Round 3: What are the implications for patients approaching major depressive disorder (MDD) treatment episodically vs continuously?

In our final round of this debate, our debaters highlight the implications for patients when approaching major depressive disorder (MDD) treatment episodically vs continuously. While episodic treatment results in more frequent relapses, an alternative treatment strategy is recommended to reduce the risk of relapsing/recurrent illness.

Debate Transcript:

Charles Raison: All right, howdy. Hello. Welcome back to our Great Debates in Psychiatry series, brought to you by Psych Congress Network. I'm Chuck Raison. I'm the sometime moderator of these debates. And of course, we have Dr Vlad Maletic and Dr Michael Thase with us arguing around the data and ways of thinking about whether depression is better conceived as continuous condition or better conceived of as an episodic condition that can sometimes be continuous.

So in our final round of this debate, we'll be discussing the implications for patients when we approach MDD treatment, either continuously or episodically. And again, we're going to start with Dr Maletic for his opening argument. So Vlad, here again, we're actually talking about the implications. What are the implications of thinking about treatment, in this case, as a continuous endeavor?

Vladimir Maletic: Chuck, here's my great concern. There are a number of studies that indicate that major depressive disorder, even though it's a syndrome, not a disease, tends to have progressive course in many individuals. So there is evidence that if we interrupt treatment, patients are going to be relapsing. The more relapses there are, the greater the risk that there will be a change in underlying substrate. So going from the studies that Yvette Sheline conducted decade and two decades ago, where she found that it is duration of untreated depression that correlates with decreasing gray matter volume of hippocampus. And as we know, hippocampus is an area that has to do with episodic memory, with declarative memory, with spatial memory, with endocrine regulation. Do we really want to withhold treatment when duration of untreated MDD is associated with decline in hippocampus?

If indeed we withhold treatment, and again, this is mostly based on monoamine-modulating treatments. Philip Gorwood's group in Paris looked at the cognitive footprint or cognitive scarring of multiple depressive episodes. And it appears that with the first two or three episodes, patients will pretty much bounce back cognitively once they attain remission. But the concerning part is if non-treatment leads to frequent recurrences, individuals who have had four and five depressive episodes did not bounce back, and their cognitive function did not come back even close to baseline.

There are studies based on structural neuroimaging, Thomas Frodl has done studies looking at patients who have failed to achieve remission. And again, the evidence suggests that if we stop treatment, many patients will not be in remission. So we can look at remission as a proxy to suppressing the underlying disease process; but if the remission is not there, these individuals had progressive changes in gray matter volume of dorsal lateral prefrontal cortex, anterior cingulate, hippocampus. So the areas that are associated with stress regulation, emotional regulation, cognitive function, it seems that if we do not only attain our goal of getting rid of all the symptoms, and the best way so far appears that if we have continuous treatment, that substrate will suffer in that brains will be changed. And that is my concern, that no matter what we do later on, we may not be able to achieve optimal outcomes.

Charles Raison: So let me say that back to you. So if we think about agents that tend to be used continuously, like sort of standard antidepressants, SSRIs, SNRIs. If I hear you correctly, you may be suggesting that, especially in this case, these are not agents that are very wisely used episodically. If by episodically you mean that you take them for a while and then whatever, and then you crash into another episode. If it's a relapse that drives every reinitiation of the medicine, then you are accumulating the cost of those relapses, right?

Vladimir Maletic: And that would be the case in two-thirds of the patients treated with monamine-modulating antidepressants.

Charles Raison: And so, then your argument would be something along the lines of whatever the costs of continuous, say monoamine-modulating agents, that the cost is kind of worth the benefit. I mean, I guess one way of thinking about this though is that these may be agents where it's like—there's an expression, you buy the ticket, you take the ride—that once you start these agents, you may be looking at taking them for an indefinite period or a lifetime, and that's something people need to think about. Or how do you think about that?

Vladimir Maletic: I would say if they're lucky enough to maintain their response, I would say it is an uneasy compromise at best. I don't disagree with any point that Michael has made in terms of side effects and negative impact on quality of life through blunting emotions. My question, well, what is the alternative? And we don't know the alternative for every single patients, but the studies do have really got concerning findings in what happens if there are frequent recurrences and if there are extended periods, so where major depressive disorder is not treated effectively.

Charles Raison: Yeah. Michael, your opening statement on the implications for patients if approaching MDD, I think in this case, episodically, though if you've got something to say about the dangers of chronic treatment, that would certainly bolster your case too. But go ahead.

Michael Thase: In the latter part of the 20th century and maybe into the 21st century, if you developed a first lifetime episode of depression in your twenties or thirties, that you had on average about five years illness free before your second episode. And if you had a second episode, then maybe two to three years on average. And each time I say on average, you recall that there are half the people who didn't run that course and read a better course than that. So I think that Vlad's point is a good one, that there are people who have a deteriorative progressive illness that require extra protective treatment to minimize their illness. But there are many more people who don't require this. And do you subject everyone? Do you try to subject everyone to protect the subset?

That study done at the University of Pittsburgh that I was one of the attendings for, in which there were 125 people with highly recurrent unipolar depression that were followed in a series of double-blind studies out to five years, for that 125, there were 250 that were treated. Half of them didn't get well enough to be in the study, and we screened about a thousand other people who didn't have a history characteristic enough to come into the study. And so here's a highly influential study, but it really reflects 10%, 15% of the whole.

And so coming back, I think this continuous model does apply to a very at-risk subset but a more episodic and idiographic, I mean a group that you would look at on an individual basis and make the best judgments for that person. And look, if I'm treated for my first lifetime episode of depression and I require a reuptake inhibitor, I know I need to take it for six months, maybe nine months because of the relapse prevention data. But what if I have sexual dysfunction? Or what if I'm gaining weight? Can I switch to psychotherapy? Is there another model of treatment that can be used?

And then thinking about now moving into the third, deeper into the third decade of the 21st century, what about treatments that don't modulate monoamines directly and may have other ways of working?

Charles Raison: Do you think that or what's your view of the data that bounces around that maybe antidepressants have some iatrogenic problems in patients? That, in fact, they may make people over time more likely to relapse when they stop or more likely to develop treatment resistance, even though this is one of these things that people argue about.

Michael Thase: I think it is true that your hazard of relapse is higher with abrupt discontinuation of an antidepressant than it would be if you had recovered spontaneously. And so the abrupt discontinuation, it has an iatrogenic effect, I don't have a doubt about that. I don't really know if that means that that person's true risk of recurrent illness has been worsened by virtue of taking. I simply think that when you suppress an illness pathology, the brain doesn't have the chance to recover spontaneously or naturally. And so the health's to be paid when you stop an illness-suppressing treatment. I mean, we know this in asthma, we know it in a few other episodic illnesses.

Charles Raison: Right. Where they're rebound phenomena basically, right?

Michael Thase: Yes.

Charles Raison: The body or the brain or whatever the relevant system is over time, I think this is flat-

Michael Thase: I think it's true in epilepsy also, so.

Charles Raison: Mm-hmm. Right, like an oppositional tolerance. I think Giovanni Faber calls it, right? That the brain pushes back against the treatment. But what's interesting then is if there are some advantages, let's say, as you said, to letting the brain recover naturally, then clearly, of course, some kind of treatment where it's not on the brain all the time might offer that. But you got to have those kind of treatments, right? I mean I think that the on-again, off-again with the monoamine-modulating agents, that doesn't seem to be such a good strategy, right?

Michael Thase: Oh, no. In our studies at Pitt, for example, each time someone suffered a relapse or recurrence on placebo in those studies, and we retreated them, 10%, 15% of the patients did not recover the next time around. So there's a hazard when you suffer a discontinuation-emergent relapse or recurrence. That didn't happen in the psychotherapy-treated patients.

Charles Raison: And your theory for why not? Why do you think psychotherapy was different?

Michael Thase: I think that the folks who recovered with psychotherapy probably represented a less biologically perturbed subset of patients than those who required antidepressants. I'm an old fashioned psychiatrist though, I actually think there is a substrate of depressive illness beyond which a psychotherapy as a monotherapy has real limitations.

Charles Raison: Well, and of course, you were the one to publish those data back in the day. Those are famous sort of foundational data at the psychotherapy medication interface. And you still think that?

Michael Thase: I've not been disconfirmed or disabused.

Charles Raison: Thank you both. 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 be sure to tune in next time for closing arguments.