Activity Transcript

Joseph F. Goldberg, MD: Well, hello everyone. Welcome to our presentation today. I'm Dr Joe Goldberg. I'm a clinical professor of psychiatry at the Icahn School of Medicine at Mount Sinai in New York, and I want to welcome you to our program entitled Treatment Augmentation in Major Depressive Disorder, Expert Insights on real world considerations.

Joining me today are Brooke Kempf, who's a psychiatric mental health nurse practitioner at the Hamilton Center in Terre Haute, Indiana, and Dr Michael Thase, who's a professor in the Department of Psychiatry Mood and Anxiety Disorders Treatment and Research Program at the University of Pennsylvania, Perelman School of Medicine in Philadelphia, Pennsylvania.

Welcome to you both!

Michael E. Thase, MD: Thanks, Jeff. Great to be here.

Dr Goldberg: So, this topic is something we've confronted daily as mental healthcare professionals. Are our patients with major depression adequately managed? If they're adherent to their treatment, are their symptoms improving? So, let me sort of start off by asking the both of you, when we talk about improvement, we can discuss response, remission, incomplete response, partial response, non response.

How do you define and think about, and how should the clinician think about, operationally defining remission, response, partial response, non response.

Brooke A. Kempf, PMHNP: I'll go ahead and get us started with that.

If we look at some definitions of what non response vs remission might be, I want to emphasize our goal, remember, to treat major depressive disorder is always to get to remission, and that is basically the pre depressed level of an individual. Back to normal functioning.

So the exact opposite of that would be non response. Your patient coming back and saying, Hey, the treatment that you gave me did nothing. I've had no response to that. Then we have what we have in the middle there is a response. A response would be patients getting at least half better. So at least 50 percent better and then in between that a partial response.

We're talking about 25% to 50% improvement.

Dr Goldberg: And then if you're not even 25% improved... We don't count that.

Ms Kempf: Technically, yes, and less than 25% improvement. We're considering that to be non-response.

Dr Goldberg: Let's take this step further between in and out.

Dr Thase: So, if you think about it you've got 2 categorical outcomes in which the individual is not well enough to be considered a responder. And you can put those 2 together and call those an inadequate response.

So the complete non response and the partial response you need to do something different because the person is generally not functioning better and not nearly back to their better self. And so we use the term treatment resistance sometimes to say that person was resistant to that treatment that led to an inadequate response. But more commonly, we'll use the term treatment resistant depression to describe somebody who has not benefited.

At that level for 2 consecutive treatment trials, at least 2 consecutive treatment trials. Some people think that's too inclusive a definition or too generous a definition but it is the official starting point for new treatments being evaluated for difficult to treat depression in the eyes of the FDA.

Dr Goldberg: So, metrics. How do you quantify these things? Rating scales that practitioners can take into their own clinical centers. Do they need formal training for that? Are rating scales time consuming or are they time liberating? Brooke?

Ms Kempf: I feel their time liberating. So if we look truly at data, we know that measurement-based care can provide better care for our patients, better outcomes for our patients. I think of it a lot as our. Vital signs to our patients, how we can measure if a patient's responding, doing better, helping us with some of our diagnostic assessments.

So there are a majority of different tools that we can use. We have everything from the PHQ 9, MADRS QIDS, the Beck Inventory. All of those are listed here and some things to think about. Each of these have different scoring levels in what you might consider moderate depression, severe depression.

These guidelines can help base your decision. Do I need to augment a treatment strategy? Do I need to switch a strategy? What kind of response am I getting to medication? And looking specifically at key symptoms, what might be getting better.

Now, I know in my world, our electronic medical record includes the PHQ 9. So if you look on this next slide at the PHQ 9, it shows the 9 specific symptoms of depression, and often, these can be Either done by the patient themselves or as a clinician, you can go through these. When I'm assessing a patient, I can go through each one of these items and assist them in obtaining a score during my initial assessment.

So it doesn't have to be additional time in your appointment. You're already asking these questions anyway. What it's going to do is allow you a score so that you can measure outcomes.

Dr Goldberg: this is very helpful when you're thinking about parameters to help inform your own decision making. Should you augment? Should you switch? After, let's say, an incomplete response, are there particular guideposts or guidelines that, that you think about? Michael you've written some and thought a great deal about, do I switch or do I augment?

Dr Thase: Well, obviously you would switch if the first antidepressant was really poorly tolerated. You don't want to stay on a medication that's got deal breaking side effects, and so about 5 to 10 percent of first trials of antidepressants end with switching because the patient couldn't stand the side effects of the first medication.

I guess it is a little harder. What's the right thing to do when the medicine's been reasonably well tolerated, but there's been like a complete non response, that less than 20 25 percent improvement. In practice, we often switch to a different first line antidepressant when the first medicine has been completely ineffective, even if it's been reasonably well tolerated.

But there are some circumstances in which urgency might lead you, since the medicine is well tolerated, to go ahead and do an adjunctive treatment strategy. I think generally, if the person is moving towards a response, but they're at maximum dose or they've got... Just enough tolerability issues, you don't feel like you can maximize or optimize the treatment dose, we will sometimes then go to an adjunctive treatment strategy there, where you're just trying to get that extra 20 25 percent improvement, which is, you know, A reduction in 2 or 3 symptoms, basically to get the person over the line.

I think importantly patient preference has to be taken into account here too. And this is where deal breaking side effects come in. That's the number one reason a person might disprefer to remain on a medication. Now, if you go the converse way an adjunctive treatment strategy really makes sense when the first medicine's been partly effective, reasonably well tolerated, and you can see in your patient clear targets to use one of our reliable proven adjunctive treatment strategies to address.

Dr Goldberg: It's easier to build on something than to build on nothing.

Let's take a hypothetical case. Here we have Valerie, a 27-year-old woman referred by her psychotherapist for her first lifetime major depression. That's been present for about 3 months.

Done a 9-Item Patient Health Questionnaire (PHQ 9) on her. Her baseline score is 18, so that's in the moderate towards severe end of the spectrum.

She's begun on escitalopram, 10 mg a day, and then after 2 weeks, her scores come down from 18 to 16. And her dose is then increased to 20, and then now at 5 weeks, her PHQ 9 score is down to 13 from having started out at 18. So she's tolerating the drug without significant side effects. Based on these data, what do you both think?

Should we increase the dose further? Should we augment? Or should we switch? What should we do with Valerie?

Ms Kempf:

Valid. I'll get started here and kind of give an idea of what I'm thinking whenever I'm going to evaluate a patient like Valerie.

As Dr Thase said, we have to consider the patient's choice. Sometimes they are not going to be willing to give up that medication. But some key things that I noted within there, yes, she has had partial response to the medicine. And no side effects. But this is her first antidepressant. So before I add an additional medication, I'd like to get by with monotherapy if at all possible.

She's only been tried on a selective serotonin reuptake inhibitor (SSRI). So I think I might try to go over to a norepinephrine and dopamine reuptake inhibitor (NDRI) or switch over to a serotonin and norepinephrine reuptake inhibitor (SNRI) to see if we can get that same benefit and then get even better. But... Also again, talking with her, she may not want to give up that option. So what do you think, Dr Thase?

Dr Thase: Well, I think if we were doing a quality assurance review you'd pass because what you've suggested is a very reasonable strategy and that you've got alternate first line medication that, that probably in this scenario have 40, 50 percent chance of success. You can pick a mechanistically different one, or if you're convinced in your heart that the SSRI was the right way to go the first place, you can even do a second trial within the SSRI group.

I think the thing I look at is that she's on the maximum dose of escitalopram. And so there's probably no. advantage to trying to raise it above the usual maximum dose. And so if I were going to switch, I might use the same medicine to switch that I would use to augment in her case, which is bupropion.

It's mechanistically different and may well target a different constellation of signs and symptoms than the SSRI did. But I think the most important thing is we should do something. Because she's now 6 weeks into treatment and she's only about a third of the way better and the odds are that additional weeks standing path on this treatment strategy won't lead to her getting the response she came to us for in the first place.

Ms Kempf: Exactly, and I do believe we've been guilty of stopping at just that response and not pushing for the patient to get to remission.

Dr Thase: I spend 2 of my days at the VA and the most common pathway to chronic depression I see are people that got started on an antidepressant, had some partial benefit, and then stayed for months. On, on that antidepressant. I'm not intentionally bad mouthing the VA. If I could consult it in primary care, I might see the same thing.

So this is where measurement based care really helps us be smarter about when to stay and when to switch or when to do something different.

Dr Goldberg: Yeah, I'm just going to add, this is where the PHQ 9 is your friend. If she went from an 18 to a 13, I mean, that puts her right on the border of, you know, is she any better or not, 27, 28 percent. So you can make an argument either way, and certainly, you don't want to do nothing. At this point, so you mentioned bupropion is something that you might have either chosen as an augmentation for SSRI or even a possible switch, but let me ask y'all, you know, there's at one time, I think our field has been quite enamored with bupropion as a preferred augmentation strategy onto serotonergic or noradrenergic.

For dopaminergic drugs some surveys identified bupropion as the go to for many clinicians as the next thing to do. It seems like the landscape is starting to change. There was a recent meta-analysis in JAMA, we'll put a slide up for it in just a moment, that actually challenged this clinical wisdom and said that the size of the effect with adding bupropion is really not as big as we might've assumed it to be.

Michael, can you help us understand that?

Dr Thase: Well, yeah. So I think that the Hensler paper's big finding was that a different kind of, combination of antidepressants, namely an SSRI or an SNRI combined with Mirtazapine or outside of the US a related medicine called mianserin led to I think almost 3 times the size of an effect that was seen with bupropion.

And so I think this may be because let's just pick Mirtazapine. If your patient has insomnia you may have rapid benefit there. If your patient has an inhibited appetite, mirtazapine may be helpful there. And if your patient's got significant anxiety we know that mirtazapine has a better anxiolytic effect than bupropion on average.

So, so there are 3 kinds of low hanging fruit, if you will, that, that you may pluck with the switch to mirtazapine. I think that bupropion has many other values.

I'm pretty sure, since I was involved with some of the studies that failed to find the predicted benefit for bupropion, I'm pretty sure that one of its strongest suits is not enhancing, strongly enhancing the effects of an SSRI.

Dr Goldberg: People sometimes think of it as having value for weight neutrality or sexual dysfunction being fairly neutral. I wonder if part of our intrigue with this drug is that it seems fairly well tolerated.

Dr Thase: We all like not to gain weight and not to have our sex lives blunted by a medicine that we take. And those are 2 of buproprion strong suits. Not getting sleepy is a third one. It is, it's not exactly alerting, but it is not a sedating medicine.

Dr Goldberg: Let's talk about a couple of other time honored augmentation strategies in major depression. So adding thyroid hormone. or adding lithium. These are both options that were looked at in the Star D trial, which Michael you were a big part of and neither of these strategies did all that well in star D, but in the broader research literature can you speak to the broader evidence space for both of these strategies?

Dr Thase: Well, about 5 percent of reproductive aged women have either subclinical or actually on the border of clinical hypothyroidism that's gone undetected. And this is a population at reasonably high risk for depression. There are old data from the 60s and 70s in which you could hasten an antidepressant response by adding thyroid hormone.

Interestingly, these studies were done in female populations. And then in STAR D, although T3 wasn't a super great treatment, there was a 25 percent remission rate. It was tangibly better than lithium. And the thing that made thyroid hormone better than lithium in the STAR D study was that it was just easier to implement and easier to use and the STAR D docs had trouble following the blood level protocol for lithium and such and our docs in STAR D were better than average doctors, so if they were having trouble implementing lithium, you would think a lot of the rank and file might have trouble implementing lithium.

So, so I like thyroid hormone on occasion, particularly for female patients. I mean, obviously if she's had weight gain and reports fatigue, and maybe there's some hair or skin changes along with it, it doesn't hurt to get a thyroid-stimulating hormone (TSH) level and actually see if what you're really doing is treating subclinical hypothyroidism as opposed to augmenting an antidepressant.

Interestingly, we did a study at the University of Pittsburgh in patients with bipolar depression, and we found that even patients with higher than average, not abnormally high, but higher than average TSH levels were less responsive to antidepressants. . So, so it may be that you need your thyroid axis in tip top shape in order to get the best chances of responding to an antidepressant.

We did not test whether thyroid augmentation fixed that in that study. I regret that we didn't because I think it is an important question.

Dr Goldberg: Thanks, can I ask you both, what do you think about lithium? I know in STAR D it's response rate, remission rate wasn't all that spectacular, but have we... Have we lost sight of lithium's value outside of bipolar disorder, maybe even within bipolar, but for unipolar augmentation?

Dr Thase: Brooke, I've been babbling on, why don't you take the

Ms Kempf: I'll jump in there a little. I think when it comes to bipolar disorder, I definitely think that we've gone away for an unknown reason. I think some new treatment options have kind of drawn people's attention. But I think it definitely can still play a role, despite some of STAR D data , particularly in individuals with major depressive disorder in improvement in their overall mood.

I think that Dr Thase hit on the barrier that always I know personally in my experience is having to do blood draws and if I have individuals that are already struggling with thyroid issues. I have a lot of patients that might be diabetic that have a multitude of kidney issues. They're on a multitude of different medications, maybe diuretics, so sometimes it can be hard to manage, but I can also get by with a lower dose of lithium in those individuals with major depressive disorder.

Dr Thase: I think in our treatment resistant depression clinic, we might. save one or 2 patients a year with unipolar depression with lithium augmentation. It's not commonly done any longer. Most of the evidence about its benefit came from an era in which the tricyclics were the foundational antidepressant, not SSRIs.

And maybe lithium was enhancing tricyclics through an indirect serotonergic mechanism that doesn't apply or isn't pertinent to the SSRIs, but there still is a role, and , if you're not a good lithium prescriber yourself, you should have a colleague or know someone who's a good lithium prescriber because there still is a good place for it in the treatment of mood disorders.

Dr Goldberg: so nowadays when it comes to adjunctive pharmacotherapies in major depression, it seems as though the atypical antipsychotics, perhaps some more than others even, have really emerged as a preferred next step in treatment I'd like to ask you both to comment on an overall basis. We've got some meta analysis data looking at how a typical anti psychotic augmentation fits it and some of the newer agents that we have data on.

So, who'd like to tell us about this?

Dr Thase: So as you can see in the slide if you start at the top with the largest chances of benefit. You will see that that the top 2 are with quetiapine and aripiprazole, which just so happened to be 2 of the most commonly prescribed second generation antipsychotics used as adjuncts to, to antidepressant.

I think there is evidence for olanzapine and then more recently now we have cariprazine and brexpiprazole. Also having evidence of such benefit. And to me, there are several fascinating common threads here. Number one is that these medicines are generally helpful as adjuncts at doses about one half or even one third their antipsychotic dose. So they are not treating subtle psychotic depression, and although they are punitive mood stabilizers, the doses that we're using here are lower than their anti manic doses. But you can't find 2 drugs more different than each other in the same area of therapeutics than aripiprazole and quetiapine, and that certainly suggests that there are multiple mechanisms at play here. And so it may well be that one patient does way better on quetiapine and yet another does better on aripiprazole. And I really doubt if 2 patients will have the identically good response to 2 so different medications.

Dr Goldberg: Tolerability though, as we see on the right hand side.

Dr Thase: Well, tolerability is an issue, a problem for all of these medicines. I think the more recent ones more recently introduced ones have certain advantages over, over the older ones. But I mean, you shouldn't prescribe a second generation antipsychotic if you're not prepared to take a weight chart and to talk with your patients about the possibility of metabolic side effects . And if treatment goes on beyond you know, 6 or 8 weeks to make sure that you've got a baseline aims in the chart. And if it goes on beyond 6 months begin periodic follow ups to make sure. The risk of tardive dyskinesia is small with these medications, maybe less than one per hundred patients treated per year.

But at the same time, if you're the one person who got it, you're not going to forgive your doctor for not being vigilant.

Ms Kempf: Yes, and I think they won't forgive us if we don't educate them on that piece of it. So, in a couple additional anti psychotic medications that were not included in the list that Dr Thase just covered, this first one here being brexpiprazole.

This study looks primarily at the core symptoms of major depressive disorder So they took 6 of the core symptoms of major depressive disorder from the Montgomery–Åsberg Depression Rating Scale (MADRS), and then they pooled data from 1 milligram, 2 milligrams, and 3 milligrams of brexpiprazole, and what you'll see is statistical significant improvement as early as week 1 and all the way through week 6.

And when we're developing these new medications, not only are we looking for better efficacy, but we're also looking at a side effect profile. So the way that they did the clinical trials were antidepressant therapy, this is adjunctive treatment to antidepressant medications, plus placebo or antidepressant therapy, plus brexpiprazole.

And if you look at the brexpiprazole group, you'll see akathisia, weight increase, and somnolence being the most common side effects. Then we also have cariprazine.

That was a newer antipsychotic approved for adjunct treatment in major depressive disorder. Again, looking adjunctively with an antidepressant therapy.

Looking at MADRS scores and the clinical global impression scores. The thing to note significance here they're looking at 1. 5 milligrams and 3 milligrams and it's the 1. 5 milligram that reached statistical significance that showed the efficacy of cariprazine . And then you'll see the side effect profile here of akathisia, nausea, headache, insomnia, and somnolence. So again, a different side effect profile maybe than some of the other previous medications we saw. And again, Additional treatment options for adjunctive treatment with antipsychotic medication.

Dr Goldberg: Now, here's another idea. Some people talk about the role of stimulants or stimulant like drugs, such as modafinil or armodafinil, as an augmentation to a monoaminergic antidepressant.

Brooke, would you say there are any particular instances where you might favor an approach such as that?

Ms Kempf: Yeah, I think one of the biggest complaints that I get from patients when it comes to residual symptoms of depression are the cognitive symptoms, that lack of motivation, the dulling of emotions. And so for those individuals, I do think about using these stimulant medications. Now, the ones that I'm going to avoid that in are a lot of individuals that might have some cardiac issues, anxiety issues, but if you look at the odds ratios of these medications and these randomized trials, it shows these medications using adjunctively with antidepressant therapies can definitely be an effective treatment for your patients with major depressive disorder.

But again, when you're kind of picking and choosing amongst those different options that we have, I really think about that low motivation, those individuals that cannot get out of bed, individuals that are trying to do well, but they're cognitively, they just can't even put together their day to day schedule.

I think this is a good treatment option for those individuals.

Dr Goldberg: So these are all off-label uses, but they do have an evidence base to support their value in certain kinds of patients. Well, this has been really informative and helpful. Let's kind of wrap up with a sort of a broad case. I'm going to just present this to Victor, a 34-year-old man presents with his third lifetime episode of major depression.

He also has comorbid generalized anxiety disorder. He's also obese with a body mass index of 32, and he also has a family history of type 2 diabetes. Previous depressions have been treated with a variety of agents, sertraline, paroxetine, venlafaxine, with or without adding arepiprazole, and collectively leading no more to, to no more than partial improvements, but he has a iatrogenic weight gain from those treatments.

So this current episode begins and he's taking duloxetine 90 mg a day in conjunction with quietapine 100mg/day switched from duloxetine to velazodone, maximized to 40 mg a day, and his PHQ-9 score improves from 22 to 13, about half.

So, partial improvement in his anxiety symptoms as well and no further weight gain. So now the question for you both to think about is if you were to continue on the velazodone and you were going to think about an augmentation strategy and its pros and cons, I've listed for you several here, all the things that we've been talking about, lithium, bupropion, mirtazepine, brexpiprazole, cariprazine, stimulant, or something else.

You know, there's no one right answer, but in just a couple of minutes, how would you tell our participants to think about the pros and cons of these options?

Ms Kempf: I'll get started with a couple of thoughts of when I think about the case presentation. Obviously, we saw multiple different failed antidepressant treatments, so I'm thinking there I got to look a little bit closer at the diagnosis and treatment resistant depression options, but things that I'm going to avoid are probably things like mirtazapine or other weight gaining medications.

He already has obesity he's dealing with diabetes. I'm going to avoid adding that stimulant due to anxiety disorders. I think an option such as cariprazine would be a good augmentation strategy as it has less association with the risk of weight gain and does have evidence-based that it can improve his depression.

What do you think, Dr Thase?

Dr Thase: I am with you entirely. I would take mirtazapine off the list at this moment. I likewise would would not think of adding lithium for a man with already metabolic challenges who doesn't seem to have an illness with any close relation to the bipolar. Classic bipolar subtypes or even the bipolar spectrum.

So now I'm down to bupropion, brexpiprazole, criprazine, and a stimulant like you. I would worry about the stimulant activating his only partially remitted anxiety. So now we've got brex vs cariprazine vs bupropion I would follow the Hensler data, and this guy has had multiple antidepressant trials already, so he has a more advanced case of treatment resistant depression, assuming he's been adherent to these medicines over the years, and so I think bupropion has less to offer for him. Plus, it's not a friend to anxiety that's not SSRI responsive. And so, that leads brexpiprazole and cariprazine. And so, given the metabolic advantage to my eyes, I see in the data for cariprazine vs brexpiprazole, I would go with cariprazine with brexpiprazole as the alternative if he gets too restless or just doesn't get an adequate benefit with cariprazine.

Dr Goldberg: He's certainly getting an evidence based approach, and he finally got onto vilazodone, which gave him about a 50 percent improvement, so there's the response. And I think it was you, Mike, who showed that in the setting of anxiety with major depression, vilazodone is a pretty good choice in terms of robustness.

So building upon that with something like brexpiprazole or cariprazine certainly would be very rationale based, and the one thing we hope to promise our patients is a good rationale for whatever we recommend.

Dr Thase: I think when vilazodone comes off patent and you don't have to do prior authorizations as often, we'll see an increase in its use as a, as maybe not the first line antidepressant but in a second tier, especially for patients that don't get a remitting anxiety with an SSRI.

Dr Goldberg: And indeed, it came off patent this year. It is now available as a generic.

Dr Thase: This year it's off, so I should get out more often. I'm sorry.

Ms Kempf: Time flies when you're having fun, Dr Thase.

One of the things I was going to mention that was highlighted on our previous screen is we are offering an atypical antipsychotic to our patient. So again, We're going to include him in this discussion, and as we mentioned, there are some additional side effects that we're going to have to monitor for if we're using these treatment options, but I think it's really important to address with our patients that when we are prescribing what we still refer to as an anti psychotic option, That we are giving this to the patient to treat depression, that we don't feel that they're psychotic because they're going to go to the pharmacy, they're going to pick up that big white pamphlet that comes out, and they're going to question, why are you giving me this antipsychotic?

So doing that education up front I find is always beneficial and it ensures maybe that they're going to take the medication rather than waiting to take the medication before they talk to you at next visit.

Dr Thase: My patients are consistently reassured by knowing that they're taking one third of the dose that they're taking. They would be taking, if I was prescribing this for a psychotic disorder, that this happens to be a medicine, or these happen to be medicines with a multi potential for benefit. And they can treat depression at doses way lower than they are needed to treat psychosis.

Ms Kempf: And when we talk about the side effect profile, I assure that I'm going to continue to monitor for those. And that's why we do the blood work. That's why we weigh them at each visit. That's why we do AIMS assessments. We're going to monitor them throughout to give them that reassurance.

Dr Goldberg: Indeed, and I think the nomenclature is important to point out to patients. We use drugs nowadays based on where they've been shown to have evidence, but their moniker kind of lingers from where they were first studied, whether that's in the case of an antipsychotic or an anticonvulsant. I no longer call monoamine oxidase inhibitors (MAOIs) tuberculosis drugs, but I probably should by rights and ketamine is still an anesthetic, even though that's not why we're giving it to people.

So what's in a name in part is our obligation to make sure patients. Understand. Well, this has been very eye opening for me and very helpful, I hope, for all of you who've been attending and listening.

Brooke and Michael, I want to thank you both for this terrific discussion, and I want to thank you all for participating in this activity.

Please now continue on to answer the questions that follow and complete your evaluation, and thank you once again.

This transcript has not been copyedited.