Round 3: How do you balance risk/reward, efficacy vs tolerability?

In the final round of this debate, Dr Banov and Dr Measom describe how to balance risk/reward and efficacy vs tolerability when treating patients for major depressive disorder (MDD).

Dr Charles Raison: Hello, and welcome back to our Great Debates in Psychiatry series, brought to you by Psych Congress Network. Now this, in our third and final round of this debate, we're going to be discussing how we should think about balancing the risk and the reward, the efficacy vs the tolerability of a monotherapy vs a multimodal therapy approach. These are central questions to thinking about this core, very, very practical clinical issue. And so, once again, we're going to start with Dr Banov, who is representing a monotherapy approach. So, Dr Banov, go ahead and please give us your opening argument.

Dr Michael Banov: Balancing risk and reward is actually very easy because I just follow one simple motto, the one that we took when we graduated medical school, which says, “Above all, do no harm.” And that's my goal. Now, there's two ways to do harm. I cannot do enough, which means the patients have a bad outcome, or I can do too much, which means they have a bad outcome. So, that's simply how you balance that equation. And that's going to vary depending on the patient. Again, patients who were acutely ill, who were worried about the risk of self-harm or, again, consequences, work, home, functioning, that's somebody I'm going to be more aggressive with. Somebody where I feel like I've got more time—I don't feel like there's an acute sense of real decompensation—then I'm going to try to focus more on tolerability because if patients don't take their medicine, they're definitely not going to work.

Dr Banov: And if patients don't like how they feel on their medicine, they're definitely not going to work. So, how does that fit into the debate about multimodal vs monotherapy? I think it's fair to say, in general, most patients are going to be at greater risk for side effects and drug-drug interactions. And, by the way, compliance, if they're on two medications, particularly started at the same time. Now, let's say a patient is on monotherapy, maybe having some tolerability issues, and instead of being able to optimize the dose, you want to augment—that's kind of a different story. And that may be something that might happen later into treatment. But coming out of the gate, coming in too early with two different agents, even if a patient is accepting of that, has a lot of risks. And again, we don't have evidence that combining medications works better or faster.

Dr Banov: Yes, there are studies here and there that will show with small subjects, number of subjects in it, small n's. You might see some studies that look very promising and interesting. We know that there may be some added benefit with adding some of the atypicals, but not necessarily faster. I think a lot of us get kind of brainwashed with the pharmaceutical companies coming in showing us data about early responses, separation from placebo in the first few days, or first week or so. But something that's statistically significant may not necessarily be very clinically meaningful. So again, comes back to I want my patients to be safe, but I want them to come back for visit number two. And I think the smart decision is if you can, and in most cases, I believe you can stick with what's evidence-based, which is using one medication out of the gate. And if there's a need for something down the road, then so be it. Maybe add that down the road. But I think to come out with too aggressive puts your patients at great risk with really not that much added benefit.

Dr Raison: Okay, Dr Measom. Please give us your opening statement.

Dr Michael Measom: Well, I thought what he said was excellent, but you know, when they survey people that struggle with this chronic recurrence, severe lethal illness, and they ask them, “What do you value more, efficacy or tolerability?” In the surveys, they want efficacy. So, we do it all the time anyway. We do adjunctive treatment. We do multimodal therapy, sometimes in one pill. But why not start from the beginning and get somebody where you want them to be and where they want to be in the room with you? So let's, you know, this chronic severe illness, let's get them where we want them to be.

Dr Raison: Okay. Dr Banov, your rebuttal, please.

Dr Banov: Very, very simple rebuttal, which is we just don't have evidence that polypharmacy is better than monotherapy. I mean, look at Russia's co-med study. Six hundred fifty-five patients looking at escitalopram monotherapy, escitalopram plus bupropion, mirtazapine, and venlafaxine just didn't show any greater outcomes. I think patients sometimes might feel better when you use multiple medications. Maybe they're getting some benefits of side effects. We know that adding bupropion may give somebody more energy. Maybe giving mirtazapine makes someone feel more relaxed, or sedated, or sleep better; doesn't mean their depression's getting better. And clearly, there's greater risks of side effects using these multimodal agents without strong evidence that they really work any better. So, let's not fall down that trap. And again, let's not communicate to our patients that the answer is a pill alone. Medications are very important. It's what I do for a living. I'm a psychopharmacologist. But I do try to communicate to my patients this pill is not the answer to your problem. This pill is one part of a comprehensive treatment program that's going to get you better.

Dr Raison: Okay. Dr Measom, your rebuttal to what Dr Banov just said.

Dr Measom: Well, just citing the same study, right? You know, switching from one SSRI to another SSRI  may or may not make a difference. We never, of course; people most commonly go from SSRI to an SNRI, which may or may not make a difference. You know, eventually, down the road, we end up augmenting. So, why not start out earlier and get it going earlier rather than waiting and seeing what's going to happen? So, I get the joy of discussing the multimodal sort of thing. I'm a mechanism of action guy. I believe the more mechanisms of action that you have, the more likely you are to achieve a response.

Dr Raison: Okay. So, now we are at the stage of the closing argument for this particular round of the debate. Dr Banov, I'm gonna start with you. Please go ahead and give us your closing argument.

Dr Banov: Yeah, well, first of all, let me reemphasize, always think the hepatic oath. Always come back to that; that's your grounding mantra as a physician. But I do want to address this issue that was brought up regarding mechanisms of action. And, you know, if you look at how the antidepressants have evolved or devolved, whatever way you want to look at it, over the last 30, 40 years. You have tricyclics, which, of course, we know are multimodal. And then, everyone went to these selective serotonin reuptake inhibitors. And I would argue that maybe the medications we have now are more multimodal. They may not be as multimodal, or maybe as multimodal, but in a better way than the tricyclics. So, why do we necessarily need to combine medications when we have medicines right now that may be multimodal as monotherapy agents? Of course, we don't have comparator data to say that these newer agents are going to quote better than the older, newer agents. But it's something worth thinking about and considering before we put patients at risk for more side effects, more compliance problems, and all the things that come along with multimodal treatments.

Dr Raison: Okay, Dr. Measom. Please, your closing argument.

Dr Measom: Yeah, I just kind of want to go back to our first debate where we talked about, you know, what matters to the patient, what matters in the room. And multimodal, you know, we add atypical antipsychotics, antidepressants all the time. And going back to discussing response vs remission. This is a severe illness. I feel strongly that we need to get people to as much of a response as we can, hopefully to remission. And sooner is better because we don't want those residual symptoms. And I absolutely agree with Dr Banov: first, do no harm. But let's help everybody out there, and let's go kick depression's butt.

Dr Raison: Okay. Well, we can all, we both, all the three of us can agree with that idea. Boy, I tell you. Okay, thank you both. So, this concludes round three of this installment of our Great Debates series. Please be sure to tell us who you think won this round by answering the poll question that you see on your screen. And, hey, please be sure to stay tuned for our next time, where we're going to hear closing arguments for this entire three rounds of the debate.