Round 2: What are the pros and cons of episodic treatments vs continuous treatments for major depressive disorder (MDD)?

In this round Dr Maletic and Dr Thase get into the pros and cons of episodic treatments vs continuous treatments for major depressive disorder (MDD) to support their positions. While, one argues that continuation and maintenance phase therapy have been the standard of care for years, sometimes, those who had the treatment long-term, were still in treatment months later.

Debate Transcript:

Charles Raison, MD: Hi everyone, and welcome back to our Great Debates in Psychiatry series brought to you by Psych Congress network. Okay, so we're now in round 2 of this debate. You remember round 1 had to do with the debate about how depression should be conceptualized. Is it more profitable to overall conceptualize it as a chronic condition or are there advantages to thinking about it at least in many cases as an episodic condition? Now we're coming to the really important sort of implications and sequelae of that regarding how then do we think about treatment. So in this round 2 of the debate, we're going to be discussing the pros and cons of episodic treatments versus continuous treatments for major depressive disorder or MDD. And we're going to start again with Dr Maletic. So Vlad, do you want to give your argument for continuous treatment?

Vladimir Maletic, MD: Sure. I would say that there is abundant evidence with monoamine-modulating antidepressants, and majority of this evidence is based on tricyclics and then subsequently SSRIs and SNRIs where treatment discontinuation led to very rapid relapse and recurrence. And to make that distinction, if the patient develops symptoms of depression, within a matter of weeks, it's usually six weeks to two months after discontinuation, it is very often counted as relapse, so it is the same depressive episode. On the other hand, if a recurrence of symptoms occurs six months later, according to some of the studies, even two years later, it is actually a new episode. So it is not a relapse, it really is a recurrence of the disease. But be it as it may, there are studies that went on for nine, 10 years, there are studies that went on for two years and interruption in antidepressant treatment invariably had disastrous consequences.

One of the studies that comes to mind, if antidepressants were stopped within 24 months, roughly 70% to 80% of the sample had either relapse or recurrence of the disease. So at least when it comes to monoamine treatments, there's really not a whole lot to support that stopping treatment for majority of the patients would be an effective strategy.

Charles Raison, MD: Okay. Michael, why don't we hear your opening argument for the potential value of episodic treatment as opposed to this sort of continuous treatment paradigm that we've been sort of operating under for quite a while now.

Michael Thase, MD: Much of what we think to be true about the need for continuation and maintenance-phase therapy is tied to the therapeutics that were available in the 1960s, 70s, 80s, and 90s. I'll just remind you that initially, antidepressants were given for weeks or months and only began to be given for longer-term courses when it was evident that people suffered relapses fairly quickly when their antidepressants were stopped. Yet, when we began to do placebo-controlled studies and there were follow-ups of placebo responders, it turns out that they didn't show the same rapid relapse on placebo that patients coming off antidepressants showed. So here's a therapeutic, a placebo that is not associated with this rapid relapse. And then we began to do studies of psychotherapy. And when our 12-, or 16-, or 24-week course of psychotherapy ended, our patients didn't go down like flies at the psychotherapy.

So the notion that you were suppressing the illness with the reuptake inhibitor really is tied to the mechanism of action of the reuptake inhibitor. And all the while we are subjecting 30%, 40%, 50%, 60% of the treated sample unnecessarily to ongoing antidepressant treatment. It's true we did not have another thing to offer other than psychotherapy and of course we wouldn't have offered placebo outside of a placebo-controlled trial. But we've known all along that certain interventions were not associated with abrupt withdrawal and discontinuation-initiated risk for relapse. So therefore we have distorted the natural history of the illness with our very agents. This leaves open the possibility when we have treatment, new pharmacotherapies that are not monoamine uptake inhibitors or do not modify postsynaptic monoamine mechanisms, we may not have the same rules for ongoing treatment.

Charles Raison, MD: Absolutely. Vlad, do you want to argue against that?

Vladimir Maletic, MD: It's very hard to argue with facts, right? What I can provide is some additional data. So in terms of antidepressants, monamine-modulating antidepressants, there are a lot of explanations in how they work in addition to what we find in the package insert, which is mechanism of action of this medication is unknown, but we really do have a little bit better understanding. There’s some interesting data that come from preclinical studies. This is a model of depression which is associated with essentially a little animal, which will be an alpha mouse or rat, is exposed to an aggressive... I'm sorry, omega mouse or rat is exposed to an aggressive alpha rat, and they are in the same cage for a number of hours. There's a partition in between, the animal that is omega can definitely smell the larger, more aggressive animal. It's charging the partition and eventually the animal develops something that is called social defeat. So this is social defeat model of depression, which is believed to biologically coincide quite a bit with major depressive disorder in human beings.

Well, what happens after this is repeated several times the omega rodent, so the more inferior one, develops a pattern that is similar to symptomatic presentation of depression in that the animal loses interest in sucrose water. The animal stays away from the partition and the aggressive more predatorial animal, and they move very little. When they're caged with their litter mates, they show no interest in reproductive activities. So a lot of resemblance to what we see in depressed patients. Well the interesting part is when these animals are sacrificed, what has been noted is that monoamine-modulating antidepressants influence epigenetics. So histone deacetylase was inhibited, and antidepressant was inhibiting, and that may have been associated with the reversal of these behaviors in that the animal was now comfortable coming close to the partition. It was drinking sucrose water, it was moving more. It was interested in the reproductive behaviors.

But the moment monoamine-modulating antidepressant is withdrawn, its impact on epigenetic modulation disappears. And many of these depression-related behaviors start coming back. So it fully supports what Michael has said, and I think unfortunately that is the story, but he's making a very, very good point. Placebo response neurobiologically is probably different than response to monamine-modulating agents. And what we do know is even if we are abruptly discontinuing, if abrupt discontinuation is combined with psychotherapy, there is not that disastrous drop off. So I will admit that a lot of what I've shared is related to specific form of treatment and monamine-modulating agents.

Charles Raison, MD: Vlad, I –

Vladimir Maletic, MD: I do want to point just one thing and then I’m done. I want to point out one fact. In the two-year study that I mentioned previously, patients who had psychotherapy before the onset of the controlled phase of the study did much better than patients who were on antidepressants that were abruptly discontinued. But even in that group, by the time two years were up, about 45% to 50% did have recurrence of depressive symptoms.

Charles Raison, MD: ... And Vlad, I’m going to toss you an easy pass here. We were at Psych Congress and we were talking about your, sort of, clinical experience with ketamine or esketamine, we'll circle back to that I think. But you were talking to me about how... So esketamine is sort of a classic episodic treatment but that many people that are now taking it on a fairly regular basis for extended periods, and you're beginning to see some tachyphylaxis there too. Does that maybe suggest that some of these episodic treatments, even, are not so episodic for many patients?

Vladimir Maletic, MD: Well, it's an excellent point and I think that we were rightfully blaming monoamine-modulating treatments for this phenomenon of early recurrence after stopping the treatment. So now we, for the first time, have a four-year longitudinal data with esketamine. And I will just provide one answer description of what happened: 30 months into the treatment, 70% of the patients were still taking esketamine.

Charles Raison, MD: Michael, an episodic position has to deal with something like that. Thoughts and response to what Vlad was saying?

Michael Thase, MD: Well, for esketamine, the therapeutic effect lasts for four, seven, nine days, and so the kind of natural frequency of that treatment, if it were done ideographically, would match to the time the patient remained well between treatments. And so maybe you wouldn't subject everybody to twice-weekly treatment for eight weeks and then everybody to once-weekly treatment. And you may turn out that you have some people who are only better for two days and some others who are better for 14 days. So here is an episodicity that is different than seen with tricyclics, or SNRIs, or SSRIs. And then you move on to other treatments, TMS for example. The decay to relapse, the time to relapse for TMS is slower than that for antidepressants, but it does happen. ECT, if you must divide, is this a person with treatment-resistant depression or not? If the person has treatment-resistant depression, the time to relapse is much faster than if not.

So I think you can see differences in episodicity across our different treatments. And we've not yet talked about the truly outside-of-the-box new treatments here including treatments like the GABAA allosteric-modulating treatments such as zuranolone, and now what we're seeing in the early studies of psychedelics such as psilocybin, for which people appear to require only a single course of treatment for six months or even longer.

Charles Raison, MD: So of course this is what I do, as you know I'm much involved in the psychedelic world. And to your point, Michael, it is true. So the early studies of psychedelics where they were looking at generally high-functioning people that did not have particularly lengthy psych history, they were depressed and anxious because they had been diagnosed with a lethal cancer, yeah, single treatment and like 75% to 80% of these people were in remission six months later. But there's been some top-line data presentation in treatment-resistant depressed patients where, to your point, you see a very, very powerful rapid drop but over the next three months, there's a decrement of effect. That's been shown in a couple of treatment-resistant populations. They don't go back to baseline. They don't go back to baseline. So it really is quite striking that the effect is longer than we see with other agents. But you do see that beginning, sort of, loss of effect. So maybe a question about—is episodic treatment more or less indicated for people that are more or less treatment-resistant?

Michael Thase, MD: I believe it is. And I think that part of what leads to you becoming treatment-resistant is that you may have fewer internal resources, fewer external resources; the very factors that promote recovery in a world without treatment also promote recovery when you're receiving treatment. And so I believe that treatment-resistant depression is an end stage and reflects both the cumulative effects of a bad illness, often untreated or poorly treated over time, and then all of the potential prognostic difficulties and liabilities, the negative prognostic difficulties and liabilities, that the individual carries with them, including early trauma.

Charles Raison, MD: Vlad, do you think that chronic treatment is basically taking care of the disorder or do you think that it's just sort of perpetually suppressing symptoms such that when the treatment stops, the symptoms come roaring back? Because there's some kind of disturbing data from, again, these are cohort studies generally, but suggesting that longer treatment, people are more likely to relapse when they stop it. It's a little bit the opposite of some of the other data you were arguing. How would you think about that? What do you think we're doing with continuous treatment if we're going to defend that point of view?

Vladimir Maletic, MD: It's really interesting because I think you may be referring to the studies that were published by Giovanni Fava and his colleagues talking about gradual and layered treatment of major depressive disorder where psychotherapy would be the first line and then introduction of pharmacotherapy. I'm not opponent to a layered approach of treatment of major depressive disorder. But on the other hand, I have to also look at the data and say that even with ECT, which is believed to be the most efficient treatment for individuals who have more advanced forms of major depressive disorder, still even after maintenance ECT, about 40% of the patients will relapse once we stop. So far I think that our treatments are much better at addressing symptoms rather than the disease substrate. And in some individuals, I completely agree with Michael, it may be that we have a very good match and that our treatment will match up with underlying pathophysiology, in which case we may suppress the illness for an extended period of time or possibly forever.

Unfortunately, we don't have any clear indicators upfront that would allow us to match up treatments to an underlying pathophysiology with any kind of great success.

Charles Raison, MD: There is the rub, huh? That's really the issue. Okay. So Michael, why don't we start with you? Why don't you give us... Feel free to rebut what Vlad is saying and maybe give us a closing argument for the point of view of the sort of defense of episodic treatments.

Michael Thase, MD: I think in every cohort that is judged to be at high risk for relapse or recurrence without continuous treatment, there is a subset of patients who indeed will relapse when their medication is discontinued. And a subset who would've remained well whether or not they had continued to take the medication. And it is true that we do not have good markers of who might be in which bin, but it's also true that the cost of staying on that medicine over six, nine, twelve, eighteen months, whatever, might include things like not having your normal sex life for a year and a half, or a slow weight gain, or a loss of joie de vivre, just the sense that you are not quite able to experience peak experiences the way you were, the emotional blunting that people complain about. Even things not really thought of is an increased frequency of dental cavities, which medications that cause dry mouth are well associated, just ask your dentist.

So there is a cost well beyond the prescription cost of staying on the medication that would, I think, compel us to at least think of going at the more individual level and looking at alternatives to management, such as slower withdrawal of medication and the use of focus psychotherapies with relapse prevention aims, to mitigate the risk.

Charles Raison, MD: Okay, excellent. Vlad, closing argument?

Vladimir Maletic, MD: I really don't have any argument with that. I would agree that with currently available treatments, although chronic treatment may be associated with better clinical outcomes, I think that Michael is absolutely right when he's talking about quality-of-life functioning and adverse reaction burden. I think we always have to weigh it, and I completely agree with his conclusion. Ultimately, it lands on a dialogue with the patient in trying to tailor the treatment so it is most suitable to a specific scenario. I would not disagree with that point of view, and frankly, whether we like it or not, most of the treatment of MDD is episodic for a very simple reason. We're dealing with astounding levels of non-adherence. So no matter what our intent is, ultimately it does end up being episodic.

Charles Raison, MD: Mm-hmm. That's also very true. It's interesting, I think about this a lot because there's some real opportunities and challenges to my way of thinking with episodic treatment. So one opportunity is what Michael was saying, that if I have an episodic treatment that I take for a while and I get a response for remission, I'm doing well, I stop that treatment because it's episodic. And then I go for a while and I'm feeling okay and there's not a medicine on my brain every day. So maybe I'm not exposing myself to not only the side effects, but maybe risk of tachyphylaxis or secondary brain changes because of that constant pressure. And if it's an episodic treatment that you can re-initiate, then theoretically, you may be somebody that you've done it and you don't get depressed again or maybe you don't get depressed again for three years, you're not taking medicine all that time.

And if you do need the medicine, you can go back on it for another course. But of course then there's challenges of, well yes, but then who decides when you're depressed enough? How do you set that up? What if you're late getting in there and you have a full relapse? So I also think it's a complex issue, but I do think that there's some real interesting opportunities with these episodic treatments. Okay, so thank you both. Got to put my glasses back on to look at you guys in the face here. Okay, so this concludes round 2 of our Great Debate series. Now again, please be sure to tell us who you think won this round, and you know can see for all these rounds, I have two very gracious opponents here. They cannot be lured into outrageous positions that are not supported by the data.

So you can hear these sort of subtle shadings, but I want you all to vote on the subtle shadings. So please answer the poll question you see on your screen and join us next time for our final round where things are going to get really ugly. No, not really. They're going to continue to be perfectly appropriate and data-informed. Please join us on our final round where we will be discussing the implications for patients of approaching MDD treatment continuously or episodically. This is really important. You're going to want to hear this because both options are available to us now pharmacologically and of course also psychotherapeutically. So how we think about this is of really profound pragmatic importance. So stick around and we'll come back for round 3.