Round 1: Should major depressive disorder (MDD) be thought of as a chronic or episodic disorder?

In this first round of the debate, our debaters share compelling arguments to support their positions to classify najor depressive disorder (MDD) as either a chronic or episodic disorder. While one debates that MDD is not a single disease entity, it is a syndrome with diverse phenotypical presentation and has a heterogeneous etiopathogenesis, the other points out that what is good for a significant minority should not guide the treatment of everyone.

Debate Transcript:

Charles Raison, MD: Hi, I'm Dr Charles Raison. Welcome to Great Debates in Psychiatry, brought to you by Psych Congress Network. Now in this series of debates, we're going to discuss especially whether major depressive disorder, which I'm going to refer to as MDD for short, should be classified as a chronic condition or an episodic condition. Now before we begin, we've got a quick poll that we'd like you to respond to. So you're going to see some questions on your screen next to where this video is playing. So just take a minute here and if you don't mind, respond to these questions now.

Great. Okay. Before we begin, I got to tell you, I am really excited about this debate because this topic is so important. So joining us today are Dr Vladimir Maletic and Dr Michael Thase. I don't need to tell you that they are highly renowned, really world experts in the realm of mood disorders. So we are really fortunate in that way. Now, Dr Maletic is going to support the side of major depressive disorder, or MDD, being a continuous condition, and Dr Thase is going to take the other side, the perspective of MDD as an episodic condition. And as you'll see, how we think about major depression in this way has huge implications. It has implications in what we tell our patients what to expect when they come into a depressive episode. It has real implications for how we think about treating patients; whether we think about this as something like say, hypertension or diabetes, which is one of these chronic conditions that you have to address medically often for the rest of people's lives. Or whether we consider this more as something that's a relapsing or a remitting condition, in which more episodic treatments may in fact be preferable. You'll see that there's strong arguments for both sides. And the reason this is an interesting debate is because there's not a simple answer. Although we're going to ask you to vote and weigh in on which side you think has better supporting data, depending on the positions that our presenters present. Okay, so let's dive into round one, and begin by addressing our first debate topic. And the first topic is should MDD, should major depressive disorder be thought of as a chronic or episodic disorder? So Dr Maletic, please start with your opening argument.

Vladimir Maletic, MD: Thank you very much, Chuck. It's indeed a fascinating question. And I do want to begin by saying I'm really not dogmatic about this issue. Because if you ask me is it a chronic or episodic or recurrent, my answer will always be yes. For a very simple reason. MDD is not a single disease entity, it's a syndrome. And syndrome would assume that there is not a common underlying neurobiology to this condition. And there's not even a common phenotypical presentation, as in, individuals may have different symptom constellations. We have learned something very interesting about MDD as a result of more recent genome-wide association studies in that there are probably about eight dozen genes that are implicated in etiopathogenesis of major depressive disorder. They all have very small contribution. But one can actually add up these genes and come up with something that would be called polygenic risk score.

And therefore, individuals who have low polygenic risk score and who have high polygenic risk score, actually have very different pattern of disease. So what we know is that high polygenic risk score is associated with early onset of this condition, and it is associated with a recurrent form of this condition. And when I say recurrence, we're talking about exacerbations that are clinically observable. But it does not mean that between the episodes, the disease process that is submerged, that is under the surface, is dormant and not active. So I would say that in its underpinning, it is more chronic condition with exacerbation and recurrences.

Charles Raison, MD: Okay. Michael, why don't you give us your opening argument?

Michael Thase, MD: Well, I too agree that it is, yes, both potentially a chronic condition and one that can be episodic. And indeed 10% or 20% of people who first become depressed, whether they're young or old, will become chronically depressed. For these poor individuals, they do not have an episodic illness. They have a chronic illness. Yet there are others who have a single lifetime episode and who recover fully and never become depressed again. Now, if your first episode is in your 20s and you have the good fortune to live 70 more years, the chances that you will only have one episode in your life may be as little as 10%. So for the balance of those individuals, 60%, 70% of those at morbid risk, it is an episodic condition. Now, 70% does not define the whole, but for most of us who have suffered one episode of depression, we will suffer another if we have the good fortune to live long enough.

I think importantly, as Vlad says, there are aspects of the illness that are indeed state dependent. Your cortisol levels, for example, tend to go up when you're depressed and when you've recovered they tend to go back to normal. But for those at highest risk, perhaps those with family history, those who have suffered prior episodes, those who have had psychotic features, sometimes the cortisol levels stay high even when the person is better. So here you can have a mixed marker. It's both state dependent and can be persistent into early recovery. So even here, the biology does not clearly separate. Importantly, as clinicians, we have to make decisions about how we treat the individual after they've begun to get better. And until we have better therapeutics and until we have better ways of sorting this out, we've taken the position of treating everybody who's responded to medication for six to nine months and those who we judge to be at high risk for episodic illness indefinitely. And for those individuals, we recommend a chronic treatment to suppress an episodic condition.

Vladimir Maletic, MD: Indeed, I would agree with that position. Because there are different views that are based on the course of the illness, namely early in the illness. I would agree with Michael's statement. It looks like majority of the patients recover. So one of the longer longitudinal studies just published about five years ago that observed the course of depression over the course of six years. And the end of two years, things looked good. So 60% of the patients were in recovery, meaning that almost two years they've not had any recurrence of illness. So it was very optimistic, and it would be hard to justify ongoing treatment with that kind of course. But on the other hand, if we look at the cross-section at year six, it is the law of the thirds.

So one-third of the patients were still in the recovery. One-third had recurrent course but without chronic episodes. Chronic episodes for the purpose of this study were defined as lasting two years. So patients would be depressed for about 85% of those two years. And then another third had chronic condition with episodes that are up to two years long. So bottom line, only one-third of the patients could be well treated based on those data in episodic fashion and would require an ongoing treatment.

Charles Raison, MD: So gentlemen, I'm interested in this area also. And there have been some large, like, 25-year longitudinal studies in sort of general populations that find that even over 23 years, I'm thinking of one study in particular out of Europe, only 50% of people had a second episode over 23 years. Anybody want to take the bait on whether or not we as psychiatrists, or folks working in the mental health space, are seeing a biased sample? That in some ways we're stacking the deck to get people that are more likely to have chronic courses? And how would you think about that impacting overall what we tell people? Especially maybe when they're first coming to see us with initial episodes.

Michael Thase, MD: I rarely ever see someone in their first lifetime episode of depression. So just here and there I'm seeing a biased sample. Indeed, folks have often either become chronically ill or in their fifth, or sixth, or seventh lifetime episode by the time they come to a tertiary care referral system. I think the milder and the more natural, and I'll come back to what I mean by that, that the first depressive episode is, the less likely it will run a recurrent illness course. And the more likely it might be a one pothole in an otherwise depression-free life. And by natural, I mean in the context of heartbreak, in the context of a vocational, professional failure. Some grief. Some insurmountable difficulty that has temporarily caused your ability to cope to just become overwhelmed. And this is a kind of depression that I don't think was even declared to be depression 50 or 60 years ago. It was considered misery. And folks went to the bed sometimes in their misery, but they didn't go see a psychiatrist unless they were hallucinating and contemplating suicide, and so forth.

Charles Raison, MD: Right. So that would strengthen, if we look at the world of depression as defined in the DSM—if one was a strict, what do they call it? Like, interpretation just of the DSM—two weeks of the symptoms and you've got it. That would support, would it not, perhaps more of an episodic course. Whereas Dr Maletic, you want to weigh in on, in terms of pragmatics, for what we're likely to see in a mental health sort of space, whether higher rates of a continuous condition is a more realistic way of looking at it.

Vladimir Maletic, MD: Well, I think you have summarized it very well, Chuck. And there certainly is a bias, but that bias is inherent to our profession. In that we really don't deal with epidemiologic samples, we deal with clinical samples. And the odds are two to one that patients we’ll be seeing will have some form of highly recurrent or chronic continuous major depressive disorder. In which case we would not be serving well our patients if we suggested interruption or early interruption of treatment. Because there is evidence that if there is an early interruption of treatment, they're much more likely to become depressed sooner. So actually studies were done when they looked at what happens if we interrupt treatment after one month, in which case 60% of the patients needed reinitiation.

So we stopped it early and again, 60% needed reinitiation. If we went on for six months, only 20% needed reinitiation in this study. So duration of treatment and how soon we recognize the condition and how soon we start treating it are important factors. And I would say that from what we know of the underlying neurobiology for major depressive disorder, it would be... I don't want to make farfetched arguments, but it would be more like malaria in a sense that there are acute exacerbations that attract our clinical attention. But in between the attacks it doesn't mean that malaria is gone. And I would say that major depressive disorder, to really root it out and to keep all symptoms at bay, at least in my experience and based on the studies that I've read, is pretty unusual scenario. So again, we're talking about clinical sample. I think you're making a valid argument that in epidemiological sample it may be a different story.

Charles Raison, MD: I think Vlad, that counts as a really nice closing statement. I don't know that you can do better than that. Really well said. Michael, why don't you give us a closing statement for this part of the debate.

Michael Thase, MD: There are people who suffer a chronic illness from the first time in their life that they've become depressed. They are also people who have only a single lifetime episode and never become ill in between. But the vast majority of people suffering from depression who come to the attention of mental health professionals suffer from episodic illnesses. Some who recover completely, some who have some persistent minor symptoms but who are better and return more or less to their old selves. And for those people, a careful treatment plan that takes into account both their vulnerability, as well as their own natural history, is warranted.

Charles Raison, MD: Okay, so thank you both. So this is going to conclude round one of our Great Debates series. And again, remember that Dr Maletic took the position, in general, that depression is perhaps most profitably considered as a chronic condition.

Dr Thase, while certainly recognizing that, argued that there was much to be gained by perhaps considering it first as an episodic condition, and moving toward a chronic perspective when it's just patently obvious that somebody has chronic depression.

And again, these two positions, as we'll see as we go on in these debates, have very different treatment implications. So this is not an abstract question. It really is clinically quite relevant and quite practical.

So now if you don't mind, be sure to tell us who you think won this round by answering the poll question you will see on your screen. And join us next time for round 2, during which we're going to be discussing the pros and cons of episodic versus chronic treatments for major depressive disorder.