating agents are not friend of sleep architecture. That does not appear to be the case, especially not with GABAA-modulating treatment. There is a preliminary evidence suggesting that GABAA-positive allosteric modulators actually dramatically improve quality of sleep. And there's really not much evidence suggesting that esketamine harms sleep.

Especially look at it this way, most of the esketamine adverse reactions, about 85%, are gone within 2 hours; 97% of adverse reactions are gone by the end of first day. Is that the case with monoamine-modulating antidepressants? Do their side effects really disappear within a day? I don't think so.

Charles Raison: Greg, your rebuttal of his rebuttal.

Greg Mattingly: So once again, let's step back, and Vlad said something that I think is very important. He talks about the historic role of the monoamine antidepressants. But once again, he excludes part of the distinction here. Not all monoamine antidepressants are the same. Monoamines can reach and touch the brain in very different ways. We have some of our monoamine antidepressants that tend to be energizing as a side effect, bupropion. We have other monoamine antidepressants that help to improve sleep. Mirtazepine is an example. So it's not a one-size-fit-all. It's not an either or. It's tailoring the needs of the monoamine system to your patient. What's the antidepressant there that's going to have the best benefit for the symptom profile of my patient? Perhaps that's someone who's had a history of childhood trauma. Perhaps that's someone who has disrupted sleep. Perhaps that's someone who has significant anxiety. Perhaps that's someone who has significant obsessionality as part of their depression.

So choosing among our monoamine treatments, helping to use them in conjunction, using them in augmentation with each other to improve the outcomes with our patients. When we look at inflammation, we certainly know it's there when it comes to our patients. And Chuck, you've been at the forefront of that. Our good friend Roger McIntyre up at University of Toronto has looked at that in bipolar disorder. We can go back to some of the pioneers in this field, like Charlie Nemeroff and others from Duke and places like that when I was in training, looking at the role of inflammation. Unfortunately, the research there has been fairly inconsistent about using anti-inflammatories as treatment for mood disorders. We'll have one study that comes out positive and then a second study trying to replicate that result quite often misses the mark. Now we know that clinical research is hard to do. I've been a part of it for years. We know the inflammatory system is a key system, but basic treatments guided purely at inflammation, I'd say have not been as consistent as we all hoped they might be.

I would come back to, once again, if you say, where can you put your money? Use the classic antidepressants that are approved for treatment for our patients, and then use holistic treatment for other strategies that have been shown to decrease inflammation. Good sleep hygiene, exercise, lifestyle issues to try to overcome obesity, adiposity, insulin resistance. All of those things that we know have been shown to help calm the inflammatory system in our patients that are struggling with depression.

Charles Raison:
Yeah, you're quite right, Greg. In fact, we know that anti-inflammatory strategies only work in depressed people who have indices of elevated inflammation and may, in fact, have some negative consequences in people that are just as depressed that don't have that signal. That's one of, I think, the most amazing findings in the last 5 or 10 years is really that inflammation is relevant for a subgroup of depressed people who also may respond differently to monoaminergic and, as Vlad noted, to glutamatergic and GABAergic agents also. All right, Vlad, closing statement.

Vladimir Maletic: Sure. I think that I can't possibly argue with Greg's point. I think that synergy is important. I think that monoamines are here to stay and they will have a role in treatment of depression in the future. I also agree with Greg that holistic approach using non-pharmacologic strategies has an advantage. But on the other hand, I also have to agree with Greg that much of the value of monoamine-modulating agents is based on the history. So the way I would look at it, making a comparison between monoamine-modulating agents and newer glutamate- and GABA-modulating agents is kind of like comparing steam locomotives with magnetic levitation engines. We have much more data on how steam locomotives work. They have been used in many different railroads and few things that we know about them is they are slow, they do pollute environment as in adverse reactions. And they're not always reliable in that many patients, that strategy will not be successful. When it comes to GABA- and glutamate-modulating agents, they are much more like magnetic levitation engines.

They operate in 6 railroads in the world, but what do we know about them? They're fast, they are reliable, and they don't pollute. So adverse reactions that are emanating from the use of these agents tend to be very time limited. I'm not saying they're none, but if they 97% disappear by the end of first day, and if we're using GABAA-positive allosteric modulators only 2 weeks at a time, couple of times a year, the rest of the time, we really do not have to deal with adverse reaction burden. And when it comes to specific treatment domains such as anhedonia, such as inflammatory signaling, I think that there is a clear advantage. We don't have the volume of evidence that there is with monoamine-modulating agents, but I think it's important to realize that in these symptom domains, when it comes to suicidality, when it comes to anhedonia, when it comes to neuroinflammation, I think that positive data are more exception than the rule. While it is the opposite with glutamate- and GABA-modulating agents, it's more of a rule. Very rarely an exception.

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

Greg Mattingly: Vlad, thank you for this very intriguing and spirited debate. As I was listening to your thoughts, your analogy is spot on. If we're trying to care for the needs of not just a handful of people in 6 cities, but the global needs of people across the entire United States. If we want to improve the burden of depression, our patients then come to us with a host of backgrounds, childhood trauma, a history of recurrent depression, anxiety, and other comorbidities. You know that the first-line agents will be the monoamine treatments. Those first-line agents are here to stay. They've helped to improve the burden of depression for our patients. As Chuck said, they've probably prevented millions of suicides across our country. So for specific patients, these more targeted agents may be the way to go in the future. They may be things that you get to for people who have not responded to the classic monoamine treatments, these monoamine modulators, the different ways we have now of touching the monoamine system.

And what I'd say once again to improve the overall global burden of depression, the tried-and-true monoamine therapy is going to be here to stay. I want to thank everyone for joining us in this really exciting time when it comes to mental health care, all the different options that are being made available for our patients. And Vlad, as always, thank you for joining me. My good friend, my good colleague.

Charles Raison: All right, so thank you both. Both you guys did fantastic job in defending these positions and explicating so much important information that's relevant, so clinically relevant. All right, so this concludes round 3 of our Great Debate series. Be sure to tell us who you think won this round by answering the poll question you see on your screen. And listen, please be sure to tune in next time for the closing arguments from Dr Maletic and Dr Mattingly.